Patent Application
20080202514
Embodiments of this invention are related to medical devices and drug delivery devices, specifically to delivery of aerosolized drugs, to inhalation of drugs for delivery to lungs and gastrointestinal tract, and to intranasal drug delivery.
Devices for delivery of aerosolized drug substances, including delivery via inhalation, are known in the art, examples including U.S. Pat. Nos. 5,694,920, 6,026,809, 6,142,146, all by 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 Genova et al., 6,748,944 by DellaVecchia et al., 5,590,645 by Davies et al. The above patents also provide an overview of various aerosolization and inhalation devices and techniques.
A range of aerosolization and inhalation drug delivery devices is known, including metered dose inhalers, nebulizers, dry powder inhalers, thermal vaporizers, and other systems, with differences related to methods and efficiency of aerosolization and delivery of drug substances to the patient. Metered dose inhalers are typically using pressurized gas to aerosolize the drug substance. Disadvantages of these inhalers are related to difficulties to control the delivered dose of the drug substance and also to high speed of aerosol particles, resulting in particles impinging and depositing on various surfaces in the mouth and in the throat of a patient. Inhalation devices delivering drug substances as a dry powder are known as dry powder inhalers. Passive dry powder inhalers rely on the patient's inspiratory effort to de-aggregate and aerosolize drug substance 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 deaggregation and aerosolization, to decrease the inspiratory effort needed from the patient, and to achieve better inspiratory flow independence of the inhaler performance. Typically for delivery of drug substances to the lungs of a patient via inhalation, the drug aerosol particle size has to be less than about 10 microns, more preferably less than about 6 microns, and for delivery to deep lung less than about 3.3 microns. Larger size particles will be delivered to the mouth and throat of the patient and as a result will be delivered to the gastrointestinal tract of the patient. There is a need to increase the quantities of a drug that dry powder inhalers are capable of aerosolizing during a single inhalation by a patient, e.g. within one to three-four seconds. There is also a need to increase the speed of deaggregation and aerosolization of powders by dry powder inhalers.
Dry powder inhalation devices described in U.S. Pat. Nos. 5,694,920, 6,026,809, 6,142,146, all by Abrams and Gumaste, utilize vibratory means to deaggregate and aerosolize dry powder medication for delivery to the patient as an aerosol. US Patent Publication 2005/0183724 by Gumaste and Bowers discloses a synthetic jet-based medicament delivery method and apparatus.
Briefly, an embodiment of the invention comprises a device for inhalation of aerosolized drug substances, wherein a high frequency vibrator is coupled to a container filled with a dry powder drug substance. Vibrations of the vibrator result in deaggregating, aerosolizing and ejecting of the drug substance from the container for inhalation by a patient. One or more apertures in the container are substantially opposite the vibrator and are used primarily for drug ejection, via synthetic jetting or other mechanisms of ejecting the powder from the container. At least one other aperture in the container is used primarily for ingress of outside gas or air into the container.
Unexpected results, as illustrated in the examples to follow, were obtained when performing experimental testing of the embodiments of the present invention for use as an inhalation and/or aerosolization device, with observations of substantially faster aerosolization and ejection of dry powders, as well as capability of aerosolizing substantially larger quantities of dry powders vs. prior art.
In the drawings, like numerals refer to like parts or features throughout the several views.
A cross-sectional view of an embodiment of the present invention is schematically illustrated in
Container 110 has at least one drug ejection aperture 150 substantially opposite vibrator 100 and serving primarily for ejection of drug substance 120. However, outside air or gas can also enter container through apertures 150. Further, container 110 has at least one side wall aperture 200 which is not substantially opposite to vibrator 100. Side wall aperture 200 is not used for ejection of drug substance but permits air or gas to enter container 110 from outside and thus facilitates deaggregation, aerosolization, and ejection of drug substance 120 from container 110 via drug ejection apertures 150.
Drug substance or substances 120 are provided as a dry powder, but other forms of drug substance are possible, such as liquid or gas. A single component drug substance (neat drug) can be used, as well several drug substances, or drug substances combined with excipients, such as lactose, or combinations thereof. Other additives, such as pharmaceutically inactive ingredients, de-aggregation agents, etc. can also be added to the pharmaceutically active drug substance or substances.
Container 110 is made of metal, plastic, or composite materials. In one embodiment of the present invention, container 110 is a blister pack made of cold formed or thermoformed film, with film materials being polymer, metallic foil, multi-layer polymer-metallic foil clad films, and barrier coated metallic or polymeric films. In an embodiment of the present invention illustrated in
A number of possible shapes and forms of blister pack or container 110 are schematically shown in
The dimensions of 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 utilized according to this invention. In another embodiment, the diameter of container 110 is from about 3 to about 12 mm, while the height of container 110 is from about 3 to about 12 mm.
