Inhaler

1/28

INHALER

Modalities of the present invention are related to medical devices and devices for drug delivery, specifically, the distribution of drugs for aerosol treatment, for inhalation of drugs for delivery to the lungs and gastrointestinal tract, and for the delivery of intranasal drugs.

Devices for dispensing pharmacological substances for aerosol treatment, including delivery via inhalation, are known in the art, examples including US patents No. 5,694,920, 6,026,809, 6,142,146, all to Abrams and Gumaste, 3,948 .264, by Wilke et al., 6,971,383, by Hickey et al., 7,117,867, by Cox et al., 6,901,929, by Burr et al., 6,779,520, by Genoa et al. , 6,748,944 by Delia Vecchia et al., 5,590,645 by Davies et al .. The above patents also provide an overview of various devices and techniques for treatment by aerosol and inhalation.

A range of drug delivery devices for inhalation and for aerosol treatment are known, including metered dose inhalers, nebulizers, dry powder inhalers, thermal vaporizers, and other systems, with differences related to treatment methods and efficiency by aerosol and distribution of pharmacological substances to patients. Metered dose inhalers typically use a pressurized gas for the aerosol treatment of pharmacological substances. The disadvantages of these inhalers are related to the difficulties in controlling the distributed dose of pharmacological substances and the speed of

2/28 aerosol particles, resulting in particles spraying and depositing on various surfaces in a patient's mouth and throat. Inhalation devices delivering substances with drugs as a dry powder are known as dry powder inhalers. Passive dry powder inhalers rely on the patient's inspiratory effort for breakdown and aerosol treatment of pharmacological substances for inhalation, while active dry powder inhalers typically add additional energy, such as mechanical or electrical energy, to improve efficiency of the breakdown of the powder and the aerosol treatment, to decrease the inspiratory effort needed by the patient, and to obtain a better inspiratory flow regardless of the performance of the inhaler. Typically for the delivery of pharmacological substances to a patient's lungs through inhalation, the size of the aerosol particle with drug must be less than about 10 microns, more preferably, less than about 6 microns, and for deeper distribution in the lung less than about 3.3 microns. Larger particles will be distributed to the patient's mouth and throat and, as a result, will be distributed to the patient's gastrointestinal tract. There is a need to increase the amounts of a drug for dry powder inhalers that are capable of aerosolizing during a single inhalation by a patient, for example, within one to three and four seconds. There is also a need to increase the speed of disintegration and aerosol treatment of powders in dry powder inhalers.

Dry powder inhaler devices described in

3/28 US patents No. 5,694,920, 6,026,809, 6,142,146, all from Abrams and Gumaste, use a vibrating device to break down and aerosolize the dry powder medication to be delivered to the patient as an aerosol. US patent publication 2005/0183724, by Gumaste and Bowers, describes a method and apparatus for dispensing medicine based on a synthetic jet.

Briefly, one embodiment of the invention comprises a device for inhaling pharmacological substances for treatment by aerosol, in which a high frequency vibrator is coupled to a container filled with a dry powder pharmacological substance. Vibrations from the vibrator result in breakdown, aerosol treatment and ejection of the drug substance into the container for inhalation by a patient. One or more openings in the container are substantially opposed to the vibrator and are used primarily for the ejection of drug, through synthetic blasting or other powder ejection mechanisms from the container. At least one other opening in the container is used primarily for the entry of gas or air outside the container.

Unexpected results, such as those illustrated in the examples below, are obtained when performing experimental tests of the modalities of the present invention for use as an inhalation and / or aerosol treatment device, with observations of aerosol treatment and powder ejection substantially faster dry times, as well as the ability to aerosolize substantially greater amounts of dry powders versus the technique

Previous 4/28.

Figure 1 is a view is a cross-sectional view of an embodiment of the present invention illustrating a container with a pharmacological substance coupled to a vibrator.

Figure 2 is a cross-sectional view of an embodiment of the present invention illustrating a container with a pharmacological substance coupled to a vibrator.

Figure 3 is a cross-sectional view of various embodiments of the present invention illustrating containers with a pharmacological substance coupled to vibrators.

Figure 4 is a cross-sectional view of an embodiment of the present invention illustrating a container with a pharmacological substance coupled to a vibrator.

Figure 5 is a cross-sectional view of the various embodiments of the present invention illustrating containers with a pharmacological substance coupled to vibrators.

Figure 6 is a cross-sectional view of an embodiment of the present invention illustrating a container with a pharmacological substance coupled to a vibrator.

Figure 7 is a cross-sectional view of modalities of the present invention illustrating an inhalation device.

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

Figure 9 is a cross-sectional view of modalities of the present invention illustrating inhalation devices.

5/28

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

In the drawings, similar reference numbers refer to similar parts or characteristics through different views.

