Method and device for correcting the drift offset of a pressure sensor of a flowmeter

ES 2 179 068 T3

DESCRIPTION

Method and device for correcting drift displacement of a flow pressure detector.

This invention relates to improvements in the automated delivery of aerosolized drugs and compounds for inspiration by patients, more specifically to a durable, electronically controlled, breath actuated metered dose inhaler device having replaceable drug cassettes. Background of the invention

Known devices for delivering aerosolized medication for inhalation by a patient include metered dose inhalers that are manually actuated and breath activated. Breath activated inhalers typically automatically deliver a metered dose when the patient's inspiratory effort moves a mechanical lever or the sensed flow rises above a predetermined threshold, sensed by a hot wire anemometer. See, for example, US Patents 3,187,748; 3,565,070; 3,814,297;

3.826.413; 4.592.348; 4.648.393; 4.803.978; 4.896.832;

a product available from 3M Healthcare called Aerosol Sheathed Actuator and Cap; and a product available from Riker Laboratories called Autohaler. As used herein, references to "effort" and "flow" are to the inlet and outlet of air from the patient's pulmonary system. Flow is typically detected as a flow rate (l / min), a flow volume (l), or a combination of a flow rate and flow volume or more than a flow rate and / or more than a flow volume. A major problem with manual metered dose inhalers is that the patient frequently actuates the device at the wrong time during inspiratory flow, without inhaling, or during expiration and does not obtain the benefits of the intended drug therapy. Consequently, patients may breathe in too little medication, or take a second dose and receive too much medication.

A problem with breath-activated drug delivery is that the dose is triggered when crossing a fixed threshold inspiratory effort. Thus, an inspiratory effort may be sufficient to deliver a metered dose, but the inspiratory flow following delivery may not be sufficient to cause the aerosol drug to pass into the desired portion of the patient's airways. Another problem exists with patients whose inspiratory effort is not sufficient to rise above the threshold to fire the release valve all or part of the time. This results in frustration and ineffective therapy.

Known metered dose inhalers include a box and a body. The box contains a pressurized aerosol propellant and medication reservoir, a metering valve that includes a fixed-size chamber that captures a defined and uniform volume of material, and a valve stem that delivers a metered dose. The dosing chamber is typically kept open to the tank. To deliver a dose, the valve stem is pushed into the metering valve. This causes the metering valve to close, in sequence, the chamber in relation to the deposit and capture a fixed volume of material under pressure, open the chamber in relation to the valve stem to release the captured amount of material by expelling it through a flow path in the valve stem, close the chamber in relation to the valve stem, and then open the chamber to the reservoir so that the chamber is positively filled with a pressurized medication / aerosol mixture, providing the next dose to be administered.

The metered dose inhaler body contains a canister receptacle and a valve actuator (also called a valve stem receptacle) that contains a flow path that terminates in a mouthpiece and receives the valve stem in alignment with the path. flow. The nozzle is typically at an angle to the flow path and directs the released aerosol into the patient's mouth (or nostrils). The valve stem receptacle is typically passive. Thus, when the box is pressed relative to the valve stem receptacle, by manual or automated advancement, the valve stem is pressed to the metering valve and causes the metered dose to be released via the flow paths in the valve stem. and the valve stem receptacle and is ejected from the mouthpiece. Typically, the valve stem receptacle has a frictional fit with the valve stem so that the housing is therefore fixed to the body.

A problem with conventional pressure metered dose box devices is that the dosing chamber must be held open to the atmosphere for a period of time sufficient to release the entire dose from the chamber. The period of time required is a function of the interior dimensions of the valve stem, the valve stem receptacle, and the mouthpiece. Consequently, commercial metered dose manual inhalers are limited to valves and drug formulations that have release times of less than about one-tenth of a second. This is so so that the patient does not have to control the valve release time in addition to synchronizing drug release with inspiration.

Metered dose inhalers must also be shaken sufficiently to obtain a homogeneous mixture of the drug and the propellant mixture to fill the dosing chamber after the administration of a dose. A problem with some breath actuated metered dose inhalers is that their sequence of operation leaves the dosing chamber open to the valve stem and atmosphere and closed to the reservoir, rather than vice versa. Consequently, the patient must reposition or mount the inhaler to fill the dosing chamber with a dose. If this occurs for a period of time after the last dose is delivered, or without sufficiently shaking the device before mounting, an inhomogeneous mixture of drug and propellant may be loaded into the dosing chamber.

ES 2

This results in the patient being administered more or less medication than intended.

Another problem with existing metered dose inhalers, whether they are breath actuated or not, is that the boxes and valve stem receptacles are factory set to deliver a fixed dose in a relatively short period of time. This results in a given particle size distribution. However, such a distribution cannot provide a maximum or optional desired respirable fraction of the aerosol mist that is suitable for a desired drug delivery position in the particular patient. Known devices that attempt to solve this problem process the aerosol after it is generated and are thus inefficient and uneconomical. See, for example, US Patent 4,790,305, US Patent 4,926,852, US Patent 4,677,975, and US Patent 3,658,059.

A problem with electronically controlled breath actuated metered dose inhalers is that the actuators for depressing the metered dose box consume considerable amounts of electrical current to provide the force required to deliver a dose. Consequently, they are not practical for use as battery powered devices. See, for example, Newman et al., Thorax, 1981, 36: 52-55; Newman et al., Thorax, 1980, 35: 234; Newman et al., Eur. J. Breathe. Dis., 1981, 62: 321; and Newman et al., Am. Rev. Respir. Dis., 1981, 124: 317-320 (the "Newman references").

It is known that lung functions, such as forced expiratory volume in one second, forced vital capacity, and maximum expiratory flow rate, can be measured based on measured flow rates and used to diagnose the existence of medical conditions, to prescribe medication, and to find out the efficiency of a drug therapy program. See, for example, US Patents 3,991,304 and 4,852,582 and the Newman references. Until now, these tests have been performed using available spirometers. US Patent 4,852,582 also relates to using a peak flow meter to measure changes in peak flow before and after administration of a bronchodilator. The results of such tests before and after the administration of several different drugs are used to evaluate the effectiveness of the drugs.

One problem with earlier lung function test devices is that they are complicated. Another problem is that the test data must be examined and interpreted by a medical specialist to be meaningful. Another problem is that they do not adequately alter the dose of the drug administered to a single patient during the course of therapy, or from patient to patient, using the same delivery device to generate an aerosol of the same drug or different drugs.

Another problem with the known techniques is that they do not satisfy the needs of a portable device that is hand-held, powered by

068 T3 4 battery, and measure the flow in two directions such that each direction has a different range of flow values ​​with good resolution in each range.

The present invention relates to improvements over the basic invention disclosed in United States Patent US-A-5 404 871.

Said United States Patent US-A-5 404 871 describes methods and apparatus for the administration of aerosolized medicaments for inspiration that increase the effectiveness and usefulness of the devices for administering aerosolized medicaments and that overcome many problems of the devices known in the art. previous. Said application refers to methods and apparatus based on detecting the patient's inspiratory flow and delivering a controlled amount of an aerosolized drug as one or more pulses to one or more corresponding identified points in the detected inspiratory flow, to provide an efficient administration of a selected amount of medicine.

Each pulse may be provided with a pulse width, shape, and frequency that will provide the respirable fraction of the aerosolized compound to be delivered and the accumulated particle size distribution to improve delivery of the aerosolized compound to the desired locations in the airway. The time the valve opens is selected to produce an aerosol mist having a cumulative particle size distribution that selectively favors small or large particles, as desired. The opening time can be selected between 10 and 1000 msec. The valve may operate asynchronously or synchronously to produce one or more pulses such that each full aerosol dose includes one pulse or more than one pulse of non-uniform or uniform pulse widths, shapes, and intervals between pulses.

The administration threshold can be based on an inspiratory flow rate, more specifically, a selected speed before the appearance of the maximum inspiratory flow rate, for example, for a preselected threshold a speed of the order of 20 to 30 liters per minute, a volume of inspiratory flow, for example, for a preselected threshold a volume of approximately 1.0 liter. Mine preferably, the delivery threshold is a combination of a flow rate parameter and a flow volume parameter such as a pair.

The US application also relates to methods and apparatus for delivering an aerosol from a supply of aerosol generating material for inspiration by a person in response to the person's sensed inspiratory flow. Such apparatus includes:

a valve in communication with the supply of aerosol generating material;

means for operating the valve to release an amount of aerosol generating material to form an aerosol; means for detecting an inspiratory flow from the person;

means for controlling the valve operating means in response to sensed inspiratory flow including:

ES 2 179 068 T3 first means of determining whether each detected inspiratory flow is one of a first flow or a subsequent flow, the first flow corresponding to one of the first attempt to deliver an aerosol quantity and the first attempt to deliver an aerosol quantity after administration of a quantity of aerosol, the following flow corresponding to a detected inspiratory flow subsequent to a detected preceding inspiratory flow not followed by the administration of an amount of aerosol;

means for obtaining a delivery threshold corresponding to a point in the detected inspiratory flow at which an amount of aerosol is to be delivered, the predicted delivery threshold being a preselected delivery threshold in response to the detected inspiratory flow that is determined to be a first flow, and a delivery threshold determined in response to the detected inspiratory flow that is determined to be a subsequent flow, the providing means including means for calculating the determined delivery threshold based on the detected preceding inspiratory flow; and second means for determining whether or not the detected inspiratory flow meets the predicted delivery threshold so that the control means operates the valve to deliver an amount of aerosol in response to the second determining means determining that the detected inspiratory flow meets the expected threshold of administration.

The calculation means and the method step to obtain the determined administration threshold determine the administration threshold based on the detection of an inspiratory flow that does not meet the predicted administration threshold, and can recursively determine new administration thresholds for each flow. successive inspiratory rate detected that does not meet each predicted delivery threshold. This can be obtained by measuring a selected flow parameter of the sensed inspiratory flow and regulating the selected delivery threshold in response to the measured flow parameter. The selected flow parameter can be a point corresponding to the maximum detected flow rate, flow volume, or a combination of flow rate and flow volume, such that the setting is a percentage of the detected flow parameter.

A flow reset event is declared upon system initialization and after the delivery of an aerosol in response to a first detected flow or subsequent flow that meets a predicted threshold. It can also be declared after a predetermined time interval. A flow detected after a flow reset event is treated as a first flow. Thus, a flow replenishment event separates successive attempts to deliver a controlled amount of a drug.

The United States application also describes an embodiment in which the preselected delivery threshold is initially determined based on the person's measured inspiratory flow that is detected as a calibration breath, and not as an attempt to deliver medication. The attempt to administer medication is made when a later detected inspiratory flow is detected and compared with the determined administration threshold. Afterwards, the administration is performed if the detected flow meets the predetermined administration threshold, and the administration threshold is recursively lowered as in said embodiment, that is, based on the flow parameter of the preceding failed attempt, if any detected flow afterwards it does not meet the threshold. A preselected delivery schedule, corresponding to the optimal delivery threshold (and optionally additional delivery points) for delivery of the selected aerosol drug can also be determined based on measured inspiratory flow parameters.

