Method of forming an aerosol for inhalation delivery

Description

FIELD OF THE INVENTION

The present invention relates to the inhalation delivery of aerosols containing small particles. Specifically, it relates to a method of forming an aerosol for use in inhalation therapy.

BACKGROUND OF THE INVENTION

Currently, there are a number of approved devices for the inhalation delivery of drugs, including dry powder inhalers, nebulizers, and pressurized metered dose inhalers. The aerosols produced by the devices, however, typically contain an excipient.

It is desirable to provide a method that can produce aerosols in the absence of excipients. The provision of such a device is an object of the present invention.

SUMMARY OF THE INVENTION

The present invention relates to the inhalation delivery of aerosols containing small particles. Specifically, it relates to a method of forming an aerosol for use in inhalation therapy.

In a method aspect of the present invention, a method of forming an aerosol for use in inhalation therapy is provided. The method involves the following steps: (a) heating a substrate coated with a composition comprising a drug at a rate greater than 1000° C./s, thereby forming an vapor; and, (b) allowing the vapor to cool, thereby forming an aerosol, which is used in inhalation therapy. Preferably, the substrate is heated at a rate greater than 2,000° C./s, 5,000° C./s, 7,500° C./s, or 10,000° C./s.

In certain cases, the substrate is heated at a rate of about 2,000° C./s.

Typically, the composition is coated on the substrate as a film that is less than 10 μm thick. Preferably, the film thickness is less than 5 μm, 4 μm, 3 μm, 2 μm, or 1 μm thick.

Typically, the composition is coated on the substrate as a film that is between 10 μm and 10 nm in thickness. Preferably, the film thickness is between 5 μm and 10 nm, 4 μm and 10 nm, 3 μm and 10 nm, 2 μm and 10 nm, or 1 μm and 10 nm in thickness.

Typically, greater than 0.1 mg of the composition is vaporized in less than 100 milliseconds from the start of heating. Preferably, 0.25 mg, 0.5 mg, 0.75 mg, or 1 mg of the composition is vaporized in less than 100 milliseconds from the start of heating. More preferably, the same amount of composition list above is vaporized in less than 75 milliseconds, 50 milliseconds, 25 milliseconds, or 10 milliseconds from the start of heating.

Typically, the formed aerosol is greater than 10 percent by weight of the drug. Preferably, it is greater than 20 percent by weight of the drug. More preferably, it is greater than 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent or 97 percent by weight of the drug.

Typically, the formed aerosol contains less than 10 percent by weight of drug decomposition products. Preferably, it contains less than 5 percent by weight of drug decomposition products. More preferably, it contains less than 3 percent, 2 percent or 1 percent by weight of drug decomposition products.

Typically, the drug has a decomposition index less than 0.15. Preferably, the drug has a decomposition index less than 0.10. More preferably, the drug has a decomposition index less than 0.05.

Typically, the drug of the composition is of one of the following classes: antibiotics, anticonvulsants, antidepressants, antiemetics, antihistamines, antiparkisonian drugs, antipsychotics, anxiolytics, drugs for erectile dysfunction, drugs for migraine headaches, drugs for the treatment of alcoholism, drugs for the treatment of addiction, muscle relaxants, nonsteroidal anti-inflammatories, opioids, other analgesics and stimulants.

Typically, where the drug is an antibiotic, it is selected from one of the following compounds: cefmetazole; cefazolin; cephalexin; cefoxitin; cephacetrile; cephaloglycin; cephaloridine; cephalosporins, such as cephalosporin C; cephalotin; cephamycins, such as cephamycin A, cephamycin B, and cephamycin C; cepharin; cephradine; ampicillin; amoxicillin; hetacillin; carfecillin; carindacillin; carbenicillin; amylpenicillin; azidocillin; benzylpenicillin; clometocillin; cloxacillin; cyclacillin; methicillin; nafcillin; 2-pentenylpenicillin; penicillins, such as penicillin N, penicillin O, penicillin S, penicillin V; chlorobutin penicillin; dicloxacillin; diphenicillin; heptylpenicillin; and metampicillin.

Typically, where the drug is an anticonvulsant, it is selected from one of the following compounds: gabapentin, tiagabine, and vigabatrin.

Typically, where the drug is an antidepressant, it is selected from one of the following compounds: amitriptyline, amoxapine, benmoxine, butriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine, kitanserin, lofepramine, medifoxamine, mianserin, maprotoline, mirtazapine, nortriptyline, protriptyline, trimipramine, viloxazine, citalopram, cotinine, duloxetine, fluoxetine, fluvoxamine, milnacipran, nisoxetine, paroxetine, reboxetine, sertraline, tianeptine, acetaphenazine, binedaline, brofaromine, cericlamine, clovoxamine, iproniazid, isocarboxazid, moclobemide, phenyhydrazine, phenelzine, selegiline, sibutramine, tranylcypromine, ademetionine, adrafinil, amesergide, amisulpride, amperozide, benactyzine, bupropion, caroxazone, gepirone, idazoxan, metralindole, milnacipran, minaprine, nefazodone, nomifensine, ritanserin, roxindole, S-adenosylmethionine, tofenacin, trazodone, tryptophan, venlafaxine, and zalospirone.

Typically, where the drug is an antiemetic, it is selected from one of the following compounds: alizapride, azasetron, benzquinamide, bromopride, buclizine, chlorpromazine, cinnarizine, clebopride, cyclizine, diphenhydramine, diphenidol, dolasetron methanesulfonate, droperidol, granisetron, hyoscine, lorazepam, metoclopramide, metopimazine, ondansetron, perphenazine, promethazine, prochlorperazine, scopolamine, triethylperazine, trifluoperazine, triflupromazine, trimethobenzamide, tropisetron, domeridone, and palonosetron.

Typically, where the drug is an antihistamine, it is selected from one of the following compounds: azatadine, brompheniramine, chlorpheniramine, clemastine, cyproheptadine, dexmedetomidine, diphenhydramine, doxylamine, hydroxyzine, cetrizine, fexofenadine, loratidine, and promethazine.

Typically, where the drug is an antiparkisonian drug, it is selected one of the following compounds: amantadine, baclofen, biperiden, benztropine, orphenadrine, procyclidine, trihexyphenidyl, levodopa, carbidopa, selegiline, deprenyl, andropinirole, apomorphine, benserazide, bromocriptine, budipine, cabergoline, dihydroergokryptine, eliprodil, eptastigmine, ergoline pramipexole, galanthamine, lazabemide, lisuride, mazindol, memantine, mofegiline, pergolike, pramipexole, propentofylline, rasagiline, remacemide, spheramine, terguride, entacapone, and tolcapone.

Typically, where the drug is an antipsychotic, it is selected from one of the following compounds: acetophenazine, alizapride, amperozide, benperidol, benzquinamide, bromperidol, buramate, butaperazine, carphenazine, carpipramine, chlorpromazine, chlorprothixene, clocapramine, clomacran, clopenthixol, clospirazine, clothiapine, cyamemazine, droperidol, flupenthixol, fluphenazine, fluspirilene, haloperidol, mesoridazine, metofenazate, molindrone, penfluridol, pericyazine, perphenazine, pimozide, pipamerone, piperacetazine, pipotiazine, prochlorperazine, promazine, remoxipride, sertindole, spiperone, sulpiride, thioridazine, thiothixene, trifluperidol, triflupromazine, trifluoperazine, ziprasidone, zotepine, zuclopenthixol, amisulpride, butaclamol, clozapine, melperone, olanzapine, quetiapine, and risperidone.

