Systems for the intrapulmonary delivery of aerosolized aqueous formulations

• US 5,544,646 A
• Filed: 05/20/1994
• Issued: 08/13/1996
• Est. Priority Date: 05/21/1993
• Status: Expired due to Term

• Current Assignee: Aradigm Corporation
• Original Assignee: Aradigm Corporation
• Inventors: Lloyd, Peter M., Schuster, Jeffrey A., Rubsamen, Reid M., Lloyd, Lester J.
• Primary Examiner(s): Lewis, Aaron J.
• Application Number:
  US08/247,012
• Time in Patent Office: 816 Days
• Field of Search: 128/200.14, 128/200.22, 128/203.12, 222/541.3, 222/541.4, 206/531, 206/532
• US Class Current: 128/200.14
• CPC Class Codes: A61J 1/035 Blister-type containers blisters in general B65D75/36
• CPC Class Codes: A61J 1/1418 Threaded type
• CPC Class Codes: A61J 7/04 Arrangements for time indication or reminder for taking medicine, e.g. programmed dispensers
• CPC Class Codes: A61J 7/0418 with electronic history memory
• CPC Class Codes: A61K 51/1206 Administration of radioactive gases, aerosols or breath tests
• CPC Class Codes: A61M 11/002 by flow deviation causing inertial separation of transported particles
• CPC Class Codes: A61M 15/00 Inhalators drug delivery in endotracheal tubes A61M16/04
• CPC Class Codes: A61M 15/001 using ultrasonic means
• CPC Class Codes: A61M 15/0031 by bursting or breaking the package, i.e. without cutting or piercing
• CPC Class Codes: A61M 15/0043 Non-destructive separation of the package, e.g. peeling
• CPC Class Codes: A61M 15/0051 the dosages being arranged on a tape, e.g. strips
• CPC Class Codes: A61M 15/0055 the used dosages being coiled
• CPC Class Codes: A61M 15/008 Electronic counters
• CPC Class Codes: A61M 15/0085 using ultrasonics spraying or atomising liquids using ultrasonic vibrations in general B05B17/06
• CPC Class Codes: A61M 2016/0021 with a proportional output signal, e.g. from a thermistor
• CPC Class Codes: A61M 2016/0039 in the inspiratory circuit
• CPC Class Codes: A61M 2205/8206 battery-operated
• CPC Class Codes: A61M 2230/005 Parameter used as control input for the apparatus
• CPC Class Codes: A61M 2230/40 Respiratory characteristics
• CPC Class Codes: B65D 81/32 for packaging two or more different materials which must be maintained separate prior to use in admixture containers with removable or destructible partitions B65D25/08 ; closures combined with auxiliary containers B65D51/28; in aerosol containers B65D83/682; amalgam capsules A61C5/66; containers for pharmaceutical purposes A61J1/20, A61M5/19; medical syringes A61M3/005, resin cartridges for grouting anchoring-bolts in mines E21D20/026

Abstract

A disposable package, tape, and cassette are provided which makes it possible to hold and disperse therefrom liquid, flowable formulations including aqueous formulations (solutions or dispersions with particles less than 0.25 microns in diameter) of a pharmaceutically active drug. In one embodiment formulation is packaged in individual dosage unit containers which containers are preferably interconnected. The package is designed to be integrated into a cassette which can be loaded into a dispersing device capable of individually opening dosage unit containers and aerosolizing the contents through a porous membrane, into a mouth piece on the cassette, for delivery to a patient. In addition to and alongside of each porous membrane, the package may include one or more openings through which air is forced in order to aid in avoiding the accumulation of aerosolized particles. The package may be configured so that the formulation is held in a container not positioned directly vertical to and below the porous membrane, thus making it necessary to channel formulation horizontally to the porous membrane and making it possible to include a vibrating mechanism directly below a chamber covered by the porous membrane. Release of aerosolized drug is breath actuated based on simultaneous measurements of inspiratory flow and volume so as to provide for repeatable dosing of drug to the patient.