The means for detecting the inspiratory flow for drug delivery is a tube defining an inspiratory flow path having a mouth end and an open end and a flow transducer arranged in the flow path. The flow transducer may be selected from a flow restriction device or structure that generates a pressure drop across the device (referred to as a differential pressure transducer or structure) and associated means for converting the measured differential pressure to a flow rate. inspiratory, for example, a pneumotachograph, a hot-wire anemoometer, and means to convert measured temperature changes to an inspiratory flow rate, and similar devices for obtaining a flow signal. The inspiratory flow path may include a means for obtaining a laminar flow through the inspiratory flow path so that the flow transducer detects the differential pressure through a laminar flow of air. Laminar flow provides a flow path and flow with linear characteristics to convert differential pressures into flow. In embodiments that do not have a laminar flow means or that use structures, transducers, and / or inspiratory flow paths that do not have such linear flow characteristics, such as venturi orifices or a single resistive flow screen, the flow path may be encoded by an array of predetermined calibration constants. Thus, the non-linear characteristics of the differential pressures detected through the resistive flow device can be converted into flow rates by using the matrix of calibration constants for the range of detected pressures, directly or indirectly. Differential pressure transducers are described having a differential pressure sensitivity of the order of ± 25.4 cm of water corresponding to a flow rate of from about 0 to about 800 liters per minute.

The United States Application also describes methods and apparatus for monitoring patient breath flow patterns du4.

ES 2 179 068 T3 during the course of an aerosolized drug inspiration therapy program and determine the patient's lung function, for example, forced expiratory volume in one second, forced vital capacity, and maximum expiratory flow, based on to the detected breath flow. The same flow transducer used to detect inspiration flow is also used to measure lung function. A display device is provided to visualize quantitatively and / or qualitatively the determined lung function of the patient. The display device can be used to indicate the patient's instantaneous condition when measuring an instantaneous lung function. The display device can also be used to indicate relative changes in condition when a subsequent measurement of lung function is compared with a previous measurement (or with a historical mean of measurements, for example, a weighted average) of lung function. The device can also be configured to acquire a second measurement of pulmonary function, compare said measurement with a previous measurement, and display trend data to the patient, to indicate therefore if the patient's medical condition improves, deteriorates or remains. approximately the same. It is important that this display indicated to the patient when the measured functions indicate that the patient should seek medical attention.

Relative changes in measured lung function can be used to regulate drug dose based on determined changes in determined function. This can be done based on a determined relative change from one drug administration to the next, or from a baseline measured lung function (or a historical record of weighted means) to the next drug administration.

The method also includes acquiring a second breath parameter after the previously measured lung function and measuring a second lung function, comparing the second measured lung function with the first measured lung function, indicating whether the patient's determined lung function has changed or not. the first to the second determination, provide first, second and third visual indicators, and visualize whether the second measured lung function has improved in the first visual indicator, has remained nominally the same in the second visual indicator, and has degenerated in the third visual indicator, in relation to the previously measured lung function.

It should be understood that, in the context of comparing two measured lung functions, the term first breath flow or first detected lung function may be one of the previously acquired measurement, a lone base measurement made at the beginning of drug therapy, and a changing weighted average of previously acquired measurements, so the weights can be selected to favor more recently or less recently acquired measurements. Thus, this latest acquired measurement can be compared to that first measurement to indicate relative short-term changes, absolute changes from a base line, or relative changes to the longer term.

The United States Application also refers to a portable, hand-held, battery-powered device for use in administering aerosolized medications to a patient and checking lung functions, recording pertinent information such as a calendar record of detected flow parameters, aerosol delivery amounts together with a signal corresponding to the detected flow parameter that triggers the release, and lung function. Summary of the invention

According to a first aspect of the present invention, a method is provided to correct the drift displacement of a transducer that has an analog output signal corresponding to the detected pressure of a flow in any direction through a flow path, including:

(a) providing an analog-to-digital converter that has a defined range of digital counts and identifies a base digital count value of the digital range corresponding to base zero flow in any direction;

(b) converting the output signal from the transducer to a digital value at a given sample rate;

(c) identifying a zero flow condition through the flow path when the converted voltage signal from the transducer does not vary more than a selected number of digital counts in a first period of time;

(d) determining a counted offset value based on the difference between the identified base digital count value and the digital count output from the analog-to-digital converter during an identified zero flow condition; and (e) regulating the output of the analog-to-digital converter after the zero flow condition identified by the determined offset value.

Preferably, in the first aspect of the present invention step (c) further includes:

maintaining a buffer containing a selected number of digital values ​​acquired last in time;

buffering each converted digital value of a sampled voltage signal and subtracting the oldest digital value from the buffer for each new added value;

determining the difference between the maximum and monym values ​​in the buffer; and determining that a zero flow condition exists when the determined difference is less than a selected second number of digital counts. In this arrangement, the second selected number of digital counts is on the order of 4.

In this preferred arrangement, step (a) further includes providing an analog-to-digital converter with a digital count range on the order of 65,536 counts, step (c) further includes selecting the number of digital values ​​in the buffer so that is of the order of 25 values ​​and determine that a zero flow condition occurs when the difference determines

ES 2 179 068 T3 nothing is less than four digital counts, and step (d) further includes determining the average value of the selected number of digital values ​​in the buffer, and determining the offset value as the difference between the base digital count identified and the mean value determined.

According to a second aspect of the present invention, an apparatus is provided for correcting the drift displacement of a transducer having an analog output signal corresponding to the sensed pressure of a flow in any direction through a flow path, including:

an analog-to-digital converter that has a defined range of digital counts and a digital value in the digital range corresponding to the base zero flow in any direction;

means for controlling the analog-to-digital converter to convert the output signal of the transducer to a digital value at a given sampling rate;

means for identifying a zero flow condition through the flow path when the digital values ​​do not vary more than a selected number of digital counts in a first period of time;

first means for determining an offset value based on the difference between the identified base digital count and the digital value output from the analog-to-digital converter during a zero flow condition; and means for regulating the output of the analog-to-digital converter by the determined offset value.

According to a third aspect of the present invention, a handheld, autonomous device is provided to correct the drift displacement of a transducer that has an analog output signal corresponding to the detected pressure of a flow in any direction through a path of flow, including:

(a) means for providing an analog-to-digital converter that has a defined range of digital counts and identifies a base digital count value of the digital range corresponding to base zero flow in any direction;

(b) means for converting the output signal of the transducer to a digital value at a given sample rate;

(c) means for identifying a zero flow condition through the flow path when the converted voltage signal from the transducer does not vary beyond a selected number of digital counts in a first period of time;

(d) means for determining a counted offset value based on the difference between the identified base digital count value and the digital count output from the analog-to-digital converter during an identified zero flow condition; and (e) means for regulating the output of the analog-to-digital converter after the zero flow condition identified by the determined offset value.

The device of the third aspect of the present invention further preferably includes:

(f) means for maintaining a buffer containing a selected number of digital values ​​acquired last in time;

(g) means for buffering each converted digital value of a sampled voltage signal and subtracting from the buffer the oldest digital value for each new added value;

(h) means for determining the difference between the maximum and maximum values ​​in the buffer; and (i) means for determining that a zero flow condition occurs when the determined difference is less than a selected second number of digital counts.

In the device of the third aspect of the present invention, means (a) preferably provide an analog-to-digital converter with a digital count range of the order of 65,536 counts, and means (c) select a number of digital values ​​in memory. intermediate of the order of 25 values ​​and determine that a zero flow condition occurs when the determined difference is less than four digital counts.

Furthermore, the device of the third aspect of the present invention also preferably includes:

means for determining the average value of the selected number of digital values ​​in the buffer; and means for determining the offset value as the difference between the identified base digital count and the determined mean value.

Brief description of the drawings

Other characteristics of the invention, its nature and various advantages will be more apparent from the accompanying drawings and the following detailed description of the invention, in which analogous reference numbers refer to analogous elements and parts, and in which:

Figure 1 is an elevational perspective view of an aerosol delivery device according to a preferred embodiment of the present invention.

Figure 2 is a view of the device of Figure 1 with the mouthpiece closed.

Figure 3 is a cross-sectional view taken along line 3-3 of Figure 1.

Figure 3A is a top view of the nozzle of Figure 1.

Figure 3B is a sectional side view taken along line 3B-3B of Figure 3A.

Figure 3C is a rear sectional view taken along the line 3C-3C of Figure

3B.

Figure 4 is an elevational perspective view of the replaceable cassette of Figure 1.

Figure 5 is an exploded view of the replaceable cassette of Figure 4.

Figures 6-10 are cutaway elevational perspective views of a cycle sequence of the actuator mechanism and the actuator release mechanism for delivering an aerosol dose of drug.

Figure 11 is a sectional side view

ES 2 partial of the actuator release mechanism of Figure 3.

Figure 11A is a front perspective view in elevation of the composite lever firing mechanism of Figure 11.

Figure 12 is a side elevational perspective view of the tip of the firing pin of Figure 11.

Figures 13A and 13B are respectively a side view and an exposed view of the rotary cam of Figure 6.

Figure 14A is a top plan view of the release ring of Figure 6.

Figure 14B is a side view taken along line 14B-14B of Figure 14A.

Figure 15 is a top perspective view of the driver of Figure 6.

Figures 16A, 16B and 16C are respectively side, top and bottom views of a housing of the durable body of Figure 1.

Figure 16D is an enlarged view of the flow sensor surface of the embodiment of Figure 1.

Figures 16E, 16F and 16G are respectively side, top and bottom views of the other durable body shell of Figure

1.

Figure 16H is a front view of the chassis of Figure 3.

Figure 17A is a top view taken along line 17A-17A of Figure 3 of the airway cover of Figure 1.

Figure 17B is a cross-sectional view taken along line 17B-17B of Figure 17A.

Figure 17C is an end view taken through line 17C-17C of Figure 17A.

Figure 18A is a cross-sectional view of an asymmetric orifice meter for use in the flow transducer of Figure 1.

Figure 18B is a schematic cross-sectional view of the surface of the flow transducer of Figure 1.

Figure 18C is a rear view taken along the line 18C-18C of Figure 18B.

Fig. 19A is a flow chart of the operation of the actuator mechanism and actuator release mechanism of Fig. 1.

Figure 19B is a flow chart of a process for delivering aerosol in accordance with one embodiment of the present invention.

And FIG. 20 is a graph of analog-to-digital converter counts versus time (data points) illustrating the corrected and uncorrected flow data following the offset drift correction of the present invention.

Detailed description of the invention

With reference to Figures 1-4, an aerosol delivery device is depicted following a preferred embodiment of the present invention. It includes a durable body 2 and a drug cassette 4, which are interconnected to provide a handheld aerosol device 6 according to the present invention. The device 6 includes an outer body 10, a mouthpiece 20, a box containing a deposit of

068 T3 12 drug 30 to be delivered, a housing 40, an actuator mechanism 200, an actuator release mechanism 300, control electronics 50, a battery 60, and a flow transducer system 600.

The battery 60 is illustrated in Figure 3 as two conventional 1.5 volt AAA size batteries, which are inserted into suitable receptacles in the durable body 2, which has an access cover panel 61. Battery sources could be used alternatives, including rechargeable batteries. Battery 60 can also be replaced or supplemented with an AC / DC converter to operate device 6 on conventional line current.

Referring to Figures 3-5, box 30 includes a body 31 containing a reservoir of drug to be released, a valve stem 32 for releasing a quantity of drug, and a bottom portion 34. Box 30 is preferably constructed so as that an amount of the stored drug is released when the valve stem 32 is sufficiently depressed relative to the body 31 (also referred to as "squeezing" or "pulsing").