Typically, where the drug is an anxiolytic, it is selected from one of the following compounds: mecloqualone, medetomidine, metomidate, adinazolam, chlordiazepoxide, clobenzepam, flurazepam, lorazepam, loprazolam, midazolam, alpidem, alseroxlon, amphenidone, azacyclonol, bromisovalum, buspirone, calcium N-carboamoylaspartate, captodiamine, capuride, carbcloral, carbromal, chloral betaine, enciprazine, flesinoxan, ipsapiraone, lesopitron, loxapine, methaqualone, methprylon, propanolol, tandospirone, trazadone, zopiclone, and zolpidem.

Typically, where the drug is a drug for erectile dysfunction, it is selected from one of the following compounds: cialis (IC351), sildenafil, vardenafil, apomorphine, apomorphine diacetate, phentolamine, and yohimbine.

Typically, where the drug is a drug for migraine headache, it is selected from one of the following compounds: almotriptan, alperopride, codeine, dihydroergotamine, ergotamine, eletriptan, frovatriptan, isometheptene, lidocaine, lisuride, metoclopramide, naratriptan, oxycodone, propoxyphene, rizatriptan, sumatriptan, tolfenamic acid, zolmitriptan, amitriptyline, atenolol, clonidine, cyproheptadine, diltiazem, doxepin, fluoxetine, lisinopril, methysergide, metoprolol, nadolol, nortriptyline, paroxetine, pizotifen, pizotyline, propanolol, protriptyline, sertraline, timolol, and verapamil.

Typically, where the drug is a drug for the treatment of alcoholism, it is selected from one of the following compounds: naloxone, naltrexone, and disulfiram.

Typically, where the drug is a drug for the treatment of addiction it is buprenorphine.

Typically, where the drug is a muscle relaxant, it is selected from one of the following compounds: baclofen, cyclobenzaprine, orphenadrine, quinine, and tizanidine.

Typically, where the drug is a nonsteroidal anti-inflammatory, it is selected from one of the following compounds: aceclofenac, alminoprofen, amfenac, aminopropylon, amixetrine, benoxaprofen, bromfenac, bufexamac, carprofen, choline, salicylate, cinchophen, cinmetacin, clopriac, clometacin, diclofenac, etodolac, indoprofen, mazipredone, meclofenamate, piroxicam, pirprofen, and tolfenamate.

Typically, where the drug is an opioid, it is selected from one of the following compounds: alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, carbiphene, cipramadol, clonitazene, codeine, dextromoramide, dextropropoxyphene, diamorphine, dihydrocodeine, diphenoxylate, dipipanone, fentanyl, hydromorphone, L-alpha acetyl methadol, lofentanil, levorphanol, meperidine, methadone, meptazinol, metopon, morphine, nalbuphine, nalorphine, oxycodone, papaveretum, pethidine, pentazocine, phenazocine, remifentanil, sufentanil, and tramadol.

Typically, where the drug is an other analgesic it is selected from one of the following compounds: apazone, benzpiperylon, benzydramine, caffeine, clonixin, ethoheptazine, flupirtine, nefopam, orphenadrine, propacetamol, and propoxyphene.

Typically, where the drug is a stimulant, it is selected from one of the following compounds: amphetamine, brucine, caffeine, dexfenfluramine, dextroamphetamine, ephedrine, fenfluramine, mazindol, methyphenidate, pemoline, phentermine, and sibutramine.

Typically, the drug has a decomposition index less than 0.15. Preferably, the drug has a decomposition index less than 0.10. More preferably, the drug has a decomposition index less than 0.05.

Typically, where the drug is an antibiotic, it is selected from one of the following compounds: cefinetazole; cefazolin; cephalexin; cefoxitin; cephacetrile; cephaloglycin; cephaloridine; cephalosporins, such as cephalosporin C; cephalotin; cephamycins, such as cephamycin A, cephamycin B, and cephamycin C; cepharin; cephradine; ampicillin; amoxicillin; hetacillin; carfecillin; carindacillin; carbenicillin; amylpenicillin; azidocillin; benzylpenicillin; clometocillin; cloxacillin; cyclacillin; methicillin; nafcillin; 2-pentenylpenicillin; penicillins, such as penicillin N, penicillin O, penicillin S, penicillin V; chlorobutin penicillin; dicloxacillin; diphenicillin; heptylpenicillin; and metampicillin.

Typically, where the drug is an anticonvulsant, it is selected from one of the following compounds: gabapentin, tiagabine, and vigabatrin.

Typically, where the drug is a drug for the treatment of alcoholism, it is selected from one of the following compounds: naloxone, naltrexone, and disulfiram.

Typically, where the drug is a drug for the treatment of addiction it is buprenorphine.

Typically, where the drug is a muscle relaxant, it is selected from one of the following compounds: baclofen, cyclobenzaprine, orphenadrine, quinine, and tizanidine.

In another method aspect of the present invention, a method of forming an aerosol for use in inhalation therapy is provided. The method involves the following steps: (a) heating a substrate-coated with a composition comprising a drug to form a vapor in less than 100 milliseconds, wherein the vapor has a mass greater than 0.1 mg; and, (b) allowing the vapor to cool, thereby forming an aerosol, which is used in inhalation therapy. Preferably, 0.25 mg, 0.5 mg, 0.75 mg, or 1 mg of the composition is vaporized in less than 100 milliseconds from the start of heating. More preferably, the same amount of composition list above is vaporized in less than 75 milliseconds, 50 milliseconds, 25 milliseconds, or 10 milliseconds from the start of heating.

Typically, the drug has a decomposition index less than 0.15. Preferably, the drug has a decomposition index less than 0.10. More preferably, the drug has a decomposition index less than 0.05.

Typically, where the drug is an anticonvulsant, it is selected from one of the following compounds: gabapentin, tiagabine, and vigabatrin.

Typically, where the drug is a drug for the treatment of alcoholism, it is selected from one of the following compounds: naloxone, naltrexone, and disulfiram.

Typically, where the drug is a drug for the treatment of addiction it is buprenorphine.

