Inhaler

[0001] Embodiments of the present invention relate to medical devices and drug delivery devices, in particular for administering drugs in the form of an aerosol, for inhaling drugs for delivery to the lungs and gastrointestinal tract, and for administering drugs to the nasal cavity. Devices for administering drug substances in the form of an aerosol, including administration by inhalation, are known in the art, and examples include patents US 5 694 920, 6 026 809, 6 142 146, all Abrams and Gumaste, 3 948 264 Wilke et al., 6 971 383 Hickey et al., 7 117 867 Cox and others, 6 901 929 Burr and others, 6 779 520 Genova and others, 6 748 944 DellaVecchia and others, 5 590 645 Davies and others, 2006/0174869 Gumaste and others and 6 026 809 Abrahms et al. The above patents or published documents also provide an overview of various aerosolization and inhalation devices and techniques.

[0002] A number of aerosolization and inhalation devices are known for administering drugs, including metered dose inhalers, nebulizers, dry powder inhalers, thermal vaporizers and other systems, the differences being in the methods and efficiency of aerosolization and administration of medicinal substances to a patient. Metered dose inhalers typically use pressurized gas to aerosolize a drug substance. The disadvantages of these inhalers are associated with difficult control of the administered dose of the drug substance and the speed of the aerosol particles, which causes the particles to hit and settle on various surfaces in the patient's mouth and throat. Inhalation devices for administering drug substances in the form of dry powder are known as dry powder inhalers. Passive dry powder inhalers rely on the patient's breathing effort to disintegrate and aerosolize the drug substance for inhalation, while active dry powder inhalers usually provide extra energy, such as mechanical or electrical energy to improve powder comminution and aerosolization efficiency, to reduce the patient's respiratory effort and to achieve better independence of the inhaler performance from inspiratory flow. Typically, for delivering drug substances to the patient's lungs by inhalation, the aerosol drug particle size should be less than about 10 μm, more preferably less than about 6 μm, and for delivery to deep lung areas less than about 3.3 μm . Larger particles will be delivered to the patient's mouth and throat and, as a result, will end up in the patient's digestive tract. There is therefore a need to increase the amount of drug that dry powder inhalers are able to aerosolize in a single inhalation by a patient, e.g., within one to three - four seconds. There is also a need to increase the speed of powder grinding and aerosolization by dry powder inhalers.

[0003] Dry powder inhalation devices described in US Patent 5,694,920, 6,026 809, 6,142,146 all Abrams and Gumaste use vibrating means to crush and aerosolize the drug in the form of a dry powder for administration to the patient in the form of an aerosol. Patent Publication US 2005/0183724 Gumaste and Bowers discloses a method and device for administering a drug using a synthetic stream.

[0004] The problem with these drug delivery devices by aerosolization and inhalation techniques is that substantially faster aerosolization and ejection of dry powders and the ability to aerosolize larger amounts of dry powders are required.

[0005] This problem can be solved by a dry powder inhaler according to claim 1. Such a dry powder inhaler has an inhaler body, a container containing a dry powder housed in the inhaler body, a vibrating element, a flow channel and an electronic system for electrically driving the vibrating element, the container has a first flat surface, a second surface and a side wall connecting the second surface and the first surface. The inhaler has at least one opening for ejecting the drug in the second surface of the container, and the vibrating element has a flat surface for causing the container to vibrate and ejecting the drug substance from the container through the at least one opening for ejecting the drug substance into the flow channel for inhalation by the patient. The inhaler of the invention further has at least one air inlet in the container sidewall, and the vibrating element is connected to the flat surface of the container to expel the drug substance from the container by means of a synthetic stream.

In short, an example of the invention is an aerosolized medicinal substance inhalation device in which a high-frequency vibrator is connected to a container filled with the drug substance in the form of a dry powder. Vibrator vibrations cause grinding, aerosolization and ejection of the drug substance from the container for inhalation by the patient. One or more openings in the container are generally opposite the vibrator serving primarily to eject the drug, using a synthetic stream or other mechanisms to eject the powder from the container. At least one opening in the container is mainly used for inflow of gas from outside or air into the container.

[0007] As shown in the examples below, when experimental studies of embodiments of the present invention were carried out to be used as an inhalation and / or aerosolization device, unexpected results were obtained, with substantially faster aerosolization and ejection of dry powders as well as the ability to aerosolization of substantially larger amounts of dry powders compared to prior art solutions.

