US20080053431A1 - Device and method for creating aerosols for drug delivery - Google Patents
Device and method for creating aerosols for drug delivery Download PDFInfo
- Publication number
- US20080053431A1 US20080053431A1 US11/926,926 US92692607A US2008053431A1 US 20080053431 A1 US20080053431 A1 US 20080053431A1 US 92692607 A US92692607 A US 92692607A US 2008053431 A1 US2008053431 A1 US 2008053431A1
- Authority
- US
- United States
- Prior art keywords
- gas
- liquid
- drug
- pressure chamber
- feeding source
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 41
- 238000012377 drug delivery Methods 0.000 title claims abstract description 12
- 239000000443 aerosol Substances 0.000 title description 68
- 239000007788 liquid Substances 0.000 claims abstract description 179
- 239000002245 particle Substances 0.000 claims abstract description 111
- 239000003814 drug Substances 0.000 claims abstract description 40
- 229940079593 drug Drugs 0.000 claims abstract description 39
- 239000000725 suspension Substances 0.000 claims description 8
- 238000004140 cleaning Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 51
- 238000009472 formulation Methods 0.000 abstract description 46
- 210000004072 lung Anatomy 0.000 abstract description 20
- 239000007789 gas Substances 0.000 description 121
- 239000012530 fluid Substances 0.000 description 81
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 27
- 150000001875 compounds Chemical class 0.000 description 17
- 230000003434 inspiratory effect Effects 0.000 description 15
- 239000000463 material Substances 0.000 description 15
- 230000000694 effects Effects 0.000 description 14
- 230000008901 benefit Effects 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000007921 spray Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 7
- 230000009325 pulmonary function Effects 0.000 description 7
- 230000000241 respiratory effect Effects 0.000 description 7
- 230000001133 acceleration Effects 0.000 description 6
- 239000011248 coating agent Substances 0.000 description 6
- 238000000576 coating method Methods 0.000 description 6
- 230000033001 locomotion Effects 0.000 description 6
- 230000004199 lung function Effects 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 238000000889 atomisation Methods 0.000 description 5
- 230000001419 dependent effect Effects 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 239000012669 liquid formulation Substances 0.000 description 5
- 230000002411 adverse Effects 0.000 description 4
- 230000004323 axial length Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000009969 flowable effect Effects 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 230000005499 meniscus Effects 0.000 description 4
- 239000004005 microsphere Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 239000013583 drug formulation Substances 0.000 description 3
- 229940112141 dry powder inhaler Drugs 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 229940071648 metered dose inhaler Drugs 0.000 description 3
- 230000010355 oscillation Effects 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 239000003380 propellant Substances 0.000 description 3
- 238000013125 spirometry Methods 0.000 description 3
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 239000000919 ceramic Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 230000016507 interphase Effects 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000003595 mist Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000004062 sedimentation Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000008399 tap water Substances 0.000 description 2
- 235000020679 tap water Nutrition 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 108010065920 Insulin Lispro Proteins 0.000 description 1
- 241000973497 Siphonognathus argyrophanes Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000024716 acute asthma Diseases 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000007885 bronchoconstriction Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004581 coalescence Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000001687 destabilization Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- -1 e.g. Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- WNRQPCUGRUFHED-DETKDSODSA-N humalog Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1.C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 WNRQPCUGRUFHED-DETKDSODSA-N 0.000 description 1
- 229960002068 insulin lispro Drugs 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 238000009688 liquid atomisation Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012806 monitoring device Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000003094 perturbing effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000010408 sweeping Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- 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
-
- 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
- A61M16/10—Preparation of respiratory gases or vapours
- A61M16/14—Preparation of respiratory gases or vapours by mixing different fluids, one of them being in a liquid phase
-
- 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
- A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
- A61M11/001—Particle size control
-
- 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
- A61M15/02—Inhalators with activated or ionised fluids, e.g. electrohydrodynamic [EHD] or electrostatic devices; Ozone-inhalators with radioactive tagged particles
- A61M15/025—Bubble jet droplet ejection devices
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
- B01F23/20—Mixing gases with liquids
- B01F23/23—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids
- B01F23/232—Mixing gases with liquids by introducing gases into liquid media, e.g. for producing aerated liquids using flow-mixing means for introducing the gases, e.g. baffles
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
- B01F25/30—Injector mixers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F33/00—Other mixers; Mixing plants; Combinations of mixers
- B01F33/30—Micromixers
- B01F33/301—Micromixers using specific means for arranging the streams to be mixed, e.g. channel geometries or dispositions
- B01F33/3011—Micromixers using specific means for arranging the streams to be mixed, e.g. channel geometries or dispositions using a sheathing stream of a fluid surrounding a central stream of a different fluid, e.g. for reducing the cross-section of the central stream or to produce droplets from the central stream
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B7/00—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas
- B05B7/02—Spray pistols; Apparatus for discharge
- B05B7/04—Spray pistols; Apparatus for discharge with arrangements for mixing liquids or other fluent materials before discharge
- B05B7/0416—Spray pistols; Apparatus for discharge with arrangements for mixing liquids or other fluent materials before discharge with arrangements for mixing one gas and one liquid
- B05B7/0441—Spray pistols; Apparatus for discharge with arrangements for mixing liquids or other fluent materials before discharge with arrangements for mixing one gas and one liquid with one inner conduit of liquid surrounded by an external conduit of gas upstream the mixing chamber
- B05B7/0475—Spray pistols; Apparatus for discharge with arrangements for mixing liquids or other fluent materials before discharge with arrangements for mixing one gas and one liquid with one inner conduit of liquid surrounded by an external conduit of gas upstream the mixing chamber with means for deflecting the peripheral gas flow towards the central liquid flow
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B7/00—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas
- B05B7/02—Spray pistols; Apparatus for discharge
- B05B7/06—Spray pistols; Apparatus for discharge with at least one outlet orifice surrounding another approximately in the same plane
- B05B7/061—Spray pistols; Apparatus for discharge with at least one outlet orifice surrounding another approximately in the same plane with several liquid outlets discharging one or several liquids
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B7/00—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas
- B05B7/02—Spray pistols; Apparatus for discharge
- B05B7/06—Spray pistols; Apparatus for discharge with at least one outlet orifice surrounding another approximately in the same plane
- B05B7/062—Spray pistols; Apparatus for discharge with at least one outlet orifice surrounding another approximately in the same plane with only one liquid outlet and at least one gas outlet
- B05B7/065—Spray pistols; Apparatus for discharge with at least one outlet orifice surrounding another approximately in the same plane with only one liquid outlet and at least one gas outlet an inner gas outlet being surrounded by an annular adjacent liquid outlet
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B7/00—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas
- B05B7/02—Spray pistols; Apparatus for discharge
- B05B7/06—Spray pistols; Apparatus for discharge with at least one outlet orifice surrounding another approximately in the same plane
- B05B7/062—Spray pistols; Apparatus for discharge with at least one outlet orifice surrounding another approximately in the same plane with only one liquid outlet and at least one gas outlet
- B05B7/066—Spray pistols; Apparatus for discharge with at least one outlet orifice surrounding another approximately in the same plane with only one liquid outlet and at least one gas outlet with an inner liquid outlet surrounded by at least one annular gas outlet
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B7/00—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas
- B05B7/02—Spray pistols; Apparatus for discharge
- B05B7/08—Spray pistols; Apparatus for discharge with separate outlet orifices, e.g. to form parallel jets, i.e. the axis of the jets being parallel, to form intersecting jets, i.e. the axis of the jets converging but not necessarily intersecting at a point
- B05B7/0884—Spray pistols; Apparatus for discharge with separate outlet orifices, e.g. to form parallel jets, i.e. the axis of the jets being parallel, to form intersecting jets, i.e. the axis of the jets converging but not necessarily intersecting at a point the outlet orifices for jets constituted by a liquid or a mixture containing a liquid being aligned
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y10/00—Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F02—COMBUSTION ENGINES; HOT-GAS OR COMBUSTION-PRODUCT ENGINE PLANTS
- F02M—SUPPLYING COMBUSTION ENGINES IN GENERAL WITH COMBUSTIBLE MIXTURES OR CONSTITUENTS THEREOF
- F02M43/00—Fuel-injection apparatus operating simultaneously on two or more fuels, or on a liquid fuel and another liquid, e.g. the other liquid being an anti-knock additive
- F02M43/04—Injectors peculiar thereto
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F02—COMBUSTION ENGINES; HOT-GAS OR COMBUSTION-PRODUCT ENGINE PLANTS
- F02M—SUPPLYING COMBUSTION ENGINES IN GENERAL WITH COMBUSTIBLE MIXTURES OR CONSTITUENTS THEREOF
- F02M67/00—Apparatus in which fuel-injection is effected by means of high-pressure gas, the gas carrying the fuel into working cylinders of the engine, e.g. air-injection type
- F02M67/10—Injectors peculiar thereto, e.g. valve less type
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F02—COMBUSTION ENGINES; HOT-GAS OR COMBUSTION-PRODUCT ENGINE PLANTS
- F02M—SUPPLYING COMBUSTION ENGINES IN GENERAL WITH COMBUSTIBLE MIXTURES OR CONSTITUENTS THEREOF
- F02M69/00—Low-pressure fuel-injection apparatus ; Apparatus with both continuous and intermittent injection; Apparatus injecting different types of fuel
- F02M69/04—Injectors peculiar thereto
- F02M69/047—Injectors peculiar thereto injectors with air chambers, e.g. communicating with atmosphere for aerating the nozzles
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F02—COMBUSTION ENGINES; HOT-GAS OR COMBUSTION-PRODUCT ENGINE PLANTS
- F02M—SUPPLYING COMBUSTION ENGINES IN GENERAL WITH COMBUSTIBLE MIXTURES OR CONSTITUENTS THEREOF
- F02M69/00—Low-pressure fuel-injection apparatus ; Apparatus with both continuous and intermittent injection; Apparatus injecting different types of fuel
- F02M69/08—Low-pressure fuel-injection apparatus ; Apparatus with both continuous and intermittent injection; Apparatus injecting different types of fuel characterised by the fuel being carried by compressed air into main stream of combustion-air
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F23—COMBUSTION APPARATUS; COMBUSTION PROCESSES
- F23D—BURNERS
- F23D11/00—Burners using a direct spraying action of liquid droplets or vaporised liquid into the combustion space
- F23D11/10—Burners using a direct spraying action of liquid droplets or vaporised liquid into the combustion space the spraying being induced by a gaseous medium, e.g. water vapour
- F23D11/106—Burners using a direct spraying action of liquid droplets or vaporised liquid into the combustion space the spraying being induced by a gaseous medium, e.g. water vapour medium and fuel meeting at the burner outlet
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/01—Arrangements or apparatus for facilitating the optical investigation
-
- 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
- A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
- A61M11/001—Particle size control
- A61M11/002—Particle size control by flow deviation causing inertial separation of transported particles
-
- 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
- A61M2202/00—Special media to be introduced, removed or treated
- A61M2202/06—Solids
- A61M2202/064—Powder
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00277—Apparatus
- B01J2219/00351—Means for dispensing and evacuation of reagents
- B01J2219/00378—Piezoelectric or ink jet dispensers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B1/00—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means
- B05B1/02—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means designed to produce a jet, spray, or other discharge of particular shape or nature, e.g. in single drops, or having an outlet of particular shape
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B60/00—Apparatus specially adapted for use in combinatorial chemistry or with libraries
- C40B60/14—Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
- G01N15/10—Investigating individual particles
- G01N15/14—Optical investigation techniques, e.g. flow cytometry
- G01N15/1404—Handling flow, e.g. hydrodynamic focusing
- G01N15/1409—Handling samples, e.g. injecting samples
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
- G01N15/10—Investigating individual particles
- G01N15/14—Optical investigation techniques, e.g. flow cytometry
- G01N15/1404—Handling flow, e.g. hydrodynamic focusing
- G01N2015/1406—Control of droplet point
Definitions
- This invention relates generally to the field of aerosols and more particularly to devices and methods for creating aerosols of pharmaceutical formulations for delivery to a human patient, preferably by inhalation.
- Aerosolizing formulations for inhalation has been considered as a convenient alternative to injection for decades. This alternative to injections is particularly interesting for drugs which cannot be delivered orally, e.g. insulin. Although most compounds will effectively move from the lungs into the circulatory system there is considerable unpredictability in how much aerosolized formulation reaches the areas of the lungs where the material can move into the circulatory system. This results in inefficiency and unpredictability of dosing.
- a number of devices have been proposed for improving the efficiency of aerosol delivery, monitoring patients and teaching patients to correctly use delivery devices.
- MDI metered dose inhaler
- Devices of this type are disclosed in U.S. Pat. No. 5,404,871 issued Apr. 11, 1995 and U.S. Pat. No. 5,364,838 issued Nov. 15, 1994.
- DPI dry powder inhaler
- each of these devices has some advantages and disadvantages.
- the object of each is substantially the same—to repeatedly produce a fine mist aerosol wherein the particles are substantially uniform in size and within a size range of about 1 micron to about 5 microns.
- a patient can be accurately dosed if the device can repeatedly start with a given amount of formula and produce a known amount of aerosol with particles having sizes within a known range.
- the present invention endeavors to provide a device and method for obtaining accurate repeatable dosing of a patient with an aerosol.
- Aerosolized particles within a desired size range are produced from a liquid formulation comprised of a pharmaceutical active drug and a carrier.
- the particles produced all have substantially the same particle diameter ⁇ 3% to ⁇ 30%, e.g. all particles in the aerosol have a diameter of 2 microns ⁇ 3% to ⁇ 10%.
- the formulation is provided in any desired manner (e.g., forced through a channel of a feeding needle and expelled out of an exit opening of the needle).
- gas contained in a pressure chamber (which surrounds at least the area where the formulation is provided, e.g., surrounds the exit opening of the needle) is forced out of an opening positioned in front of the formulation, e.g., directly in front of the flow path of the formulation being expelled from the feeding needle.
- a pressure chamber which surrounds at least the area where the formulation is provided, e.g., surrounds the exit opening of the needle
- an opening positioned in front of the formulation e.g., directly in front of the flow path of the formulation being expelled from the feeding needle.
- Various parameters are adjusted to obtain a super critical flow of liquid characterized by a stable liquid-gas interface and a stable capillary jet of the liquid which forms particles on exiting the opening of the pressurized chamber which particles will all (90% or more) have substantially the same diameter, i.e., a monodisperse aerosol.
- An object of the invention is to provide a device for aerosolized delivery of a pharmaceutically active drug formulation or a diagnostic formulation.
- Another object is to provide a method of creating an aerosol of consistent particle size ( ⁇ 3 to 30% or preferably ⁇ 3 to 10% difference in diameter) which aerosol is inhalable by a patient for aerosolized delivery of drugs or diagnostics.
- a feature of the invention is that the diameter of the opening from which liquid is expelled, the diameter of the opening from which gas is expelled and the distance between these two openings is adjustable and is adjusted to obtain a stable liquid-gas interface which results in a stable capillary microjet being formed by the liquid expelled which microjet is focused on an exit opening by the flow of surrounding gas.
- Another feature of the invention is that the viscosities and velocities of the fluids can be chosen with consideration to other adjusted parameters to obtain a supercritical flow of liquid.
- the liquid can be a single liquid, two or more (miscible or immiscible) liquids mixed, a solution or a suspension.
- An advantage of the invention is that the gas flowing with the particles prevents the particles from agglomerating thereby maintaining a monodisperse aerosol.
- An advantage of the invention is that it consistently produces aerosols having particles with a desired particle diameter e.g. 1 to 5 microns.
- An advantage of the invention is that the device of the invention is energy efficient in terms of the energy used to create small particles for inhalation.
- Another advantage is that the structure of the device and its use are simple.
- Another advantage is that clogging of the exit opening of the pressure chamber is substantially eliminated because liquid is kept out of contact with the surface of the exit opening by a surrounding focused funnel of gas which flows out of the pressure chamber exit opening.
- Yet another advantage is that particles produced are substantially smaller in size than would be expected based on the diameter of the exit opening of the pressure chamber due to focusing the flow of the liquid with the flow of surrounding gas.
- An aspect of the invention is a hand-held, self-contained portable drug delivery device which consistently produces small aerosolized particles which are relatively uniform in size.
- Another aspect of the invention is a device and method which produces multiple streams of aerosol thereby quickly aerosolizing a large dose of formulation for inhalation by a patient.
- FIG. 1 is a schematic view showing the basic components of one embodiment of the invention with a cylindrical feeding needle as a source of formulation.
- FIG. 2 is a schematic view of another embodiment of the invention with two concentric tubes as a source of formulation.
- FIG. 3 is a schematic view of yet another embodiment showing a wedge-shaped planar source of formulation.
- FIG. 3 a illustrates a cross-sectional side view of the planar feeding source and the interaction of the fluids
- FIG. 3 b show a frontal view of the openings in the pressure chamber, with the multiple openings through which the atomizate exits the device.
- FIG. 3 c illustrates the channels that are optionally formed within the planar feeding member. The channels are aligned with the openings in the pressure chamber.
- FIG. 4 is a schematic view of a stable capillary microjet being formed and flowing through an exit opening to thereafter form a monodisperse aerosol.
- FIG. 5 is a graph of data where 350 measured valves of d j /d o versus Q/Q o are plotted.
- formulation is used to describe any single liquid, mixture, solution, suspension or the like which is a flowable liquid at room temperature and comprises either a pharmaceutically active compound, a diagnostic compound or a compound which becomes an active compound after entering a patient, e.g. prodrugs or DNA encoding proteins.
- the formulation is preferably further comprised of a carrier and more preferably is a liquid that has physical properties (e.g., viscosity) such that when the formulation is moved through a device of the invention the formulation is aerosolized into particles (0.1 to 10 microns in diameter) which are inhaled into the lungs of a patient and preferably reach the circulatory system.
- the carrier may be any pharmaceutically acceptable material and is preferably a flowable liquid which is compatible with the active agent.
- Formulations are preferably solutions, e.g., aqueous solutions, ethanolic solutions, aqueous/ethanolic solutions, saline solutions, colloidal suspensions and microcrystalline suspensions.
- Formulations can be solutions or suspensions of drugs (including systemically active drugs, e.g. insulin, insulin analogs including monomeric insulin such as insulin lispro) in the above mentioned liquids.
- carrier shall mean a substantially inactive (biologically) component of a formulation such as a pharmaceutically acceptable excipient material which an active ingredient such as a drug, a diagnostic agent, prodrug or a gene vector is mixed with, suspended or dissolved in.
- the carrier is preferably a flowable liquid.
- Useful carriers do not adversely interact with the drug, diagnostic or gene vector and have properties which allow for the formation of aerosolized particles preferably particles having a diameter in the range of 0.1 to 10.0 microns (more preferably 1 to 5 microns) when a formulation comprising the carrier and active ingredient is aerosolized out of a device of the invention.
- Carriers include water, ethanol, saline solutions and mixtures thereof with pure water being preferred. Other carriers can be used provided that they can be formulated to create a suitable aerosol and do not adversely effect the active component or human lung tissue.
- active compound means a compound which is either a pharmaceutically active drug, becomes or produces a therapeutic compound in the body or is a detectably labeled compound.
- a “pharmaceutically active drug” or therapeutic compound shall be interpreted to mean any pharmaceutically effective compound used in the treatment of disease.
