HK1142286B - Inhaler - Google Patents

Abstract

A dry powder inhaler has a vibrator coupled to a blister filled with a dry powder drug substance. One or more of drug ejection apertures in the blister are substantially opposite the vibrator. One or more air intake apertures in the blister are not opposite the vibrator. Upon vibration of the vibrator, the drug substance is deaggregated, aerosolized, and ejected from the drug ejection apertures for inhalation by a patient.

Description

Inhaler

Technical Field

Embodiments of the present invention relate to medical devices and drug delivery devices, and in particular, to delivery of aerosolized drugs, inhalation of drugs for delivery to the lungs and gastrointestinal tract, and nasal delivery.

Background

Drug delivery devices for aerosolized medicaments, including administration via inhalation, are known in the art, examples include U.S. patents: U.S. Pat. Nos. 5,694,920, 6,026,809, 6,142,146 to Abrams and Gumaste, 3,948,264 to Wilke et al, 6,971,383 to Hickey et al, 7,117,867 to Cox et al, 6,901,929 to Burr et al, 6,779,520 to Genova et al, 6,748,944 to Della Vecchia et al, 5,590,645 to Davies et al. The above patents also provide an overview of various aerosolization and inhalation devices and techniques.

Some aerosolization and inhalation delivery devices are known, including metered dose inhalers, nebulizers, dry powder inhalers, thermal vaporizers, and other systems, the differences of which relate to the method and effect of delivery and aerosolization of the drug used by the patient. Metered dose inhalers typically utilize a compressed gas to aerosolize the medicament. The disadvantages of these inhalers are related to the difficulty in controlling the delivered dose of the medicament and to the velocity of the aerosol particles, resulting in particles colliding with and depositing on different surfaces in the mouth and throat of the patient. Inhalation devices that deliver medicament in dry powder form are known as dry powder inhalers. Passive dry powder inhalers rely on the patient's inspiratory effort (inhalation effort) to disperse and aerosolize the drug for inhalation, while active dry powder inhalers typically input additional energy, such as mechanical or electrical energy, in order to improve the efficiency of powder dispersion and aerosolization, reduce the need for inspiratory effort from the patient, and achieve better inspiratory flow autonomy of inhaler performance. Typically, the aerosol particle size of the drug must be less than about 10 microns, more preferably less than about 6 microns, for delivery of the drug to the patient's lungs by inhalation, and less than about 3.3 microns for delivery to the deep lungs. The larger sized particles will be deposited in the mouth and throat of the patient and as a result will be transported to the gastrointestinal tract of the patient. It is desirable to increase the amount of medicament that a dry powder inhaler can aerosolize in a single inhalation, e.g., 1 to 3-4 seconds, by a patient. There is also a need to increase the speed at which powder is dispersed and aerosolized by a dry powder inhaler.

The dry powder inhalation devices described in U.S. Pat. Nos. 5,694,920, 6,026,809, 6,142,146, to Abrams and Gumaste, utilize a vibratory means to disperse and aerosolize the dry powder medicament for delivery to the patient as an aerosol. U.S. patent publication 2005/0183724 to Gumaste and Bowers discloses a synthetic jet based drug delivery method and device.

Disclosure of Invention

Briefly, embodiments of the present invention include a device for inhalation of aerosolized medicaments in which a high frequency vibrator is coupled to a reservoir (manifold) filled with a dry powder medicament. The vibration of the vibrator causes the dispersion, aerosolization and ejection of the medicament in the container for inhalation by the patient. One or more holes in the container are substantially opposite the vibrator and are primarily used for ejection of the drug via a synthetic jet or other mechanism for ejecting powder from the container. At least one other aperture in the container is primarily for the entry of outside gas or air into the container.

When the embodiments of the present invention are experimentally tested as inhalation and/or aerosolization devices, unexpected results are obtained as shown in the following examples, observing a substantially faster aerosolization and ejection of dry powders and the ability to aerosolize substantially increased amounts of dry powders as compared to the prior art.

