Inhaler

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of the blister was approximately 5.5 mm and the diameter of the blister chamber at the base was approximately 11 mm, with a blister shape similar to that shown 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 to each other. The upper (hemispherical) part of the blister was perforated with 4 ejection openings using 5 metallic needles 320 micrometers in diameter, similar to those in Figure 3C, in which only two drug ejection openings 150 are shown. 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 needle with a diameter of 240 micrometers was used to pierce the opening of the side wall. An air flow rate was established through the device flow channel of 30 liters per minute (LPM) using a vacuum pump. The blister is

10 filled with varying amounts of a type of dry powder, and the blister gravimetric extraction test was performed under various experimental conditions.

The experimental results are presented in Table 1. As can be seen in Table 1, unexpected results were obtained, in which the presence of one or more lateral wall openings caused a significant increase in the ejection rate of the drug and also in The amount of dust that could actually be extracted, compared to conditions without sidewall openings. The comparison of tests 1 and 2; 2 and 2a; 3 and 3a; 7 and 7a; 9 and 9a indicates that the opening of the side wall caused a very significant increase in the extraction of dust from the blister, when compared, under the same conditions, with blisters without side wall openings. Also the comparison of tests 4 and 4a; 5 and 5a; 6 and 6a indicates that without piezoelectric drive, no appreciable extraction was detected even when side wall openings were present. The 20 side wall openings allowed a very high gravimetric extraction of regular amounts of powder from the blister, ie amounts of the order of 3-6 mg, but also very large amounts of dust, for example of the order of 15-20 mg and so high as 37 mg, in which practically no dust extraction from the blisters could be observed under the same conditions without side wall openings, as evidenced by tests 3 and 3a; 7 and 7a; and 8 and 9a. It was visually detected that the removal of the blister packs with lateral wall openings occurred rapidly,

25 times in less than a second, and faster compared to blisters with side wall openings, which have not cleared completely even in 4 seconds. It was not observed that any appreciable amount of dust was extracted from the side wall openings during the test performed.

TABLE 1

<dl><dt> </dt><dd>Powder in blister, mg Blister openings Dosing procedure Powder extracted from the blister, mg Gravimetric extraction a% Test conditions </dd></dl>

<dl><dt>1 </dt><dd>5,037 4 medication ejection openings and perforated side wall opening Piezoelectric driven, vacuum pump powered 4,807 95.4% Blister with side wall opening operated with piezo </dd></dl>

<dl><dt>2 </dt><dd>4,204 4 perforated medication ejection openings Piezoelectric driven, vacuum pump powered 1,035 24.6% Blister without side wall opening operated with piezo </dd></dl>

<dl><dt>2nd </dt><dd>3,169 2 sidewall openings and 4 perforated medication ejection openings Piezoelectric driven, vacuum pump powered 3,061 96.6% Blister # 2 repeated after 2 perforated side wall openings </dd></dl>

<dl><dt>3 </dt><dd>19,028 4 perforated medication ejection openings Piezoelectric driven, vacuum pump powered 1,051 5.5% Blister without opening in the side wall operated with piezo </dd></dl>

<dl><dt>3rd </dt><dd>17,977 Side wall opening and 4 perforated medication ejection openings Piezoelectric driven, vacuum pump powered 17,903 99.6% Repeated blister # 3 with side wall opening </dd></dl>

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<dl><dt> </dt><dd>Powder in blister, mg Blister openings Dosing procedure Powder extracted from the blister, mg Gravimetric extraction a% Test conditions </dd></dl>

<dl><dt>4 </dt><dd>12,215 Side wall opening and 4 perforated medication ejection openings Vacuum pump operated for 20 seconds 0.634 5.2% Blister with exposed side wall opening to pump air flow for 20 s; without piezo drive</dd></dl>

<dl><dt>4th </dt><dd>11,581 Side wall opening and 4 perforated medication ejection openings Piezoelectric driven, vacuum pump powered 11,483 99.2% Repeated blister # 4 with piezo drive </dd></dl>

<dl><dt>5 </dt><dd>7,388 Side wall opening and 4 perforated medication ejection openings Vacuum pump operated for 20 seconds 0.072 1.0% Blister with opening in the side wall exposed to air flow for 20 s; without piezo drive</dd></dl>

<dl><dt>5th </dt><dd>7,316 Side wall opening and 4 perforated medication ejection openings Piezoelectric driven, vacuum pump powered 7.22 98.7% Blister # 5 (with opening in the side wall) repeated with piezoelectric drive </dd></dl>

<dl><dt>6 </dt><dd>5,147 Side wall opening and 4 perforated medication ejection openings Vacuum pump operated for 20 seconds 0.025 0.5% Blister with opening in the side wall exposed to air flow for 20 s; without piezo drive</dd></dl>

<dl><dt>6a </dt><dd>5,122 Side wall opening and 4 perforated medication ejection openings Piezoelectric driven, vacuum pump powered 5,015 97.9% Blister # 6 (with opening in the side wall) repeated with piezoelectric drive </dd></dl>

<dl><dt>7 </dt><dd>17,139 4 perforated medication ejection openings Piezoelectric driven, vacuum pump powered 1.67 9.7% Blister without side wall opening operated with piezo </dd></dl>

<dl><dt>7a </dt><dd>15,469 Side wall opening and 4 perforated medication ejection openings Piezoelectric driven, vacuum pump powered 14,482 93.6% Blister # 7 repeated with opening in the side wall </dd></dl>