In the preferred embodiment, the box 30 and the valve stem 32 are part of a standard metered dose box such as can be used with conventional manually actuated metered dose inhaler devices. In an alternative embodiment, the case 30 and the valve stem 32 can be constructed as a single valve and the reservoir body 31 that releases an aerosol while the valve stem 32 is sufficiently depressed relative to the body 31. Thus, the dose delivered by a straight valve box can vary with the time that the valve stem 32 is held down. Both box constructions include internal return springs (not shown) that return the valve stem 32 to the outer position that seals the reservoir closed to the atmosphere, when the actuation force is removed.

The reservoir in box 30 may contain any selected drug (or other material to be administered) in liquid, gas, or dry powder form. Where appropriate, a suitable propellant or vehicle or agitator is also provided to form an aerosol of the liquid, gas, or powder for administration to the patient.

The box 30 is combined with the mouthpiece 20 and the housing 40 to form the cassette 4. The cassette 4 is used to provide medicament to the durable body 2 for automatic delivery according to the present invention. The cassette 4 is also constructed so that it can be used as a conventional manually operated metered dose inhaler device, apart from the durable body 2. This is to allow the patient to perform manual administration of medication in the event that the durable body 2, or some of its components, for example, discharges the battery 60, fails. The cassette 4 is a replaceable component. It can be inserted and removed from the durable body 2 by the user. Thus, the cassette 4 can be disposable and / or recyclable.

The casing 40 is constructed with an inner shape that corresponds to the shape of the box body.

ES 2 179 068 T3

31, for example, a cylindrical structure. The housing 40 is also constructed with an outer shape that fits a complementary shaped receptacle 520 in the durable body 2. The housing 40 has a lower end 45 that has an outer dimension that is larger than the outer dimension of the upper portion. . The dimension of the lower portion 45 provides a support seat 47 that contacts a protrusion 447 constructed in a receptacle 520 of the durable body 2 for proper positioning of the cassette 4 (see Figures 16E, 16G). A pair of locking tabs 42 extend downward from lower end 45. Tabs 42 are configured to interlock with a corresponding pair of holes 28 in mouthpiece 20 to secure housing 30 within and between mouthpiece 20 and housing 40.

Housing 40 has at its upper end 46 an inwardly turned annular flange 48 that is dimensioned to hold housing 30 in position within cassette 4 with valve stem 32 seated in valve stem receptacle 21, but not depressed. in relation to the body 31. This fixes the drug inside the cassette 4 so that the patient cannot easily remove the box 30, or more preferably it cannot be destroyed by destroying it from the cassette. Annular flange 48 is also dimensioned to allow a person to manually depress box 30, pressing body 31 relative to valve stem 32, to deliver a dose of medication. Most of the boxes 30 containing a mixture of medicament and pressurized propellant have a concave bottom 34. Therefore, it is advantageous to provide a disk 35 between the flange 48 and the bottom of the box 34. The disk 35 does this. It is easier to manually actuate the case 30. The disk 35 can be flat or convex and can be made of a rigid plastic or metal.

In an alternative embodiment, the cassette 4 is made so that it is reusable with different boxes 30, and the tab 48 is omitted. In such a case, a friction engagement of the valve stem 32 and the valve stem receptacle 21 will hold the valve stem. box 30 within housing 40. In another embodiment, cassette 4 can be sealed at end 46 so that it cannot be manually actuated. This is useful when the drug to be administered is a narceotic and is to be administered only by the long-term body under programmed control.

Upper portion 46 of housing 40 also includes two slots (or holes) 49. These are utilized by an actuator element of actuation mechanism 200 in connection with automated drug delivery and are described below.

Housing 40 also contains a multi-bit code that is representative of its content. In one embodiment, as illustrated in Figures 4 and

7-9, the code is in the form of a series of projections 41 (or buttons) on its periphery at a selected position. To fully and correctly insert the cassette 4 into the body 2 to form an operating device 6, the projections 41 must be engaged with a corresponding slotted disk or keyhole 440, which has previously been fixed to a chassis 400 within the durable body 2 (see figure 6). Thus, keyed projections 41 and keyhole 440 can be used to provide drug identification and a level of protection against the introduction of a wrong or unauthorized drug into the body 2.

In one embodiment, there are a maximum of six protrusions 41 spaced to physically provide a six-bit codeword, based on the presence or absence of a protrusion 41 at each location. Each durable body 2 may also be provided with a keyhole 440 that is constructed to receive only cassettes 4 having a selected codeword matching keyhole 440. This construction provides for a special durable body 2 that can only be used to administer medication from a cassette having the first code, unless the keyhole 440 is changed.

In an alternative embodiment, multi-bit words represented by overhangs 41 can be used to identify the delivery characteristics relevant to a selected drug. Such information may include information on concentration and dose administration, how many doses are initially in box 30, the frequency of the dose, the time between successive doses, when during inspiration the dose is to be released, the duration of the dose. release dose or a combination of the above. This can be achieved by assigning each code word an administration protocol for the particular parameters to be used by the control electronics to administer the drug. Thus, the durable body 2 is adapted to read the multibit code provided by the protrusions, for example, by a series of microswitches that are closed by pressing them with the protrusions 41, consult a library of stored administration protocols for the word code read, and select from the library the corresponding administration protocol that is loaded into the control electronics 50 to administer the medication. In this alternative embodiment, the drug identification can also be a part of the code word. It is noted that more or less than six bits and corresponding projections may be used 41. Likewise, the code word read may be an identification code of the selected drug, which may be determined from a library together with the correct administration parameters. of said medicine.

In another alternative embodiment, instead of or in addition to physical projections 41, an active or passive electronic circuit element 41B (see Figures 4 and 9) is provided that provides code information to a corresponding decoder circuit in the durable body 2 ( not represented). Such an electronic circuit could be of an impedance value that has a corresponding administration protocol and / or the meaning of the drug identification, a digital code word or, in even a more sophisticated version, a memory device containing electronically readable data, for example, a read-only memory device8

ES 2 179 068 T3 mind (ROM), programmable read-only memory device (PROM), non-volatile random access memory (RAM) or the like. Such a memory device may contain one or more code words identifying the drug, the drug dose number in box 30, and optionally the administration protocol (complete or relevant parts) for said drug. In such a case, the durable body 2 will have electrical contacts (not shown) to connect with the electrical circuit 41B and obtain the code and / or data contained digitally, in series, in parallel, or as an analog signal value.

In addition, the code and / or electronically readable data could uniquely identify each box (or cassette). This allows the durable body 2 to record a usage record for each individual box 30 inserted and keep a running count of the number of doses remaining in a given box 30 or the number of doses delivered from that box 30. This unique identification allows a patient to administer more than one drug using 4 different drug cassettes and the same durable body 2. In this embodiment, the durable body 2 contains corresponding sensing contacts (not shown) that mate with the cassette 4, for example, during the insertion of the cassette 4 into the body 2, or whenever the cassette 4 is placed in the open position. , to read the information represented by the projections 41 and / or any electronic circuit 41B. Optionally, the electrically readable data may be downloaded to memory in the control electronics 50, for example, during input, and downloaded back to the cassette, for example, during extraction. This will avoid the need to always be connected to the electrical circuit of the cassette 41B. Different uanically identified cassettes 4 can be used in the same durable body 2, whereby the control electronics 50 can keep a separate count of the doses remaining and / or the doses administered for each cassette 4 using the uanic code of they will be identified as an address.

In another alternative, the cassette 4 provided with memory 41B containing programming information for use by the durable body 2 can be reprogrammed by the durable body 2 to keep in memory 41B an accurate count of the number of doses remaining and / or already administered, and other detected parameters to be recorded. This will allow the same cassette 4 to be used on different durable bodies 2 without losing the count or other recorded information.

Referring again to Figure 6, the larger protrusion 41A is used to align the cassette 4 for insertion into the body 2 in the first case and to retain the cassette 4 within the chassis 400 of the durable body 2 except for when the Boss 41A is aligned for insertion and extraction. A vertical recess 406 is provided in chassis 400 (or receptacle 520) to guide cassette insertion and removal so that projections 41 align with keyhole 440. Alignment is also used so that the actuator mechanism 200 easily seats in slots 49. In the preferred embodiment, referring to Figure 3, the insertion / removal position is when the mouthpiece 20 is in the open position to deliver a quantity of medication (as illustrated in Figure 1) and a catch 39 is used to fit under boss 41A to hold cassette 4 in receptacle 520, once fully inserted. A spring 39A is used to push the catch 39 under the boss 41A as soon as the cassette 4 is seated. A button or slide (not shown) is used to remove the pin 39 to remove the cassette 4 from the body 2.

An annular recess 405 is provided in the chassis 400 (and / or the receptacle 520) to receive the projection 41A whenever the cassette 4 is fully inserted into the body 2 and in a position other than the insertion / extraction position (see Figure 16H). The annular recess 405 is used to prevent the cassette 4 from inadvertently falling from the durable body 2.

Lower portion 45 of housing 40 includes a hole 43 that cooperates with nozzle 20 to form a flow path 24 through nozzle 20 and lower portion 45 of housing 40. When nozzle 20 is in the open position , hole 43 cooperates with airway cover 13 to provide flow communication via device 6 as explained below. Housing 40 is preferably made of a polypropylene material, which is preferably clear. This allows the user to read the product labeling provided by the drug box manufacturer through the walls of the housing. It also avoids the need to provide drug labeling on housing 40. Housing 40 is preferably recyclable.

Referring to Figure 4, housing 40 also includes a position mark 44, preferably in the form of a surface or protruding indentation, more preferably an indentation located at a selected distance from or on said support seat 47 in housing 40. Position mark 44 cooperates with a suitable contact switch 460, for example, an Omron model D2MQ-i available from Digi-key, Thief River Falls, MN, properly positioned in the durable body 2. This switch Contact provides a signal to control electronics 50 indicating when cassette 4 is in the open position to deliver medication.

Referring to Figures 3, 3A, 3B, and 3C, nozzle 20 is a tubular body having a muzzle end hole 23, an upper end hole 29, a valve stopper 21 incorporating a flow path 21A, and a nozzle 22, a pair of holes 28, and provides a flow path 24 generally along an axis designated A that passes through the hub end center 23 and nozzle 22. Nozzle 22 and its flow path 21A are of conventional design and are directed to release an aerosol cloud along axis A. A preferred embodiment of nozzle 22 and flow path 26 includes a 0.46mm orifice. (0.018 inch) diameter for nozzle 22 and a diameter

ES 2 of 23.88 mm (0.04 in.) For flow path 26.

The nozzle 20 is illustrated with a symmetrically flattened oval tube, with rounded sides and relatively flat top and bottom faces. The interior dimensions should be selected so as not to adversely interfere with the dispersion pattern of an aerosol released at the mouthpiece 22 during inhalation. The outer dimensions are selected to be comfortable for a patient to latch on to the lips with a reasonable seal. The nozzle 20 can be made of a polypropylene material.

The upper end 29 of the nozzle 20 opens to mate with the lower portion 45 of the housing 40. The flattened oval section of the nozzle 20 is contoured to blend into a rounded and curved interior or bowl-shaped rear section illustrated generally like region 29A. Region 29A allows flow to pass between hole 43 in housing 40 and mouth end 23 smoothly enough to carry an aerosol generated by mouthpiece 22 during inhalation. It also allows flow in the other direction to measure exhalation. Preferably, nozzle flow axis A intersects the rear wall of region 29A near the interface of nozzle 23 and housing 40.

The hole 43 is a substantially rectangular hole (when the curved wall is flattened) that is approximately as wide as the diameter of the upper end 29 and has a height that in curved form has a chord of approximately 75% of the height of the mouth end. 23. Other dimensional relationships could be used.