The dimensions of drug ejection apertures 150 are from about 10 microns to about 1000 microns, with preferred dimensions from about 50 microns to about 500 microns. Dimensions of side wall apertures 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 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, with number of drug ejection apertures 150 in another embodiment being from about 3 to about 6. The number of side wall apertures 200 is from 1 to about 10, with number of side wall apertures 200 in another embodiment being from 1 to 2.
In one embodiment of the present invention, vibrator 100 is directly coupled to container 110 and has substantially the same dimensions as the dimensions of the container 110 on the coupling surfaces, so that the areas of coupling of corresponding surfaces of vibrator 100 and container 110 are substantially the same, as shown in
The directionality of drug ejection apertures 150 shown in
In operation of an embodiment of the present invention, upon actuation of vibrator 100 and initiation of vibrations, vibration energy is transferred to container 110 whereas drug substance is ejected from container 110 though at least one drug ejection aperture 150. In one embodiment of the invention, a synthetic jet of fluid, which can be gas or gas/drug substance mixture, is established through the drug ejection aperture 150. Synthetic jet is characterized in that the fluid is moving in both directions through aperture 150 with simultaneous formation of vortices on both sides of the aperture. Synthetic jetting of gas or liquid is known to these skilled in the art and is characterized by high speed jets of gas or other fluid emanating from an orifice in an enclosed chamber, with fluid entering and exiting the chamber multiple times through an orifice, so that fluid expelled from the chamber is replenished by fluid entering the chamber from outside. Reference is made to US Patent Publication 2005/0183724 by Gumaste and Bowers which describes synthetic jets. Due to gas moving through an orifice in both directions, synthetic jets can continue indefinitely. Forming synthetic jets may require establishment of acoustic waves which can be established, for example, by piezo-vibrators, and may require a combination of specific parameters, including frequencies, orifice dimensions, and container shape and dimensions for establishment of strong, sustained, and reproducible synthetic jets.
Referring now to
Referring now to
Upon actuation of vibrator 100, drug substance 120 is deaggregated, aerosolized, and ejected from the container 110 through drug ejection aperture 150. The sequence of the deaggregation, aerosolization, and ejection of drug substance 120 is not necessarily proceeding in the above order, wherein all three processes can be occurring simultaneously, or consecutively in any order depending on the parameters of the process, with the end result being drug substance 120 ejected from container 110 through drug ejection aperture 150, and aerosolized drug substance 120 appearing inside flow channel 300. Aerosol of the drug substance 120 is then being picked up by stream of air 310 outside of container 110, resulting in drug substance 120 being delivered to the inhaling patient as shown by arrow 320. The ingress of outside air through side wall aperture 200, as shown by arrow 205, facilitates process of deaggregation, aerosolization, and ejection of drug substance 120 through drug ejection apertures 150.
Referring now to
Referring now to
Similarly, in
The piercing of apertures in container 110 can be performed immediately before drug substance delivery to the patient. In one embodiment, the invention operates as follows: the inhaler is activated for use, apertures in the drug container are pierced either simultaneously or sequentially by piercing means 400, or lidding material 630 in case of tape-based drug packs 610 is removed or sheared, or tape-based pouch 710 is opened, and then drug substance 120 is aerosolized as the patient is inhaling through the inhaler. In other embodiments, the opening or piercing of individual drug packs occurs automatically upon inhalation of the patient, through electromechanical or mechanical means, such as spring or electromagnetic actuator, or thermal porator, all optionally activated by inhalation detecting sensor 420.
In another embodiment, as illustrated in
Other embodiments and applications of the invention are contemplated. Drug substance for the delivery to the patient can be a vaccine, DNA or RNA fragment, medication for treatment of pain, asthma, emphysema, chronic bronchitis, cystic fibrosis, COPD, diabetes treatment, or any other medication capable of preventing or treating a disease or reliving symptoms of a disease when delivered in the aerosolized form to the patient and having localized and/or systemic effect.
In another embodiment, the present invention is used to deliver aerosolized drug not for inhalation but for intranasal delivery, oral delivery, eye delivery, or skin surface delivery. In another embodiment, a liquid drug formulation is delivered using the present invention.