- a “detectably labeled compound” includes compounds which are radioactively labeled see U.S. Pat. No. 5,829,436 issued Nov. 3, 1998 Re: detectable labels.
- compositions for use in the invention may be comprised of any therapeutic agent that can be atomized for patient delivery, e.g. for pulmonary delivery using an inhalation delivery system.
- examples of such pharmaceutical compositions may be found in the Physicians Desk Reference (1998), and Remington: The Science and Practice of Pharmacy 19 th Edition (1995), both of which are incorporated herein by reference.
- These formulations may be in any form capable of atomization, such as a solution, a suspension, an emulsion, a slurry, etc., provided the dynamics of the form render it capable of forming a capillary microjet upon exposure to a second fluid.
- electrosenor particle sensing device and “electronic detection system” refer to a device or other means for measuring and counting particles present in an aerosol mist.
- reporting means is used herein to indicate a means by which information obtained from a monitoring device such as an electronic particle sensing device or a device which monitors and records information relating to the patient's respiratory movement, may be provided to the user.
- aerosol bolus is used herein to describe a volume of air greater than 50 ml and less than 4 liters which has suspended within it particles of a formulation wherein the particles have a diameter in the range of 0.1 to 10 microns, preferably 1 to 5 microns, and preferably the total volume of formulation is from 5 ⁇ l to 10,000 ⁇ l.
- About 10 ⁇ l of particles having a diameter of about 1 to 3 microns are present in a volume of about 50 ml to 2 liters, preferably 100 ml to 1,000 ml.
- aerosol means any part of an aerosol bolus as described above.
- air air
- particle free air particles of formulation which create the aerosol.
- aerosol free air is used interchangeably herein to describe a volume of air which is substantially free of other material and, in particular, free of particles intentionally added such as particles of formulation which create the aerosol.
- the term means that the air does not include particles of formulation which have been intentionally added but is not intended to imply that the normal surrounding air has been filtered or treated to remove all particles although filtering can take place.
- Air is the preferred gas to use with drug delivery it being noted that other non-toxic gases, e.g., C0 2 can be used.
- measuring describes an event whereby the (1) total lung capacity, (2) inspiratory flow rate or (3) inspiratory volume of the patient is measured and/or calculated.
- the information is preferably used in order to determine an optimal point in the inspiratory cycle at which to release an aerosol and/or a particle free volume of air.
- An actual measurement of both rate and volume may be made or the rate can be directly measured and the volume calculated based on the measured rate.
- the total lung capacity can be measured or calculated based on the patient's height, sex and age. It is also preferable to continue measuring inspiratory flow during and after aerosol delivery and to record inspiratory flow rate and volume before, during and after the release of formulation. Such reading makes it possible to determine if aerosolized formulation was properly delivered to the patient.
- monitoring event shall comprise determining the character of an aerosol such as the size, number and speed of the particles in the aerosol, further, monitoring may comprise measuring lung functions such as inspiratory flow, inspiratory flow rate, and/or inspiratory volume so that a patient's lung function as defined herein, can be evaluated during before and/or after delivery thereby making it possible to evaluate the effect of formulation such as respiratory drug delivery on the patient's lung function.
- inspiratory flow rate shall mean a value of air flow rate determined, calculated or measured based on the speed of the air passing a given point in a measuring device assuming atmospheric pressure ⁇ 5% and a temperature in the range of about 10° C. to 40° C.
- inspiratory flow shall be interpreted to mean a value of air flow calculated based on the speed of the air passing a given point along with the volume of the air that has passed that point with the volume calculation being based on integration of the flow rate data and assuming atmospheric pressure, ⁇ 5% and temperature in the range of about 10° C. to about 40° C.
- inspiratory volume shall mean a determined, measured or calculated volume of air passing a given point into the lungs of a patient assuming atmospheric pressure ⁇ 5% and a temperature in the range of 10° C. to 40° C.
- lung function and “pulmonary function” are used interchangeably and shall be interpreted to mean physically measurable operations of a lung including but not limited to (1) inspiratory and (2) expiratory flow rates as well as (3) lung volume, i.e., total lung capacity.
- Methods of quantitatively determining pulmonary function are used to measure lung function. Quantitative determination of pulmonary function may be important when delivering any formulation and in particular respiratory drugs in order to direct the aerosol to a specific area of the lung and to determine effectiveness.
- Methods of measuring pulmonary function most commonly employed in clinical practice involve timed measurement of inspiratory and expiratory maneuvers to measure specific parameters. For example, forced vital capacity (FVC) measures the total volume in liters exhaled by a patient forcefully from a deep initial inspiration.
- FVC forced vital capacity
- This parameter when evaluated in conjunction with the forced expired volume in one second (FEV 1 ), allows bronchoconstriction to be quantitatively evaluated.
- a problem with forced vital capacity determination is that the forced vital capacity maneuver (i.e. forced exhalation from maximum inspiration to maximum expiration) is largely technique dependent. In other words, a given patient may produce different FVC values during a sequence of consecutive FVC maneuvers. The FEF 25-75 or forced expiratory flow determined over the mid-portion of a forced exhalation maneuver tends to be less technique dependent than the FVC. Similarly, the FEV 1 tends to be less technique dependent than FVC.
- the flow in liters per minute measured over differing portions of the expiratory cycle can be useful in determining the status of a patient's pulmonary function.
- the peak expiratory flow taken as the highest air flow rate in liters per minute during a forced maximal exhalation, is well correlated with overall pulmonary function in a patient with asthma and other respiratory diseases.
- the present invention carries out treatment by administering formulation in a delivery event and monitoring lung function in a monitoring event. A series of such events may be carried out and repeated over time to determine if lung (see U.S. Pat. No. 5,404,871) function is improved.
- Each of the parameters discussed above is measured during quantitative spirometry.
- a patient's individual performance can be compared against his personal best data, individual indices can be compared with each other for an individual patient (e.g. FEV 1 divided by FVC, producing a dimensionless index useful in assessing the severity of acute asthma symptoms), or each of these indices can be compared against an expected value.
- Expected values for indices derived from quantitative spirometry are calculated as a function of the patient's sex, height, weight and age. For instance, standards exist for the calculation of expected indices and these are frequently reported along with the actual parameters derived for an individual patient during a monitoring event such as a quantitative spirometry test.
- particles are used interchangeably herein and shall mean particles of formulation comprised of any pharmaceutically active ingredient, a compound which becomes such in the body (e.g. a prodrug or DNA encoding a protein) or a diagnostic compound. Any of these is preferably with a carrier, (e.g., a pharmaceutically active respiratory drug and carrier). Particles of a liquid formulation are formed upon forcing the formulation from anywhere it is provided (e.g., the feeding needle) and then out of the pressure chamber exit orifice.
- a carrier e.g., a pharmaceutically active respiratory drug and carrier
- the particles have a size which is sufficiently small such that when the particles are formed they remain suspended in the air for a sufficient amount of time such that the patient can inhale the particles into the patient's lungs.
- the particles have a size in the range of 0.1 micron to about 10 microns, preferably 1 to 5 microns.
- Particle diameter is an aerodynamic diameter.
- the diameter measurement given is the “aerodynamic diameter” measurement which is the diameter of a sphere of unit density that has the same terminal sedimentation velocity in air under normal atmospheric conditions as the particle in question. This is pointed out in that it is difficult to accurately measure the diameter of small particles using current technology and the shape may be continually changing. Thus, the diameter of one particle of material of a given density will be said to have the same diameter as another particle of the same or a different material if the two particles have the same terminal sedimentation velocity in air under the same conditions.
- the present disclosure focuses on the use of an aerosol creation device to produce aerosolized liquid formulations for delivery of drugs to patients—preferably by inhalation into the lungs.
- the basic technology of the invention comprises (1) a means for supplying a first fluid; and (2) a pressure chamber supplied with a second fluid.
- the first fluid is generally a liquid and preferably aqueous.
- the second fluid is generally a gas and preferably air.
- the first fluid may be a gas and second fluid a liquid or both fluids may be liquid provided the first and second fluid are sufficiently different from each other (immiscible) so as to allow for the formation of a stable microjet of the first fluid moving from the supply means to an exit port of the pressure chamber.
- Formation of the microjet and its acceleration and ultimate particle formation are based on the abrupt pressure drop associated with the steep acceleration experienced by the first fluid (e.g., a liquid) on passing through an exit orifice of the pressure chamber which holds the second fluid.
- the flow undergoes a large pressure difference between the first fluid (e.g., a liquid) and the second fluid (e.g., a gas), which in turn produces a highly curved zone on the first fluid (e.g., liquid) surface near the exit port of the pressure chamber and in the formation of a cuspidal point from which a steady microjet flows provided the amount of the first fluid (e.g., the liquid) withdrawn through the exit port of the pressure chamber is replenished.
- the first fluid e.g., a liquid
- the flow of the gas surrounds and focuses the liquid into a stable microjet.
- the focusing effect of the surrounding flow of gas creates a stream of liquid which is substantially smaller in diameter than the diameter of the exit orifice of the pressure chamber. This allows liquid to flow out of the pressure chamber orifice without touching the orifice, providing advantages including (1) clogging of the exit orifice is virtually eliminated, (2) contamination of flow due to contact with substances (e.g. bacteria) on the orifice opening is virtually eliminated, and (3) the diameter of the stream and the resulting particles are smaller than the diameter of the exit orifice of the chamber. This is particularly desirable because it is difficult to precisely engineer holes which are very small in diameter.
- a first embodiment of the invention where the supply means is a cylindrical feeding needle supplying liquid into a pressurized chamber of gas is described below with reference to FIG. 1 .
- Feeding needle also referred to generally as a fluid source and a tube.
- Orifice used as gas inlet.
- Atomizate also referred to as aerosol.
- An aerosolized drug delivery device of the invention may be any size but is preferably designed to be a hand-held, portable, self-contained device weighing less than 1 kilogram. Although the device can be configured in a variety of designs, the different designs will all include the essential components shown in FIG. 1 or components which perform an equivalent function and obtain the desired results.
- a drug delivery device of the invention will be comprised of at least one source of formulation (e.g., a feeding needle with an opening 2 ) into which a liquid flowable formulation can be fed and an exit opening 5 from which the formulation can be expelled.
- the chamber 3 has inlet opening 4 which is used to feed gas into the chamber 3 and an exit opening 6 through which gas from the pressure chamber and liquid formulation from the feeding needle 3 are expelled creating an aerosol.
- the feeding needle and pressure chamber are configured to obtain a desired result of producing an aerosol wherein the particles are small and uniform in size.
- the particles Preferably have a size which is in a range of 0.1 to 10 microns, more preferably 1 to 5 microns. Particles of less than 1 micron in diameter can be produced via the present invention. However, particles below 1 micron may be too small for inhalation as the particles may not settle in the lung during a normal breath hold and as such would be exhaled.
- the particles of any given aerosol all have about the same diameter with a relative standard deviation of 10% to 30% or more preferably 3% to 20%.
- particles of the aerosol have a particle diameter in a range of 1 to 5 microns does not mean that different particles will have different diameters and that some will have a diameter of 1 micron while others of 5 microns.
- the particles in a given aerosol will all (preferably about 90% or more) have the same diameter ⁇ 3% to ⁇ 30%. For example, the particles of a given aerosol will have a diameter of 2 microns ⁇ 3% to ⁇ 10%.
- Such a monodisperse aerosol is created using the components and configuration as described above. However, other components and configurations will occur to those skilled in the art.
- the object of each design will be to supply formulation so that it creates a stable capillary microjet which is accelerated and stabilized by tangential viscous stress exerted by the gas on the liquid surface.
- the stable microjet created by the gas leaves the area of the pressurized gas (e.g., leaves the pressure chamber and exits the pressure chamber orifice) and splits into particles which have the desired size and uniformity.
- the aerosol created is a monodisperse aerosol meaning that the size of the particles produced are relatively uniform in size.
- the relative standard deviation in particle size is in the range of from about 10% to about 30%, preferably 3% to 10% and most preferably 3% or less.
- the size of aerosolized particles useful for inhalation is a diameter in the range of from about 0.1 micron to about 10 microns, more preferably about 1 micron to about 3 microns.
- the parameter window used i.e. the set of special values for the liquid properties, flow-rate used, feeding needle diameter, orifice diameter, pressure ratio, etc.
- the parameter window used should be large enough to be compatible with virtually any liquid (dynamic viscosities in the range from 10 ⁇ 4 to 1 kg m ⁇ 1 s ⁇ 1 ); in this way, the capillary microjet that emerges from the end of the feeding needle is absolutely stable and perturbations produced by breakage of the jet cannot travel upstream.
- the microjet splits into evenly shaped drops simply by effect of capillary instability (see, for example, Rayleigh, “On the instability of jets”, Proc. London Math. Soc., 4-13, 1878), similar in a manner to a laminar capillary jet falling from a half-open tap.
- the capillary jet that emerges from the end of the drop at the outlet of the feeding point is concentrically withdrawn into the nozzle.
- the liquid is accelerated by tangential sweeping forces exerted by the gas stream flowing on its surface, which gradually decreases the jet cross-section.
- the gas flow acts as a lens and focuses and stabilizes the microjet as it moves toward and into the exit orifice of the pressure chamber.
- the forces exerted by the second fluid (e.g., a gas) flow on the first fluid (e.g., a liquid) surface should be steady enough to prevent irregular surface oscillations. Therefore, any turbulence in the gas motion should be avoided; even if the gas velocity is high, the characteristic size of the orifice should ensure that the gas motion is laminar (similar to the boundary layers formed on the jet and on the inner surface of the nozzle or hole).
- FIG. 4 illustrates the interaction of a liquid and a gas to form atomizate using the method of the invention.
- the feeding needle 60 has a circular exit opening 61 with an internal radius R 0 which feeds a liquid 62 out of the end, forming a drop with a radius in the range of R 0 to R 0 plus the thickness of the wall of the needle.
- the exiting liquid forms an infinite amount of liquid streamlines 63 that interact with the surrounding gas to form a stable cusp at the interface 64 of the two fluids.
- the surrounding gas also forms an infinite number of gas streamlines 65 , which interact with the exiting liquid to create a virtual focusing funnel 66 .
- the exiting liquid is focused by the focusing funnel 66 resulting in a stable capillary microjet 67 , which remains stable until it exits the opening 68 of the pressure chamber 69 .
- the microjet begins to break-up, forming monodispersed particles 70 .
- the gas flow which affects the liquid withdrawal and its subsequent acceleration after the jet is formed, should be very rapid but also uniform in order to avoid perturbing the fragile capillary interface (the surface of the drop that emerges from the jet).
- Liquid flows out of the end of a capillary tube and forms a small liquid drop at the end.
- the tube has an internal radius R o .
- the drop has a radius in a range of from R o to R o plus the structural thickness of the tube as the drop exits the tube, and thereafter the drop narrows in circumference to a much smaller circumference as is shown in the expanded view of the tube (i.e. feeding needle) 5 as shown in FIGS. 1 and 4 .
- the exit opening 61 of the capillary tube 60 is positioned close to an exit opening 68 in a planar surface of a pressure chamber 69 .
- the exit opening 68 has a minimum diameter D and is in a planar member with a thickness L.
- the diameter D is referred to as a minimum diameter because the opening may have a conical configuration with the narrower end of the cone positioned closer to the source of liquid flow.
- the exit opening may be a funnel-shaped nozzle although other opening configurations are also possible, e.g. an hour glass configuration.
- Gas in the pressure chamber continuously flows out of the exit opening. The flow of the gas causes the liquid drop expelled from the tube to decrease in circumference as the liquid moves away from the end of the tube in a direction toward the exit opening of the pressure chamber.
- the opening shape which provokes maximum gas acceleration is a conically shaped opening in the pressure chamber.
- the conical opening is positioned with its narrower end toward the source of liquid flow.
- R o , D, H and L are all preferably on the order of hundreds of microns.
- R o 400 ⁇ m
- D 150 ⁇ m
- H 1 mm
- L 300 ⁇ m.
- the end of the liquid stream develops a cusp-like shape at a critical distance from the exit opening 68 in the pressure chamber 69 when the applied pressure drop ⁇ P g across the exit opening 68 overcomes the liquid-gas surface tension stresses ⁇ /R* appearing at the point of maximum curvature—e.g. 1/R* from the exit opening.
- a steady state is then established if the liquid flow rate Q ejected from the drop cusp is steadily supplied from the capillary tube.
- This is the stable capillary cusp which is an essential characteristic of the invention needed to form the stable microjet. More particularly, a steady, thin liquid jet with a typical diameter d j is smoothly emitted from the stable cusp-like drop shape and this thin liquid jet extends over a distance in the range of microns to millimeters.
- the length of the stable microjet will vary from very short (e.g. 1 micron) to very long (e.g. 50 mm) with the length depending on the (1) flow-rate of the liquid and (2) the Reynolds number of the gas stream flowing out of the exit opening of the pressure chamber.
- the liquid jet is the stable capillary microjet obtained when supercritical flow is reached.
- This jet demonstrates a robust behavior provided that the pressure drop ⁇ P g applied to the gas is sufficiently large compared to the maximum surface tension stress (on the order of ⁇ /d j ) that act at the liquid-gas interface.
- the jet has a slightly parabolic axial velocity profile which is, in large part, responsible for the stability of the microjet.
- the stable microjet is formed without the need for other forces, i.e. without adding force such as electrical forces on a charged fluid. However, for some applications it is preferable to add charge to particles, e.g. to cause the particles to adhere to a given surface.
- the shaping of liquid exiting the capillary tube by the gas flow forming a focusing funnel creates a cusp-like meniscus resulting in the stable microjet. This is a fundamental characteristic of the invention.
- the fluid stream flowing from the tube has substantially more density and develops substantially more inertia as compared to the gas, which has lower viscosity than the liquid. These characteristics contribute to the formation of the stable capillary jet.
- the stable capillary microjet is maintained stably for a significant distance in the direction of flow away from the exit from the tube.
- the liquid is, at this point, undergoing “supercritical flow.”
- the microjet eventually destabilizes due to the effect of surface tension forces. Destabilization results from small natural perturbations moving downstream, with the fastest growing perturbations being those which govern the break up of the microjet, eventually creating a uniform sized monodisperse aerosol 70 as shown in FIG. 4 .
- the microjet even as it initially destabilizes, passes out of the exit orifice of the pressure chamber without touching the peripheral surface of the exit opening.
- This provides an important advantage of the invention which is that the exit opening 68 (which could be referred to as a nozzle) will not clog from residue and/or deposits of the liquid. Clogging is a major problem with very small nozzles and is generally dealt with by cleaning or replacing the nozzle. When fluid contacts the surfaces of a nozzle opening some fluid will remain in contact with the nozzle when the flow of fluid is shut off. The liquid remaining on the nozzle surface evaporates leaving a residue. After many uses over time the residue builds up and clogging takes place. The present invention substantially reduces or eliminates this clogging problem.
- Cylindrical coordinates (r,z) are chosen for making a mathematical analysis of a stable microjet, i.e. liquid undergoing “supercritical flow.”
- the cusp-like meniscus formed by the liquid coming out of the tube is pulled toward the exit of the pressure chamber by a pressure gradient created by the flow of gas.