A cross-sectional view of an embodiment of the present invention is schematically illustrated in Figure 1. A vibrator 100 is coupled to a blister or container 110 containing a substance or pharmacological substances 120. Vibrator 100 can be an activating piezo or transducer piezo, or a mechanical vibrator, an electromagnetic vibrator, a restrictive magnet element, or other vibration mechanism, as known in the art. In one embodiment, an activating piezo is typically used consisting of a ceramic piezo element and a metallic body, both from a unimorphic and a bimorph design. The piezo activator designs known in the art can be used, including, but not limited to, air transducers and electrical piezo detector elements. In addition, polymeric piezo materials and activators based on polymeric piezo materials can be used as vibrators. Activating piezo-based vibrators are energized, as known in the art, by supplying electrical energy, typically alternating electrical current of appropriate frequencies and amplitudes, for the component piezo. The coordinated piezo activators for the various resonant frequencies can be used, for example, with resonant frequencies in the range of about 1 kHz to about 100 kHz, more

6/28 typically in the ultrasonic range of about 30 kHz to about 45 kHz, and the amplitude of mechanical oscillations from about 1 micron to about 50 microns from peak to peak. The vibrator 100 is able to vibrate, either with a fixed or variable frequency, or with several frequencies simultaneously, and to transmit the vibratory movement to the container 110. The frequency of vibration can vary from less than 1 Hz to hundreds of kHz, more typically, the frequency of vibration is about 25 kHz to about 50 kHz. In the embodiment illustrated in Figure 1, the vibrator 100 is in direct contact with the container 110 and thus is directly coupled to the container 110.

The container 110 has at least one drug ejection opening 150 substantially opposite the vibrator 100 and serving primarily for the ejection of the pharmacological substance 120. However, external air or gas may also enter the container through openings 150. Additionally, the container 110 has at least one side wall opening 200, which is not substantially opposite to vibrator 100. The side wall opening 200 is not used for the ejection of the pharmacological substance, but it allows air or gas to enter the container 110 on the external side and thus facilitates the breakdown, aerosol treatment and ejection of the pharmacological substance 120 from the container 110 through the drug ejection openings 150.

Pharmacological substance or substances 120 are provided as a dry powder, but other forms of pharmacological substance are possible, such as liquid or gas. A single-component pharmacological substance (drug

7/28 natural) can be used, as well as various pharmacological substances, or pharmacological substances combined with excipients, such as lactose, or combinations thereof. Other additives, such as pharmaceutically inactive ingredients, disintegrating agents, etc., can also be added to the pharmaceutically active substance or pharmacological substances.

Container 110 is made of metal, plastic or composite materials. In an embodiment of the present invention, container 110 is a blister pack made of cold formed or thermoformed film, with film materials being polymer, foil, multilayered metal-polymer coated films, and films polymeric or coated with metal barrier. In an embodiment of the present invention illustrated in Figure 2, container 110 is a single-use blister pack generally comprising a conical, pyramidal, semi-spherical, elliptical, or similar upper part 111 and a flat lower part 112, wherein the upper part 111 and lower part 112 are hermetically sealed to each other by methods known in the art including, but not limited to, adhesion, heat sealing, pressure sealing, ultrasonic sealing and the like. The fusion or adhesion area 113 is also schematically illustrated in Figure 2, in the contact area between the upper part 111 and the lower part 112. The vibrator 100 is illustrated in direct contact with the flat lower part 112 of the container 110.

A number of possible shapes and shapes of the blister pack or container 110 are schematically illustrated in Figures 3A through 3F, including tapered part shapes

8/28 flat top (Figures 3A, 3D, 3G), cylindrical shapes (Figures 3B and 3E), which is also illustrated in Figure 4; and semi-spherical or conical shapes (Figures 3C, 3F, 3H).

The dimensions of the container 110 in one embodiment are from about 1 mm to about 30 mm in diameter, and from about 1 mm to about 30 mm in height, however, larger or smaller containers 110 can be used accordingly. with that invention. In another embodiment, the diameter of the container 110 is about 3 to about 12 mm, while the height of the container 110 is about 3 to about 12 mm.

The dimensions of the drug ejection openings 150 are from about 10 microns to about 1000 microns, with preferred dimensions from about 50 microns to about 500 microns. The dimensions of the side wall openings 200 are from about 1 micron to about 1000 microns, with preferred dimensions from about 25 microns to about 500 microns. In one embodiment of the present invention, the total area (cross section) of all drug ejection openings 150 is at least two or more times the total area (cross section) of all sidewall openings 200. In another embodiment of the present invention, the total area (cross section) of all drug ejection openings 150 is at least five times the total area (cross section) of all sidewall openings 200.

The number of drug ejection openings 150 is about 1 to about 10, with the number of drug ejection openings 150 in another embodiment being about 3 to about 6. The number of wall openings side 200 is about 1 to about 10, with the number of side wall openings 200 in another embodiment

9/28 being 1 to 2.

In one embodiment of the present invention, the vibrator 100 is directly coupled to the container 110 and has substantially the same dimensions as the dimensions of the container 110 on the coupling surfaces, so that the coupling areas of the corresponding surfaces of the vibrator 100 and the container 110 they are substantially the same, as illustrated in Figures 1, 3B, 3C, 3D, 3E, 3H and in Figure 4. In another embodiment of the present invention, illustrated in Figures 2, 3A, 3F and 3G, the dimensions of the vibrator 100 are larger or smaller versus the dimensions of the container 110 on the coupling surfaces. With reference now to the modalities of the present invention illustrated in Figure 5, the vibrator 100 can also be coupled to the container 110 through a mechanical spacer or integral pin 130, as shown in Figure 5A, or through a spacing 140, as shown in Figure 5B. The vibrator 100 can also be coupled to the container 110 from one side of the container 110 (embodiment not shown). Vibrator 100 can also be arranged directly or partially within container 110 (embodiment not shown).