As noted, holes 28 allow housing tabs 42 to be received and to securely lock housing 40 and mouthpiece 20. This is so that the patient cannot remove housing 30 from housing 40 without considerable effort. The locking tabs 42 and holes 28 also cooperate to transfer the force of a compression spring 210 to the projection 41A and the locking pin 39, and to rotate the cassette 4 in the body 2, after insertion, by rotating the nozzle 20 around the axis B formed by the flow path 21A of the valve stopper 21, and the housing 30. It should be understood that the construction of the locking tab hole also includes one or both of the locking tabs protruding from the nozzle and engaging a corresponding hole in the housing.

In an alternative embodiment (not shown), instead of locking tabs 42 and holes 28, nozzle 20 and housing 40 could be interlocked in a way that allows separation to change box 30 inside and reuse housing 40 and / or or nozzle 20 with a different box 30 and to clean nozzle 20 and nozzle 22. This can be achieved, for example, with a threaded interconnection or a bayonet type connection between the lower part of the housing 45 and the upper part of the nozzle and the hole 29, provided that the cassette 4 can be rotated around. axis B through nozzle 20 without separating nozzle 20 from housing 40.

068 T3 18 take care to ensure that the force of compression spring 210 will not cause nozzle 20 to separate from housing 40 or change the axial distance between nozzle 20 and boss 41A. Such a design is useful for adapting standard metered dose boxes for use in the present invention and allowing the patient to obtain refills of the same drug, for example, from sources other than the source that supplied the cassette.

Referring now to Figures 3 and 6-15, actuator mechanism 200 and actuator release mechanism 300 allow box 30 to be electromechanically triggered, under the control of control electronics 50, in response to inspiratory sensed flow meeting a predicted flow management threshold. The predetermined flow delivery threshold can be a selected flow rate, a selected flow volume, or a combination of the two. In the preferred embodiment, the flow delivery threshold is a combination of the detected flow rate that is within a range defined by a selected minimum threshold flow rate and a maximum threshold flow rate, and the flow volume that is within a band defined by a selected minimum threshold volume and a maximum threshold volume.

The administration threshold is met as follows. First, the detected flow rate is verified. If the flow rate is in the correct range between the upper and lower limits, the flow volume is checked. If the flow volume is also within the correct range between the upper and lower volume limits, the delivery threshold is met and delivery will occur. Otherwise administration is inhibited.

If delivery is inhibited for the entire inhalation, the flow volume and flow rate threshold parameters can be recursively lowered. In this regard, during inspiratory flow, the flow transducer system verifies and saves the maximum flow rate and the total inhaled volume. At the end of the inhalation, which is detected by passing through a state of zero flow, the control electronics check if an administration event has occurred. If so, the remaining and / or delivered dose shot count is updated and the system waits for the next inhalation (and delivery attempt). The control electronics may also include a timer to avoid too frequent administration of medication (over-medication).

If no administration was performed, the administration threshold is verified. More specifically, the peak flow rate and inhaled volume values ​​of the flow that did not produce an administration are reduced by a selected percentage, eg 25%. The reduced values ​​are compared to respective preselected (programmable) default values ​​for the minimum flow volume and flow thresholds. If the percentage of the maximum detected flow rate for the failed breath is less than the default minimum threshold flow, it is used as the minimum threshold flow rate for the next detected breath. Otherwise the default value is used. Similarly, if the percentage of the total volume detected for failed breath is

ES 2 179 068 T3 lower than the default minimum flow volume value, is used as the minimum flow volume value for the next breath. Otherwise the default value is used. If the next breath also falls, its maximum sensed flow rate and inhaled volume are also processed in this recursive manner, selecting a new administration threshold suitable for the patient's condition at the time of administration.

In a useful embodiment, the default values, each of which is programmable, are: upper flow 80 l / m, lower flow 40 l / m, upper flow volume 1.25 L, and lower flow volume 1, 0 l. Although in the preferred embodiment the upper limits are not changed recursively, in an alternative embodiment they could be changed, for example, as a selected multiple of the lower thresholds or the maximum detected values. Other flow management threshold parameters can also be used.

The actuator mechanism 200 includes a compression spring 210, a torsion coil spring 220, a rotary eccentric (helical) 230, and an exciter 240. Each of these elements is oriented in axial alignment with the longitudinal axis B of the case 30. The actuator release mechanism 300 includes a trigger mechanism and a motor 321 for activating the trigger mechanism, which are located off axis B.

Rotary cam 230, which is also illustrated in Figures 13A, has a first cam surface 232 that cooperates with a pair of cam followers 430. Cam followers 430 are attached to chassis 400 on durable body 2 on opposite sides of the cam. the eccentric 230 in an appropriate position. The rotary cam 230 will thus rotate in one direction with the cam surface 232 sliding against the cam followers 430 so that the rotary cam 230 moves upward along the axis B depicted in Figure 6 as it rotates. Rotary cam 230 has no effective lower cam surface. This allows cam 230 to travel down along axis B without rotating. Vertical motion is imparted by releasing the compression spring 210. Rotational motion is imparted by releasing the torsion spring 220. The distance that the eccentric 230 raises and lowers corresponds to the distance that the valve stem 32 must be pressed relative to the box body 31 to deliver a metered dose of aerosol. For standard boxes of metered dose inhalers 30, the distance that the valve stem must be depressed is on the order of 2.5 mm (0.1 inch). The cam 230 can be made of any suitable material, such as DELRIN AF.

Referring to Figure 13B, rotary cam 230 is illustrated in an exposed view illustrating pitch of 8.46 mm (0.333 inch), height of 5.77 mm (0.227 inch), distance D1 of 2.5 mm (0.1 inch) plus the thickness of the 430 cam followers, and a helical face cam.

The rotary eccentric 230 is fixed in its upper part to the compression spring 210 and to the torsion spring 220, as shown in figure 6. The other ends of the springs 210 and 220 are fixed, for example, to the chassis 400 or to the body 2 . The rotary cam 230 is attached at its bottom to the release ring 233, by a keyed interconnect including a key protrusion 239 (shown in the front view of Figure 13A) of the cam 230 and the slot.

235 release ring 233. Eccentric 230 does not rotate relative to release ring 233.

Referring now also to Figures 14A and 14B, the release ring 233 is an annular ring, having a radial groove (or recess) 236, a radial groove 234, and the keyhole 235 for attaching the release ring 233 to the eccentric 230. Release ring 233 can also be surface treated to improve toughness, eg, chrome plating. It is preferably a hardened tool steel ring (65-70 Rockwell C).

Referring now also to Figures 610, 11, and 11A, the release ring 233 and its radial groove 236 and radial groove 234 cooperate with the trigger mechanism and motor 321 in the following manner. The trigger mechanism includes a trigger pin 312 with a generally rectangular cross-sectional base 311 and a multi-faceted tip 313. As shown in Figure 6, the trigger pin 312 has a first position where the upper surface 343 of its tip 312 rests under the release ring 233 in the slot 236, with the compression spring 210 in compression and the torsion spring 220 in torsion. Compression spring 210 urges release ring 233 down, slot 236 enclosing the tip of firing pin 313 securely seated within. The torsion spring 220 pushes the release ring 233 to rotate, but the trigger tip 313 that was in the slot

236 and / or slot 234 prevents such rotation.

According to the present invention, the upper surface 343 of the trigger tip 313, which was in contact with the groove 236 in the lower part of the release ring 233, is cut at an angle α1 to the upper surface 342 of the base 311. Surface 342 is essentially parallel to the plane of release ring 233. Consequently, the downward pressure exerted by compression spring 210 acted on surface 343 ejecting trigger pin 312 from under the release ring.

233. However, the trigger pin 312 is held in the first position, below the release ring 233, by the motor 321 (not shown in FIG. 6), in the manner described below.

Referring to Figure 7, the trigger mechanism has a second position where trigger pin 312 is offset from slot 236 and below release ring 233 and is located in slot 234. Slot 234 and slot 236 are in alignment. radial, with groove 234 located on the outer perimeter of release ring 233. This is illustrated in FIG. 14B. This movement allows slot 234 to travel down, riding on trigger pin 312, and as a result presses on case 30. However, torsion spring 220 pushes release ring 233 so that slot 234

ES 2 179 068 T3 presses against a side wall 341 of trigger tip 313. Consequently, torsion spring 200 remains torsionally.

Side wall 341 was also provided with an angle α3 relative to base wall 311A ​​(see Figure 12B) that responds to rotational pressure exerted by the opposite inner wall of slot 234 to eject trigger tip 313 from the slot. slot 324. The result of this ejection, when it occurs, is that release ring 233 (and rotating eccentric 230) rotated when torsion spring 220 is released. However, motor 321 retains trigger pin 312 in its second position for a selected period of time, so eccentric 230 does not rotate (not shown in FIG. 7), as described below. Side wall 341 is also cut at an angle α2 relative to base wall 311 opposite wall 311A ​​to correspond to release ring 233 to minimize or reduce energy lost from compression spring 210 due to friction, to maximize hence the transfer of energy from spring 210 to box 30; front end wall 311B can be cut to a suitable angle to provide clearance when tip 313 is pivoted, as described later.

Slot 234 was configured with its walls cut at an angle β1 relative to axis B as shown in FIG. 14B. Referring to Fig. 12, the upper surface 343 of the trigger pin tip 313 is formed at an angle α1 relative to a horizontal plane to the B axis, and the lateral surface 341 of the trigger tip is provided with an angle. of α3 in relation to a plane parallel to the B axis. Angles α1, α2, α3, and βΐ are selected so that the predetermined force magnitudes, if not counteracted by motor 321 holding trigger pin 312 in place, will cause trigger pin 312 to be ejected from under ring 233 to release compression spring 210 to deliver medication, and after slot 234 after medication release to release torsion spring 220 to reassemble compression spring 210. Although the angles are a matter of design choice, a suitable angle for each of α1, α2, α3 and β1 has been found to be approximately 15 degrees.

Referring to Figures 3, 6-11 and 15, between the release ring 233 and the cassette 4 was positioned the driver 240. The driver 240 has a base 241 having a top surface including a stepped drive 245, and a bottom surface that includes two drive tabs 242 and two bottom surfaces 248, as illustrated in Figure 15. The drive lugs 242 are respectively seated in the grooves 49 of the cassette 4 (casing 40) and the bottom surfaces 248 are in contact with the base 34 of the casing 30 (or a disk 35, if used). The top of the base 241 has a flat top surface 243 on a first portion and a second flat surface 244 on a second portion that lay in a plane below the flat top surface 243. There are two stepped drive steps 245 corresponding to the difference in height between surfaces 243 and 244 as illustrated in Figure 15. One of the two steps 245 serves as a drive step to rotate the eccentric 230 that acted on eccentric projection. / step 239 as long as cassette 4 is rotated to the closed position. The other step 245 serves as a stop to prevent the cassette 4 from over-rotating through the open position. The two steps limit the cassette 4 to a rotation of approximately 180 degrees from the open to the closed position. The position for insertion and withdrawal is in the fully open position (180 degree position) relative to the closed position. Preferably, there are two drive lugs 242 and corresponding slots 49, although more than two of each could be used.

The exciter 240 is used to mount the rotary eccentric 230. This is produced by rotating the cassette 4 around the B-axis to turn the exciter 240. This causes a stepped drive 245 to engage and rotate the eccentric 230. This in turn does that eccentric 230 and release ring 233 rotate and put torsion spring 220 in torsion. Release ring 233 and eccentric 230 are then locked in position with torsion spring 220 in torsion, when rotated so that upper surface 343 of trigger pin 313 engages slot 236. (See Figures 8-10) .