Typically, where the drug is a muscle relaxant, it is selected from one of the following compounds: baclofen, cyclobenzaprine, orphenadrine, quinine, and tizanidine.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages will become apparent from the following description of various examples of the invention, as illustrated in the accompanying drawings in which:

FIG. 1 is a schematic diagram of the overall system for conducting experiments using a laboratory example of a device of the present invention;

FIG. 2 is a top, right end and front perspective view of the example depicted in FIG. 1;

FIG. 3 is a partial cross-sectional and partial schematic side view of the example shown in FIG. 2;

FIG. 4 is a partial cross-sectional and partial schematic end view of the example shown in FIG. 2;

FIG. 5 is a partial cross-sectional and partial schematic top view of the example shown in FIG. 2;

FIG. 6 is a schematic cross-sectional side view of an alternate example of the device of the present invention using an annunciating device;

FIG. 7 is a top, left end and front perspective views of the removable sub-assembly containing the compound and a movable slide of the example shown in FIG. 2 showing the sub-assembly being mounted within the slide;

FIG. 8 is a schematic view of the heating element of the example shown in FIG. 2 showing the electric drive circuit;

FIG. 9 is a schematic side view of a second example of the present invention using a venturi tube;

FIG. 10 is a schematic side view of a fourth example of the present invention using a thin-walled tube coated with the compound;

FIG. 11 is a schematic side end view of the example shown in FIG. 10;

FIG. 12 is a schematic side end view of the example shown in FIG. 10 showing an inductive heating system generating an alternating magnetic field;

FIG. 13 is a schematic side view of an alternate example of that shown in FIG. 10 using a flow restrictor within the thin-walled tube;

FIG. 14 is a schematic side view of a fifth example of the present invention using an expandable container for the compound;

FIG. 15 is a schematic side view of a sixth example of the present invention using a container for the compound in an inert atmosphere;

FIG. 16 is a schematic side view of the example shown in FIG. 15 using a re-circulation of the inert atmosphere over the compound's surface;

FIG. 17 is a schematic side view of a seventh example of the present invention using a tube containing particles coated with the compound;

FIG. 18 is a schematic side view of the example shown in FIG. 17 using a heating system to heat the gas passing over the coated particles;

FIG. 19 is a schematic side view of an eighth example of the present invention referred to herein as the “oven device”;

FIG. 20 is a schematic side view of an ninth example of the present invention using gradient heating;

FIG. 21 is a schematic side view of a tenth example of the present invention using a fine mesh screen coated with the compound;

FIG. 22 is a top, right end and front perspective view of the example shown in FIG. 21;

FIG. 23 is a plot of the rate of aggregation of smaller particles into larger ones;

FIG. 24 is a plot of the coagulation coefficient (K) versus particle size of the compound;

FIG. 25 is a plot of vapor pressure of various compounds, e.g., diphenyl ether, hexadecane, geranyl formate and caproic acid, versus temperature;

FIG. 26 is a plot of blood levels for both the IV dose and the inhalation dose administered to various dogs during the experiments using the system shown in FIG. 1;

FIG. 27 is a plot of calculated and experimental mass median diameter (MMD) versus compound mass in the range of 10 to 310 μg;

FIG. 28 is a plot of calculated and experimental MMD versus compound mass in the range of 10 to 310 μg; and

FIG. 29 is a plot of the theoretical size (diameter) of an aerosol as a function of the ratio of the vaporized compound to the volume of the mixing gas.

DETAILED DESCRIPTION

Definitions

“Aerodynamic diameter” of a given particle refers to the diameter of a spherical droplet with a density of 1 g/mL (the density of water) that has the same settling velocity as the given particle.

“Aerosol” refers to a suspension of solid or liquid particles in a gas.

“Decomposition index” refers to a number derived from an assay described in Example 9. The number is determined by substracting the percent purity of the generated aerosol from 1.

“Drug” refers to any chemical compound that is used in the prevention, diagnosis, treatment, or cure of disease, for the relief of pain, or to control or improve any physiological or pathological disorder in humans or animals. Such compounds are oftentimes listed in the Physician's Desk Reference (Medical Economics Company, Inc. at Montvale, N.J., 56^thedition, 2002), which is herein incorporated by reference.

Exemplary drugs include the following: cannabanoid extracts from cannabis, THC, ketorolac, fentanyl, morphine, testosterone, ibuprofen, codeine, nicotine, Vitamin A, Vitamin E acetate, Vitamin E, nitroglycerin, pilocarpine, mescaline, testosterone enanthate, menthol, phencaramkde, methsuximide, eptastigmine, promethazine, procaine, retinol, lidocaine, trimeprazine, isosorbide dinitrate, timolol, methyprylon, etamiphyllin, propoxyphene, salmetrol, vitamin E succinate, methadone, oxprenolol, isoproterenol bitartrate, etaqualone, Vitamin D3, ethambutol, ritodrine, omoconazole, cocaine, lomustine, ketamine, ketoprofen, cilazaprol, propranolol, sufentanil, metaproterenol, prentoxapylline, testosterone proprionate, valproic acid, acebutolol, terbutaline, diazepam, topiramate, pentobarbital, alfentanil HCl, papaverine, nicergoline, fluconazole, zafirlukast, testosterone acetate, droperidol, atenolol, metoclopramide, enalapril, albuterol, ketotifen, isoproterenol, amiodarone HCl, zileuton, midazolam, oxycodone, cilostazol, propofol, nabilone, gabapentin, famotidine, lorezepam, naltrexone, acetaminophen, sumatriptan, bitolterol, nifedipine, Phenobarbital, phentolamine, 13-cis retinoic acid, droprenilamin HCl, amlodipine, caffeine, zopiclone, tramadol HCl, pirbuterol naloxone, meperidine HCl, trimethobenzamide, nalmefene, scopolamine, sildenafil, carbamazepine, procaterol HCl, methysergide, glutathione, olanzapine, zolpidem, levorphanol, buspirone and mixtures thereof.

Typically, where the drug is an anticonvulsant, it is selected from one of the following compounds: gabapentin, tiagabine, and vigabatrin.

Typically, where the drug is an antiemetic, it is selected from one of the following compounds: alizapride, azasetron, benzquinamide, bromopride, buclizine, chlorpromazine, cinnarizine, clebopride, cyclizine, diphenhydramine, diphenidol, dolasetron methanesulfonate, dronabinol, droperidol, granisetron, hyoscine, lorazepam, metoclopramide, metopimazine, ondansetron, perphenazine, promethazine, prochlorperazine, scopolamine, triethylperazine, trifluoperazine, triflupromazine, trimethobenzamide, tropisetron, domeridone, and palonosetron.

Typically, where the drug is a drug for the treatment of alcoholism, it is selected from one of the following compounds: naloxone, naltrexone, and disulfiram.

Typically, where the drug is a drug for the treatment of addiction it is buprenorphine.

Typically, where the drug is a muscle relaxant, it is selected from one of the following compounds: baclofen, cyclobenzaprine, orphenadrine, quinine, and tizanidine.

Typically, where the drug is a cannabanoid, it is tetrahydrocannabinol (e.g., delta-8 or delta-9).

“Drug degradation product” refers to a compound resulting from a chemical modification of a drug. The modification, for example, can be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.

“Mass median aerodynamic diameter” or “MMAD” of an aerosol refers to the aerodynamic diameter for which half the particulate mass of the aerosol is contributed by particles with an aerodynamic diameter larger than the MMAD and half by particles with an aerodynamic diameter smaller than the MMAD.

“Stable aerosol” refers to an aerosol where the MMAD of its constituent particles does not vary by more than 50% over a set period of time. For example, an aerosol with an MMAD of 100 nm is stable over 1 s, if at a time 1 second later it has an MMAD between 50 nm and 150 nm. Preferably, the MMAD does not vary by more than 25% over a set period of time. More preferably, the MMAD does not vary by more than 20%, 15%, 10% or 5% over time.