Fig. 1 is a cross-sectional view of an embodiment of the present invention showing a container with a drug substance connected to a vibrator.

Fig. 2 is a cross-sectional view of an embodiment of the present invention showing a drug container connected to the vibrator.

Fig. 3 is a cross-sectional view of a number of embodiments of the present invention showing drug containers connected to the vibrators.

Fig. 4 is a cross-sectional view of an embodiment of the present invention showing a container with a drug substance connected to a vibrator.

Fig. 5 is a cross-sectional view of a number of embodiments of the present invention showing drug containers connected to the vibrators.

Fig. 6 is a cross-sectional view of an embodiment of the present invention showing a container with a drug substance connected to a vibrator.

Fig. 7 is a cross-sectional view of embodiments of the present invention showing inhalation devices.

Fig. 8 is a cross-sectional view of an embodiment of the present invention showing an inhalation device.

Fig 9 is a cross-sectional view of embodiments of the present invention showing inhalation devices.

Fig 10 is a cross-sectional view of an embodiment of the present invention showing an inhalation device.

[0008] In the drawings, similar references relate to similar parts or properties in individual views.

[0009] Fig. 1 is a schematic cross-sectional view of an embodiment of the present invention. The vibrator 100 is connected to a blister or container 110 that contains the medicinal substance or substances 120. The vibrator 100 may be a piezoelectric actuator or piezoelectric transducer or mechanical vibrator, electromagnetic vibrator, magnetostrictive element or other vibration mechanism known in the art. In one embodiment, a piezoelectric actuator is utilized, typically consisting of a ceramic piezoelectric element and a metallic body, of both single-plate and double-plate design. Constructions of prior art piezoelectric actuators can be used that include air transducers and piezoelectric sensor elements, but are not limited to those listed. In addition, polymeric piezoelectric materials and actuators based on polymeric piezoelectric materials can be used as vibrators. Vibrators based on piezoelectric actuators are excited, as is known in the state of the art, by supplying the piezoelectric element with electricity, usually alternating current of the correct frequency and amplitude. Piezoelectric actuators tuned to different resonance frequencies can be used, e.g. with resonant frequencies in the range from about 1 kHz to about 100 kHz, usually in the ultrasonic range from about 30 kHz to about 45 kHz and the mechanical oscillation amplitude from about 1 μm to about 50 μm of total peak. The vibrator 100 may vibrate at a constant or variable frequency or multiple frequencies simultaneously, and may transmit vibrating motion to container 110. The oscillation frequency may range from less than 1 Hz to several hundred kHz, typically the oscillation frequency is from about 25 kHz to about 50 kHz. In the embodiment shown in Fig. 1, the vibrator 100 is in direct contact with the container 110 and is thus directly connected to the container 110.

[0010] The container 110 has at least one drug ejection opening 150 located substantially opposite the vibrator 100, and mainly for ejecting the drug substance 120. However, gas or air may also flow through the openings 150 from outside. In addition, the container 110 has at least one opening 200 in the side wall which is not substantially opposite the vibrator 100. The sidewall opening 200 is not intended for ejecting drug substance, but allows external air or gas to enter into container 110, and thus facilitates comminution, aerosolization, and ejection of drug substance 120 from container 110 through drug ejection holes 150.

[0011] The drug substance or substances 120 is provided in the form of a dry powder, but other forms of drug substance such as liquid or gas are possible. It is possible to use a single-component medicinal substance (pure drug) as well as many medicinal substances or medicinal substances in combination with excipients, e.g. lactose or combinations thereof. Other additives, such as pharmaceutically inactive ingredients, disintegrating agents, etc., may also be added to the pharmaceutical active drug substance or substance.

[0012] The container 110 is made of metal, plastic or composite materials. In one embodiment of the present invention, the container 110 is a blister made of a cold or hot formed film, the film forming materials being polymers, metal foil, multilayer polymeric films clad with metal foil, and metal or polymeric films coated with a barrier layer. In one embodiment of the present invention shown in Fig. 2, the container 110 is a single-use blister having generally a conical, pyramidal, hemispherical, elliptical or similar upper part 111 and flat lower part 112, the upper part 111 and lower part 112 being hermetically connected to each other by methods known in the art, including gluing, hot welding, pressure bonding, ultrasonic welding, etc., but not limited to those listed. The gluing or welding area 113 is also schematically shown in Fig. 2 in the contact area between the upper part 111 and the lower part 112. The vibrator 100 is shown to be in direct contact with the flat bottom 112 of the container 110.