The directionality of the drug ejection openings 150 shown in Figures 1, 2, 3A through 3F, substantially normal or perpendicular to and 5 and the upper surface of the vibrator 100, or of the coupling plane between vibrator

100 container 110, while directionality of the side wall openings 200 is substantially parallel to the upper surface of the vibrator 10 0, or to the coupling plane between the vibrator 110 and the

10/28

<td>container 110.</td><td>Yet,</td><td>another</td><td>directionality</td><td>of</td>

<td>openings 150 and</td><td>2 00 can</td><td>be used,</td><td>as illustrated</td><td>in</td>

<td>Figures 3G and 3H,</td><td>in which</td><td>openings</td><td colspan="2">drug ejection</td>

150 they are not normal or perpendicular to the upper surface of the vibrator 100, or to the coupling plane between the vibrator 100 and the container 11, and the side wall openings 200 are not substantially parallel to the upper surface of the vibrator 100, or to the coupling plane between the vibrator 100 and the container 110.

In the operation of a modality of the present invention, by activating the vibrator 100 and initiating vibrations, the vibration energy is transferred to the container 110, while the pharmacological substance is ejected from the container 110 through at least one ejection opening. drug 150. In one embodiment of the present invention, a jet of synthetic fluid, which can be gas or a drug / gas mixture, is established through the drug ejection port 150. A synthetic jet is characterized by the fact that the fluid is moving in both directions through the opening 150 with the simultaneous formation of vortices on both sides of the opening. Synthetic gas or liquid blasting is known to those skilled in the art and is characterized by high-speed jets of gas or other fluid emanating from an orifice in a closed chamber, with fluid entering and leaving the chamber multiple times through an orifice. , so that the flow expelled from the chamber is replenished by the flow entering the chamber from the outside. Reference is made to the published patent application US 2005/0183724, by Gumaste and Bowers, which describes jets

11/28 synthetic. Due to the movement of the gas through an orifice in both directions, synthetic jets can continue indefinitely. The formation of synthetic jets may require the establishment of acoustic waves that can be established, for example, by piezo vibration, and may require a combination of specific parameters, including frequencies, orifice dimensions and shape and container dimensions to establish strong synthetic jets. , sustainable and reproducible.

Reference is now made to Figure 6, in which a modality of the present invention in operation is illustrated, in which, by activating the vibrator 100, the side wall opening 200 allows external air or gas to enter the container 110 (as schematically illustrated) by arrow 205) and thus facilitate the efficient ejection of pharmacological substance 120 from drug eject opening 150 (as schematically illustrated by arrow 207), increasing the ejection speed and the quantities of pharmacological substances capable of being ejected from the container 110.

Referring now to Figure 7, one embodiment of the present invention is illustrated as a schematic representation of a dry powder inhaler, comprising a container 110, a vibrator 100 and a flow channel 300. The flow channel 300 illustrated in Figure 7A it is of a cross-flow type, in which air is generally flowing perpendicularly to the direction of ejection of the pharmacological substance 120 from the container 110, said ejection direction is indicated by the arrow 207. The flow channel 300 shown in Figure 7B is of the parallel flow type, where the air is generally flowing parallel to the

12/28 direction of ejection of pharmacological substance 120 from container 110, with the direction of ejection indicated by the arrow 207. A range of intermediate arrangements of flow channel 300 and container 110 are possible, where air is moving in a more complex intermediate path between the parallel flow and the cross flow (modality not shown). Upon inhalation by the patient, air is flowing through flow channel 300, with air entering as illustrated by arrows 310 and exiting the device for inhalation, as illustrated by arrows

320 .

Upon activation of the vibrator 100, the pharmacological substance 120 is disintegrated, transformed into an aerosol, and ejected from the container 110 through drug ejection openings 150. The sequence of disintegration, aerosol treatment, and ejection of the pharmacological substance 120 does not necessarily proceed in the above order, in which all three processes can be occurring simultaneously, or consecutively in any order depending on the process parameters, with the final result being the pharmacological substance 120 ejected from container 110 through drug ejection opening 150, and the drug substance 120 aerosolized appearing within the flow channel 300 drug substance 120 is then airflow 310 on the outer side of the container 110, resulting in the drug substance 120 being delivered for inhalation by the patient, as illustrated by the arrow 320. The entry of external air through the side wall opening 200, as illustrated by arrow 205,

The aerosol collected by

13/28 facilitates the process of disintegration, aerosol treatment, and ejection of the pharmacological substance 120 through the drug ejection openings 150.