The exciter 240 is also used to press the box body 31 down, relative to the valve stem 32 and the cassette housing 40, to deliver an amount of aerosol. In this regard, release of compression spring 210 moves rotary eccentric 230 and exciter 240 axially downward (without rotation) along axis B. See Figure 7, where drive lugs 242 are illustrated fully seated in housing slots 49.

Referring now to Figures 3, 11, and 11A, the actuator release mechanism 300 is shown including the motor 321 and the trigger mechanism. In the preferred embodiment, motor 321 includes a lead screw 322 that rotates only in a single direction of rotation. Preferably, lead screw 322 has multiple lead threads, eg, three or five leads. The trigger mechanism has a ratcheting action including a ratchet element 323 whose movement is controlled by the lead screw 322, a return spring 326, a main lever 314 and a secondary lever 315. The return spring 326 is used to make return ratchet element 323 to an initial position in the absence of an external force pressing ratchet element 323 against return spring 326. Ratchet member 323 is configured to grip on lead screw 322 so that an external force directed against return spring 326 causes ratchet member 323 to seat against a thread of lead screw 322. As a result, while When the external force is applied, the position of the ratchet element 323 can be controlled by turning the lead screw 322.

In one embodiment, the ratchet element

ES 2 179 068 T3

323 is a curved piece of spring steel approximately 0.05 mm (0.002 inch) thick having an upturned edge 324 that is attached to a pusher plate 328, for example, by a plastic rivet 329. Rivet 329 it may have a hole 330 to pass along the lead screw 322. A guide bar 325 is provided which extends between an engine mount 450 and a chassis portion 400 and parallel to the lead screw 322, over which the return spring 326 passes. The guide bar 325 provides stability, minimizes binding, and prevents plate 328 from rotating. In this regard, plate 328 also has a bushing 328A having a hole 331 that receives guide rod 325 and thus advances the length of lead screw 322 and guide 325, with return spring 326 between plate 328 and motor 321. Preferably, motor 321 is attached to motor bracket 450 so that spring 326 is between plate 328 and motor bracket 450.

The trigger pin 312 is preferably mounted on a compound lever having a main lever 314, with the trigger pin 312 protruding from one side of the main lever 314, a secondary lever 315 that is pivotally connected to the main lever 314 by the rod 316 , and a notched portion 317 in the secondary lever 315. The main lever 314 is attached to the chassis 400 so as to pivot about an axis 318 at its lower end. Secondary lever 315 is also connected to chassis 400 around reaction pivot 319. Motor 321 may be, for example, part no. DNI2K51N1B, which is available from Canon, Inc. It is important that the 321 motor consumes very little current, on the order of 130 ma when the motor is running, which occurs during an operation of 2.5 seconds, of which the motor is deactivated for a programmable period of time, for For example, one second, which is typical for releasing a dose of medication and reassembling the actuator 200. This amount is unexpectedly less than the energy consumed by a solenoid that is used to press the box 30.

Holes 330 and 331 are preferably made of a low friction material, eg, Teflon, or an acetal resin such as DEIRIN. The hole 331 is configured so that the guide rod 325 passes through it, in such a way that the return spring 326 is fixed between the plate 328 and the motor support 450.

Motor 321 and lead screw 322 are mounted in alignment with secondary lever 315 so that lead screw 322 passes through notched portion 317 of lever 315. Return spring 326 pushes metal spring 323 outward. ie, away from motor 321, and presses plate 328 against secondary lever 315. Lever 315 is in turn pushed against plate 328 by forces exerted on trigger pin 312 by springs 210 and 220. These latter forces, when they exist, are greater than the force of return spring 326. As a result, trigger pin 312, via levers 314 and 315, presses plate 328 toward motor 321 so that the upturned end 324 is pressed against and captures on a thread of lead screw 322. Thus, when motor 321 is rotated, the threads of lead screw 322 will allow the upturned end 324 of metal spring member 324 to approach motor 321, under the pressure forces exerted by levers 314 and 315. This in turn allows the trigger pin 312 to be controllably ejected from under the release ring 233.

When the trigger pin 312 is pushed out from under the release ring 233, from the slot 236 and the slot 234, the torsion spring 220 will release and the eccentric 230 will rotate. As a result, the eccentric 230 will ride the eccentric followers 430 to its top position. As a result of this, the forces pressing the trigger pin 312, which has been pushing the upturned end 234 against the release spring 236 and the threads of the lead screw 322, are removed. Consequently, the return spring 326 releases and pushes the plate 328 outward, pressing the levers 314 and 315 and the trigger pin 312. This causes the trigger pin 312 to rotate into position under the release ring 233. In this regard, it is noted that the position of the cam followers 430 on the cam surface 232 raises the cam 230 high enough so that the return spring 326 can push the trigger pin 312 into position below the release ring 233. Lead screw 322 preferably has 12 turns per inch and 3 lead threads.

To reduce the power required from the motor for the battery-powered device, and thereby extend the service life, the helical angle of lead screw 322 is configured to approach, but not exceed, the angle of friction between edge 324 and edge. screw 322. This ordinarily requires a relatively large pitch, eg, 12 turns per inch in a lead screw 322 of 3.5 mm (0.138 inch) OD. As long as there is no control of the rotational position of lead screw 322 when stopped, the return of edge 324 will be imprecise. It was discovered that, to increase the accuracy of the detent position where edge 324 engages a screw thread 322, a multi-lead thread is employed, specifically a three-lead thread. Thus, where a single entry has a distance of 2.23 mm (0.088 inch) between adjacent threads, a three entry thread has a distance of 0.68 mm (0.027 inch) between adjacent threads. This is because the three lead thread is the superposition of three one lead threads each equally offset, along the length of the screw. This provides better placement resolution without checking the rotational position of screw 322, turning screw 322, or using additional position sensing contact switches. The use of a five lead thread provides improved position control.

The guide 325 and the lead screw 322 allow to keep the plate 328 and the metal spring

ES 2 179 068 T3

323 correctly oriented so that the upturned edge 324 will again catch on one of the lead screw threads 322 in the next advance event. In this manner, motor 321 operates only in one direction of rotation and operates primarily only as a brake to prevent plate 328 and secondary lever 315 and trigger pin 313 from being withdrawn. By holding the trigger pin 312 in position when the motor 321 is stopped and not consuming, the motor 321 efficiently controls the movement of the trigger pin 312 to deliver a dose of aerosol drug. In contrast to prior art devices, the electric motor does not provide the driving force that moves the box 30 to release the aerosol.

The upturned edge 324 is preferably curved with a curved edge, rather than a straight curve, so that it is easily curved and captured by the vertical wall of the lead screw threads 322. Thus, the upturned end 324 was pushed into a lead screw thread 322 by lever 315, and passed to ride over and over the inclined flights of the thread successively by return spring 326 (until the trigger pin 312 is positioned under the release ring 233 and is pushed back by the spring 210).

Having described the components of the apparatus, the method of operation of the actuator mechanism 200 and the actuator release mechanism 300 were now reviewed. Beginning with Figure 6, the apparatus was in the ready-to-fire position with the nozzle 20 already rotated by the user to the open position. Compression spring 210 is held in compression between chassis 400 and rotating eccentric 230. Torsion spring 220 is held in torsion between chassis 400 and rotating eccentric 230. Trigger pin 312 was positioned under release ring 233 and is seated in slot 236 with metal spring edge 324 engaged with lead screw. 322 and return spring 326 in slight compression. The exciter 240 was positioned with the bottom surfaces 248 flush against the disk 35 which was flush against the bottom 34 of the case 30, without pressing the valve stem 32, and the actuation lugs 242 were partially inserted into the grooves. 49. The projection 41A was positioned in the annular recess 405 in the open position and locked in position by the latch 39 so that the cassette 4 did not come off the chassis 400, the receptacle 520, and the body 2. The action of rotating cassette 4 to the open position places position mark 44 in a position that is detected by contact switch 460 attached to chassis 400. This actuation is detected by control electronics 50 and used to supply power to the electronics of the device 6. A second microswitch (not shown) is also used to determine whether or not a cassette 4 is inserted into the receptacle 520.

To deliver a dose, control electronics 50 monitors the user's inspiratory flow, as described elsewhere, and determines when a predicted delivery threshold is met. When this occurs, motor 321 is driven to rotate lead screw 322 so that plate 328 can be withdrawn to a first stage position. This is depicted in figure 7. The position can be controlled by turning lead screw 322 a selected number of revolutions or preferably using a contact switch 327 that is positioned so that it is contacted by plate 328 and turns off motor 321 in response to such contact. The latter is the easiest to implement.

During this movement, plate 328 is moved away from housing 30 a first distance (when levers 314 and 315 pivot in response to pressure exerted on trigger pin 312 by release ring 232). The first distance is selected so that the tip 313 of the trigger pin 312 exits the slot 236 under the release ring 233 and enters the ring slot.

2. 3. 4. When this occurs, the eccentric 230 is no longer supported by the trigger pin 312 and is translated downward releasing the compression spring 210. Consequently, the actuation surfaces 246 are also pressed down and press the box body 31 with related to valve stem 32 to deliver a dose of aerosolized medication. However, eccentric 230 is prevented from rotating under the force of torsion spring 220, which was still in torsion, because trigger pin 312 is held in slot 234. However, torsion spring 220 exerts a force to push slot 234 of release ring 233 against trigger pin 312 and keep edge 324 of metal spring 323 pressed against the vertical thread wall of lead screw 322.

At the time that the engine 321 stops with the trigger pin 312 in the first stage position, that is, engaged in the slot 234 of the release ring with the valve stem 32 of the box 30 fully depressed relative to the body of the box 31, control electronics 50 start a tuner. The timer controls how long motor 321, and therefore trigger pin 312, is kept in the first stage position. The period of time is selected to be long enough to be sure that the desired dose of aerosol is delivered from the box 30 in its selected form, namely, dry powder, liquid or aerosol gas through the nozzle 22.

At the end of the selected period of time, which can be controlled by a timer (more preferably a programmable value in a microprocessor controlled device), the motor 321 is advanced again to allow the plate 328 to react more under the force exerted by the ring groove 234. This allows lever 314 and lever 315 to rotate downward and trigger pin 312 to be ejected from slot 234 by the opposite sloping faces of trigger pin 312, side face 341, and slot 234. This is shown in Fig. Figure 8. The further advance of the motor can be limited by another contact switch or by a set period of time corresponding to a given number of rotations and therefore the distance of

ES 2 advance element 324 along lead screw 322.

When trigger pin 312 exits slot 234, torsion spring 220 is released (in this case uncoiled). Since torsion spring 220 produces more force than compression spring 210, release of torsion spring 220 causes rotary cam 230 to rotate. As rotary cam 230 rotates, its upper cam surface 232 advances against stationary cam followers 430 and up cam 230. When the rotary cam 230 moves upward, it compresses the compression spring 210. The rotation and rise of the cam 230 also results in the release of the valve path 32 so that the box 30 closes to the atmosphere.

In the preferred embodiment, where the box 30 is a metered dose box, this release action places the box 30 with its metered dose chamber in fluid communication with the drug reservoir and aerosol precursor material or vehicle and fills the chamber. dosing machine. Refilling occurs relatively soon after the dose is administered and, consequently, additional agitation of the drug and vehicle or aerosol precursor is not required prior to filling. Thus, cam 230 comes to rest in its top position, with cam followers 430 at one end of cam surface 232, torsion spring 220 released, compression spring 210 compressed, and metered dose box 30 with a dosing chamber filled and ready to deliver the next dose.