Aerosolization Device

Example 1 is described in terms of an in vivo dog experiment. The example, however, is easily modified to suit human inhalation primarily through increasing airflow through it.

Referring to FIGS. 1-8, a first example (1) of an aerosolization device of the present invention will be described. The device 1 as shown in FIG. 1 is operably connected to flow meter 4 (e.g. , a TSI 4100 flow meter). The readings from flow meter 4 are fed to the electronics within chassis 8 shown in FIG. 2. Flow meter 4 is shown in FIG. 1 within a dotted line to indicate housing 10. Device controller 20 includes Chembook model #N30W laptop computer having actuator switch 22 (FIG. 3) and National Instruments I/O Board (model #SC2345) (not shown) that interfaces with computer 20 to control device 1 and to control the recording of all data collected during the experiments. A software program to carry out these functions was developed using National Instruments' Labview software program.

Connection between device 1 and the I/O board is accomplished with a cable (e.g., DB25, not shown). A standard power supply (e.g., Condor F15-15-A+ not shown) delivers power to device 1. Inhalation controller 30 is used to control the rate and volume of inhalation through device 1 into an anesthetized dog through an endotracheal tube 34. Controller 30 has a programmable breath hold delay, at the end of which, exhaust valve 40 in exhaust line 42 opens and the dog is allowed to exhale. Filter 50 in line 42 measures the amount of exhaust and its composition to monitor any exhaled drug. The source air through inlet line 54, inlet valve 58, flow meter 4 and inlet orifice 59 is from a compressed air cylinder (not shown).

Now referring to FIGS. 3-5 and 7, a dose of compound 60 is deposited onto thin, stainless steel foil 64 so that the thickness of compound 60 is less than 10 microns. In most cases, compound 60 is deposited by making a solution of the compound with an organic solvent. This mixture is then applied to the foil substrate with an automated pump system. As shown, the size of the entire foil 64 (e.g., alloy of 302 or 304 with 0.004 in. thickness) is 0.7 by 2.9 inches and the area in which compound 60 is deposited is 0.35 by 1.6 inches. Other foil materials can be used but stainless steel has an advantage over other materials like aluminum in that it has a much lower thermal conductivity value, while not appreciably increasing the thermal mass. A low thermal conductivity is helpful because the heat generated in foil 64 should stay in the area of interest (i.e., the heating/vaporization zone 70). Foil 64 should have a constant cross section, because otherwise the electrical currents induced by the heater will not be uniform. Foil 64 is held in frame 68, made so that the trailing edge of foil 64 has no lip on movable slide 78 and so compound 60, once mixed with the air, is free in a downstream direction as indicated by arrow 127 of FIG. 3. Frame 68 is typically made of a non-conductive material to withstand moderate heat (e.g., 200° C.) and to be non-chemically reactive with the compound (e.g., DELRIN AF®, a copolymer of acetal and TEFLON®).

Sub-assembly 80, shown in FIG. 7, consists of frame 68 having compound (60) coated foil 64 mounted therein. Sub-assembly 80 is secured within movable slide 78 by setting each of the downstream, tapered ends of frame 68 to abut against small rods 86 protruding from each downstream end of slide 78, as shown in FIG. 7. Slide 78 is driven by stepper motor 88, shown in FIG. 3, that moves sub-assembly 80 containing compound 60 along the longitudinal axis of example 1. This, in turn, moves stainless steel foil 64 through an alternating magnetic field. (It is preferable for the magnetic field to be confined within heating/vaporization zone 70, shown in FIG. 5, as in this laboratory example.) Ferrite toroid 90 is used to direct the magnetic field and is placed below foil 64 (e.g., approximately 0.05 inches below). As shown in FIG. 5, heated area 70 is approximately 0.15 by 0.4 inches, with the smaller dimension along the direction of travel from left to right (i.e., from the upstream to the downstream ends of device 1) and the large dimension across the direction of travel (i.e., the width of device 1).

Foil 64 functions as both a substrate for the drug to be delivered to the subject and the heating element for the vaporization of the drug. Heating element 64 is heated primarily by eddy currents induced by an alternating magnetic field. The alternating magnetic field is produced in ferrite toroid 90 (e.g., from Fair-Rite Company) with slit 94 (e.g., 0.10 in. wide), which was wrapped with coil 98 of copper magnet wire. When an alternating current is passed through coil 98, an alternating magnetic field is produced in ferrite toroid 90. A magnetic field fills the gap formed by slit 94 and magnetic field fringe lines 100, shown in FIGS. 5 and 6, extend out from toroid 90. The magnetic field line fringe lines 100 intersect heating element 64. When using a ferrite core, the alternating frequency of the field is limited to below 1 MHz. In this device, a frequency between 100 and 300 kHz is typically used.

The location and geometry of the eddy currents determine where foil 64 will be heated. Since magnetic field fringe lines 100 pass through foil 64 twice, once leaving ferrite toroid 90 and once returning, two rings of current are produced, and in opposite directions. One of the rings is formed around magnetic field lines 100 that leave toroid 90 and the other ring forms around magnetic field lines 100 that return toroid 90. The rings of current overlap directly over the center of slit 94. Since they were in opposite directions, they sum together. The greatest heating effect is therefore produced over the center of slit 94.

Slide 78 and its contents are housed in airway 102 made up of upper airway section 104 and lower airway section 108 shown in FIG. 3. Upper airway section 104 is removable and allows the insertion of movable slide 78, sub-assembly 80 and foil 64. Lower airway section 108 is mounted on top of chassis 8 that houses the electronics (not shown), magnetic field generator 110, stepper motor 88 and position sensors (not shown). Referring again to FIG. 1, mounted in upper airway section 104 is upstream passage 120 and inlet orifice 59 that couples upper airway section 104 to flow meter 4. The readings from the flow meter 4 are fed to the electronics housed in chassis 8. Additionally, at the downstream end of airway passage 102, outlet 124 is connected to mouthpiece 126. During administration of compound 60 to the dog, when joined to the system, air is forced through inlet line 54, flow meter 4, airway 102, and outlet 124 into the dog.

Additionally, a pyrometer at the end of TC2 line 130 is located within airway 102 and is used to measure the temperature of foil 64. Because of the specific geometry of the example shown in FIGS. 1-7, the temperature reading of foil 64 is taken after heating zone 70. Calibration of the thermal decay between heating zone 70 and the measurement area is required. Temperature data is collected and used for quality control and verification and not to control any heating parameters. A second temperature sensor is located at the end of TC1 line 132 in outlet 124 and is used to monitor the temperature of the air delivered to the dog.

In a preferred example of the experimental device, removable block 140, mounted on upper airway section 104, restricts a cross-sectional area of airway 102 and provides a specific mixing geometry therein. In this preferred example, airway 140 lowers the roof of upper airway section 104 (e.g., to within 0.04 inch of) with respect to foil 64. Additionally, block 140 contains baffles (e.g., 31 steel rods 0.04 in. in diameter, not shown). The rods are oriented perpendicular to the foil and extend from the top of upper airway section 104 to within a small distance of the foil (e.g., 0.004 in.). The rods are placed in a staggered pattern and have sharp, squared off ends, which cause turbulence as air passes around them. This turbulance assures complete mixing of vaporized compounds with air passing through the device.