With reference now to Figure 8, one embodiment of the present invention is illustrated schematically of a dry powder inhaler with an inhaler body 480, in which various and inhaler components are arranged inside and outside the inhaler body 480, including a container 110, a vibrator 100, a flow channel 300, a printed and electronic circuit 462 serving to electrically drive the vibrator 100 and other electronic components of the inhaler. A 464 battery is used to energize the electronic components and the vibrator, said battery can be from any source of energy, such as a battery pack, which can be a primary or rechargeable battery, or a fuel cell. Other optional components of the inhaler illustrated in Figure 8 are a piercing device 400, for piercing the drug ejection openings and or the sidewall openings in the container or blister 110; 450 additional single-dose drug containers; a sensor 420 for sensing and detecting inspiration by a user or patient, adapted to detect the inspiratory air flow by a user, as illustrated by arrows 310 and interconnected to electronic circuit 462 to activate the vibrator 100 and the aerosol treatment process and drug ejection. The sensor 420 is preferably capable, together with the printed and electronic circuit 462, of detecting the presence and the force of the air flow in the inhaler and, optionally, the direction of the air flow. The devices

14/28 patient setbacks 460 and 466 are providing sensory feedback to the patient, as well as optional dose counters and indication displays indicating the user the drug delivery status and the various options. Arrows 320 illustrate the air being inhaled by the patient. Channels 220 provide access to the outside air for the side wall opening 200, so that upon activation of the vibrator 10 0 the outside air can enter the container 110, as illustrated by arrows 205.

Referring now to Figure 9, embodiments of the present invention are illustrated as a schematic representation of dry powder inhalers with a multi-purpose container 118, wherein the drug substance 120 is provided in single-use drug packs 610 and 710 arranged in a carrier tape 620 and 700. The direction of movement of the tape is illustrated by the arrow 650. In the embodiment illustrated in Figure 9A, single-use drug packs 610 are covered with a cover strip 630, which is collected from a reel 635, thereby exposing the drug substance 120 for ejection through drug ejection openings 150. In another embodiment (not shown), the cover strip 630 is not removed from single-use drug packs 610, but is punctured before or through the entry of the multi-purpose container 118, thereby exposing the pharmacological substance 120 for ejection through of the drug ejection openings 150. The multi-purpose container 118 is in contact with a carrier tape 620 through the compressible gasket or O-ring 600. Upon inhalation by the patient, the vibrator 100 is activated, thus ejecting the pharmacological substance 120

15/28 through drug ejection openings 150. External air enters container 118, as illustrated by arrows 205, through side wall openings 200, while the pharmacological substance for aerosol treatment is being inhaled by the patient, as illustrated by arrow 320, and air entering flow channel 300 is illustrated by arrow 310.

Similarly, in Figure 9B, pharmacological substance 120 is provided in single-use drug packages 710 comprising tape packages folded over itself, arranged on a carrier tape 700. The direction of movement of the tape is illustrated by arrow 650. Pulling the carrier tape 700 results in the opening of the tape packages 710 under the multi-purpose container 118, with the multi-purpose container 118 in contact with the carrier tape 700 through the compressible gasket or O-ring 600. Upon inhalation by the patient, the vibrator 100 is actuated, thus ejecting the pharmacological substance 120 through the drug ejection opening 150. The external air enters the container 118 as illustrated by arrow 205 through the side wall opening 200, while the substance pharmacological treatment for aerosol treatment is inhaled by the patient as illustrated by arrow 320 and the air entering the flow channel 300, triggered by the patient's inhalation, is illustrated by arrow 310.

Perforation of the openings in the container 110 can be carried out just before delivery of the drug substance to the patient. In one embodiment, the invention operates as follows: the inhaler is activated for use, the openings in the drug container are punctured

16/28 either simultaneously or sequentially by the drilling device 400, or cover material 630, in case the 610 tape-based drug packs are removed or punctured, or a tape-based pouch 710 is opened and then the pharmacological substance 120 is aerosolized as the patient is inhaling through the inhaler. In other modalities, the opening or perforation of individual drug packages occurs automatically by inhaling the patient, through a mechanical or electromechanical device, such as a spring or electromagnetic activator, or micro thermal pore, all optionally activated by the detection sensor inhalation 420.

In another embodiment, as illustrated in Figure 10, the multi-purpose container 118 is used to dispense the drug substance 120, so the side wall opening 200 is connected to a source of drug substance 900 through a conduit 910. A pharmacological substance source 900 has at least two or more doses of pharmacological substance 120. The amount of pharmacological substance 120 delivered to a patient is controlled by the device activation time, or by a sensor detecting the actual amount of pharmacological substance 120 delivered and controlling the activation of vibrator 100.

Other embodiments and applications of the invention are contemplated. The pharmacological substance for distribution to the patient may be a vaccine, fragment of DNA or RNA, medication to treat pain, asthma, emphysema, chronic bronchitis, cystic fibrosis, COPD, treatment for diabetes, or any other medication capable

17/28 to prevent or treat a disease or alleviate symptoms of a disease when distributed as an aerosol to the patient and having a systemic and / or localized effect.

In another embodiment, the present invention is used to deliver a drug for aerosol treatment not for inhalation, but for intra nasal delivery, oral delivery, eye delivery or delivery over the skin surface. In another embodiment, a liquid drug formulation is delivered using the present invention.