- ⁇ P g which for a given pressure drop ⁇ P g is independent of geometrical parameters (hole and tube diameters, tube-hole distance, etc.), liquid and gas viscosities, and liquid-gas surface tension. This diameter remains almost constant up to the breakup point since the gas pressure after the exit remains constant.
- the shed vorticity influences the breakup of the jet and thus the formation of the particles.
- the gas stream Upstream from the hole exit, in the accelerating region, the gas stream is laminar. Typical values of the Reynolds number range from 500 to 6000 if a velocity of the order of the speed of sound is taken as characteristic of the velocity of the gas.
- the cylindrical mixing layer between the gas stream and the stagnant gas becomes unstable by the classical Kelvin-Helmholtz instability.
- the growth rate of the thickness of this layer depends on the Reynolds number of the flow and ring vortices are formed at a frequency of the order of v g /D, where D is the hole diameter. Typical values of v g and D as those found in our experimental technique lead to frequencies or the order of MHz which are comparable to the frequency of drop production (of order of t b ⁇ 1 ).
- particles which are uniform in size or to create aerosols of liquid particles which are uniform in size For example, particles of a liquid formation containing a pharmaceutically active drug could be created and designed to have a diameter of about 2 microns ⁇ 3%. These particles could be inhaled into the lungs of a patient for intrapulmonary drug delivery. Moreover, particle size can be adjusted to target a particular area of the respiratory tract.
- the gas flow should be laminar in order to avoid a turbulent regime—turbulent fluctuations in the gas flow which have a high frequency and would perturb the liquid-gas interface.
- v g is the kinematic viscosity of the gas. Even though this number is quite high, there are large pressure gradients downstream (a highly convergent geometry), so that a turbulent regime is very unlikely to develop.
- the essential difference from existing pneumatic atomizers (which possess large Weber numbers) and the present invention is that the aim of the present invention is not to rupture the liquid-gas interface but the opposite, i.e. to increase the stability of the interface until a capillary jet is obtained.
- the jet which will be very thin provided the pressure drop resulting from withdrawal is high enough, splits into drops the sizes of which are much more uniform than those resulting from disorderly breakage of the liquid-gas interface in existing pneumatic atomizers.
- the proposed atomization system obviously requires delivery of the liquid to be atomized and the gas to be used in the resulting spray. Both should be fed at a rate ensuring that the system lies within the stable parameter window. Multiplexing is effective when the flow-rates needed exceed those on an individual cell. More specifically, a plurality of feeding sources or feeding needles may be used to increase the rate at which aerosols are created. The flow-rates used should also ensure the mass ratio between the flows is compatible with the specifications of each application.
- the gas and liquid can be dispensed by any type of continuous delivery system (e.g. a compressor or a pressurized tank the former and a volumetric pump or a pressurized bottle the latter). If multiplexing is needed, the liquid flow-rate should be as uniform as possible among cells; this may entail propulsion through several capillary needles, porous media or any other medium capable of distributing a uniform flow among different feeding points.
- a compressor or a pressurized tank the former and a volumetric pump or a pressurized bottle the latter e.g. a compressor or a pressurized tank the former and a volumetric pump or a pressurized bottle the latter.
- Each individual atomization device should consist of a feeding point (a capillary needle, a point with an open microchannel, a microprotuberance on a continuous edge, etc.) 0.002-2 mm (but, preferentially 0.01-0.4 mm) in diameter, where the drop emerging from the microjet can be anchored, and a small orifice 0.002-2 mm (preferentially 0.01-0.25 mm) in diameter facing the drop and separated 0.01-2 mm (preferentially 0.2-0.5 mm) from the feeding point.
- the orifice communicates the withdrawal gas around the drop, at an increased pressure, with the zone where the atomizate is produced, at a decreased pressure.
- the atomizer can be made from a variety of materials (metal, polymers, ceramics, glass).
- FIG. 1 depicts a tested prototype where the liquid to be atomized is inserted through one end of the system 2 and the propelling gas in introduced via the special inlet 4 in the pressure chamber 3 .
- the prototype was tested at gas feeding rates from 100 to 2000 mBar above the atmospheric pressure P ⁇ at which the atomized liquid was discharged.
- the whole enclosure around the feeding needle 1 was at a pressure P 0 >P ⁇ .
- the liquid feeding pressure, P 1 should always be slightly higher than the gas propelling pressure, P o .
- the pressure difference (P 1 ⁇ P 0 >0) and the flow-rate of the liquid to be atomized, Q, are linearly related provided the flow is laminar—which is indeed the case with this prototype.
- the critical dimensions are the distance from the needle to the plate (H), the needle diameter (D 0 ), the diameter of the orifice through which the microjet 6 is discharged (d 0 ) and the axial length, e, of the orifice (i.e. the thickness of the plate where the orifice is made).
- the quality of the resulting spray 7 did not vary appreciably with changes in H provided the operating regime (i.e. stationary drop and microjet) was maintained.
- the other atomizer dimensions had no effect on the spray or the prototype functioning provided the zone around the needle (its diameter) was large enough relative to the feeding needle.
- Adjusting parameters to obtain a stable capillary microjet and control its breakup into monodisperse particle is governed by the Weber number and the liquid-to-gas velocity ratio or ⁇ which equal V 1 /V g .
- ⁇ g is the density of the gas
- d is the diameter of the stable microjet
- ⁇ is the liquid-gas surface tension
- V g 2 is the velocity of the gas squared.
- the parameters should be adjusted so that the Weber number is greater than 1 in order to produce a stable capillary microjet.
- the parameters should be adjusted so that the Weber number is less than 40.
- the monodisperse aerosol is obtained with a Weber number in a range of about 1 to about 40 when the breaking time is sufficiently small to avoid non-symmetric perturbations (1 ⁇ We ⁇ 40).
- a measure of the relative importance of viscosity on the jet breakup can be estimated from the Ohnesorge number defined as the ratio between two characteristic times: the viscous time t v and the breaking time t b .
- the breaking time t b is given by [see Rayleigh (1878)] ⁇ t b ⁇ _ ⁇ ( ⁇ l ⁇ d 2 ⁇ ) 0 / 00 . ( 2 )
- the speed, pressure, viscosity and miscibility of the first and second fluids are chosen to obtain the desired results of a stable microjet of the first fluid focused into the center of a funnel formed with the second fluid.
- These results are also obtained by adjusting or tuning physical parameters of the device, including the size of the opening from which the first fluid flows, the size of the opening from which both fluids exit, and the distance between these two openings.
- FIG. 1 can, itself, be arranged in a variety of configurations. Further, as indicated above, the embodiment may include a plurality of feeding needles. A plurality of feeding needles may be configured concentrically in a single construct, a shown in FIG. 2 .
- Orifice used as gas inlet.
- First liquid to be atomized (inner core of particle).
- Second liquid to be atomized (outer coating of particle).
- the embodiment of FIG. 2 is preferably used when attempting to form a spherical particle of one substance coated by another substance.
- the device of FIG. 2 is comprised of the same basic component as per the device of FIG. 1 and further includes a second feeding source 32 which is positioned concentrically around the first cylindrical feeding source 31 .
- the second feeding source may be surrounded by one or more additional feeding sources with each concentrically positioned around the preceding source.
- the outer coating may be used for a variety of purposes, including: coating particles to prevent small particles from sticking together; to obtain a sustained release effect of the active compound (e.g. a pharmaceutically active drug) inside, and/or to mask flavors; and to protect the stability of another compound (e.g. a pharmaceutically active drug) contained therein.
- the process is based on the microsuction which the liquid-gas or liquid-liquid interphase undergoes (if both are immiscible), when said interphase approaches a point beginning from which one of the fluids is suctioned off while the combined suction of the two fluids is produced.
- the interaction causes the fluid physically surrounded by the other to form a capillary microjet which finally breaks into spherical drops.
- a capillary jet composed of two or more layers of different fluids is formed which, when it breaks, gives rise to the formation of spheres composed of several approximately concentric spherical layers of different fluids.
- the size of the outer sphere (its thickness) and the size of the inner sphere (its volume) can be precisely adjusted. This can allow the manufacture of coated particles for a variety of end uses. For example the thickness of the coating can be varied in different manufacturing events to obtain coated particles which have gradually decreasing thicknesses to obtain a controlled release effect of the contents, e.g. a pharmaceutically active drug. The coating could merely prevent the particles from degrading, reacting, or sticking together.
- the method is based on the breaking of a capillary microjet composed of a nucleus of one liquid or gas and surrounded by another or other liquids and gases which are in a concentric manner injected by a special injection head, in such a way that they form a stable capillary microjet and that they do not mix by diffusion during the time between when the microjet is formed and when it is broken.
- a capillary microjet composed of a nucleus of one liquid or gas and surrounded by another or other liquids and gases which are in a concentric manner injected by a special injection head, in such a way that they form a stable capillary microjet and that they do not mix by diffusion during the time between when the microjet is formed and when it is broken.
- the injection head 25 consists of two concentric tubes with an external diameter on the order of one millimeter.
- the material that will constitute the nucleus of the microsphere while between the internal tube 31 and the external tube 32 the coating is injected.
- the fluid of the external tube 32 joins with the fluid of tube 31 as the fluids exit the feeding needle, and the fluids (normally liquids) thus injected are accelerated by a stream of gas that passes through a small orifice 24 facing the end of the injection tubes.
- the drop in pressure across the orifice 24 is sufficient, the liquids form a completely stationary capillary microjet, if the quantities of liquids that are injected are stationary.
- This microjet does not touch the walls of the orifice, but passes through it wrapped in the stream of gas or funnel formed by gas from the tube 32 . Because the funnel of gas focuses the liquid, the size of the exit orifice 26 does not dictate the size of the particles formed.
- the movement of the liquid is uniform at the exit of the orifice 26 and the viscosity forces are sufficiently small so as not to alter either the flow or the properties of the liquids; for example, if there are biochemical molecular specimens having a certain complexity and fragility, the viscous forces that would appear in association with the flow through a micro-orifice might degrade these substances.
- FIG. 2 shows a simplified diagram of the feeding needle 21 , which is comprised of the concentric tubes 30 , 31 through the internal and external flows of the fluids 28 , 29 that are going to compose the microspheres comprised of two immiscible fluids.
- the difference in pressures P 0 ⁇ P ⁇ (P 0 >P ⁇ ) through the orifice 26 establishes a flow of gas present in the chamber 23 and which is going to surround the microjet at its exit.
- the same pressure gradient that moves the gas is the one that moves the microjet in an axial direction through the hole 26 , provided that the difference in pressures P 0 ⁇ P ⁇ is sufficiently great in comparison with the forces of surface tension, which create an adverse gradient in the direction of the movement.
- the breakage of the microjet must be regular and axilsymmetric, so that the drops will have a uniform size, while the extra pressure ⁇ P cannot be greater than a certain value that is dependent on the surface tension of the outside liquid with the gas ⁇ 1 and on the outside diameter of the microjet. It has been experimentally shown that this difference in pressures cannot be greater than 20 times the surface tension ⁇ 1 divided by the outside radius of the microjet.
- the viscosity values of the liquids must be such that the liquid with the greater viscosity ⁇ max verifies, for a diameter d of the jet predicted for this liquid and a difference through the orifice ⁇ P, the inequality: ⁇ MAX ⁇ ⁇ ⁇ ⁇ Pd 2 ⁇ D Q
- the pressure gradients can overcome the extensional forces of viscous resistance exerted by the liquid when it is suctioned toward the orifice.
- the distance between the planes of the mouths of the concentric tubes can vary, without the characteristics of the jet being substantially altered, provided that the internal tube 31 is not introduced into the external one 32 more than one diameter of the external tube 32 and provided that the internal tube 31 does not project more than two diameters from the external tube 32 .
- the best results are obtained when the internal tube 31 projects from the external one 32 a distance substantially the same as the diameter of the internal tube 31 .
- This same criterion is valid if more than two tubes are used, with the tube that is surrounded (inner tube) projecting beyond the tube that surrounds (outer tube) by a distance substantially the same as the diameter of the first tube.
- the distance between the plane of the internal tube 31 (the one that will normally project more) and the plane of the orifice may vary between zero and three outside diameters of the external tube 32 , depending on the surface tensions between the liquids and with the gas, and on their viscosity values. Typically, the optimal distance is found experimentally for each particular configuration and each set of liquids used.
- Multiplexing i.e. several sets of concentric tubes may be used, if the flows required are greater than those of an individual cell.
- the characteristic time of this variation must be less than the hydrodynamic residence times of liquid and gas in the microjet, and less than the inverse of the first natural oscillation frequency of the drop formed at the end of the injection needle.
- any means for continuous supply of gas compressors, pressure deposits, etc.
- liquid volumetric pumps, pressure bottles
- the flow of liquid must be as homogeneous as possible between the various cells, which may require impulse through multiple capillary needles, porous media, or any other medium capable of distributing a homogeneous flow among different feeding points.
- Each atomizing device will consist of concentric tubes 31 , 32 with a diameter ranging between 0.05 and 2 mm, preferably between 0.1 and 0.4 mm, on which the drop from which the microjet emanates can be anchored, and a small orifice (between 0.001 and 2 mm in diameter, preferably between 0.1 and 0.25 mm), facing the drop and separated from the point of feeding by a distance between 0.001 and 2 mm, preferably between 0.2 and 0.5 mm.
- the orifice puts the suction gas that surrounds the drop, at higher pressure, in touch with the area in which the atomizing is to be attained, at lower pressure.
- FIGS. 1 and 2 are similar in a number of ways. Both have a feeding piece which is preferably in the form of a feeding needle with a circular exit opening. Further, both have an exit port in the pressure chamber which is positioned directly in front of the flow path of fluid out of the feeding source. Precisely maintaining the alignment of the flow path of the feeding source with the exit port of the pressure chamber can present an engineering challenge particularly when the device includes a number of feeding needles.
- the embodiment of FIG. 3 is designed to simplify the manner in which components are aligned.
- planar feeding piece (which by virtue of the withdrawal effect produced by the pressure difference across a small opening through which fluid is passed) to obtain multiple microjets which are expelled through multiple exit ports of a pressure chamber thereby obtaining multiple aerosol streams.
- a single planar feeding member as shown in FIG. 3 it, of course, is possible to produce a device with a plurality of planar feeding members where each planar feeding member feeds fluid to a linear array of outlet orifices in the surrounding pressure chamber.
- the feeding member need not be strictly planar, and may be a curved feeding device comprised of two surfaces that maintain approximately the same spatial distance between the two pieces of the feeding source.
- Such curved devices may have any level of curvature, e.g. circular, semicircular, elliptical, hemi-elliptical etc.
- Orifice used as gas inlet.
- d j diameter of the microjet formed;
- ⁇ A liquid density of first fluid ( 48 );
- ⁇ B liquid density of second fluid ( 49 );
- v A velocity of the first liquid ( 48 );
- v B velocity of the second liquid ( 49 );
- e axial length of the orifice through which withdrawal takes place;
- H distance from the feeding needle to the microjet outlet;
- P 0 pressure inside the chamber;
- the proposed dispersing device consists of a feeding piece 41 which creates a planar feeding channel through which a where a first fluid 48 flows.
- the flow is preferably directed through one or more channels of uniform bores that are constructed on the planar surface of the feeding piece 41 .
- a pressure chamber 43 that holds the propelling flow of a second liquid 49 houses the feeding piece 41 and is under a pressure above maintained outside the chamber wall 50 .
- One or more orifices, openings or slots (outlets) 46 made in the wall 52 of the propulsion chamber face the edge of the feeding piece.
- each bore or channel of the feeding piece 41 has its flow path substantially aligned with an outlet 46 .
- Formation of the microjet and its acceleration are based on the abrupt pressure drop resulting from the steep acceleration undergone by the second fluid 49 on passing through the orifice 46 , similarly to the procedure described above for embodiments of FIGS. 1 and 2 when the second fluid 49 is a gas.
- the microthread formed is quite long and the liquid velocity is much smaller than the gas velocity.
- the low viscosity of the gas allows the liquid to flow at a much lower velocity; as a result, the microjet is actually produced and accelerated by stress forces normal to the liquid surface, i.e. pressure forces.
- one effective approximation to the phenomenon is to assume that the pressure difference established will result in the same kinetic energy per unit volume for both fluids (liquid and gas), provided gas compressibility effects are neglected.
- the diameter d j of the microjet formed from a liquid density ⁇ 1 that passes at a volumetric flow-rate Q through an orifice across which a pressure difference ⁇ P g exists will be given by d j ⁇ _ ⁇ ( 8 ⁇ ⁇ l ⁇ 2 ⁇ ⁇ ⁇ ⁇ P g ) 1 / 4 ⁇ Q 0 / 00
- the second fluid 49 is a liquid and the first fluid 48 is a gas
- the facts that the liquid is much more viscous and that the gas is much less dense virtually equalize the fluid and gas velocities.
- the gas microthread formed is much shorter; however, because its rupture zone is almost invariably located in a laminar flowing stream, dispersion in the size of the microbubbles formed is almost always small.
- the diameter of the gas microjet is given by d j ⁇ _ ⁇ ( 8 ⁇ ⁇ l ⁇ 2 ⁇ ⁇ ⁇ P l ) 1 / 4 ⁇ Q g 1 / 2
- the diameter of a microjet of the first liquid at a volumetric flow-rate of A Q A and an overpressure of B ⁇ P B will be given by d j ⁇ _ ⁇ ( 8 ⁇ ⁇ A ⁇ 2 ⁇ ⁇ ⁇ ⁇ P B ) 1 / 4 ⁇ Q A 1 / 2
- the diameter of the microjet of the first liquid will be given by d j ⁇ _ ⁇ ( 8 ⁇ ⁇ ⁇ B ⁇ 2 ⁇ ⁇ ⁇ ⁇ P B ) 1 / 4 ⁇ Q A 1 / 2
- the proposed atomization system obviously requires delivery of the fluids 48 , 49 to be used in the dispersion process at appropriate flow-rates.
- the characteristic time for the variation should be shorter than the hydrodynamic residence times for the liquid and gas in the microjet, and smaller than the reciprocal of the first natural oscillation frequency of the drop formed at the end of the feeding piece.
- the gas and liquid can be dispensed by any type of continuous delivery system (e.g. a compressor or a pressurized tank the former and a volumetric pump or a pressurized bottle the latter).
- a compressor or a pressurized tank the former e.g. a compressor or a pressurized tank the former and a volumetric pump or a pressurized bottle the latter.
- the atomizer can be made from a variety of materials (metal, plastic, ceramics, glass).
- the various embodiments of components for creating aerosols described above can be used in devices for the delivery of an aerosol to a patient.
- the device is preferably a hand-held, self-contained device which a patient can easily carry about and use for the administration of drugs.
- the pressurized canister of a device as disclosed in U.S. Pat. Nos. 5,364,838 or 5,404,871 is replaced with an aerosol generating device of the type shown here in any of FIGS. 1, 2 or 3 .
- the device preferably includes a means for measuring a patient's respiratory flow rate and respiratory volume.
- the aerosol may be generated when the patient manually actuates release of aerosol.
- the device preferably operates as the device in the U.S. Pat. No. 5,364,838 patent and is actuated automatically in response to a measured inspiratory flow rate and inspiratory volume. This makes it possible to repeatedly deliver aerosol to a patient at the same point in the respiratory cycle thereby improving repeatability of dosing.