Drawings

FIG. 1 is a cross-sectional view of an embodiment of the present invention showing a drug-containing container coupled to a vibrator;

FIG. 2 is a cross-sectional view of an embodiment of the present invention showing a container coupled to a shaker;

FIG. 3 is a cross-sectional view of several embodiments of the present invention showing a drug-containing container coupled to a vibrator;

FIG. 4 is a cross-sectional view of an embodiment of the present invention showing a drug-containing container coupled to a vibrator;

FIG. 5 is a cross-sectional view of several embodiments of the present invention showing a drug-containing container coupled to a vibrator;

FIG. 6 is a cross-sectional view of an embodiment of the present invention showing a drug-containing container coupled to a vibrator;

figure 7 is a cross-sectional view of several embodiments of the present invention showing an inhalation device;

figure 8 is a cross-sectional view of an embodiment of the invention showing an inhalation device;

figure 9 is a cross-sectional view of several embodiments of the present invention showing an inhalation device;

figure 10 is a cross-sectional view of an embodiment of the invention showing an inhalation device;

in the drawings, like numerals refer to like parts or features throughout the several views.

Fig. 1 schematically illustrates a cross-sectional view of an embodiment of the present invention. The vibrator 100 is coupled to a blister or container 110 containing a medication 120. Vibrator 100 may be a piezoelectric actuator or transducer, or a mechanical vibrator, an electromagnetic vibrator, a magnetostrictive element, or other vibrating mechanism as is known in the art. In one embodiment, a piezoelectric actuator is used, typically consisting of a piezoelectric ceramic element and a metal body, in either unimorph or bimorph design. Piezoelectric actuator designs known in the art may be used, including but not limited to air sensors and piezoelectric sensing elements. In addition, a polymer piezoelectric material and an actuator based on the polymer piezoelectric material can be used as the vibrator. As is known in the art, a piezoelectric actuator based vibrator is powered by supplying electrical power (typically an alternating current of appropriate frequency and amplitude) to a piezoelectric element. Piezoelectric actuators tuned to various resonant frequencies can be used, for example, with resonant frequencies in the ultrasonic range of about 1kHz to about 100kHz, more typically about 30kHz to about 45kHz, and amplitudes of mechanical oscillations having peak-to-peak values of about 1 micron to about 50 microns. The vibrator 100 can vibrate synchronously at a fixed or variable frequency, or multiple frequencies, and transmit the vibratory motion to the container 110. The frequency of the vibration may be in the range of less than 1Hz to several hundred kHz, more typically the vibration frequency is about 25kHz to about 50 kHz. In the embodiment shown in fig. 1, vibrator 100 is in direct contact with container 110 and is therefore directly coupled to container 110.

The container 110 has at least one drug ejection hole 150 substantially opposite the vibrator 100, and is mainly used for ejection of the drug 120. However, outside air or gas can also enter the container through the holes 150. Further, container 110 has at least one sidewall aperture 200 that is not substantially opposite vibrator 100. Rather than being used for ejection of the medicament, sidewall apertures 200 allow air or gas to enter container 110 from the outside and thus facilitate dispersion, aerosolization and ejection of medicament 120 from container 110 via medicament ejection apertures 150.

The drug 120 is provided as a dry powder, but other forms of drugs are possible, such as a liquid or a gas. A single component drug (pure drug), multiple drugs, or a drug in combination with an adjuvant (e.g., lactose), or a combination thereof, may be used. Other additives, such as pharmaceutically inactive ingredients, dispersing agents, etc., may also be added to the pharmaceutically active drug.

The container 110 is made of metal, plastic or composite material. In one embodiment of the invention, the container 110 is a blister pack (blister pack) made from a cold-formed or a hot-formed film, the film material being a polymer, a metal foil, a multilayer polymer-metal foil film, a metal or polymer film coated with a protective layer. In the embodiment of the invention shown in fig. 2, the container 110 is a single-use blister package generally comprising a conical, pyramidal, hemispherical, oval or similar top 111 and a flat bottom 112, wherein the top 111 and bottom 112 are sealed to each other by methods known in the art, including but not limited to adhesive, heat sealing, pressure sealing, ultrasonic sealing, and the like. The bonded or sealed area 113 is also schematically shown in fig. 2 at the contact between the top 111 and the bottom 112. The vibrator 100 is shown in direct contact with the flat bottom 112 of the container 110.

Many possible shapes and forms of blister packs or containers 110 are schematically shown in fig. 3A to 3F, including a flat-top conical shape (fig. 3A, 3D, 3G); cylindrical (FIGS. 3B and 3E), also shown in FIG. 4; and hemispherical or conical (fig. 3C, 3F, 3H).