[0013] A number of possible shapes and forms of the blister or container 110 are schematically shown in Figs. 3A to 3F, including frusto-cone shapes (Figs. 3A, 3D, 3G); cylindrical shapes (Figures 3B and 3E), which is also shown in Fig. 4, and hemispherical or conical shapes (Figs. 3C, 3F, 3H).

[0014] The dimensions of the container 110 in one embodiment are: diameter from about 1 mm to about 30 mm and height from about 1 mm to about 30 mm, although larger or smaller containers 110 may be used in accordance with the present invention. In another embodiment, the diameter the container 110 is from about 3 to about 12 mm, while the height of the container 110 is from about 3 to about 12 mm.

[0015] The dimensions of the drug ejection apertures 150 are from about 10 μm to about 1000 gm, with preferred dimensions being from about 50 μm to about 500 gm. The dimensions of the side wall holes 200 are from about 1 μm to about 1000 μm, with preferred dimensions being from about 25 μm to about 500 μm. In one embodiment of the present invention, the total area (cross section) of all drug ejection holes 150 is at least two or more times the total area (cross section) of all side wall holes 200. In another embodiment of the present invention, the total area (cross section) of all drug ejection holes 150 is at least five times greater than the total area (cross section) of all side wall holes 200.

[0016] The number of drug ejection holes 150 is from 1 to about 10, and the number of drug ejection holes 150 in another embodiment is from about 3 to about 6. The number of sidewall holes 200 is from 1 to about 10, and the number the holes 200 in the side wall in another embodiment is from 1 to 2.

[0017] In one embodiment of the present invention, the vibrator 100 is directly connected to the container 110 and has substantially the same dimensions as the dimensions of the container 110 on the connecting surfaces, so the connection fields of the respective surfaces of the vibrator 100 and the container 110 are substantially the same as shown in Figs. 1, 3B, 3C, 3D, 3E, 3H and in Fig. 4. In another embodiment of the present invention, shown in Figs. 2, 3A, 3F and 3G, the dimensions of the vibrator 100 are larger or smaller compared to the dimensions of the container 110 on the connecting surfaces. Referring to the embodiments of the present invention shown in Fig. 5, the vibrator 100 may also be connected to the container 110 via a mechanical spacer or integral pin 130 as shown in Fig. 5A, or through an air gap 140 as shown in Fig. 5B . The vibrator 100 can also be connected to the container 110 at the side of the container 110 (embodiment not shown). The vibrator 100 may also be located directly or partially inside the container 110 (embodiment not shown).

[0018] The direction of the drug ejection holes 150 shown in Figures 1, 2, 3A to 3F, 4 and 5 is substantially normal or perpendicular to the upper surface of the vibrator 100 or to the plane of connection between the vibrator 100 and the container 110 while the direction of the holes 200 in the side wall it is substantially parallel to the upper surface of the vibrator 100 or to the plane of connection between the vibrator 100 and the container 110. However, another direction of the holes 150 and 200 may be used, as shown in Figures 3G and 3H, where the drug ejection holes 150 are not in a normal or perpendicular position to the top surface of the vibrator 100 or to the plane of connection between the vibrator 100 and the container 110 and the holes 200 in the side wall are not substantially parallel to the upper surface of the vibrator 100 or to the plane of connection between the vibrator 100 and the container 110.

[0019] In the operation of the exemplary embodiment of the present invention, after the vibrator 100 has been activated and the vibrations initiated, the vibration energy is transferred to the container 110 while the drug substance is ejected from the container 110 through at least one drug ejection opening 150. In one embodiment of the present invention, a synthetic fluid stream is generated through the drug ejection opening 150, which may be a gas or a gas / drug mixture. The synthetic stream is characterized in that the fluid moves in both directions through the orifice 150 with simultaneous vortexing on both sides of the orifice. The synthetic stream of gas or liquid is known to those skilled in the art and is characterized by high speed streams of gas or streams of other fluid flowing out of the opening in the closed chamber, the fluid repeatedly entering and leaving the chamber through the opening, so the fluid leaving the chamber is replenished fluid flowing into the chamber from the outside. Reference is made herein to US Patent Publication US 2005/0183724 Gumaste and Bowers, which describes a synthetic stream. Due to the gas movement through the opening in both directions, the synthetic streams can last indefinitely. The production of synthetic streams may require the generation of acoustic waves, which can be generated e.g. using piezoelectric vibrators, and may require a combination of specific parameters, including frequencies, hole sizes, and container shape and dimensions, to produce strong, supported and reproducible synthetic streams.