- the disposable containers and porous membranes of the device disclosed in U.S. Pat. No. 5,544,646 is replaced with an aerosol generating device of the type shown here in FIGS. 1, 2 or 3 .
- the aerosol generating device is likely to include a plurality of sources of liquid drug formulation (e.g. a plurality of feeding needles) so that a sufficient amount of formulation can be aerosolized in a sufficiently short period of time that the patient can, in a single inhalation, inhale all of the aerosol needed for a dose of the drug being delivered.
- An aerosol generating device of the type shown in FIG. 3 is generally easier to manufacture and as such is preferred in this embodiment.
- an aerosol with particles having a particle diameter in the range of about 1 to about 3 microns. This allows the particles to penetrate into the smallest channels of the lungs. However, such particles are not so small that they will not settle on the surface of these channels when inhaled—failure to settle would cause the particles to be exhaled as with particles of smoke.
- the source of aerosol of a device as disclosed in U.S. Pat. No. 4,484,577 is replaced with an aerosol generating device of the type described here and shown in FIGS. 1, 2 or 3 .
- the device of U.S. Pat. No. 4,484,577 includes a large container into which the aerosol is dispersed. The aerosol then “hangs” in the air in the large container until it is inhaled by the patient.
- the aerosol particles can be made very small, e.g. about 1 micron or less. Particles of this size will be suspended in air in the container until inhaled. The patient can then breath normally in and out of the container until all or substantially all particles in the container have deposited themselves on the channels of the lung.
- the liquids of Table 1 were forced through a feeding needle of the type shown in FIG. 1 .
- the end 5 of the feeding needle had an internal radius R o .
- the exit orifice 6 had a diameter D and the wall of the pressure chamber 3 had a thickness of L.
- the jet diameter was measured at the hole exit and was plotted as a function of the pressure difference ⁇ P g and flow rate Q respectively.
Landscapes
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- Combustion & Propulsion (AREA)
- General Health & Medical Sciences (AREA)
- Nanotechnology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Anesthesiology (AREA)
- Animal Behavior & Ethology (AREA)
- Physics & Mathematics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pulmonology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Physics & Mathematics (AREA)
- Biophysics (AREA)
- Mathematical Physics (AREA)
- Composite Materials (AREA)
- Condensed Matter Physics & Semiconductors (AREA)
- Theoretical Computer Science (AREA)
- Materials Engineering (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Emergency Medicine (AREA)
- Medicinal Preparation (AREA)
Abstract
A drug delivery device and method is disclosed which produces aerosolized particles of pharmaceutically active drug for delivery to a patient by inhalation. The device is comprised of a liquid feeding source such as a channel to which formulation is added at one end and expelled through an exit opening. The feeding channel is surrounded by a pressurized chamber into which gas is fed and out of which gas is expelled from an opening. The opening from which the gas is expelled is positioned directly in front of the flow path of liquid expelled from the feeding channel. Various parameters are adjusted so that pressurized gas surrounds liquid flowing out of the feeding channel in a manner so as to maintain a stable capillary microjet of liquid until the liquid exits the pressure chamber opening and is aerosolized. The aerosolized particles having a uniform diameter in the range of about 1 to 5 microns are inhaled into a patient's lungs and thereafter reach the patient's circulatory system.
Description
- This application is a continuation of Ser. No. 11/288,881 filed Nov. 28, 2005 which application is a continuation of Ser. No. 10/886,923 filed Jul. 7, 2004 (now U.S. Pat. No. 7,059,321) which is a continuation of application Ser. No. 10/216,517 filed Aug. 9, 2002 (now U.S. Pat. No. 6,792,940), which is a continuation of application Ser. No. 09/191,317, filed Nov. 13, 1998 (now abandoned), and which is a continuation-in-part of application Ser. No. 09/171,518 filed Apr. 21, 1999 (now U.S. Pat. No. 6,119,953), which is a national phase filing of PCT/ES97/00034 under 35 USC §371 filed Feb. 18, 1997 (now WO 97/43048), which claims priority of international application 9601101 filed May 13, 1996 under 35 U.S.C. §119 and also claims priority to P9702654 filed Dec. 17, 1997 under 35 U.S.C. §119, all of which are incorporated herein by reference in their entireties and to which applications we claim priority under 35 USC §120 and 35 USC § 119.
- This invention relates generally to the field of aerosols and more particularly to devices and methods for creating aerosols of pharmaceutical formulations for delivery to a human patient, preferably by inhalation.
- Aerosolizing formulations for inhalation has been considered as a convenient alternative to injection for decades. This alternative to injections is particularly interesting for drugs which cannot be delivered orally, e.g. insulin. Although most compounds will effectively move from the lungs into the circulatory system there is considerable unpredictability in how much aerosolized formulation reaches the areas of the lungs where the material can move into the circulatory system. This results in inefficiency and unpredictability of dosing. A number of devices have been proposed for improving the efficiency of aerosol delivery, monitoring patients and teaching patients to correctly use delivery devices.
- There are several different types of devices which use generally different mechanisms and methodologies to produce aerosols for inhalation. The most commonly used device is a metered dose inhaler (MDI) which comprises a drug formulation container with the formulation including a low boiling point propellant. The formulation is held in the container under pressure and a metered dose of formulation is released as an aerosol when the valve on the container is opened. The low boiling point propellant quickly evaporates or “flashes” when the formulation is exposed to atmospheric pressure outside the container. The particles of formulation containing the drug without the propellant are inhaled into the patient's lungs and thereafter migrate into the patient's circulatory system. There are a number of different types of MDI devices. Devices of this type are disclosed in U.S. Pat. No. 5,404,871 issued Apr. 11, 1995 and U.S. Pat. No. 5,364,838 issued Nov. 15, 1994.
- Another type of device is the dry powder inhaler (DPI) device. As indicated by the name such devices use formulations of dry powder which powder is blown into an aerosolized cloud via a burst of gas. Typical DPI devices are shown in U.S. Pat. No. 5,775,320 issued Jul. 7, 1998 and U.S. Pat. No. 5,740,794 issued Apr. 21, 1998.
- Yet another type of aerosol delivery device forces a formulation through a porous membrane. Formulation moving through the pores breaks up to form small particles which are inhaled by the patient. Devices of this type are shown in U.S. Pat. No. 5,554,646 issued Aug. 13, 1996 and U.S. Pat. No. 5,522,385 issued Jun. 4, 1996.
- Each of these devices has some advantages and disadvantages. The object of each is substantially the same—to repeatedly produce a fine mist aerosol wherein the particles are substantially uniform in size and within a size range of about 1 micron to about 5 microns. A patient can be accurately dosed if the device can repeatedly start with a given amount of formula and produce a known amount of aerosol with particles having sizes within a known range. The present invention endeavors to provide a device and method for obtaining accurate repeatable dosing of a patient with an aerosol.
- Aerosolized particles within a desired size range (e.g., 1 micron to about 5 microns) are produced from a liquid formulation comprised of a pharmaceutical active drug and a carrier. The particles produced all have substantially the same particle diameter ±3% to ±30%, e.g. all particles in the aerosol have a diameter of 2 microns ±3% to ±10%. The formulation is provided in any desired manner (e.g., forced through a channel of a feeding needle and expelled out of an exit opening of the needle). Simultaneously, gas contained in a pressure chamber (which surrounds at least the area where the formulation is provided, e.g., surrounds the exit opening of the needle) is forced out of an opening positioned in front of the formulation, e.g., directly in front of the flow path of the formulation being expelled from the feeding needle. Various parameters are adjusted to obtain a super critical flow of liquid characterized by a stable liquid-gas interface and a stable capillary jet of the liquid which forms particles on exiting the opening of the pressurized chamber which particles will all (90% or more) have substantially the same diameter, i.e., a monodisperse aerosol.
- An object of the invention is to provide a device for aerosolized delivery of a pharmaceutically active drug formulation or a diagnostic formulation.
- Another object is to provide a method of creating an aerosol of consistent particle size (±3 to 30% or preferably ±3 to 10% difference in diameter) which aerosol is inhalable by a patient for aerosolized delivery of drugs or diagnostics.
- A feature of the invention is that the diameter of the opening from which liquid is expelled, the diameter of the opening from which gas is expelled and the distance between these two openings is adjustable and is adjusted to obtain a stable liquid-gas interface which results in a stable capillary microjet being formed by the liquid expelled which microjet is focused on an exit opening by the flow of surrounding gas.
- Another feature of the invention is that the viscosities and velocities of the fluids can be chosen with consideration to other adjusted parameters to obtain a supercritical flow of liquid.
- Another feature of the invention is that the liquid can be a single liquid, two or more (miscible or immiscible) liquids mixed, a solution or a suspension.
- An advantage of the invention is that the gas flowing with the particles prevents the particles from agglomerating thereby maintaining a monodisperse aerosol.
- An advantage of the invention is that it consistently produces aerosols having particles with a desired particle diameter e.g. 1 to 5 microns.
- An advantage of the invention is that the device of the invention is energy efficient in terms of the energy used to create small particles for inhalation.
- Another advantage is that the structure of the device and its use are simple.
- Another advantage is that clogging of the exit opening of the pressure chamber is substantially eliminated because liquid is kept out of contact with the surface of the exit opening by a surrounding focused funnel of gas which flows out of the pressure chamber exit opening.
- Yet another advantage is that particles produced are substantially smaller in size than would be expected based on the diameter of the exit opening of the pressure chamber due to focusing the flow of the liquid with the flow of surrounding gas.
- An aspect of the invention is a hand-held, self-contained portable drug delivery device which consistently produces small aerosolized particles which are relatively uniform in size.
- Another aspect of the invention is a device and method which produces multiple streams of aerosol thereby quickly aerosolizing a large dose of formulation for inhalation by a patient.
- These and other aspects, objects, features and advantages will become apparent to those skilled in the art upon reading this disclosure in combination with the figures provided.
-
FIG. 1 is a schematic view showing the basic components of one embodiment of the invention with a cylindrical feeding needle as a source of formulation. -
FIG. 2 is a schematic view of another embodiment of the invention with two concentric tubes as a source of formulation. -
FIG. 3 is a schematic view of yet another embodiment showing a wedge-shaped planar source of formulation.FIG. 3 a illustrates a cross-sectional side view of the planar feeding source and the interaction of the fluidsFIG. 3 b show a frontal view of the openings in the pressure chamber, with the multiple openings through which the atomizate exits the device.FIG. 3 c illustrates the channels that are optionally formed within the planar feeding member. The channels are aligned with the openings in the pressure chamber. -
FIG. 4 is a schematic view of a stable capillary microjet being formed and flowing through an exit opening to thereafter form a monodisperse aerosol. -
FIG. 5 is a graph of data where 350 measured valves of dj/do versus Q/Qo are plotted. - Before the present aerosol device and method are described, it is to be understood that this invention is not limited to the particular components and steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the It must be noted that as used herein and in the appended claims, the singular form s “a”, “and,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a particle” includes a plurality of particles and reference to “a fluid” includes reference to a mixture of fluids, and equivalents thereof known to those skilled in the art, and so forth, present invention will be limited only by the appended claims.
- Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
- The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
- The term “formulation” is used to describe any single liquid, mixture, solution, suspension or the like which is a flowable liquid at room temperature and comprises either a pharmaceutically active compound, a diagnostic compound or a compound which becomes an active compound after entering a patient, e.g. prodrugs or DNA encoding proteins. The formulation is preferably further comprised of a carrier and more preferably is a liquid that has physical properties (e.g., viscosity) such that when the formulation is moved through a device of the invention the formulation is aerosolized into particles (0.1 to 10 microns in diameter) which are inhaled into the lungs of a patient and preferably reach the circulatory system. The carrier may be any pharmaceutically acceptable material and is preferably a flowable liquid which is compatible with the active agent. Formulations are preferably solutions, e.g., aqueous solutions, ethanolic solutions, aqueous/ethanolic solutions, saline solutions, colloidal suspensions and microcrystalline suspensions. Formulations can be solutions or suspensions of drugs (including systemically active drugs, e.g. insulin, insulin analogs including monomeric insulin such as insulin lispro) in the above mentioned liquids.
- The term “carrier” shall mean a substantially inactive (biologically) component of a formulation such as a pharmaceutically acceptable excipient material which an active ingredient such as a drug, a diagnostic agent, prodrug or a gene vector is mixed with, suspended or dissolved in. The carrier is preferably a flowable liquid. Useful carriers do not adversely interact with the drug, diagnostic or gene vector and have properties which allow for the formation of aerosolized particles preferably particles having a diameter in the range of 0.1 to 10.0 microns (more preferably 1 to 5 microns) when a formulation comprising the carrier and active ingredient is aerosolized out of a device of the invention. Carriers include water, ethanol, saline solutions and mixtures thereof with pure water being preferred. Other carriers can be used provided that they can be formulated to create a suitable aerosol and do not adversely effect the active component or human lung tissue.
- The term “active compound” means a compound which is either a pharmaceutically active drug, becomes or produces a therapeutic compound in the body or is a detectably labeled compound. In turn, a “pharmaceutically active drug” or therapeutic compound shall be interpreted to mean any pharmaceutically effective compound used in the treatment of disease. A “detectably labeled compound” includes compounds which are radioactively labeled see U.S. Pat. No. 5,829,436 issued Nov. 3, 1998 Re: detectable labels.
- Pharmaceutical formulations for use in the invention may be comprised of any therapeutic agent that can be atomized for patient delivery, e.g. for pulmonary delivery using an inhalation delivery system. Examples of such pharmaceutical compositions may be found in the Physicians Desk Reference (1998), and Remington: The Science and Practice of Pharmacy 19th Edition (1995), both of which are incorporated herein by reference. These formulations may be in any form capable of atomization, such as a solution, a suspension, an emulsion, a slurry, etc., provided the dynamics of the form render it capable of forming a capillary microjet upon exposure to a second fluid.
- The terms “electronic particle sensing device” and “electronic detection system” refer to a device or other means for measuring and counting particles present in an aerosol mist.
- The term “reporting means” is used herein to indicate a means by which information obtained from a monitoring device such as an electronic particle sensing device or a device which monitors and records information relating to the patient's respiratory movement, may be provided to the user.
- The term “aerosol bolus” is used herein to describe a volume of air greater than 50 ml and less than 4 liters which has suspended within it particles of a formulation wherein the particles have a diameter in the range of 0.1 to 10 microns, preferably 1 to 5 microns, and preferably the total volume of formulation is from 5 μl to 10,000 μl. About 10 μl of particles having a diameter of about 1 to 3 microns are present in a volume of about 50 ml to 2 liters, preferably 100 ml to 1,000 ml.
- The term “aerosol” means any part of an aerosol bolus as described above.
- The terms “air”, “particle free air”, “aerosol free air,” and the like, are used interchangeably herein to describe a volume of air which is substantially free of other material and, in particular, free of particles intentionally added such as particles of formulation which create the aerosol. The term means that the air does not include particles of formulation which have been intentionally added but is not intended to imply that the normal surrounding air has been filtered or treated to remove all particles although filtering can take place. Air is the preferred gas to use with drug delivery it being noted that other non-toxic gases, e.g., C02 can be used.
- The term “measuring” describes an event whereby the (1) total lung capacity, (2) inspiratory flow rate or (3) inspiratory volume of the patient is measured and/or calculated. The information is preferably used in order to determine an optimal point in the inspiratory cycle at which to release an aerosol and/or a particle free volume of air. An actual measurement of both rate and volume may be made or the rate can be directly measured and the volume calculated based on the measured rate. The total lung capacity can be measured or calculated based on the patient's height, sex and age. It is also preferable to continue measuring inspiratory flow during and after aerosol delivery and to record inspiratory flow rate and volume before, during and after the release of formulation. Such reading makes it possible to determine if aerosolized formulation was properly delivered to the patient.
- The term “monitoring” event shall comprise determining the character of an aerosol such as the size, number and speed of the particles in the aerosol, further, monitoring may comprise measuring lung functions such as inspiratory flow, inspiratory flow rate, and/or inspiratory volume so that a patient's lung function as defined herein, can be evaluated during before and/or after delivery thereby making it possible to evaluate the effect of formulation such as respiratory drug delivery on the patient's lung function.
- The term “inspiratory flow rate” shall mean a value of air flow rate determined, calculated or measured based on the speed of the air passing a given point in a measuring device assuming atmospheric pressure ±5% and a temperature in the range of about 10° C. to 40° C.
- The term “inspiratory flow” shall be interpreted to mean a value of air flow calculated based on the speed of the air passing a given point along with the volume of the air that has passed that point with the volume calculation being based on integration of the flow rate data and assuming atmospheric pressure, ±5% and temperature in the range of about 10° C. to about 40° C.
- The term “inspiratory volume” shall mean a determined, measured or calculated volume of air passing a given point into the lungs of a patient assuming atmospheric pressure ±5% and a temperature in the range of 10° C. to 40° C.
- The terms “lung function” and “pulmonary function” are used interchangeably and shall be interpreted to mean physically measurable operations of a lung including but not limited to (1) inspiratory and (2) expiratory flow rates as well as (3) lung volume, i.e., total lung capacity. Methods of quantitatively determining pulmonary function are used to measure lung function. Quantitative determination of pulmonary function may be important when delivering any formulation and in particular respiratory drugs in order to direct the aerosol to a specific area of the lung and to determine effectiveness. Methods of measuring pulmonary function most commonly employed in clinical practice involve timed measurement of inspiratory and expiratory maneuvers to measure specific parameters. For example, forced vital capacity (FVC) measures the total volume in liters exhaled by a patient forcefully from a deep initial inspiration. This parameter, when evaluated in conjunction with the forced expired volume in one second (FEV1), allows bronchoconstriction to be quantitatively evaluated. A problem with forced vital capacity determination is that the forced vital capacity maneuver (i.e. forced exhalation from maximum inspiration to maximum expiration) is largely technique dependent. In other words, a given patient may produce different FVC values during a sequence of consecutive FVC maneuvers. The FEF 25-75 or forced expiratory flow determined over the mid-portion of a forced exhalation maneuver tends to be less technique dependent than the FVC. Similarly, the FEV1 tends to be less technique dependent than FVC. In addition to measuring volumes of exhaled air as indices of pulmonary function, the flow in liters per minute measured over differing portions of the expiratory cycle can be useful in determining the status of a patient's pulmonary function. In particular, the peak expiratory flow, taken as the highest air flow rate in liters per minute during a forced maximal exhalation, is well correlated with overall pulmonary function in a patient with asthma and other respiratory diseases. The present invention carries out treatment by administering formulation in a delivery event and monitoring lung function in a monitoring event. A series of such events may be carried out and repeated over time to determine if lung (see U.S. Pat. No. 5,404,871) function is improved.
- Each of the parameters discussed above is measured during quantitative spirometry. A patient's individual performance can be compared against his personal best data, individual indices can be compared with each other for an individual patient (e.g. FEV1 divided by FVC, producing a dimensionless index useful in assessing the severity of acute asthma symptoms), or each of these indices can be compared against an expected value. Expected values for indices derived from quantitative spirometry are calculated as a function of the patient's sex, height, weight and age. For instance, standards exist for the calculation of expected indices and these are frequently reported along with the actual parameters derived for an individual patient during a monitoring event such as a quantitative spirometry test.