5

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35

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<dl><dt> </dt><dd>Powder in blister, mg Blister openings Dosing procedure Powder extracted from the blister, mg Gravimetric extraction a% Test conditions </dd></dl>

<dl><dt>8 </dt><dd>23,949 Side wall opening and 4 perforated medication ejection openings Piezoelectric driven, vacuum pump powered 23,636 98.7% Blister with side wall opening operated with piezo </dd></dl>

<dl><dt>9 </dt><dd>37,582 4 perforated medication ejection openings Piezoelectric driven, vacuum pump powered 0.229 0.6% Blister without opening in the side wall operated with piezo </dd></dl>

<dl><dt>9a </dt><dd>37,353 Side wall opening and 4 perforated medication ejection openings Piezoelectric driven, vacuum pump powered 37,105 99.3% Blister # 9 repeated with opening in the side wall </dd></dl>

 Tests with at least one opening in the side wall

Example 2

An experimental test was performed using an experimental configuration similar to the configuration described in Example 1, but with a patented G9 piezoelectric actuator tuned to the resonant frequency of 34.5 kHz, driven 90% of the time at a frequency of 34 kHz and 10% of the time at a frequency of 35 kHz, switching between these frequencies with a sequence of 10 Hz (duty cycle). Alternate voltage of approximately 160-200 volts generated by a step-wave reversing converter circuit was used to drive the piezoelectric actuator. Insulin powder was used and showed a very good blister extraction. In the experiment, a considerably larger amount of drug powder was used compared to the typical amounts of 1-3 mg per blister. In two tests of a blister containing 5 mg of medicated powder and that had a side wall opening, in addition to four medication ejection openings, 94.6% and 95.9% of blister dust extraction were observed during a Piezoelectric drive time of 4 seconds. It was observed that the actual extraction time was less than the 4 seconds of piezoelectric drive time. So unexpectedly, much more dust was expelled from the blister that had a side wall opening compared to what was normally observed in the same blister but without side wall opening, which achieved extractions of about 80 to 95% only when filled with much smaller amounts of insulin, that is, up to about 2 mg.

Example 3

Using an experimental configuration similar to the configuration described in Example 2, a test was conducted with a type of medicated powder mixture with lactose with very good extraction, in which 6 mg of the mixture was extracted with a gravimetric extraction of 97, 5% of the blister that had a side wall opening. The same blisters but without lateral wall opening, showed much lower gravimetric extractions.

Example 4

Experiments were performed with a configuration similar to the experimental configuration described in Example 1, but with a Murata Electronics unmodified air transducer that serves as a piezoelectric actuator, which has a resonance frequency of 45 kHz. Piezoelectric actuators with other resonance frequencies can also be used, usually in the range of 30 to 45 kHz. The air flow through the device was set at 28 liters per minute using a vacuum pump. Blisters were used with the cone-shaped plastic and cone-shaped top, flat top with flat aluminum foil bottom as single-use containers containing a type of spray-forming powder, similar to blister packs represented in the corresponding figures 3F and 3D. The cone-shaped blister tops had the straight cone upper part, while the cone-shaped blister, the flat top blisters had a conical top that reached a flat end with the diameter of approximately 2mm. 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 part of the blisters was made by thermoforming of PVC or PETG plastic, and thermally sealed to the bottom of the blister, made of polymer coated aluminum foil. The upper part of the blisters was punched with 3 holes using 240 micrometer diameter metal needles, thus forming

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medication ejection openings, similar to those in 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 needle with a diameter of 240 micrometers was used to pierce the side wall opening. The results of these experiments are presented in Table 2.

TABLE 2

<dl><dt>## </dt><dd>Blister Shape Powder in blister, mg Piezoelectric drive time Powder extracted from the blister, mg Gravimetric Extraction% Test conditions </dd></dl>

<dl><dt>10 </dt><dd>Conical shape 4,006 4 seconds 3,902 97.4% Side wall opening </dd></dl>

<dl><dt>11 </dt><dd>Conical shape 5,514 4 seconds 5,454 98.9% Side wall opening </dd></dl>

<dl><dt>12 </dt><dd>Conical shape 3,764 4 seconds 2,516 66.8% No side wall opening </dd></dl>

<dl><dt>13 </dt><dd>Flat top conical shape 6,769 2 seconds 6,617 97.8% Side wall opening </dd></dl>

<dl><dt>14 </dt><dd>Flat top conical shape 3,194 2 seconds 2,984 93.4% No side wall opening </dd></dl>

 Tests with at least one opening in the side wall

As can be seen in Table 2, unexpected results were obtained, in which a significant increase in the ejection rate of the dust and also the amount of dust that could be extracted from a blister was experimentally observed, compared to conditions without openings in the side wall.

10 Example 5

An air flow test was performed in and out of the blister that had several medication ejection openings and at least one opening was made in the side wall. The experimental setup was similar to the setup described in Example 1, but without dust present in the blisters in these experiments and without air flow being established using a vacuum pump. In addition, a plastic capillary tube was connected to the

fifteen side wall opening from outside. In the first test, when the blister was operated intermittently with the piezoelectric actuator, a light flag of sensitive weight was observed that moved towards the entrance of the plastic capillary tube thus recording the vacuum or air flow through the tube capillary and through the opening in the side wall towards the blister, while the air was being drawn through the ejection openings of the medicine in the upper part of the blister.

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