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

Drug ejection orifice 150 has a diameter of about 10 microns to about 1000 microns, with a preferred diameter of about 50 microns to about 500 microns. Sidewall holes 200 have a diameter of about 1 micron to about 1000 microns, with a preferred diameter of about 25 microns to about 500 microns. In one embodiment of the present invention, the total area (cross-section) of all drug ejection apertures 150 is at least two or more times the total area (cross-section) of all side wall apertures 200. In another embodiment of the present invention, the total area (cross-section) of all drug ejection apertures 150 is at least five times the total area (cross-section) of all side wall apertures 200.

The number of drug ejection apertures 150 is from 1 to about 10, and in another embodiment the number of drug ejection apertures 150 is from about 3 to about 6. The number of sidewall apertures 200 is from 1 to about 10, and in another embodiment the number of sidewall apertures 200 is from 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 size as the diameter of the container 110 on the coupling surface such that the coupling area of the respective surfaces of the vibrator 100 and the container 110 is substantially the same, as shown in fig. 1, 3B, 3C, 3D, 3E, 3H and 4. In another embodiment of the present invention, as shown in FIGS. 2, 3A, 3F and 3G, the size of vibrator 100 is larger or smaller on the bonding surface than the size of container 110. Referring now to the embodiment of the invention shown in FIG. 5, vibrator 100 may also be coupled to container 110 via a mechanical spacer or integral insert (integral pin)130 as shown in FIG. 5A or via an air space 140 as shown in FIG. 5B. Vibrator 100 may also be positioned directly or partially within container 110 (embodiment not shown)

Drug ejection apertures 150 are shown in fig. 1, 2, 3A-3F, 4 and 5 to be oriented substantially conventional or perpendicular to the top surface of vibrator 100 or to the plane of engagement between vibrator 100 and container 110, while side wall apertures 200 are oriented substantially parallel to the top surface of vibrator 100 or to the plane of engagement between vibrator 100 and container 110. However, other orientations of apertures 150 and 200 may be used, as shown in FIGS. 3G and 3H, in which drug ejection aperture 150 is not conventional or perpendicular to the top surface of vibrator 100 or the plane of engagement between vibrator 100 and container 110, and sidewall aperture 200 is not substantially parallel to the top surface of vibrator 100 or to the plane of engagement between vibrator 100 and container 110.

In operation of one embodiment of the present invention, when vibrator 100 is actuated and begins to vibrate, vibrational energy is transferred to reservoir 110 such that drug is ejected from reservoir 110 through at least one drug ejection aperture 150. In one embodiment of the present invention, a synthetic jet of fluid, which may be a gas or a gas/drug mixture, is formed through drug ejection orifice 150. The synthetic jet is characterized by the fluid moving in both directions through the hole 150, creating vortices on both sides of the hole simultaneously. Synthetic jets of gas or liquid are known to those skilled in the art and are characterized by a high velocity jet of gas or other liquid emanating from an orifice of an enclosed chamber, with fluid passing through the orifice into and out of the chamber multiple times such that fluid exiting the chamber is replenished by fluid entering the chamber from the outside. See U.S. patent publication 2005/0183724 to Gumaste and Bowers, which describes synthetic jets. The synthetic jet can continue indefinitely as the gas moves in both directions through the orifice. The formation of a synthetic jet may require the establishment of an acoustic wave, which may be established, for example, by a piezoelectric vibrator; specific combinations of parameters, including frequency, orifice size, vessel shape and size, may also be required in order to create a strong, durable, reproducible synthetic jet.

Referring now to fig. 6, there is shown an embodiment of the present invention in operation wherein upon actuation of vibrator 100, sidewall apertures 200 allow external air or gas to enter container 110 (schematically illustrated by arrow 205) and thereby promote efficient ejection of drug substance 120 from drug ejection apertures 150 (schematically illustrated by arrow 207), increasing the ejection rate and quantity of drug substance that can be ejected from container 110.

Referring now to fig. 7, an embodiment of the present invention shows a schematic of a dry powder inhaler, including a container 110, a vibrator 100, and a fluid channel 300. The fluid channel 300 shown in fig. 7A is of the cross-flow type, so that air flows generally perpendicular to the direction of ejection of the drug 120 from the reservoir 110, which is indicated by arrow 207. The fluid channel 300 shown in fig. 7B is of the parallel flow type, so that air flows generally in a direction parallel to the direction in which the medicament 120 is ejected from the container 110, the direction of ejection being indicated by the arrow 207. A series of intermediate arrangements of the fluid channels 300 and the container 100 are also possible whereby the air is moved in a more complex path between parallel and transverse flows (embodiments not shown). When inhaled by a patient, air flows through the fluid passageway 300, into the device as indicated by arrows 310, and out of the device for inhalation as indicated by arrows 320.

