Dry powder inhaler devices, multi−dose dry powder drug packages, control systems, and associated methods

<td>REPUBLIC POLAND</td><td>(12) PATENT DESCRIPTION (19) PL (21) Application number: 358133</td><td>(11) 201275 (13) B1</td>

<td>γίγ</td><td>(22) Date of notification: January 24, 2001</td><td>(51) Int.Cl. A61M 15/00 (2006.01)</td>

<td></td><td>(86) Date and number of the international application: 2001-01-24, PCT / US01 / 02262</td><td>B05B 17/06 (2006.01)</td>

<td>patent Office</td><td>(87) Date and publication number of the international application:</td><td></td>

<td>Polish Republic</td><td>2001-09-20, WO01 / 68169 PCT Gazette No. 38/01</td><td></td>

(54) (30) Priority:

03/10/2000, US, 60 / 188,543 (43) Application announced:

09.08.2004 BUP 16/04 (45) The following was announced about the grant of the patent:

March 31, 2009 WUP 03/09

Dry powder inhaler (73) Patent holder:

UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL, Chapel Hill, US (72) Inventor (s):

Anthony J. Hickey, Chapel Hill, US Timothy M. Crowder, Chapel Hill, US (74) Agent:

Marek Ginter, GINTER &amp; GINTER, Kancelaria Rzecznikowska SC ⁽⁵⁷⁾ The present invention relates to a dry powder inhaler having an electromechanically assisted dispersion system which is characterized by: a housing (75) containing therein a multi-dose dry powder package (20), the housing having an air flow exit path (12) and a system a control (100) disposed within the housing (75), the control circuit (100) comprising: a controller (125) comprising a computer-readable storage medium having a computer-readable program code, a power source (150) operatively connected to the controller (125), a transformer (130) operatively connected to the controller (125) and electrically connected to the selected multi-dose area dry powder packs (20).

<img file="PL201275B1_D0001.tif" />

<img file="PL201275B1_D0002.tif" />

PL 201 275 B1

Description of the invention

The present invention relates to a dry powder inhaler, and more particularly to a dry powder inhaler with an adjustable dose to be administered.

The delivery of medicaments in the form of inhalation aerosols is well known. In fact, asthma and other respiratory ailments have long been treated with inhalation sprays. There is also current interest in expanding this concept of administering topical agents such as antimicrobials, protease inhibitors and nucleic acids as well as systemic agents such as peptides such as leuprolide and proteins such as insulin. These include, for example, the administration of antibacterial agents such as anti-tuberculosis compounds by inhaler, proteins such as insulin for the treatment of diabetes mellitus and other disorders related to insulin resistance, peptides such as leuprolide acetate for the treatment of prostate cancer and endometriosis. and nucleic acids or oligonucleotides for gene therapy of cystic fibrosis. See, for example, Wolff et al., Generation of Aerosolized Drugs, J. Aerosol: Med. pages 89-106 (1994).

In general, there are three types of inhaler used to administer and deliver drug therapies via aerosol inhalation. The most common type used (usually associated with the treatment of asthma) is a metered pressurized inhaler (pMDI). This type of inhaler uses an ozone depleting CFC propellant, such as freon, which is banned for most industrial applications but which is currently exempted from the medical field. Alternative devices to pMDI devices represent an important area of ​​aerosol delivery research primarily because the number of CFC-free propellants is limited and reformulation is difficult.

Drug aerosols for inhalation can also be generated using nebulizers. Until recently, the use of nebulizers was usually restricted to clinics and homes primarily due to the power requirements of such devices. In operation, the nebulizers deliver droplets sized to reach the periphery of the lung through the patient's airways. However, because these droplets are very small (on the order of less than about 2.0 µm), a relatively long treatment time is usually required to deliver a clinically significant dose.

A third type of inhaler is the dry powder inhaler (DPI), which is a promising alternative to pMDI devices for the delivery of drug aerosols. Typically, DPI devices are configurable to deliver a powdered drug or drug blend containing an excipient and / or other ingredients. Many traditional DPI devices operate passively, based on the patient's inspiratory effort to dose medication delivered by the powder. Unfortunately, this passive effect can lead to poor uniformity in dosing as inspiratory capacity can vary from patient to patient (and sometimes even to individual uses by the same patient, particularly if the patient is having an asthma attack or suffers from a condition such as with a tendency to close the airways).

Generally, known DPI single and multi dose dry powder inhalers use each of an individually pre-measured dose, such as drug-containing capsules, that may be inserted into the device prior to dispensing. Alternatively, the DPI devices may operate on powder reservoirs that are configured to deliver sequential amounts of drug to a patient through a dosing chamber that dispenses the appropriate dose of drug. See Prime et al., Rewiew of Dry Powder Inhalers, 26 Adv. Drug Delivery Rev., pages 51-58 (1997); and Hickey et al., A new millennium for inhaler technology, 21 Pharm. Tech. No. 6, pp. 116-125 (1997).

In operation, especially of the DPI devices, it is desirable that an even amount of dispersion and the desired physical form (such as particle size) of the dry powder be dispersed throughout the patient's respiratory tract and directed to the desired destination. If the patient is unable to make sufficient respiratory effort, the degree of drug penetration, especially into the lower airway, may be reduced. This may result in premature deposition of the powder on the patient's mouth or throat.

In addition, a number of obstacles can desirably affect the performance of the DPI. For example, the small size of inhaled particles in a dry powder drug mixture can subject them to agglomeration and / or cohesion forces (certain types of dry powders are prone to agglomeration, which is usually caused by drug particles sticking to each other), which is non-cohesive. The favorable result is low flow and uneven dispersion. In addition, as noted above, many dry powder formulations use larger excipient particles to improve drug flowability. However, separating the drug from the excipient as well as the occurrence of agglomeration may require additional inspiratory effort which can again result in a stable dispersion of the powder within the patient's airflow such that the powder reaches the desired deposition / destination and reduces the amount of drug that is prematurely deposited therein. elsewhere.

In addition, multiple dry powder inhalers can retain a significant amount of the drug within the device, which can be particularly problematic over time. Typically, in view of this problem, it is required that the device be cleaned to maintain its proper condition. In addition, the hygroscopic properties of many of these dry powder drugs may also require the device to be cleaned (and dried) periodically.

Some installation devices have been designed to solve the problems found in traditional passive inhalers. For example, US 5,655,523 proposes a dry powder inhalation device with an anti-agglomeration / aerosolization plunger rod or a deflected hammer and solenoid, and US 3,948,264 proposes the use of a battery powered buzzer with a solenoid to shake the capsule to induce release. the powder contained in it.

These devices propose to facilitate the release of the dry powder by using an input energy that is independent of the patient's breathing effort. However, there still remains a need for improved, easy-to-use, cost-effective and reliable dry powder inhalers.