- The terms “particles”, “aerosolized particles” and “aerosolized particles of formulation” are used interchangeably herein and shall mean particles of formulation comprised of any pharmaceutically active ingredient, a compound which becomes such in the body (e.g. a prodrug or DNA encoding a protein) or a diagnostic compound. Any of these is preferably with a carrier, (e.g., a pharmaceutically active respiratory drug and carrier). Particles of a liquid formulation are formed upon forcing the formulation from anywhere it is provided (e.g., the feeding needle) and then out of the pressure chamber exit orifice. The particles have a size which is sufficiently small such that when the particles are formed they remain suspended in the air for a sufficient amount of time such that the patient can inhale the particles into the patient's lungs. The particles have a size in the range of 0.1 micron to about 10 microns, preferably 1 to 5 microns. Particle diameter is an aerodynamic diameter.
- In referring to particle diameter, the diameter measurement given is the “aerodynamic diameter” measurement which is the diameter of a sphere of unit density that has the same terminal sedimentation velocity in air under normal atmospheric conditions as the particle in question. This is pointed out in that it is difficult to accurately measure the diameter of small particles using current technology and the shape may be continually changing. Thus, the diameter of one particle of material of a given density will be said to have the same diameter as another particle of the same or a different material if the two particles have the same terminal sedimentation velocity in air under the same conditions.
- The present disclosure focuses on the use of an aerosol creation device to produce aerosolized liquid formulations for delivery of drugs to patients—preferably by inhalation into the lungs.
- The basic technology of the invention comprises (1) a means for supplying a first fluid; and (2) a pressure chamber supplied with a second fluid. The first fluid is generally a liquid and preferably aqueous. The second fluid is generally a gas and preferably air. However, the first fluid may be a gas and second fluid a liquid or both fluids may be liquid provided the first and second fluid are sufficiently different from each other (immiscible) so as to allow for the formation of a stable microjet of the first fluid moving from the supply means to an exit port of the pressure chamber. Notwithstanding these different combinations of gas-liquid, liquid-gas, and liquid-liquid the invention is generally described with a liquid formulation being expelled from the supply means and forming a stable microjet due to interaction with surrounding air flow focusing the microjet to flow out of an exit of the pressure chamber.
- Formation of the microjet and its acceleration and ultimate particle formation are based on the abrupt pressure drop associated with the steep acceleration experienced by the first fluid (e.g., a liquid) on passing through an exit orifice of the pressure chamber which holds the second fluid. On leaving the chamber the flow undergoes a large pressure difference between the first fluid (e.g., a liquid) and the second fluid (e.g., a gas), which in turn produces a highly curved zone on the first fluid (e.g., liquid) surface near the exit port of the pressure chamber and in the formation of a cuspidal point from which a steady microjet flows provided the amount of the first fluid (e.g., the liquid) withdrawn through the exit port of the pressure chamber is replenished. Thus, in the same way that a glass lens or a lens of the eye focuses light to a given point, the flow of the gas surrounds and focuses the liquid into a stable microjet. The focusing effect of the surrounding flow of gas creates a stream of liquid which is substantially smaller in diameter than the diameter of the exit orifice of the pressure chamber. This allows liquid to flow out of the pressure chamber orifice without touching the orifice, providing advantages including (1) clogging of the exit orifice is virtually eliminated, (2) contamination of flow due to contact with substances (e.g. bacteria) on the orifice opening is virtually eliminated, and (3) the diameter of the stream and the resulting particles are smaller than the diameter of the exit orifice of the chamber. This is particularly desirable because it is difficult to precisely engineer holes which are very small in diameter. Further, in the absence of the focusing effect (and formation a stable microjet) flow of liquid out of an opening will result in particles which have about twice the diameter of the exit opening. An additional advantage is that the particles are not prone to agglomeration following exit from the chamber.
- Specific embodiments of aerosol creation devices are now described.
- A first embodiment of the invention where the supply means is a cylindrical feeding needle supplying liquid into a pressurized chamber of gas is described below with reference to
FIG. 1 . - The components of the embodiment of
FIG. 1 are as follows: - 1. Feeding needle—also referred to generally as a fluid source and a tube.
- 2. End of the feeding needle used to insert the liquid to be atomized.
- 3. Pressure chamber.
- 4. Orifice used as gas inlet.
- 5. End of the feeding needle used to evacuate the liquid to be atomized.
- 6. Orifice through which withdrawal takes place.
- 7. Atomizate (spray)—also referred to as aerosol.
- D0=diameter of the feeding needle; d0=diameter of the orifice through which the microjet is passed; e=axial length of the orifice through which withdrawal takes place; H=distance from the feeding needle to the microjet outlet; P0=pressure inside the chamber; Pα=atmospheric pressure.
- An aerosolized drug delivery device of the invention may be any size but is preferably designed to be a hand-held, portable, self-contained device weighing less than 1 kilogram. Although the device can be configured in a variety of designs, the different designs will all include the essential components shown in
FIG. 1 or components which perform an equivalent function and obtain the desired results. Specifically, a drug delivery device of the invention will be comprised of at least one source of formulation (e.g., a feeding needle with an opening 2) into which a liquid flowable formulation can be fed and anexit opening 5 from which the formulation can be expelled. The feedingneedle 1, or at least itsexit opening 5, is encompassed by apressure chamber 3. Thechamber 3 has inlet opening 4 which is used to feed gas into thechamber 3 and an exit opening 6 through which gas from the pressure chamber and liquid formulation from the feedingneedle 3 are expelled creating an aerosol. - In
FIG. 1 , the feeding needle and pressure chamber are configured to obtain a desired result of producing an aerosol wherein the particles are small and uniform in size. Preferably the particles have a size which is in a range of 0.1 to 10 microns, more preferably 1 to 5 microns. Particles of less than 1 micron in diameter can be produced via the present invention. However, particles below 1 micron may be too small for inhalation as the particles may not settle in the lung during a normal breath hold and as such would be exhaled. The particles of any given aerosol all have about the same diameter with a relative standard deviation of 10% to 30% or more preferably 3% to 20%. Stating that particles of the aerosol have a particle diameter in a range of 1 to 5 microns does not mean that different particles will have different diameters and that some will have a diameter of 1 micron while others of 5 microns. The particles in a given aerosol will all (preferably about 90% or more) have the same diameter ±3% to ±30%. For example, the particles of a given aerosol will have a diameter of 2 microns ±3% to ±10%. - Such a monodisperse aerosol is created using the components and configuration as described above. However, other components and configurations will occur to those skilled in the art. The object of each design will be to supply formulation so that it creates a stable capillary microjet which is accelerated and stabilized by tangential viscous stress exerted by the gas on the liquid surface. The stable microjet created by the gas leaves the area of the pressurized gas (e.g., leaves the pressure chamber and exits the pressure chamber orifice) and splits into particles which have the desired size and uniformity.
- The aerosol created is a monodisperse aerosol meaning that the size of the particles produced are relatively uniform in size. The relative standard deviation in particle size is in the range of from about 10% to about 30%, preferably 3% to 10% and most preferably 3% or less. The size of aerosolized particles useful for inhalation is a diameter in the range of from about 0.1 micron to about 10 microns, more preferably about 1 micron to about 3 microns.
- For purposes of simplicity the remainder of the detailed description of the operation of the device of
FIG. 1 will refer to the first fluid as liquid and the second fluid as gas. The parameter window used (i.e. the set of special values for the liquid properties, flow-rate used, feeding needle diameter, orifice diameter, pressure ratio, etc.) should be large enough to be compatible with virtually any liquid (dynamic viscosities in the range from 10−4 to 1 kg m−1 s−1); in this way, the capillary microjet that emerges from the end of the feeding needle is absolutely stable and perturbations produced by breakage of the jet cannot travel upstream. Downstream, the microjet splits into evenly shaped drops simply by effect of capillary instability (see, for example, Rayleigh, “On the instability of jets”, Proc. London Math. Soc., 4-13, 1878), similar in a manner to a laminar capillary jet falling from a half-open tap. - When the stationary, steady interface is created, the capillary jet that emerges from the end of the drop at the outlet of the feeding point is concentrically withdrawn into the nozzle. After the jet emerges from the drop, the liquid is accelerated by tangential sweeping forces exerted by the gas stream flowing on its surface, which gradually decreases the jet cross-section. Stated differently the gas flow acts as a lens and focuses and stabilizes the microjet as it moves toward and into the exit orifice of the pressure chamber.
- The forces exerted by the second fluid (e.g., a gas) flow on the first fluid (e.g., a liquid) surface should be steady enough to prevent irregular surface oscillations. Therefore, any turbulence in the gas motion should be avoided; even if the gas velocity is high, the characteristic size of the orifice should ensure that the gas motion is laminar (similar to the boundary layers formed on the jet and on the inner surface of the nozzle or hole).
-
FIG. 4 illustrates the interaction of a liquid and a gas to form atomizate using the method of the invention. The feedingneedle 60 has a circular exit opening 61 with an internal radius R0 which feeds a liquid 62 out of the end, forming a drop with a radius in the range of R0 to R0 plus the thickness of the wall of the needle. The exiting liquid forms an infinite amount ofliquid streamlines 63 that interact with the surrounding gas to form a stable cusp at theinterface 64 of the two fluids. The surrounding gas also forms an infinite number of gas streamlines 65, which interact with the exiting liquid to create a virtual focusingfunnel 66. The exiting liquid is focused by the focusingfunnel 66 resulting in a stablecapillary microjet 67, which remains stable until it exits theopening 68 of thepressure chamber 69. After exiting the pressure chamber, the microjet begins to break-up, formingmonodispersed particles 70. - The gas flow, which affects the liquid withdrawal and its subsequent acceleration after the jet is formed, should be very rapid but also uniform in order to avoid perturbing the fragile capillary interface (the surface of the drop that emerges from the jet).
- Liquid flows out of the end of a capillary tube and forms a small liquid drop at the end. The tube has an internal radius Ro. The drop has a radius in a range of from Ro to Ro plus the structural thickness of the tube as the drop exits the tube, and thereafter the drop narrows in circumference to a much smaller circumference as is shown in the expanded view of the tube (i.e. feeding needle) 5 as shown in
FIGS. 1 and 4 . - As illustrated in
FIG. 4 , the exit opening 61 of thecapillary tube 60 is positioned close to anexit opening 68 in a planar surface of apressure chamber 69. Theexit opening 68 has a minimum diameter D and is in a planar member with a thickness L. The diameter D is referred to as a minimum diameter because the opening may have a conical configuration with the narrower end of the cone positioned closer to the source of liquid flow. Thus, the exit opening may be a funnel-shaped nozzle although other opening configurations are also possible, e.g. an hour glass configuration. Gas in the pressure chamber continuously flows out of the exit opening. The flow of the gas causes the liquid drop expelled from the tube to decrease in circumference as the liquid moves away from the end of the tube in a direction toward the exit opening of the pressure chamber. - In actual use, it can be understood that the opening shape which provokes maximum gas acceleration (and consequently the most stable cusp and microjet with a given set of parameters) is a conically shaped opening in the pressure chamber. The conical opening is positioned with its narrower end toward the source of liquid flow.
- The distance between the
end 61 of thetube 60 and the beginning of theexit opening 68 is H. At this point it is noted that Ro, D, H and L are all preferably on the order of hundreds of microns. For example, Ro=400 μm, D=150 μm, H=1 mm, L=300 μm. However, each could be 1/100 to 100× these sizes. - The end of the liquid stream develops a cusp-like shape at a critical distance from the
exit opening 68 in thepressure chamber 69 when the applied pressure drop ΔPg across theexit opening 68 overcomes the liquid-gas surface tension stresses γ/R* appearing at the point of maximum curvature—e.g. 1/R* from the exit opening. - A steady state is then established if the liquid flow rate Q ejected from the drop cusp is steadily supplied from the capillary tube. This is the stable capillary cusp which is an essential characteristic of the invention needed to form the stable microjet. More particularly, a steady, thin liquid jet with a typical diameter dj is smoothly emitted from the stable cusp-like drop shape and this thin liquid jet extends over a distance in the range of microns to millimeters. The length of the stable microjet will vary from very short (e.g. 1 micron) to very long (e.g. 50 mm) with the length depending on the (1) flow-rate of the liquid and (2) the Reynolds number of the gas stream flowing out of the exit opening of the pressure chamber. The liquid jet is the stable capillary microjet obtained when supercritical flow is reached. This jet demonstrates a robust behavior provided that the pressure drop ΔPg applied to the gas is sufficiently large compared to the maximum surface tension stress (on the order of γ/dj) that act at the liquid-gas interface. The jet has a slightly parabolic axial velocity profile which is, in large part, responsible for the stability of the microjet. The stable microjet is formed without the need for other forces, i.e. without adding force such as electrical forces on a charged fluid. However, for some applications it is preferable to add charge to particles, e.g. to cause the particles to adhere to a given surface. The shaping of liquid exiting the capillary tube by the gas flow forming a focusing funnel creates a cusp-like meniscus resulting in the stable microjet. This is a fundamental characteristic of the invention.
- The fluid stream flowing from the tube has substantially more density and develops substantially more inertia as compared to the gas, which has lower viscosity than the liquid. These characteristics contribute to the formation of the stable capillary jet. The stable capillary microjet is maintained stably for a significant distance in the direction of flow away from the exit from the tube. The liquid is, at this point, undergoing “supercritical flow.” The microjet eventually destabilizes due to the effect of surface tension forces. Destabilization results from small natural perturbations moving downstream, with the fastest growing perturbations being those which govern the break up of the microjet, eventually creating a uniform sized
monodisperse aerosol 70 as shown inFIG. 4 . - The microjet, even as it initially destabilizes, passes out of the exit orifice of the pressure chamber without touching the peripheral surface of the exit opening. This provides an important advantage of the invention which is that the exit opening 68 (which could be referred to as a nozzle) will not clog from residue and/or deposits of the liquid. Clogging is a major problem with very small nozzles and is generally dealt with by cleaning or replacing the nozzle. When fluid contacts the surfaces of a nozzle opening some fluid will remain in contact with the nozzle when the flow of fluid is shut off. The liquid remaining on the nozzle surface evaporates leaving a residue. After many uses over time the residue builds up and clogging takes place. The present invention substantially reduces or eliminates this clogging problem.
- Cylindrical coordinates (r,z) are chosen for making a mathematical analysis of a stable microjet, i.e. liquid undergoing “supercritical flow.” The cusp-like meniscus formed by the liquid coming out of the tube is pulled toward the exit of the pressure chamber by a pressure gradient created by the flow of gas.
- The cusp-like meniscus formed at the tube's mouth is pulled towards the hole by the pressure gradient created by the gas stream. From the cusp of this meniscus, a steady liquid thread with the shape of radius r=ξ is withdrawn through the hole by the action of both the suction effect due to ΔPg, and the tangential viscous stresses τs exerted by the gas on the jet's surface in the axial direction. The averaged momentum equation for this
configuration may be written: - where Q is the liquid flow rate upon exiting the feeding tube, P1 is the liquid pressure, and ρ1 is the liquid density, assuming that the viscous extensional term is negligible compared to the kinetic energy term, as will be subsequently justified. In addition, liquid evaporation effects are neglected. The liquid pressure P1 is given by the capillary equation.
P 1 =P g+γ/ξ (2) - where γ is the liquid-gas surface tension. As shown in the Examples, the pressure drop ΔPg is sufficiently large as compared to the surface tension stress γ/ξ to justify neglecting the latter in the analysis. This scenario holds for the whole range of flow rates in which the microjet is absolutely stable. In fact, it will be shown that, for a given pressure drop ΔPg, the minimum liquid flow rate that can be sprayed in steady jet conditions is achieved when the surface tension stress γ/ξ is of the order of the kinetic energy of the liquid p1Q2/(2π2ξ4), since the surface tension acts like a “resistance” to the motion (it appears as a negative term in the right-hand side term of Eq. (1)). Thus,
- For sufficiently large flow rates Q compared to Qmin, the simplified averaged momentum equation in the axial direction can be expressed as
- where one can identify the two driving forces for the liquid flow on the right-hand side. This equation can be integrated provided the following simplification is made: if one uses a thin plate with thickness L of the order or smaller than the hole's diameter D (which minimizes downstream perturbations in the gas flow), the pressure gradient up to the hole exit is on the average much larger than the viscous shear term 2τs/ξ owning to the surface stress. On the other hand, the axial viscous term is of the order O[μ2Q/D2dj 2], since the hole diameter D is actually the characteristic distance associated with the gas flow at the hole's entrance in both the radial and axial directions. This term is very small compared to the pressure gradient in real situations, provided that ΔPg>>μ2/D2ρ1 (which holds, e.g., for liquids with viscosities as large as 100 cpoises, using hole diameters and pressure drops as small as D˜10 μm and ΔPg≧100 mbar). The neglect of all viscous terms in Eq. (4) is then justified. Notice that in this limit on the liquid flow is quasi-isentropic in the average (the liquid almost follows Bernoulli equation) as opposed to most micrometric extensional flows. Thus, integrating (4) from the stagnation regions of both fluids up to the exit, one obtains a simple and universal expression for the jet diameter at the hole exit:
- which for a given pressure drop ΔPg is independent of geometrical parameters (hole and tube diameters, tube-hole distance, etc.), liquid and gas viscosities, and liquid-gas surface tension. This diameter remains almost constant up to the breakup point since the gas pressure after the exit remains constant.
- Above the stable microjet undergoing “supercritical flow” is described and it can be seen how this aspect of the invention can be made use of in a variety of industrial applications—particularly where the flow of liquid through small holes creates a clogging problem. An equally important aspect of the invention is obtained after the microjet leaves the pressure chamber.
- When the microjet exits the pressure chamber the liquid pressure P1 becomes (like the gas pressure Pg) almost constant in the axial direction, and the jet diameter remains almost constant up to the point where it breaks up by capillary instability. Defining a Weber number We=(ρgvg 2dj)/γ≅2 ΔPgdj/γ (where vg is the gas velocity measured at the orifice), below a certain experimental value Wec˜40 the breakup mode is axisymmetric and the resulting droplet stream is characterized by its monodispersity provided that the fluctuations of the gas flow do not contribute to droplet coalescence (these fluctuations occur when the gas stream reaches a fully developed turbulent profile around the liquid jet breakup region). Above this Wec value, sinuous nonaxisymmetric disturbances, coupled to the axisymmetric ones, become apparent. For larger We numbers, the nonlinear growth rate of the sinuous disturbances seems to overcome that of the axisymmetric disturbances. The resulting spray shows significant polydispersity in this case. Thus, it can be seen that by controlling parameters to keep the resulting Weber number to 40 or less, allows the particles formed to be all substantially the same size. The size variation is about ±3% to ±30% and move preferably ±3% to ±10%. These particles can have a desired size e.g. 0.1 microns to 50 microns.
- The shed vorticity influences the breakup of the jet and thus the formation of the particles. Upstream from the hole exit, in the accelerating region, the gas stream is laminar. Typical values of the Reynolds number range from 500 to 6000 if a velocity of the order of the speed of sound is taken as characteristic of the velocity of the gas. Downstream from the hole exit, the cylindrical mixing layer between the gas stream and the stagnant gas becomes unstable by the classical Kelvin-Helmholtz instability. The growth rate of the thickness of this layer depends on the Reynolds number of the flow and ring vortices are formed at a frequency of the order of vg/D, where D is the hole diameter. Typical values of vg and D as those found in our experimental technique lead to frequencies or the order of MHz which are comparable to the frequency of drop production (of order of tb −1).