[0020] Referring now to Fig. 6, an embodiment of the present invention is shown in operation, in which, after actuating the vibrator 100, the opening 200 in the side wall allows outside air or gas to flow into the container 110 (as schematically indicated by arrow 205), and thus facilitates the efficient discharge of the drug 120 from the drug ejection hole 150 (as schematically indicated by arrow 207), increasing the ejection speed and amount of drug substances, which can be thrown out of the container 110.

[0021] Referring now to Fig. 7, an embodiment of the present invention is shown as a schematic representation of a dry powder inhaler comprising container 110, vibrator 100 and flow channel 300. The flow channel 300 shown in Fig. 7A is in the form of a cross flow channel so that air flows generally perpendicular to the discharge direction of the drug substance 120 from the container 110, which discharge direction is indicated by arrow 207. The flow channel 300 is shown in Fig. 7B in a kind of parallel flow channel, whereby the air flows generally parallel to the ejection direction of the drug substance 120 from the container 110, which ejection direction is indicated by arrow 207. A number of intermediate flow channel and container systems 300 are possible , as a result of which the air follows a more complex path intermediate between the parallel flow and the cross flow (embodiment not shown). After inhalation by the patient, air flows through the flow channel 300, with air entering as indicated by arrows 310 and exiting the device for inhalation as indicated by arrows 320.

[0022] When the vibrator 100 is actuated, the drug substance 120 is comminuted, aerosolized and ejected from the container 110 through the drug ejection opening 150. The shredding, aerosolization and ejection cycle of the drug substance 120 does not necessarily take place in the order given, because all three processes can occur simultaneously or sequentially in any order depending on the process parameters, and the final result is the drug substance 120 being discharged from the container 110 through the opening 150 to drug ejection and drug substance 120 appears as an aerosol in the flow channel 300. The drug aerosol 120 is then captured by an air stream 310 outside the container 110, as a result of which the drug substance 120 is delivered to the inhaler patient, as indicated by arrows 320. The inflow of outside air through the opening 200 in the sidewall, as indicated by arrow 205, facilitates the process comminution, aerosolization and ejection 120 through the ejection apertures 150.

[0023] Referring now to Figure 8, an embodiment of the present invention is schematically illustrated in the form of a dry powder inhaler with an inhaler body 480, in which a series of inhaler components, including container 110, are arranged inside and outside the inhaler body 480; vibrator 100; flow channel 300; electronic board and system 462 for electrically driving the vibrator 100 and other electronic components of the inhaler. The 464 battery is used to power electronic systems and the vibrator, which battery can be any source of energy, such as a set of batteries, which can be a galvanic battery or accumulator, or a fuel cell. Other optional components of the inhaler shown in Fig. 8 there are piercing means 400, for piercing the drug ejection holes and / or sidewall holes in the container or blister 110, additional containers of a single drug dose 450, a sensor 420 for sensing and detecting inhalation by the patient, adapted to detect the user's inspiratory air flow, as indicated by arrows 310, connected to the electronic system 462 to activate the vibrator 100 and the ejection and aerosolization process of the drug. The sensor 420 may advantageously, in conjunction with the electronic board and system 462, detect the presence and strength of air flow in the inhaler and optionally the air flow direction. Patient feedback circuit devices 460 and 466 provide the patient with sensory feedback, as well as optional information about dose counters, and displays indicate to the user drug delivery status and various options. The arrow 320 symbolizes the air inhaled by the patient. The duct 220 provides external air access to the opening 200 in the side wall, so that when the vibrator 100 is actuated, external air can flow into the container 110 as indicated by arrow 205.