Hence, it is an object of the present invention to provide an improved dry powder inhaler that can disperse more even doses of medicament.

Another object of the present invention is to provide a DPI system to actively facilitate the dispersion and release of dry powder drug formulations upon inhalation, which may increase the amount of fine particles dispersed or separated from the device by conventional DPI systems.

Yet another object of the invention is to provide an economical disposable blister pack with active dispersion elements and multiple doses of dry powder disposed therein to reduce the difficulty of cleaning and the frequency of cleaning the inhaler.

An additional object of the invention is to provide an integrated inhaler control system that can adjust the operation of the inhaler based on actively sensed or predetermined parameters.

Yet another object of the invention is to provide control systems that are configured to analyze predetermined conditions and / or parameters that can dynamically adjust the operation of the inhaler during use.

A further object of the invention is to provide logic-based control systems for defining and adjusting the operation of devices and / or devices using and / or dispensing dry powder substances.

These and other objects of the invention are provided by methods, systems and computer program products for the administration and dispensing of dry powder based on anxiety preparations delivered via inhalers. Preferably, the multilayer active drug package is shaped to vibrate in response to an excitation voltage being applied thereto. The multilayer drug package is preferably a drug blister package configured to protect the drug from moisture until an active dose of the drug is dispersed. A multi-layer blister drug package uses a thin film of a piezoelectric polymeric material such as a polyvinylidene fluoride (PVDF) film with electrical tracks formed thereon to apply an electrical excitation voltage across the film at a desired package area and oscillate the drug package around the area of ​​the blister package drug, to actively assist and disperse the dose of the dry powder in the stream of air from the user while inhaling. In addition, the inhaler may use a fuzzy logic control system and one or more sensors to provide active control / feedback and dynamic set-up with respect to the dispersion control system based on real-time detected conditions (such as user air flow rate, temperature, humidity and the like) and / or

Pre-defined conditions and parameters corresponding to the delivered drug or its systemic purpose.

According to the invention, a dry powder inhaler having an electromechanically assisted dispersion system is characterized by having:

a housing containing a multi-dose dry powder package therein, and the housing having an exit airflow path, a control system disposed within the housing, the control system comprising:

a controller comprising a computer-readable storage medium having a computer-readable program code, a power source operably connected to the controller, and a transformer operably connected to the controller and electrically connected to a selected area of ​​the multi-dose dry powder package.

Preferably, the inhaler further includes an air flow sensor located in the downstream path of the air flow, the air flow sensor operatively connected to the regulator.

Preferably, a multi-dose dry powder package comprises a plurality of spatially separated dry powder drug doses held thereon, the multi-dose dry powder package thereon having a polymer piezoelectric substrate layer thereon and a plurality of spatially separated electrical excitation paths, and a multi-dose dry powder package disposed thereon. it is in the housing, and one of the electric excitation paths is electrically connected to the transformer.

Preferably, the exit flow path of the air flow is an irregularly shaped exit flow path.

Preferably, the irregularly shaped exit flow path includes a baffle, the baffle attached to the housing and extending across the width of the exit air flow path for a distance.

Preferably, the inhaler further comprises a depressed recess in the exit flow path of the air flow located between the air flow sensor and the end of the exit flow path.

Preferably, the power source comprises a battery having a first voltage output operably connected to a regulator.

A first aspect of the present invention is directed to a multi-dose dry powder blister pack. The package has a platform body comprising a layer of piezoelectric material with opposing first and second major surfaces. The first major surface of the piezoelectric material layer includes a first series of spatially separated metal tracks disposed thereon. The first series of metal paths are configured to include a transmission line and an active contact area. The second major surface of the piezoelectric material includes a second series of spatially separated metal tracks disposed thereon. The second series of metal paths is configured to include a transmission line and an active pad area. Each of the second series of metal paths is positioned so as to align with a corresponding one of the first series of separated metal paths to define a corresponding pair of opposing metal paths with separately actuated electrical excitation path between them. The package also includes a series of depressed recesses formed in the platform body. The recesses are configured to hold a predetermined amount of dry powder pharmaceutical drug therein. Each of the depressed recesses is disposed on the platform body to substantially cover the respective active area of ​​the contact area of ​​one pair of corresponding first and second metal paths.

In a preferred embodiment, in operation, in response to application of the excitation voltage difference to one of the selected electric paths, the piezoelectric material layer deforms in the active area of ​​the contact field to thereby actively disperse the dry powder pharmaceutical drug from the lowered state. recesses. The package may include one or more sealed, removable polymer caps positioned to cover a plurality of depressed recesses and a non-responsive barrier disposed in each of the depressed recesses to define a dry powder drug contact surface therein.

PL 201 275 B1

In a preferred embodiment, the multi-dose dry powder blister pack is configured to be inserted into a dry powder inhaler. The dry powder inhaler includes a housing and a control system disposed therein wherein, in operation, the housing is configured to be in fluid communication with a user and define an exit flow path therefrom. The control system includes a regulator configured to communicate with one selected of individually operable electrical paths. The control system also includes a battery having a first voltage output operably connected to the regulator and a transformer for raising the first voltage to a desired excitation voltage operably connected to the regulator and a selected individually operable electrical path. The control system also includes an air flow sensor located in the exit flow path, and is preferably located behind a depressed recess in the exit flow path (the recess is between the sensor and the user). This placement can reduce deposition of drug particles on the sensor. In operation, the controller is configured to adjust the excitation voltage corresponding to predetermined parameters related to the dispersion of the dry powder drug.

Similar to the first aspect of the invention described above, another aspect of the invention is directed to a disposable multi-dose dry powder package with at least one integrated active element formed thereon. The dry powder package comprises a layer of piezoelectric material having a substantially flat profile and a top and bottom surface. The first metal path pattern is placed on the top surface. The first metal path pattern has a plurality of first contact area regions and a plurality of first line transmission lines. Each first area of ​​the contact field is connected to a corresponding one line from among the first line transmission lines. The second metal path pattern is located on the lower surface. The second metal track pattern has a plurality of second contact area areas and a plurality of second line transmission lines. Each second area of ​​the contact field is connected to a corresponding one second linear transmission line. The first and second metal trace patterns are aligned across the piezoelectric polymeric material layer. The package also includes a plurality of individual quantities of dry powder medicament arranged to substantially cover each of the first contact area regions on said top surface. The sealant layer is arranged to cover each of the individualized amounts of dry powder medicament to protect it in the disposable dry powder pack.

In one embodiment, the piezoelectric polymer film is a thin film PVDF and the substrate material layer may be arranged to cover a substantial portion of the lower surface of PVDF.

The present invention may also employ a baffle or irregularly shaped wall in the entrainment tube (exit flow channel) in an inhaler to facilitate turbulent air flow to increase the fraction of powder released or dispersed from the device to the user.