Upon actuation of vibrator 100, drug substance 120 is dispersed, aerosolized, and ejected from reservoir 110 through drug ejection apertures 150. The sequence of dispersion, aerosolization, and ejection of drug substance 120 need not be in the order described above, wherein all three processes may occur simultaneously, or sequentially in any order depending on the parameters of the processes, with the end result that drug substance 120 is ejected from container 110 through drug ejection aperture 150, and aerosolized drug substance 120 is present inside fluid passageway 300. The aerosol of the drug 120 is then carried by the air flow 310 outside the container, resulting in delivery of the drug 120 to the inspiratory patient as indicated by arrow 320. The entry of outside air through side wall apertures 200, as indicated by arrows 205, facilitates the dispersion, aerosolization, and ejection of drug substance 120 through drug ejection apertures 150.

Referring now to fig. 8, one embodiment of the present invention is shown as a schematic view of a dry powder inhaler with an inhaler body (inhaler body)480, wherein the inhaler body 480 has disposed within and outside thereof a plurality of inhaler elements, including a container 110; a vibrator 100; a fluid channel 300; for electrically driving the electronic board and circuitry 462 of the vibrator 100 and other electronic components of the inhaler. A battery 464, which may be any source of energy, such as a battery pack, which may be a primary or rechargeable battery, or a fuel cell, is used to power the electronics and vibrator. An additional optional element of the inhaler shown in fig. 8 is a piercing device 400 for piercing the drug ejection and/or side wall apertures of the container or blister 110; an additional single dose drug container 450; a sensor 420 for sensing and detecting inhalation by the user or patient, adapted to detect air flow inhaled by the user as indicated by arrow 310, and is associated with electronic circuitry 462 for activating vibrator 100 and the drug ejection and aerosolization process. The sensor 420 is preferably capable of detecting the presence and intensity of air flow in the inhaler, and optionally the direction of the air flow, in conjunction with the electronic board and circuitry 462. Patient feedback devices 460 and 466 are for providing sensory feedback to the patient and optional dose counters and indications are displayed to indicate to the user the status of the drug delivery and various options. Arrows 320 indicate air inhaled by the patient. Channel 220 provides a path for outside air to enter sidewall hole 200 so that when vibrator 100 is actuated, outside air can enter container 110 as indicated by arrow 205.

Referring now to fig. 9, an embodiment of the present invention is shown as a schematic of a dry powder inhaler with a multi-use container 118, wherein the medicament 120 is provided in single-use medicament packages 610 and 710 disposed on carrier tapes 620 and 700. The direction of movement of the carrier tape is shown by arrow 650. In the embodiment shown in fig. 9A, single-use drug package 610 is covered by a lidding tape 630, and lidding tape 630 is gathered on spool 635, thereby exposing drug 120 for ejection through drug ejection aperture 150. In another embodiment (not shown), lidding tape 630 is not removed from single-use drug package 610, but is perforated prior to or upon entry into multi-use container 118, thereby exposing the drug for ejection through drug-ejection apertures 150. The multi-use container 118 is in contact with the carrier tape 620 by a compressible gasket or O-ring 600. When the patient inhales, vibrator 100 is actuated, thereby ejecting drug substance 120 through ejection aperture 150. External air enters container 118 via sidewall aperture 200 as indicated by arrow 205, while aerosolized drug is inhaled by the patient as indicated by arrow 320, and air enters fluid channel 300 as indicated by arrow 310.

Similarly, in fig. 9B, the medication 120 is provided in a single-use medication package 710 disposed on a carrier tape 700, the medication package 710 comprising a pouch (pocket) with a tape folded over itself. The direction of belt travel is shown by arrow 650. Pulling carrier tape 700 causes the pouch of 710 underneath multi-use container 118 to open, and multi-use container 118 is brought into contact with carrier tape 700 by means of compressible gasket or O-ring 600. When the patient inhales, vibrator 100 is actuated, thereby ejecting drug substance 120 through ejection aperture 150. External air enters container 118 via sidewall aperture 200 as indicated by arrow 205, while aerosolized drug is inhaled by the patient as indicated by arrow 320, and air is driven into fluid passage 300 by the patient's inhalation as indicated by arrow 310.