EXAMPLE 1

A model of inhaler device similar to the designs illustrated in Figure 7A, capable of working with both blisters having only drug ejection openings and with drug ejection openings and side wall openings, was used in experimental tests. The device had integrated electronic circuits and a removable flow channel. An activating piezo based on a modified air transducer manufactured by Murata Electronics, Japan, was used as a vibrator. The activating piezo was activated for 4 seconds and was activated 90% of the time at a frequency of 33 kHz and 10% of the time at a frequency of 34.4 kHz, switching between these frequencies at a rate of 10 Hz (duty cycle) . Alternating current of approximately 160 to 200 volts generated by a feedback loop (fly back) in one step in the waveform was used to actuate the activating piezo. A blister with an approximately semi-spherical top and a flat bottom was used as a single-use container containing the dry powder model for the treatment

18/28 by aerosol. The height of the blister was approximately 5.5 mm and the diameter of the blister chamber at the base was approximately 11 mm, with the shape of the blister similar to the shape illustrated in Figure 3C. The blister was made of aluminum foil coated with polymeric layers. The upper and lower parts of the blister were heat sealed together. The upper (semi-spherical) part of the blister was perforated with four openings for drug ejection using metallic needles of 320 microns in diameter, similar to that of Figure 3C, in which only two drug ejection openings 150 are illustrated. In some experiments, the side wall of the upper part of the blister was perforated with at least one side wall opening 200, similar to that of Figure 3C. A 240 micron diameter needle was used to pierce the side wall opening. An air flow through the device's flow channel was set at 30 liters per minute (LPM) using a vacuum pump. The blister was filled with varying amounts of a dry powder model, and the gravimetric release test from the blister was performed under varying experimental conditions.

The experimental results are shown in Table 1. As can be seen from Table 1, unexpected results were obtained, in which the presence of one or more side wall openings results in a significant increase in the ejection speed of the drug and also in the amount of dust that can be effectively ejected, compared to conditions without side wall openings. The comparison of tests 1 and 2; 2 and 2a; 3 and 3a; 7 and 7a; 9 and 9a indicate that sidewall openings result in an increase

19/28 very significant in the powder clearance of the blister, when compared, under the same conditions, with the blister without the side wall openings. Also the comparison of tests 4 and 4a; 5 and 5a; 6 and 6a indicates that without the piezo activation, no appreciable gap was detected even when the side wall openings are present. The side wall openings enable very high gravimetric clearances of regular amount of powder from the blister, that is, quantities in the order of 3 to 6 mg, but also very large amounts of powder, for example, in the order of 15 to 20 mg and so as large as 37 mg, where virtually no powder ejection can be seen in the blisters under the same conditions without the side wall openings, as demonstrated by tests 3 and 3a; 7 and 7a; 8 and 9a. It was visually detected that the clearance of the blisters with the side wall openings occurs fast, sometimes in less than a second, and faster with the blisters without the side wall openings, which are not completely emptied even in 4 seconds. It was not observed that any appreciable amount of powder was ejected from the side wall openings during the test run.

TABLE 1

<td>No.</td><td>Dust on blister, mg</td><td>Openings in blister</td><td>Procedure - ment of dosage</td><td>Powder withdrawn of blister, mg</td><td>Day off gravi- metric- here</td><td>Conditions of test</td>

<td> 1*</td><td> 5,037</td><td>4 Vents</td><td>Piezo</td><td> 4,807</td><td> 95,4%</td><td>Blister with</td>

<td></td><td></td><td>ejection &amp; wall</td><td>acted,</td><td></td><td></td><td>opening of</td>

20/28

<td></td><td></td><td>side with opening perforated</td><td>bomb a vacuum acted</td><td></td><td></td><td>side wall piezo actuated</td>

<td> 2</td><td> 4,204</td><td>4 openings</td><td>Piezo</td><td> 1,035</td><td> 24,6%</td><td>Blister without</td>

<td></td><td></td><td>ejection of</td><td>acted,</td><td></td><td></td><td>opening of</td>

<td></td><td></td><td>drug</td><td>bomb a</td><td></td><td></td><td>side wall</td>

<td></td><td></td><td>perforated</td><td>vacuum</td><td></td><td></td><td>piezo actuated</td>

<td></td><td></td><td></td><td>acted</td><td></td><td></td><td></td>

<td>2a</td><td> 3,169</td><td>2 openings</td><td>Piezo</td><td> 3,061</td><td> 96,6%</td><td>Blister # 2</td>

<td> * *</td><td></td><td>side wall</td><td>acted,</td><td></td><td></td><td>repeated after</td>

<td></td><td></td><td>and 4 openings</td><td>bomb a</td><td></td><td></td><td>the openings</td>

<td></td><td></td><td>ejection</td><td>vacuum</td><td></td><td></td><td>of Wall</td>

<td></td><td></td><td>perforated</td><td>acted</td><td></td><td></td><td>side</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>perforated</td>

<td> 3</td><td> 19,028</td><td>4 openings</td><td>Piezo</td><td> 1,051</td><td> 5,5%</td><td>Blister without</td>