A second example (150) of an aerosolization device of the present invention, in which the cross-sectional area is also restricted along the gas/vapor mixing area, will be described in reference to FIG. 9. In this example, venturi tube 152 within housing 10 having inlet 154, outlet 156 includes a throat 158 between inlet 154 and outlet 156, which is used to restrict the gas flow through venturi tube 152. Additionally, a controller 160 is designed to control the flow of air passing through a valve 164 based on readings from the thermocouple 168 of the temperature of the air, which can be controlled by heater 166.

Block 140 is located directly over heating zone 70 and creates a heating/vaporization/mixing zone. Prior to commencing aerosol generation, slide 78 is in the downstream position. Slide 78, with its contents, is then drawn upstream into this heating/vaporization/mixing zone 70 as energy is applied to foil 64 through the inductive heater system described in detail below.

The device of the present invention is optionally equipped with an annunciating device. One of the many functions for the annunciating device is to alert the operator of the device that a compound is not being vaporized or is being improperly vaporized. The annunciating device can also be used to alert the operator that the gas flow rate is outside a desired range. FIG. 6 is a schematic diagram illustrating a third example of a hand held aerosolization device 180 of the present invention. As shown, device 180 includes many of the components of device 150, discussed above, and additionally includes an annunciating device 170. During the use of device 180 in which the patient's inhalation rate controls the airflow rate, a signal from annunciating device 170 would alert the patient to adjust the inhalation rate to the desired range. In this case, controller 160 would be connected to annunciating device 170 to send the necessary signal that the flow rate was not within the desired range.

The induction drive circuit 190 shown in FIG. 8 is used to drive the induction-heating element of device 1. The purpose of circuit 190 is to produce an alternating current in drive coil 98 wrapped around ferrite core 90. Circuit 190 consists of two P-channel transistors 200 and two N-channel MOSFET transistors 202 arranged in a bridge configuration. MOSFET transistors 200 and 202 connected to clock pulse generator 219 are turned on and off in pairs by D-type flip-flop 208 through MOSFET transistor drive circuit 210. D-type flip-flop 208 is wired to cause the Q output of the flip-flop to alternately change state with the rising edge of the clock generation signal. One pair of MOSFET transistors 200 is connected to the Q output on D-type flip-flop 208 and the other pair, 202, is connected to the Q-not output of flip-flop 208. When Q is high (5 Volts), a low impedance connection is made between the D.C. power supply (not shown) and the series combination of drive coil 98 and the capacitor through the pair of MOSFET transistors 200 controlled by the Q output. When D-type flip-flop 208 changes state and Q-not is high, the low impedance connection from the power supply to the series combination drive coil 98 and capacitor 220 is reversed. Since flip-flop 208 changes state on the rising edge of the clock generation signal, two flip-flop changes are required for one complete drive cycle of the induction-heating element. The clock generation signal is typically set at twice the resonant frequency of the series combination of drive coil 90 and capacitor 220. The clock signal frequency can be manually or automatically set.

A second example (150) of an aerosolization device of the present invention, in which the cross-sectional area is also restricted along the gas/vapor mixing area, will be described in reference to FIG. 9. In this example, venturi tube 152 within housing 10 having inlet 154, outlet 156 and throat 158 between inlet 154 and outlet 156 is used to restrict the gas flow through venturi tube 152. Controller 160 is designed to control the flow of air passing through valve 164 based on readings from the thermocouple 168 of the temperature of the air as a result of heater 166.

A fourth example (300) of an aerosolization device of the present invention will be described in reference to FIGS. 10 and 11. A gas stream is passed into thin walled tube 302 having a coating (310) of compound 60 on its inside. The flow rate of the gas stream is controlled by valve 314. The device of example 300, as with others, allows for rapid heat-up using a resistive heating system (320) while controlling the flow direction of vaporized compound. After activating heating system 320 with actuator 330, current is passed along tube 302 in the heating/vaporization zone 340 as the carrier gas (e.g., air, N₂and the like) is passed through tube 302 and mixes with the resulting vapor.

FIG. 12 shows an alternative heating system to resistive heating system 320 used in connection with the fourth example. In this case, inductive heating system 350 consists of a plurality of ferrites 360 for conducting the magnetic flux to vaporize compound 310.

FIG. 13 shows a variation on the fourth example in which flow restrictor 370 is mounted within thin-walled tube 302 by means of support 374 within a housing (not shown) to increase the flow of mixing gas across the surface of compound 310.

A fifth example 400 of an aerosolization device of the present invention will be described in reference to FIG. 14. For this example, compound 60 is placed within expandable container 402 (e.g., a foil pouch) and is heated by resistance heater 406, which is activated by actuator 410 as shown in FIG. 14. The vaporized compound generated is forced into container 420 through outlet passage 440 and mixed with the gas flowing through tube 404. Additional steps are taken, when necessary, to preclude or retard decomposition of compound 60. One such step is the removal or reduction of oxygen around 60 during the heat up period. This can be accomplished, for example, by sealing-the small container housing in an inert atmosphere.

A sixth example 500 of an aerosolization device of the present invention will be described in reference to FIG. 15. Compound 60 is placed in an inert atmosphere or under a vacuum in container 502 within housing 10 and is heated by resistance heater 504 upon being activated by actuator 508 as shown in FIG. 15. Once compound 60 has become vaporized it can then be ejected through outlet passage 510 into the air stream passing through tube 520.

FIG. 16 shows a variation of device 500 in which fan 530 recirculates the inert atmosphere over the surface of compound 60. The inert gas from a compressed gas cylinder (not shown) enters through inlet 540 and one-way valve 550 and exits through outlet passage 510 into tube 502.

A seventh example (600) of an aerosolization device of the present invention will be described in reference to FIG. 17. A compound (not shown), such as compound 60 discussed above, is deposited onto a substrate in the form of discrete particles 602 (e.g., aluminum oxide (alumina), silica, coated silica, carbon, graphite, diatomaceous earth, and other packing materials commonly used in gas chromatography). The coated particles are placed within first tube 604, sandwiched between filters 606 and 608, and heated by resistance heater 610, which is activated by actuator 620. The resulting vapor from tube 604 is combined with the air or other gas passing through second tube 625.

FIG. 18 shows a variation of device 600 in which resistance heater 630 heats the air prior to passing through first tube 604 and over discrete particles 602.

An eighth example 700 of an aerosolization device of the present invention will be described in reference to FIG. 19. Compound 60 is deposited into chamber 710 and is heated by resistance heater 715, which is activated by actuator 720. Upon heating, some of compound 60 is vaporized and ejected from chamber 710 by passing an inert gas entering housing 10 through inert gas inlet 725 and valve 728 across the surface of the compound. The mixture of inert gas and vaporized compound passes through passage 730 and is then mixed with a gas passing through tube 735.