- Given the liquid flow rate and the hole diameter, a resonance frequency which depends on the gas velocity (or pressure difference driving the gas stream) can be adjusted (tuned) in such a way that vortices act as a forcing system to excite perturbations of a determined wavelength on the jet surface. Experimental results obtained clearly illustrates the different degree of coupling between the two gas-liquid coaxial jets. In one set of experimental results the particle sizes are shown to have a particle size of about 5.7 microns with a standard deviation of 12%. This results when the velocity of the gas has been properly tuned to minimize the dispersion in the size of droplets resulting from the jet breakup. In this case, the flow rate of the liquid jet and its diameter are 0.08 μl s−1 and 3 μm, respectively. Data have been collected using a MASTERSIZER from MALVERN Instruments. As the degree of coupling decreases, perturbations at the jet surface of different wavelengths become excited and, as it can be observed from the size distributions, the dispersion of the spray increases.
- It is highly desirable in a number of different industrial applications to have particles which are uniform in size or to create aerosols of liquid particles which are uniform in size. For example, particles of a liquid formation containing a pharmaceutically active drug could be created and designed to have a diameter of about 2 microns ±3%. These particles could be inhaled into the lungs of a patient for intrapulmonary drug delivery. Moreover, particle size can be adjusted to target a particular area of the respiratory tract.
- The gas flow should be laminar in order to avoid a turbulent regime—turbulent fluctuations in the gas flow which have a high frequency and would perturb the liquid-gas interface. The Reynolds numbers reached at the orifice are
- where vg is the kinematic viscosity of the gas. Even though this number is quite high, there are large pressure gradients downstream (a highly convergent geometry), so that a turbulent regime is very unlikely to develop.
- The essential difference from existing pneumatic atomizers (which possess large Weber numbers) and the present invention is that the aim of the present invention is not to rupture the liquid-gas interface but the opposite, i.e. to increase the stability of the interface until a capillary jet is obtained. The jet, which will be very thin provided the pressure drop resulting from withdrawal is high enough, splits into drops the sizes of which are much more uniform than those resulting from disorderly breakage of the liquid-gas interface in existing pneumatic atomizers.
- The proposed atomization system obviously requires delivery of the liquid to be atomized and the gas to be used in the resulting spray. Both should be fed at a rate ensuring that the system lies within the stable parameter window. Multiplexing is effective when the flow-rates needed exceed those on an individual cell. More specifically, a plurality of feeding sources or feeding needles may be used to increase the rate at which aerosols are created. The flow-rates used should also ensure the mass ratio between the flows is compatible with the specifications of each application.
- The gas and liquid can be dispensed by any type of continuous delivery system (e.g. a compressor or a pressurized tank the former and a volumetric pump or a pressurized bottle the latter). If multiplexing is needed, the liquid flow-rate should be as uniform as possible among cells; this may entail propulsion through several capillary needles, porous media or any other medium capable of distributing a uniform flow among different feeding points.
- Each individual atomization device should consist of a feeding point (a capillary needle, a point with an open microchannel, a microprotuberance on a continuous edge, etc.) 0.002-2 mm (but, preferentially 0.01-0.4 mm) in diameter, where the drop emerging from the microjet can be anchored, and a small orifice 0.002-2 mm (preferentially 0.01-0.25 mm) in diameter facing the drop and separated 0.01-2 mm (preferentially 0.2-0.5 mm) from the feeding point. The orifice communicates the withdrawal gas around the drop, at an increased pressure, with the zone where the atomizate is produced, at a decreased pressure. The atomizer can be made from a variety of materials (metal, polymers, ceramics, glass).
-
FIG. 1 depicts a tested prototype where the liquid to be atomized is inserted through one end of thesystem 2 and the propelling gas in introduced via the special inlet 4 in thepressure chamber 3. The prototype was tested at gas feeding rates from 100 to 2000 mBar above the atmospheric pressure Pα at which the atomized liquid was discharged. The whole enclosure around the feedingneedle 1 was at a pressure P0>Pα. The liquid feeding pressure, P1, should always be slightly higher than the gas propelling pressure, Po. Depending on the pressure drop in the needle and the liquid feeding system, the pressure difference (P1−P0>0) and the flow-rate of the liquid to be atomized, Q, are linearly related provided the flow is laminar—which is indeed the case with this prototype. The critical dimensions are the distance from the needle to the plate (H), the needle diameter (D0), the diameter of the orifice through which the microjet 6 is discharged (d0) and the axial length, e, of the orifice (i.e. the thickness of the plate where the orifice is made). In this prototype, H was varied from 0.3 to 0.7 mm on constancy of the distances (D0=0.45 mm, d0—0.2 mm) and e—0.5 mm. The quality of the resulting spray 7 did not vary appreciably with changes in H provided the operating regime (i.e. stationary drop and microjet) was maintained. However, the system stability suffered at the longer H distances (about 0.7 mm). The other atomizer dimensions had no effect on the spray or the prototype functioning provided the zone around the needle (its diameter) was large enough relative to the feeding needle. - Adjusting parameters to obtain a stable capillary microjet and control its breakup into monodisperse particle is governed by the Weber number and the liquid-to-gas velocity ratio or α which equal V1/Vg. The Weber number or “We” is defined by the following equation:
- wherein ρg is the density of the gas, d is the diameter of the stable microjet, γ is the liquid-gas surface tension, and Vg 2 is the velocity of the gas squared.
- When carrying out the invention the parameters should be adjusted so that the Weber number is greater than 1 in order to produce a stable capillary microjet. However, to obtain a particle dispersion which is monodisperse (i.e. each particle has the same size ±3 to ±30%) the parameters should be adjusted so that the Weber number is less than 40. The monodisperse aerosol is obtained with a Weber number in a range of about 1 to about 40 when the breaking time is sufficiently small to avoid non-symmetric perturbations (1≦We≦40).
- A measure of the relative importance of viscosity on the jet breakup can be estimated from the Ohnesorge number defined as the ratio between two characteristic times: the viscous time tv and the breaking time tb. The breaking time tb is given by [see Rayleigh (1878)]
- Perturbations on the jet surface are propagated inside by viscous diffusion in times tv of the order of
tv— ρ1d2_μ1, (3) - where μ1 is the viscosity of the liquid. Then, the Ohnesorge number, Oh, results
- If this ratio is much smaller than unity viscosity plays no essential role in the phenomenon under consideration. Since the maximum value of the Ohnesorge number in actual experiments conducted is as low as 3.7×10−2, viscosity plays no essential role during the process of jet breakup.
- A variety of configurations of components and types of fluids will become apparent to those skilled in the art upon reading this disclosure. These configurations and fluids are encompassed by the present invention provided they can produce a stable capillary microjet of a first fluid from a source to an exit port of a pressure chamber containing a second fluid. The stable microjet is formed by the first fluid flowing from the feeding source to the exit port of the pressure chamber being accelerated and stabilized by tangential viscous stress exerted by the second fluid in the pressure chamber on the surface of the first fluid forming the microjet. The second fluid forms a focusing funnel when a variety of parameters are correctly tuned or adjusted. For example, the speed, pressure, viscosity and miscibility of the first and second fluids are chosen to obtain the desired results of a stable microjet of the first fluid focused into the center of a funnel formed with the second fluid. These results are also obtained by adjusting or tuning physical parameters of the device, including the size of the opening from which the first fluid flows, the size of the opening from which both fluids exit, and the distance between these two openings.
- The embodiment of
FIG. 1 can, itself, be arranged in a variety of configurations. Further, as indicated above, the embodiment may include a plurality of feeding needles. A plurality of feeding needles may be configured concentrically in a single construct, a shown inFIG. 2 . - The components of the embodiment of
FIG. 2 are as follows: - 21. Feeding needle—tube or source of fluid.
- 22. End of the feeding needle used to insert the liquids to be atomized.
- 23. Pressure chamber.
- 24. Orifice used as gas inlet.
- 25. End of the feeding needle used to evacuate the liquid to be atomized.
- 26. Orifice through which withdrawal takes place.
- 27. Atomizate (spray) or aerosol.
- 28. First liquid to be atomized (inner core of particle).
- 29. Second liquid to be atomized (outer coating of particle).
- 30. Gas for creation of microjet.
- 31. Internal tube of feeding needle.
- 32. External tube of feeding needle.
- D=diameter of the feeding needle; d=diameter of the orifice through which the microjet is passed; e=axial length of the orifice through which withdrawal takes place; H=distance from the feeding needle to the microjet outlet; γ=surface tension; P0=pressure inside the chamber; Pα=atmospheric pressure.
- The embodiment of
FIG. 2 is preferably used when attempting to form a spherical particle of one substance coated by another substance. The device ofFIG. 2 is comprised of the same basic component as per the device ofFIG. 1 and further includes asecond feeding source 32 which is positioned concentrically around the firstcylindrical feeding source 31. The second feeding source may be surrounded by one or more additional feeding sources with each concentrically positioned around the preceding source. The outer coating may be used for a variety of purposes, including: coating particles to prevent small particles from sticking together; to obtain a sustained release effect of the active compound (e.g. a pharmaceutically active drug) inside, and/or to mask flavors; and to protect the stability of another compound (e.g. a pharmaceutically active drug) contained therein. - The process is based on the microsuction which the liquid-gas or liquid-liquid interphase undergoes (if both are immiscible), when said interphase approaches a point beginning from which one of the fluids is suctioned off while the combined suction of the two fluids is produced. The interaction causes the fluid physically surrounded by the other to form a capillary microjet which finally breaks into spherical drops. If instead of two fluids (gas-liquid), three or more are used that flow in a concentric manner by injection using concentric tubes, a capillary jet composed of two or more layers of different fluids is formed which, when it breaks, gives rise to the formation of spheres composed of several approximately concentric spherical layers of different fluids. The size of the outer sphere (its thickness) and the size of the inner sphere (its volume) can be precisely adjusted. This can allow the manufacture of coated particles for a variety of end uses. For example the thickness of the coating can be varied in different manufacturing events to obtain coated particles which have gradually decreasing thicknesses to obtain a controlled release effect of the contents, e.g. a pharmaceutically active drug. The coating could merely prevent the particles from degrading, reacting, or sticking together.
- The method is based on the breaking of a capillary microjet composed of a nucleus of one liquid or gas and surrounded by another or other liquids and gases which are in a concentric manner injected by a special injection head, in such a way that they form a stable capillary microjet and that they do not mix by diffusion during the time between when the microjet is formed and when it is broken. When the capillary microjet is broken into spherical drops under the proper operating conditions, which will be described in detail below, these drops exhibit a spherical nucleus, the size and eccentricity of which can be controlled.
- In the case of spheres containing two materials, the
injection head 25 consists of two concentric tubes with an external diameter on the order of one millimeter. Through theinternal tube 31 is injected the material that will constitute the nucleus of the microsphere, while between theinternal tube 31 and theexternal tube 32 the coating is injected. The fluid of theexternal tube 32 joins with the fluid oftube 31 as the fluids exit the feeding needle, and the fluids (normally liquids) thus injected are accelerated by a stream of gas that passes through asmall orifice 24 facing the end of the injection tubes. When the drop in pressure across theorifice 24 is sufficient, the liquids form a completely stationary capillary microjet, if the quantities of liquids that are injected are stationary. This microjet does not touch the walls of the orifice, but passes through it wrapped in the stream of gas or funnel formed by gas from thetube 32. Because the funnel of gas focuses the liquid, the size of theexit orifice 26 does not dictate the size of the particles formed. - When the parameters are correctly adjusted, the movement of the liquid is uniform at the exit of the
orifice 26 and the viscosity forces are sufficiently small so as not to alter either the flow or the properties of the liquids; for example, if there are biochemical molecular specimens having a certain complexity and fragility, the viscous forces that would appear in association with the flow through a micro-orifice might degrade these substances. -
FIG. 2 shows a simplified diagram of the feedingneedle 21, which is comprised of theconcentric tubes fluids orifice 26 establishes a flow of gas present in thechamber 23 and which is going to surround the microjet at its exit. The same pressure gradient that moves the gas is the one that moves the microjet in an axial direction through thehole 26, provided that the difference in pressures P0−Pα is sufficiently great in comparison with the forces of surface tension, which create an adverse gradient in the direction of the movement. - There are two limitations for the minimum sizes of the inside and outside jets that are dependent (a) on the surface tensions γ1 of the
outside liquid 29 with thegas 30 and γ2 of theoutside liquid 29 with theinside liquid 28, and (b) on the difference in pressures ΔP=P0−Pα through theorifice 26. In the first place, the jump in pressures ΔP must be sufficiently great so that the adverse effects of the surface tension are minimized. This, however, is attained for very modest pressure increases: for example, for a 10 micron jet of a liquid having a surface tension of 0.05 N/m (tap water), the necessary minimum jump in pressure is in the order of 0.05 (N/m)/0.00001 m=ΔP=50 mBar. But, in addition, the breakage of the microjet must be regular and axilsymmetric, so that the drops will have a uniform size, while the extra pressure ΔP cannot be greater than a certain value that is dependent on the surface tension of the outside liquid with the gas γ1 and on the outside diameter of the microjet. It has been experimentally shown that this difference in pressures cannot be greater than 20 times the surface tension γ1 divided by the outside radius of the microjet. - Therefore, given some inside and outside diameters of the microjet, there is a range of operating pressures between a minimum and a maximum; nonetheless, experimentally the best results are obtained for pressures in the order of two to three times the minimum.
- The viscosity values of the liquids must be such that the liquid with the greater viscosity μmax verifies, for a diameter d of the jet predicted for this liquid and a difference through the orifice ΔP, the inequality:
- With this, the pressure gradients can overcome the extensional forces of viscous resistance exerted by the liquid when it is suctioned toward the orifice.
- Moreover, the liquids must have very similar densities in order to achieve the concentricity of the nucleus of the microsphere, since the relation of velocities between the liquids moves according to the square root of the densities v1/v2=(ρ2/ρ1)1/2 and both jets, the inside jet and the outside jet, must assume the most symmetrical configuration possible, which does not occur if the liquids have different velocities (
FIG. 2 ). Nonetheless, it has been experimentally demonstrated that, on account of the surface tension γ2 between the two liquids, the nucleus tends to migrate toward the center of the microsphere, within prescribed parameters. - When two liquids and gas are used on the outsider the distance between the planes of the mouths of the concentric tubes can vary, without the characteristics of the jet being substantially altered, provided that the
internal tube 31 is not introduced into theexternal one 32 more than one diameter of theexternal tube 32 and provided that theinternal tube 31 does not project more than two diameters from theexternal tube 32. The best results are obtained when theinternal tube 31 projects from the external one 32 a distance substantially the same as the diameter of theinternal tube 31. This same criterion is valid if more than two tubes are used, with the tube that is surrounded (inner tube) projecting beyond the tube that surrounds (outer tube) by a distance substantially the same as the diameter of the first tube. - The distance between the plane of the internal tube 31 (the one that will normally project more) and the plane of the orifice may vary between zero and three outside diameters of the
external tube 32, depending on the surface tensions between the liquids and with the gas, and on their viscosity values. Typically, the optimal distance is found experimentally for each particular configuration and each set of liquids used. - The proposed atomizing system obviously requires fluids that are going to be used in the resulting spray to have certain flow parameters. Accordingly, flows for this use must be:
- Flows that are suitable so that the system falls within the parametric window of stability. Multiplexing (i.e. several sets of concentric tubes) may be used, if the flows required are greater than those of an individual cell.
- Flows that are suitable so that the mass relation of the fluids falls within the specifications of each application. Of course, a greater flow of gas may be supplied externally by any means in specific applications, since this does not interfere with the functioning of the atomizer.
- If the flows are varied, the characteristic time of this variation must be less than the hydrodynamic residence times of liquid and gas in the microjet, and less than the inverse of the first natural oscillation frequency of the drop formed at the end of the injection needle.
- Therefore, any means for continuous supply of gas (compressors, pressure deposits, etc.) and of liquid (volumetric pumps, pressure bottles) may be used. If multiplexing is desired, the flow of liquid must be as homogeneous as possible between the various cells, which may require impulse through multiple capillary needles, porous media, or any other medium capable of distributing a homogeneous flow among different feeding points.
- Each atomizing device will consist of
concentric tubes - The embodiments of
FIGS. 1 and 2 are similar in a number of ways. Both have a feeding piece which is preferably in the form of a feeding needle with a circular exit opening. Further, both have an exit port in the pressure chamber which is positioned directly in front of the flow path of fluid out of the feeding source. Precisely maintaining the alignment of the flow path of the feeding source with the exit port of the pressure chamber can present an engineering challenge particularly when the device includes a number of feeding needles. The embodiment ofFIG. 3 is designed to simplify the manner in which components are aligned. The embodiment ofFIG. 3 uses a planar feeding piece (which by virtue of the withdrawal effect produced by the pressure difference across a small opening through which fluid is passed) to obtain multiple microjets which are expelled through multiple exit ports of a pressure chamber thereby obtaining multiple aerosol streams. Although a single planar feeding member as shown inFIG. 3 it, of course, is possible to produce a device with a plurality of planar feeding members where each planar feeding member feeds fluid to a linear array of outlet orifices in the surrounding pressure chamber. In addition, the feeding member need not be strictly planar, and may be a curved feeding device comprised of two surfaces that maintain approximately the same spatial distance between the two pieces of the feeding source. Such curved devices may have any level of curvature, e.g. circular, semicircular, elliptical, hemi-elliptical etc. - The components of the embodiment of
FIG. 3 are as follows: - 41. Feeding piece.
- 42. End of the feeding piece used to insert the fluid to be atomized.
- 43. Pressure chamber.
- 44. Orifice used as gas inlet.
- 45. End of the feeding needle used to evacuate the liquid to be atomized.
- 46. Orifices through which withdrawal takes place.
- 47. Atomizate (spray) or aerosol.
- 48. first fluid containing material to be atomized.
- 49. second fluid for creation of microjet.
- 50. wall of the propulsion chamber facing the edge of the feeding piece.
- 51. channels for guidance of fluid through feeding piece.
- dj=diameter of the microjet formed; ρA=liquid density of first fluid (48); ρB=liquid density of second fluid (49); vA=velocity of the first liquid (48); vB=velocity of the second liquid (49); e=axial length of the orifice through which withdrawal takes place; H=distance from the feeding needle to the microjet outlet; P0=pressure inside the chamber;
- Δpg=change in pressure of the gas, Pα=atmospheric pressure; Q=volumetric flow rate
- The proposed dispersing device consists of a
feeding piece 41 which creates a planar feeding channel through which a where afirst fluid 48 flows. The flow is preferably directed through one or more channels of uniform bores that are constructed on the planar surface of thefeeding piece 41. Apressure chamber 43 that holds the propelling flow of asecond liquid 49, houses the feedingpiece 41 and is under a pressure above maintained outside thechamber wall 50. One or more orifices, openings or slots (outlets) 46 made in the wall 52 of the propulsion chamber face the edge of the feeding piece. Preferably, each bore or channel of thefeeding piece 41 has its flow path substantially aligned with anoutlet 46. - Formation of the microjet and its acceleration are based on the abrupt pressure drop resulting from the steep acceleration undergone by the
second fluid 49 on passing through theorifice 46, similarly to the procedure described above for embodiments ofFIGS. 1 and 2 when thesecond fluid 49 is a gas. - When the
second fluid 49 is a gas and thefirst fluid 48 is a liquid, the microthread formed is quite long and the liquid velocity is much smaller than the gas velocity. In fact, the low viscosity of the gas allows the liquid to flow at a much lower velocity; as a result, the microjet is actually produced and accelerated by stress forces normal to the liquid surface, i.e. pressure forces. Hence, one effective approximation to the phenomenon is to assume that the pressure difference established will result in the same kinetic energy per unit volume for both fluids (liquid and gas), provided gas compressibility effects are neglected. The diameter dj of the microjet formed from a liquid density ρ1 that passes at a volumetric flow-rate Q through an orifice across which a pressure difference ΔPg exists will be given by - See Gañàn-Calvo, Physical Review Letters, 80:285-288 (1998).