A model inhaler device similar to the designs shown in
The experimental results are presented in Table 1. As can be seen from Table 1, unexpected results were obtained, wherein presence of one or more side wall apertures resulted in a significant increase in the speed of drug ejection and also in the quantity of powder that can be effectively ejected, compared with conditions without side wall apertures. Comparison of tests 1 and 2; 2 and 2a; 3 and 3a; 7 and 7a; 9 and 9a indicates that side wall aperture resulted in very significant increase in clearance of the powder from the blister, when compared, at the same conditions, with blisters without side wall apertures. Also comparison of tests 4 and 4a; 5 and 5a; 6 and 6a indicates that without piezo actuation, no appreciable clearance was detected even when side wall apertures were present. Side wall apertures enabled very high gravimetric clearance of regular quantities of powder from the blister, i.e. quantities of the order of 3-6 mg, but also very large quantities of powder, for instance of the order of 15-20 mg and as high as 37 mg, wherein practically no powder ejection can be observed from blisters under same conditions without side wall apertures, as demonstrated by tests 3 and 3a; 7 and 7a; and 8 and 9a. It was visually detected that the clearance of the blisters with side wall apertures occurred fast, sometimes in less than a second, and faster vs. blisters without side wall apertures, which have not completely cleared even in 4 seconds. It was not seen that any appreciable amount of powder was ejected from side wall apertures during the testing performed.
Experimental testing was performed using an experimental setup similar to the setup described in Example 1, but with a proprietary piezo actuator G9 tuned to 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 at rate of 10 Hz (duty cycle). Alternating voltage of approximately 160-200 volts generated by a fly-back circuit in a step wave-form was used to actuate the piezo actuator. A model drug powder (insulin) was used, and demonstrated a very good clearance from the blister. In the experiment, a quantity of drug powder considerably larger vs. typical quantities of 1-3 mg per blister was used. In two tests a blister containing 5 mg of drug powder and having a side wall aperture, in addition to four drug ejection apertures demonstrated 94.6% and 95.9% clearance of powder from the blister during piezo actuation time of 4 seconds. It was observed that the actual clearance time was lower than 4 seconds of piezo actuation time. Thus unexpectedly, much larger quantity of powder is cleared from the blister having a side wall aperture vs. typically seen with the same blisters but without side wall aperture, which achieved clearances of around 80 to 95% only when filled with much lower quantities of insulin, i.e. up to about 2 mg.
Using an experimental setup similar to the setup described in Example 2, a test of a model drug powder blend with lactose was performed with very good clearance, wherein 6 mg of the blend cleared with 97.5% gravimetric clearance from a blister having a side wall aperture. The same blisters but without side wall aperture, demonstrated much lower gravimetric clearances.
Experiments were performed in a setup similar to the experimental setup described in Example 1, but with a non-modified Murata Electronics air transducer serving as a piezo actuator, having resonant frequency of 40 kHz. Piezo actuators with other resonant frequencies can also be used, typically in the range from 30 to 45 kHz. Flow of air through the device was established at 28 LPM using a vacuum pump. Plastic cone-shaped top and cone-shaped, flat top blisters with flat metal foil bottom were utilized as single use containers containing model powder for aerosolization, similar to the blisters depicted in correspondingly
As can be seen from the Table 2, unexpected results were obtained, wherein a significant increase in the speed of powder ejection and also quantity of powder that can be ejected form a blister was experimentally observed, compared with conditions without side wall apertures.
Testing of the air flow in and out of the blister having several drug ejection apertures and at least one side wall aperture was performed. Experimental setup was similar to the setup described in Example 1, but no powder was present in the blisters in these experiments and no air flow was established using a vacuum pump. In addition, a plastic capillary tubing was connected to the side wall aperture from outside. In the first test, when the blister was intermittently actuated with the piezo actuator, a sensitive lightweight flag was observed moving towards the inlet of the plastic capillary tubing thus registering the vacuum and/or air flow through the capillary tubing and through side wall aperture into the blister, while air is being ejected from the drug ejection apertures on top of the blister.
In the second test, a second lightweight flag was placed above drug ejection apertures on top of the blister, said lightweight flag was observed moving upwards detecting jets of air emanating from drug ejection apertures. At the same time the first sensitive lightweight flag was observed moving towards the inlet of the plastic capillary tubing thus registering the vacuum and/or air flow through the capillary tubing and through the side wall aperture into the blister, said first flag being suctioned to the plastic capillary tubing inlet and blocking it. It was further observed that when said first flag was manually removed from blocking the plastic capillary tubing inlet and thus from blocking the air intake into the side wall aperture, the second flag indicated notable increase in air jets emitted from the drug ejection apertures on top of the blister. Thus is appears that side wall aperture helped increasing the jetting of air emanating from the blister by providing air supply into the blister.
Experiments were performed in a setup similar to the experimental setup described in Example 2, but without activating a vacuum pump and driving any air through the flow channel of the experimental setup. A model lactose dry powder was used in the experiments. In a blister without the side wall aperture, filled with 6.390 mg of lactose, a clearance of only 28.4% was observed. In blisters with side aperture, filled with 5.013 and 6.560 mg of lactose powder, a clearance of correspondingly 80.8% and 93.4% was observed. Thus unexpected results were obtained, wherein a significant increase in the speed of powder ejection and also quantity of powder that can be ejected was experimentally observed, compared with conditions without side wall apertures.
While the present invention has been particularly described, in conjunction with specific preferred embodiments, 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.