A ninth example 800 of an aerosolization device of the present invention will be described in reference to FIG. 20. Thermally conductive substrate 802 is heated by resistance heater 810 at the upstream end of tube 820, and the thermal energy is allowed to travel along substrate 802. This produces, when observed in a particular location, a heat up rate that is determined from the characteristics of the thermally conductive substrate. By varying the material and its cross sectional area, it was possible to control the rate of heat up. The resistive heater is embedded in substrate 802 at one end. However, it could be embedded into both ends, or in a variety of positions along the substrate and still allow the temperature gradient to move along the carrier and/or substrate.

A tenth example 900 of an aerosolization device of the present invention will be described in reference to FIGS. 21 and 22. Air is channeled through a fine mesh metal screen 902 on which drug is deposited. Screen 902 is positioned across airway passage 910 (e.g., constructed from 18 mm glass tubing). The two sides of the screen are electrically connected to charged capacitor 920 through silicon-controlled rectifier (SCR) 922 to make a circuit. The charge of the capacitor is calculated and set at a value such that, when actuator 930 closes SCR 922, the energy from capacitor 920 is converted to a desired temperature rise in screen 902.

General Considerations

The device of the present invention utilizes a flow of gas (e.g., air) across the surface of a compound (60) to sweep away vaporized molecules. This process drives vaporization as opposed to condensation and therefore enables aerosol formation at relatively moderate temperatures. Nicotine (1 mg, bp 247° C./745 mm), for example, vaporized in less than 2 s at about 130° C. in a device of the present invention. Similarly, fentanyl (bp>300° C./760 mm) was vaporized around 190° C. in quantities up to 2 mg.

Purity of an aerosol produced using a device of the present invention is enhanced by limiting the time at which a compound (60) is exposed to elevated temperatures. This is accomplished by rapidly heating a thin film of the compound to vaporize it. The vapors are then immediately cooled upon entry into a carrier gas stream.

Typically, compound 60 is subjected to a temperature rise of at least 1,000° C./second. In certain cases, the compound is subjected to a temperature rise of at least 2,000° C./second, 5,000° C./second, 7,500° C. or 10,000° C./second. A rapid temperature rise within the compound is facilitated when it is coated as a thin film (e.g., less than 10 μm, 5 μm, 4 μm, 3 μm, 2 μm, or 1 μm in thickness). The compound is oftentimes coated as a film between 10 μm and 10 nm, 5 μm and 10 nm, 4 μm and 10 nm, 3 μm and 10 nm, 2 μm and 10 nm, or even 1 μm to 10 nm in thickness.

Rapid temperature rises and thin coatings ensure that compounds are substantially vaporized in a short time. Typically, greater than 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg or 1 mg of a compound is vaporized in less than 100 milliseconds from the start of heating. Oftentimes, the same amount of compound is vaporized in less than 75 milliseconds, 50 milliseconds, 25 milliseconds, or 10 milliseconds from the start of heating.

Examples of compounds that have benefited from rapid heating in a device of the present invention include lipophilic substance #87 and fentanyl. Lipophilic substance #87 decomposed by more than 90% when heated at 425° C. for 5 minutes, but only 20% when the temperature was lowered to 350° C. Decomposition of the substance was further lowered to about 12% when the heating time was decreased to 30 seconds and to less than 2% at 10-50 milliseconds. A fentanyl sample decomposed entirely when heated to 200° C. for 30 seconds, and only 15-30% decomposed when heated for 10 milliseconds. Vaporizing fentanyl in device 1 led to less than 0.1% decomposition.

FIG. 23 is a plot of theoretical data calculated from a mathematical model. See “Aerosol Technology” W. C. Hinds, second edition 1999, Wiley, New York. It shows the time in seconds it takes for the number concentration of an aerosol to aggregate to half of its original value as a function of the particle concentration. For example, a 1.0 mg vaporized dose of a compound with a molecular weight of 200 that is mixed into 1 liter of aire will have approximately 3×10¹⁸molecules (particles)-in the liter. This results in a number concentration of 3×10¹⁵/cc. Extrapolating from FIG. 23, one can see that it takes less than 10 milliseconds for the number of particles to halve in this example. Therefore, to insure uniform mixing of a vaporized compound, the mixing must occur in a very short time. FIG. 23 also shows that when the number concentration of the mixture reaches approximately 10⁹particles/cc, the particle size is “stable” for the purpose of drug delivery by inhalation.

FIG. 23 is for an aerosol having a Coagulation Coefficient (K) of 5×10⁻¹⁶meters³/second. This K value corresponds to a particle size of 200 nm. As the particle size changes, so can its K value. Table 1 below gives the K values for various particle sizes. As K increases, the time required for the aerosol to aggregate from a particular particle size to a larger particle size is reduced. As can be seen from Table 1 and FIG. 24, when the particle is in the 10 nm to 100 nm range, the effect of a changing K value tends to accelerate the coagulation process towards 100 nm in size.

TABLE 1

Coagulation Coefficient (× e⁻¹⁵

Particle size (diameter in nm)
meters³/second)

1
3.11

5
6.93

10
9.48

20
11.50

50
9.92

100
7.17

200
5.09

500
3.76

1000
3.35

2000
3.15

5000
3.04

10000
3.00

In creating an aerosol of a particular particle size, the ratio of mass of vaporized compound to the volume of the mixing gas is the controlling condition. By changing this ratio, the particle size can be manipulated (see FIG. 29). However, not all compounds and not all gases, with the same ratio will result in the same particle size distribution (PSD). Other factors must be known to be able to accurately predict the resultant particle size. A compound's density, polarity, and temperature are examples of some of these factors. Additionally, whether the compound is hydrophilic or hydrophobic will affect the eventual particle size, because this factor affects an aerosol's tendency to grow by taking on water from the surrounding environment.

In order to simplify the approach used to predict the resulting particle size, the following assumptions were made:

1. The compound is non polar (or has a weak polarity).

2. The compound is hydrophobic or hydrophilic with a mixing gas that is dry.

3. The resultant aerosol is at or close to standard temperature and pressure.

4. The coagulation coefficient is constant over the particle size range and therefore the number concentration that predicts the stability of the particle size is constant.

Consequently, the following variables are taken into consideration in predicting the resulting particle size:

1. The amount (in grams) of compound vaporized.

2. The volume of gas (in cc's) that the vaporized compound is mixed into.

3. The “stable” number concentration in number of particles/cc.

4. The geometric standard deviation (GSD) of the aerosol.

Where the GSD is 1, all of the particle sizes are the same size and therefore the calculation of particle size becomes a matter of dividing a compound's mass into the number of particles given by the number concentration and from there calculating the particle size diameter using the density of the compound. The problem becomes different, though, if the GSD is other than 1. As an aerosol changes from a GSD of 1 to a GSD of 1.35, the mass median diameter (MMD) will increase. MMD is the point of equilibrium where an equal mass of material exists in smaller diameter particles as exists in larger diameter particles. Since total mass is not changing as the GSD changes, and since there are large and small particles, the MMD must become larger as the GSD increases because the mass of a particle goes up as the cube of its diameter. Therefore larger particles, in effect, carry more weight and the MMD becomes larger to “balance” out the masses.