Claims

1. A disposable package, comprising:

a container having at least one wall which is collapsible by the application of a force the container having therein a dry pharmaceutically active drug with at least one wall having an opening;

a porous membrane covering the opening wherein the membrane pores have a diameter in the range of from about 0.25 micron to about 6 microns; and

a liquid container having a flowable liquid therein, the liquid container being in fluid connection with the container having the dry drug therein, wherein the liquid container is separated from the container having the dry drug therein by a membrane which is ruptured upon the application of force.

2. The disposable package as claimed in claim 1, further comprising one or more additional containers interconnected together by an interconnecting component wherein each addition container has an opening covered by a porous membrane with pores having a diameter in the range of about 0.25 to about 6 microns and is in fluid connection with a liquid container.

3. The disposable package as claimed in claim 1, wherein the porous membrane is comprised of an area of a surface of the container which area includes pores having a diameter in a range of 0.25 micron to about 6 microns.

4. The disposable package as claimed in claim 3, wherein the membrane includes from 10 to 10,000 pores positioned over the area having a size in the range of from about 1 mm. sq. to about 1 cm. sq.

5. The disposable package as claimed in claim 1, wherein the pores are present in the porous membrane with a pore density of from about 1×

10⁴ through about 1×

10⁸ pores/cm² and the wall is collapsed by the application of force causing a pressure of about 20 psi to 100 psi.

6. The disposable package as claimed in claim 1, wherein the container includes a barrier separating the content of the container from the porous membrane the barrier being rupturable upon the application of a force.

7. The disposable package of claim 1, wherein the container and the liquid container are each collapsible by the application of force to a bottom wall so as to collapse each side wall and can be collapsed in a manner so as to force essentially all of the flowable liquid out of the liquid container into the container to contact with the dry drug to form a formation which is forced out of the porous membrane and aerosolized into particles having a diameter in the range of from about 0.5 to 12 microns.

8. The disposable package of claim 1, further comprising a removable cover sheet positioned over the porous membrane, the cover sheet being held in place by a seal.

9. A disposable package, comprising:

a container having an opening leading to a channel, the container having a liquid, flowable formulation therein which formulation comprises a pharmaceutically active drug, wherein at least one wall of the container is collapsible in a manner so as to allow the formulation in the container to be forced out of the opening into the channel;

a resonance cavity in fluid connection with the container by means of the channel, the resonance cavity having a porous membrane wherein pores of the membrane have a diameter in the range of 0.25 to 6 microns.

10. The disposable package of claim 9, wherein the pharmaceutically active drug is a respiratory drug.

11. The disposable package of claim 9, wherein the pharmaceutically active drug is a systemic drug.

12. The disposable package of claim 9, wherein the pharmaceutically active drug is asteroid selected from the group consisting of beclomethasone dipropionate, flunisolide, fluticasone, budesonide and triamcinolone acetonide.

13. The disposable package of claim 9, wherein the pharmaceutically active drug is a non-steroidal, anti-inflammatory drug.

14. The disposable package of claim 9, wherein the pharmaceutically active drug is selected from the group consisting of isoproterenol, cromolyn sodium, albuterol sulfate, metaproterenol sulfate, salmeterol xinaforate and formotorol.

15. A disposable drug delivery cassette for use in aerosolized delivery of drugs to lungs, comprising:

an outer protective cover having positioned therein;

a disposable package comprised of a plurality of interconnected individual disposable drug containers, with each container having an opening which opening leads to an open channel which includes an abutment which is broken on the application of force and an area beyond the abutment which is covered by a disposable porous membrane having pores with a diameter of about 0.25 to 6 microns, with each container containing a liquid formulation comprising a pharmaceutically active drug;

wherein the formulation has a viscosity of which is sufficiently low such that the formulation is aerosolized to particles having a diameter of about 0.5 to 12 microns when moved out of the pores.

16. The cassette as claimed in claim 15, further comprising:

an air dispersion vent having an opening positioned in a manner such that air exiting the vent will exit in substantially the same direction as liquid formulation exiting from the porous membrane, the porous membrane having 10 to 10,000 pores over an area of from about 1 mm² to about 1 cm².

17. The cassette as claimed in claim 15, further comprising:

a vibrating device capable of vibrating at a frequency in the range of 800 to 4,000 kilohertz.