Advantageously, in the present invention, the torsion coil spring 220 is used to reassemble the compression spring 210, transferring its energy to it without the user having to perform any operation. It should be understood that a more complex spring could be used in place of compression spring 210 and torsion spring 220, such that the release of trigger pin 312 will transfer the energy that has been stored by a prior rotary mounting event to be stored. on the axial compression component, for later use by pressing the box 30 to release the next dose. It should also be understood that the direction of rotation about the B-axis for the various operations described herein may be to the right or to the left, using appropriate mirror image angles and portions.

Referring now to Figure 9, after trigger pin 312 exits slot 234, motor 321 continues to advance for a period of time, for example 0.5 to 2 seconds, or a number of revolutions, which it is enough for the cam 230 to rotate upward on the cam followers 430. In this regard, the top position of cam 230 is high enough that, when return spring 326 is released, it moves plate 328 along guide rod 325 back to the initial ready-to-fire position and return the trigger pin 312 to a pre-ready-to-fire position located below the release ring 233. In this condition, the compression spring 210 is compressed, the torsion spring

068 T3 28

220 is released, and the rotary cam 230 is held in its upper position by cam followers 430 on the trigger pin.

312.

The pre-condition to ready to fire is followed by a mounting operation, which places the device 6 in the ready-to-fire condition. With reference to Fig. 10, the mounting operation is carried out by rotating the cassette 4 to the closed position. As a result, one of the drive pins 245 of the exciter 240 engages the protruding step 239 at the bottom of the rotary cam 230 and causes the cam 230 to rotate. This rotates cam 230 relative to cam followers 430. As a result, cam 230 will move downward on cam surface 232 as it rotates until it is supported by trigger pin 312 acting on release ring 233. At that point, the cam 230 would continue to rotate only until the slot 236 of the release ring 233 engages the top surface of the trigger pin 312 again and places the cam followers 430 at the other end of the cam surface 232. Latching occurs less than approximately 10 ° from the fully closed (0 °) position. When the user releases the cassette 4 after being fully closed, the torsion spring 220 would tend to release. This results in the slot 234 acting on the tip of the trigger 313, which also inhibits rotation. This locks the torsion spring 220 in torsion. Thus, device 6 is ready to open to deliver aerosol medication.

Since the nozzle 20 is approximately 35 mm (1.38 inches) long from the center of rotation (B-axis), the patient has enough multiplication to rotate the eccentric 230 and put the torsion spring 220 into torsion, forcefully sufficient to move cam 230 to compress spring 210 after the next drug delivery. Preferably, compression spring 210 stores on the order of 3,629 kg (8 pounds) which is sufficient to depress valve stem 32 when spring 210 is released. Torsion spring 220 preferably stores on the order of (1.0 kg- cm (0.9 inch-pounds)) which is sufficient to compress compression spring 210 after delivery of a dose of medication.

It would be appreciated that the present invention can also be practiced by variations of the mechanical structure described above. For example, it is possible to use a release ring 233 that does not have a slot 233. In such an embodiment, the trigger pin 312 is used to engage the slot 234 to prevent the torsion spring 220 from releasing and resting under the release ring. 233 to prevent compression spring 210 from releasing. The advantage of this structure is that the advance distance of the eccentric 230 along the axis B to press the box 30 and to reinsert the trigger 312 under the release ring 233 increases the depth of the groove 233, for example , 0.38 mm (0.015 inch). In such an embodiment, the angular configuration of the trigger tip 313 can be modified if necessary, to provide the space

ES 2 free required as well as retention and expulsion functions.

As another example, it is possible to replace the compression-type release spring 326 with a helical torsion spring that was mounted around the pivot 318 and provide the pusher plate 328 with a flange that engages the secondary lever 315 (not shown). . In this embodiment, the torsion spring is used to actuate the primary lever 314, which in turn will push the secondary lever and plate 328 toward the housing 30 to reposition the trigger pin 312 under the release ring 233 when the clips are removed. forces pressing plate 328 toward motor 321. Another variation could use a torsion spring attached around pivot 316 of secondary lever 315.

The use of a compound lever 314, 315 minimizes the force requirements of the motor 321, the elastic member 323, and the return spring 326. This is important in reducing the power consumption requirements for a battery powered handheld device. In effect, fuel consumption requirements are further reduced by running the motor as a controlled brake that resists the forces exerted by springs 210 and 220 and by shutting down the motor to act as a passive brake, except when a brake is to occur. Controlled retraction of the trigger pin 312. During the time that the motor 321 stops in the first stage position, it consumes no power. Advantageously, the motor 321 can be operated directly from the battery 60, which simplifies the circuitry of the power supply and minimizes the volume of the device 6.

Another advantage of the present invention is that it provides for opening the nozzle 20 as a passive event, thus requiring little effort. It also eliminates the need for the patient to assemble the device immediately prior to use. This can be important for patients suffering from pain or severe asthma attack who, panicking, may forget or be unable to mount a device.

The time that the motor 321 is kept in the first stage, with the valve stem 32 depressed relative to the box body 31, can be selected and controlled by the control electronics 50. Accordingly, the present invention is especially useful with boxes, valve stem receptacle flow paths, and / or nozzles that have relatively slow or long release times, that is, the time that the valve stem must be depressed to keep the dosing chamber (for a metered dose inhaler) or a straight valve box open to release the appropriate dose of aerosol medicine. In this regard, most available metered dose inhalers have a release time of the order of 90-100 msec, such that the valve stem must be held down for approximately one tenth of a second to ensure complete release. This is easily accomplished by most individuals. Slow release valves may have a longer release time, for example, on the order of a quarter of a

068 T3 30 seconds, three-quarters of a second, two seconds, or more. The release time of this duration is more difficult to reliably achieve manually.

Advantageously, the present invention is capable of administering medicaments formulated in such a way that they have long release times that hitherto could not be used in a metered dose inhaler because of the difficulty of providing the required release time. This feature is also especially useful with straight valve boxes and dry powder delivery systems where the release time controls the amount of drug released.

With reference to Figures 1-3, 16A-H, and 17AC, the durable body 2 can be formed of a left half 11, a right half 12, and an airway cover 13, which provide a handheld portable device. The body 2 also includes a screen 510, preferably mounted in one of the housings 11 and 12. Inside the housings 11 and 12 are enclosed one or more batteries 60, the actuator mechanism 200, the actuator release mechanism 300, the chassis 400, the control electronics 50, a receptacle 520 to receive cassettes, and a flow transducer. 600.

Display 510 may be a liquid crystal display (LCD) device for displaying alphanumeric characters of measured flow or lung function paraometers, or instructions to the patient to use device 6 under microprocessor control. The LCD screen can display quantitative or qualitative measurements. Such a 510 LCD screen is a special part model No. 0219-3211-F14 available from DCI, Olathe, Kansas. Displays, in response to software programming, one or more of the counts of drug doses released (administered) and / or remaining, a low battery indication, a warning icon, for example, "check with your doctor ”, Three arrows to indicate inadequate, nominal or acceptable lung function, indications of total exhaled volume, maximum flow and indications indicating the day of the week, time, month and year.

The display features of device 6 may also include an array of light emitting diodes (LEDs) 510 'to indicate various parameters, for example (1) that the device is on, (2) ranges of breath flows determined, for example , good flow corresponding to successful administration, bad flow corresponding to suspended administration, (3) a qualitative measurement of a measured lung function, for example, normal, nominal, and abnormal, and (4) relative changes in measured lung function, for example, that ameliorate the same degrading conditions. The LED array 510 'may include three LED fixtures, for example green, or amber, and red (or three of the same color), and appropriate labeling printed on the housing 11 or

12. A selector switch can also be provided to indicate which parameter is being displayed on matrix 510 '.

The control electronics 50 preferably includes a microcontroller device including a microprocessor, RAM memory and

ES 2 179 068 T3

ROM, and buffers, and also includes external analog-to-digital converters, latches, RAM / ROM memory, and signal conditioning circuits for receiving and transmitting signals to and from the control electronics 50, in digital and / or analog form. Such devices include a Model 68HCllD3 microcontroller available from Motorola, Part No. AD7701 Analog-to-Digital Converter available from Analog Devices, and Model No.^° AD22050 available from Analog Devices to condition the pressure transducer signal for digitization.

The microcontroller, memory, and analog-to-digital converter must have sufficient capacity and processing speed to handle the output signal produced by the flow transducer 600, convert the output signal into the flow signal, and, following selected protocols, deriving a flow value signal from the sensed flow rate to cause actuator release mechanism 300 to deliver an aerosol dose during patient inspiration and determine pulmonary functions based on the acquired flow signals. A suitable sample rate is greater than 60 Hz, eg 75 Hz, for analog to digital conversion and processing.

The chassis 400 is attached to one or both housings 11 and 12 in such a way that it is adjacent to an inner receptacle 520 to receive the cassette 4. On the chassis 400 are mounted eccentric followers 430, the keyhole 440 to receive only the cassette 4 having projections 41 corresponding to the plurality of slots cut in the keyhole 440, the motor bracket 450 to mount the actuator release mechanism 300, annular recess 405 and contact switch 460 for detecting the presence of a position mark 44 on cassette 4 indicating that cassette 4 has fully rotated to the open position. Chassis 400 is securely mounted to body 2. Receptacle 520 includes a first section that receives the upper portion of the housing 40 and a second section that receives the lower portion 45 of the housing 40. A boss 447 separates the upper sections. and bottom of the receptacle and receives the support surface 47 of the cassette 4. The contact switch 462 is used to indicate that the cassette 4 has been inserted into the receptacle next to the chassis 400.

With reference to Figures 16A to 16H a suitable shape of the durable body 2 is shown, excluding the airway cover 13. With reference to Figure 16E, the housing 11 is shown with the receptacle 520 for receiving the cassette 4 having a annular recess 405 and keyhole 440. This embodiment includes two batteries 60 and LCD screen 510 and LED matrix 510 'inside housings 11 and 12.

With reference to Figures 16B, 16C, 16E and 16F, the body 2 is provided with a contour that the patient can easily grasp safely. The largest flat side walls of the housings 11 and 12 are inclined at an angle of approximately 4.5^°. It should be understood that alternative configurations of housings 11 and 12 could be used.

With reference to Figures 3 and 17A-17C, the airway cover 13 connects with the lower part of the body 2, more specifically, the housings 11 and 12, after being fixed. The airway cover 13 includes holes 507 in the larger end distal to the patient's airway, and has a curved edge 501 in a horizontal plane at the proximal end, adapted to receive the perimeter of region 29A of the end hole. upper 29 of nozzle 20. This allows the nozzle 20 to rotate and maintain a close fit with the airway between the airway cover 13 and the bottom of the housings 11 and 12. In addition, the airway cover 13 is provided with a curved corner surface. indicated by 509, which receives the mouth end 25 of the mouthpiece 20 when the cassette 4 is rotated to the closed position. This provides a nice outward appearance and a relatively smooth surface for the durable body 2, which makes it convenient to carry in a pocket or purse. It also provides a convenient mechanism for blocking the open end 23 of the airway so that no material is lodged in the flow path. It also eliminates the need for a separate plug to cover the hole. The distance between the designated flat wall section 508 of the airway cover 15 and the bottom of the housings 11 and

12, designated wall 506, is on the order of 9.65 mm (0.38 inches) and a width of 22.86 mm (0.90 inches) at maximum dimensions. Sidewalls taper to nine degrees, 4-1 / 2^°per side, to follow the outer casing 11 and 12. Although these dimensions are not critical, they should be large enough to provide a flow path between the mouth end 25 of the nozzle 20 and the holes 507 of the airway cover 13 when the nozzle 20 is rotated in the open position and provide a detectable pressure difference between the pressure tap 516 and the atmospheric pressure while maintaining an acceptable air flow.