To determine the effect of a changing GSD, one can start with the formula for the mass per unit volume of an aerosol given a known MMD, GSD, density, and number concentration. The formula is from Finlay's “The Mechanics of Inhaled Pharmaceutical Aerosols” (2001, Academic press). Formula 2.39 states that the mass per unit volume of an aerosol is:

M=(ρNπ/6)(MMD)³exp[−9/2(lnσ_g)²]

Where:

- ρ=density in gm/cc
- N=Number concentration in particles/cc
- MMD=mass median diameter (in cm)
- σ_g=the GSD
- M=the mass per unit volume of the aerosol in gms/cc

If the change in the MMD is considered as an aerosol changes from one GSD to another, while the density, number concentration, and the mass remain unchanged the following equality can be set up:

ρNπ/6(MMD₁)³exp[−9/2(lnσ_g1)²]=ρNπ/6(MMD₂)³exp[−9/2(lnσ_g2)²]

simplifying:

(MMD₁)³exp[−9/2(lnσ_g1)²]=(MMD₂)³exp[−9/2(lnσ_g2)²]

Or

(MMD₁)³/(MMD₂)³=exp[−9/2(lnσ_g2)²]/exp[−9/2(lnσ_g1)²]

If one sets the GSD of case 1 to 1.0 then:

exp[−9/2(lnσ_g1)²=1

And therefore:

(MMD₁/MMD₂)³=exp[−9/2(lnσ_g2)²]

Or:

MMD₁/MMD₂=exp[−3/2(lnσ_g2)²]

It is advantageous to calculate the change in the MMD as the GSD changes. Solving for MMD₂as a function of MMD₁and the new GSD₂yields:

MMD₂=MMD₁/exp[−3/2(lnσ_g2)²] for a σ_g1=1

To calculate MMD₁, divide the compound's mass into the number of particles and then, calculate its diameter using the density of the compound.

MMD₁=(6C/ρNV)^1/3for an aerosol with a GSD of 1

Where:

- C=the mass of the compound in gm's
- ρ=Density in gm/cc (as before)
- N=Number concentration in particles /cc (as before)
- V=volume of the mixing gas in cc

Insertion of MMD₁into the above equation leads to:

MMD₂=(6C/ρNVπ)^1/3/[exp[−3/2(lnσ_g2)²], measured in centimeters.

A resultant MMD can be calculated from the number concentration, the mass of the compound, the compound density, the volume of the mixing gas, and the GSD of the aerosol.

The required vaporization rate depends on the particle size one wishes to create. If the particle size is in the 10 nm to 100 nm range, then the compound, once vaporized, must be mixed, in most cases, into the largest possible volume of air. This volume of air is determined from lung physiology and can be assumed to have a reasonable upper limit of 2 liters. If the volume of air is limited to below 2 liters (e.g., 500 cc), too large a particle will result unless the dose is exceedingly small (e.g., less than 50 μg).

In the 10 nm to 100 mm range, doses of 1-2 mg are possible. If this dose is mixed into 2 liters of air, which will be inhaled in 1-2 seconds, the required, desired vaporization rate is in the range of about 0.5 to about 2 mg/second.

The first example of the present invention is shown in FIG. 1 and is the basic device through which the principles cited above have been demonstrated in the laboratory. This device is described in detail in the EXAMPLES.

In the second example of the present invention shown in FIG. 9, the use of a reduced airway cross section increases the speed of the air across the compound's surface to about 10 meters/second. If complete mixing is to happen within 1 millisecond, then the distance the gas and vaporized mixture must travel to achieve complete mixing must be no longer than 10 millimeters. However, it is more desirable for complete mixing to happen before the compound has aggregated to a larger size, so a desirable mixing distance is typically about 1 millimeter or less.

In the fourth example of the present invention shown in FIGS. 10-13, an aerosol having particles with an MMAD in the 10 nm to 100 nm range is generated by allowing air to sweep over a thin film of the compound during the heating process. This allows the compound to become vaporized at a lower temperature due to the lowering of the partial pressure of the compound near the surface of the film.

The fifth example shown in FIG. 14, the sixth example shown in FIGS. 15 and 16, and the eighth example shown in FIG. 19 overcome a problem with certain compounds that react rapidly with oxygen at elevated temperatures. To solve this problem, the compound is heated in an expandable container (fourth example), a small container housing under a vacuum or containing a small amount, e.g., about 1 to about 10 ml, of an inert gas (fifth example). Once a compound is vaporized and mixed with an inert gas while the gaseous mixture is maintained at a temperature sufficient to keep the compound in its vaporized state, the gaseous mixture is then injected into an air stream. The volume of inert gas can also be re-circulated over the surface of the heated compound to aid in its vaporization as shown in FIG. 16. In the seventh example, the compound is introduced into the gas as a pure vapor. This involves vaporizing the compound in an oven or other container and then injecting the vapor into an air or other gas stream through one or more mixing nozzles.

In the sixth example shown in FIGS. 17-18, gas is passed through a first tube and over discrete substrate particles, having a large surface area to mass ratio, and coated with the compound. The particles are heated as shown in FIG. 17 to vaporize the compound, or the gas is heated and the heated gas vaporizes the compound as shown in FIG. 18. The gaseous mixture from the first tube is combined with the gas passing through second tube to rapidly cool the mixture before administering it to a patient.

The eighth example shown in FIG. 20 is a thermal gradient device that is similar to device 1 used in the laboratory experiments. This example also has a moving heating zone without any moving parts, accomplished by establishing a heat gradient that transverses from one end of the device to the other over time. As the heating zone moves, exposed portions of the compound are sequentially heated and vaporized. In this manner the vaporized compound can be introduced into a gas stream over time.

The ninth example shown in FIGS. 21-22 is the screen device and is preferred for generating a aerosols containing particles with an MMAD greater than 100 nm. In this example, air is channeled through a fine mesh screen upon which the drug to be administered to the patient has been deposited.

The examples above can create aerosols without significant drug decomposition. This is accomplished while maintaining a required vaporization rate for particle size control by employing a short duration heating cycle. An airflow over the surface of the compound is established such that when the compound is heated and reaches the temperature where vaporization is first possible, the resulting compound vapors will immediately cool in the air. In the preferred examples, this is accomplished by extending the increased velocity and mixing region over an area that is larger than the heating zone region. As a result, precise control of temperature is not necessary since the compound vaporizes the instant its vaporization temperature is reached. Additionally because mixing is also present at the point of vaporization, cooling is accomplished quickly upon vaporization.

Application of the present invention to human inhalation drug delivery must accommodate constraints of the human body and breathing physiology. Many studies of particle deposition in the lung have been conducted in the fields of public health, environmental toxicology and radiation safety. Most of the models and the in vivo data collected from those studies, relate to the exposure of people to aerosols homogeneously distributed in the air that they breathe, where the subject does nothing actively to minimize or maximize particle deposition in the lung. The International Commission On Radiological Protection (ICRP) models are examples of this. (See James AC, Stahlhofen W, Rudolph G, Egan M J, Nixon W, Gehr P, Briant J K, The respiratory tract deposition model proposed by the ICRP Task Group, Radiation Protection Dosimetry, 1991; vol. 38: pgs. 157-168).