[0024] Referring now to Fig. 9, schematically illustrated are embodiments of the present invention in the form of dry powder inhalers with a reusable container 118, in which the drug substance 120 is provided in disposable packages 610 and 710 disposed on carrier tape 620 and 700. The direction of movement of the band is marked by an arrow 650. In the embodiment shown in Fig. 9A, individual drug packets 610 are covered by a cover tape 630 that collects on spool 635, thereby exposing drug substance 120 to be ejected through drug ejection holes 150. In another embodiment (not shown), the cover tape 630 is not removed from the individual drug packs 610, but is pierced before or after entering the reusable container 118, thereby exposing the drug substance 120 to be thrown through the drug ejection holes 150 . The reusable container 118 contacts the carrier band 620 via a compressible seal or O-ring 600. When inhaled by the patient, the vibrator 100 is actuated, thereby ejecting the drug substance 120 through the drug ejection holes 150. Outside air enters container 118 as indicated by arrow 205 through sidewall opening 200, while the aerosol drug substance is inhaled by the patient as indicated by arrow 320, and air entering flow channel 300 is indicated by arrow 310.

[0025] Similarly in Fig. 9B, the drug substance 120 is supplied in disposable packages 710 containing pockets of folded tape arranged in two on carrier tape 700. The direction of movement of the tape is indicated by arrow 650. Pulling of the carrier tape 700 opens the tape pocket 710 under container 118 reusable wherein the reusable container 118 contacts the carrier tape 700 via a compressible seal or O-ring 600. When inhaled by the patient, the vibrator 100 is actuated, thereby ejecting the drug substance 120 through the drug ejection opening 150. Outside air enters container 118 as indicated by arrow 205 through sidewall opening 200, while the aerosol drug substance is inhaled by the patient as indicated by arrow 320, and air entering the flow channel 300 is indicated by arrow 310.

[0026] Piercing of the holes in the container 110 can be done immediately before delivery of the drug substance to the patient. In one embodiment, the invention operates as follows: the inhaler is put into use, the openings in the drug container are pierced either simultaneously or sequentially by the piercing means 400, or the cover material 630 in the case of packets 610 on the tape is removed or sheared, or the bag 710 in the tape is opened and then the drug 120 is aerosolized as the patient inhales through the inhaler. In other embodiments, the opening or puncturing of individual drug packages is performed automatically when the patient inhales, by electromechanical or mechanical means, such as a spring or electromechanical actuator or heat punch, all of which are optionally actuated by an inhalation detecting sensor 420.

[0027] In another embodiment, as shown in Figure 10, the reusable container 118 is for delivering the drug substance 120, wherein the sidewall opening 200 is connected through a channel 910 to a drug substance source 900. The drug source 900 has at least two or more doses of drug substance 120. The amount of drug substance 120 delivered to the patient is controlled by adjusting the device activation time or by a sensor detecting the actual amount of drug substance 120 controlling the activation of the vibrator 100.

[0028] Other embodiments and uses of the invention are also contemplated. The medicinal substance to be administered to the patient may be a vaccine, DNA or RNA fragment, painkillers, asthma medications, emphysema, chronic bronchitis, cystic fibrosis, COPD, diabetes medications, or any other medicine that may prevent or treat the condition or which may alleviate the symptoms of the condition. when administered to a patient in the form of an aerosol having local and / or systemic effects. [0038] In another embodiment, the present invention is used for delivering an aerosol medicament not for inhalation but for nasal or oral administration, to the eyes or on the skin surface. In another embodiment, the liquid therapeutic preparation is administered by the present invention.

EXAMPLE 1 [0029] A model inhalation device similar to the structures shown in Fig. 7A, capable of operating with blisters having only drug ejection holes or drug ejection holes and sidewall holes, was used for experimental tests. The device had built-in electronics and a detachable flow channel. As a vibrator, a piezoelectric transducer was used based on a modified air transducer manufactured by Murata Electronics from Japan. The piezoelectric actuator was started for 4 seconds and controlled for 90% with a frequency of 33 kHz and for 10% of the time with a frequency of 34.4 kHz, and switching between these frequencies took place at a rate of 10 Hz (working cycle). To operate the piezoelectric actuator, an alternating voltage of about 160-200 V was generated, generated by a stepped-type flyback converter. A blister pack with an approximately hemispherical top and flat bottom, containing a model dry aerosolization powder, served as a disposable container. The height of the blister was about 5.5 mm and the diameter of the blister chamber at the base was about 11 mm, and the shape of the blister was similar to the shape shown in Fig. 3C. The blister was made of aluminum foil coated with polymer layers. The upper and lower parts of the blister were heat-sealed. In the upper (hemispherical) part, the blister was pierced with four (4) drug ejection holes using metal needles with a diameter of 320 μm, as in Figure 3C, where only two drug ejection holes 150 are shown. In some experiments, the side wall of the top of the blister was pierced with at least one hole 200 in the side wall, as in Fig. 3C. A needle with a diameter of 240 μm was used to pierce the hole in the side wall. The air flow through the flow channel was set at 30 liters per minute (l / min) using a vacuum pump. The blister was filled with varying amounts of model dry powder and a weight release test from the blister was carried out under varying experimental conditions.