Referring to Figures 3, 16D, 18B, and 18C, the flow transducer system 600 includes a pressure transducer 505, a durable flow measurement section that has a contoured surface incorporated into the wall 506 at the bottom of the housings. 11 and 12, the airway cover 13, and a pressure hole 516. Preferably, the contour of wall 506 is flat in the cross-sectional end view shown in FIG. 18C. Airway 601 engages airflow path 24 (via end 23 of nozzle 20 and upper end hole 29, lower portion 45 of housing 40, and exits through hole 43). Airway 601 includes bottom wall 506, made of mating housings 11 and 12, and airway cover

13.

In the operation of the present invention, when the patient inhales or exhales through the device, flow through path 601 is detected at pressure tap 516 in wall 506 and at atmospheric pressure (not shown) by the pressure transducer. 505. The output signal of the transducer 505 is converted into a digital value by the control electronics 50 at a selected sample rate and integrated at said sample rate to obtain the volume

ES 2 179 068 T3 inhaled or exhaled. Drug dispensing timing and therapeutic decisions are based on these flow and volume measurements.

The airway cover 13 is removable to facilitate cleaning of the durable flow meter section. It has a rectilinear wall section 508 that defines an area in cross section with the opposing wall 506. Wall section 508 has a corner 509 that opens at nearly a 90 ° angle to provide a larger chamber 550. The distal end of chamber 550 has holes (orifices) 507 for air flow through it without considerable pressure drop through holes 507. The type of hole is not critical as long as chamber 550 allows flow to expand. to the camera. Therefore, a 90 curve is desirable.^°, but it is not required.

Wall 506 has at the near end a tapered inlet section that includes a ramp indicated by 511. The ramp

511 reduces the cross-sectional area between walls 506 and 508 at the beginning of ramp 511 (indicated by reference 513) to a minimum cross-sectional area at the throat of the hole

515. Wall 506 includes a notched portion

512 below throat 515, which connects throat 515 to a wall segment 519, is in the same plane as wall 506 proximal ramp 511 and provides approximately the same cross-sectional area as at the beginning of ramp 511.

Walls 506 and 508 are thus constructed to form an asymmetrical structure that includes elements of a pneumatic diode, a fixed orifice flowmeter, and a venturi orifice flowmeter. A pneumatic diode is a structure that exhibits a resistance to flow when air passes in one direction through the surface and a different resistance to flow when air flow passes in the reverse direction. A fixed orifice meter is one that has a hole in the path that is generally symmetrical with the air flow path, but smaller in size. Flow through the orifice creates a differential pressure across the orifice that can be measured by sensing the pressure on either side of the orifice in a conventional manner. It is noted that the sides of the airway cover 13 could be made straight, rather than tapered. If so, the cross-sectional area between groove 515 and wall 508 must accordingly be adjusted to provide the same hole area as when tapering the side walls.

The principle of the orifice gauge is simple. To generate flow through an orifice there must be a pressure difference across the orifice. If there is no pressure difference, there will be no flow. Likewise, if there is a flow through an orifice, there will be a differential pressure that can be measured. The flow rate, Q, depends on a chain of constants, the square root of the inverse of the air density and the square root of the pressure difference across the orifice.

Qreal = K VA2p 2g_and -y / Pl - P2 The terms K and A are constants dependent on the geometry of the system and gc is a dimensional constant. In the present invention, only the pressure at the orifice side next to the patient and the atmospheric pressure are measured.

The flow curve as a function of the pressure drop is parabolic. Therefore, it will require an immense dynamic signal range to detect the small pressures generated at flows near zero but without stabilizing the system signal during high flows. Low flow sensitivity in one direction is necessary to accurately measure inhalation maneuvers, which are typically 0-200 liters per minute. The range of large flow rates in the other direction is necessary to measure high flow rates, for example during a forced exhalation maneuver which is typically 0-800, more preferably 0-720 liters per minute. AND^toThe latter are used to measure lung function.

It has been discovered that, by using an asymmetric orifice, instead of the usual symmetrical orifice, such different flow bands can be effectively measured by the same flow transducer on a relatively natural scale for maximum signal resolution in the different bands.

When the device is in inhalation mode, flow is developed by the reduced pressure on the patient side, drawing air over notch 512 in wall 506. In this mode, wall 506 behaves essentially like an orifice meter, except that there is a counter-swirl created by notch 512. The counter-swirl contributes to increasing resistance to flow in the inhalation direction, thus increasing the total differential pressure.

On exhalation, there is a different effect. The flow finds a smooth transition along the ramp 511 to the throat 515 of the orifice, which requires a certain amount of pressure to push it. The required pressure is approximately 40% of that of the same inhaled flow rate. However, the pressure detected depends on the position of the pressure tap 516 on the wall 506. If the pressure tap 516 is placed at position 518 as illustrated in FIG. 18A, the difference between sensed exhaled and inhaled pressures (for the same flow rate) is approximately 2: 5. If pressure tap 516 is positioned on ramp 511 as illustrated at 518 'in FIG. 18A, there is also a venturi effect that comes into play. In this regard, as the flow rate increases, there is also a pressure drop that overlaps the pressure required to generate the flow. The venturi effect is also paraboalic with respect to flow. The relative position of the pressure tap 516 on the ramp 511 determines the magnitude of the venturi effect. This allows the difference between the detected exhaled and inhaled pressures to be varied, which is of the order of between 2: 5 and 1: 100 or more, based on a careful selection of the position of the pressure tap 516 on ramp 511. The venturi effect can be made sufficiently intense so that the pressure detected can be negative with respect to the atmospheric pressure at the exhaled flow rates by placing the pressure tap 516 very close to the throat of the valve.

ES 2 179 068 T3 hole 515.

As a result, the wall 506 of the present invention produces a structure where the sensed pressure resulting from a flow in one direction can be radically different from the sensed pressure from the flow of the same magnitude in the other direction. The curve of inhaled flow versus pressure drop depends for the most part on the selected size of the orifice, that is, the distance between the throat 515 and the wall 508, and somewhat on the shape of the notch 512. It also depends on the position of the tap 516 on the ramp 511. The exhalation curve also depends on the size of the orifice, but is radically changed by the position of the tap 516 along the ramp 511 in relation to the venturi throat. 515. This allows flow rates to be measured in both directions using the full range of the transducer in each direction, even though the maximum flow rates have different magnitudes.

Referring to Figures 3, 16D and 18B, in one embodiment, the distance between throat 515 and wall 508 is 4.69 mm (0.185 inches). The dimensions of the notch 512 are a 1.7 mm (0.067 inch) radius that has a center point that is approximately 18.9 mm (0.745 inches) from the rear wall 517. The rear wall 517 is part of the durable body 2 and interconnects with the rear airway cover wall 13 which includes the holes 507. Wall thickness 506 at throat 515 is approximately 4.24mm (0.161 inch). Ramp 511 consists of two cylindrical segments that have opposite curvatures. The first curve begins tangential with wall 506 and at end 513 has a radius of approximately 18.6 mm (0.732 in.) From a center point spaced 152.4 mm (0.6 in.) From hole throat 515, perpendicular to wall 506 and wall 508. The other bend, which ends as hole throat 515, has a radius of approximately 20.09 mm (0.791 inch) having a center point spaced 19.8 mm (0.78 inch) from throat 515 on the other side wall 506.

Pressure tap 516 is preferably a circular hole that extends through wall 506 and ends at ramp 511 facing wall 508. Pressure tap 516 is preferably normal to the surface of wall 506 where ends and is spaced on one side or the other of the median plane as illustrated in Figure 18C. The exact position of the tappet 516 is a matter of design choice for the particular use of the device. Pressure tap 516 is connected to transducer 505 by flexible plastic tubing 520, eg PVC. The PVC pipe does not have to have the same diameter as the socket

516. The diameter should not be so small that moisture infiltrates, for example, have an internal diameter of 0.793 to 1.58 mm (1/32 to 1/16 of an inch). The tap hole 516 will be approximately 0.76 mm (0.030 inch).

In the present invention, the pressure versus flow curve along flow path 601 is typically non-linear in both directions. Applicants have observed that it is not practical to design and construct a flow path 601 with exact dimensions to obtain a flow that has linear characteristics of pressure as a function of flow rate.

One problem with using linear devices is that they are too bulky for a portable handheld device and typically contain sieves or other orifice matrices that become clogged or plugged during use and must be cleaned or replaced to avoid inaccurate measurements. However, Applicants have also observed that a linear relationship is not required and can be dispensed with by calibrating the actually constructed flow path 601 to produce calibrated data from the actual detected flow. Furthermore, by envisioning the flow transducer system 600 as part of the durable body 2, Applicants have observed that only the flow path 601 has to be calibrated, and not the flow path 24. This further simplifies the construction of the nozzle 20 and cassette 4, and avoids the need to maintain strict tolerance controls for the construction of the other parts. In this respect, the measurement performed is not the pressure drop through all flow paths 24 and 601 of the system, which could change slightly due to small variations in the cassette.

Four. Rather, the pressure drop measurement is obtained only through the flow path 601 between the housings 11 and 12 and the airway cover 13, and is therefore independent of small variations in the cassette 4. Furthermore, the total pressure drop through the entire system which is also largely independent of the manufacturing variations of cassette 4 between hole 515 in the flow measurement section is substantially less and thus more restrictive than hole 23. and nozzle 20 in cassette 4.

Accordingly, according to the present invention, a calibration look-up table is derived and stored in the non-volatile memory of the control electronics 50 for each body 2. This allows a flow-dependent pressure signal to be measured, that is, the signal output voltage of the 505 transducer and consult the corresponding calibrated flow value. In one embodiment, the look-up table is a selected number of data points of, for example, 59 points. The look-up table can be thought of as two matrices or tables, each having 28 data points for flow in each direction and sharing zero flow.

The control electronics 50 thus obtains the flow-dependent signal, applies the obtained value to the look-up table, and performs piecewise linear interpolation between the points in real time so that it can measure rapidly changing flow rates. The calculated flow values ​​are then integrated to determine volume or used to measure lung function, whichever is the case. The look-up table is generated during the calibration of each device 6. Although in the preferred embodiment valid flow values, that is, values ​​above a selected noise threshold, are always integrated, in an alternative embodiment, integration does not have to occur unless a flow volume is required. .

ES 2 179 068 T3

In a preferred embodiment, an automatic calibration routine is used to determine the look-up table.

First, the non-calibrated durable body 2 is placed in an accessory that ends in a simulated disposable cassette 4, in the same way that a patient drug cassette 4 would be inserted into the device. Second, a known air flow is introduced through the durable flow path 601 by a calibrated flow controller. Third, a computer (not shown) records the flow rate and the response of the transducer 505 to a known flow. Furthermore, the flow rate is regulated to the next flow level by the flow controller, and the second and third steps 2 are repeated, for example, for up to 59 different flow rates in the two flow directions. Fifth, the recorded data is transformed to a calibration table and can be run by a curve fit routine to search for bad or strange data points. These points, if any, are re-measured. A curve fit routine can alternatively be used to find the best fit by printing data to a desired degree of accuracy, for example 2^° order. Sixth, a calibration table is then generated and downloaded to the RAM of the control electronics 50. The table can be the raw data or curve fit data points. The calibration is then checked by probing at various flow levels to ensure proper loading of the table. A checksum is also stored in memory with the calibration table so that it can be verified if the look-up table is corrupt every time device 2 is activated.