- The relation between the diameter of the microjet, dj, and that of the resulting drops, _, depends on the ratio between viscous forces and surface tension forces on the liquid on the one hand, and between dynamic forces and surface tension forces on the gas on the other (i.e. on the Ohnesorge and Weber numbers, respectively) (Hinds (Aerosol Technology, John & Sons, 1982), Lefevre (Atomization and Sprays, Hemisphere Pub. Corp., 1989) and Bayvel & Orzechowski (Liquid Atomization, Taylor & Francis, 1993)). At moderate to low gas velocities and low viscosities the relation is roughly identical with that for capillarity instability developed by Rayleigh:
—=1.89 dj - Because the liquid microjet is very long, at high liquid flow-rates the theoretical rupture point lies in the turbulent zone created by the gas jet, so turbulent fluctuations in the gas destabilize or rupture the liquid microjet in a more or less uneven manner. As a result, the benefits of drop size uniformity are lost.
- On the other hand, when the
second fluid 49 is a liquid and thefirst fluid 48 is a gas, the facts that the liquid is much more viscous and that the gas is much less dense virtually equalize the fluid and gas velocities. The gas microthread formed is much shorter; however, because its rupture zone is almost invariably located in a laminar flowing stream, dispersion in the size of the microbubbles formed is almost always small. At a volumetric gas flow-rate Qg and a liquid overpressure ΔP1, the diameter of the gas microjet is given by - The low liquid velocity and the absence of relative velocities between the liquid and gas lead to the Rayleigh relation between the diameters of the microthread and those of the bubbles (i.e. d=1.89 dj).
- If both
fluids - The diameter of a microjet of the first liquid at a volumetric flow-rate of A QA and an overpressure of BΔPB will be given by
- At viscosities such that the velocities of both
fluids - The proposed atomization system obviously requires delivery of the
fluids - (1) Both flow-rates should be adjusted for the system so that they lie within the stable parameter window.
- (2) The mass ratio between the flows should be compatible with the specifications of each application. Obviously, the gas flow-rate can be increased by using an external means in special applications (e.g. burning, drug inhalation) since this need not interfere with the atomizer operation.
- (3) If the flow-rates are altered, the characteristic time for the variation should be shorter than the hydrodynamic residence times for the liquid and gas in the microjet, and smaller than the reciprocal of the first natural oscillation frequency of the drop formed at the end of the feeding piece.
- (4) Therefore, the gas and liquid can be dispensed by any type of continuous delivery system (e.g. a compressor or a pressurized tank the former and a volumetric pump or a pressurized bottle the latter).
- (5) The atomizer can be made from a variety of materials (metal, plastic, ceramics, glass).
- The various embodiments of components for creating aerosols described above can be used in devices for the delivery of an aerosol to a patient. The device is preferably a hand-held, self-contained device which a patient can easily carry about and use for the administration of drugs.
- In one embodiment the pressurized canister of a device as disclosed in U.S. Pat. Nos. 5,364,838 or 5,404,871 is replaced with an aerosol generating device of the type shown here in any of
FIGS. 1, 2 or 3. The device preferably includes a means for measuring a patient's respiratory flow rate and respiratory volume. The aerosol may be generated when the patient manually actuates release of aerosol. However, the device preferably operates as the device in the U.S. Pat. No. 5,364,838 patent and is actuated automatically in response to a measured inspiratory flow rate and inspiratory volume. This makes it possible to repeatedly deliver aerosol to a patient at the same point in the respiratory cycle thereby improving repeatability of dosing. - In another embodiment the disposable containers and porous membranes of the device disclosed in U.S. Pat. No. 5,544,646 is replaced with an aerosol generating device of the type shown here in
FIGS. 1, 2 or 3. In such an embodiment the aerosol generating device is likely to include a plurality of sources of liquid drug formulation (e.g. a plurality of feeding needles) so that a sufficient amount of formulation can be aerosolized in a sufficiently short period of time that the patient can, in a single inhalation, inhale all of the aerosol needed for a dose of the drug being delivered. An aerosol generating device of the type shown inFIG. 3 is generally easier to manufacture and as such is preferred in this embodiment. - In the two embodiments described above it is preferable to create an aerosol with particles having a particle diameter in the range of about 1 to about 3 microns. This allows the particles to penetrate into the smallest channels of the lungs. However, such particles are not so small that they will not settle on the surface of these channels when inhaled—failure to settle would cause the particles to be exhaled as with particles of smoke.
- In yet another embodiment the source of aerosol of a device as disclosed in U.S. Pat. No. 4,484,577 is replaced with an aerosol generating device of the type described here and shown in
FIGS. 1, 2 or 3. The device of U.S. Pat. No. 4,484,577 includes a large container into which the aerosol is dispersed. The aerosol then “hangs” in the air in the large container until it is inhaled by the patient. Using an aerosol generation device of the invention the aerosol particles can be made very small, e.g. about 1 micron or less. Particles of this size will be suspended in air in the container until inhaled. The patient can then breath normally in and out of the container until all or substantially all particles in the container have deposited themselves on the channels of the lung. - The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.
- The properties of sixteen different liquids are provided in Table 1
TABLE 1 Liquids used and some of their physical properties at 24.5° C. (ρ: kg/m3, μ: cpoise, γ: N/m). Also given, the symbols used in the plots. Liquid ρ μ γ Symbol Heptane 684 0.38 0.021 ◯ Tap Water 1000 1.00 0.056 ⋄ Water + glycerol 90/10 v/v 1026 1.39 0.069 − Water + glycerol 80/20 v/v 1052 1.98 0.068 ∇ Isopropyl alcohol 755.5 2.18 0.021 X Water + glycerol 70/30 v/v1078 2.76 0.067 0 Water + glycerol 60/40 v/v1104 4.37 0.067 • Water + glycerol 50/50 v/v1030 6.17 0.066 ◯ 1-Octanol 827 7.47 0.024 ⋄ Water + glycerol 40/60 v/v 1156 12.3 0.065 − Water + glycerol 35/65 v/v 1167 15.9 0.064 ∇ Water + glycerol 30/70 v/v1182 24.3 0.064 X Water + glycerol 25/75 v/v1195 38.7 0.063 + Propylene glycol 1026 41.8 0.036 • - The liquids of Table 1 were forced through a feeding needle of the type shown in
FIG. 1 . Theend 5 of the feeding needle had an internal radius Ro. The exit orifice 6 had a diameter D and the wall of thepressure chamber 3 had a thickness of L. Three different devices were tested having the following dimensions: (D=0.15, 0.2, and 0.3 mm; L=0.1, 0.2 and 0.35 mm; Ro+0.2, 0.4, and 0.6 mm, respectively), and several distances H from the tube mouth to the orifice ranging from H=0.5 mm to H=1.5 mm have been used. The jet diameter was measured at the hole exit and was plotted as a function of the pressure difference ΔPg and flow rate Q respectively. Although this technique allows for jet diameters even below one micron, larger flow rates and diameters have been used in this study to diminish the measuring errors. - In order to collapse all of the data, we define a reference flow rate Qo and diameter do based on the minimal values, from expressions (3) and (5), that can be attained in stable regime for a given ΔPg:
- These definitions provide the advantage of a nondimensional expression for (5), as
d j /d o=(8/π2)1/4(Q/Q o)1/2 (7) - which allows for a check for the validity of neglecting the surface tension term in (4) (i.e., Q/Qo should be large).
- Notice that if the measured dj follows expression (5), the surface tension cancels out in (7). Also notice that dj/do≅We/2.
- 350 measured values of dj/do versus Q/Qo are plotted in
FIG. 5 . A continuous line represents the theoretical prediction (7), independent of liquid viscosity and surface tension. The use of different hole and tube diameters as well as tube-hole distances does not have any appreciable influence on dj. The collapse of the experimental data and the agreement with the simple theoretical model is excellent. Finally, the experimental values of Q are at least four times large than Qo (being in most cases several hundreds times larger), which justifies the neglect of the surface tension term in Eq. (4). - While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.
Claims (26)
1.-20. (canceled)
21. A method of substantially eliminating the clogging of an exit orifice in a drug delivery nozzle, comprising the steps of:
feeding a pharmaceutically active liquid drug through a feeding source in a manner which causes the drug to be expelled from an exit opening of the feeding source in a liquid stream;
forcing a gas through a pressure chamber which surrounds the exit opening of the feeding source, whereby the gas is fed in a manner which causes the gas and the drug to exit the pressure chamber from an exit orifice of the pressure chamber, the gas and drug exiting downstream of a flow path of the drug expelled from the exit opening of the feeding source;
wherein the exit opening of the feeding source is separated by a distance of from about 0.002 mm to about 2 mm from the exit orifice of the pressure chamber;
wherein the liquid drug is kept out of contact with any surface of the exit opening of the pressure chamber by the gas from the pressure chamber surrounding the liquid stream.
22. The method of claim 21 , carried out using the feeding source, pressure chamber, and drug of a hand-held, self-contained portable drug delivery device
23. The method of claim 21 , further comprising:
allowing the liquid stream to exit the pressure chamber and disassociate into particles having an aerodynamic diameter in a range of from 0.1 micron to about 10 microns.
24. The method of claim 23 , wherein liquid stream disassociates into particles having an aerodynamic diameter in a range of from 1 to 5 microns.
25. The method of claim 21 , wherein the exit opening of the feeding source has a diameter in a range of about 0.002 mm to about 2 mm.
26. The method of claim 25 , wherein the exit orifice of the pressure chamber has a diameter in a range of about 0.002 mm to about 2 mm.
27. The method of claim 24 , wherein the pharmaceutically active liquid drug is a solution.
28. The method of claim 24 , wherein the pharmaceutically active liquid drug is a suspension.
29. The method of claim 21 , wherein the liquid drug has a viscosity in a range of from about 10−4 to about 1 kg/m/sec.
30. The method of claim 24 , wherein the gas is air.
31. The method of claim 22 , wherein the gas is CO2.
32. The method of claim 25 , wherein the exit opening of the pressure chamber has a diameter in the range of from about 0.01 mm to about 0.4 mm.
33. The method of claim 22 , wherein the drug fed through the feeding source has a volume in the range of 5 microliters to 10,000 microliters.
34. The method of claim 21 , wherein gas is forced into an area around the feeding source outlet at a pressure above 10 mBar above atmospheric pressure.
35. The method of claim 34 , wherein gas is forced into an area around the feeding source outlet at a pressure below 50,000 mBar above atmospheric pressure.
36. A hand-held self-contained portable drug delivery device during operation, comprising:
a feeding source having therein a liquid drug which flows through the feeding source and is expelled from an exit opening of the feeding source in a liquid stream;
a pressure chamber containing a pressurized gas, said pressure chamber comprising an exit orifice configured such that the gas and liquid stream exit downstream of a flow path of the drug expelled from the exit opening of the feeding source;
wherein the exit opening of the feeding source is separated by a distance of from about 0.002 mm to about 2 mm from the exit orifice of the pressure chamber;
wherein during operation of the device the liquid stream is maintained out of contact with any surface of the exit opening by gas surrounding the liquid stream;
wherein clogging of the nozzle is substantially eliminated;
wherein the device does not require cleaning of the nozzle; and
further wherein the device does not require replacement of the nozzle.
37. The device of claim 36 , wherein during operation of the device the drug and gas exiting the pressure chamber comprises particles having an aerodynamic diameter in a range of from 0.1 micron to about 10 microns.
38. The device of claim 37 , wherein during operation of the device the drug and gas exiting the pressure chamber comprises particles having an aerodynamic diameter in a range of from 1 to 5 microns.
39. The device of claim 37 , wherein the pharmaceutically active drug is a solution.
40. The device of claim 37 , wherein the pharmaceutically active drug is a suspension.
41. The device of claim 38 , wherein the gas is CO2.
42. The device of claim 41 , wherein the exit opening has a diameter in the range of from about 0.01 mm to about 0.4 mm.
43. The device of claim 38 , wherein during operation of the device the drug fed through the feeding source has a volume in the range of 5 microliters to 10,000 microliters.
44. The device of claim 38 , wherein during operation of the device gas is forced into an area around the feeding source outlet at a pressure above 10 mBar above atmospheric pressure.
45. The device of claim 44 , wherein during operation of the device gas is forced into an area around the feeding source outlet at a pressure below 50,000 mBar above atmospheric pressure.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/926,926 US20080053431A1 (en) | 1996-05-13 | 2007-10-29 | Device and method for creating aerosols for drug delivery |
Applications Claiming Priority (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES9601101 | 1996-05-13 | ||
ES009601101A ES2140998B1 (en) | 1996-05-13 | 1996-05-13 | LIQUID ATOMIZATION PROCEDURE. |
PCT/ES1997/000034 WO1997043048A1 (en) | 1996-05-13 | 1997-02-18 | Liquid atomization process |
US09/171,518 US6119953A (en) | 1996-05-13 | 1997-02-18 | Liquid atomization process |
ES9702654A ES2158741B1 (en) | 1997-12-17 | 1997-12-17 | SIPERSION DEVICE OF A FLUID IN ANOTHER IMMISCIBLE IN THE FORM OF MICROGOTS OR MICROBUBBLES UNIFORM SIZE. |
ESP9702654 | 1997-12-17 | ||
US17151898A | 1998-10-20 | 1998-10-20 | |
US19131798A | 1998-11-13 | 1998-11-13 | |
US10/216,517 US6792940B2 (en) | 1996-05-13 | 2002-08-09 | Device and method for creating aerosols for drug delivery |
US10/886,923 US7059321B2 (en) | 1996-05-13 | 2004-07-07 | Device and method for creating aerosols for drug delivery |
US11/288,881 US7293559B2 (en) | 1996-05-13 | 2005-11-28 | Device and method for creating aerosols for drug delivery |
US11/926,926 US20080053431A1 (en) | 1996-05-13 | 2007-10-29 | Device and method for creating aerosols for drug delivery |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/288,881 Continuation US7293559B2 (en) | 1996-05-13 | 2005-11-28 | Device and method for creating aerosols for drug delivery |
Publications (1)
Publication Number | Publication Date |
---|---|
US20080053431A1 true US20080053431A1 (en) | 2008-03-06 |
Family
ID=28678567
Family Applications (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/216,517 Expired - Lifetime US6792940B2 (en) | 1996-05-13 | 2002-08-09 | Device and method for creating aerosols for drug delivery |
US10/865,597 Expired - Fee Related US7059319B2 (en) | 1996-05-13 | 2004-06-09 | Device and method for creating aerosols for drug delivery |
US10/886,923 Expired - Fee Related US7059321B2 (en) | 1996-05-13 | 2004-07-07 | Device and method for creating aerosols for drug delivery |
US11/288,881 Expired - Fee Related US7293559B2 (en) | 1996-05-13 | 2005-11-28 | Device and method for creating aerosols for drug delivery |
US11/926,926 Abandoned US20080053431A1 (en) | 1996-05-13 | 2007-10-29 | Device and method for creating aerosols for drug delivery |
US11/926,936 Expired - Fee Related US8733343B2 (en) | 1996-05-13 | 2007-10-29 | Device and method for creating aerosols for drug delivery |
Family Applications Before (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/216,517 Expired - Lifetime US6792940B2 (en) | 1996-05-13 | 2002-08-09 | Device and method for creating aerosols for drug delivery |
US10/865,597 Expired - Fee Related US7059319B2 (en) | 1996-05-13 | 2004-06-09 | Device and method for creating aerosols for drug delivery |
US10/886,923 Expired - Fee Related US7059321B2 (en) | 1996-05-13 | 2004-07-07 | Device and method for creating aerosols for drug delivery |
US11/288,881 Expired - Fee Related US7293559B2 (en) | 1996-05-13 | 2005-11-28 | Device and method for creating aerosols for drug delivery |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/926,936 Expired - Fee Related US8733343B2 (en) | 1996-05-13 | 2007-10-29 | Device and method for creating aerosols for drug delivery |
Country Status (1)
Country | Link |
---|---|
US (6) | US6792940B2 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070102533A1 (en) * | 1999-06-11 | 2007-05-10 | Aradigm Corporation; Universidad De Sevilla | Aerosol created by directed flow of fluids and devices and methods for producing same |
US9695482B2 (en) | 2007-10-12 | 2017-07-04 | Fio Coporation | Flow focusing method and system for forming concentrated volumes of microbeads, and microbeads formed further thereto |
US10369579B1 (en) | 2018-09-04 | 2019-08-06 | Zyxogen, Llc | Multi-orifice nozzle for droplet atomization |
Families Citing this family (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6792940B2 (en) * | 1996-05-13 | 2004-09-21 | Universidad De Sevilla | Device and method for creating aerosols for drug delivery |
