Patent Grant
8196573
The present invention generally relates to systems and methods for the delivery of aerosolized medicaments. More specifically, embodiments of the invention relate to the coupling of aerosol generators with ventilator circuits, permitting an aerosolized medicament to be inhaled directly by a patient.
Aerosolized medicaments are used to treat patients suffering from a variety of respiratory ailments. Medicaments can be delivered directly to the lungs by having the patient inhale the aerosol through a tube and/or mouthpiece coupled to the aerosol generator. By inhaling the aerosolized medicament, the patient can quickly receive a dose of medicament that is concentrated at the treatment site (e.g., the bronchial passages and lungs of the patient). Generally, this is a more effective and efficient method of treating respiratory ailments than first administering a medicament through the patient's circulatory system (e.g., intravenous injection). However, may problems still exist with the delivery of aerosolized medicaments.
Patients who cannot breathe normally without the aid of a ventilator may only be able to receive aerosolized medicaments through a ventilator circuit. The aerosol generator should therefore be adapted to deliver an aerosol through the ventilator. Unfortunately, medicament delivery efficiencies for combination nebulizer-ventilator systems are quite low, often dropping below 20%. The ventilator circuits typically force the aerosol to travel through a number of valves, conduits, and filters before reaching the patient's mouth or nose, and all the surfaces and obstacles provide a lot of opportunity for aerosol particles to condense back into the liquid phase.
One problem is that conventional aerosolizing technology is not well suited for incorporation into ventilator circuits. Conventional jet and ultrasonic nebulizers normally require 50 to 100 milliseconds to introduce the aerosolized medicament into the circuit. They also tend to produce aerosols with large mean droplet sizes and poor aerodynamic qualities that make the droplets more likely to form condensates on the walls and surfaces of the circuit.
Delivery efficiencies can also suffer when aerosols are being delivered as the patient exhales into the ventilator. Conventional nebulizers deliver constant flows of aerosol into the ventilator circuit, and the aerosol can linger, or even escape from the circuit when the patient is not inhaling. The lingering aerosol is more likely to condense in the system, and eventually be forced out of the circuit without imparting any benefit to the patient.
The failure of substantial amounts of an aerosolized medicament to reach a patient can be problematic for several reasons. First, the dosage of drug actually inhaled by the patient may be significantly inaccurate because the amount of medication the patient actually receives into the patient's respiratory system may vary with fluctuations of the patient's breathing pattern. Further, a significant amount of drug that is aerosolized may end up being wasted, and certain medications are quite costly, thus health-care costs are escalated.
Some of the unused medication may also escape into the surrounding atmosphere. This can end up medicating individuals in proximity to the patient, putting them at risk for adverse health effects. In a hospital environment, these individuals may be health-care providers, who could be exposed to such air pollution over a prolonged period of time, or other patients, who may be in a weakened condition or otherwise sensitive to exposure to unprescribed medications, or an overdose of a medication.
For these reasons, it's desirable to increase the aerosol delivery efficiencies of nebulizer-ventilator systems. Embodiments of the present invention address these and other problems with conventional systems and methods of treating patients with aerosolized medicaments.
The present invention provides devices and methods for improving a level of safety to the patient and for providing an increased efficiency of delivery of an aerosol to the patient.
Embodiments of the invention include a method of treating a patient with a pulmonary disease. The method includes delivering a dose of aerosolized medicament intermittently to a ventilator circuit coupled to the respirator system of the patient.
Embodiments of the invention also include a method of treating a patient with a pulmonary disease by administering to the patient, through a ventilator circuit, a nebulized aerosol comprising from about 100 μg to about 500 mg of a medicament. The efficiency of the method is such that at least 40% of the nebulized aerosol is delivered to the patient.
Embodiments of the invention also include a method of treating a patient with a pulmonary disease by taking the patient off a ventilator, and administering to the patient, a nebulized aerosol comprising from about 100 μg to about 500 mg of a medicament.
Embodiments of the invention still further include methods of treating a pulmonary disease by administering to a patient a medicament comprising an antibiotic dissolved in an aqueous solution comprising sodium chloride that is adjusted to a pH between 5.5 and 6.3. The medicament is administered by nebulization using a vibratable member with apertures, the member configured to produce 70% or more of aerosol particles with mass mean aerodynamic diameters from about 1 μm to about 7 μm.
Embodiments of the invention additionally include a method of treating a patient with a pulmonary disease by administrating an aerosolized medicament to the patient, and administrating, intravenously, a second medicament to the patient that also treats the pulmonary disease.
Embodiments of the invention yet still further include an aerosolized medicament for the treatment of a pulmonary disease. The medicament includes amikacin mixed with an aqueous solution having an adjusted pH from about 5.5 to about 6.3. The pH is adjusted by adding hydrochloric acid and sodium hydroxide to the aqueous solution.
Embodiments also include methods of nebulizing a liquid. The method comprises taking one or more breaths and measuring characteristics of the breath. Another breath is taken and an aerosol generator is operated based on the measured characteristics of the one or more measured breaths.
Still further embodiments of the invention include methods of providing a nebulizer system comprising a housing, an aerosol generator, a controller coupled to the aerosol generator, and a reservoir in communication with the aerosol generator.
In still more embodiments, the present invention provides a nebulizer system comprising a housing that defines a passageway that is adapted to deliver an aerosolized liquid to a user. An aerosol generator is positioned to provide an aerosolized liquid into the passageway. A controller having a memory and a plurality of aerosol generator operation programs that control operation of the aerosol generator is coupled to the aerosol generator.
In yet still more embodiments, the present invention provides a nebulizing element positioned to provide nebulized fluid into a ventilator breathing circuit to provide nebulized fluid to a patient receiving air from a ventilator. It will be appreciated that a nebulizing element may also be referred to herein an aerosolization element, and a ventilator may also be referred to herein as a respirator.
Embodiments of the invention also provide operation sequences by which aerosol is provided a predetermined points in a breath cycle provided by a ventilator. In one aspect, the present invention provides for an operation sequence in which aerosol production begins at a predetermined point within an inhalation phase, which may also be referred to herein as an inspiratory phase, and stops at a second predetermined point within the same inhalation phase. In another aspect, the present invention provides for an operation sequence, which may be referred to as an operation program, in which aerosol production begins at a predetermined point in an inhalation phase and stops at a point after the inhalation phase has ended, i.e. at a certain point in the exhalation phase. It will be appreciated that the exhalation phase may also be referred to as the expiratory phase, and may encompass the entire period of time during which no inhalation phase is taking place; in other words, the exhalation phase may include not only the actual exhalation of the patient, but also any pause that may occur before or after exhalation. In another aspect, the present invention provides an operation sequence in which aerosolization begins at a predetermined point within the exhalation phase and stops within that exhalation phase, or, alternatively, begins at a predetermined point within an exhalation phase and stops at a predetermined point in the succeeding inhalation phase.
Embodiments of the invention also provide for selection of a particular operating sequence from a plurality of available operating sequences. Similarly, the present invention provides for modes of operation, which modes may include one or more operating sequences.
Embodiments additionally provide for algorithms to set forth operation sequences, choice of operation sequences or choice of modes of operation.
Embodiments also provide for consideration of the identity of a drug to be administered in executing an algorithm, choosing a mode of operation, or selecting or running an operation sequence.
Embodiments of the invention also provide for nebulization of particular drug groups or drugs, such as, for example, antibodies, such as IgG or antibiotics, such as aminoglycosides, such as amikacin.
Embodiments still further provide for a nebulized droplet ejection device for use with a ventilator, wherein the device produces droplets by a vibratory apertured element during a selected interval of a breathing cycle.
Embodiments additionally provide for apparatus and methods for varying the particle size distribution of a nebulized mist by varying the aperture exit diameter of an apertured vibratory aerosolization element.
Additional embodiments and features are set forth in part in the description that follows, and in part will become apparent to those skilled in the art upon examination of the specification or may be learned by the practice of the invention. The features and advantages of the invention may be realized and attained by means of the instrumentalities, combinations, and methods described in the specification.
Overview
As noted above, conventional nebulizer-ventilator systems have low medicament delivery efficiency (e.g., less than 20%). Embodiments of the invention include methods and systems for increasing delivery efficiencies to at least 40%, and in many instances to about 70% or more. The increased efficiency for delivering the aerosolized medicament may be attributable, in part, to one or more features that may be implemented in embodiments of the invention. These features include synchronizing the generation of aerosol with an inspiratory phase of the ventilator cycle (e.g., phasic delivery). The features may also include supplying air (e.g., an “air chaser”) following aerosol generation, which can clear the endotracheal tube and reduce the amount of medicament exhaled by the patient. Features may further include connecting the aerosol generating unit directly to the hub of the endotrcheal tube that is connected to the patient. Still other features include generating aerosolized medicament with smaller particle sizes (e.g., about 1 to 5 μm average diameter). Additional features may also include storing the medicament in a conical shaped reservoir to minimize the residual medicament volume.
Embodiments of the systems are configurable to administer aerosolized medicament to a patient both on-ventilator and off-ventilator. On-ventilator treatment methods include administering the nebulized aerosol through a ventilator circuit to the patient. Aerosol doses, containing about 1 to about 500 mg of a medicament, may be delivered through the ventilator circuit in a phasic or non-phasic manner. Off-ventilator treatment methods may include taking the patient off the ventilator before administering the nebulized aerosol. Once the treatment session is completed the patient may be put back on the ventilator, or may breathe on his or her own without assistance.