A preferred flow sensing transducer 505 used to measure these pressure changes is a resistive strain gauge type device having two orifices. One orifice is vented at ambient pressure. The other orifice is connected by tube 520 to pressure tap 516 which is located within airway 601, preferably at ramp 511 (see Figure 18c). The pressure changes in the airway orifice 516 cause the resistances within the sensor 505 to change. These resistance changes are obtained in the form of a variable voltage output that is digitized by the control electronics 50. The digital value is converted at a corresponding flow value using the default calibration lookup table stored in system memory PROM, ROM, or non-volatile RAM. A suitable 505 transducer is Model NPH-8-002.5DH, available from Lucas Novasensor, Fremont, California.

Pressure sensors 505 of this type are known to have various problems. First, the devices exhibit long-term and thermal drift, causing the output signal to wander slightly after power-up. The output signal also varies with the orientation of the sensor. These effects would normally be negligible. However, in the application of the present invention, the paraboilic nature of the flow-pressure curve makes the conversion accuracy of the look-up table very sensitive to these drift changes. This is because, at low flow rates, a very small change in the pressure signal becomes a relatively large change in the calculated flow rate.

For example, it was discovered that if the drift of the pressure signal was only measured at the power supply and if the orientation of the transducer was changed or if the device 6 was left on for more than a few minutes, enormous flow rates would frequently be reported. up to ± 30 liters / minute. Therefore, it was observed that drift would have to be checked and taken into account. The simple method is to linearize the flow-pressure curve (mechanically or electronically) to eliminate this problem. However, as has already been observed, this effort proved to be unfeasible and unnecessary.

As the authors of the invention have observed, since the sensitivity of the system to changes in the drift of the pressure transducer cannot be easily reduced to an acceptable level, the magnitude of the drift changes must be reduced in some way, specify tolerances Stringent drift sensitivity and orientation would make the transducer 505, or the control electrode 50, prohibitively expensive. The inventors noted, however, that a cost-effective solution is to measure and correct for drift changes when they occur in real time. The inventors also noted that it is important to correct for zero flow drift changes during zero flow conditions and that this presented a different problem of determining when zero flow conditions occur even in the face of drift displacement.

The inventors found that the inherent noise of the unfiltered digitized signal during a zero flow state is approximately ± 2 A / D counts. The inventors found that even at low flow rates, when the sensitivity to flow variations is low, maintain an airway flow that produces a constant pressure signal within +2 A / D counts for any length of time. it is virtually impossible. Therefore, they observed that a pressure signal that remains constant for a relatively long period of time is indicative of a state of zero flow. Therefore, this criterion was selected and used to determine appropriate times to measure and modify the zero flow drift value.

The method assumes that all drift occurs slowly enough not to influence the calculated peak-to-peak variance over the specified time period, and that orientation changes are transient events.

Following a preferred embodiment of drift correction, the device maintains a buffer containing the last 25 A / D values, corresponding to 1/3 of a second of pressure data. The A / D values ​​are the digitized output of pressure sensor 505. After placing a new data point in this buffer, the difference between the minimum and maximum values ​​in the buffer is calculated. If the calculated difference is less

ES 2 179 068 T3 or equal to three, the system concludes that a zero flow condition exists, and a new displacement is calculated.

To calculate the new offset, first the average value of the 25 values ​​stored in the buffer is calculated. The difference between this calculated mean, which represents the current zero flow reading, and the base value for this zero flow signal is calculated. This difference is later stored as a new A / D offset term. If each flow direction is to have a symmetric range of A / D counts, the base zero flow condition is the midpoint of the A / D range, for example, zero for a bipolar A / D converter, or 32768 for a converter. 16-bit unipolar A / D.

The offset drift correction aspect of the present invention will be better understood by the following example. Upon initialization by power supply, the system measures a mean zero flow pressure signal of 30,000 A / D counts. The range of the unipolar AS / D converter is 0-65535 counts, corresponding to an input range of 2.5 volts, such that each A / D count is 38 μν. For a symmetric sample of A / D counts, the ideal base zero flow signal is like this:

= 32768 counts.

Then the A / D displacement term is calculated so that it is:

30000-32768 = -2678 counts.

The displacement term is subtracted from all subsequent A / D measurements before applying these readings to flow values ​​using the look-up table.

After some operating time, the pressure transducer output drifts slightly, resulting in an unadjusted mean output of 31,000 counts for the current zero flow condition. When the original calculated offset of -2678 counts is subtracted from this value, an adjusted mean of 33768 counts is obtained, which would normally cause a large erroneous flow to be referred. However, the peak-to-peak variance over the previous 25 values ​​will eventually turn out to be less than 4 A / D counts. At this point, the system will assume that there is a zero flow state and compute a new displacement term that is:

31000-32768 = -1678 counts.

A following unadjusted pressure reading of 31000 counts will now result in an adjusted value of:

31000 - (- 1678) = 32768 counts.

Note that the new offset now compensates for the 1000-count drift in the pressure signal.

The parameters specified above have been implemented in a prototype device, and appear to work well by allowing the system to quickly compensate for drift drift and orientation changes. See Figure 20, which is a representative graph showing the actual displacement drift of the flow sensor in the lower curve with time (in number of data points, where the time interval between data points is 13.3 ms ) and in the upper curve the corrected value follows the offset correction routing of the present invention. It is noted that many other combinations of filter length and peak-to-peak difference can work just as well. Non-symmetrical ranges of A / D counts can also be used if higher resolution or higher flow range is desired in one of the two directions. This approach could also be accomplished using hardware circuitry as well as software controlled microprocessor signal processing.

Referring to Figure 19A, a block diagram is depicted illustrating the interaction of control electronics 50, actuator release mechanism 300, actuator mechanism 200, and position sensor 460, for example, a position switch. Contact. A flow chart showing the essentials of a process for controlling the delivery of an aerosol drug dose is depicted in Figure 19B. A suitable routine is the following. When the nozzle 20 is rotated to the open position, the position sensor 460 detects the position mark 44 and initializes the control electrogen in step 801. Step 801 is followed by processing flow data, including digitizing the output signal provided by transducer 505, passing the digitized data to a temporary storage memory, applying the pressure data acquired using the look-up table at determined flow rates, and determine the current calibrated flow information in step 802.

In step 803, the system determines whether or not the time to release a dose has occurred. In this regard, the flow rate is checked to determine if it is an inhalation. If it is, the acquired flow data is compared to preselected management threshold parameters. For example, as previously described in detail, the flow rate is first checked to determine if it is within a flow range. If yes, the flow volume information is checked to see if it is in a flow volume range. If both ranges are met simultaneously, in step 804 motor 321 is turned on, a "trip" flag is set, a "motor1" flag is set, and a 2 second alarm is set. This causes lead screw 322 to rotate so that ratchet member 323 approaches motor 321 when trigger pin 312 is pushed out from under release ring 233 and into slot 234, and processing returns to step 802. to process new data. If it is not time to fire, the routine asks if the "fire" flag is set in step 805. If the "trigger" flag is not set, the routine reprocesses additional new data in step 802. If the "trigger" flag was set, the routine checks to see if it is also set.

ES 2 179 068 T3 set the "motor" flag in step 806. If the motor flag is set, the routine checks in step 807 if a position sensor was activated or triggered active (contact switch 327), which indicates that the trigger pin 3l2 has moved sufficiently to release the compression spring 2l0 and a dose of medication. If switch 327 was not active, the routine proceeds to step 808 where the two second alarm is verified. If the alarm has not expired, the routine proceeds to step 802 for new data. If the alarm has expired, motor 321 is deactivated in step 809 and the "trip" flag is removed. The two second alarm is used to extend the battery life. An error can be reported. Optionally, the error message is displayed on screen 15. The routine then returns to data processing step 802.

If the active trip switch 327 has tripped in step 807, the routine proceeds to step 810 where the motor is deactivated, a "motor2" flag is set, the "motorl" flag is cleared, and an * alarm is set. seconds, where * is the programmed delay interval. The motor is then deactivated during the programmed delay interval. The interval is selected to perform the complete delivery of the drug dose. As has been observed, this time depends on the dimensions of the nozzle and can be any number of milliseconds, for example, from less than 1/10 second to more than 2 seconds. It is important that this performs the administration of drug formulations, using a timed (slow) release valve, which is currently not available with conventional metered dose devices. For example, the use of timed-release valves and small diameter mouthpieces (less than 0.45 mm (0.018 in.)) Can improve the delivery of inhaled steroid formulations, that is, reduce the amount of drug deposited in the mouth.

After steps 808, 809, and 810, the routine reprocesses new data in step 802. If the "trigger" flag is set in step 806 and the "motor" flag is not set, the routine waits for the dose to be administered and goes to step 811 where the "motor2" flag is checked. If the "motor2" flag is set, the routine checks if the delay interval * programmed in step 812 has expired. If it has not expired, the routine reprocesses new data in step 802. If it has expired, the routine proceeds to step 813 where the motor is turned on, the "motor3" flag is set, the "motor2" flag is cleared and sets a 0.5 second alarm, and then the routine proceeds to process the new data in step 802. If the "motor2" flag is not set in step 811, the routine checks if the 0.5 second alarm has elapsed in step 814. If it has not elapsed, the routine returns to step 802 for new data. If it has elapsed, the routine disables the motor in step 815, removes the trigger flag, removes the “motor3” flag, adjusts the shot counter (decreasing the number of doses remaining and / or increasing the number of doses delivered from the given cassette 4), saves the record (for example, maximum flow rate and total volume inhaled or flow rate and volume of flow to drug delivery), and returns to obtain new data in step 802.

The selected time interval, for example, 1/2 second, provides sufficient time for trigger tip 313 to exit slot 234 and release torsion spring 220, recharge compression spring 210, and fill chamber. measured dose from box 31 after drug release. Although not shown in Figure 19B, device 6 is deactivated by turning nozzle 20 so that contact switch 460 no longer engages position mark 44.

Advantageously, the pressure, controlled grip and release behavior of the present invention allows the internal dosing chamber of metered dose box 30 to be refilled shortly after releasing the drug dose. This is important because the dosing chamber must be refilled, that is, the box released, after shaking the box. Topically, the patient is instructed to shake the drug before releasing a dose, but such shaking is to fill the chamber for the next dose.

The precisely timed pressure and release behavior also guarantees reproducible actuation of the box. It also allows the use of box nozzle combinations with various emptying times because the emptying time parameter, that is, the maintained actuation time, can be selected and is programmable. It should be understood that those of ordinary skill in the art could perform considerably more complicated processes for detecting flow analysis information and determining when to press the box to deliver an aerosol dose of medication. Such modifications are considered within the capacity of a person of ordinary skill in the art.

All specific numbers and dimensions offered herein are exemplary. It is to be understood that the dimensions can be varied in general to obtain the desired release and flow characteristics, specifically different pressure ranges in the two directions, as desired.

Those skilled in the art appreciate that the present invention may be practiced differently from the described embodiments, which are presented for illustrative and non-limiting purposes.