[0030] The results of the experiments are shown in Table 1. As can be seen from Table 1, unexpected results were obtained, with the presence of one or more sidewall holes resulting in a significant increase in the ejection speed of the drug as well as the amount of powder that can be effectively ejected compared with conditions without sidewalls. Comparison of samples 1 and 2; 2 and 2a; 3 and 3a; 7 and 7a; 9 and 9a indicates that the sidewall opening resulted in a very significant increase in powder release from the blister under the same conditions as compared to blisters without sidewall openings. Also comparison of tests 4 and 4a; 5 and 5a; 6 and 6a indicates that no significant release was detected without piezoelectric actuation, even if there were holes in the side wall. The holes in the sidewall made it possible to release very large amounts of powder from the blister by weight, i.e. in the order of 3-6 mg, but also very large amounts of powder, e.g. in the order of 15-20 mg and even 37 mg, and it was practically impossible observe the ejection of powder from the blisters under the same conditions without holes in the side wall as demonstrated in tests 3 and 3a; 7 and 7a and 8 and 9a. It was visually detected that release from blisters with sidewall holes occurred quickly, sometimes in less than a second, and faster compared to blisters without sidewall holes that were not completely emptied even within 4 seconds. It was not observed that any significant amount of powder was ejected from the sidewall holes during the tests.

TABLE 1

<td> ##</td><td>Powder in blister, mg</td><td>Holes in the blister</td><td>Procedure dosage</td><td>Powder released from the blister, mg</td><td>Weight release</td><td>Test conditions</td>

<td> 1*</td><td> 5,037</td><td>4 drug ejection holes &amp; sidewall hole</td><td>Piezo on, vacuum pump on</td><td> 4,807</td><td> 95,4%</td><td>Blister with a hole in the side wall moved by piezo</td>

<td> 2</td><td> 4,204</td><td>4 holes for ejecting the medicine</td><td>Piezo on, vacuum pump on</td><td> 1,035</td><td> 24,6%</td><td>Blister pack without side hole, moved by piezo</td>

<td>2a **</td><td> 3,169</td><td>2 holes in the side wall and 4 holes for ejecting the medicine</td><td>Piezo on, vacuum pump on</td><td> 3,061</td><td> 96,6%</td><td>Blister # 2 repeat after punching 2 holes in the side wall</td>

<td> 3</td><td> 19,028</td><td>4 holes for ejecting the medicine</td><td>Piezo on, vacuum pump on</td><td> 1,051</td><td> 5,5%</td><td>Blister pack without side hole, moved by piezo</td>

<td>3a</td><td> 17,977</td><td>Hole pierced in</td><td>Piezo on,</td><td> 17,903</td><td> 99,6%</td><td>Blister # 3 replay with</td>

<td> ##</td><td>Powder in blister, mg</td><td>Holes in the blister</td><td>Procedure dosage</td><td>Powder released from the blister, mg</td><td>Weight release</td><td>Test conditions</td>

<td> *</td><td></td><td>sidewall and 4 drug ejection holes</td><td>enabled pump vacuum</td><td></td><td></td><td>hole in the wall the side</td>

<td> 4*</td><td> 12,215</td><td>Pierced side wall and 4 drug ejection holes</td><td>enabled pump vacuum for 20 seconds</td><td> 0,634</td><td> 5,2%</td><td>Blister with a hole in the side wall with air flow to the vacuum pump for 20 s; without moving with piezo</td>

<td>4a_*</td><td> 11,581</td><td>Pierced side wall and 4 drug ejection holes</td><td>Piezo on, vacuum pump on</td><td> 11,483</td><td> 99,2%</td><td>Blister # 4 replay with piezo movement</td>

<td> 5*</td><td> 7,388</td><td>Pierced side wall and 4 drug ejection holes</td><td>enabled pump vacuum for 20 seconds</td><td> 0,072</td><td> 1,0%</td><td>Blister with a hole in the side wall of air flow to the vacuum pump for 20 s; without moving with piezo</td>

<td>5a_*</td><td> 7,316</td><td>Pierced side wall and 4 drug ejection holes</td><td>Piezo on, vacuum pump on</td><td> 7,22</td><td> 98,7%</td><td>Blister # 5 (with a hole in the side wall), replay with piezo movement</td>

<td> 6*</td><td> 5,147</td><td>Pierced side wall and 4 drug ejection holes</td><td>enabled pump vacuum for 20 seconds</td><td> 0,025</td><td> 0,5%</td><td>Blister with a hole in the side wall of air flow for 20 s; without moving with piezo</td>

<td>6a_*</td><td> 5,122</td><td>Pierced side wall and 4 drug ejection holes</td><td>Piezo on, vacuum pump on</td><td> 5,015</td><td> 97,9%</td><td>Blister # 6 (with a hole in the side wall), replay with piezo movement</td>

<td> 7</td><td> 17,139</td><td>4 ejection holes pierced drug</td><td>Piezo on, vacuum pump on</td><td> 1,67</td><td> 9,7%</td><td>Blister pack without side hole moving with piezo</td>

<td>7a_*</td><td> 15,469</td><td>Pierced side wall and 4 drug ejection holes</td><td>Piezo on, vacuum pump on</td><td> 14,482</td><td> 93,6%</td><td>Blister # 7, repeat with a hole in the side wall</td>

<td> 8*</td><td> 23,949</td><td>Pierced side wall and 4 drug ejection holes</td><td>Piezo on, vacuum pump on</td><td> 23,636</td><td> 98,7%</td><td>Blister with a hole in the side wall of moving with piezo</td>

<td> 9</td><td> 37,582</td><td>4 ejection holes pierced drug</td><td>Piezo on, vacuum pump on</td><td> 0,229</td><td> 0,6%</td><td>Blister pack without side hole moving with piezo</td>

<td>9a_*</td><td> 37,353</td><td>Pierced side wall and 4 drug ejection holes</td><td>Piezo on, vacuum pump on</td><td> 37,105</td><td> 99,3%</td><td>Blister # 9, repeat with a hole in the side wall</td>

<td> ##</td><td>Powder in blister, mg</td><td>Holes in the blister</td><td>Procedure dosage</td><td>Powder released from the blister, mg</td><td>Weight release</td><td>Test conditions</td>

<td colspan="7">* Tests with at least one hole in the side wall</td>

EXAMPLE 2 [0031] Experimental tests were carried out using an experimental set similar to the one described in example 1, but with its own piezoelectric actuator G9 tuned to a resonance frequency of 34.5 kHz, operating 90% of the time at a frequency of 34 kHz, and by 10% time with a frequency of 35 kHz, with a switchover between these frequencies of 10 Hz (duty cycle). To operate the piezoelectric actuator, an alternating voltage of approximately 160-200 V was generated, generated by a stepped flyback converter. Powdered insulin was used and very good release from the blister was demonstrated. A much larger amount of powder was used in the experiment compared to typical amounts of 1-3 mg per blister. In two trials, a blister containing 5 mg of powdered drug and having a sidewall opening in addition to four drug ejection holes showed 94.6% and 95.9% release of powder from the blister during a 4 second piezoelectric actuator operation time. It was observed that the actual release time was less than 4 seconds of the piezoelectric actuator operating time. Thus, surprisingly much more powder is released from the blister having a side wall opening compared to the same blisters, but without a side wall opening where only about 80 to 95% release is obtained when filled with much smaller amounts of insulin, i.e. up to about 2 mg.

EXAMPLE 3 [0032] Using an experimental set-up similar to the set-up described in Example 2, a model drug powder mixed with lactose was tested, obtaining very good release, with 6 mg of the mixture released at 97.5% by weight release from a blister having a hole in sidewall. The same blisters, but without a sidewall hole, showed significantly less weight release.

EXAMPLE 4 [0033] The experiments were carried out with a set similar to the experimental set-up described in example 1, but with an unmodified Murata Electronics air transducer serving as a piezoelectric actuator having a resonance frequency of 40 kHz. Other piezoelectric actuators with different resonance frequencies can be used, usually in the range of 30 to 45 kHz. The air flow through the device was set at 28 l / min using a vacuum pump. Flat disposable plastic blisters having a cone-shaped top and a truncated cone with a flat bottom of metal foil similar to the blisters shown in Figs. 3F and 3D, respectively, were used as disposable containers containing the model aerosolization powder. The conical top blisters had a purely conical top, while the truncated blisters had a bevel top with a diameter of about 2 mm. The height of the blisters was about 4.5 mm and the diameter of the blister chamber at the base was about 8 mm. The tops of the blisters are made of PVC or PETG hot formed and heat sealed with the bottom of the blister made of polymer-coated aluminum foil. In the upper part of the blisters, 3 holes were pierced with metal needles with a diameter of 240 μm, thus creating drug ejection holes, as in Fig.