<td></td><td></td><td>perforated ejection</td><td>acted,</td><td></td><td></td><td>opening of</td>

<td></td><td></td><td>of</td><td>bomb a</td><td></td><td></td><td>side wall</td>

<td></td><td></td><td></td><td>vacuum</td><td></td><td></td><td>piezo actuated</td>

<td></td><td></td><td></td><td>acted</td><td></td><td></td><td></td>

<td>3rd</td><td> 17,977</td><td>Opening of</td><td>Piezo</td><td> 17,903</td><td> 99,6%</td><td>Blister # 3</td>

<td> *</td><td></td><td>side wall</td><td>acted,</td><td></td><td></td><td>repeated with</td>

<td></td><td></td><td>and 4 openings</td><td>bomb a</td><td></td><td></td><td>opening of</td>

<td></td><td></td><td>ejection</td><td>vacuum</td><td></td><td></td><td>side wall</td>

<td></td><td></td><td>perforated</td><td>acted</td><td></td><td></td><td></td>

<td> 4*</td><td> 12,215</td><td>Opening of</td><td>Pump a</td><td> 0,634</td><td> 5,2%</td><td>Blister with</td>

<td></td><td></td><td>side wall</td><td>vacuum</td><td></td><td></td><td>opening of</td>

<td></td><td></td><td>and 4 openings</td><td>acted</td><td></td><td></td><td>side wall</td>

<td></td><td></td><td>ejection</td><td>for 2 0</td><td></td><td></td><td>exposed to the</td>

<td></td><td></td><td>drug</td><td>second</td><td></td><td></td><td>air flow from</td>

<td></td><td></td><td>perforated</td><td>From</td><td></td><td></td><td>pump for 20s;</td>

21/28

<td></td><td></td><td></td><td></td><td></td><td></td><td>without piezo activation</td>

<td> 4^The*</td><td> 11,581</td><td>Opening of</td><td>Piezo</td><td> 11,483</td><td> 99,2%</td><td>Blister # 4</td>

<td></td><td></td><td>side wall</td><td>acted,</td><td></td><td></td><td>repeated with</td>

<td></td><td></td><td>and 4 openings</td><td>bomb a</td><td></td><td></td><td>piezo activation</td>

<td></td><td></td><td>ejection</td><td>vacuum</td><td></td><td></td><td></td>

<td></td><td></td><td>drug</td><td>acted</td><td></td><td></td><td></td>

<td></td><td></td><td>perforated</td><td></td><td></td><td></td><td></td>

<td> 5*</td><td> 7,388</td><td>Opening of</td><td>Pump a</td><td> 0,072</td><td> 1,0%</td><td>Blister with</td>

<td></td><td></td><td>side wall</td><td>vacuum</td><td></td><td></td><td>opening of</td>

<td></td><td></td><td>and 4 openings</td><td>acted</td><td></td><td></td><td>side wall</td>

<td></td><td></td><td>ejection</td><td>for 2 0</td><td></td><td></td><td>exposed to</td>

<td></td><td></td><td>drug</td><td>second</td><td></td><td></td><td>air flow through</td>

<td></td><td></td><td>perforated</td><td>From</td><td></td><td></td><td>20s; without piezo</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>activation</td>

<td>5th</td><td> 7,316</td><td>Opening of</td><td>Piezo</td><td> 7,22</td><td> 98,7%</td><td>Blister # 5 (with</td>

<td> *</td><td></td><td>side wall</td><td>acted,</td><td></td><td></td><td>opening of</td>

<td></td><td></td><td>and 4 openings</td><td>bomb a</td><td></td><td></td><td>side wall)</td>

<td></td><td></td><td>ejection</td><td>vacuum</td><td></td><td></td><td>repeated with</td>

<td></td><td></td><td>drug</td><td>acted</td><td></td><td></td><td>piezo activation</td>

<td></td><td></td><td>perforated</td><td></td><td></td><td></td><td></td>

<td> 6*</td><td> 5,147</td><td>Opening of</td><td>bomb a</td><td> 0,025</td><td> 0,5%</td><td>Blister with</td>

<td></td><td></td><td>side wall</td><td>vacuum</td><td></td><td></td><td>opening of</td>

<td></td><td></td><td>and 4 openings</td><td>acted</td><td></td><td></td><td>side wall</td>

<td></td><td></td><td>ejection</td><td>for 2 0</td><td></td><td></td><td>exposed to flow</td>

<td></td><td></td><td>drug</td><td>second</td><td></td><td></td><td>air for 20 s;</td>

<td></td><td></td><td>perforated</td><td>From</td><td></td><td></td><td>without piezo</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>activation</td>

22/28

<td>6th *</td><td> 5,122</td><td>Opening of side wall and 4 openings ejection drug perforated</td><td>Piezo acted, bomb a vacuum acted</td><td> 5,015</td><td> 97,9%</td><td>Blister # 6 (with opening of side wall) repeated with piezo activation</td>

<td> 7</td><td> 17,139</td><td>4 openings</td><td>Piezo</td><td> 1,67</td><td> 9,7%</td><td>Blister without</td>