Embodiments of the invention provide treatments for a variety of ailments using a variety of aerosolizable medicaments. The ailments may include pulmonary ailments such as ventilator-associated pneumonia, hospital-acquired pneumonia, cystic fibrosis, mycobacterial infection, bronchitis, staph infection, fungal infections, viral infections, protozal infections, and acute exacerbation of Chronic Obstructive Pulmonary Disease, among others. The aerosolizable medicaments used to treat the ailments may include antibiotics, anti-oxidants, bronchodialators, corticosteroids, leukotrienes, protease inhibitors, and surfactants, among other medicaments.
Exemplary Pulmonary Drug Delivery Systems
Coupled to one of the ventilator limbs 110 or 112 may be an air pressure feedback unit 114, which equalizes the pressure in the limb with the air pressure feedback tubing 116 connected to the control module 118. In the embodiment shown, feedback unit 114 has a female connection end (e.g., an ISO 22 mm female fitting) operable to receive ventilator limb 112, and a male connection end (e.g., an ISO 22 mm male fitting) facing opposite, and operable to be inserted into the ventilator. The feedback unit may also be operable to receive a filter 115 that can trap particulates and bacteria attempting to travel between the ventilator circuit and tubing 116.
The control module 118 may monitor the pressure in the ventilator limb via tubing 116, and use the information to control the nebulizer 102 through system cable 120. In other embodiments (not shown) the control module 118 may control aerosol generation by transmitting wireless signals to a wireless control module on the nebulizer 102.
During the inhalation phase of the patient's breathing cycle, aerosolized medicament entering T-adaptor 106 may be mixed with the respiratory gases from the inspiratory ventilator limb 112 flowing to the patient's nose and/or lungs. In the embodiment shown, the aerosol and respiratory gases flow through nose piece 122 and into the nasal passages of the patient's respiratory tract.
Other embodiments of the circuit wye 108 shown in
In contrast to a “Y”-shaped junction device, junction device 135 provides for gas flow 150 (containing aerosolized medicament) to follow a straight unobstructed path through the respiratory circuit without any portion being diverted into branch member 145. In other words, there is virtually no change in the angle of the path of gas flow 150. As a result, the full amount of aerosol particles of medicament contained in gas flow 150 is efficiently delivered through the respiratory circuit to the patient. Upon expiratory effort by the patient, expiratory gas flow 152 follows a path through lumen 142 to lumen 146 of branch member 145 and through expiratory tube 110 back to the ventilator (not shown).
Referring to
PDDS systems like the ones described above in
For example, one exemplary breathing characteristic that may be sensed by a sensor is the cycle of a ventilator providing air to a patient; for example, the start of an inhalation cycle generated by the ventilator. The sensor may also sense other parameters, for example, it may be an acoustic sensor that is activated through passing the respiratory flow of the patient through an acoustic chamber so as to produce an acoustic tone, which is proportional to the inspiratory flow rate. The frequency of the acoustic tone indicates the inspiratory flow rate at any instant of the breathing cycle. The acoustic signal can be detected by the controller such that integration of the flow rate with time produces the tidal volume. Both the flow rate and the tidal volume can then be used by the controller to determine when the aerosol generator generates the droplets and at what mass flow rate such that maximum deposition of droplets is obtained. Further, the acoustic tone may be recorded to produce a record of the breathing pattern of the patient which may be stored in the microprocessor. This information can be later used to synchronize the ejection of droplets for the same patient. Such information may also be later employed for other diagnostic purposes. A more complete description of such sensors are described in commonly owned, U.S. Pat. No. 5,758,637, which was previously incorporated by reference.
In some embodiments, the sensors can be used to monitor the breathing characteristics of the patient throughout the delivery regime so as to ensure that the aerosol is efficiently delivered throughout the aerosolization procedure. In such embodiments, the controller can adjust the aerosol delivery based on any measured change in the breathing pattern of the patient during the aerosolization. With this monitoring and adjustment predetermined times for the beginning and ending of aerosolization can be reset based on the actual breathing of the patent. In other embodiments, however, the breathing sensor can be used to determine the breathing cycle of a tidal breath and to choose the appropriate pre-programmed delivery cycle that is stored in the memory of the controller. In other embodiments, the controller may be configured to provide aerosol based on the time. For example, the controller may be configured to start aerosol production at the beginning of an inhalation phase of a breathing cycle and stop at a point at which a predetermined percentage of the inhalation has taken place. Alternatively, the controller may be configured to start aerosolization at a first point at which a first predetermined percentage has taken place, and stop aerosolization at a second point at which a second predetermined percentage of that inhalation has taken place. Alternatively, aerosol may begin during an inhalation phase and end during the subsequent exhalation phase. Alternatively, the controller may be configured to begin aerosol production at a certain point during exhalation and stop during that exhalation or during the subsequent inhalation. Thus, embodiments of the PDDS may include a nebulizer having an aerosol generator and a controller configured to have the controller begin aerosolization during exhalation and stop during that exhalation or in the subsequent inhalation. In still other embodiments, the controller may be configured to begin aerosol production at a start point in the breathing cycle, and continue to generate aerosol for a set period of time regardless of how a patient's breathing cycle varies. At the end of the time period, aerosol generation stops until the next start point is in the breathing cycle. In further embodiments, the controller may be configured to start and stop aerosol production for preprogrammed periods of time that are independent of the patient's breathing cycle.
The controller may be operable to allow for a choice of modes of operation, for example, a mode in which aerosolization begins once a certain breath characteristic is detected, such as a sufficient level of inhalation, and ends when there is no longer a sufficient level; another mode in which aerosolization begins once a certain breath characteristic is detected, such as a sufficient level of inhalation, and ends at a predetermined time within the inhalation cycle, such as for example, before the level of inhalation falls below that required for operation of an aerosolization element, or, alternatively, at any other point within the inhalation cycle, such as after the inhalation phase of the cycle before exhalation has begun, or after exhalation has begun.
The level of inhalation may be sensed by a pressure sensor. Such a transducer may monitor a drop in air pressure or a rise in air pressure within a chamber that is in fluid communication with the ventilator circuit. In this manner, a pressure drop may be sensed by a patient inhaling through the circuit, for example, in an instance in which the ventilator provides assisted ventilation initiated by a patient's commencement of an inhalation. Similarly, a pressure rise may be sensed in an instance in which the ventilator pushes inhalation air to the patient without the patient initiating a breath. Another mode in which the controller may be operable is a mode in which the on/off operation of the aerosol generator is triggered by time, which may be ascertained from an internal clock device, such as a clock built into a microprocessor, or from an external source. Another mode in which the controller may be operable is in which the on/off operation of the aerosol is triggered by the controller receiving an external signal, such as a signal from a ventilator, which can correspond to the point in the ventilator's cycle of that is the start of an inhalation phase in which the ventilator begins to push inspiratory air into the ventilator circuit. The controller may be operable between such modes, including a mode in which the aerosolization begins at a predetermined time in the breathing cycle and ends at a predetermined time in the breathing cycle. The first and second predetermined times in the third mode may be during inhalation. Alternatively, the first and second predetermined times may be during exhalation, or at the first predetermined time may be during exhalation and the second predetermined time may be during subsequent inhalation. These times may correspond to certain percentages of the inhalation phase taking place, or any other points of reference within a breathing cycle.
Alternatively, the first predetermined time and the second predetermined time may be designated as any point within a single breathing cycle, or alternatively, the first predetermined point may be at any point within one breathing cycle and the second predetermined point may be at any point in a subsequent breathing cycle. The controller may make the determination of when to begin, and operate to begin aerosolization, and may make the determination of when to stop aerosolization to stop, and cause aerosolization to stop. The controller may make such determinations and take such actions based on accessing stored algorithms. The controller may receive a signal from the ventilator that establishes a reference point, nonetheless, the controller, by making the determinations an taking the actions based on stored algorithms, and/or information obtained as to the identity of a drug to be administered, may cause aerosol production to begin and/or end independent of the instantaneous position of the ventilator with respect to the ventilator cycle.
Embodiments also include a controller operable to allow for a single mode of operation, where the single mode of operation may be any mode, including but not limited to the modes described above. For example, a mode in which aerosolization begins once a certain breath characteristic is detected, such as a sufficient level of inhalation, and ends when there is no longer a sufficient level. Similarly, the controller may operable in a mode in which aerosolization begins once a certain breath characteristic is detected, such as a sufficient level of inhalation, and ends at a predetermined time within the inhalation before there is no longer a sufficient level or an aerosolization element.
Alternatively, the mode may be a mode in which the aerosolization is commenced based on a signal from the ventilator indicating the attainment of a certain point within the ventilation output cycle or the inhalation cycle of the patient. (The ventilation output cycle of the ventilator may coincide with the inhalation cycle of the patient, such that the ventilation output phase of the ventilator output cycle and the inhalation phase of the inspiratory cycle of the patient occur substantially simultaneously. Such may be the case where a patient is completely passive and the only inhalation that occurs is by generation of air from the ventilator during the output phase of the ventilator cycle). Such point may be during the output phase of the output cycle of the ventilator or during the inhalation phase of the inhalation cycle of the patient. The predetermined point can be chosen to coincide with a certain level of output from the ventilator or at a certain point in time during the ventilator output cycle. Such a predetermined point may be a specific point within the output phase of the ventilator cycle, or, a specific point within the non-output phase of the ventilator cycle, based, for example, on the timing of the previous or succeeding output phase of the ventilator. In another aspect, the present invention provides for a ventilator along with the aerosol generator and controller. In an aspect of the invention, a predetermined time may be based on the timing of a ventilator supplying air to a user. In this manner, the controller may be set to work off of the timing of the ventilator in one mode, while working off the patient's inspiratory effort in another mode, or mode that allows for a combination of the patient's inspiratory effort and the timing of the ventilator, for example, where the ventilator is set to assist the patient by supplying air upon the patient's effort or where the patient has not made a sufficient effort within a predetermined period of time.
Exemplary Off-Ventilator Configurations
Referring now to
The off-ventilator PDDS 400 may also include a second wye limb 420, which includes a filter 422 and one-way valve 424, through which gases may pass during an exhalation cycle. The filter 422 may filter out aerosolized medicament and infectious agents exhaled by the patient to prevent these materials from escaping into the surrounding atmosphere. The one-way valve 424 can prevent ambient air from flowing back into the PDDS 400.
The on and off-ventilator configurations of the PDDS allow continuity of treatment as the patient switches between on-vent and off-vent treatment configurations. In both configurations, a patient is able to receive the same aerosolized medicament at the same dosage level, providing a continuity of treatment as the patient transitions from on-ventilator care to off-ventilator care. This can be particularly useful for extended treatment regimens, when the patient receives the aerosolized medicament for several days or weeks.
Exemplary Nebulizers
In regard to the nebulizers (i.e., aerosol generators), they may be of the type, for example, where a vibratable member is vibrated at ultrasonic frequencies to produce liquid droplets. Some specific, non-limiting examples of technologies for producing fine liquid droplets is by supplying liquid to an aperture plate having a plurality of tapered apertures and vibrating the aperture plate to eject liquid droplets through the apertures. Such techniques are described generally in U.S. Pat. Nos. 5,164,740; 5,938,117; 5,586,550; 5,758,637, 6,014,970, and 6,085,740, the complete disclosures of which are incorporated by reference. However, it should be appreciated that the present invention is not limited for use only with such devices.
Referring now to
The nebulizer 502 may also include a power inlet 512 that can receive a plug 514 that supplies electric power to the nebulizer. Alternatively, the power inlet 512 may be replaced or supplemented by a power cord that terminates with a plug that can be plugged into a power source (not shown). The inlet 512 may also receive an electronic control signal that can control the timing and frequency which the nebulizer aerosolizes medicament from the reservoir 506.
The aerosolization element 604 may have a vibratable member that moves with respect to an aperture plate to aerosolized the liquid medicament. By utilizing an aerosol generator that produces aerosol by the electric powering of the vibratable member that causes the aperture plate to eject liquid at one face thereof, through its apertures, as a mist from the other face thereof, as generally described above (and as described generally in U.S. Pat. Nos. 5,164,740; 5,938,117; 5,586,550; 5,758,637, 6,085,740; and 6,235,177, the complete disclosures of which are, and have been above, incorporated herein by reference), the starting and stopping of aerosol generation may be controlled on the level of accuracy of microseconds or milliseconds, thus providing accurate dosing. The timing of aerosol generation can be done based solely on a predetermined timing within a breathing cycle, on timing in conjunction with the length of a prior breath or portions thereof, on other breathing characteristics, on particular medication being administered, or a combination of any of these criteria.
The aerosolization element may be constructed of a variety of materials, comprising metals, which may be electroformed to create apertures as the element is formed, as described, for example, in U.S. Pat. No. 6,235,177 assigned to the present assignee and incorporated by reference herein in its entirety. Palladium is believed to be of particular usefulness in producing an electroformed, multi-apertured aerosolization element, as well as in operation thereof to aerosolize liquids. Other metals that can be used are palladium alloys, such as PdNi, with, for example, 80 percent palladium and 20% nickel. Other metals and materials may be used without departing from the present invention.
Referring now to
The aerosolization element may be mounted on an aerosol actuator 80, which defines an aperture 81 therethrough. This may be done in such a manner that the dome portion of the aerosolization element protrudes through the aperture 81 of the aerosol actuator 80 and the substantially planar peripheral ring portion 75, on the second face 72 of the aerosolization element 70 abuts a first face 82 of the aerosol actuator 80. A vibratory element 84 may be provided, and may be mounted on the first face 82 of the aerosol actuator 80, or alternatively may be mounted on an opposing second face 83 of the aerosol actuator 80. The aerosolization element may be vibrated in such a manner as to draw liquid through the apertures 74 of the aerosolization element 70 from the first face to the second face, where the liquid is expelled from the apertures as a nebulized mist. The aerosolization element may be vibrated by a vibratory element 84, which may be a piezoelectric element. The vibratory element may be mounted to the aerosol actuator, such that vibration of the vibratory element may be mechanically transferred through the aerosol actuator to the aerosolization element. The vibratory element may be annular, and may surround the aperture of the aerosol actuator, for example, in a coaxial arrangement.
Embodiments of the invention include the aerosolization element, or the aerosol generator, comprising the aerosolization element 70, the aerosol actuator 80 and the vibratory element 86 may be replaced with a respective assembly that has apertures of a different size, such as a different exit diameter, to produce a mist having a different aerosol particle size. A circuitry 86 may provide power from a power source. The circuitry may include a switch that may be operable to vibrate the vibratory element and thus the aerosolization element, and aerosolization performed in this manner may be achieved within milliseconds of operation of the switch. The circuitry may include a controller 87, for example, a microprocessor that can provide power to the vibratory element 84 to produce aerosol from the aerosolization element 70 within milliseconds or fractions of milliseconds of a signal to do so. For example, aerosol production may begin within about 0.02 to about 50 milliseconds of such a signal and may stop within about 0.02 to about 50 milliseconds from the cessation of a first signal or a second signal either of which may act as a trigger to turn of aerosolization. Similarly, aerosol production may begin and end within about 0.02 milliseconds to about 20 milliseconds of such respective signaling. Likewise, aerosol production may begin and end within about 0.02 milliseconds to about 2 milliseconds of such respective signaling. Further, this manner of aerosolization provides full aerosolization with a substantially uniform particle size of low velocity mist 79 being produced effectively instantaneously with operation of the switch.
The switch, described above, may be operable by a pressure transducer, which may be positioned in the mouthpiece of the nebulizer. The pressure transducer may be in electrical communication with the circuitry, and a microprocessor may also be in electrical communication with the circuitry, and the microprocessor may interpret electrical signals from the pressure transducer, and may also operate the switch to begin aerosolization. In this manner, nebulization can begin substantially instantaneously with the inhalation of a user upon the mouthpiece. An example of such a sensor switch can be found U.S. application Ser. No. 09/705,063, now abandoned, assigned to the present assignee, the entire content of which is hereby incorporated herein by reference.
Another transducer may be used to sense the absence or presence of liquid in the reservoir, by sensing, for example, a difference between vibration characteristics of the aerosolization element, such as, for example, differences in frequency or amplitude, between wet vibration and substantially dry vibration. In this manner, the circuitry, may, for example by way of the microprocessor, turn the vibration off when there is essentially no more liquid to aerosolize, i.e., when the end of the dose has been achieved, thus minimizing operation of the aerosolization element in a dry state. Likewise, the switch may prevent vibration prior to delivery of a subsequent dose into the reservoir. An example of such a switch is shown in co-assigned U.S. application Ser. No. 09/805,498, now U.S. Pat. No. 6,546,927, the entire content of which is hereby incorporated herein by reference.
Exemplary Nebulizer-Filter Configurations
The pressure in the apparatus may be monitored throughout the breathing cycle with a pressure sensor coupled to pressure port 916. The pressure sensor (not shown) may generate an analog or digital electronic signal containing information about the pressure level in the apparatus. This signal may be used to control the amount of aerosolized medicament and/or gases entering the apparatus over the course of the patient's breathing cycle. For example, when the pressure in the apparatus decreases as the patient inhales, the pressure signal may cause the nebulizer 902 to add aerosolized medicament to the apparatus, and/or cause the gas source or pump to add gas through inlet 914. Then, when the pressure in the apparatus increases as the patient exhales, the pressure signal may cause the nebulizer 902 to stop adding aerosolized medicament to the apparatus, and/or cause the gas source or pump to stop adding gas through inlet 914. Controlling the aerosol and/or gas flow based on the patient's breathing cycle, i.e., phasic delivery of the gases and aerosols, will be described in additional detail below.
Exemplary Aerosol Chamber
Embodiments of the invention may include a chamber 1102 that can hold gas and aerosol mixtures for delivery to the patient's lungs. The chamber may be used in both on-ventilator and off-ventilator configurations. The expanded volume within the chamber reduces the surface area to volume ratio at the patient interface end of the system, which can increase the aerosol delivery efficiency.
Port 1108 may include a valve 1110 that can change the fluid flow path through the port 1108 depending on phase of a patient's breathing cycle. For example, during an inhalation phase (
Exemplary Medicaments
Embodiments of the invention contemplate a variety of medicaments that can be aerosolized and delivered to a patient's lungs. These medicaments may include antibiotics such as aminoglycosides, β-lactams, and quinolines, among others. The aminoglycosides may include amikacin, gentamycin, kanamycin, streptomycin, neomycin, netilmicin, and tobramycin, among other aminoglycosides. Other medicaments may also be used, including anti-oxidants, bronchodilators, corticosteroids, leukotrienes, prostacyclins, protease inhibitors, and surfactants, among other medicaments. Table 1 lists classes of medicaments and some of the aliments they may be used to treat in their aerosolized state.
Exemplary Phasic Delivery Methods
Embodiments of the invention take advantage of this discovery by controlling delivery to a predetermined percentage of the breathing cycle, such as a predetermined percentage of the inhalation phase of the breathing cycle, to provide greater delivery efficiency than either continuous delivery or delivery during the entire inhalation phase. Embodiments of the invention also take advantage of the surprising discovery that the percentage of increase in efficiency in delivery for such a predetermined portion of the inhalation phase over delivery during the entire inhalation phase is itself greater than the increase in efficiency of delivery during the inhalation phase compared to aphasic administration of the aerosol.
Phasic delivery methods may include measuring the characteristics of a patient's inhaled breath, typically a tidal breath, and using the measurements to control the operation of the aerosol generator.
The user can take another tidal breath and the aerosol generator can be operated based on the measured characteristics of the tidal breath 1324. It should be appreciated however, that instead of a tidal breath, the person can take other types of breath. Alternatively, the controller may base the timing of operation of the aerosol generator so that aerosol is generated at specific time periods within a breathing cycle. For example, the controller may operate the aerosol generator for the first 50 percent of inspiration. Alternatively, the controller may operate the aerosol generator to generate aerosol after a portion of inhalation has taken place and to cease producing aerosol after another portion of inhalation has taken place. For example, the controller may cause aerosol to be generated beginning after 20% of the inspiration has taken place and cause aerosol production to cease after 70% of inspiration has taken place. The controller may cause aerosol production to start after, for example, after 90% of exhalation has taken place and, for example, cause aerosol production to stop after 30% of the following inspiration has taken place. By controlling the specific timing within the breathing cycle that aerosolized medication is provided into the breathing circuit, greater efficiency of drug administration can be achieved.
Since some of the pharmaceuticals to be aerosolized may be more effective when delivered near the beginning of a patient's breathing cycle, while other pharmaceuticals may be more effective when delivered near the end of the patient's breathing cycle, the timing of the aerosol generation depends on the type of medicament delivered. If it is known what type of medication or drug is being delivered, the controller can select the best time during the patient's breathing cycle to deliver the aerosol, based upon a predetermined regimen for that drug that is stored in memory. As an additional benefit, an estimate of the patient's age and/or distress can be made, for example, by measuring the tidal volume and breathing rate. Such measurements can influence the efficiency requirements of the dose per breath. These or other variables can be used in establishing various regimes for aerosol delivery, in particular delivery into the breathing circuit of a ventilator. These regimes can be stored in memory and then accessed by the controller as appropriate for a given patient condition.
For example, for a bronchodilator the best time to delivery may be half way through the inhalation phase of a breath when impaction would be reduced since inhalation flows are reducing. For steroids, it may be best to deliver towards the end of the inhalation phase of a breath. For antibiotics, it may be best to slightly pre-load, e.g., deliver aerosol during the exhalation phase, or deliver right at the start of the breath. For example, antibiotics may be delivered at the beginning of a ventilator provided inhalation, and the aerosol delivery may stop after a predetermined percentage of the inhalation has been provided. One class of antibiotics that may be administered in accordance with the present invention is the class known as the aminoglycoside class of antibiotics. This class of antibiotics has typically been administered intravenously, however, such delivery can sometimes have unwanted side effects, which may be systemic. Embodiments of the invention provide for the administration of antibiotics, such as aminoglycosides including amikacin by delivering them in aerosolized form into the breathing circuit of a patient on a ventilator. In this manner, amikacin can be used to treat pulmonary infection conditions that typically arise when patients are mechanically ventilated, and the amikacin, or other aminoglycoside or other antibiotic, can be delivered directly to the target of treatment, the pulmonary tract, avoiding side effects that may otherwise arise from intravenous administration. Further, because of the great cost of such drugs, far greater efficiency is achieved through this pulmonary delivery. As noted above with reference to
Embodiments of the invention provide for conducting various regimes of aerosolization, depending on the situation. For example, in
In step 1400, a choice is made to follow a particular regime. In this case, regime I is a regime in which aerosol is generated continuously (step 1402). Regime II provides aerosol generation during the inhalation phase only (step 1404). In this case, in step 1406, aerosol generation is set to start at the start of the inhalation phase and, in step 1408, aerosol generation is set to stop when the inhalation phase stops. In step 1410, aerosol generation begins at the start of the inhalation phase. In step 1412, when the inhalation phase ends, aerosol generation stops (step 1414).
Regime III provides for inhalation during a predetermined percentage of the inhalation phase (step 1416). A predetermined percentage of an inhalation (or exhalation) phase may be based on a measured time from a discrete point in the ventilator cycle, such as the instantaneous commencement of inspiratory air generation by the ventilator. Alternatively, such predetermined percentage may be based on the time interval between successive discrete points in the ventilator, such as successive commencements of successive inhalation air generation by the ventilator. Alternatively, such percentages may be based upon air pressure in the ventilator circuit, or any other parameter. With respect to Regime III, in this case, in step 1418, a first predetermined point is set to correspond with the completion of a first predetermined percent of the inhalation. In step 1420, a second predetermined point is set to correspond to a second predetermined percent of inhalation percent being completed. For example, as described above, the first predetermined point may correspond to 20% of the inhalation phase being completed, and the second predetermined point may correspond to a point at which 70% of that same inhalation has taken place. In step 1422, aerosol generation begins at the first predetermined point in the inhalation phase. In step 1424, when the second predetermined point is reached, the controller carries out step 1414 and stops the aerosol generation.
Similarly, as noted above, other regimes may be followed, for example, in which aerosol generation begins during the inhalation phase and ends during the exhalation phase, or begins during exhalation and ends during that exhalation, or begins during exhalation and ends in the subsequent breath cycle, for example, at a predetermined point in the subsequent inhalation phase. Accordingly, turning to
In this example, with the controller having a selection choice between operation sequences corresponding to regimes II, III and IV, schematic representation of the operation sequences are shown in
In the case of regime III, the controller does not take any action to begin aerosol generation, until a predetermined point in the inhalation phase, corresponding to a percentage of the inhalation phase being completed (step 1464). In step 1466, at a predetermined point in the inhalation phase, the controller turns on aerosol generator. In step 1468, aerosol generation continues until a second predetermined point inhalation phase, corresponding to a second percentage point of completion of the inhalation phase. At this point, the controller carries out step 1462 and turns off aerosol generator. With respect to regime IV, aerosol generation begins after a predetermined point of completion of the inhalation phase (step 1464) and this point may be predetermined to occur after the inhalation phase has been completed and the exhalation phase has begun (step 1470). In step 1472, the controller turns the aerosol generator on to begin aerosolization. Variations can be made as to the point at which the aerosol generation is turned off. If it is desired that aerosol generation be completed before the completion of the exhalation phase (regime IVa), then aerosol generation may continue until a predetermined point prior to the subsequent inhalation (step 1476). Alternatively, it may be desirable to continue aerosolization until the end of exhalation, which may correspond to the point of commencement of the subsequent inhalation, as in regime IVb (step 1478). Alternatively, it may be desired to follow a regimen such as regime IVc, where aerosol generation continues through into the subsequent breath cycle (step 1480), until, for example, a predetermined percent of the subsequent inhalation phase has been completed (step 1482). In these regimes, aerosolization will continue until the satisfaction of these conditions (step 1476 for regime IVa, step 1478 for regime IVb or step 1482 for regime IVc), at which point the controller carries out step 1462 and stops the aerosol generator. The process may continue with the next signal indicating that the ventilator has begun to provide an inhalation phase, step 1454.
Further, the choice of which operating sequence to follow may rely at least in part on the identity of a drug to be administered, which information can be considered by the controller as described above. In addition, it should be appreciated that modifications may be made to these examples without departing from the present invention. For example, a system may be configured, or a method may be carried out, to be able to select more than three initial regimes to follow. For example, regimes I, II, III and IV as described above may be simultaneously selectable. Further, various steps may be altered; for example, some steps may not be discrete steps. Thus, step 1456 may not be a discrete step but rather the following of an operation sequence according to a selected regime. Similarly, the order of the steps may be changed, such as the controller may select an operating sequence (step 1452) after receiving a signal that the ventilator has commenced to provide an inhalation phase (step 1454). Steps may also be combined, such as, for example, in regime IV steps 1464 and 1470 may be combined as a single step, as these two steps represent successive criteria for the determining a single first predetermined point has been met. Likewise, step 1474 may be combined with steps 1476, 1478 or 1480, as step 1474 is the predicate for the condition test specified in each of the other successive tests, steps 1476, 1478 or 1480. The algorithm examples may be altered to form other operating sequences. For example, an operating sequence may call for the controller to start aerosol generation at the start of the inhalation cycle provided by the nebulizer, as in regime II, at step 1458, and turn off the aerosol generator at a point at which a predetermined percentage of the inhalation phase has been completed, as in regime III, step 1468 (and step 1462). In a similar manner, other criteria may be used to trigger the turning on or off of the aerosol generator. For example, as described above, the start of aerosolization may be triggered by the sensing of a particular pressure or change in pressure in the ventilator circuit, and may end by following the turning off sequence of regimes III (steps 1468 and 1462) or IV (steps 1474, 1476, 1478 or 1480 and 1482, followed by step 1462, as described above.
The phasic delivery methods outlined above may also be practiced with additional systems such as continuous positive airway pressure (“CPAP”) systems, such as the ones described in U.S. patent application Ser. No. 10/828,765, filed Apr. 20, 2004, U.S. patent application Ser. No. 10/883,115, filed Jun. 30, 2004, now U.S. Pat. No. 7,290,541, and U.S. patent application Ser. No. 10/957,321, filed Sep. 9, 2004, now U.S. Pat. No. 7,267,121, where the entire continents of all the applications are herein incorporated by reference for all purposes.
Delivery efficacy tests were conducted with an on-ventilator PDDS aerosolizing an aqueous solution of amikacin sulfate. The PDDS ventilator circuit configuration was similar to the one shown and described in
Table 2 presents efficiency data for the delivery of aerosolized medicament to through systems according to embodiments of the invention. In the experimental setup, aerosolized droplets deposited on an inspiratory filter placed at a patient end interface are weighed and compared to the total weight of the dose of medicament that was aerosolized. The percentage of a dose deposited on the inspiratory filter represents the fraction of the total aerosolized dose that would be inhaled by a patient, and thus quantifies the efficiency of the system.
Table 2 shows the efficiencies of 7 runs for a system according to an embodiment of the invention had a mean efficiency of 71%±6%. This efficiency level is well above conventional systems for the delivery of aerosolized medicaments, where the efficiency levels are typically 10% or less.
Having described several embodiments, it will be recognized by those of skill in the art that various modifications, alternative constructions, and equivalents may be used without departing from the spirit of the invention. Additionally, a number of well known processes and elements have not been described in order to avoid unnecessarily obscuring the present invention. Accordingly, the above description should not be taken as limiting the scope of the invention.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included.
As used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a process” includes a plurality of such processes and reference to “the electrode” includes reference to one or more electrodes and equivalents thereof known to those skilled in the art, and so forth.
Also, the words “comprise,” “comprising,” “include,” “including,” and “includes” when used in this specification and in the following claims are intended to specify the presence of stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more other features, integers, components, steps, acts, or groups.
This application is a continuation of prior U.S. patent application Ser. No. 11/090,328, filed Mar. 24, 2005, which is a continuation-in-part of U.S. patent application Ser. No. 10/345,875, filed Jan. 15, 2003, now U.S. Pat. No. 6,968,840, Ser. No. 09/849,194, filed May 4, 2001, now U.S. Pat. No. 6,615,824, Ser. No. 09/812,755,filed Mar. 20, 2001, now U.S. Pat. No. 7,100,600 and Ser. No. 10/284,068, filed Oct. 30, 2002, now U.S. Pat. No. 7,600,511. The entire content of all of the aforementioned applications are herein incorporated by reference for all purposes. U.S. patent application Ser. No. 11/090,328 is related to U.S. patent application Ser. No. 09/876,542, filed Jun. 7, 2001, now abandoned, Ser. No. 09/876,402, filed Jun. 7, 2001, now abandoned, and Ser. No. 09/812,987, filed Mar. 20, 2001, now U.S. Pat. No. 6,948,491, which are incorporated herein by reference, in their entirety, for all purposes. U.S. patent application Ser. No. 09/849,194, now U.S. Pat. No. 6,615,824, claims the benefit of Patent Cooperation Treaty Application No. PCT/IE/00051, filed May 5, 2000, which is incorporated herein by reference, in its entirety, for all purposes. U.S. patent application Ser. No. 10/284,068, now U.S. Pat. No. 7,600,511, claims the benefit of U.S. Provisional Application Nos. 60/344,484, filed Nov. 1, 2001, and 60/381,830, filed May 20, 2002, which are incorporated herein by reference, in their entirety, for all purposes.
| Number | Name | Date | Kind |
|---|---|---|---|
| 550315 | Allen | Nov 1895 | A |
| 809159 | Willis et al. | Jan 1906 | A |
| 1680616 | Horst | Aug 1928 | A |
| 2022520 | Philbrick | Nov 1935 | A |
| 2101304 | Wright | Dec 1937 | A |
| 2158615 | Wright | May 1939 | A |
| 2187528 | Wing | Jan 1940 | A |
| 2223541 | Baker | Dec 1940 | A |
| 2266706 | Fox et al. | Dec 1941 | A |
| 2283333 | Martin | May 1942 | A |
| 2292381 | Klagges | Aug 1942 | A |
| 2360297 | Wing | Oct 1944 | A |
| 2375770 | Dahlberg | May 1945 | A |
| 2383098 | Wheaton | Aug 1945 | A |
| 2404063 | Healy | Jul 1946 | A |
| 2430023 | Longmaid | Nov 1947 | A |
| 2474996 | Wallis | Jul 1949 | A |
| 2512004 | Wing | Jun 1950 | A |
| 2521657 | Severy | Sep 1950 | A |
| 2681041 | Zodtner et al. | Jun 1954 | A |
| 2693178 | Gilroy | Nov 1954 | A |
| 2705007 | Gerber | Mar 1955 | A |
| 2735427 | Sullivan | Feb 1956 | A |
| 2764946 | Henderson | Oct 1956 | A |
| 2764979 | Henderson | Oct 1956 | A |
| 2779623 | Eisenkraft | Jan 1957 | A |
| 2935970 | Morse et al. | May 1960 | A |
| 3066669 | De Melfy | Dec 1962 | A |
| 3083707 | Seeler | Apr 1963 | A |
| 3103310 | Lang | Sep 1963 | A |
| 3247849 | Wise | Apr 1966 | A |
| 3325031 | Singier | Jun 1967 | A |
| 3411854 | Rosler et al. | Nov 1968 | A |
| 3515348 | Coffman et al. | Jun 1970 | A |
| 3530856 | Bird | Sep 1970 | A |
| 3550864 | East | Dec 1970 | A |
| 3558052 | Dunn | Jan 1971 | A |
| 3561444 | Boucher | Feb 1971 | A |
| 3563415 | Ogle | Feb 1971 | A |
| 3680954 | Frank | Aug 1972 | A |
| 3719328 | Hindman | Mar 1973 | A |
| 3738574 | Guntersdorfer et al. | Jun 1973 | A |
| 3771982 | Dobo | Nov 1973 | A |
| 3790079 | Berglund et al. | Feb 1974 | A |
| 3804329 | Martner | Apr 1974 | A |
| 3812854 | Michaels et al. | May 1974 | A |
| 3826413 | Warren | Jul 1974 | A |
| 3838686 | Szekely | Oct 1974 | A |
| 3842833 | Ogle | Oct 1974 | A |
| 3858739 | Turner et al. | Jan 1975 | A |
| 3861386 | Harris et al. | Jan 1975 | A |
| 3865106 | Palush | Feb 1975 | A |
| 3903884 | Huston et al. | Sep 1975 | A |
| 3906950 | Cocozza | Sep 1975 | A |
| 3908654 | Lhoest et al. | Sep 1975 | A |
| 3950760 | Rauch et al. | Apr 1976 | A |
| 3951313 | Coniglione | Apr 1976 | A |
| 3958249 | DeMaine et al. | May 1976 | A |
| 3970250 | Drews | Jul 1976 | A |
| 3983740 | Danel | Oct 1976 | A |
| 3993223 | Welker, III et al. | Nov 1976 | A |
| 4005435 | Lundquist et al. | Jan 1977 | A |
| 4020834 | Bird | May 1977 | A |
| 4030492 | Simburner | Jun 1977 | A |
| 4052986 | Scaife | Oct 1977 | A |
| 4059384 | Holland et al. | Nov 1977 | A |
| D246574 | Meierhoefer | Dec 1977 | S |
| 4076021 | Thompson | Feb 1978 | A |
| 4083368 | Freezer | Apr 1978 | A |
| 4094317 | Wasnich | Jun 1978 | A |
| 4101041 | Mauro, Jr. et al. | Jul 1978 | A |
| 4106503 | Rosenthal et al. | Aug 1978 | A |
| 4109174 | Hodgson | Aug 1978 | A |
| 4113809 | Abair et al. | Sep 1978 | A |
| D249958 | Meierhoefer | Oct 1978 | S |
| 4119096 | Drews | Oct 1978 | A |
| 4121583 | Chen | Oct 1978 | A |
| 4159803 | Cameto et al. | Jul 1979 | A |
| 4163450 | Kirk et al. | Aug 1979 | A |
| 4207990 | Weiler et al. | Jun 1980 | A |
| 4210155 | Grimes | Jul 1980 | A |
| 4226236 | Genese | Oct 1980 | A |
| 4240081 | Devitt | Dec 1980 | A |
| 4240417 | Holever | Dec 1980 | A |
| 4248227 | Thomas | Feb 1981 | A |
| 4261512 | Zierenberg | Apr 1981 | A |
| D259213 | Pagels | May 1981 | S |
| 4268460 | Boiarski et al. | May 1981 | A |
| 4291838 | Williams | Sep 1981 | A |
| 4294407 | Reichl et al. | Oct 1981 | A |
| 4298045 | Weiler et al. | Nov 1981 | A |
| 4299784 | Hense | Nov 1981 | A |
| 4300546 | Kruber | Nov 1981 | A |
| 4301093 | Eck | Nov 1981 | A |
| 4319155 | Makai et al. | Mar 1982 | A |
| 4334531 | Reichl et al. | Jun 1982 | A |
| 4336544 | Donald et al. | Jun 1982 | A |
| 4338576 | Takahashi et al. | Jul 1982 | A |
| 4368476 | Uehara et al. | Jan 1983 | A |
| 4368850 | Szekely | Jan 1983 | A |
| 4374707 | Pollack | Feb 1983 | A |
| 4389071 | Johnson, Jr. et al. | Jun 1983 | A |
| 4408719 | Last | Oct 1983 | A |
| 4428802 | Kanai et al. | Jan 1984 | A |
| 4431136 | Janner et al. | Feb 1984 | A |
| 4454877 | Miller et al. | Jun 1984 | A |
| 4465234 | Maehara et al. | Aug 1984 | A |
| 4470412 | Nowacki et al. | Sep 1984 | A |
| 4474251 | Johnson, Jr. | Oct 1984 | A |
| 4474326 | Takahashi | Oct 1984 | A |
| 4475113 | Lee et al. | Oct 1984 | A |
| 4479609 | Maeda et al. | Oct 1984 | A |
| 4512341 | Lester | Apr 1985 | A |
| 4530464 | Yamamoto et al. | Jul 1985 | A |
| 4533082 | Maehara et al. | Aug 1985 | A |
| 4539575 | Nilsson | Sep 1985 | A |
| 4544933 | Heinzl | Oct 1985 | A |
| 4546361 | Brescia et al. | Oct 1985 | A |
| 4550325 | Viola | Oct 1985 | A |
| 4566452 | Farr | Jan 1986 | A |
| 4591883 | Isayama | May 1986 | A |
| 4593291 | Howkins | Jun 1986 | A |
| 4605167 | Maehara | Aug 1986 | A |
| 4613326 | Szwarc | Sep 1986 | A |
| 4620201 | Heinzl et al. | Oct 1986 | A |
| 4628890 | Freeman | Dec 1986 | A |
| 4632311 | Nakane et al. | Dec 1986 | A |
| 4658269 | Rezanka | Apr 1987 | A |
| 4659014 | Soth et al. | Apr 1987 | A |
| 4677975 | Edgar et al. | Jul 1987 | A |
| 4678680 | Abowitz | Jul 1987 | A |
| 4679551 | Anthony | Jul 1987 | A |
| 4681264 | Johnson, Jr. | Jul 1987 | A |
| 4693853 | Falb et al. | Sep 1987 | A |
| 4702418 | Carter et al. | Oct 1987 | A |
| 4722906 | Guire | Feb 1988 | A |
| 4753579 | Murphy | Jun 1988 | A |
| 4790479 | Matsumoto et al. | Dec 1988 | A |
| 4793339 | Matsumoto et al. | Dec 1988 | A |
| 4796807 | Bendig et al. | Jan 1989 | A |
| 4799622 | Ishikawa et al. | Jan 1989 | A |
| 4805609 | Roberts et al. | Feb 1989 | A |
| 4819629 | Jonson | Apr 1989 | A |
| 4819834 | Thiel | Apr 1989 | A |
| 4823784 | Bordoni et al. | Apr 1989 | A |
| 4826080 | Ganser | May 1989 | A |
| 4826759 | Guire et al. | May 1989 | A |
| 4828886 | Hieber | May 1989 | A |
| 4843445 | Stemme | Jun 1989 | A |
| 4849303 | Graham et al. | Jul 1989 | A |
| 4850534 | Takahashi et al. | Jul 1989 | A |
| 4865006 | Nogi et al. | Sep 1989 | A |
| 4871489 | Ketcham | Oct 1989 | A |
| 4872553 | Suzuki et al. | Oct 1989 | A |
| 4877989 | Drews et al. | Oct 1989 | A |
| 4888516 | Daeges et al. | Dec 1989 | A |
| 4922901 | Brooks et al. | May 1990 | A |
| 4926915 | Deussen et al. | May 1990 | A |
| 4934358 | Nilsson et al. | Jun 1990 | A |
| 4954225 | Bakewell | Sep 1990 | A |
| 4957239 | Tempelman | Sep 1990 | A |
| 4964521 | Wieland et al. | Oct 1990 | A |
| D312209 | Morrow et al. | Nov 1990 | S |
| 4968299 | Ahlstrand et al. | Nov 1990 | A |
| 4971665 | Sexton | Nov 1990 | A |
| 4973493 | Guire | Nov 1990 | A |
| 4976259 | Higson et al. | Dec 1990 | A |
| 4979959 | Guire | Dec 1990 | A |
| 4994043 | Ysebaert | Feb 1991 | A |
| 5002048 | Makiej et al. | Mar 1991 | A |
| 5002582 | Guire et al. | Mar 1991 | A |
| 5007419 | Weinstein et al. | Apr 1991 | A |
| 5016024 | Lam et al. | May 1991 | A |
| 5021701 | Takahashi et al. | Jun 1991 | A |
| 5022587 | Hochstein | Jun 1991 | A |
| 5024733 | Abys et al. | Jun 1991 | A |
| 5046627 | Hansen | Sep 1991 | A |
| 5062419 | Rider | Nov 1991 | A |
| 5063396 | Shiokawa et al. | Nov 1991 | A |
| 5063922 | Hakkinen | Nov 1991 | A |
| 5073484 | Swanson et al. | Dec 1991 | A |
| 5076266 | Babaev | Dec 1991 | A |
| 5080093 | Raabe et al. | Jan 1992 | A |
| 5080649 | Vetter | Jan 1992 | A |
| 5086765 | Levine | Feb 1992 | A |
| 5086785 | Gentile et al. | Feb 1992 | A |
| 5099833 | Michaels et al. | Mar 1992 | A |
| 5115803 | Sioutas | May 1992 | A |
| 5115971 | Greenspan et al. | May 1992 | A |
| D327008 | Friedman | Jun 1992 | S |
| 5122116 | Kriesel et al. | Jun 1992 | A |
| 5129579 | Conte | Jul 1992 | A |
| 5134993 | Van Der Linden et al. | Aug 1992 | A |
| 5139016 | Waser | Aug 1992 | A |
| 5140740 | Weigelt | Aug 1992 | A |
| 5147073 | Cater | Sep 1992 | A |
| 5152456 | Ross et al. | Oct 1992 | A |
| 5157372 | Langford | Oct 1992 | A |
| 5164740 | Ivri | Nov 1992 | A |
| 5169029 | Behar et al. | Dec 1992 | A |
| 5170782 | Kocinski | Dec 1992 | A |
| 5180482 | Abys et al. | Jan 1993 | A |
| 5186164 | Raghuprasad | Feb 1993 | A |
| 5186166 | Riggs et al. | Feb 1993 | A |
| 5198157 | Bechet | Mar 1993 | A |
| 5201322 | Henry et al. | Apr 1993 | A |
| 5213860 | Laing | May 1993 | A |
| 5217148 | Cater | Jun 1993 | A |
| 5217492 | Guire et al. | Jun 1993 | A |
| 5227168 | Chvapil | Jul 1993 | A |
| 5230496 | Shillington et al. | Jul 1993 | A |
| 5241954 | Glenn | Sep 1993 | A |
| 5245995 | Sullivan et al. | Sep 1993 | A |
| 5248087 | Dressler | Sep 1993 | A |
| 5258041 | Guire et al. | Nov 1993 | A |
| 5261601 | Ross et al. | Nov 1993 | A |
| 5263992 | Guire | Nov 1993 | A |
| 5279568 | Cater | Jan 1994 | A |
| 5287849 | Piper et al. | Feb 1994 | A |
| 5297734 | Toda | Mar 1994 | A |
| 5299739 | Takahashi et al. | Apr 1994 | A |
| 5303854 | Cater | Apr 1994 | A |
| 5304125 | Leith | Apr 1994 | A |
| 5309135 | Langford | May 1994 | A |
| 5312281 | Takahashi et al. | May 1994 | A |
| 5313955 | Rodder | May 1994 | A |
| 5319971 | Osswald et al. | Jun 1994 | A |
| 5320603 | Vetter et al. | Jun 1994 | A |
| 5322057 | Raabe et al. | Jun 1994 | A |
| 5342011 | Short | Aug 1994 | A |
| 5342504 | Hirano et al. | Aug 1994 | A |
| 5347998 | Hodson et al. | Sep 1994 | A |
| 5348189 | Cater | Sep 1994 | A |
| 5350116 | Cater | Sep 1994 | A |
| 5355872 | Riggs et al. | Oct 1994 | A |
| 5357946 | Kee et al. | Oct 1994 | A |
| 5372126 | Blau | Dec 1994 | A |
| 5378231 | Johnson et al. | Jan 1995 | A |
| 5383906 | Burchett et al. | Jan 1995 | A |
| 5388571 | Roberts et al. | Feb 1995 | A |
| 5388572 | Mulhauser et al. | Feb 1995 | A |
| 5392768 | Johansson et al. | Feb 1995 | A |
| 5396883 | Knupp et al. | Mar 1995 | A |
| 5414075 | Swan et al. | May 1995 | A |
| 5415161 | Ryder | May 1995 | A |
| 5419315 | Rubsamen | May 1995 | A |
| 5426458 | Wenzel et al. | Jun 1995 | A |
| 5431155 | Marelli | Jul 1995 | A |
| 5435282 | Haber et al. | Jul 1995 | A |
| 5435297 | Klein | Jul 1995 | A |
| 5437267 | Weinstein et al. | Aug 1995 | A |
| 5445141 | Kee et al. | Aug 1995 | A |
| D362390 | Weiler | Sep 1995 | S |
| 5449502 | Igusa et al. | Sep 1995 | A |
| 5452711 | Gault | Sep 1995 | A |
| 5458135 | Patton et al. | Oct 1995 | A |
| 5458289 | Cater | Oct 1995 | A |
| 5474059 | Cooper | Dec 1995 | A |
| 5477992 | Jinks et al. | Dec 1995 | A |
| 5479920 | Piper et al. | Jan 1996 | A |
| 5482030 | Klein | Jan 1996 | A |
| 5485850 | Dietz | Jan 1996 | A |
| 5487378 | Robertson et al. | Jan 1996 | A |
| 5489266 | Grimard | Feb 1996 | A |
| 5497944 | Weston et al. | Mar 1996 | A |
| D369212 | Snell | Apr 1996 | S |
| 5508269 | Smith et al. | Apr 1996 | A |
| 5511726 | Greenspan et al. | Apr 1996 | A |
| 5512329 | Guire et al. | Apr 1996 | A |
| 5512474 | Clapper et al. | Apr 1996 | A |
| 5515841 | Robertson et al. | May 1996 | A |
| 5515842 | Ramseyer et al. | May 1996 | A |
| 5516043 | Manna et al. | May 1996 | A |
| 5518179 | Humberstone et al. | May 1996 | A |
| 5529055 | Gueret | Jun 1996 | A |
| 5533497 | Ryder | Jul 1996 | A |
| 5542410 | Goodman et al. | Aug 1996 | A |
| 5549102 | Lintl et al. | Aug 1996 | A |
| 5560353 | Willemot et al. | Oct 1996 | A |
| 5560837 | Trueba | Oct 1996 | A |
| 5563056 | Swan et al. | Oct 1996 | A |
| D375352 | Bologna | Nov 1996 | S |
| 5570682 | Johnson | Nov 1996 | A |
| 5579757 | McMahon et al. | Dec 1996 | A |
| 5582330 | Iba | Dec 1996 | A |
| 5584285 | Salter et al. | Dec 1996 | A |
| 5586550 | Ivri et al. | Dec 1996 | A |
| 5588166 | Burnett | Dec 1996 | A |
| 5598836 | Larson et al. | Feb 1997 | A |
| 5601077 | Imbert | Feb 1997 | A |
| 5609798 | Liu et al. | Mar 1997 | A |
| 5617844 | King | Apr 1997 | A |
| 5632878 | Kitano | May 1997 | A |
| 5635096 | Singer et al. | Jun 1997 | A |
| 5637460 | Swan et al. | Jun 1997 | A |
| 5647349 | Ohki et al. | Jul 1997 | A |
| 5653227 | Barnes et al. | Aug 1997 | A |
| 5654007 | Johnson et al. | Aug 1997 | A |
| 5654162 | Guire et al. | Aug 1997 | A |
| 5654460 | Rong | Aug 1997 | A |
| 5657926 | Toda | Aug 1997 | A |
| 5660166 | Lloyd | Aug 1997 | A |
| 5664557 | Makiej, Jr. | Sep 1997 | A |
| 5664706 | Cater | Sep 1997 | A |
| 5665068 | Takamura | Sep 1997 | A |
| 5666946 | Langenback | Sep 1997 | A |
| 5670999 | Takeuchi et al. | Sep 1997 | A |
| 5685491 | Marks et al. | Nov 1997 | A |
| 5692644 | Gueret | Dec 1997 | A |
| 5694920 | Abrams et al. | Dec 1997 | A |
| 5707818 | Chudzik et al. | Jan 1998 | A |
| 5709202 | Lloyd et al. | Jan 1998 | A |
| 5714360 | Swan et al. | Feb 1998 | A |
| 5714551 | Bezwada et al. | Feb 1998 | A |
| 5718222 | Lloyd et al. | Feb 1998 | A |
| D392184 | Weiler | Mar 1998 | S |
| 5724957 | Rubsamen et al. | Mar 1998 | A |
| 5744515 | Clapper | Apr 1998 | A |
| 5752502 | King | May 1998 | A |
| 5755218 | Johansson et al. | May 1998 | A |
| 5758637 | Ivri et al. | Jun 1998 | A |
| 5775506 | Grabenkort | Jul 1998 | A |
| 5788665 | Sekins | Aug 1998 | A |
| 5788819 | Onishi et al. | Aug 1998 | A |
| 5790151 | Mills | Aug 1998 | A |
| 5797389 | Ryder | Aug 1998 | A |
| 5810004 | Ohki et al. | Sep 1998 | A |
| 5819730 | Stone et al. | Oct 1998 | A |
| 5823179 | Grychowski et al. | Oct 1998 | A |
| 5823428 | Humberstone et al. | Oct 1998 | A |
| 5829723 | Brunner et al. | Nov 1998 | A |
| 5836515 | Fonzes | Nov 1998 | A |
| 5839617 | Cater et al. | Nov 1998 | A |
| 5842468 | Denyer et al. | Dec 1998 | A |
| 5848587 | King | Dec 1998 | A |
| 5862802 | Bird | Jan 1999 | A |
| 5865171 | Cinquin | Feb 1999 | A |
| 5878900 | Hansen | Mar 1999 | A |
| 5893515 | Hahn et al. | Apr 1999 | A |
| 5894841 | Voges | Apr 1999 | A |
| 5897008 | Hansen | Apr 1999 | A |
| 5910698 | Yagi | Jun 1999 | A |
| 5915377 | Coffee | Jun 1999 | A |
| 5918637 | Fleischman | Jul 1999 | A |
| 5921232 | Yokoi et al. | Jul 1999 | A |
| 5925019 | Ljungquist | Jul 1999 | A |
| 5938117 | Ivri | Aug 1999 | A |
| 5950619 | Van Der Linden et al. | Sep 1999 | A |
| 5954268 | Joshi et al. | Sep 1999 | A |
| 5960792 | Lloyd et al. | Oct 1999 | A |
| 5964417 | Amann et al. | Oct 1999 | A |
| 5970974 | Van Der Linden et al. | Oct 1999 | A |
| 5976344 | Abys et al. | Nov 1999 | A |
| 5993805 | Sutton et al. | Nov 1999 | A |
| 6000396 | Melker et al. | Dec 1999 | A |
| 6006745 | Marecki | Dec 1999 | A |
| 6007518 | Kriesel et al. | Dec 1999 | A |
| 6012450 | Rubsamen | Jan 2000 | A |
| 6014970 | Ivri et al. | Jan 2000 | A |
| 6026809 | Abrams et al. | Feb 2000 | A |
| 6029666 | Aloy et al. | Feb 2000 | A |
| 6032665 | Psaros | Mar 2000 | A |
| 6037587 | Dowell et al. | Mar 2000 | A |
| 6039696 | Bell | Mar 2000 | A |
| 6044841 | Verdun et al. | Apr 2000 | A |
| 6045215 | Cooulman | Apr 2000 | A |
| 6045874 | Himes | Apr 2000 | A |
| 6047818 | Warby et al. | Apr 2000 | A |
| 6055869 | Stemme et al. | May 2000 | A |
| 6060128 | Kim et al. | May 2000 | A |
| 6062212 | Davison et al. | May 2000 | A |
| 6068148 | Weiler | May 2000 | A |
| 6085740 | Ivri et al. | Jul 2000 | A |
| 6096011 | Trombley, III et al. | Aug 2000 | A |
| 6105877 | Coffee | Aug 2000 | A |
| 6106504 | Urrutia | Aug 2000 | A |
| 6116234 | Genova et al. | Sep 2000 | A |
| 6123413 | Agarwal et al. | Sep 2000 | A |
| 6139674 | Markham et al. | Oct 2000 | A |
| 6142146 | Abrams et al. | Nov 2000 | A |
| 6145963 | Pidwerbecki et al. | Nov 2000 | A |
| 6146915 | Pidwerbecki et al. | Nov 2000 | A |
| 6152130 | Abrams et al. | Nov 2000 | A |
| 6155676 | Etheridge et al. | Dec 2000 | A |
| 6158431 | Poole | Dec 2000 | A |
| 6161536 | Redmon et al. | Dec 2000 | A |
| 6163588 | Matsumoto et al. | Dec 2000 | A |
| 6182662 | McGhee | Feb 2001 | B1 |
| 6186141 | Pike et al. | Feb 2001 | B1 |
| 6196218 | Voges | Mar 2001 | B1 |
| 6196219 | Hess et al. | Mar 2001 | B1 |
| 6205999 | Ivri et al. | Mar 2001 | B1 |
| 6216025 | Kruger | Apr 2001 | B1 |
| 6216690 | Keitel et al. | Apr 2001 | B1 |
| 6216916 | Maddox et al. | Apr 2001 | B1 |
| 6223746 | Jewett et al. | May 2001 | B1 |
| 6235177 | Borland et al. | May 2001 | B1 |
| 6254219 | Agarwal et al. | Jul 2001 | B1 |
| 6260549 | Sosiak | Jul 2001 | B1 |
| 6269810 | Brooker et al. | Aug 2001 | B1 |
| 6270473 | Schwebel | Aug 2001 | B1 |
| 6273342 | Terada et al. | Aug 2001 | B1 |
| 6315397 | Truninger et al. | Nov 2001 | B2 |
| 6318361 | Sosiak | Nov 2001 | B1 |
| 6318640 | Coffee | Nov 2001 | B1 |
| 6328030 | Kidwell et al. | Dec 2001 | B1 |
| 6328033 | Avrahami | Dec 2001 | B1 |
| 6336453 | Scarrott et al. | Jan 2002 | B1 |
| 6341732 | Martin et al. | Jan 2002 | B1 |
| 6358058 | Strupat et al. | Mar 2002 | B1 |
| 6367470 | Denyer | Apr 2002 | B1 |
| 6387886 | Montgomery et al. | May 2002 | B1 |
| 6390091 | Banner et al. | May 2002 | B1 |
| 6394363 | Arnott et al. | May 2002 | B1 |
| 6402046 | Loser | Jun 2002 | B1 |
| 6405934 | Hess et al. | Jun 2002 | B1 |
| 6412481 | Bienvenu et al. | Jul 2002 | B1 |
| 6427682 | Klimowicz et al. | Aug 2002 | B1 |
| 6443146 | Voges | Sep 2002 | B1 |
| 6443366 | Hirota et al. | Sep 2002 | B1 |
| 6467476 | Ivri et al. | Oct 2002 | B1 |
| 6516798 | Davies | Feb 2003 | B1 |
| 6530370 | Heinonen | Mar 2003 | B1 |
| 6539937 | Haveri | Apr 2003 | B1 |
| 6540153 | Ivri | Apr 2003 | B1 |
| 6540154 | Ivri et al. | Apr 2003 | B1 |
| 6543443 | Klimowicz et al. | Apr 2003 | B1 |
| 6546927 | Litherland et al. | Apr 2003 | B2 |
| 6550472 | Litherland et al. | Apr 2003 | B2 |
| 6554201 | Klimowicz et al. | Apr 2003 | B2 |
| 6576224 | Osbakken et al. | Jun 2003 | B1 |
| 6578571 | Watt | Jun 2003 | B1 |
| 6581595 | Murdock et al. | Jun 2003 | B1 |
| 6596261 | Adjei et al. | Jul 2003 | B1 |
| 6598602 | Sjoholm | Jul 2003 | B1 |
| 6601581 | Babaev | Aug 2003 | B1 |
| 6606989 | Brand et al. | Aug 2003 | B1 |
| 6612303 | Grychowski et al. | Sep 2003 | B1 |
| 6615824 | Power | Sep 2003 | B2 |
| 6629646 | Ivri | Oct 2003 | B1 |
| 6631721 | Salter et al. | Oct 2003 | B1 |
| 6640804 | Ivri | Nov 2003 | B2 |
| 6644304 | Grychowski et al. | Nov 2003 | B2 |
| 6651650 | Yamamoto et al. | Nov 2003 | B1 |
| 6694978 | Bennarsten | Feb 2004 | B1 |
| 6705315 | Sullivan et al. | Mar 2004 | B2 |
| 6732944 | Litherland et al. | May 2004 | B2 |
| 6745768 | Colla et al. | Jun 2004 | B2 |
| 6745770 | McAuliffe et al. | Jun 2004 | B2 |
| 6755189 | Ivri et al. | Jun 2004 | B2 |
| 6761161 | Scarrott et al. | Jul 2004 | B2 |
| 6769626 | Haveri | Aug 2004 | B1 |
| 6776155 | Farrell et al. | Aug 2004 | B2 |
| 6782886 | Narayan et al. | Aug 2004 | B2 |
| 6810876 | Berthon-Jones | Nov 2004 | B2 |
| 6814071 | Klimowicz et al. | Nov 2004 | B2 |
| 6817361 | Berthon-Jones et al. | Nov 2004 | B2 |
| 6840240 | Berthon-Jones et al. | Jan 2005 | B1 |
| 6845770 | Klomowicz et al. | Jan 2005 | B2 |
| 6851626 | Patel et al. | Feb 2005 | B2 |
| 6860268 | Bohn et al. | Mar 2005 | B2 |
| 6915962 | Power et al. | Jul 2005 | B2 |
| 6921020 | Ivri | Jul 2005 | B2 |
| 6926208 | Ivri | Aug 2005 | B2 |
| 6948491 | Loeffler et al. | Sep 2005 | B2 |
| 6968840 | Smith et al. | Nov 2005 | B2 |
| 6978941 | Litherland et al. | Dec 2005 | B2 |
| 7100600 | Loeffler et al. | Sep 2006 | B2 |
| 7156917 | Moriyama et al. | Jan 2007 | B2 |
| 7267121 | Ivri | Sep 2007 | B2 |
| 20010013554 | Borland et al. | Aug 2001 | A1 |
| 20010015737 | Truninger et al. | Aug 2001 | A1 |
| 20020011247 | Ivri et al. | Jan 2002 | A1 |
| 20020023639 | Ivri et al. | Feb 2002 | A1 |
| 20020023650 | Gunaratnam et al. | Feb 2002 | A1 |
| 20020033178 | Farrell et al. | Mar 2002 | A1 |
| 20020036601 | Puckeridge et al. | Mar 2002 | A1 |
| 20020078958 | Stenzler | Jun 2002 | A1 |
| 20020088461 | Alksnis | Jul 2002 | A1 |
| 20020104530 | Ivri et al. | Aug 2002 | A1 |
| 20020121274 | Borland et al. | Sep 2002 | A1 |
| 20020134372 | Loeffler et al. | Sep 2002 | A1 |
| 20020134374 | Loeffler et al. | Sep 2002 | A1 |
| 20020134375 | Loeffler et al. | Sep 2002 | A1 |
| 20020134377 | Loeffler et al. | Sep 2002 | A1 |
| 20020162551 | Litherland | Nov 2002 | A1 |
| 20020162554 | Loescher | Nov 2002 | A1 |
| 20020195107 | Smaldone | Dec 2002 | A1 |
| 20030140921 | Smith et al. | Jul 2003 | A1 |
| 20030145859 | Bohn et al. | Aug 2003 | A1 |
| 20030150445 | Power et al. | Aug 2003 | A1 |
| 20030150446 | Patel et al. | Aug 2003 | A1 |
| 20030205229 | Crockford | Nov 2003 | A1 |
| 20030226906 | Ivri | Dec 2003 | A1 |
| 20040000598 | Ivri | Jan 2004 | A1 |
| 20040004133 | Ivri et al. | Jan 2004 | A1 |
| 20040011358 | Smaldone et al. | Jan 2004 | A1 |
| 20040035413 | Smaldone et al. | Feb 2004 | A1 |
| 20040035490 | Power | Feb 2004 | A1 |
| 20040050947 | Power et al. | Mar 2004 | A1 |
| 20040123974 | Marler et al. | Jul 2004 | A1 |
| 20040139963 | Ivri et al. | Jul 2004 | A1 |
| 20040139968 | Loeffler et al. | Jul 2004 | A1 |
| 20040188534 | Litherland et al. | Sep 2004 | A1 |
| 20040194783 | McAuliffe et al. | Oct 2004 | A1 |
| 20040226561 | Colla et al. | Nov 2004 | A1 |
| 20040226566 | Gunaratnam et al. | Nov 2004 | A1 |
| 20040256488 | Loeffler et al. | Dec 2004 | A1 |
| 20050011514 | Power et al. | Jan 2005 | A1 |
| 20050039746 | Grychowski et al. | Feb 2005 | A1 |
| 20050139211 | Alston et al. | Jun 2005 | A1 |
| 20050150496 | Smaldone | Jul 2005 | A1 |
| 20050172954 | Smith et al. | Aug 2005 | A1 |
| 20050178847 | Power et al. | Aug 2005 | A1 |
| 20050211245 | Smaldone et al. | Sep 2005 | A1 |
| 20050211253 | Smaldone et al. | Sep 2005 | A1 |
| 20050217666 | Fink et al. | Oct 2005 | A1 |
| 20050220763 | Condos et al. | Oct 2005 | A1 |
| 20050229927 | Fink et al. | Oct 2005 | A1 |
| 20050229928 | Ivri et al. | Oct 2005 | A1 |
| 20050235987 | Smaldone et al. | Oct 2005 | A1 |
| 20050279851 | Ivri | Dec 2005 | A1 |
| Number | Date | Country |
|---|---|---|
| 531640 | Dec 1957 | BE |
| 477 885 | Sep 1969 | CH |
| 555 681 | Nov 1974 | CH |
| 11 03 522 | Mar 1961 | DE |
| 0 049 636 | Apr 1982 | EP |
| 0 103 161 | Mar 1984 | EP |
| 0 134 847 | Mar 1985 | EP |
| 0 178 925 | Apr 1986 | EP |
| 0 387 222 | Sep 1990 | EP |
| 0 432 992 | Jun 1991 | EP |
| 0 476 991 | Mar 1992 | EP |
| 0 480 615 | Apr 1992 | EP |
| 0 510 648 | Oct 1992 | EP |
| 0 516 565 | Dec 1992 | EP |
| 0 542 723 | May 1993 | EP |
| 0 933 138 | Apr 1999 | EP |
| 0 923 957 | Jun 1999 | EP |
| 1 142 600 | Oct 2001 | EP |
| 2622113 | Apr 1989 | FR |
| 2624017 | Jun 1989 | FR |
| 2 692 569 | Dec 1993 | FR |
| 973 458 | Oct 1964 | GB |
| 1 454 597 | Nov 1976 | GB |
| 2 073 616 | Oct 1981 | GB |
| 2 101 500 | Jan 1983 | GB |
| 2 177 623 | Jan 1987 | GB |
| 2 240 494 | Jul 1991 | GB |
| 2 272 389 | May 1994 | GB |
| 2 279 571 | Jan 1995 | GB |
| 57-023852 | Feb 1982 | JP |
| 57-105608 | Jul 1982 | JP |
| 58-061857 | Apr 1983 | JP |
| 58-139757 | Aug 1983 | JP |
| 59-142163 | Aug 1984 | JP |
| 60-004714 | Jan 1985 | JP |
| 61-008357 | Jan 1986 | JP |
| 61-215059 | Sep 1986 | JP |
| 02-135169 | May 1990 | JP |
| 02-189161 | Jul 1990 | JP |
| 60-07721 | Jan 1994 | JP |
| WO 8203548 | Oct 1982 | WO |
| WO 9207600 | May 1992 | WO |
| WO 9211050 | Sep 1992 | WO |
| WO 9217231 | Oct 1992 | WO |
| WO 9301404 | Jan 1993 | WO |
| WO 9310910 | Jun 1993 | WO |
| WO 9409912 | May 1994 | WO |
| WO 9609229 | Mar 1996 | WO |
| WO9707896 | Mar 1997 | WO |
| WO 9917888 | Apr 1999 | WO |
| WO9963746 | Dec 1999 | WO |
| WO9963946 | Dec 1999 | WO |
| WO 0037132 | Jun 2000 | WO |
| WO0118280 | Mar 2001 | WO |
| WO 03059424 | Jul 2003 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20080142002 A1 | Jun 2008 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60381830 | May 2002 | US | |
| 60344484 | Nov 2001 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11090328 | Mar 2005 | US |
| Child | 12018716 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10345875 | Jan 2003 | US |
| Child | 11090328 | US | |
| Parent | 10284068 | Oct 2002 | US |
| Child | 10345875 | US | |
| Parent | 09849194 | May 2001 | US |
| Child | 10284068 | US | |
| Parent | 09812755 | Mar 2001 | US |
| Child | 09849194 | US |