The piercing of the aperture in the container 110 may be performed immediately prior to the delivery of the medicament to the patient. In one embodiment, the invention operates as follows: the inhaler is activated for use, and the holes in the medicament container are simultaneously or sequentially pierced by the piercing device 400; or in the case of a tape-based medication package 610, the lidding material 630 is removed or severed; or the band-based pouch 710 is opened; the medicament 120 is then aerosolized when the patient inhales through the inhaler. In other embodiments, the opening or puncturing of individual drug packs is automated by electromechanical or mechanical means, such as a spring or electromagnetic actuator, or a thermal vaporizer, all optionally activated by the inhalation detection sensor 420, when the patient inhales.

In another embodiment, shown in FIG. 10, multiple use container 118 is used to deliver drug 120 such that sidewall aperture 200 is connected to drug source 900 via conduit 910. The drug source 900 has at least two or more doses of the drug 120. The amount of drug 120 delivered to the patient is controlled by the actuation time of the device or by a sensor that detects the actual amount of drug 120 delivered and controls the actuation of the vibrator 100.

Other embodiments and applications of the invention are also contemplated. The drug delivered to the patient may be a vaccine, DNA or RNA fragment, a drug for the treatment of pain, asthma, emphysema, chronic bronchitis, cystic fibrosis, COPD, diabetes, or other drug which when delivered to the patient in aerosolized form is capable of preventing or treating the disease or alleviating the symptoms of the disease and has local and/or systemic effects.

In another embodiment, the invention is used to deliver aerosolized medicaments, not for inhalation but for nasal, buccal, ocular or dermal administration. In another embodiment, liquid drug formulations can be delivered using the present invention.

Example 1

A model inhalation device similar to the design shown in figure 7A was used in experimental testing and was able to work with blisters having drug ejection apertures only or with both drug ejection apertures and side wall apertures. The device has an integrated circuit and a removable fluid channel. A piezoelectric actuator based on a modified air sensor manufactured by Murata Electronic, japan was used as the vibrator. The piezo actuator was actuated for 4 seconds and 90% of the time was at a frequency of 33kHz and 10% of the time was actuated at a frequency of 34.4kHz, switching between these frequencies at a rate of 10Hz (duty cycle). The piezoelectric actuator is actuated using an ac voltage of approximately 160-200 volts generated by the flyback circuit in the step waveform. A blister with a near hemispherical top and a flat bottom is used as a single use container containing a model dry powder for aerosolization. The height of the blister was about 5.5mm and the diameter of the blister chamber at the base was about 11mm, the shape of the blister being similar to that shown in figure 3C. The blister was made of aluminum foil coated with a polymer layer. The top and bottom of the blister are heat sealed to each other. The (hemispherical) top of the blister was pierced with 4 drug ejection apertures using a 320 micron diameter metal needle, similar to fig. 3C, where only two drug ejection apertures 150 are shown in fig. 3C. In some experiments, the side wall of the top of the blister was pierced with at least one side wall hole 200, similar to fig. 3C. The sidewall holes were pierced using a needle of 240 microns diameter. The air flow through the fluid channel of the device was determined to be 30 Liters Per Minute (LPM) using a vacuum pump. The blisters were filled with different amounts of model dry powder and tested for gravimetric clearance in the blisters under different experimental conditions.

The results are shown in Table 1. As can be seen from table 1, unexpected results were obtained, wherein the presence of one or more side wall apertures resulted in a significant increase in the velocity of the drug ejection and the amount of powder that could be effectively ejected, compared to the case without the side wall apertures. Tests 1 and 2; 2 and 2 a; 3 and 3 a; 7 and 7 a; a comparison of 9 and 9a shows that the side wall apertures result in a very significant increase in the rate of removal of powder from the blister under the same conditions when compared to a blister without side wall apertures. Tests 4 and 4 a; 5 and 5 a; comparison of 6 and 6a also shows that without piezoelectric actuation, no significant clearance is detected even in the presence of the sidewall hole. The side wall apertures allow for very high weight removal rates from the blister for conventional amounts of powder, i.e., on the order of 3-6mg, as well as for large amounts of powder, e.g., 15-20mg and up to 37mg, where virtually no powder ejection from the blister is observed under the same conditions without the side wall apertures, as in tests 3 and 3 a; 7 and 7 a; 8 and 9 a. It was visually detectable that the removal of the blister with side wall apertures proceeded quickly, sometimes less than 1 second, faster than the blister without side wall apertures, which were not completely removed even within 4 seconds. It can be seen that no appreciable amount of powder was ejected from the side wall apertures during the test run.