<td></td><td></td><td>ejection of</td><td>acted,</td><td></td><td></td><td>opening of</td>

<td></td><td></td><td>drug</td><td>bomb a</td><td></td><td></td><td>side wall</td>

<td></td><td></td><td>perforated</td><td>vacuum</td><td></td><td></td><td>with piezo</td>

<td></td><td></td><td></td><td>acted</td><td></td><td></td><td></td>

<td>7th</td><td> 15,469</td><td>Opening of</td><td>Piezo</td><td> 14,482</td><td> 93,6%</td><td>Blister # 7</td>

<td> *</td><td></td><td>side wall</td><td>acted,</td><td></td><td></td><td>repeated with</td>

<td></td><td></td><td>and 4 openings</td><td>bomb a</td><td></td><td></td><td>opening of</td>

<td></td><td></td><td>ejection</td><td>vacuum</td><td></td><td></td><td>side wall</td>

<td></td><td></td><td>drug</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>perforated</td><td></td><td></td><td></td><td></td>

<td> 8*</td><td> 23,949</td><td>Opening of</td><td>Piezo</td><td> 23,636</td><td> 98,7%</td><td>Blister with</td>

<td></td><td></td><td>side wall</td><td>acted,</td><td></td><td></td><td>opening of</td>

<td></td><td></td><td>and 4 openings</td><td>bomb a</td><td></td><td></td><td>side wall</td>

<td></td><td></td><td>ejection</td><td>vacuum</td><td></td><td></td><td>actuated piezo</td>

<td></td><td></td><td>drug</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>perforated</td><td></td><td></td><td></td><td></td>

<td> 9</td><td> 37,582</td><td>4 openings</td><td>Piezo</td><td> 0,229</td><td> 0,6%</td><td>Blister without</td>

<td></td><td></td><td>ejection of</td><td>acted,</td><td></td><td></td><td>opening of</td>

<td></td><td></td><td>drug</td><td>bomb a</td><td></td><td></td><td>side wall</td>

<td></td><td></td><td>perforated</td><td>vacuum</td><td></td><td></td><td>actuated piezo</td>

23/28

<td>9a</td><td> 37,353</td><td>Opening of</td><td>Piezo</td><td> 37,105</td><td> 99,3%</td><td>Blister # 9</td>

<td> *</td><td></td><td>side wall</td><td>acted,</td><td></td><td></td><td>repeated with</td>

<td></td><td></td><td>and 4 openings</td><td>bomb a</td><td></td><td></td><td>opening of</td>

<td></td><td></td><td>ejection</td><td>vacuum</td><td></td><td></td><td>side wall</td>

<td></td><td></td><td>drug</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>perforated</td><td></td><td></td><td></td><td></td>

* Test with at least one side wall opening.

EXAMPLE 2

Experimental tests were performed using an experimental setting similar to the setting described in Example 1, but with a proprietary piezo activator G9 set to the resonant frequency of 34.5kHz, triggered 90% of the time at the frequency of 34 kHz and 10% of the time at frequency of 35 kHz, switched between these frequencies at the rate of 10 Hz (duty cycle). The alternating current of approximately 160 to 200 volts generated by a feedback circuit in a waveform stage was used to actuate the activating piezo. Powdered insulin was used and very good blister clearance was demonstrated. In the experiment, a considerably larger amount of powdered drug was used versus the typical amount of 1 to 3 mg per blister. In two tests, a blister containing 5 mg of drug powder and having a side wall opening, in addition to four drug ejection openings demonstrated 94.6% to 95.9% of clearance of the powder from the blister during Piezo activation time of 4 seconds. It was observed that the real time off was less than 4 seconds of the piezo activation time. Thus, unexpectedly, a much larger amount of dust was recovered from the blister having a side wall opening versus what is typically seen with the same

24/28 blisters without the side wall opening, whose gaps are around 80 to 95% only when filled with much lower amounts of insulin, for example, about 2 mg.

EXAMPLE 3

Using an experimental fit similar to the fit described in Example 2, a test of a drug powder mix with lactose model was performed with very good clearance, in which 6 mg of the mixture was recovered with 97.5% of the gravimetric release of a blister having a side wall opening. The same blisters, but without a side wall opening, showed much lower gravity gaps.

EXAMPLE 4

Experiments were performed in a setting similar to the experimental setting described in Example 1, but with an unmodified Murata Electronics air transducer serving as an activating piezo, having a resonance frequency of 40kHz. Piezo activators with other resonant frequencies can also be used, typically in the range from 30 to 45 kHz. The air flow through the device was set at 28 LPM using a vacuum pump. A cone-shaped plastic top and cone-shaped flat top blisters with a flat sheet metal bottom were used as single-use containers containing a powder model for aerosol treatment, similar to the illustrated blisters corresponding Figures 3F and 3D. Blisters with a cone-shaped top have a straight cone top, while blisters with a

25/28 flat top in the shape of a cone have a cone part coming from a flat end with a diameter of approximately 2 mm. The height of the blisters was approximately 4.5 mm and the diameter of the blister chamber at the base was approximately 8 mm. The upper parts of the blister were made by thermoforming PVC or PETG plastic and thermally sealed to the bottom of the blister, made of a sheet of aluminum coated with polymer. The upper part of the blisters was punctured with 3 holes using metallic needles of 240 microns in diameter, thus forming drug ejection openings, similar to those of Figure 3D. In some experiments, the side wall of the conical part of the blister was perforated with at least one side wall opening, similar to that of Figures 3A, 3B, 3C. A 240 micron diameter needle was used to pierce the side wall opening. The results of these experiments are shown in Table 2.