A yet additional aspect of the present invention provides a computer program product for directing the operation of a dry powder inhaler to actively facilitate dispersion of the dry powder medicament into the inhaler's exit flow path and into the user's inhalation flow path. The computer program product includes a computer-readable storage medium having computer-readable program code embedded in the medium, the computer-readable program code including computer-readable program code that controls the excitation pulse sent to an active drug delivery mechanism in an inhaler configured with a drug dispersion system. electromechanically assisted. The computer-readable program code also includes the computer-readable program code that determines the fuzzy logic analysis model to control the amount of energy delivered to the electromechanical assisted system, and the computer-readable code that determines the degree of dry powder drug presence it has. be fed to the first dry powder drug flow fuzzy logic function. The computer-readable program code also includes computer-readable code that regulates at least one of parameters such as the type, frequency, or magnitude of an excitation signal directed to an electromechanically assisted inhaler system with an energy based, at least in part, on a certain degree of affiliation to the first function. fuzzy logic.

PL 201 275 B1

In a preferred embodiment, the computer program product also includes a computer readable program code that measures the airflow rate of the user's inspiratory effort in the vicinity of the active dispersion of dry powder medicament in the inhaler exit flow path, and also includes the computer readable program code. which defines a fuzzy logic analysis model to adapt the supplied excitation signal to an electromechanically assisted system including a computer readable code medium for analyzing a user-measured air flow rate.

The computer program product may also include computer-readable program code that takes into account one or more parameters such as the type of excipient used in the dry powder formulation, the cohesiveness of the dry powder drug, inhaler geometry, and a systemic delivery target in determining the excitation pulse that is is to be sent.

Advantageously, therefore, treatment methods can be provided for more reliable and consistent inspiratory dry powder drug delivery with improved operational features. A DPI inhaler, PVDF blister pack, and a fuzzy logic control system can provide one or more of the following advantages over traditional DPI inhalers: reproducible dosing, secretion / emission of a high percentage of respirable / exhalable particles, reduced chance of accidental multiple dosing, ease of handling, protection of the powder drug mix from moisture, and reduced cleaning requirements.

Brief description of the drawings

Figure 1 is a perspective view of a DPI of the present invention, Figure 2 is a plan view of a dry powder blister pack that is insertable into the DPI of Figure 1 of the invention, Figure 3A is a partial sectional view taken along line 3A-3A from fig. Fig. 2, Fig. 3B is a schematic diagram of an individually selectable electric excitation path formed on a dry powder blister pack with a single piezoelectric substrate layer according to the invention. Fig. 3C is a schematic diagram of an alternative embodiment of an individually selectable electric excitation path on a multiple dry powder drug package. layers of a piezoelectric substrate according to the invention, Fig. 3D is a schematic diagram of yet another embodiment of a drug pack with an individually selectable electrical excitation path with multiple piezoelectric substrate layers according to the invention, Figure 4 is a perspective view of an alternative embodiment of a DPI of the present invention, Figure 4. 5A-5C are plan views of alternative embodiments of linear platform multi-dose blister packs according to the present invention, Figs. 6A and 6B are top plan views of alternative embodiments of round platform blister packs according to the present invention, Figs. 7A and 7B are perspective side views. blister packs with an endless linear platform according to additional embodiments, Fig. 8A, 8B and 8C are partial perspective views of alternative embodiments of a DPI constructed to receive endlessly configured blister packs such as those shown in Figures 7A and 7B, Figure 9 is a diagram illustrating an exemplary wake up signal having an adjustable frequency and / or the amplitude according to the invention, Fig. 10A-10C are perspective views of alternative embodiments of DPIs configured to contain blister packs, such as those shown in Figures 2, 6A and 6B, Figure 11A is a side sectional view of a DPI illustrating an integrated control system of the invention, 11B is a side cross-sectional view of the DPI shown in Fig. 11A with the blister pack raised to place it in the path of the inhaler's exit airflow such that the dry powder drug is actively dispersed through the inspiratory air and directed out of the inhaler, FIG. 11C is a top plan view of an alternate embodiment of the pack. blister card with a round platform according to the invention showing the seals positioned on the periphery of the drug cavities, Fig. 12 is a block diagram of a control system for a DPI of the present invention, Figure 13 is a schematic diagram of a fuzzy set theory inference system to determine the degree of occurrence of selected functions based on the fuzzy set theory and to regulate the DPI operation of the present invention, 14 is a membership function graph based on fuzzy set theory for flow rate modeling flow rate as low, medium, and high according to the invention, and Fig. 15 is a membership function graph based on diffuse set theory as poor, good, or otherwise, according to the present invention.

Generally speaking, the present invention relates to dry powder inhalers with integrated, patient-operated, electro-mechanically assisted dispersion-generating systems that are configured with control systems that provide an adjustable output energy to a dispersion-generating active element responsive to the user's inspiratory capacity and / or administered flow rate. dry powder medicine. Inhalers can be used for nasal and / or oral breathing. Preferably, the inhalation dose of the dry powder is packaged in a dry powder drug-containing multi-dose package that contains a piezoelectric polymeric support (such as PVDF-polyvinylidene fluoride) that flexes to rapidly deform and provide mechanical oscillation in an individually selectable path. signal on the package. The signal path directs the signal to an area of ​​the drug reservoir or cavity to cause the cavity to oscillate in conjunction with an inspiratory effort by the user, and thus actively direct the dry powder out of the cavity and upwardly into the exit flow path. As a result, the powder is actively dispersed in the exit flow path of the inhaler during inhalation activities by the user. The dry powder inhaler may also employ control systems with fuzzy flow logic models of the individual drug formulations (which may also be able to compensate for or allow the use of a particular type of excipient or other additive) and systems that may take into account real-time measured inspiratory effort of the user.

1, there is shown one embodiment of a dry powder inhaler (DPI) configured to receive and orally dispense a dry powder inhalation powder from a multi-dose dry powder medicament package 20. Examples of suitable dry powder medicament packages are also shown in Figures 2 and 3A. As shown, multi-dose dry powder medicament package 20 includes a platform body 20b with integrated active elements formed by upper and lower metal track patterns 22u, 22b, respectively, that are disposed over the piezoelectric substrate layer 28. The platform body 20b includes a first track pattern. metal 22u on the upper surface 21u of the platform body 20b. As shown, the first metal trace pattern 22u includes a series of spaced apart pads 25u and a corresponding transmission line 26u connected to and extending away from each of the active pads 25u. The underside of the platform body 21b includes a second metal trace pattern 22b (Fig. 3A). Preferably, the second metal track pattern 22b is substantially the same as the first metal track pattern 22u and is symmetric therewith such that the track patterns are aligned on top of each other with the piezo substrate layer 28 therebetween.

As shown in Figures 1 and 2, a plurality of unit and unit doses of the dry powder formulation mixture are disposed on the bridge body 20b such that each drug dose 30 is on and substantially covers each active contact area 25u. According to the invention, protective films, moisture separators, drug barrier baffles or coatings may also be provided over the piezoelectric substrate layer 28, tracks 22u, 22b, or other portions of the platform body 20b. Preferably, if they are superimposed near the area of ​​active oscillation or near the depressions 40, then they appear substantially transparent to the active elements. Preferably, as shown in Fig. 3 A, an inert or non-reactive barrier 35 is positioned over at least the upper contact field 25u to protect the purity and stability of the dry powder drug from possible contamination or interaction with the dry powder drug that contacts and rests on the surface. In a preferred embodiment, the inert or non-reactive baffle 35 is a thin polymeric coating (or coating) that is applied to the upper surface of the platform body 20b such that, in use, it is substantially simultaneously responsive to deformation of the piezoelectric substrate layer 28.

As shown in Fig. 3A, it is also preferred that the first and second metal track patterns 22u, 22b contact and are transversely oriented with respect to the piezoelectric substrate layer 28. That is, the first metal track pattern 22u is oriented on the first surface of the main piezoelectric substrate layer 28 so that it substantially covers the second track pattern 22b to define pairs of respective transmission lines 26u, 26b and active contact fields 25u, 25b. As schematically shown in Fig. 3B, in operation, each pair of respective transmission lines 26u, 26b and active contact fields 25u, 25b can provide an individually excited electrical excitation path 33.

PL 201 275 B1

As also shown in Fig. 3A, it is preferred that the platform body 20b is shaped to provide a plurality of reservoirs or depressed recesses 40 to contain the drug. As shown, the recesses 40 are shaped to hold a dose or quantity of a one dimensional bulky dose of dry powder drug 30. In a preferred embodiment, the depressions 40 are defined by concave contours formed in the piezoelectric substrate layer 28. It is also preferred that the dry powder drug dose is enclosed in the recess by a seal layer 45 such as a polymer cap. When the multilayer package is closed after filling it with the desired drug, it is shaped such that, with the connected layers of the platform body comprising opposing active contact areas 25u and 25b and non-reactive partitions 35 (and optionally the backing layer 50), it has a conformal concave shape. . That is, each layer substantially takes the shape of the piezoelectric substrate layer 28. In other words, in operation, each layer 35, 25u, 28, 25b moves uniformly when an excitation signal is applied across the piezoelectric substrate layer 28. Other non-circular tank shapes, such as a flattened or elongated rotational ellipsoid shape, may also be used, although not limited to those instances.

As shown in Fig. 3A, optionally a backing layer 50 may be applied to the underside of the platform body 20b. Preferably, backing layer 50 is applied such that it is conformal to the piezoelectric substrate layer 28 and moves accordingly upon activation of the selected cavity. 40. The backing layer 50 can contribute to enhancing the oscillation of the reservoir or cavity 40 caused by the application of an excitation signal across the piezoelectric substrate layer 28 by providing increased weight on the opposite side of the powder surface. An example of a material suitable for backing layer 50 is, but is not limited to, PVC, i.e. polyvinyl chloride.

As shown in Fig. 1, transmission lines 26u extend radially inward toward the center of multi-dose dry powder package 20 where a portion of a dry powder inhaler (DPI) 10 holding regulator 125 and power supply 150 (Fig. 11A) is located, preferably a battery with a push button, at least 5V or 9V. Likewise, the bottom transmission lines 26b also run towards the center of such a package 20. In this embodiment, the package center comprises a slot or an opening 20o formed therein (Fig. 2). As shown in Figure 11A, the dry powder inhaler 100 (DPI) is formed with an upper lower portion 75u, 75l and a central opening 20 ° of the multi-dose dry powder package 20 allows easy electrical connection between components located in the lower portion 75l and those located in the upper portion. parts of 75u. Fig. 11A and 11B also illustrate that dry powder inhaler (DPI) housing 75 may be configured with or without bottom 75].

When assembled into a dry powder inhaler 10 (DPI) as shown in Figure 1, the ends of the transfer lines near the center opening 20o in the inhalation chamber 11 are individually electrically activated by the regulator 125 in the dry powder inhaler 10 (DPI), and thus determined by suitably selected pairs of transmission lines 26u_s, 26b_s and an associated electrical excitation signal path 33 or circuit. Transmission lines 26u_s, 26b_s connect to the housing 75 of the dry powder inhaler at an electrical connector location, schematically illustrated as box 100j, which provides signal / ground or +/- connections to the appropriate side (top or bottom transmission lines 26u, 26b) of the drug pack. The joint can be formed in a number of ways, such as the use of traces arranged on surfaces, circuits with flexible insulated wires, windings, etc.

The control system 100, therefore, preferably operates to electrically activate selected transmission lines 26u_s, 26b_s and the control system 100 can send a wake-up signal to selectively cause mechanical oscillation in the associated region of the package cavity 40. Since only selected transmission lines are electrically connected to the power source, other non-selected drug cavities 40 remain static (not electrically activated and electrically insulated against mechanical oscillation). As the next dose in the closed cavity 40 is rotated into the inhalation chamber 11 (which defines the outlet path 12 of the air stream from the dry powder inhaler 10), punch members not shown near the inhalation chamber 11 can remove sealant to remove the sealant. expose the dose of dry powder drug 30 in cavity 40 and allow it to disperse freely when cavity 40 is oscillating, as described above. Rotation is shown in R in Fig. 1. The direction of rotation can be either clockwise or counterclockwise.

PL 201 275 B1

As noted above, the dry powder formulation mixture may be a one-component mixture or a plurality of active or inactive ingredients. The inactive ingredients may contain additives added to enhance flow or to facilitate delivery to a desired systemic target (such as additives to inhibit premature deposition in the respiratory system, e.g. in the mouth, during inhalation). Dry powder drug formulations may contain active molecules, the size of which may vary. The device may be particularly suitable for dry powder formulations having a particle size in the range of 0.5 to 50 μm, preferably in the range of 0.5 to 20 μm, and most preferably in the range of 0.5 to 8.0 μm. . The dry powder formulation may also contain flow-assisting ingredients, which usually contain particles larger than the particles of the active ingredient. Preferably, the flow-enhancing ingredients include excipients having a particle size on the order of about 50 to 100 µm. Preferred excipients include lactose and trehalose. Other types of excipients may also be used, such as sugars that are FDA approved, such as cryoprotectants, such as mannitol, or solubilizers, such as cyclodextrin, or other excipients generally recognized as completely safe. in use ("GRAS).

Pharmacological treatment with dry powder medications can be used to treat asthma, flu and other respiratory diseases. As noted above, there is an interest in developing this mode of drug delivery to ensure the delivery of antibacterial agents such as anti-tuberculosis compounds, proteins such as insulin for the treatment of diabetes or other insulin-resistant disorders related thereto, nucleic acids or oligonucleotides for cystic fibrosis gene therapy, and peptides such as leuproleline acetate for the treatment of prostate cancer and / or endometriosis.

The typical unit dose amounts of dry powder mixtures dispersed in an inhaler will vary depending upon patient size, systemic target, and the specific drug. An exemplary amount of a dry powder dose for an average adult patient is about 200 mg, and for an adolescent patient from about 5 to 10 mg.

Examples of dry powder medicaments are, but are not limited to, albuterol, fluficasone, beclomethasone, cromoglycan, terbutaline, fenoterol, β-agonists, and glucocorticoids.

Preferably, since the active elements are integrated into and contained as part of a disposable multi-dose dry powder (medicament) package, unlike many conventional active dispersion systems, cleaning of the active part of the inhaler mechanism is no longer required.

Referring again to Fig. 3A, it should be noted that the piezoelectric substrate layer 28 is a piezoelectric polymer material. In a preferred embodiment, the piezoelectric polymer layer is formed from a piezoelectrically active material such as polyvinylidene fluoride PVDF (known as KYNAR or polyvinylidene fluoride film) and copolymers thereof or polyvinylidene difluoride and copolymers thereof (such as PVDF with its copolymer with trifluoroethylene (PVDF-TrFe)).

In a preferred embodiment, the piezoelectric substrate layer 28 is a thin polyvinylidene fluoride (PVDF) film. As used herein, the term "thin film" means that the piezoelectric substrate layer 28 is formed as a structurally flexible or pliable layer which preferably has a thickness of from about 10 to 200 nm.

Metal tracing patterns 22u, 22b are preferably provided by applying a conductive pattern to the outer surfaces of the piezoelectric substrate layer 28. Any deposition or layering technique such as electron beam vapor deposition, thermal vapor deposition, painting, spraying, dipping or sputtering a conductive material or metallic paint or material on selected surfaces of the piezoelectric substrate ( preferably polyvinylidene fluoride layers as given above. Of course, alternative metallic circuits, foils, surfaces or techniques such as attaching a mylar layer or an insulated flexible conduit circuit to a desired portion of the outer surface of the piezoelectric substrate layer 28 may also be used. It is preferred that when circuits with an insulated flexible wire are used, the circuits are shaped or attached to the piezoelectric substrate layer 28 in a substantially transparent form to the sensor array structure to minimize any potential interference suppression with that substrate layer.

PL 201 275 B1

It should be noted that specific conductive patterns are shown in the drawing, however, the present invention is not limited thereto as alternative conductive patterns may also be used.

Preferably, the top and bottom surface metal tracing patterns 22u, 22b do not merge at the platform body 20b. For example, conductive paint or ink (silver or gold) is applied to the major surfaces of the platform body 20b such that it does not extend beyond the peripheral edge portion 28e of the piezoelectric substrate layer 28, thereby maintaining metal trace patterns on the top and bottom surfaces 22u, 22b. which are separated from each other by a piezoelectric substrate layer 28. This configuration creates an electrical excitation path when coupled to the control circuit 100 (FIG. 12) to provide the input / excitation signal to create an electric field that activates the deformation of the piezoelectric substrate layer 28 during operation. As such, the electrical excitation path 33 for each contact field 25u, 25b passes through the respective transmission line 26u, 26b to electrical terminals operatively connected to the regulator 125 (Fig. 12).

Again referring to Figures 3A and 3B, it should be noted that the circuit configuration of the excitation path 33 may be such that the upper path is positive, while the lower path is negative or connected to ground, or vice versa, thus providing an electric field / voltage difference for excitation of the piezoelectric substrate in the area of ​​the selected cavity 40. Of course, the polarities can be swiftly reversed when an excitation signal is applied (such as + to -, + to -) depending on the type of excitation signal used.

Fig. 4 shows an alternative embodiment of a Dry Powder Inhaler (DPI) generally designated 10 '. As shown, the DPI housing is shaped to seat a linearly shaped multi-dose dry powder package therein. Likewise, transmission lines 26u on the package extend laterally towards the edge of the platform body 20e to allow electrical connection to the power source 150 and regulator 125 in the DPI 10 'inhaler. In this embodiment, instead of rotating multi-dose dry powder pack 20 so that the next dose of dry powder medicament 30 is moved to inhalation chamber 11, multi-dose medicament pack 20 may be moved into place in a direction that is perpendicular to the direction of delivery line 26u. . A serrated edge or other tearing or perforating means may be provided on or near the inhalation chamber to expose the recess to allow the dry powder drug to disperse freely. Of course, the closure layer 45 could also be removed manually.

Figures 5A, 5B, and 5C show exemplary and alternative embodiments of a multi-dose dry powder drug package with active elements. Fig. 5A shows that, instead of the single cavity or single excitation pad used for the single dose dispensing described above, package 20 may be formed with two separate pads 25u.₂, 25u ?. As above, the bottom metal track patterns are substantially similarly shaped, and preferably also a symmetrical image of the first track pattern. These two separate pads 25ip, 25u ', (along with their respective bottom pads 26b₁, 26b₂), as shown, are aligned along the length direction (denoted by axis "L) of the inhalation chamber 11. Or they may alternatively be configured by aligning along the width direction (denoted by axis" W "in Figure 4), and / or spaced apart from the L axis, but maintained in a configuration positioned within inhalation chamber 11 to disperse the medicament during a single inhalation by the user. This means each contact field is 25ip, 25u₂ (and 25h, 25b?) is activated simultaneously via its respective transmission lines 26u₂, 26u? (26b₂, 26b₂) for dispensing your doses into the outlet flow path 12. Due to the fact that smaller amounts are dispensed from the two cavities 40 in the inhalation chamber 11 (dosing the same single total dose), less energy may be needed and / or may be achieved a more even dispersion (or even a room of two components which can be administered together and which are separated before use).

Fig. 5B shows that transmission lines 26u, 26b may alternate on alternate edges of the platform body 20b. Figure 5C shows that the pads 25u and transmission lines 26u (and 25b and 26b, respectively) can be arranged such that after dose dispensing along one side of multi-dose package 20, the package can be turned over, reinserted, and activated along the other. side (providing a dosing pack with increased drug density). Fig. 6A and 6B show similar configurations for an exemplary embodiment

For round packages of multi-dose package 20. Of course, although Figures 5A and 6B show a package with two simultaneously actuated pads 251, 25u,₂(and 25b and 25b₂) configured to be placed in an inhalation chamber, the multi-dose dry powder pack 20 may also use multiple fields in various combinations (such as one or more combinations of pads, side-by-side, in-line, offset, etc.) . Similarly, instead of a series of separately excited contact pads connected by transmission lines as shown in Fig. 5A and 6B, a single longer pad can be used along with multiple depressions, not shown.

Figures 7A and 7B show yet another embodiment of a multi-dose dry powder drug package 20 with active elements in accordance with the present invention. As shown, the package is an endless loop. Fig. 7B shows that multi-dose dry powder package 20 may also include a sealing ridge 129 at an intermediate position between each recess or upper contact area 25u. The purpose of the sealing ridge 129 will be discussed later in the description.

Figures 8A-8C show exemplary embodiments of DPI inhalers, each at 10, configured to seat a multi-dose dry powder package 20 in an endless loop (such as those shown in Figures 7A and 7B). As illustrated, the inhaler 10 (DPI) is shaped to contain a packet 20 of dry powder. As package 20 rotates (such as through known translation means), piercing means 200 located adjacent to inhalation chamber 11 and outlet flow path 12 pierce selected recess 40. As shown, each embodiment includes inhalation chamber 11 that is connected to each other. with the respective activated pair of tracks 25u, 25b, 26u, 26b. These inhalation chambers 11 may be formed with recesses that extend a distance within the enclosure to abut against the multi-dose dry powder package 20, such as the sealing ridges 129 described above to seal, at least partially, the inhalation chamber 11 to engage with it. reducing the patient's inhalation effort. Alternatively, the entire enclosure or housing may form an inhalation chamber 11 (not shown).

Figs. 10A-10C show embodiments of a DPI, each at 10, configured to cover and preferably seal the circular multi-dose dry powder medicament package 20 shown in Figs. 2, 6A, and 6B. As shown in Figures 10B and 10C, the DPI body may be shaped with variable shapes that can help make small patients more receptive to the use of such a device. Fig. 10B illustrates a science fiction aircraft model, and Fig. 10C shows a turtle-shell-shaped enclosure model, and other configurations such as ladybug shell, basketball glove, etc. may also be appropriate. Of course, other circular or substantially circular designs may also be used. such as shells, wheels, hats, pets etc.

Figures 11A-11B show a partially sealed inhaler (DPI). In this embodiment, an opening 111 is provided in the lower floor 111f of the inhalation chamber 11 in the lower floor 111f of the inhalation chamber 11 in this embodiment. An extension member 172 may be used to raise the multi-dose package 20 of dry powder into a sealed position on the lower floor 111f of the inhalation chamber. as shown in Fig. 11C, and a seal 229 may be positioned around the periphery of the recess 40. Likewise, a suitable seal 111s may be placed proximate the opening of inhalation chamber 111. As shown in Fig. 11B, as the extension member 172 pushes a portion of the package 20 into the operating position, the control circuit 100 makes electrical contact with the tracks 25u, 25b, 26u, 26b. signal to activate the powder dispersion as a drug dose 30 into the partially closed inhalation chamber 11, directing the dry powder formulation outwardly into the outlet flow path. It may be desirable to configure the extension member 172 with a center portion that is made flexible such that it can substantially conform to the piezoelectric substrate layer 28 (acting as an oscillation-assisting backing layer, not shown). Alternatively, extension member 172 may be configured with a central opening corresponding to the active region of the medicament contained in the package to allow the recess to oscillate without significantly inhibiting the movement of the recess 40 (also not shown).

As also shown in Figures 11A and 11B, in a preferred embodiment, the inhaler 10 (DPI) includes an air flow sensor 300 located in the inhalation chamber 11. The air flow sensor 300 is electrically connected to a regulator 125 in the control circuit 100. Sensor 12

The air flow indicator 300 is used to measure the inhalation effort of the user. One suitable type of air flow sensor 300 is a "hot wire" configuration that uses an electrical circuit to heat the wire according to the amount of air flow detected. Other flow sensors may also be used. For example, flow sensors using a powered impeller or bundles may be suitable for use with inhalation devices. It is also preferred that the air flow sensor 300 is positioned slightly behind the drug-filled cavity 40 (the cavity is in an intermediate position between the outlet flow path and the sensor 300) so as not to interfere with the dispersion of the drug into the outlet flow path 12. This position also reduces the likelihood (and / or amount) of dry particles being deposited on the sensor during use.

Fig. 11A also illustrates the use of a baffle 302 located in the exit flow path 12 of the air flow near (preferably immediately downstream) sensor 300 to pass across the air flow passage around the recess 40. The baffle 302 interrupts the air flow path by guiding the air flow with turbulence. which can amplify or cause a larger fraction of the fine particle powder to be separated or dispersed from the device. The baffle 302 may be attached to the ceiling of the air flow passage and extend therefrom across the main portion of the air flow passage. In one embodiment, for a 17mm wide air flow conduit, the septum may be a lightweight component (formed of sterilized plexiglass or the like) shaped and dimensioned to be approximately 12mm wide (2mm thick) and to fit around entering the flow channel while leaving a gap of about 5 mm from the bottom (recess area). Of course, other configurations or components in the turbulent flow air flow duct may be used, such as creating the inner walls themselves with contours or shapes / features that facilitate / introduce turbulence in the air stream which can increase the amount of fine particle fraction (FPF ) separated from the device.

Preferably, the air flow measurement is performed dynamically during or just prior to actively dispersing the dose of the drug into a dry powder form. In addition, air flow measurements made by the dry powder inhaler (DPI) may be stored in memory in the controller 125 and retrieved for analysis by the clinician at a later date. Such airflow measurement data may then provide actual usage data and may allow for customization regarding the type of inhaler that is best for a particular user, the type of drug to be dispersed, or even the design of the drug package (such as recommending an increased number of cavities for the simultaneous dispersion of a drug dose as discussed). above). Such data may also allow treatment to be performed according to the patient's requirements and / or to deliver the drug according to the user's particular inspiratory capabilities. In addition, the data may allow a physician to monitor the intensity or change in the loss of airflow in the presence of asthma or a patient's respiratory disease.

Whenever at least one real-time or dynamic measurement is acquired, this data is coupled to a controller 125 which is programmed with logic capable of adjusting the excitation signal 135 to be delivered to drug well 40 to increase or decrease the amount or the degree of oscillation in this basin. Alternatively, controller 125 may receive an airflow measurement and set the next active energy excitation pulse based on the average value of the waveform.

Fig. 12 illustrates a control system 100 according to one embodiment of the present invention. As shown, the control system includes a regulator 125 (with a timer 125t), a battery power supply 150, and a boost transformer 130. The control system 100 preferably also includes an airflow sensor 300. In operation, the control system 100 controls the active dispersion of the drug by being able to match the excitation signal to the electric excitation path 33 based on selected parameters that correspond to the drug flow. For example, the parameters selected may be one or more of the parameters selected from: the type of drug administered (its flowability along with its associated particle size), dose amount in the cavity (s), inhaler geometry, presence or absence of additives in a drug formulation ( such as excipients), systemic target of drug delivery, user's inspiratory capacity (preferably at a specific time of use). Many of these parameters may be predefined and programmed into the controller as a computer readable look-up table or as an operating program. Preferred control system logic systems will be discussed later in the description.

PL 201 275 B1

In operation, the piezoelectric substrate layer 28 functions as an electromechanical transducer and as an oscillator. Generally speaking, with reference to Fig. 3A, the cavity 40 is shaped such that when the piezoelectric substrate layer 28 is subjected to an electric potential or a voltage, it deforms to deflect in proportion to the absolute value of the electric field produced by the excitation signal across the thickness. piezoelectric material. By rapidly exposing the selected well 40 to a varying voltage potential, the activated well 40 oscillates. The varying voltage potential can be provided by a series of excitation signals (some of them are continuous signals and have positive or negative polarity such as cosine, sine and other types of waveforms, and some of them have one polarity such as square wave).

It is preferred that the input excitation voltage signal provides from about 50-300 V of total voltage potential, and more preferably in the range of about 100-200 V of total voltage potential across the activated region of cavity 40 (as shown in Figure 9). The frequency of the excitation signal (an example of which is shown as fe in Fig. 9) and / or the amplitude of the excitation signal may vary depending on certain factors such as the type of powder, the powder dose, the design of the dose package, and the presence of additives such as excipients etc. Moreover, as also shown in Fig. 9, the frequency and / or the amplitude of the excitation signal can be adjusted (fe adj) during the inhalation cycle (the user usually has a weaker inhalation during the last part of the inhalation cycle). Of course, the adjustment can be made based on the real-time airflow sensor measurements corresponding to the current effort of the user.

In one embodiment, a low frequency excitation pulse (i.e., between about 3-100 Hz, and more preferably between about 3-60 Hz) may be used. This low frequency excitation signal is expected to act to fluidize the dry powder into an outlet flow stream. In another embodiment, especially where additives are included in the drug formulation, it is preferable to use higher frequencies (e.g., about 10-100 kHz, and preferably about 25 kHz - 2 MHz). This higher frequency can break any cohesive or caking tendencies that drug particles may have when the drug is dispersed. For multi-dose drug packs 20 to simultaneously disperse the drugs from more than one cavity 40 (as shown in FIG. 5), the cavity may be individually excited using different excitation frequencies.

While the preferred embodiment of a dry powder drug package is shown and described as employing a single piezoelectric substrate layer 28, other configurations may also be used. For example, as schematically shown in Fig. 3C, the platform body 20b may include two piezoelectric substrate layers 28, 28 'separated by an intermediate flexible core 128, each having the metal tracing patterns 22u, 22b described above. The core is flexible and at the same time deforms together with the piezoelectric substrates 28, 28 'in the same direction to oscillate the cavity of the package. In operation, all of these (the four path patterns) would respond simultaneously to the application of an electric field in the area of ​​the activated tank (s) or cavity 40. The double shape of the substrate can enhance the mechanical oscillation.

The core 128 may be a neoprene layer with a thin film of adhesive on each side. The piezoelectric substrate layers 28, 28 'can then be readily attached to each outer surface of core 128 to accommodate the core 128 therebetween.

Preferably, core 128 is dimensioned to be larger in thickness, and preferably about an order of magnitude larger in thickness, than the piezoelectric substrate layers 28, 28 '. For example, for the piezoelectric substrate layer 28, 28 'being 60 microns wide, the core 128 may have a depth or width thickness of about 600 microns.

As another alternative, as shown in Fig. 3D, two piezoelectric substrate layers 28, 28 'may be used with the intermediate core 128 as above, but each of the piezoelectric substrate layers 28, 28' may have a single single signal metal path pattern disposed on their inner surfaces (surfaces oriented towards the central core 128). In this embodiment, an outer common ground surface 122g may be provided on the outer major surfaces of each piezoelectric substrate layer 28, 28 'by applying a continuous layer of conductive ink or paint, or by applying and surrounding the substrates with a mylar film or other electrically conductive means.

PL 201 275 B1

As shown in Fig. 3D, for the signal paths 22b (for the upper piezoelectric substrate layer 28) and 22u (for the lower piezoelectric substrate layer 28), the poly (vinylidene fluoride) (PVDF) of each piezoelectric substrate layer 28, 28 'is oriented such that the polarization is such that activation of single signal path patterns on each layer of the piezoelectric substrate 28, 28 'deforms the substrates simultaneously in the same direction to oscillate the recess of the multi-dose dry powder package 20. As shown, polyvinylidene fluoride (PVDF) is disposed on the core so that each exhibits negative to positive polarity, and a track is applied to the side of the film associated with the positive polarity. Electrical connections may be accomplished by extending the polyvinylidene fluoride (PVDF) film a certain length on each of the piezoelectric substrate layers 28, 28 'separate from the common mass 122g to the controller 125 near the control system 100.

In order to "enhance the piezoelectric effect in a PVDF material" perceptibly, the material is typically exposed to a suitable electric potential of polarity adjustment across the thickness of the film for an extended period of time to piezoelectrically "activate the film.

Preferably, for multiple piezoelectric substrate layer configurations as described above, the core 128 is formed by inserting neoprene or flexible core material material into a matrix. The piezoelectric substrate layers 28, 28 'preferably extend over the core layer 128 such that the desired polarity of the substrate materials takes the correct orientation. For example, a first piezoelectric substrate layer 28 is disposed on core 128 such that it has a first polarity, and an outer layer 60 of the second piezoelectric substrate layer 28 'is positioned to contact core 128 opposite the first outer layer 50 such that that it has a second polarity, the second polarity being the inverse of the first polarity (as shown in Figure 3D). Alternatively, the polarity of the piezoelectric substrate layer 28, 28 'may have the same orientation as shown in Fig. 3C.

Another aspect of the present invention is control systems for dry powder applications, particularly DPI inhalers. As noted above, fluidization and dispersion of the dry powder drug may be assisted by mechanically oscillating the piezoelectric polymeric material incorporated into the drug package. Thus, the excitation path and the oscillators are included in the drug package (i.e., the disposable multi-dose drug package in powder form with active elements). Excitation signals to aid dry powder dispersion may depend on the flowability properties of a particular drug formulation, which may be predetermined, as will be described later in the description.

Referring now to Figs. 13, 14, and 15, it should be noted that preferred fuzzy logic models for dry powder control systems having fuzzy inference patterns and membership functions are graphically shown here.

As shown, for the fuzzy inference systems of the models of the present invention, the parameters of the powder flow rate (Fig. 15) and the inspiratory air flow rate (Fig. 14) are selected. As shown in Fig. 15, the powder flow rate characterizes the powder along a continuum of values ​​as if it had a poor and good flowability. Identification of poor and good flowability can be based on a number of properties such as particle size, density, added excipients, dosages, desired administration (systemic or local), tendency to agglomerate, etc. Similarly, as shown in Figure 14, the value of the air flow rate is characterized along a continuum from bottom to top. The airflow function, when identifying airflow rates as high, low, or somewhere between the two, can take into account a number of factors such as age, inhaler size, length of drug delivery (inhalation effort), user flow rate, fallout of effort on inhalation by the time of drug administration, the initial amount of use, the systemic goal, etc. the data or values ​​of these inputs represent the degree of belonging to particular fuzzy logic functions.

As shown in Fig. 14, the degree of the membership of the variable rate and the variable airflow rate are then input into another fuzzy logic based algorithm or function / model that analyzes the data according to predetermined fuzzy logic rules and determines the excitation signal at the output. This fuzzy logic model can define fuzzy logic rules regarding desired energy output values ​​/ frequencies for individual drug formulations. An example of a fuzzy logic output function is discussed below.

PL 201 275 B1

If the powder is cohesive and the flow rate is low, the energy input increases. Preferably, the fuzzy logic control system preferably takes into account (by the fuzzy logic functions used) one or more of the following parameters: a specific drug formulation (such as particle size, cohesiveness tendency, etc.), excipient type, inhaler geometry, and user inhalation capability. Fuzzy logic models can combine a number of parameters together in a way that is computationally less intensive and less complex than conventional powder flow control systems.

It should be noted that the fuzzy logic model can be defined and can provide information to the physician to assist in selecting a powder drug and type of inhaler. For example, for a user with systemic target A, inspiratory medium flow rate B, drug allergy C, using other drugs D having the potential to reduce drug efficacy, and other identified risk characteristics (age, heart disease, diabetes, etc. ), the fuzzy logic model can provide the physician with data that lists suitable inhaler types (geometries), and / or drugs, and / or drug formulations (such as based on easy flow and efficacy).

The control system in the DPI inhaler may be preset to function with a specific drug formulation, or may be programmed to receive encoded (for security) input from a pharmacist or physician based on a Universal Bar Code (UPC) or other code associated with the drug to be used. dosing. Of course, the DPI inhaler may also be configured to electronically read the bit rate code based on the computer readable code (barcode or memory chip) located on the package itself.

It should also be emphasized that the control systems of the present invention may also be used in dry powder production systems and devices. That is, where dry powder substances are dispersed in the manufacturing process, the control system of the present invention can provide better control systems by monitoring, feedback, analysis, and tuning of operational process inputs to ensure a more reliable and reproducible process. Typically, the process inputs are such as to be of the dry powder that is used and its characteristics regarding flow, temperature, humidity, flow rate, etc. Thus, the control systems of the invention can be used for improved conveying rates, orifice sizes, feed time, nozzle size, and mixing, milling, transporting, or capsule-filling pharmaceutical products. Moreover, it is expected that the concept of using powder specific signals (which may also be specific to a particular polyvinylidene fluoride (PVDF) formula can also be used for powder transfer in industrial processes.

The control systems can be used with other active energy dispersion systems, such as those described above, including the DPI inhaler with mechanical oscillators and other vibration based systems.

Each block of the flowcharts (or the block in the flowchart pictures), and the combinations of these blocks in the flowchart pictures (or the blocks in the flowchart drawings) may be implemented by means of a computer program instruction. These computer program instructions may be input into a computer or other programmable data processing device to produce a machine such that the instructions which run the program on the computer or other programmable data processing device form a means for implementing the functions specified in the block diagram or blocks. . The computer program instructions may also be stored in a computer-readable memory, which can direct a computer or other programmable data processing device to operate in a specific manner such that the instructions stored in the computer-readable memory produce an article containing an instruction means. which implement a function given in the flowchart or in blocks. The computer program instructions may also be inserted into a computer or other programmable data processing device to cause a series of operational steps to be performed on a computer or other programmable data processing device to produce a computer implemented process such that the instructions, which run a program on a computer or other programmable data processing device, provide steps for implementing the functions specified in the flowchart or in blocks and / or flowcharts.

PL 201 275 B1

Accordingly, the blocks of the flowcharts or graphs support combinations of the means for executing certain functions and the means of program instructions for executing certain functions. Each block of the flowchart or graph, and combinations of blocks in the flowcharts or graphs, may be implemented by hardware-based special purpose computer systems that perform specific functions or steps, or combinations of special purpose instructions to hardware and a computer.

Example

An experimental embodiment of a DPI using a piezoelectric excitation element to vibrate the powder during dispersion uses a design in which a polymer membrane vibrator element has a capacitance "C" of about 1,800 picofarads. The value of the capacitive reactance corresponds to the size, i.e. the area (and therefore shape), of the bubble or the vibration element. The transformer used to boost the 5 V peak-to-peak input voltage now has an inductance of about 23 mH on the secondary. The transformer is used to increase the voltage to 150 V of the total (peak-to-peak) excitation voltage to the bladder. Thus, together, the transformer and the piezoelectric element form an amplifier that can be described as having the resonant frequency given by the equation: f = 1 / (2n (LC)^1/2), where L is the transformer inductance and C is the capacitive reactance of the vibrating element of the polymer membrane. This gives a calculated resonant frequency for the experimental performance of about 25 kHz. The resonant frequency determined experimentally was 24 kHz. At this frequency, the output signal measured approximately 7mm from the front of the loudspeaker was 72.4db. The powder was placed on the active element and the motion of the powder was observed. The maximum powder displacement, as determined by observation, occurred at approximately 31 kHz. Thus, the frequency of 31 kHz was chosen for experimental purposes.

In order to obtain higher resonant frequencies, the transformer and / or the piezoelectric polymer element may be reconfigured. The polymer capacity reactance is about 250 picofarads / cm². Preferred piezoelectric elements may be configured to have inductances of from about 1000-2000 picrofarads, and more preferably about 1500 picrofarads. In other words, the size of the bladder is preferably such that it has an area in the range of about 4-8 cm²and more preferably about 6 cm². That is, for a circular bladder, at least a bladder having a radius of about 1 to 1.5 cm may be used.

In order to reduce the capacitive reactance of the circuit and thus enable the use of higher frequency signals, a new active element with a smaller area has been constructed.

Preferably, recent results comparing the fine particle fraction (FPF) coming out of the device when a signal is applied to the active element with that, without any signal, indicates that a much larger percentage of FPF is achieved with the piezoelectric active element. The FPF may be considered that portion of the aerosols that would be substantially delivered to the lungs when used. The experimental determination of FPF was carried out using an 8-stage Andersen cascade impactor. At 31 kHz signal amplitude modulated at 60 Hz, the outgoing FPF was 0.11 = +/- 0.002 (n = 4). Without signal, FPT was 0.05 = +/- 0.003 (n = 4). Thus, in comparison, approximately twice the amount of FPF was generated with the PVDP element. Using one final fraction test, it was determined that the FPF was increased by applying a signal of p &lt;0.05. It is expected that a baffle located in the airflow can cause a larger fraction of the powder to separate from the device.