Table 1:

##

powder in blisters, mg

Holes of bubble caps

Medication program

Powder removed from blister

Weight clearance%

Test conditions

Powder, mg

1*

5.037

4 drug injection holes pierced&Side wall hole

Piezoelectric actuation, vacuum pump actuation

4.807

95.4％

Blister with side wall aperture, actuated by piezo-electric

2

4.204

4 drug injection holes pierced

Piezoelectric actuation, vacuum pump actuation

1.035

24.6％

Blisters without side wall apertures, actuated by piezoelectricity

2a**

3.169

Pierced 2 side wall holes and 4 drug ejection holes

Piezoelectric actuation, vacuum pump actuation

3.061

96.6％

Repeated #2 blister after piercing 2 side wall apertures

3

19.028

4 drug injection holes pierced

Piezoelectric actuation, vacuum pump actuation

1.051

5.5％

Blisters without side wall apertures, actuated by piezoelectricity

3a*

17.977

Pierced side wall hole and 4 drug ejection holes

Piezoelectric drive, vacuum pump drive

17.903

99.6％

#3 blister with side wall hole repeat

4*

12.215

Pierced side wall hole and 4 drug ejection holes

Vacuum pump actuation for 20 seconds

0.634

5.2％

Bubble caps with side wall apertures exposed to the pump air stream for 20 seconds; non-voltage electric actuation

4a*

11.581

Pierced side wall hole and 4 drug ejection holes

Piezoelectric actuation, vacuum pump actuation

11.483

99.2％

#4 blister repeated with piezoelectric actuation

5*

7.388

Pierced side wall hole and 4 drug ejection holes

Vacuum pump actuation for 20 seconds

0.072

1.0％

Bubble caps with side wall apertures exposed to the pump air stream for 20 seconds; non-voltage electric actuation

5a*

7.316

Pierced side wall hole and 4 drug ejection holes

Piezoelectric actuation, vacuum pump actuation

7.22

98.7％

Repeated with piezo actuation #5 bubble cap (with side wall hole)

6*

5.147

Pierced side wall hole and 4 drug ejection holes

Vacuum pump actuation for 20 seconds

0.025

0.5％

Bubble caps with side wall apertures exposed to the pump air stream for 20 seconds; non-voltage electric actuation

6a*

5.122

Pierced side wall hole and 4 drug ejection holes

Piezoelectric actuation, vacuum pump actuation

5.015

97.9％

Piezoelectric actuated repetitive slapping cap (with side wall hole)

7

17.139

Pierced 4 drugs

The actuation is carried out by a piezoelectric actuator,

1.67

9.7％

bubble caps without side wall apertures, using piezoelectrics

Injection hole

Vacuum pump actuation

Actuation

7a*

15.469

Pierced side wall hole and 4 drug ejection holes

Piezoelectric actuation, vacuum pump actuation

14.482

93.6％

#7 blister with side wall hole repeat

8*

23.949

Pierced side wall hole and 4 drug ejection holes

Piezoelectric actuation, vacuum pump actuation

23.636

98.7％

Bubble cap with side wall aperture actuated by piezo-electricity

9

37.582

4 drug injection holes pierced

Piezoelectric actuation, vacuum pump actuation

0.229

0.6％

Blisters without side wall apertures, actuated by piezoelectricity

9a*

37.353

Pierced side wall hole and 4 drug ejection holes

Piezoelectric actuation, vacuum pump actuation

37.105

99.3％

#9 blister with side wall hole repeat

Testing with at least one side wall hole

Example 2

Experimental tests were carried out with a test set-up similar to that of example 1, except that with a proprietary piezoelectric actuator G9 tuned to a resonant frequency of 34.5kHz, 90% of the time was actuated at a frequency of 34kHz and 10% of the time was actuated at a frequency of 35kHz, switching between these frequencies at a rate of 10Hz (duty cycle). The piezoelectric actuator is actuated using an ac voltage of approximately 160-200 volts generated by the flyback circuit in the step waveform. A blister with a near hemispherical top and a flat bottom was used as a single use container containing a model dry powder for aerosolization. Powdered insulin was used and showed very good clearance from the blister. In this experiment, a larger amount of drug was used than is typical of 1-3mg per blister. In both tests, blisters containing 5mg of drug powder and side wall apertures in addition to four drug ejection apertures showed 94.6% and 95.9% clearance of the powder from the blister over a piezoelectric actuation time of 4 seconds. The actual clearing time was observed to be less than 4 seconds of piezoelectric actuation time. Thus, surprisingly, a greater amount of powder is removed from blisters with a side wall aperture than is typically seen in identical blisters but without a side wall aperture; the same blister, but without the side wall apertures, only reached about 80 to 95% clearance when filled with much lower amounts of insulin, i.e., up to about 2 mg.

Example 3

The test of the model drug powder mixed with lactose was carried out with a test apparatus similar to the one described in example 2, with very good clearance, where 6mg of the mixture was removed from the blister with side wall aperture with a weight clearance of 97.5%. The same blister without side wall apertures showed much lower weight clearance.

Example 4

Experiments were performed using an experimental setup similar to that described in example 1, but with a non-modified Murata Electronics air sensor as the piezoelectric actuator, having a resonant frequency of 40 kHz. Piezoelectric actuators of other resonant frequencies may also be used, typically in the range of 30-45 kHz. Gas flow through the apparatus was established at 28LPM using a vacuum pump. Plastic conical-topped and conical-topped blisters with flat metal foil bottoms were used as single-use containers containing model powder for aerosolization, similar to the blisters depicted in fig. 3F and 3D, respectively. The conical top blister had a straight conical top, while the conical flat top blister had a conical top with a diameter of about 2mm towards a flat end. The height of these blisters was about 4.5mm and the diameter of the blister chamber at the base was about 8 mm. The top of the blister was made of thermoformed PVC or PETG plastic and heat sealed to the bottom of the blister made of polymer clad aluminum foil. The top of the blister was pierced with 3 holes with a 240 micron diameter metal needle to form drug ejection apertures, similar to figure 3D. In some experiments, the side wall of the conical portion of the blister was pierced with at least one side wall hole, similar to fig. 3A, 3B, 3C. The sidewall holes were pierced using a 240 micron diameter needle. The results of these experiments are listed in table 2:

table 2:

##

blister shape

Powder in blister, mg

Time of piezoelectric actuation

Powder removed from the blister, mg

Weight clearance%

Test conditions

10*

Conical shape

4.006

4 seconds

3.902

97.4％

Side wall hole

11*

Conical shape

5.514

4 seconds

5.454

98.9％

Side wall hole

12

Conical shape

3.764

4 seconds

2.516

66.8％

Without side wall holes

13*

Conical flat top

6.769

2 seconds

6.617

97.8％

Side wall hole

14

Conical flat top

3.194

2 seconds

2.984

93.4％

Without side wall holes

Testing with at least one side wall hole

As can be seen from table 2, unexpected results were obtained in which it was experimentally observed that the speed of powder ejection and the amount of powder ejected from the blister were significantly increased compared to the condition without the side wall aperture.

Example 5

Air flow testing was conducted both inside and outside of the blister having several drug ejection apertures and at least one side wall aperture. The experimental setup was similar to that described in example 1, but no powder was present in the blisters in these experiments and no air pump was used to generate the air flow. In addition, a plastic capillary is connected to the side wall hole from the outside. In the first experiment, when the blister was intermittently actuated with a pressure actuator, a sensitive light flag (lightweight flag) was observed to move towards the entrance of the plastic capillary tube, thereby registering the vacuum and/or air flow into the blister through the capillary tube and through the side wall aperture, while air was ejected from the drug ejection aperture at the top of the blister.

In a second test, a second lightweight marker was placed over the drug ejection apertures at the top of the blister, and the lightweight marker was observed to move upward, detecting air jets emanating from the drug ejection apertures. At the same time, the first sensitive light mark was observed to move towards the inlet of the plastic capillary tube, thereby registering the vacuum and/or air flow through the capillary tube and through the side wall aperture into the blister. The first mark is drawn into the plastic capillary inlet and blocks it. It was further observed that the second indicia showed a significant increase in the air jet from the drug ejection apertures at the top of the blister when the first indicia were manually removed from the blocked plastic capillary inlet and thus the blocked air inlet into the side wall apertures. It thus appears that the side wall apertures help to increase the air jets emitted from the blister by providing a supply of air into the blister.

Example 6

Experiments were performed in an apparatus similar to the experimental apparatus described in example 2, but without activating the vacuum pump and without driving any air through the fluid channels of the experimental apparatus. A model lactose dry powder was used in this experiment. In blisters without side wall apertures, 6.390mg of lactose were filled and only 28.4% clearance was observed. In blisters with side walls, filled with 5.013 and 6.560mg lactose powder, clearance of 80.8% and 93.4% was observed. In this regard, the side wall apertures help to increase the jet of air emitted from the blister by providing a supply of air into the blister. Unexpected results were obtained in which it was experimentally observed that both the speed of powder ejection and the amount of powder that can be ejected were significantly increased compared to the case without the side wall holes.

While the present invention has been described in detail with reference to specific preferred embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art in light of the foregoing description. It is therefore contemplated that the appended claims will embrace any such alternatives, modifications and variations as falling within the true scope and spirit of the present invention.

Claims (25)

1. A dry powder inhaler cooperatively mounting a container having a dry powder medicament disposed therein, said container characterized by at least one medicament ejection aperture and at least one sidewall air intake aperture, and a vibratory element coupled to said container, wherein said container is mounted within said inhaler, said at least one medicament ejection aperture of said container is located opposite said vibratory element, and said at least one sidewall air intake aperture is not opposite said vibratory element, and said vibratory element is cooperatively vibrating said container and ejecting said medicament from said container through said at least one medicament ejection aperture.

2. An inhaler according to claim 1, wherein the medicament is dispersed and atomised as it is ejected from the container.

3. An inhaler according to claim 1, wherein ejection of the medicament from the container is by synthetic jet.

4. An inhaler according to claim 1, wherein the medicament is ejected from the container in less than 2 seconds.

5. An inhaler according to claim 1, wherein the medicament is ejected from the container at a gravimetric clearance of from 80% of the medicament to 100% of the medicament.

6. The inhaler of claim 1, wherein the medicament is a powder, a mixture of the powder and an excipient, a mixture of several pharmaceutically active ingredients, a mixture of the several pharmaceutically active ingredients and the excipient, or a combination thereof.

7. The inhaler of claim 1, wherein the at least one sidewall air intake aperture has a diameter of 25 microns to 400 microns.

8. The inhaler of claim 1, wherein the shape of the at least one sidewall air intake aperture is circular or polygonal.

9. The inhaler of claim 1, wherein the container is a foil blister, a foil pouch, a plastic blister, or a combination thereof.

10. The inhaler of claim 1, wherein the container is reusable.

11. The inhaler of claim 1, wherein the container is constructed of metal.

12. The inhaler of claim 1, wherein the container is comprised of a metal foil.

13. The inhaler of claim 1, wherein the container is comprised of a polymer coated metal foil.

14. The inhaler of claim 1, wherein the container is comprised of a polymer film.

15. The inhaler of claim 1, wherein the container is comprised of a polymer film coated with a protective layer.

16. The inhaler of claim 1, wherein the container is comprised of a polymer.

17. The inhaler of claim 1, wherein the container is constructed from a polymer sheet.

18. The inhaler of claim 1, wherein the vibrating element is a piezoelectric actuator, a piezoelectric transducer, or a piezoelectric vibrator.

19. The inhaler of claim 1, wherein the vibrating element is adapted to vibrate at an ultrasonic frequency and aerosolize the medicament for inhalation by a patient.

20. The inhaler of claim 1, wherein the at least one sidewall air intake aperture in the container is adapted to receive air from outside the container.

21. An inhaler according to claim 1, wherein the container has a side wall air inlet aperture and four medicament ejection apertures.

22. An inhaler according to claim 1, wherein substantially all of said medicament is ejected from said medicament ejection apertures.

23. The inhaler of claim 1, wherein the medicament is present in the container in an amount of 1mg to 100 mg.

24. A dry powder inhaler comprising:

a container in which a dry powder medicament is placed, the container having a top and a bottom, the bottom sealed to the top;

a vibrating element coupled to the base; and

at least two holes in said top portion, wherein at least one of said holes is opposite said vibratory element to serve as a drug ejection hole, and wherein at least one of said holes is not opposite said vibratory element, wherein upon actuation of said vibratory element, said dry powder drug is ejected from said hole opposite said vibratory element.

25. A dry powder inhaler comprising:

a container having a bottom surface, a top surface, and a sidewall;

at least one aperture in the sidewall;

at least one aperture in said top surface;

a medicament disposed within the container; and

a vibrator coupled to the bottom surface, wherein the at least one aperture of the top surface is in communication with a flow of air inhaled by a patient;

wherein upon vibrating said vibrator, said medicament is ejected from said at least one aperture in said top surface and carried by said flow of air inhaled by said patient, wherein said at least one aperture in said side wall is adapted to receive air from outside said container.