TABLE 2

<td>No.</td><td>Format of blister</td><td>Dust on blister, mg</td><td>Time to activation piezo</td><td>Powder removed blister, mg</td><td>Day off gravi- metric</td><td>Conditions of the test</td>

<td> 10*</td><td>Shape of</td><td> 4,006</td><td>4 s</td><td> 3,902</td><td> 97,4%</td><td>Opening</td>

<td></td><td>cone</td><td></td><td></td><td></td><td></td><td>of Wall</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>side</td>

<td> 11*</td><td>Shape of</td><td> 5,514</td><td>4 s</td><td> 5,454</td><td> 98,9%</td><td>Opening</td>

<td></td><td>cone</td><td></td><td></td><td></td><td></td><td>of Wall</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>side</td>

<td> 12</td><td>Shape of</td><td> 3,764</td><td>4 S</td><td> 2,516</td><td> 66,8%</td><td>None</td>

<td></td><td>cone</td><td></td><td></td><td></td><td></td><td>opening</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>of Wall</td>

26/28

<td></td><td></td><td></td><td colspan="4">side</td>

<td> 13 *</td><td>Flat top</td><td> 6,769</td><td>2 sec</td><td> 6,617</td><td> 97,8%</td><td>Opening</td>

<td></td><td>of format</td><td></td><td></td><td></td><td></td><td>of Wall</td>

<td></td><td>cone</td><td></td><td></td><td></td><td></td><td>side</td>

<td> 14</td><td>Part</td><td> 3,194</td><td>2 sec</td><td> 2,984</td><td> 93,4%</td><td>None</td>

<td></td><td>higher</td><td></td><td></td><td></td><td></td><td>opening</td>

<td></td><td>flat of</td><td></td><td></td><td></td><td></td><td>of Wall</td>

<td></td><td>shape of</td><td></td><td></td><td></td><td></td><td>side</td>

<td></td><td>cone</td><td></td><td></td><td></td><td></td><td></td>

Tests with at least one side wall opening.

As can be seen from Table 2, unexpected results were obtained, in which a significant increase in the powder ejection speed and also in the amount of powder that can be ejected from a blister was observed in an experimental way, compared to the conditions without the side wall openings.

EXAMPLE 5

An airflow test was performed in and out of a blister pack having several drug ejection openings and at least one side wall opening. The experimental fit was similar to the fit described in Example 1, but no dust was present in the blisters in this experiment and no airflow was established using an air pump. In addition, a plastic capillary tube was connected to the outside of the side wall opening. In the first test, when the blister was intermittently actuated with an activating piezo, a sensitive light weight indicator was observed moving towards the entrance of the plastic capillary tube, thus recording the vacuum and / or the

27/28 air flow through the capillary tube and through the side wall opening in the blister, while air is being ejected from the drug ejection openings in the top of the blister.

In the second test, a second light weight indicator was placed above the drug ejection openings at the top of the blister, said light weight indicator was observed moving vertically detecting jets of air emanating from the drug ejection openings. At the same time, the first sensitive light weight indicator was observed moving towards the entrance of the plastic capillary tube thus recording the vacuum and / or air flow through the capillary tube and through the side wall opening in the blister, the said first indicator being sucked in by the plastic capillary tube and blocking it. It was further observed that when the first indicator was manually removed from blocking the entry of the plastic capillary tube and thus from blocking the air entry to the side wall opening, the second indicator indicated a notable increase in the air jets emitted from the drug ejection openings at the top of the blister. Thus it appears that the side wall opening helped to increase the blast of air emanating from the blister by providing an air supply to the blister.

EXAMPLE 6

Experiments were performed in an adjustment similar to the experimental adjustment described in Example 2, but without the activation of an air pump and directing any air through the flow channel of the experimental adjustment. A model

28/28 dry powder with lactose was used in the experiments. In a blister without the side wall opening, filled with 6.390 mg of lactose, a gap of only 28.4% was observed. In blisters with wall opening, filled with 5.013 and 6.560 mg of lactose powder, a gap of 80.8% and 93.4% corresponding was observed. Thus, it appears that the side wall opening helped to increase the blast air blast of the blister by providing an air supply in the blister obtaining unexpected results, in which a significant increase in the powder ejection speed and also in the amount of dust that can ejected has been experimentally observed, compared to conditions without the sidewall openings.

Although the present invention has been particularly described, in conjunction with specific preferred embodiments, it is evident that any alternatives, modifications and variations will become apparent to those skilled in the art in the light of the description below. It should, therefore, be contemplated that the appended claims will encompass any such alternatives, modifications and variations that fall within the true scope and spirit of the present invention.

to be adapted

1/4