US6595202B2 (en) * | 1996-05-13 | 2003-07-22 | Universidad De Sevilla | Device and method for creating aerosols for drug delivery |
US6799576B2 (en) * | 1999-07-16 | 2004-10-05 | Aradigm Corporation | System for effecting smoking cessation |
JP5144070B2 (en) * | 2003-09-05 | 2013-02-13 | カーブ テクノロジー,インコーポレイティド | Integrated nebulizer and particle dispersion chamber for nasal delivery of drugs into the deep nasal cavity and sinuses |
DE102004009385A1 (en) * | 2004-02-24 | 2005-09-08 | Cavis Microcaps Gmbh | Device and arrangement for dripping liquids of different viscosity |
ES2264608B2 (en) * | 2004-09-30 | 2007-08-16 | Universidad De Sevilla | DEVICE AND PROCEDURE FOR THE PNEUMATIC ATOMIZATION OF LIQUIDS BY IMPLOSIVE GAS FLOW. |
US7290542B1 (en) * | 2004-11-16 | 2007-11-06 | The United States Of America As Represented By The Secretary Of The Army | System and method for delivering and metering powder aerosol |
DE102005032983B4 (en) * | 2005-07-14 | 2007-05-31 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | nozzle assembly |
PT2211955T (en) * | 2007-10-02 | 2017-06-29 | Philip Morris Products Sa | Dispensing method and system of a capillary aerosol generator |
MX2010003438A (en) * | 2007-10-02 | 2010-04-21 | Philip Morris Prod | Biomarkers and methods for determining sensitivity to vascular endothelial growth factor receptor-2 modulators. |
US8899230B2 (en) * | 2008-02-15 | 2014-12-02 | Nasologix, Inc. | Aerosol therapy device with high frequency delivery |
WO2009129547A1 (en) * | 2008-04-18 | 2009-10-22 | The Board Of Trustees Of The University Of Alabama | Meso-scaled combustion system |
US8974771B2 (en) * | 2010-03-09 | 2015-03-10 | Penn-Century, Inc. | Apparatus and method for aerosol delivery to the lungs or other locations of the body |
WO2011115328A1 (en) * | 2010-03-16 | 2011-09-22 | 서울대학교 산학협력단 | Microjet drug delivery system |
CN103002878B (en) | 2010-04-09 | 2015-07-01 | 帕西拉制药有限公司 | Method for formulating large diameter synthetic membrane vesicles |
USD704580S1 (en) | 2012-03-08 | 2014-05-13 | Sony Corporation | Micro flow channel chip for flow cytometer |
USD869308S1 (en) | 2010-04-29 | 2019-12-10 | Sony Corporation | Micro flow channel chip |
USD673287S1 (en) | 2010-11-24 | 2012-12-25 | Sony Corporation | Micro flow channel chip |
CN103124541B (en) | 2010-07-15 | 2015-09-30 | 艾诺维亚股份有限公司 | ophthalmic drug delivery |
US10154923B2 (en) | 2010-07-15 | 2018-12-18 | Eyenovia, Inc. | Drop generating device |
EP2608830B1 (en) | 2010-08-24 | 2018-03-28 | Trudell Medical International | Aerosol delivery device |
AU2015335618B2 (en) | 2014-10-24 | 2018-02-01 | Avectas Limited | Delivery across cell plasma membranes |
EP3059537A1 (en) * | 2015-02-20 | 2016-08-24 | Ingeniatrics Tecnologias | And apparatus and a amethod for generating droplets |
CA3009715A1 (en) * | 2015-12-30 | 2017-07-06 | Avectas Limited | Vector-free delivery of gene editing proteins and compositions to cells and tissues |
JP6840468B2 (en) * | 2016-03-29 | 2021-03-10 | 三菱重工業株式会社 | Gas turbine combustor |
JP2018130224A (en) * | 2017-02-14 | 2018-08-23 | 株式会社フェザーグラス | Inhalation device |
US10443838B2 (en) * | 2017-04-05 | 2019-10-15 | Hall Labs Llc | Method for forming consistently-sized and controllably-timed droplets |
CA3066408A1 (en) | 2017-06-10 | 2018-12-13 | Eyenovia, Inc. | Methods and devices for handling a fluid and delivering the fluid to the eye |
WO2019173561A1 (en) * | 2018-03-08 | 2019-09-12 | Graham Nichol | Devices, systems, and methods for delivery of a reperfusion-injury-modifying drug to a patient |
CN108739620B (en) * | 2018-06-20 | 2020-11-03 | 安徽惠泽园苗木花卉种植有限公司 | Air bag aeration, oxygenation and material adding integrated device for fishpond |
US20230028572A1 (en) * | 2019-11-22 | 2023-01-26 | The Trustees Of Princeton University | High-throughput monodisperse aerosols of micro-shell particles |
Citations (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3812854A (en) * | 1972-10-20 | 1974-05-28 | A Michaels | Ultrasonic nebulizer |
US4125225A (en) * | 1971-03-01 | 1978-11-14 | The Perkin-Elmer Corporation | Corrosion-free nebulizer |
US4389312A (en) * | 1981-10-05 | 1983-06-21 | Harold Beard | Variable venturi sewerage aerator |
US4454877A (en) * | 1981-05-26 | 1984-06-19 | Andrew Boettner | Portable nebulizer or mist producing device |
US4630774A (en) * | 1982-10-22 | 1986-12-23 | Nordson Corporation | Foam generating nozzle |
US5072726A (en) * | 1987-10-09 | 1991-12-17 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Vaporizer for inhalation anesthetics during high-frequency jet ventilation and associated method |
US5096615A (en) * | 1988-07-19 | 1992-03-17 | The United States Of America As Represented By The United States Department Of Energy | Solid aerosol generator |
US5312041A (en) * | 1992-12-22 | 1994-05-17 | Cca, Inc. | Dual fluid method and apparatus for extinguishing fires |
US5464157A (en) * | 1994-07-18 | 1995-11-07 | The Perkin-Elmer Corporation | Nebulizer for use in an atomic absorption system |
US5552189A (en) * | 1993-03-25 | 1996-09-03 | Shaffer; Jeffrey P. | Method and apparatus for applying a painted design to an article of clothing |
US5884846A (en) * | 1996-09-19 | 1999-03-23 | Tan; Hsiaoming Sherman | Pneumatic concentric nebulizer with adjustable and capillaries |
US5906198A (en) * | 1996-07-16 | 1999-05-25 | Flickinger; William J. | Nasal nebulizer |
US6119953A (en) * | 1996-05-13 | 2000-09-19 | Aradigm Corporation | Liquid atomization process |
US7293559B2 (en) * | 1996-05-13 | 2007-11-13 | Universidad De Sevilla | Device and method for creating aerosols for drug delivery |
Family Cites Families (68)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US442785A (en) * | 1890-12-16 | Atomizer | ||
US173194A (en) * | 1876-02-08 | Improvement in atomizers | ||
US445579A (en) * | 1891-02-03 | Vaginal atomizer | ||
US4054622A (en) * | 1970-11-03 | 1977-10-18 | Lester Victor E | Combination nebulizer and humidifier |
CS153231B1 (en) | 1970-11-18 | 1974-02-25 | ||
US3804255A (en) | 1972-10-18 | 1974-04-16 | R Speece | Recycling gas contact apparatus |
CH563807A5 (en) | 1973-02-14 | 1975-07-15 | Battelle Memorial Institute | Fine granules and microcapsules mfrd. from liquid droplets - partic. of high viscosity requiring forced sepn. of droplets |
US4162282A (en) | 1976-04-22 | 1979-07-24 | Coulter Electronics, Inc. | Method for producing uniform particles |
US4141055A (en) | 1977-04-27 | 1979-02-20 | Bell Telephone Laboratories, Incorporated | Crossover structure for microelectronic circuits |
US4268460A (en) * | 1977-12-12 | 1981-05-19 | Warner-Lambert Company | Nebulizer |
US4347935A (en) | 1979-05-16 | 1982-09-07 | The United States Of America As Represented By The United States Department Of Energy | Method and apparatus for electrostatically sorting biological cells |
DE3005857A1 (en) | 1980-02-16 | 1981-09-10 | Robert Bosch Gmbh, 7000 Stuttgart | FUEL INJECTION NOZZLE |
US4352789A (en) | 1980-03-17 | 1982-10-05 | Minnesota Mining And Manufacturing Company | Aerosol compositions containing finely divided solid materials |
CA1166413A (en) | 1980-10-30 | 1984-05-01 | Edward E. Timm | Process and apparatus for preparing uniform size polymer beads |
DE3105686A1 (en) | 1981-02-17 | 1982-09-02 | Robert Bosch Gmbh, 7000 Stuttgart | "FUEL INJECTION NOZZLE" |
DE3217887A1 (en) | 1981-05-15 | 1982-12-02 | Kabushiki Kaisha Komatsu Seisakusho, Tokyo | FUEL INJECTION SYSTEM FOR INTERNAL COMBUSTION ENGINES |
EP0083348B1 (en) | 1981-07-07 | 1986-11-05 | Piper Fm Limited | Fuel delivery to internal combustion engines |
JPS59174561A (en) | 1983-03-18 | 1984-10-03 | 三井造船株式会社 | Manufacture of porous ceramics |
US4603671A (en) | 1983-08-17 | 1986-08-05 | Nippon Soken, Inc. | Fuel injector for an internal combustion engine |
US4649911A (en) * | 1983-09-08 | 1987-03-17 | Baylor College Of Medicine | Small particle aerosol generator for treatment of respiratory disease including the lungs |
US4717049A (en) | 1984-04-05 | 1988-01-05 | Mobil Oil Corporation | Droplet generating apparatus |
CA1235367A (en) | 1984-04-05 | 1988-04-19 | Gary J. Green | Method and apparatus for producing uniform liquid droplets |
IL73598A (en) * | 1984-11-23 | 1991-01-31 | Leibinsohn Saul | Fluid control device particularly useful in liquid transfusion apparatus |
US4781968A (en) | 1986-02-28 | 1988-11-01 | Digital Equipment Corporation | Micro-electronics devices and methods of manufacturing same |
JPS62289257A (en) | 1986-06-09 | 1987-12-16 | Ikeuchi:Kk | Hyperfine mist injection nozzle |
GB8614566D0 (en) | 1986-06-16 | 1986-07-23 | Ici Plc | Spraying |
JPS63112158A (en) | 1986-10-30 | 1988-05-17 | Matsushita Electric Ind Co Ltd | Ink jet recorder |
DE3724156A1 (en) | 1987-07-22 | 1989-02-02 | Norddeutsche Affinerie | METHOD FOR PRODUCING METALLIC OR CERAMIC HOLLOW BALLS |
US5167798A (en) | 1988-01-27 | 1992-12-01 | Virginia Tech Intellectual Properties, Inc. | Apparatus and process for the separation of hydrophobic and hydrophilic particles using microbubble column flotation together with a process and apparatus for generation of microbubbles |
US4907857A (en) * | 1988-07-25 | 1990-03-13 | Abbott Laboratories | Optical fiber distribution system for an optical fiber sensor |
EP0445169A1 (en) | 1988-11-22 | 1991-09-11 | Dunne Miller Weston Limited | Liquid-gas mixing device |
DE3844365A1 (en) | 1988-12-30 | 1990-07-05 | Bosch Gmbh Robert | FUEL INJECTION DEVICE |
US5364632A (en) | 1989-04-05 | 1994-11-15 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Medicinal emulsions |
FR2645456B1 (en) | 1989-04-11 | 1994-02-11 | Air Liquide | METHOD AND PLANT FOR TREATING A LIQUID WITH A GAS |
DE3915585A1 (en) * | 1989-05-12 | 1990-11-15 | Diehl Gmbh & Co | SUBMUNITION MISSILE |
US5031613A (en) * | 1989-06-07 | 1991-07-16 | JoAnne Hahn | Nebulizing catheter |
JPH03169331A (en) | 1989-11-30 | 1991-07-23 | Fuji Debuison Kagaku Kk | Preparation of emulsion |
JPH05507439A (en) | 1990-05-30 | 1993-10-28 | ワイヤーハウザー カンパニー | Device that coats material with gas |
US5077176A (en) | 1990-07-30 | 1991-12-31 | At&T Bell Laboratories | Pre-plate cleaning process |
TW226977B (en) | 1990-09-06 | 1994-07-21 | Teijin Ltd | |
GB2248031B (en) | 1990-09-19 | 1994-07-06 | Yakuzky Ni I Pi Almazodobyva | Flotation machine |
US5194915A (en) | 1990-09-20 | 1993-03-16 | Millipore Corporation | Photometric apparatus and process |
US5095921A (en) * | 1990-11-19 | 1992-03-17 | Philip Morris Incorporated | Flavor generating article |
US5404871A (en) | 1991-03-05 | 1995-04-11 | Aradigm | Delivery of aerosol medications for inspiration |
GB2255291A (en) | 1991-05-03 | 1992-11-04 | Exxon Research Engineering Co | Bitumen emulsions. |
US5230850A (en) | 1991-05-16 | 1993-07-27 | Lewis Raymond O | Fan blade reinforcement using bonded hollow spheres |
CA2444415A1 (en) | 1991-07-02 | 1993-01-21 | Nektar Therapeutics | Method and device for delivering aerosolized medicaments |
US5180465A (en) | 1991-07-22 | 1993-01-19 | Nippon Cmk Corp. | Etching method of forming microcircuit patterns on a printed circuit board |
US5174247A (en) | 1992-01-22 | 1992-12-29 | Mitsubishi Jukogyo Kabushiki Kaisha | Water injection diesel engine |
US5554646A (en) | 1992-04-29 | 1996-09-10 | Wisconsin Alumni Research Foundation | Method for reducing body fat in animals |
US5785049A (en) | 1994-09-21 | 1998-07-28 | Inhale Therapeutic Systems | Method and apparatus for dispersion of dry powder medicaments |
JPH0699105A (en) | 1992-09-24 | 1994-04-12 | Matsushita Electric Ind Co Ltd | Atomizing nozzle |
CA2148505C (en) | 1992-11-06 | 2005-03-08 | Patrick Sundholm | Method and apparatus for coating paper or the like |
US5378355A (en) | 1992-12-04 | 1995-01-03 | Water Pollution Control Corporation | Direct delivery in-situ diffuser cleaning |
US5364838A (en) | 1993-01-29 | 1994-11-15 | Miris Medical Corporation | Method of administration of insulin |
GB9306290D0 (en) | 1993-03-26 | 1993-05-19 | Exxon Research Engineering Co | Bituminous surface construction |
US5579757A (en) * | 1994-02-02 | 1996-12-03 | Baxter International, Inc. | Anti-siphon flow restricter for a nebulizer |
GB9403702D0 (en) | 1994-02-25 | 1994-04-13 | Flow Research Evaluation Diagn | Improvements relating to spray generators |
US5458292A (en) | 1994-05-16 | 1995-10-17 | General Electric Company | Two-stage fuel injection nozzle |
US5579758A (en) * | 1994-07-13 | 1996-12-03 | Century; Theodore J. | Sub-miniature aerosolizer with helical flow path formed by threaded insert |
US5522385A (en) | 1994-09-27 | 1996-06-04 | Aradigm Corporation | Dynamic particle size control for aerosolized drug delivery |
GB9423618D0 (en) | 1994-11-23 | 1995-01-11 | North West Water Group Plc | Optical instrument |
US5697341A (en) | 1995-11-20 | 1997-12-16 | Caterpillar, Inc. | Fill metered hydraulically actuated fuel injection system and method of fuel injection |
DE69622519T2 (en) * | 1995-12-29 | 2002-11-28 | Instrumentarium Corp., Helsinki | System for filling an anesthetic vaporizer |
US6595202B2 (en) * | 1996-05-13 | 2003-07-22 | Universidad De Sevilla | Device and method for creating aerosols for drug delivery |
US5743251A (en) | 1996-05-15 | 1998-04-28 | Philip Morris Incorporated | Aerosol and a method and apparatus for generating an aerosol |
GB9610821D0 (en) | 1996-05-23 | 1996-07-31 | Glaxo Wellcome Inc | Metering apparatus |
US6494856B1 (en) * | 2001-09-12 | 2002-12-17 | Unilever Home & Personal Care Usa, Division Of Conopco, Inc. | Swab deliverable actives |
-
2002
- 2002-08-09 US US10/216,517 patent/US6792940B2/en not_active Expired - Lifetime
-
2004
- 2004-06-09 US US10/865,597 patent/US7059319B2/en not_active Expired - Fee Related
- 2004-07-07 US US10/886,923 patent/US7059321B2/en not_active Expired - Fee Related
-
2005
- 2005-11-28 US US11/288,881 patent/US7293559B2/en not_active Expired - Fee Related
-
2007
- 2007-10-29 US US11/926,926 patent/US20080053431A1/en not_active Abandoned
- 2007-10-29 US US11/926,936 patent/US8733343B2/en not_active Expired - Fee Related
Patent Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4125225A (en) * | 1971-03-01 | 1978-11-14 | The Perkin-Elmer Corporation | Corrosion-free nebulizer |
US3812854A (en) * | 1972-10-20 | 1974-05-28 | A Michaels | Ultrasonic nebulizer |
US4454877A (en) * | 1981-05-26 | 1984-06-19 | Andrew Boettner | Portable nebulizer or mist producing device |
US4389312A (en) * | 1981-10-05 | 1983-06-21 | Harold Beard | Variable venturi sewerage aerator |
US4630774A (en) * | 1982-10-22 | 1986-12-23 | Nordson Corporation | Foam generating nozzle |
US5072726A (en) * | 1987-10-09 | 1991-12-17 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Vaporizer for inhalation anesthetics during high-frequency jet ventilation and associated method |
US5096615A (en) * | 1988-07-19 | 1992-03-17 | The United States Of America As Represented By The United States Department Of Energy | Solid aerosol generator |
US5312041A (en) * | 1992-12-22 | 1994-05-17 | Cca, Inc. | Dual fluid method and apparatus for extinguishing fires |
US5552189A (en) * | 1993-03-25 | 1996-09-03 | Shaffer; Jeffrey P. | Method and apparatus for applying a painted design to an article of clothing |
US5464157A (en) * | 1994-07-18 | 1995-11-07 | The Perkin-Elmer Corporation | Nebulizer for use in an atomic absorption system |
US6119953A (en) * | 1996-05-13 | 2000-09-19 | Aradigm Corporation | Liquid atomization process |
US7293559B2 (en) * | 1996-05-13 | 2007-11-13 | Universidad De Sevilla | Device and method for creating aerosols for drug delivery |
US20080072895A1 (en) * | 1996-05-13 | 2008-03-27 | The Universidad De Sevilla | Device and method for creating aerosols for drug delivery |
US5906198A (en) * | 1996-07-16 | 1999-05-25 | Flickinger; William J. | Nasal nebulizer |
US5884846A (en) * | 1996-09-19 | 1999-03-23 | Tan; Hsiaoming Sherman | Pneumatic concentric nebulizer with adjustable and capillaries |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070102533A1 (en) * | 1999-06-11 | 2007-05-10 | Aradigm Corporation; Universidad De Sevilla | Aerosol created by directed flow of fluids and devices and methods for producing same |
US20080053436A1 (en) * | 1999-06-11 | 2008-03-06 | Aradigm Corporation | Aerosol created by directed flow of fluids and devices and methods for producing same |
US9695482B2 (en) | 2007-10-12 | 2017-07-04 | Fio Coporation | Flow focusing method and system for forming concentrated volumes of microbeads, and microbeads formed further thereto |
US10369579B1 (en) | 2018-09-04 | 2019-08-06 | Zyxogen, Llc | Multi-orifice nozzle for droplet atomization |
Also Published As
Publication number | Publication date |
---|---|
US7059321B2 (en) | 2006-06-13 |
US20050016526A1 (en) | 2005-01-27 |
US20080072895A1 (en) | 2008-03-27 |
US7059319B2 (en) | 2006-06-13 |
US20060102173A1 (en) | 2006-05-18 |
US20050000512A1 (en) | 2005-01-06 |
US6792940B2 (en) | 2004-09-21 |
US20030183222A9 (en) | 2003-10-02 |
US20030024526A1 (en) | 2003-02-06 |
US8733343B2 (en) | 2014-05-27 |
US7293559B2 (en) | 2007-11-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7293559B2 (en) | Device and method for creating aerosols for drug delivery | |
EP1039971B1 (en) | Device and method for creating aerosols for drug delivery | |
US6595202B2 (en) | Device and method for creating aerosols for drug delivery | |
US6357670B2 (en) | Stabilized capillary microjet and devices and methods for producing same | |
US6554202B2 (en) | Fuel injection nozzle and method of use | |
US6174469B1 (en) | Device and method for creating dry particles | |
EP1037858A1 (en) | Device and method for creating spherical particles of uniform size | |
AU784815B2 (en) | Device and method for creating aerosols for drug delivery | |
AU2006209366A1 (en) | Device and method for creating aerosols for drug delivery |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: UNIVERSIDAD DE SEVILLA, SPAIN Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:GANAN-CALVO, ALFONSO M.;REEL/FRAME:020165/0651 Effective date: 19990103 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |