US20050016533A1 - Systems and methods for aerosolizing pharmaceutical formulations - Google Patents
Systems and methods for aerosolizing pharmaceutical formulations Download PDFInfo
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- US20050016533A1 US20050016533A1 US10/601,127 US60112703A US2005016533A1 US 20050016533 A1 US20050016533 A1 US 20050016533A1 US 60112703 A US60112703 A US 60112703A US 2005016533 A1 US2005016533 A1 US 2005016533A1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/0001—Details of inhalators; Constructional features thereof
- A61M15/002—Details of inhalators; Constructional features thereof with air flow regulating means
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
- A61M15/003—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using capsules, e.g. to be perforated or broken-up
- A61M15/0033—Details of the piercing or cutting means
- A61M15/0035—Piercing means
- A61M15/0036—Piercing means hollow piercing means
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- A—HUMAN NECESSITIES
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- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
- A61M15/0045—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters
- A61M15/0046—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier
- A61M15/0051—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier the dosages being arranged on a tape, e.g. strips
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- A61M15/00—Inhalators
- A61M15/0065—Inhalators with dosage or measuring devices
- A61M15/0068—Indicating or counting the number of dispensed doses or of remaining doses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/0065—Inhalators with dosage or measuring devices
- A61M15/0068—Indicating or counting the number of dispensed doses or of remaining doses
- A61M15/0083—Timers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61M15/00—Inhalators
- A61M15/0091—Inhalators mechanically breath-triggered
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/0091—Inhalators mechanically breath-triggered
- A61M15/0093—Inhalators mechanically breath-triggered without arming or cocking, e.g. acting directly on the delivery valve
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- A—HUMAN NECESSITIES
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- A61M15/00—Inhalators
- A61M15/0091—Inhalators mechanically breath-triggered
- A61M15/0096—Hindering inhalation before activation of the dispenser
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
- A61M16/04—Tracheal tubes
- A61M16/0488—Mouthpieces; Means for guiding, securing or introducing the tubes
- A61M16/049—Mouthpieces
- A61M16/0493—Mouthpieces with means for protecting the tube from damage caused by the patient's teeth, e.g. bite block
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
- A61M16/04—Tracheal tubes
- A61M16/0488—Mouthpieces; Means for guiding, securing or introducing the tubes
- A61M16/049—Mouthpieces
- A61M16/0495—Mouthpieces with tongue depressors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
- A61M16/08—Bellows; Connecting tubes ; Water traps; Patient circuits
- A61M16/0866—Passive resistors therefor
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
- A61M16/20—Valves specially adapted to medical respiratory devices
- A61M16/201—Controlled valves
- A61M16/206—Capsule valves, e.g. mushroom, membrane valves
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- A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
- A61M16/20—Valves specially adapted to medical respiratory devices
- A61M16/208—Non-controlled one-way valves, e.g. exhalation, check, pop-off non-rebreathing valves
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61M2202/00—Special media to be introduced, removed or treated
- A61M2202/06—Solids
- A61M2202/064—Powder
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Abstract
Systems and methods are provided for aerosolizing a pharmaceutical formulation. According to one method, respiratory gases are prevented from flowing to the lungs when attempting to inhale. Then, respiratory gases are abruptly permitted to flow to the lungs. The flow of respiratory gases may then be used to extract a pharmaceutical formulation from a receptacle and to place the pharmaceutical formulation within the flow of respiratory gases to form an aerosol.
Description
- This application is a continuation in part application and claims the benefit of U.S. Provisional Patent Application Nos. 60/141,793, filed Jun. 30, 1999 and 60/198,060, filed Apr. 18, 2000, the complete disclosures of which are herein incorporated by reference.
- This invention relates generally to the field of drug delivery, and in particular to the delivery of pharmaceutical formulations to the lungs. More specifically, the invention relates to the aerosolization of pharmaceutical formulations using energy created by patient inhalation.
- Effective drug delivery to a patient is a critical aspect of any successful drug therapy, and a variety of drug delivery techniques have been proposed. For example, one convenient method is the oral delivery of pills, capsules, elixirs and the like. However, oral delivery can in some cases be undesirable in that many drugs are degraded in the digestive tract before they can be absorbed. Another technique is subcutaneous injection. One disadvantage to this approach is low patient acceptance. Other alternative routes of administration that have been proposed include transdermal, intranasal, intrarectal, intravaginal and pulmonary delivery.
- Of particular interest to the invention are pulmonary delivery techniques which rely on the inhalation of a pharmaceutical formulation by the patient so that the active drug within the dispersion can reach the distal (alveolar) regions of the lung. A variety of aerosolization systems have been proposed to disperse pharmaceutical formulations. For example, U.S. Pat. Nos. 5,785,049 and 5,740,794, the disclosures of which are herein incorporated by reference, describe exemplary powder dispersion devices which utilize a compressed gas to aerosolize a powder. Other types of aerosolization systems include MDI's (which typically have a drug that is stored in a propellant), nebulizers (which aerosolize liquids using compressed gas, usually air), and the like.
- Another technique which is of interest to the invention is the use of inspired gases to disperse the pharmaceutical formulation. In this way, the patient is able to provide the energy needed to aerosolize the formulation by the patient's own inhalation. This insures that aerosol generation and inhalation are properly synchronized. Utilization of the patient's inspired gases can be challenging in several respects. For example, for some pharmaceutical formulations, such as insulin, it may be desirable to limit the inhalation flow rate within certain limits. For example, PCT/US99/04654, filed Mar. 11, 1999, provides for the pulmonary delivery of insulin at rates less than 17 liters per minute. As another example, copending U.S. patent application Ser. No. 09/414,384 describes pulmonary delivery techniques where a high flow resistance is provided for an initial period followed by a period of lower flow resistance. The complete disclosures of all the above references are herein incorporated by reference.
- Another challenge in utilizing the patient's inspired gases is that the inspiration flow rate can drastically vary between individuals. For instance, as shown in
FIG. 1 , a random sample of 17 individuals which were measured twice a week for four weeks produced flow rates ranging from about 5 liters per minute to about 35 liters per minute. Such variability may affect the ability of the formulation to be dispersed within a gas stream, the ability to deagglomerate a powdered formulation, and/or the ability of the aerosolized formulation to adequately reach the deep lung. - Hence, this invention is related to techniques for regulating the flow of inspired gases that may be utilized when dispersing a pharmaceutical formulation. In one aspect, the invention is related to techniques to enhance the ability of a formulation to be dispersed within a gas stream produced by patient inhalation, to enhance the ability to deagglomerate a powdered formulation, and to enhance the ability of the aerosolized formulation to adequately reach the deep lung.
- The invention provides exemplary systems and methods to provide breath actuated, flow regulated aerosol delivery of pharmaceuticals. In one aspect, the invention utilizes the flow of respiratory gases produced by a patient to aerosolize a pharmaceutical formulation. In another particular aspect of the invention, the invention is able to extract a powdered pharmaceutical formulation from a receptacle, deagglomerate the formulation and deliver the formulation to the lungs using a wide range of patient inhalation flow rates. According to another aspect of the invention, devices and methods are provided which provide efficient delivery of a pharmaceutical aerosol to the deep lung.
- According to the invention, the flow of respiratory gases may initially be prevented from flowing to the lungs until a predetermined vacuum is produced by the user, at which point the flow of respiratory gases is abruptly initiated. In one particular embodiment, the abrupt initiation of respiratory gas flow is utilized to aerosolize a pharmaceutical formulation. According to this embodiment, respiratory gases are initially prevented from flowing to the lungs when attempting to inhale through an open mouthpiece at one end of the device. The respiratory gases are then abruptly permitted to flow to the lungs after a predetermined vacuum is produced by the user. The flow of respiratory gases is utilized to extract a pharmaceutical formulation from a receptacle and to place the pharmaceutical formulation within the flow of respiratory gases to form an aerosol.
- By initially preventing respiratory gases from flowing to the lungs when attempting to inhale, the devices and methods of the present invention provide a way to ensure that the resulting gas stream has sufficient energy to extract the pharmaceutical formulation from the receptacle. In one aspect, the flow of respiratory gases may initially be prevented from flowing to the lungs by placing a valve within an airway leading to the lungs and opening the valve to permit the flow of respiratory gases. According to the invention, the valve is opened when a threshold actuating vacuum caused by the attempted inhalation is exceeded. In this way, when the valve is opened, the resulting gas stream has sufficient energy to extract and aerosolize the pharmaceutical formulation.
- In another embodiment, the invention provides an aerosolization device that comprises a housing defining an airway, and a coupling mechanism to couple a receptacle containing a pharmaceutical formulation to the airway. The device further includes a valve to prevent respiratory gases from flowing through the airway until a threshold actuating vacuum is exceeded. At such a time, the valve opens to permit respiratory gases to flow through the airway and to extract the pharmaceutical formulation from the receptacle to form an aerosol.
- A variety of threshold valves may be employed to prevent gases from flowing through the airway as will be discussed in detail below. For example, the valve may comprise an occlusion member having an opening, and a pull through member that is pulled through the opening when the threshold actuating vacuum is produced. As one specific example, the occlusion member may comprise an elastically compliant membrane, and the pull through member may comprise a ball that is pulled through the membrane when the threshold vacuum has been achieved. In another aspect, the threshold actuating vacuum of the valve is in the range from about 20 cm H20 to about 60 cm H20. In one particular aspect, the valve is configured to be disposed within the receptacle. In this way, the valve may conveniently be manufactured along with the receptacle.
- According to another aspect, the invention provides devices and methods for regulating the flow of respiratory gases to provide consistent airflow, independent of the breathing rate of the user. In another aspect, the system includes a regulation system to regulate the flow of respiratory gases through the airway after the valve has been opened. The combination of flow regulation with the threshold valve according to the present invention results in devices and methods for aerosol delivery that are effective in delivering the aerosolized formulation to the deep lung.
- In still another aspect, the devices and methods of the invention may limit the flow of respiratory gases to a rate that is less than a certain rate for a certain time. For example, the flow rate may be limited to a rate that is less than about 15 liters per minute for a time in the range from about 0.5 second to about 5 seconds, corresponding to a volume in the range from about 125 mL to about 1.25 L. Regulation of the flow rate is advantageous in that it may increase systemic bioavailability of the active agent of certain pharmaceutical formulations via absorption in the deep lung as described generally in PCT Application No. PCT/U.S. 99/04654, filed Mar. 3, 1999 and in copending U.S. application Ser. No. 09/414,384, previously incorporated by reference.
- A variety of techniques may be employed to limit or regulate the flow of respiratory gases. For example, feedback may be provided to the user when an excessive flow rate is produced to permit a user to adjust their inhalation rate. Examples of feedback which may be provided include audio feedback, including a whistle, visual feedback, such as indicator lights or a level meter, tactile feedback, such as vibration, and the like. As another alternative, the flow of respiratory gases may be controlled by regulating the size of an airway leading to the lungs. For example, an elastically compliant valve may be used to provide flow resistance based upon the flow rate through the device and limit the flow to a certain rate.
- In one aspect, the device further includes a regulation system to regulate the flow of respiratory gases through the airway to a certain rate. For example, the regulation system may be configured to limit the flow to a rate that is less than about 15 liters per minute for a certain time or a certain inspired volume. A variety of flow regulators may be employed to regulate the flow of gases to a certain rate as will be discussed in detail below. For example, the flow regulator may comprise a valve that is constructed of an elastic element, such as a soft elastomer, that limits the flow to a certain rate while also preventing flow in the opposite direction. Such a valve may have an orifice that permits the flow of air through the valve in response to an applied vacuum, and one or more collapsible walls surrounding the orifice. In this way, an increased vacuum pressure level draws the walls toward each other, thereby reducing or closing the orifice area and providing a higher resistance or complete resistance to flow. For example such a valve may be placed in a parallel flow path. Once the flow rate becomes too great, the valve closes so that all air passing through the device must pass through the other flow path. By providing this flow path with a certain size, the flow of gases through the device may be kept below the threshold rate.
- In another particular aspect, the regulation system may comprise a feedback mechanism to provide information on the rate of flow of the respiratory gases. For example, the feedback mechanism may comprise a whistle that is in communication with the airway and produces a whistling sound when the maximum flow rate is exceeded. In another alternative, the regulation system may comprise a restriction mechanism to limit the size of the airway. Conveniently, the restriction mechanism may be adjustable to vary the rate of flow of respiratory gases through the airway. The restriction mechanism may be adjusted manually or automatically, such as by the use of an elastically compliant material.
- Optionally, an electronically governed, closed-loop control system may be provided to adjust the restriction mechanism. In one aspect, the control system is configured to limit the flow to a certain rate for a certain time or a certain inspired volume and then to sense and adjust the restriction mechanism to permit an increased flow of respiratory gases through the airway. In this manner, the flow rate of respiratory gases may be regulated to limit the flow to a certain rate for a certain time to facilitate proper delivery of the pharmaceutical formulation to the lungs. The control system may then be employed to adjust the restriction mechanism so that the user can comfortably fill their lungs with respiratory gases to deliver the pharmaceutical formulation to the deep lung. Use of the regulation system and control system according to the present invention is advantageous in that the device may be used with numerous users that have different inhalation flow rates, with the device regulating the flow of respiratory gases so that the pharmaceutical formulation is properly delivered to the lungs.
- According to another aspect of the invention, after the flow rate has been limited for the desired amount of time or inhaled volume, the size of the airway may be increased to provide for an increased flow rate. This may be accomplished, for example, by opening another airway traveling through the device. In this way, the user may comfortably inhale without substantial resistance in order to fill the user's lungs with respiratory gases and carry the pharmaceutical formulation into the deep lung.
- In an alternative aspect, the invention may optionally utilize a variety of flow integrators to permit an increased flow rate through the inhalation device after a certain amount of time to permit the user to comfortably fill their lungs at the end of the process. Such flow integrators may have one or more moving members that move based on the volume of flow through the device. In this way, when the initial (regulated) volume has been inhaled, the member has moved sufficient to open another gas channel to permit increased gas flow. Examples of flow integrators that may be used are discussed in detail below and include movable pistons, clutch mechanisms, gas filled bellows with a bleed hole, and the like.
- The pharmaceutical formulation for use with the systems and methods of the present invention may be a liquid or powder formulation. In one aspect of the method, the pharmaceutical formulation comprises a powdered medicament. The flow of respiratory gases is used to deagglomerate the powder once extracted from the receptacle. Optionally, various structures may be placed into the airway to assist in the deagglomeration process.
- In still yet another embodiment, the invention provides a receptacle that comprises a receptacle body defining a cavity that is enclosed by a penetrable access lid. The receptacle further includes a threshold valve that is coupled to the receptacle body. In one aspect, the threshold valve is configured to open when experiencing a vacuum of at least about 40 cm H2O.
- According to another aspect, the invention may also utilize a variety of techniques to ensure that the user properly positions their mouth over the mouthpiece during use of an aerosolization device. For example, a lip guard may be included on the mouthpiece to permit the user to place their lips adjacent the lip guard. As another example, the mouthpiece may include bite or other landmarks. Alternatively, one or more holes may be provided in the side of the mouthpiece. These holes must be covered by the lips in order to create a sufficient vacuum to operate the device. As a further example, the mouthpiece may have a circular-to-elliptical profile. The elliptical portion must be covered by the patient's mouth in order for a vacuum sufficient to actuate the device to be created.
- These and other aspects of the present invention will be readily apparent to one of ordinary skill in the art in view of the drawings and detailed description that follows.
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FIG. 1 is a graph illustrating the average inspiration flow rate for 17 individuals that were measured twice a week for four weeks. -
FIG. 2 is a graph illustrating the regulation of a patient's inspiration flow rate over time according to the invention. -
FIG. 3 . is a graph illustrating the regulation of another patient's inspiration flow rate over time according to the invention. -
FIG. 4 is a schematic view of one system that may be utilized to extract a pharmaceutical formulation from a receptacle, deagglomerate the formulation and to place the formulation within the flow of respiratory gases to form an aerosol according to the invention. -
FIG. 5 is a perspective view of an aerosolization device according to the invention. -
FIG. 6 is a partial cutaway view of the aerosolization device ofFIG. 5 shown in an open or loading position. -
FIG. 7 illustrates the aerosolization device ofFIG. 6 in a closed or operating position according to the invention. -
FIG. 8 illustrates the aerosolization device ofFIG. 6 when inserting a receptacle according to the invention. -
FIG. 9 illustrates the aerosolization device ofFIG. 8 when the receptacle has been inserted, when the device has been moved to the closed or operating position, and when respiratory gases are flowed through the device. -
FIG. 10 is a partial cutaway perspective view of a receptacle and a convergent nozzle through which a pharmaceutical formulation may be extracted according to the invention. -
FIG. 11 illustrates the receptacle and nozzle ofFIG. 10 , with the nozzle being moved further away from a bottom end of the receptacle to increase the rate of flow of respiratory gases through the nozzle according to the invention. -
FIG. 12 is a schematic, cross-sectional side view of an aerosolization system having a spring to regulate the flow of respiratory gases through the system according to the invention. -
FIG. 13 is a schematic, cross-sectional view of an aerosolization system having a flow regulation system to regulate the flow of respiratory gases through the aerosolization system according to the invention. -
FIG. 14 illustrates one embodiment of a nozzle that may be employed to deagglomerate a pharmaceutical formulation according to the invention. -
FIG. 15 is a perspective view of one embodiment of an aerosolization device according to the invention. -
FIG. 16 is a perspective view of another embodiment of an aerosolization device according to the invention. -
FIG. 16A illustrates a cover of the aerosolization device ofFIG. 16 . -
FIG. 17 is a perspective view of still another embodiment of an aerosolization device according to the invention illustrating the use of a flow rate feedback device. -
FIG. 18 illustrates still yet another embodiment of an aerosolization device according to the invention. -
FIG. 19 illustrates one particular embodiment of an aerosolization device according the invention. -
FIG. 19A illustrates a disk having multiple receptacles that may be inserted into the aerosolization device ofFIG. 19 . -
FIG. 19B illustrates a front end of the aerosolization device ofFIG. 19 . -
FIG. 20 illustrates another embodiment of an aerosolization device according the invention. -
FIG. 20A illustrates the aerosolization device ofFIG. 20 showing a lid moved to an open position. -
FIG. 21 is a perspective view of yet another embodiment of an aerosolization device according to the invention. -
FIG. 22 illustrates one particular embodiment of an aerosolization device according the invention capable of holding multiple drug packets. -
FIG. 22A illustrates a clip for use with the aerosolization device ofFIG. 22 . -
FIG. 23 illustrates yet another alternative embodiment of an aerosolization device according the invention. -
FIG. 23A illustrates a mouthpiece cover of the aerosolization device ofFIG. 23 . -
FIG. 24 illustrates a strip of receptacles that may be utilized within the aerosolization device ofFIG. 23 . -
FIG. 25 illustrates still another alternative embodiment of an aerosolization device according to the invention. -
FIG. 26 illustrates one embodiment of an aerosolization device according to the invention. -
FIG. 27 is a schematic diagram of a threshold valve according to the invention. -
FIG. 28 is a ball and membrane threshold valve according to the invention. -
FIG. 29 is an umbrella type threshold valve according to the invention. -
FIG. 30 schematically illustrates one embodiment of a threshold valve according to the invention. -
FIGS. 31A and 31B illustrate a flapper type threshold valve according to the invention. -
FIG. 32 illustrates a spindle type threshold valve according to the invention. -
FIG. 33 illustrates another spindle type threshold valve according to the invention. -
FIGS. 34A and 34B illustrate an umbrella type threshold valve according to the invention. -
FIG. 35 illustrates a ball and magnet type threshold valve according to the invention. -
FIGS. 36A and 36B illustrate a bistable dome type threshold valve according to the invention. -
FIGS. 37A and 37B illustrate a mechanical pressure switch type threshold valve according to the invention. -
FIG. 38 illustrates a frangible membrane type of threshold valve according to the invention. -
FIG. 39 illustrates another mechanical pressure switch type threshold valve according to the invention. -
FIG. 40 illustrates a pull through type threshold valve according to the invention. -
FIG. 41 is a schematic diagram of a flow regulator according to the invention. -
FIGS. 42A and 42B illustrate a shuttle type flow regulator according to the invention. -
FIG. 43 illustrates a ball type flow regulator according to the invention. -
FIGS. 44A and 44B illustrate a bellows type flow regulator according to the invention. -
FIG. 45 illustrates a cone type flow regulator according to the invention. -
FIG. 46 illustrates another embodiment of a flow regulator according to the invention. -
FIG. 47 illustrates a foam type flow regulator according to the invention. -
FIG. 48 illustrates an umbrella type flow regulator according to the invention. -
FIG. 49 illustrates a liquid reservoir flow regulator according to the invention. -
FIG. 50 illustrates another embodiment of a flow regulator according to the invention. -
FIG. 51 illustrates a spindle type flow regulator according to the invention. -
FIG. 52 illustrates an expandable cone type flow regulator according to the invention. -
FIGS. 53A and 53B illustrate an iris type flow regulator according to the invention. -
FIG. 54 illustrates a paddle wheel type flow regulator according to the invention. -
FIGS. 55A and 55B illustrate a flap type flow regulator according to the invention. -
FIGS. 56A and 56B illustrate an elastomeric duck bill type flow regulator according to the invention. -
FIGS. 57-59 illustrate alternative elastomeric duck bill type flow regulators according to the invention. -
FIG. 60 schematically illustrates a flow through type flow integrator according to the invention. -
FIG. 61 schematically illustrates a flow-by type flow integrator according to the invention. -
FIGS. 62A and 62B illustrate a flow through shuttle type flow integrator according to the invention. -
FIG. 63 illustrates an impeller type flow integrator according to the invention. -
FIG. 64 is an end view of a cam of the flow integrator ofFIG. 63 . -
FIG. 65 illustrates a paddle wheel that may be used in the flow integrator ofFIG. 63 . -
FIGS. 66A and 66B illustrate a shuttle type flow integrator according to the invention. -
FIG. 67 illustrates a brake timer flow integrator according to the invention. -
FIG. 68 illustrates a brake and a wheel of the flow integrator ofFIG. 67 . -
FIG. 69 schematically illustrates an aerosolization system having various components arranged in series according to the invention. -
FIG. 70 schematically illustrates an aerosolization system having a parallel flow-by type flow integrator according to the invention. -
FIG. 71 schematically illustrates an aerosolization system having a parallel flow through type flow integrator according to the invention. -
FIG. 72 is a front perspective view of one embodiment of an aerosolization device according to the invention. -
FIG. 73 illustrates the device ofFIG. 72 in a loading position. -
FIG. 74 is a rear perspective view of the device ofFIG. 72 . -
FIG. 75 is a cross sectional view of the device ofFIG. 73 . -
FIG. 76 is a cross sectional view of the device ofFIG. 72 . -
FIG. 77 is a cross sectional side view of the device ofFIG. 72 . -
FIG. 78 illustrates the device ofFIG. 72 when in the loading position. -
FIG. 79 is a front perspective view of another embodiment of an aerosolization device according to the invention. -
FIG. 80 illustrates the device ofFIG. 79 in a loading position. -
FIG. 81 is a cross sectional view of the device ofFIG. 79 . -
FIG. 82 illustrates the device ofFIG. 82 when another flow path has been opened to permit an increased flow of air through the device. -
FIG. 83 is a side view of the device ofFIG. 81 . -
FIG. 84 is a front perspective view of another embodiment of an aerosolization device according to the invention. -
FIG. 85 illustrates the device ofFIG. 84 when in a loading position. -
FIG. 86 is a cross sectional view of the device ofFIG. 84 . -
FIG. 87 is a side view of the device ofFIG. 86 . -
FIG. 88 is a front perspective view of one embodiment of a mouthpiece according to the invention. -
FIG. 89 is a side view of an alternative mouthpiece according to the invention. - “Active agent” as described herein includes an agent, drug, compound, composition of matter or mixture thereof which provides some pharmacologic, often beneficial, effect. This includes foods, food supplements, nutrients, drugs, vaccines, vitamins, and other beneficial agents. As used herein, the terms further include any physiologically or pharmacologically active substance that produces a localized or systemic effect in a patient. The active agent that can be delivered includes antibiotics, antiviral agents, anepileptics, analgesics, anti-inflammatory agents and bronchodilators, and viruses and may be inorganic and organic compounds, including, without limitation, drugs which act on the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synaptic sites, neuroeffector junctional sites, endocrine and hormone systems, the immunological system, the reproductive system, the skeletal system, autacoid systems, the alimentary and excretory systems, the histamine system and the central nervous system. Suitable agents may be selected from, for example, polysaccharides, steroids, hypnotics and sedatives, psychic energizers, tranquilizers, anticonvulsants, muscle relaxants, antiparkinson agents, analgesics, anti-inflammatories, muscle contractants, antimicrobials, antimalarials, hormonal agents including contraceptives, sympathomimetics, polypeptides, and proteins capable of eliciting physiological effects, diuretics, lipid regulating agents, antiandrogenic agents, antiparasitics, neoplastics, antineoplastics, hypoglycemics, nutritional agents and supplements, growth supplements, fats, antienteritis agents, electrolytes, vaccines and diagnostic agents.
- Examples of active agents useful in this invention include but are not limited to insulin, calcitonin, erythropoietin (EPO), Factor VIII, Factor IX, ceredase, cerezyme, cyclosporine, granulocyte colony stimulating factor (GCSF), alpha-1 proteinase inhibitor, elcatonin, granulocyte macrophage colony stimulating factor (GMCSF), growth hormone, human growth hormone (HGH), growth hormone releasing hormone (GHRH), heparin, low molecular weight heparin (LMWH), interferon alpha, interferon beta, interferon gamma, interleukin-2, luteinizing hormone releasing hormone (LHRH), somatostatin, somatostatin analogs including octreotide, vasopressin analog, follicle stimulating hormone (FSH), insulin-like growth factor, insulintropin, interleukin-1 receptor antagonist, interleukin-3, interleukin-4, interleukin-6, macrophage colony stimulating factor (M-CSF), nerve growth factor, parathyroid hormone (PTH), thymosin alpha 1, IIb/IIIa inhibitor, alpha-1 antitrypsin, respiratory syncytial virus antibody, cystic fibrosis transmembrane regulator (CFTR) gene, deoxyribonuclease (Dnase), bactericidal/permeability increasing protein (BPI), anti-CMV antibody, interleukin-1 receptor, 13-cis retinoic acid, pentamidine isethionate, albuterol sulfate, metaproterenol sulfate, beclomethasone dipropionate, triamcinolone acetamide, budesonide acetonide, ipratropium bromide, flunisolide, fluticasone, cromolyn sodium, ergotamine tartrate and the analogues, agonists and antagonists of the above. Active agents may further comprise nucleic acids, present as bare nucleic acid molecules, viral vectors, associated viral particles, nucleic acids associated or incorporated within lipids or a lipid-containing material, plasmid DNA or RNA or other nucleic acid construction of a type suitable for transfection or transformation of cells, particularly cells of the alveolar regions of the lungs. The active agents may be in various forms, such as soluble and insoluble charged or uncharged molecules, components of molecular complexes or pharmacologically acceptable salts. The active agents may be naturally occurring molecules or they may be recombinantly produced, or they may be analogs of the naturally occurring or recombinantly produced active agents with one or more amino acids added or deleted. Further, the active agent may comprise live attenuated or killed viruses suitable for use as vaccines.
- “Mass median diameter” or “MMMD” is a measure of mean particle size, since the powders of the invention are generally polydisperse (i.e., consist of a range of particle sizes). MMD values as reported herein are determined by centrifugal sedimentation, although any number of commonly employed techniques can be used for measuring mean particle size.
- “Mass median aerodynamic diameter” or “MMAD” is a measure of the aerodynamic size of a dispersed particle. The aerodynamic diameter is used to describe an aerosolized powder in terms of its settling behavior, and is the diameter of a unit density sphere having the same settling velocity, generally in air, as the particle. The aerodynamic diameter encompasses particle shape, density and physical size of a particle. As used herein, MMAD refers to the midpoint or median of the aerodynamic particle size distribution of an aerosolized powder determined by cascade impaction.
- The invention provides systems and methods for the administration of aerosolized pharmaceutical formulations using the flow of respiratory gases produced by a patient. The pharmaceutical formulations that may be aerosolized include powdered medicaments, liquid solutions or suspensions, and the like, and may include an active agent. The devices of the present invention may be used for single or multiple administrations.
- In some embodiments, the flow of respiratory gases produced by the patient is employed to extract the pharmaceutical formulation from a receptacle, to deagglomerate the pharmaceutical formulation and deliver the pharmaceutical formulation to the patient's lungs. One particular advantage of the invention is the ability to perform such functions independent of the patient's natural inhalation flow rate. Hence, in one aspect of the invention, the inhaled respiratory gases are controlled so that they remain within an acceptable range of flow rates to adequately deliver the pharmaceutical formulation to the lungs.
- In another aspect, the invention is configured to regulate the flow of inspired gases so that the gases have sufficient energy to extract the pharmaceutical formulation from a receptacle, deagglomerate the formulation, and deliver it to the patient's lungs. In some cases, the invention is further configured to maintain the inhalation flow rate below a maximum level for at least a certain time or inhaled volume when initially delivering the drug. In this way, the aerosolized formulation will flow at an acceptable flow rate to enhance its ability to traverse the patient's airway and enter into the lungs. After initial delivery of the pharmaceutical formulation to the lungs, some embodiments of the invention may be configured to permit the patient to breath at a normal inspiration flow rate to fill the patient's lungs with respiratory gases and to further deliver the pharmaceutical formulation to the deep lung.
- To aerosolize the pharmaceutical formulation, the flow of respiratory gases preferably contains sufficient energy to extract the pharmaceutical formulation from the receptacle. To ensure that the respiratory gases contain sufficient energy, the invention may be configured to prevent respiratory gases from flowing to the patient's lungs when the patient attempts to inhale. Abruptly, the respiratory gases may then be permitted to flow to the patient's lungs after a threshold vacuum has been reached. By abruptly permitting the flow of respiratory gases only when sufficient vacuum has been applied by the user, a relatively high rate of flow is achieved to provide the gas stream with sufficient energy. One way to accomplish such a process is by placing a restriction, valve, or other blocking mechanism in the patient's airway to prevent respiratory gases from entering the patient's lungs when the patient attempts to inhale. The restriction or valve may then be rapidly removed or opened to permit respiratory gases to flow to the lungs. Hence, a patient may be instructed to inhale until a threshold actuating vacuum is overcome. The threshold actuating vacuum may be configured such that it will produce sufficient energy in the resulting gas stream when the gases are allowed to flow to the patient's lungs. Preferably, the threshold vacuum is in the range from about 20 cm H20 to about 60 cm H20 so that the resulting gas stream will have sufficient energy to extract and deagglomerate the pharmaceutical formulation. Most preferably, the threshold vacuum is at least 40 cm H20.
- A variety of threshold valves may also be employed to prevent respiratory gases from reaching the patient's lungs until a threshold inhalation vacuum is obtained. For example, the threshold valve may comprise an elastically compliant valve such as a flexible membrane that is disposed across the airway and is configured to flex when the threshold vacuum is met or exceeded. Alternatively, the threshold valve may comprise a scored membrane that is configured to tear or burst once the threshold vacuum is met or exceeded. As another example, the threshold valve may comprise an elastomer membrane having an opening. A ball is pulled through the opening once the threshold pressure has been met or exceeded. Other types of threshold valves include bi-stable mechanisms, diaphragms, and the like.
- In one particular aspect of the invention, the threshold valve may be incorporated into a receptacle that also holds the pharmaceutical formulation. In this way, each time a new receptacle is inserted into an aerosolization device, the device is provided with a new threshold valve. This is particularly advantageous when the threshold valve comprises a membrane that is configured to tear or burst after the threshold vacuum is met or exceeded.
- Once the respiratory gases are allowed to flow to the lungs, the flow rate of the respiratory gases (in some cases) may need to be controlled or regulated so that the gases do not exceed a maximum flow rate during delivery of the pharmaceutical formulation to the lungs. Typically, the flow rate of respiratory gases may be regulated to be less than about 15 liters per minute for a time in the range from about 0.5 seconds to about 5 seconds, corresponding to an inhaled volume in the range from about 125 mL to about 1.25 L, to permit the aerosolized formulation to pass through the patient's airway and enter into the lungs. For example, as previously illustrated in connection with
FIG. 1 , some patients have a natural inhalation rate that exceeds a desired maximum flow rate. - For breathers that naturally breath above the maximum desired flow rate, the invention provides for the slowing of the flow rate during the time when the aerosolized formulation is being delivered to the lungs. This is illustrated graphically in
FIG. 2 . At time T1, the patient is inhaling causing respiratory gases to flow to the patient's lungs. At time T1, the flow rate is well above a starting flow rate, QSTART, which is desirable for initially extracting the pharmaceutical formulation from the receptacle as previously described. Hence, a threshold valve or other flow prevention mechanism may not be needed for such breathers. Shortly after time T1 is time T2, where the flow rate has been regulated to be below a QDELIVERY flow rate. The flow rate is maintained below the QDELIVERY rate from time T2 to time T3, where the aerosolized formulation is being delivered to the patient's lungs. After time T3, the regulation of the gas flow is ceased and the patient is permitted to inhale at their regular flow rate to fill their lungs with respiratory gases that serve to further deliver the pharmaceutical formulation to the deep lung. -
FIG. 3 graphically illustrates an example of where the patient has a natural inhalation flow rate that is below QDELIVERY As shown inFIG. 3 , by preventing the flow of respiratory gases during patient inhalation, and then abruptly permitting the flow of respiratory gases, the starting flow rate at time T1, is at QSTART. In this way, sufficient energy is provided to extract the formulation from the receptacle. After the patient continues to inhale, the flow rate rapidly falls below the QDELIVERY flow rate because the patient's natural inhalation flow rate is less than the QDELIVERY flow rate. Hence, after time T1, the patient's inhalation flow rate does not need to be regulated, thereby permitting the patient to inhale at a comfortable level. - A variety of schemes and techniques may be provided to regulate the inhalation flow rate to be below the QDELIVERY flow rate from time T2 to time T3. As one example, the patient may be provided with various types of feedback to permit the patient to self-regulate their inhalation flow rate. For instance, an aerosolization device may be provided with a whistle that creates a whistling sound when the patient's flow rate exceeds the QDELIVERY flow rate. Other types of feedback that may be utilized include visual feedback, tactile feedback, auditory feedback, and the like. Optionally, a controller may be provided with a timing mechanism to indicate to the user when time T3 has elapsed so that the user may finish their inhalation at a comfortable level.
- As another example, the patient's inhalation flow rate may be regulated by restricting or impeding the respiratory gases being inhaled. For example, the size of the airway may be varied to control the rate of flow of inspired gases. The manner of regulation may be either manual, semi-automated, or automated. For example, the user may manually adjust the size of the airway or place a restriction in the airway to control the rate of flow. Alternatively, the size of the airway may be adjusted based on the patient's own inhalation as described in greater detail hereinafter. In still another example, an automated system with one or more flow sensors may be provided to regulate the size of the airway to regulate the flow of respiratory gases.
- One particular advantage of restricting the flow of respiratory gases to control the inhalation flow rate is that a relatively high pressure drop may be created. Because power is generally proportional to both the pressure drop and flow rate, the flow rate may be kept low while still providing sufficient energy to aerosolize the formulation and to deliver the formulation to the patient's lungs.
- As another alternative, the flow of respiratory gases may be regulated by placing an orifice or other restriction member into the patient's airway that is made for use with a specific patient. In this way, an aerosolization device may be tailored to a specific patient simply by utilizing an orifice sized according to the patient's natural inhalation flow rate.
- Devices according to the present invention may comprise series or parallel flowpaths. In either case, it may be desirable to maintain a constant, predetermined flow rate across a large patient population. For series constructs, as depicted in
FIG. 4 , it is preferred that the flow resistance/vacuum relationship is substantially linear. For parallel constructs, as shown inFIG. 70 for example, it is preferable to provide that the flow resistance/vacuum relationship is highly nonlinear. - Referring now to
FIG. 4 , asystem 10 utilizing a series construct for extracting a powdered medicament from areceptacle 12 using a patient's inspired respiratory gases will be described.System 10 comprises athreshold valve 14 that may be configured to open when the vacuum within a line 16 downstream ofthreshold valve 14 experiences a vacuum of within 20-60 cm H20, preferably greater than about 40 cm H20. Also coupled to line 16 is aregulation system 18 that regulates the flow of respiratory gases throughsystem 10. As one example,regulation system 18 may include a restriction mechanism that may be employed to control the internal size of line 16 and thereby regulate the flow of respiratory gases through line 16. Conveniently,regulation system 18 may include a control system that adjusts the restriction mechanism. The control system may be either manually operated or operated in an automated manner using a controller. For example, gas flow sensors may be disposed insystem 10 and coupled to the controller to determine the rate of flow of respiratory gases through the system. Using this information, the controller may be employed to control the degree of restriction of line 16. Althoughregulation system 18 is shown upstream ofreceptacle 12, it will be appreciated thatregulation system 18 may be provided in other locations, including downstream ofreceptacle 22 and upstream ofthreshold valve 14. -
Regulation system 18 is coupled toreceptacle 12 by aline 20. Exitingreceptacle 12 is aline 22 that is in communication with adeagglomeration mechanism 24. In this way, powder extracted fromreceptacle 12 may be deagglomerated before leavingsystem 10 and passing into the patient's lungs. Exitingdeagglomeration mechanism 24 is aline 26 that may be coupled to a mouthpiece (not shown) from which the patient inhales. Hence, withsystem 10, a patient may receive a dose of an aerosolized medicament by inhaling from the mouthpiece until the patient produces a vacuum sufficient to openthreshold valve 14. Whenthreshold 14 opens, the powdered medicament is extracted fromreceptacle 12 and passes throughdeagglomeration mechanism 24. At the same time,regulation system 18 controls the flow of respiratory gases within an acceptable rate so that the aerosolized medicament may properly pass into the patient's lungs. After a certain amount of time, theregulation system 18 may be configured to cease operating so that the patient may inhale at a comfortable rate to fill the lungs with respiratory gases and to move the delivered medicament to the deep lung. - Referring now to
FIG. 5 , an exemplary embodiment of anaerosolization device 28 will be described.Device 28 comprises a generallycylindrical housing 30 having amouthpiece 32 at one end.Housing 30 further includesopenings divider 40 is provided betweenopenings housing 30. Similarly, adivider 42 is provided to facilitate the introduction of respiratory gases intohousing 30 through opening 34 (seeFIG. 6 ). - Pivotally coupled to
housing 30 is areceptacle carrier 44. Conveniently, apin 46 is employed to pivotally couplecarrier 44 tohousing 30. In this way,carrier 44 may be moved to an open position as shown inFIG. 6 to permit a receptacle to be loaded intodevice 28.Carrier 44 may then be moved to a closed or operating position as shown inFIG. 7 . As best shown inFIGS. 6 and 7 ,carrier 44 includes anopening 48 that is aligned with opening 34 whencarrier 44 is moved to the closed position.Carrier 44 further includes anotheropening 50 that is positioned below two penetratingtabs 52 onhousing 30. - As best shown in
FIG. 8 , oncecarrier 44 is moved to the open position, areceptacle 54 may be inserted intodevice 28.Receptacle 54 comprises areceptacle body 56 having a chamber 58 (shown in phantom line) which holds the powdered medicament.Receptacle body 56 is configured so that the portion abovechamber 58 is penetrable bytabs 52 as described in greater detail hereinafter. Disposed inreceptacle body 56 is athreshold valve 60 that comprises a membrane that is configured to rupture or tear at a specified threshold vacuum. -
Receptacle 54 is inserted intodevice 28 so thatthreshold valve 60 is aligned withopening 36. Also,chamber 58 rests withinopening 50. Oncereceptacle 54 is inserted ontocarrier 44,carrier 44 is moved to the closed or operating position as illustrated inFIG. 9 . When in the closed position,threshold valve 60 is aligned withopening 34. Further,tabs 52 penetratebody 56 overchamber 58 and peel back the lid to provide a pair of openings that provide access to the powder contained withinchamber 58. Oncecarrier 44 is moved to the closed position, a user may place his mouth overmouthpiece 32 and attempt to inhale. The flow of respiratory gases throughdevice 28 is prevented until the user creates sufficient vacuum to openthreshold valve 60. At this point, respiratory gases are abruptly permitted to flow throughopening 34, throughopening 36, throughchamber 58, throughopening 38 and outmouthpiece 32 as illustrated by the arrows. - Turning now to
FIGS. 10 and 11 , an example of one technique that may be employed to regulate the flow of respiratory gases through an aerosolization device, such asdevice 28, will be described. Shown inFIG. 10 is areceptacle 62 having achamber 64 that is typically filled with a pharmaceutical formulation (not shown). InFIG. 10 , a penetratingtube 66 has already penetrated the lid overchamber 64, and adistal end 68 oftube 66 is disposed withinchamber 64. InFIG. 10 ,distal end 68 oftube 66 is positioned near the bottom ofchamber 64. In this way, the airway betweendistal end 68 and the bottom ofchamber 64 is reduced in size to restrict the respiratory gases flowing intochamber 64 and out penetratingtube 66. As shown inFIG. 11 ,distal end 68 is moved vertically upward so that it is further distanced from the bottom end ofchamber 64. In this way, the flow rate of respiratory gases may be increased. - A variety of techniques may be employed to adjust the distance between
distal end 68 and the bottom ofchamber 64. For example, one technique is to employ the use of a suction force created by patient inhalation. More specifically, as the patient begins to inhale, the vacuum source created withintube 68 by the inhalation will tend to move the bottom end ofchamber 64 towarddistal end 68. Various mechanisms may then be employed to control the distance betweendistal end 68 and the bottom end ofchamber 64. For example, a variety of biasing mechanisms may be included to control the relative movement betweenreceptacle 62 and penetratingtube 66. Automated mechanisms, such as solenoids, pistons, and the like may also be employed. Further, various manual techniques may also be used, including utilization of the user's hands or fingers. - One feature of penetrating
tube 66 is that it forms a convergent nozzle that serves as a deagglomerator for the power contained withinchamber 64. More specifically, as the patient inhales to extract the powder fromchamber 64, the convergent flow path created by penetratingtube 66 tends to deagglomerate the powder to facilitate its aerosolization and deposition within the lung. - Referring now to
FIG. 12 , an embodiment of anaerosolization device 70 will be described to illustrate one technique for regulating the flow of respiratory gases through the device. For convenience of illustration, only a portion ofdevice 70 is illustrated, it being appreciated that other components may be utilized to complete the device.Aerosolization device 70 comprises ahousing 72 and areceptacle carrier 74.Receptacle carrier 74 may be configured to be movable relative tohousing 72 for convenient loading and unloading of areceptacle 76.Receptacle 76 includes achamber 78 and athreshold valve 80 that may be constructed to be similar to other embodiments described herein.Receptacle carrier 74 includes anopening 82 that is aligned withvalve 80 to permit respiratory gases to flow throughvalve 80 once opened. Coupled tohousing 72 is a penetratingtube 84 that penetratesreceptacle 76 to provide access tochamber 78 in a manner similar to that described with the previous embodiments. In this manner, when a patient inhales fromdevice 70,threshold valve 80 opens when the threshold vacuum is overcome. Respiratory gases then flow throughchamber 78 and out penetratingtube 84 as illustrated by the arrows. -
Device 70 further includes a spring 86 disposed betweenhousing 72 andreceptacle carrier 74. Oncevalve 80 is opened, the vacuum within penetratingtube 84 causes the bottom end ofchamber 78 to be drawn toward penetratingtube 84. The spring constant of spring 86 may be selected to control the distance between the bottom end ofchamber 78 and penetratingtube 84 to regulate the gas flow through the device. In some cases, it may be desirable to select the spring constant of spring 86 based on the average inhalation flow rate produced by the patient. In this way,device 70 may be tailored to a particular patient.Device 70 further includes apin 88 that maintains the spacing between the bottom ofchamber 78 and penetratingtube 84 to a certain distance. In this way,chamber 78 will not completely be drawn against penetratingtube 84. - Referring now to
FIG. 13 , anaerosolization device 90 will be described.Device 90 may be constructed from elements similar to that previously described in connection withaerosolization device 70. Hence, for convenience of discussion, similar elements used foraerosolization device 90 will be referred to with the same reference numerals used to describedevice 70 and will not be described further.Aerosolization device 90 differs fromaerosolization device 70 in that it employs anelectronic controller 92 to control the distance between penetratingtube 84 and the bottom end ofchamber 78.Controller 92 is electronically coupled to asolenoid 94 that may be extended or retracted to control the spacing between penetratingtube 84 andchamber 78. Optionally, aflow control sensor 96 may be disposed anywhere within the airway ofdevice 90 to sense the rate of flow through the device. Whencontroller 92 receives a signal fromsensor 96, it may send a signal to solenoid 94 to adjust the spacing to thereby regulate the flow rate. One advantage of usingcontroller 92 is that it may also include a timing circuit so thatsolenoid 94 may be fully extended after a certain amount of time. In this way, once the aerosolized formulation has reached the patient's lungs,solenoid 94 may be fully extended to permit the user to comfortably inhale without substantial resistance to fill their lungs with respiratory gases. - Referring now to
FIG. 14 , another embodiment of anozzle 98 that may be placed downstream of a receptacle will be described.Nozzle 98 comprises atubular structure 100 having abent section 102 and a contracted section 104. As the pharmaceutical formulation is extracted from the receptacle, it passes throughtubular structure 100 as indicated by the arrows. The change in the direction caused bybent section 102 causes the agglomerated powder to engage the walls ofstructure 100 to assist in its deagglomeration. When reaching contracted section 104, the powder is further agitated and the flow is increased to further deagglomerate the powder. Although shown with one bent section followed by a contracted section, it will be appreciated that various other tubular structures may be provided with various arrangements of direction changes and/or constrictions to facilitate deagglomeration of the powder. - Referring now to
FIGS. 15-26 , various embodiments of aerosolization devices will be described. Although not shown, the aerosolization devices ofFIGS. 15-26 will typically include a penetrating tube with one or more penetrating structures to pierce the lid of a receptacle similar to the embodiments previously described. These devices may also include threshold valves and regulation systems for regulating the flow of respiratory gases to the patient's lungs in a manner similar to that described with previous embodiments. Further, it will be appreciated that the components of the various devices ofFIGS. 15-26 may be shared, substituted and/or interchanged with each other. - First referring to
FIG. 15 , one embodiment of anaerosolization device 106 will be described.Device 106 comprises ahousing 108 having alid 110.Lid 110 is movable to an open position to receive asheet 112 ofreceptacles 114.Lid 110 includesvarious buttons 116 that may be pressed to puncture an associatedreceptacle 114 prior to inhalation. Conveniently,lid 110 includes awindow 118 to indicate thatsheet 112 is loaded and may also show a date and type of medication printed onsheet 112.Housing 108 further includes amouthpiece 120 and aslidable cover 122 that may be slid overmouthpiece 120 when not in use. - When a patient is ready to receive a treatment, the patient slides cover 122 to expose
mouthpiece 120. One ofbuttons 116 is then pressed and the user inhales while their mouth is overmouthpiece 120. Once all ofbuttons 116 have been pressed,sheet 112 may be replaced with a new sheet of receptacles. -
FIG. 16 illustrates anaerosolization device 124 that comprises a cover 126 (see alsoFIG. 16A ) and adrawer 128 that is slidable withincover 126 as indicated by the arrow.Drawer 128 is configured to hold areceptacle 130. As shown inFIG. 16A , whendrawer 128 is closed,receptacle 130 is held withincover 126. Conveniently, the chamber ofreceptacle 130 may be configured to be pierced whendrawer 128 is closed.Various press buttons 132 may be provided to allowdrawer 128 to be retracted following use. Cover 126 further includes amouthpiece 134 and a window to indicate thatreceptacle 130 is loaded, along with showing a date and type of medication. Optionally, acounter 138 may be provided to show the cumulative number of uses for the device. -
FIG. 17 illustrates anaerosolization device 140 comprising ahousing 142 having amouthpiece 144 and alid 146.Lid 146 is movable between an open position and a closed position as illustrated in phantom line. Whenlid 146 is opened, areceptacle 148 may be placed withinhousing 142. Whenlid 146 is closed,receptacle 148 is pierced anddevice 140 is ready for operation. Conveniently,lid 146 may include a raisedwindow 150 containing aball 152. The region behindwindow 150 may be placed in communication with the airflow path, thereby causingball 152 to move within the region depending on the rate of flow of respiratory gases throughdevice 140. Conveniently, plus and minus signs may be used to provide the patient with visual feedback on the rate of flow through the device. In this way, the patient may adjust their inhalation rate based on the visual feedback. Optionally,device 140 may include astorage compartment 154 for holdingextra receptacles 148. -
FIG. 18 illustrates adevice 156 comprising ahousing 158 having amouthpiece 160 and alid 162. Ahinge 164 is employed to pivotally couplelid 162 tohousing 158.Lid 162 is movable between an open position and a closed position. When in the open position, areceptacle 166 may be loaded intohousing 158.Lid 162 is then closed, withreceptacle 166 being visible through awindow 168.Lid 162 includes apress button 170 which is pushed to piercereceptacle 166 prior to use. -
FIG. 19 illustrates anaerosolization device 172 comprising ahousing 174 and adoor 176 that is coupled tohousing 174 by ahinge 178. Insertable intodevice 172 is adisk 180 havingmultiple receptacles 182 as illustrated inFIG. 19A . Conveniently, each of the receptacles may be numbered as illustrated inFIG. 19A .Door 176 includes adial 184 that is rotatable to rotatedisk 180 withindevice 172.Door 176 also includes awindow 186 to view the receptacle that has been pierced by rotatingdial 184. When ready to receive a treatment, the user places their mouth over anose 187 ofdevice 172 and begins to inhale. The patient's inhalation opens alid 188 to permit the aerosolized formulation to enter into the patient's lungs. To receive another treatment, the user simply dials dial 184 to the next receptacle which is pierced, makingdevice 172 ready for operation. - Referring now to
FIGS. 20 and 20 A, analternative aerosolization device 190 will be described.Device 190 comprises ahousing 192 and alid 194 that is coupled tohousing 192 by ahinge 196.Device 190 further includes amouthpiece 198 through which the patient inhales. As shown inFIG. 20A ,device 190 is in an open position where areceptacle 200 is placed in a loaded position.Lid 194 may then be closed to the position illustrated inFIG. 20 .Lid 194 includes apress button 202 that is pressed to piercereceptacle 200 so that the pharmaceutical formulation may be extracted.Lid 194 also includes a timer 204 that is manually set by having the user pull timer 204 towardbutton 202 prior to operation. The user then begins to inhale frommouthpiece 198 to aerosolize the pharmaceutical formulation. Preferably, the user inhales until timer 204 expires. As shown inFIG. 20A ,lid 194 may include multiple storage locations for storingadditional receptacles 200. -
FIG. 21 illustrates anaerosolization device 206 comprising ahousing 208 having aslot 210 for receiving areceptacle 212.Device 206 further includes acocking device 214 that is cocked to causereceptacle 212 to be pierced.Device 206 further includes a trap door 216 and an extendable mouthpiece 218 (shown in phantom line). When cockingdevice 214 is cocked to piercereceptacle 212, trap door 216 is also opened andmouthpiece 218 is extended. - Referring now to
FIG. 22 , anotheraerosolization device 220 will be described.Device 220 comprises ahousing 222 and aclip 224 that may be coupled tohousing 222. As best shown inFIG. 22A ,clip 224 includes astorage region 226 and awaste region 228.Storage region 226 includesmultiple receptacles 230 that may be loaded intohousing 222 as described hereinafter. Once a receptacle has been used, it is ejected intowaste region 228. Conveniently, aremovable seal 232 may be disposed overstorage region 226. Use ofclip 224 is advantageous in that replacement clips, having a fresh supply of receptacles, may easily be coupled tohousing 222, making device 220 a multi-use device. - As best shown in
FIG. 22 ,housing device 220 further includes arotatable dial 234 that is rotated to advance one of thereceptacles 230 fromstorage region 226 and intohousing 222. When placed withinhousing 222,receptacle 230 is pierced. Further,housing 222 includes acounter 236 to display how many receptacles remain unpierced. Atethered mouthpiece cover 238 is coupled tohousing 222 and is removed prior to inhalation. - Hence, to use
device 220, the user simply rotates dial 234 to advance and pierce the next receptacle. Cover 238 is removed and the patient inhales to aerosolize the pharmaceutical formulation and deposit the formulation within the patient's lungs. When ready for a next dosage, dial 234 is again dialed causing the used receptacle to be ejected intowaste region 228 and advancing another receptacle. When all receptacles have been used,clip 224 is removed and placed with a replacement clip. -
FIG. 23 illustrates anaerosolization device 240 comprising ahousing 242 and alid 244 pivotally coupled tohousing 242. Aremovable mouthpiece cover 246 is also provided (see alsoFIG. 23A ). Cover 246 is removed prior to inhalation by the patient.Device 240 is configured to hold astrip 248 of receptacles 250 (as shown inFIG. 24 ). Oncestrip 248 is withinhousing 242, aslide 252 may be moved to indicate the desired receptacle that is to be pierced.Slide 252 may then be depressed to pierce the selected receptacle. Optionally, slide 252 may be coupled to plumbing withindevice 240 so that the plumbing is moved to the appropriate receptacle along withslide 252.Device 240 may also include awhistle 254 that produces an audible signal when the user inhales in excess of a maximum inhalation flow rate. The user may simply inhale at a slower flow rate untilwhistle 254 ceases producing a whistling sound. -
FIG. 25 illustrates anaerosolization device 256 comprising ahousing 258 and amouthpiece cover 260 that is tethered tohousing 258. Cover 260 is removed prior to use.Housing 258 further includes aslot 262 that extends throughhousing 258. In this way, acontinuous strip 264 ofreceptacles 266 may be fed throughslot 262. Alternatively,strip 264 may be separated into segments so that an individual receptacle may be fed intoslot 262.Housing 258 includes abutton 268 that may be depressed to pierce the loaded receptacle. - When the patient begins to inhale, their flow rate is monitored by a
gas gauge 270. In this way, the user is provided with visual feedback to assist them in inhaling at the proper flow rate. Optionally,housing 258 may include a clip 272 to permitdevice 258 to be carried on the pocket like a pen. -
FIG. 26 illustrates anaerosolization device 274 comprising a housing 276 having a mouthpiece 278 and arotatable body 280 that is rotatable relative to housing 276.Device 274 is configured to receive areceptacle pack 282 at a back end ofdevice 274.Receptacle pack 282 includesmultiple receptacles 284 that may be pierced when ready for use. Althoughreceptacle pack 282 is shown as being cylindrical in geometry, it will be appreciated that other geometries may be employed, including square shaped tubes. - Once
receptacle pack 282 is inserted intodevice 274,rotatable body 280 is rotated to advance one of the receptacles to an engaging position where the receptacle is pierced. Conveniently, housing 276 includes acounter 286 to display the remaining number of receptacles. If the patient inhales at an excessive flow rate, housing 276 is configured to vibrate to provide the user with feedback so that they may adjust their inhalation flow rate. - A wide variety of threshold valves may be used to prevent the flow of gases to the patient's lungs until the patient has produced a sufficient vacuum needed to extract the powder from the receptacle. Such valves may be configured to prevent any flow of gases until the vacuum produced by the patient meets or exceeds the threshold actuating pressure of the valve. After the valve opens, minimal flow resistance is provided by the valve. Once the flow stops, the valve may be configured to reset to its former starting position.
- Shown in
FIG. 27 is a schematic diagram of avalve system 300 having athreshold valve 302 that may be configured to crack at a pressure in the range from about 20 cm H2O to about 60 cm H2O, and more preferably at least about 50 cm H2O, to allow gas flow through the aerosolization device in the direction indicated by the arrows. In this way, a relatively high flow rate may be achieved for a short duration at the beginning of inhalation to allow the powder to be dispersed from the receptacle. - Optionally,
system 300 may include acheck valve 304 to prevent the user from blowing through the device. Such a check valve may be incorporated anywhere in the aerosolization device, and for convenience may be integrated with the threshold valve.System 300 may be configured to have little resistance to the flow of gases oncevalve 302 is opened. In some cases,system 300 may be configured to have a reset feature to resetvalve 302, if needed. In some cases,system 300 may be configured to have an adjustment mechanism to permit the adjustment of the threshold actuating pressure, lowering of any reset vacuum level, and/or raising of back flow resistance pressure. - One type of threshold valve that may be used is a silicone rubber valve that is tailored to provide flow onset at the desired threshold pressure and to provide reverse flow inhibition. Such a valve is also self resetting, requiring no mechanical resistance. Examples of such valves are described in, for example, U.S. Pat. Nos. 4,991,745, 5,033,655, 5,213,236, 5,339,995, 5,377,877, 5,409,144, and 5,439,143, the complete disclosures of which are herein incorporated by reference.
- Examples of various types of threshold valves that may be incorporated into an aerosolization device are illustrated in
FIGS. 28-40 . Shown inFIG. 28 is a pull throughthreshold valve 306 that is constructed of ahousing 308 having aninlet 310 and anoutlet 312. Amembrane 314, such as an elastomeric membrane, is disposed across the interior ofhousing 308 and has acentral opening 316. Aball 318 is sealed withinhousing 308 and is configured to be pulled throughopening 316 when a sufficient vacuum is created by the user as shown in phantom line. Onceball 318 passes throughmembrane 314, gas flow is permitted throughhousing 308 by passing throughpassages 320. Conveniently, areset rod 322 may be used to pushball 318 back to the other side ofmembrane 314 in order to reset the valve for another use. -
FIG. 29 illustrates an umbrella pull throughvalve 324.Valve 324 comprises ahousing 326 having asupport member 328 for supporting anumbrella member 330.Housing 326 also includestabs 332 which prevent axial movement ofumbrella member 330 until the user creates a sufficient vacuum. At such a time,umbrella member 330 flexes to passtabs 332 as shown in phantom line. Gases are then permitted to flow throughopenings 334 insupport 328. Areset rod 336 may be used to pushumbrella member 330 backpast tabs 332 prior to another use. -
FIG. 30 illustrates athreshold valve 338 comprising atubular housing 340 across which avalve member 342 is pivotally disposed. A biasingmember 344biases valve member 342 against atab 346. In this way, gases are permitted to flow throughhousing 340 once a sufficient vacuum is created to overcome the biasing force and thereby permitvalve member 342 to open as shown in phantom line. -
FIG. 31A illustrates aflapper valve 348 that may be used in a tubular housing.Valve 348 comprises twovalve members 350 that are pivotally coupled to ashaft 352. A spring (not shown)biases members 350 in the position shown inFIG. 31A . When a sufficient vacuum force is provided, the spring force is overcome andmembers 350 move to the open position shown inFIG. 31B to permit to flow of gases. -
FIG. 32 illustrates aspindle type valve 354 that comprises atubular housing 356 having aspindle 358 that is held betweentabs spindle 358 when the vacuum created by the user moves the spindle totabs 361. - The frictional force between
spindle 358 andhousing 356 may be varied depending on the desired threshold force required to open the valve. -
FIG. 33 illustrates anotherspindle type valve 364 comprising atubular housing 366 having astop 368. Aspindle 370 is disposed withinhousing 366 so as to beadjacent stop 366, thereby preventing the flow of gases throughhousing 366. When a sufficient vacuum has been produced by the patient,spindle 370 slides withinhousing 366 and away fromstop 366. In this way, gases are permitted to flow throughhousing 366. -
FIG. 34A illustrates athreshold valve 372 that comprises atubular housing 374 having asupport 376 that holds anevertible umbrella member 378 having aball 380.Ball 380 serves to securemember 378 to support 376 when a vacuum is applied by the user. As shown inFIG. 34B ,member 378 is configured to evert when a sufficient vacuum is produced by the user. When in the everted position, gases flow throughopenings 382 insupport 376 as shown.Member 378 may be reset to the position shown inFIG. 34A prior to another use. - The threshold valve may be a valve designed to alternate between open and closed positions based upon a predetermined magnetic field strength. For example,
FIG. 35 illustrates athreshold valve 384 comprising ahousing 386 that holds asteel ball 388. Also disposed withinhousing 386 is amagnet 390 and anelastomeric gasket 392 having acentral opening 394 that is smaller in diameter thanball 388. In this way,magnet 390 holdsball 388 across opening 394 to prevent the flow of gases throughhousing 386. When the user provides a sufficient vacuum,ball 388 is moved against astop 396 as shown in phantom line. Gases are then free to flow throughopening 394 and aroundball 388. The magnetic field is designed to be strong enough such that the ball is reset to obstruct airflow when the user stops the inhalation. -
FIG. 36A illustrates athreshold valve 398 comprising atubular housing 400 having arestriction 402 with acentral orifice 404. Abistable dome 406 is coupled to asupport 407 and is disposed across the interior ofhousing 400 to coverorifice 404 when in the position shown inFIG. 36A . When a user provides a sufficient vacuum,dome 406 performs a bistable function to move to the position shown inFIG. 36B . In this way, gases may flow throughorifice 404 and then throughopenings 408 insupport 407 as shown by the arrows. -
FIG. 37A illustrates athreshold valve 410 that comprises atubular housing 412 having aflexible bladder 414 that is sealed tohousing 412. When the pressure is below a threshold pressure,bladder 414 maintains the shape shown inFIG. 37A . In this way, aball 416 is prevented from passing throughbladder 414, thereby preventing the flow of gases throughhousing 412.Channels 418 are in communication with the interior ofbladder 414 so that when the patient produces a vacuum that is greater in magnitude than the threshold pressure,bladder 414 moves to the position shown inFIG. 37B to permit gases to flow throughhousing 412. -
FIG. 38 illustrates athreshold valve 420 comprising atubular housing 422 having afrangible diaphragm 424.Diaphragm 424 is configured to rupture when a threshold vacuum has been applied by the user as shown in phantom line. -
FIG. 39 illustrates athreshold valve 426 comprising atubular housing 428 and avalve member 430 pivotally coupled tohousing 428.Valve member 430 prevents the flow of gases throughhousing 428 when in a closed position as shown inFIG. 39 . Astop 432 preventsvalve member 430 from opening until a threshold vacuum is produced by the user. Stop 432 is coupled to amembrane 434 that is held within achamber 436.Chamber 436 is in communication with the interior ofhousing 428 by apassage 438. In this way, when a sufficient vacuum has been produced; stop 432 is lifted up to permitvalve member 430 to open. Conveniently, a vent 440 may be provided to permit air to flow intochamber 436 whenmembrane 434 moves upward. Also, a spring 442 may be provided to movevalve member 430 to the open position when stop 432 is raised. -
FIG. 40 illustrates a pull throughtype threshold valve 444 that comprises a housing 446 and avalve member 448 that is disposed within housing 446. Astop 450 holdsvalve member 448 in place until a threshold pressure is produced by the patient. At such a time,valve member 448 collapses as shown in phantom line to permitvalve member 448 to pass beyondstop 450. - A variety of flow regulators may be used to limit the flow of gases through the aerosolization device and into the user's lungs after the powder has been extracted from the receptacle and aerosolized. Such flow regulators are provided to limit the flow rate through the device for a specified time to insure that the flow rate is slow enough for the aerosol to travel through the airways and past the anatomical dead volume.
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FIG. 41 schematically illustrates one embodiment of aflow regulator 460.Regulator 460 may be configured to limit the flow of gases to be less than about 15 L/min, and more preferably less than about 10 L/min.Regulator 460 may be configured such that the resistance to the flow is small at low vacuum and increases with the vacuum generated by the user. Conveniently,regulator 460 may be placed in a flow path that is parallel to the receptacle containing the powder. In such a case, the flow regulator may provide a system resistance to flow R that varies from about 0.1 (cm H20)1/2/standard liters per minute (SLM) up to the resistance of the receptacle flow path. Alternatively, the flow controller may be placed in series with the receptacle. In such a case, the system resistance R may vary from the resistance of the receptacle flow path up to a resistance greater than 1.0 (cm H20)1/2/SLM. - Shown in
FIGS. 42-59 are various types of flow regulators that may be used in aerosolization devices to regulate gas flow after the receptacle has been opened. For example,FIG. 42A illustrates aflow regulator 462 comprising an L shapedhousing 464 having aflow channel 466. Ashuttle 468 having skirt seals 470 is slidable withinhousing 464. Areturn spring 472 biases shuttle 468 in the position shown inFIG. 42A . As the flow rate throughhousing 464 increases,shuttle 468 moves withinhousing 464 to compressspring 472 and close offflow channel 466. In this way, the flow rate is limited to a certain rate. If the flow rate is too excessive,channel 466 closes asshuttle 468 engagesstops 474 as shown inFIG. 42B . When the flow stops,spring 472 moves shuttle 468 to the starting position. -
FIG. 43 illustrates aflow regulator 476 that also includes a threshold valve that is similar in construction to that previously described in connection withFIG. 28 .Regulator 476 comprises ahousing 478 having a taperedflow channel 480 and amembrane 482 that serves as a threshold valve in a manner similar to that previously described. InFIG. 43 , aball 484 has passed throughmembrane 482 and is forced against aspring 486 by the vacuum produced by the user. As the vacuum increases,spring 486 compresses asball 484 moves further intochannel 480 as shown in phantom line. As a result, the flow path is restricted, thereby limiting the flow of gases. The spring constant ofspring 486 may be adjusted to provide the desired flow control features. -
FIGS. 44A and 44B illustrate aflow regulator 488 comprising atubular housing 490 into which a bellows 492 is disposed.Bellows 492 may be constructed of an elastomer that is configured to compress when the flow throughhousing 490 increases as shown inFIG. 44A . Asbellows 492 compresses, aflow path 494 through the bellows decreases to limit the flow rate. -
FIG. 45 illustrates aflow regulator 496 comprising atubular housing 498 into which acone member 500 havingorifices 501 is slidably disposed. Arestriction member 502 having aflow channel 504 is also held withinhousing 498. Aspring 506 is disposed betweencone member 500 andrestriction member 502. As the flow rate through orifices and flowchannel 504 increases,spring 506 compresses andcone member 500 moves further intoflow channel 504, thereby limiting the flow of gases throughhousing 498. -
FIG. 46 illustrates aflow regulator 508 that comprises atubular housing 510 having aclosed end 512 and flowchannels 514 that permit gases to flow intohousing 510 from anotherhousing 516 havingflow channels 518. Aspring 520 biases housing 510 to the left as shown inFIG. 46 . As the flow rate increases,spring 520 extends and moveshousing 510 to the right ofFIG. 46 . In so doing, flowchannels 514 are restricted byhousing 516 to limit the gas flow. -
FIG. 47 illustrates aflow regulator 520 that comprises atubular housing 522 having acompartment 524 that is filled with anopen cell foam 526. The open cell foam material restricts and regulates the flow of gases throughhousing 522, by using the applied vacuum to compress the foam and constrict the porous flow channels. -
FIG. 48 illustrates aflow regulator 528 that comprises atubular housing 530 having asupport 532 with a plurality oforifices 534. Anumbrella member 536 is held bysupport 532 and limits gas flow throughhousing 530. Conveniently,umbrella member 536 may be evertible in a manner similar to that described in connection withFIGS. 43A and 43B to also function as a threshold valve. -
FIG. 49 illustrates a flow regular 538 that comprises ahousing 540 having aninlet tube 542 and anoutlet tube 544. Disposed withinhousing 540 is a liquid 546. As gases flow throughhousing 540, the gases bubble throughliquid 546 which regulates the flow of the gases throughhousing 540. -
FIG. 50 illustrates aflow regulator 548 that comprises atubular housing 550 having anecked region 552. Ashuttle 554 is held withinhousing 550 and is forced intonecked region 552 as the vacuum force increases. The force required to move theshuttle 554 is controlled by a spring 556. In this way, as the vacuum force increases, the flow path is restricted to limit the flow rate throughhousing 550. -
FIG. 51 illustrates a flow regulator 556 that comprises atubular housing 558 having aspindle 560 that is slidable withinhousing 558. Aspring 562 biases spindle 560 to the right as shown inFIG. 51 so that aflow path 564 ofspindle 560 is aligned withflow paths 566 inhousing 558. Hence, in the position shown inFIG. 51 , gases may flow throughhousing 558 by passing throughflow paths 564 and aflow path 568 inspindle 560. However, as the vacuum force increases,spindle 560 moves to the left to restrictflow paths 566, thereby limiting the flow of gases throughhousing 558. -
FIG. 52 illustrates aflow regulator 570 comprising atubular housing 572 having anexpandable cone 574.Cone 574 includes anorifice 576 and is configured so that gas flow may pass throughorifice 576 as well as aroundcone 574 when the flow rate is low as shown inFIG. 52 . When the flow rate is increased,cone 574 expands to provide a seal againsthousing 572 so that gas flow is only permitted throughorifice 576. -
FIGS. 53A and 53B illustrate aflow regulator 580 that comprises iniris valve 582. Oneend 584 may be fixed and anotherend 586 may be rotated to moveiris valve 582 to the position shown inFIG. 53B . In this way, the flow rate throughvalve 582 may be regulated. -
FIG. 54 illustrates aflow regulator 588 that comprises ahousing 590 having apaddle wheel 592 that is rotatable in only one direction as shown by the arrows.Paddle wheel 592 is pivotally connected tohousing 590 by a frictional connection that may be adjusted to regulate the amount of gas flow throughhousing 590. By being rotatable in only one direction,paddle wheel 592 also serves as a check valve. -
FIGS. 55A and 55B illustrate aflow regulator 594 comprising atubular housing 596 havingpivotal flaps 598.Flaps 598 are configured to close when experiencing a high gas flow as illustrated inFIG. 55B to reduce the flow rate throughhousing 596. - Another type of flow regulator comprises a valve that is constructed of a flexible material, such as a soft elastomer, e.g., a silicone rubber, that limits the flow to a certain rate while also preventing flow in the opposite direction. Such a valve is also self-resetting, requiring no mechanical assistance. Such valves have an orifice that permits the flow of air through the valve in response to an applied vacuum, and one or more collapsible walls surrounding the orifice such that an increased vacuum pressure level results in reduction of orifice area and correspond higher resistance to flow. One feature of such valves is that they may be relatively inexpensive to construct. One particular example of such a valve is described in U.S. Pat. No. 5,655,520, the complete disclosure of which is herein incorporated by reference.
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FIGS. 56A and 56B illustrate one embodiment of such aflow regulator 600. Flow regulator comprises anelastomeric body 602 having aduckbill valve 604 that includes anorifice 606. InFIG. 56A , the flow rate is low andorifice 606 is fully opened. When the flow rate increases,valve 604 begins to close as shown inFIG. 56B to limit the flow. - Other examples of such flow regulators are shown in
FIGS. 57-59 . InFIG. 57 , aflow regulator 608 has aduckbill valve 610 with atop orifice 612.FIG. 58 illustrates aflow regulator 614 having aduckbill valve 616 with anorifice 618 extending from the top and down the side.FIG. 59 illustrates aflow regulator 620 having aduckbill valve 622 with a separatetop orifice 624 and aside orifice 626. - After the flow rate through the aerosolization device has been regulated for a certain time period, the device may be configured to permit an increased flow rate. In this way, the user may fill his or her lungs with a sufficient volume of air needed to carry the aerosol to the deep lung. For example, following regulation of the flow rate, the device may be configured to permit the user to comfortably fill his or her lungs as the user continues to inhale through the device. Typically, the user may be permitted to fill their lungs at a comfortable rate once an initial volume of about 500 mL has been inhaled at the regulated flow rate. This assumes that after about 500 mL of inhaled air, the drug has traveled past the anatomical dead space.
- To provide such a feature, various timers or flow integrators may optionally be incorporated into the aerosolization devices of the invention. Such flow integrators have one or more moving members that move based on the volume of flow through the device. In this way, when the initial (regulated) volume has been inhaled, the member has moved sufficient to open another gas channel to permit increased gas flow. For example, the flow integrator may be an airfoil flap made of a film such as a polymer film having a thickness between 0.005 and 0.020 inches and preferably having a viscoelastic or other time-dependent behavior. Airflow over the airfoil flap induces aerodynamic lift. The air foil flap can be configured to allow access to a parallel flow path after a predetermined volume of air flows over the flap.
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FIG. 60 schematically illustrates a flow through type flow integrator 630 that is configured to move based on the flow velocity, assuming a low pressure drop. Integrator 630 moves based on the pressure differential between the ambient and the inlet, which can vary significantly even though the flow rate remains constant when using a flow regulator as described above. One advantage of integrator 630 is that it provides an accurate volume measurement. -
FIG. 61 schematically illustrates a flow-bytype integrator 632 that is parallel to the main flow path. Optionally,integrator 632 may trigger a switch at the end of travel to open a parallel flow path with low flow resistance. -
FIGS. 62A and 62B illustrate a flow through shuttletype flow integrator 634 that comprises a tubular housing 636 and ashuttle 638 that is slidable within housing 636. Conveniently, skirt seals 640 provide a seal between housing 636 andshuttle 638 while still permittingshuttle 638 to slide.Stops 642 and 644 are also provided to limit travel ofshuttle 638. InFIG. 62A ,shuttle 638 is in the closed position where the main flow through the aerosolization device passes through anopening 646 inshuttle 638, and a parallel flow through achannel 648 is prevented byshuttle 638.Shuttle 638 moves through housing 636 in response to the velocity of the gas flowing through housing 636. The drag force, and therefore the speed at which shuttle 638 moves, is proportional to the flow velocity. As shown inFIG. 62B ,shuttle 638 moves pastchannel 648 after a certain amount of time to permit increased flow through housing 636. -
FIG. 63 illustrates aflow integrator 650 that comprises atubular housing 652 through which the main gas flow through the aerosolization device passes. Disposed withinhousing 652 is animpeller 654 that is coupled to agear reduction 656. In turn,gear reduction 656 is coupled to acam 658 that has ahole 660 as also shown inFIG. 64 .Cam 658 is rotatable through atubular housing 662 that provides a parallel flow path through the aerosolization device. In operation, the user inhales to provide gas flow throughhousing 652 which turnsimpeller 654. In turn,cam 658 is rotated throughgear reduction 656. Whencam 658 reaches a specific angle,hole 660 is aligned withhousing 662 to open a parallel flow path for the chase air. - As an alternative to the
impeller 654, a paddle wheel 664 may be used as illustrated inFIG. 65 . In such an embodiment, paddle wheel 664 may be coupled togear reduction 656 in a manner similar to that previously described. -
FIGS. 66A and 66B illustrate aflow integrator 666 that comprises atubular housing 668 having a parallel flow path 670. Coupled tohousing 668 is amain flow path 672. Anopening 674 places housing 668 and flowpath 672 in fluid communication. Disposed withinhousing 668 is ashuttle 676 havingskirt seals 678 to provide a seal betweenshuttle 676 andhousing 668. Aspring 680 is disposed betweenhousing 668 andshuttle 676, and anumbrella valve 682 with ableed hole 684 extends throughhousing 668. - As shown in
FIG. 66B ,shuttle 676 prevents parallel gas flow through flow path 670 when the user first begins to inhale.Shuttle 676 moves under force ofspring 680, damped by bleed hole 684 (or alternatively by controlled leakage around shuttle 676).Shuttle 676 moves faster when the pressure differential between the inlet side (having bleed hole 684) and the outlet side (having opening 674) is increased due to the vacuum created by the user. Whenshuttle 676 reaches the end of its travel, parallel flow path 670 is opened for the chase air. Areset rod 686 may then be used to resetshuttle 676 to the position shown inFIG. 66B . -
FIG. 67 illustrates aflow integrator 690 comprising atubular housing 692 that serves as a main flow path. Abrake system 694 having apivotal brake arm 696 extends intohousing 692. Coupled tobrake arm 696 is abrake pad 698 as also shown inFIG. 68 .Integrator 690 further comprises awheel 700 that moves through atubular housing 702 that serves as a parallel flow path for the chase air.Wheel 700 has ahole 703 that aligns withhousing 702 whenwheel 700 is at a specified angle.Brake arm 696 is spring loaded againstwheel 700 with aspring 701. Also coupled towheel 700 is atrigger 704 that fits within agroove 706 ofbrake arm 696. - To operate
integrator 690, the user winds a spring (not shown) which rotateswheel 700 at a constant rate when released. When the user creates a main flow throughhousing 692,brake arm 696 pivots to releasetrigger 704 andbrake pad 698.Wheel 700 then rotates at a constant rate untilhole 703 becomes aligned withhousing 702, thereby opening a parallel flow path for the chase air. - The threshold valves, flow regulators and, optionally, flow integrators of the invention may be arranged in a variety of configurations within an aerosolization device. For example,
FIG. 69 illustrates anaerosolization system 710 where the various components are arranged in series.System 710 comprises, in series, an inlet 711, athreshold valve 712, aflow regulator 714, aflow integrator 716 of the flow through type, areceptacle 718 for holding a powdered medicament, and anoutlet 720. The total resistance ofreceptacle 718 may be configured to be less than or equal to the resistance of the rest of the system untilflow integrator 716 opens. Conveniently, the order ofthreshold valve 712,flow regulator 714 and flow integrator 716 (if a flow through type integrator) may be interchanged. Alternatively,flow integrator 716 may be a flow-by type integrator that may be parallel toreceptacle 718.Receptacle 718 may be last in the series to prevent the drug from depositing on the other components. Conveniently,threshold valve 712,flow regulator 714 andflow integrator 716 may be integrated into one mechanism. -
FIG. 70 illustrates anaerosolization system 722 that comprises aninlet 724, athreshold valve 726, aflow regulator 728, areceptacle 730, aflow integrator 732 of the flow-by type, and anoutlet 734.Integrator 732 is arranged parallel tothreshold valve 726 andregulator 728. Withsystem 722, the maximum system resistance may be less than or equal to the resistance ofreceptacle 730. In this way, some users may achieve flow rates above 10 L/min.Integrator 732 operates from the pressure differential between ambient andoutlet 734. Conveniently,threshold valve 726 andflow regulator 728 may be integrated. -
FIG. 71 illustrates anaerosolization system 736 that comprises aninlet 738, athreshold valve 740, aflow integrator 742 of the flow through type, aflow regulator 744, areceptacle 746 and anoutlet 748. Withsystem 736, the order ofthreshold valve 740 andflow integrator 742 may be changed. Further, the maximum system resistance may be less than or equal to the resistance ofreceptacle 746. Use of the flow through type of integrator provides a more accurate volume measurement since it operates as a result of the flow rate through it.System 736 also allows for integration ofthreshold valve 740 andflow regulator 744, orflow integrator 742 andflow regulator 744. In one aspect,system 736 may be configured so thatflow integrator 742 does not restrict the flow spike which occurs afterthreshold valve 740 opens so that the high flow rate passes entirely throughreceptacle 746 to disperse the powder. -
FIGS. 72-78 illustrate one particular embodiment of anaerosolization device 750 that incorporates a threshold valve, a flow regulator and a flow integrator.Device 750 comprises ahousing 752, adoor 754 that is pivotally coupled tohousing 752 by ashaft 756 and apivotable mouthpiece 758. As best shown inFIG. 73 ,door 754 may be opened to permit a receptacle 760 (shown already opened) to be inserted intodevice 750.Device 750 further includes a anextraction tube 762 that is in commination withmouthpiece 758 to permit the drug that is extracted fromreceptacle 760 to pass intomouthpiece 758. Adeagglomerator 764 is provided inmouthpiece 758 to deagglomerate any agglomerated powder the is extracted fromreceptacle 760. Conveniently,deagglomerator 764 also serves as a shaft about whichmouthpiece 758 pivots. Coupled toextraction tube 762 is acutter 766 that piercesreceptacle 760 whendoor 754 is closed so that the drug may be extracted. - Incorporated into
door 754 is athreshold valve 768 that comprises amembrane 770 having anopening 772. Avalve member 774 having aball 776 that is movable throughopening 772 once a threshold vacuum that is produced by the user is met or exceeded. In operation, a user inhales frommouthpiece 758 which creates a vacuum intube 762 and in apassage 778 that is in communication with a right hand side ofmembrane 770. Once the threshold vacuum pressure is met or exceeded,ball 776 is pulled throughopening 772 to permit outside air to enter into aregion 780 ofdoor 754 through a vent (not shown). In this way, air flows throughreceptacle 760 to extract the powdered drug where it is delivered tomouthpiece 758. Conveniently,device 750 further includes acam 782 that movesball 780 back throughopening 772 whendoor 754 is opened and closed to reset the valve. -
Device 750 further includes aflow regulator 784 to limit the air flow throughtube 762 to a certain rate.Regulator 784 comprises atapered opening 786 into whichball 780 is drawn as the vacuum created by the user increases. Aspring 785 controls the amount of vacuum require to close opening withball 776. Hence, if the flow rate becomes too great, aparallel flow path 788 that leads back intotube 762 is closed off byball 780. In this way, the only air passing throughtube 762 must pass throughreceptacle 760 as previously described. This flow path has sufficient resistance such that the flow is limited to the desired rate. If the user does not create a vacuum sufficient to closeflow path 788, the air flow is permitted through two parallel flow paths. -
Device 750 further includes aflow integrator 790 to permit an increased flow rate once a certain amount of time has passed so that the user may comfortably fill their lungs after the flow has been regulated for a specified time.Flow integrator 790 comprises aclutch diaphragm 792 upon which aspool 794 rests.Spool 794 is biased to rotate by atorsional spring 796. In this way, when diaphragm 792 is disengaged fromspool 794,spool 794 rotates until an opening (not shown) inspool 794 becomes aligned with an opening 798 (seeFIG. 76 ) intube 762. At this point, ambient air is able to flow through a parallel flow path and intotube 762 to permit the user to comfortably fill their lungs with air. -
Diaphragm 792 is configured to lower to releasespool 794 due to the vacuum created inflow path 788 as the user inhales frommouthpiece 758 as previously described. The rate of spool rotation (and hence the time required to open the parallel flow path) is determined by a dampingreservoir 800 which contains a damping grease. A fixedmember 802 fits withinreservoir 800 to regulate the rate of spool rotation asmember 802 frictionally engages the damping grease. Although not shown,device 750 may include a reset lever to resetspool 794 after use. -
FIGS. 79-83 illustrate another embodiment of anaerosolization device 850 that comprises alower housing 852, anupper housing 854 and arotatable mouthpiece 856. As best shown inFIG. 80 ,lower housing 852 may be separated fromupper housing 854 to permit adrug containing receptacle 858 to be inserted intodevice 850. Alower housing catch 855 is provided to limit the travel ofhousing 852 relative toupper housing 854. Coupled tomouthpiece 856 is atube 860 having acutting mechanism 862 to openreceptacle 858 whenreceptacle 858 is inserted andlower housing 852 is placed adjacentupper housing 854. - Disposed across
lower housing 852 is amembrane 862 having anopening 864. Extending throughopening 864 is alatch 866 having aball 868. Positioned belowlatch 866 is ahole 890 inlower housing 852. Such a configuration provides a threshold valve fordevice 850. In this way, when a user inhales frommouthpiece 856, a vacuum is created intube 860 and in the space abovemembrane 862. When the user creates a sufficient vacuum,ball 868 is pulled throughopening 864 inmembrane 862 to permit outside air to flow throughhole 890, throughopening 864, throughreceptacle 858 and up throughtube 860 where the aerosolized drug exits throughmouthpiece 856. - Once the drug has been aerosolized, the flow of air through
device 850 is regulated to be less than a certain rate in part through use of anelastomeric duckbill valve 892. More specifically, air is permitted to flow through two flow paths, i.e. throughvalve 892 and throughreceptacle 858 provided the flow rate is below the specified amount. As the air flow rate increases,valve 892 begins to close to prevent air from flowing through this flow path. The only available air path is then throughreceptacle 858 which provides sufficient resistance to limit the flow to a certain rate. - Coupled to a
cam 893 oflatch 866 is abypass spreader 894 that is engaged with astop 896.Spreader 894 is coupled to aspring 897 and is also slidable within abypass duckbill valve 898. As the user continues to inhale throughmouthpiece 856,cam 893 oflatch 866 movesspreader 894 away fromstop 896. This causesspring 897 to expand as shown inFIG. 82 to compress abellows 900 and to spreadvalve 898 which is normally closed. In this way, after a certain period of time,valve 898 is opened to provide another flow path so that more ambient air may flow throughdevice 850 throughhole 890. In this manner, the user is permitted to comfortably fill their lungs after the initial drug delivery. The rate of compression ofbellows 900 is controlled by fillingbellows 900 with a known volume of air and by providing a small orifice in bellows 900. In this way, the rate of compression is controlled by the time required to force the air out through the orifice oncespreader 894 is released fromstop 896. -
FIGS. 84-87 illustrate another embodiment of anaerosolization device 910 that comprises alower housing 912, amiddle housing 914, anupper housing 916 and amouthpiece 918.Lower housing 912 is movable relative tomiddle housing 914 to permit adrug containing receptacle 920 to be inserted as illustrated inFIG. 85 . Coupled tomouthpiece 918 is atube 922 that is configured to piercereceptacle 920 to provide access to the drug. -
Middle housing 914 includes amembrane 924 having anopening 926. Avalve member 928 having aball 930 is positioned withinlower housing 912 and functions as a threshold valve to ensure that a sufficient vacuum is created by the user when initially inhaling the drug. In operation, the user inhales frommouthpiece 918 to create a vacuum withintube 922 and in the space abovemembrane 924. When a sufficient vacuum has been produced,ball 930 is pulled throughopening 926 to permit ambient air to flow intolower housing 912 through ahole 932, throughopening 926, throughreceptacle 920, throughtube 922 and outmouthpiece 918. In so doing, the drug is extracted fromreceptacle 920 and is supplied to the user. -
Device 910 is further configured to regulate the flow rate of air throughdevice 910 afterball 930 is pulled throughmembrane 924. This is accomplished in part by the use of anelastomeric duckbill valve 934 inupper housing 916. As the user continues to inhale, ambient air entering throughhole 932 also passes throughopening 926 and then throughvalve 934. The air then travels through an opening 936, anopening 938 and outmouthpiece 918. However, if the flow rate becomes too great,valve 934 closes to prevent air flow through this flow path. As a result, air may only flow throughreceptacle 920 andtube 922 which, because of their limited size, regulates the flow rate to within a specified rate to permit the aerosolized drug to reach the user's lungs. - After a specified amount of time,
device 910 is configured to permit an increased flow of air throughdevice 910 so that the user may comfortably fill their lungs with air. This is accomplished by use of apiston 940 that is coupled toupper housing 916 by a pair of rollingseals Piston 940 further includes ahole 946 that moves betweenseals opening 932 also throughhole 946, through hole 936 and outmouthpiece 918. In this way, an additional flow path is provided to permit the user to comfortably fill their lungs after initial delivery of the drug. -
Piston 940 moves due to a pressure differential between aregion 950 abovepiston 940 and aregion 952 belowpiston 940. This pressure differential is produced by a vacuum that is created inregion 950 when the user begins to inhale due to ableed hole 954 that is in communication withregion 950. The size ofbleed hole 954 is configured to control the resulting vacuum withinregion 950, and therefore the rate of upward movement ofpiston 940. - A variety of techniques may be used to ensure that the user properly positions their mouth over the mouthpiece during use of the aerosolization devices of the invention. For example, a lip guard may be included on the mouthpiece to permit the user to place their lips adjacent the lip guard. As another example, the mouthpiece may include bite or other landmarks. Alternatively, one or more holes may be provided in the side of the mouthpiece. These holes must be covered by the lips in order to create a sufficient vacuum to operate the device. As a further example, the mouthpiece may have a circular-to-elliptical profile. The elliptical portion must be covered by the patient's mouth in order for a sufficient vacuum to be created. Optionally, a tongue depressor may also be used to depress the user's tongue when inhaling from the mouthpiece.
- Referring now to
FIG. 88 , one embodiment of amouthpiece 1000 will be described.Mouthpiece 1000 comprises atubular member 1002 having adistal end 1004 that is configured to be coupled to an aerosolization device and an openproximal end 1006.Distal end 1004 has a circular cross sectional profile, whileproximal end 1006 has a curved or elliptical cross sectional profile. In this way, the user must place their mouth overmouthpiece 1000 until their lips reach the circular portion in order to create the vacuum needed to operate the aerosolization device. Another mouth position device onmouthpiece 1000 is a pair ofholes 1008 that must be covered by the user's lips in order to produce the required vacuum. As another alternative,mouthpiece 1000 may includebite landmarks 1010 for the user's front teeth. Similar bite marks may be provided for the user's bottom teeth. -
FIG. 89 illustrates another embodiment of amouthpiece 1012 comprising atubular member 1014 having adistal end 1016 that is slidable over atubular extension 1018 that in turn is coupled to an aerosolization device. In this way, the user may adjust the distance between aproximal end 1020 oftubular member 1014 relative to the aerosolization device. According to one embodiment, the device is primed for actuation whentubular extension 1018 is in the patient's mouth and the patient applies a force againstextension 1018 pushingextension 1018 forward in a direction towards the device, thus priming the device for actuation. Also,tubular member 1014 includes atongue depressor 1022 that depresses the user's tongue during inhalation to facilitate passage of the aerosolized powder past the user's tongue and into the lungs. - The devices and methods of the present invention may be used with both liquid or powdered pharmaceutical formulations. The amount of active agent in the formulation will be that amount necessary to deliver a therapeutically effective amount of the active agent to achieve the desired result. In practice, this will vary widely depending upon the particular agent, the severity of the condition, and the desired therapeutic effect. According to a preferred embodiment for administering powdered formulations, pulmonary delivery is generally practical for active agents that must be delivered in doses of from 0.001 mg/day to 100 mg/day, preferably 0.01 mg/day to 50 mg/day.
- Powdered formulations suitable for use in the present invention include dry powders and particles suspended or dissolved within a propellant. The powdered formulations have a particle size selected to permit penetration into the alveoli of the lungs, that is, preferably less than 10 μm mass median diameter (MMD), preferably less than 7.5 μm, and most preferably less than 5 μm, and usually being in the range of 0.1 μm to 5 μm in diameter. The emitted dose (ED) of these powders is >30%, usually >40%, preferably >50% and often >60% and the aerosol particle size distribution is about 1.0-5.0 μm mass median aerodynamic diameter (MMAD), usually 1.5-4.5 μm MMAD and preferably 1.5-4.0 μm MMAD. These dry powders have a moisture content below about 10% by weight, usually below about 5% by weight, and preferably below about 3% by weight. Such powders are described in WO 95/24183, WO 96/32149, and WO 99/16419 which are incorporated by reference herein.
- The receptacles of the invention may conveniently be configured to have a penetrable access lid that is penetrated by one or more pointed structures when the aerosolization device is operated. Examples of such receptacles are described in U.S. Pat. Nos. 5,740,754 and 5,785,049, the complete disclosures of which are herein incorporated by reference.
- The invention may utilize various deagglomeration mechanisms to deagglomerate the pharmaceutical formulation once it is extracted from the receptacle. For example, the flow path for the gases may experience one or more changes in direction to cause the pharmaceutical formulation to,engage the walls of the flow path to deagglomerate the formulation. The flow path may also include various contractions or restrictions that may cause the pharmaceutical formulation to engage the walls of the flow path to deagglomerate the formulation. As another example, the flow path may include one or more obtrusions or obstacles that serve to engage the pharmaceutical formulation as it passes through the flow path. According to a preferred embodiment, the diameter of the deagglomeration mechanism is greater than that of the flow path.
- The invention has now been described in detail for purposes of clarity of understanding. However, it will be appreciated that certain changes and modifications may be practiced within the scope of the appended claims.
Claims (52)
1. A method for aerosolizing a pharmaceutical formulation, the method comprising:
preventing respiratory gases from flowing to the lungs when attempting to inhale, and then abruptly permitting respiratory gases to flow to the lungs; and
using the flow of respiratory gases to extract a pharmaceutical formulation from a receptacle and to place the pharmaceutical formulation within the flow of respiratory gases to form an aerosol.
2. A method as in claim 1 , further comprising limiting the flow of respiratory gases to a rate that is less than a certain rate for a certain time.
3. A method as in claim 2 , wherein the rate is less than about 15 L/min and the time is in the range from about 0.5 seconds to about 5 seconds.
4. A method as in claim 2 , wherein the rate is less than about 8 L/min and the time is in the range from about 0.5 seconds to about 5 seconds.
5. A method as in claim 2 , wherein the certain rate permits an inhaled volume that is in the range from about 125 mL to about 1.25 L
6. A method as in claim 1 , wherein the flow preventing step further comprises placing a valve within an airway leading to the lungs and opening the valve to permit respiratory gases to flow to the lungs.
7. A method as in claim 6 , further comprising opening the valve when a threshold actuating vacuum caused by the attempted inhalation is exceeded.
8. A method as in claim 7 , wherein the threshold actuating vacuum is in a range from about 20 cm H20 to about 60 cm H20.
9. A method as in claim 6 , wherein the valve comprises an occlusion member having an opening, and a pull through member that is pulled through the opening when the threshold actuating vacuum is produced.
10. A method as in claim 9 , wherein the occlusion member comprises an elastomeric membrane, and wherein the pull through member comprises a ball.
11. A method as in claim 2 , wherein the flow limiting step comprises providing feedback when an excessive flow rate is produced to permit a user to adjust their inhalation rate.
12. A method as in claim 2 , wherein the flow limiting step comprises regulating the size of an airway leading to the lungs.
13. A method as in claim 12 , further comprising regulating the size of the airway with an elastomeric duckbill valve.
14. A method as in claim 12 , further comprising regulating the size of the airway with a spring biased ball that is disposed within a tapered opening such that the ball in drawn into the opening as the flow rate increases.
15. A method as in claim 12 , further comprising regulating the size of the airway to permit an increased flow rate after the certain time has lapsed.
16. A method as in claim 2 , further comprising providing another airway to permit an increase flow of gases to the lungs after the certain time has lapsed.
17. A method as in claim 1 , wherein the pharmaceutical formulation comprises a powdered medicament, and further comprising using the flow of respiratory gases to deagglomerate the extracted powder.
18. A method for administering a pharmaceutical formulation, the method comprising:
providing an inhalation device comprising a housing having first and second openings to ambient air and a mouthpiece at one of said openings;
preventing respiratory gases from flowing to the lungs when attempting to inhale through said mouthpiece;
permitting the flow of a first predetermined volume of respiratory gases to the lungs, said first volume being sufficient to transport substantially all of a unit dose of a pharmaceutical formulation contained within the inhalation device out of the device and into the respiratory tract of a patient; and
permitting a second volume of respiratory gases to flow to the lungs.
19. A method as in claim 18 wherein the flow of respiratory gases is prevented by providing the device with a valve between said openings.
20. A method according to claim 19 wherein the flow of respiratory gases is permitted by opening said valve when a threshold actuating vacuum by the attempted inhalation is exceeded.
21. A method according to claim 20 wherein said vacuum is within 20-60 cm H2O.
22. A method as in claim 18 wherein said first predetermined volume of respiratory gases is in the range from 125 mL to 1.25 L.
23. A method as in claim 18 further comprising regulating the flow of respiratory gases at a first flow rate until said first predetermined volume of respiratory gases flows through said device.
24. A method according to claim 23 wherein the first flow rate is less than 15 L/min.
25. A method according to claim 23 further comprising regulating the flow of said second volume of respiratory gases at a second flow rate.
26. An aerosolization device, comprising:
a housing defining an airway;
a coupling mechanism adapted to couple a receptacle containing a pharmaceutical formulation to the airway; and
a valve to prevent respiratory gases from flowing through the airway until a threshold actuating vacuum is exceeded at which time the valve opens to permit respiratory gases to flow through the airway and to extract the pharmaceutical formulation from the receptacle to form an aerosol.
27. A device as in claim 26 , further comprising a regulation system to regulate the flow of respiratory gases through the airway to a certain rate.
28. A device as in claim 27 , wherein the regulation system is configured to limit the flow to a rate that is less than about 15 L/min for a certain time or a certain inhaled volume.
29. A device as in claim 27 , wherein the regulation system comprises a feedback mechanism to provide information on the rate of flow of the respiratory gases.
30. A device as in claim 29 , wherein the feedback mechanism comprises a whistle in communication with the airway.
31. A device as in claim 27 , wherein the regulation system comprises a restrictive member disposed in the airway, the restrictive member defining an orifice sized to limit the flow of respiratory gases through the airway.
32. A device as in claim 27 , wherein the regulation system comprises a restriction mechanism to limit the size of the airway.
33. A device as in claim 32 , wherein the restriction mechanism comprises an elastomeric duckbill valve that closes as the flow rate of the respiratory gases increases.
34. A device as in claim 32 , wherein the restriction mechanism comprises a spring biased ball that is drawn into a tapered opening as the flow rate of the respiratory gases increases.
35. A device as in claim 32 , wherein the restriction mechanism is adjustable to vary the rate of flow of respiratory gases through the airway.
36. A device as in claim 35 , wherein the regulation system further comprises a control system to adjust the restriction mechanism.
37. A device as in claim 36 , wherein the control system is configured to limit the flow to the certain rate for a certain time or inhaled volume and then to adjust the restriction mechanism to permit an increased flow of respiratory gases through the airway.
38. A device as in claim 28 , further comprising a flow integrator that is configured to open another airway in the housing after a certain time or inhaled volume.
39. A device as in claim 26 , wherein the valve comprises an occlusion member having an opening, and a pull through member that is pulled through the opening when the threshold actuating vacuum is produced.
40. A device as in claim 39 , wherein the occlusion member comprises an elastomeric membrane, and wherein the pull through member comprises a ball.
41. A device as in claim 26 , wherein the threshold actuating vacuum of the valve is in a range from about 20 cm H20 to about 60 cm H20.
42. A device as in claim 26 , further comprising a deagglomeration mechanism disposed in the airway downstream of the receptacle to deagglomerate the extracted pharmaceutical formulation.
43. A device as in claim 26 , wherein the valve is adapted to be disposed within the receptacle.
44. An aerosolization system comprising:
a receptacle comprising a chamber having a pharmaceutical formulation and a threshold valve;
a housing defining an airway; and
a coupling mechanism to position the valve across the airway and to place the pharmaceutical formulation in fluid communication with the airway;
wherein the threshold valve is configured to open when a threshold actuating vacuum is exceeded to permit respiratory gases to flow through the airway and extract the pharmaceutical formulation from the chamber to form an aerosol.
45. A system as in claim 44 , wherein the pharmaceutical formulation comprises a powdered medicament.
46. A system as in claim 44 , wherein the pharmaceutical formulation comprises a liquid medicament.
47. A system as in claim 44 , further comprising a regulation system to regulate the flow of respiratory gases through the airway.
48. A receptacle comprising:
a receptacle body defining a cavity enclosed by a penetrable access lid; and
a threshold valve coupled to the receptacle body.
49. A receptacle as in claim 48; wherein the threshold valve is configured to open when experiencing a vacuum of at least about 40 cm H20.
50. An aerosolization device, comprising:
a housing having a mouthpiece;
an aerosolization mechanism disposed in the housing, wherein the aerosolization mechanism is adapted to aerosolize a powdered medicament when a user inhales from the mouthpiece; and
a positioning system that is adapted to facilitate proper positioning of a user's mouth over the mouthpiece prior to inhalation.
51. A device as in claim 50 , wherein the positioning system comprises at least one hole in a side of the mouthpiece over which the user must position the mouth to produce a vacuum sufficient to cause aerosolization of the powdered medicament.
52. A device as in claim 50 , wherein the positioning system comprises a positioning landmark disposed on the mouthpiece that is interactable with a physiological feature of the user.
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