3D. In some experiments, the sidewall of the conical blister portion was pierced with at least one hole in the sidewall, as in Figs. 3A, 3B, 3C. A 240 μm diameter needle was used to pierce the side wall hole. The results of these experiments are shown in Table 2.

TABLE 2

<td> ##</td><td>Shape blister</td><td>Powder blister pack, mg</td><td>Time for piezo</td><td>Powder released from the blister, mg</td><td>Weight release</td><td>Test conditions</td>

<td> 10 _*</td><td>Cone</td><td> 4,006</td><td>4 sec</td><td> 3,902</td><td> 97,4%</td><td>Hole in the side wall</td>

<td> 11 _*</td><td>Cone</td><td> 5,514</td><td>4 sec</td><td> 5,454</td><td> 98,9%</td><td>Hole in the side wall</td>

<td> 12</td><td>Cone</td><td> 3,764</td><td>4 sec</td><td> 2,516</td><td> 66,8%</td><td>Without a hole in the side wall</td>

<td> 13 _*</td><td>Cone cut</td><td> 6,769</td><td>2 sec</td><td> 6,617</td><td> 97,8%</td><td>Hole in the side wall</td>

<td> 14</td><td>Cone cut</td><td> 3,194</td><td>2 sec</td><td> 2,984</td><td> 93,4%</td><td>Without a hole in the side wall</td>

<td colspan="7">* Tests with at least one hole in the side wall</td>

[0034] As can be seen from Table 2, unexpected results were obtained, whereby a significant increase in the powder ejection speed as well as the amount of powder that can be ejected from the blister was experimentally observed compared to conditions without sidewall openings.

EXAMPLE 5 [0035] Tests of air flow into and out of the blister having a series of drug ejection holes and at least one hole in the side wall were conducted. The experimental set-up was similar to the set-up described in example 1, but in these experiments there was no powder in the blisters and no air flow was generated using a vacuum pump. In addition, the plastic capillary was connected to the opening in the side wall from the outside. In the first test, when the blister was moved intermittently by means of a piezoelectric actuator, a sensitive, light flag was observed moving towards the inlet of the plastic capillary, thus recording the vacuum and / or air flow through the capillary and through the opening in the side wall into the blister while air was ejected through the drug ejection holes on top of the blister.

[0036] In the second trial, a second light flag was placed over the drug ejection holes on top of the blister, and the light flag was moved upwards, detecting streams flowing from the drug ejection holes. At the same time, the movement of the first sensitive, light flag towards the inlet of the plastic capillary was observed, thereby recording the vacuum and / or air flow through the capillary and through the opening in the side wall to the blister, the first flag being sucked into the plastic capillary inlet and blocked him. In addition, it was observed that when the first flag was removed manually so that it did not block the plastic capillary inlet, and thus did not block the air supply to the side wall opening, the second flag indicated a significant increase in air streams flowing from the drug ejection holes on top of the blister. . Thus, it turns out that the opening in the side wall helped to increase the production of air streams flowing out of the blister by providing air supply to the blister.

EXAMPLE 6 [0037] Experiments were carried out in an experimental set similar to the experimental set-up described in example 2, but without starting the vacuum pump and drawing in air through the flow channel of the experimental set-up. In the experiments, lactose was used as a model dry powder. Only 28.4% release was observed in a blister with no opening in the side wall, filled with 6.390 mg lactose. In side blisters filled with 5.013 and 6.560 mg lactose powder, releases of 80.8% and 93.4% were observed, respectively. Thus, it turns out that the opening in the side wall helped to increase the production of laminar streams flowing out of the blister by providing air supply to the blister, with unexpected results in which a significant increase in the speed of powder ejection was observed, as well as the amount of powder that can be ejected, compared to conditions without sidewall holes.

[0038] Although the present invention has been described in particular with reference to specific preferred embodiments, it is obvious that many alternatives, modifications and variations will be apparent to those skilled in the art in light of the description above. It is therefore to be understood that the appended claims will include any such alternatives, modifications and variations as falling within the real scope of the present invention.