However, in the field of aerosol drug delivery, a patient is directed to breathe in a way that maximizes deposition of the drug in the lung. This kind of breathing usually involves a full exhalation, followed by a deep inhalation sometimes at a prescribed inhalation flow rate range, e.g., about 10 to about 150 liters/minute, followed by a breath hold of several seconds. In addition, ideally, the aerosol is not uniformly distributed in the air being inhaled, but is loaded into the early part of the breath as a bolus of aerosol, followed by a volume of clean air so that the aerosol is drawn into the alveoli and flushed out of the conductive airways, bronchi and trachea by the volume of clean air that follows. A typical deep adult human breath has a volume of about 2 to 5 liters. In order to ensure consistent delivery in the whole population of adult patients, delivery of the drug bolus should be completed in the first 1-1½ liters or so of inhaled air.

As a result of the constraints of human inhalation drug delivery, a compound should be vaporized in a minimum amount of time, preferably no greater than 1 to 2 seconds. As discussed earlier, it is also advantageous, to keep the temperature of vaporization at a minimum. In order for a compound to be vaporized in 2 seconds or less and for the temperature to be kept at a minimum, rapid air movement, in the range of about 10 to about 120 liters/minute, should flow across the surface of the compound.

The following parameters are optimal in using a device of the present invention, due to human lung physiology, the physics of particle growth, and the physical chemistry of the desirable compounds:

(1) The compound should to be vaporized over approximately 1 to 2 seconds for creation of particles in the ultra fine range.

(2) The compound should to be raised to the vaporization temperature as rapidly as possible.

(3) The compound, once vaporized, should be cooled as quickly as possible.

(4) The compound should be raised to the maximum temperature for a minimum duration of time to minimize decomposition.

(5) The air or other gas should be moved rapidly across the surface of the compound to achieve the maximum rate of vaporization.

(6) The heating of the air or other gas should be kept to a minimum, i.e., an increase of temperature of no greater than about 15° C. above ambient.

(7) The compound should be mixed into the air or other gas at a consistent

(8) As the gas speed increases across the compound being vaporized, the cross sectional area through the device should decrease. Furthermore, as the surface area of the compound increases the heating of the gas increases.

The parameters of the design for one of the examples shown in FIGS. 2-5, 7 and 8 are the result of meeting and balancing the competing requirements listed above. One especially important requirement for an aerosol containing particles with an MMAD between 10 nm and 100 nm is that a compound, while needing to be vaporized within at least a 1-second period, also needs to have each portion of the compound exposed to a heat-up period that is as brief as possible. In this example, the compound is deposited onto a foil substrate and an alternating magnetic field is swept along a foil substrate heating the substrate such that the compound is vaporized sequentially over no more than about a one second period of time. Because of the sweeping action of the magnetic field, each segment of the compound has a heat-up time that is much less than one second.

In the example noted directly above, the compound is laid down on a thin metallic foil. In one of the examples set forth below, stainless steel (alloy of 302, 304, or 316) was used in which the surface was treated to produce a rough texture. Other foil materials can be used, but it is important that the surface and texture of the material is such that it is “wetted” by the compound when the compound is in its liquid phase, otherwise it is possible for the liquid compound to “ball” up which would defeat the design of the device and significantly change the volatilizing parameters. If the liquid compound “balls” up, the compound can be blown into and picked up by the airflow without ever vaporizing. This leads to delivery of a particle size that is uncontrolled and undesirable.

Stainless steel has advantages over materials like aluminum because it has a lower thermal conductivity value, without an appreciable increase in thermal mass. Low thermal conductivity is helpful because heat generated by the process needs to remain in the immediate area of interest.

EXAMPLES

The following examples further illustrate the method and various examples of the present invention. These examples are for illustrative purposes and are not meant to limit the scope of the claims in any way.

Example 1
In vivo Results Using Example 1

In this example, example 1, was designed to deliver an experimental dose of fentanyl between 20 μg and 500 μg, in a range of ultra fine particle sizes, in about 800 cc of air to a 10 kg dog. The lung volume of each dog under experimentation was approximately 600-700 cc and the device was designed to deliver the compound to the lung in the first half of the inhalation. Because of the value of these parameters, device 1 in this experiment can be considered a ¼ scale device for administering a dose to a human. It is believed that scaling the device to work for human subjects involves mainly increasing the airflow through the device. The time frame of the introduction of the compound into the heating/vaporization/mixing zone was set such that the compound vaporized into a volume of air that was suitable for both the volume required by dog lung anatomy (600-700 cc) and the volume needed to control the ratio of the compound to the air.

The following was the sequence of events that took place during each operation:

1. At the beginning of the run, the operator triggered inhalation controller 30 to start monitoring data from pressure transducer 240 and input flow meter 4.

2. Controller 30 signaled controller 20 to start example 1 and to begin collecting data from the two temperature sensors and flow meter 4.

3. After a pre-programmed delay, example 1 initiated the generation of the aerosol. (Note: there was a delay of about 0.4 seconds between the start of the controller 30 and the start of aerosol generation.)

4. After an independent preprogrammed delay (from original trigger signal), controller 30 opened input valve 58 to start forced inhalation to a dog under experimentation.

5. Example 1 completed the aerosol generation during the inhalation.

6. Controller 30 monitored flow meter 4 and pressure transducer 240 throughout the inhalation and closed off flow at input valve 58 when a pre-specified volume or pressure was met. (Note: the pre-specified pressure is a safety feature to prevent injury to the subject animal. Termination of the breath at the pre-specified volume is the desirable occurrence of the experiment.)

7. After a breath hold delay (5 seconds), exhaust valve 40 was opened and the dog was allowed to exhale.

8. Exhaled aerosol was trapped on exhaust filter 40 for later analysis. Controller 30 recorded values for the following: volume dispensed, terminal pressure, duration of air pulse, and average flow rate. Controller 20 continuously recorded at millisecond resolution, input flow rate, exhaust flow rate, foil temperature, mouthpiece temperature, slide position, heater on/off time, and other internal diagnostic electrical parameters.

Three weight-matched female beagle dogs received fentanyl at a 100 μg intravenous bolus dose. The same dogs received fentanyl UF for Inhalation (100 μg aerosolized and administered as two successive activations of device 1, containing approximately 50 μg fentanyl base) at a particle size of 80 nm (MMAD). The aerosol was administered to anesthetized dogs via the system schematically represented in FIG. 1, with a target delivered volume of 600-700 ml air, followed by a 5 second breath hold. After dosing, plasma samples for pharmacokinetic analysis were obtained at various time points from 2 min to 24 hr. Fentanyl remaining in device 1 was recovered and measured. Fentanyl concentrations were measured by using a validated GC method, with a limit of detection of 0.2 ng/ml.

Plasma pharmacokinetics from this example were compared to intravenous (IV) fentanyl (100 μg) in the same dogs. Inhalation of fentanyl resulted in rapid absorption (C_max, maximum concentration in plasma, 11.6 ng/ml and T_max, maximum time, 2 min.) and high bioavailability (84%). The time course of inhaled fentanyl was nearly identical to that of IV fentanyl. Thus, fentanyl UF for inhalation had an exposure profile that was similar to that of an IV injection.

Standard non-compartmental pharmacokinetic methods were used to calculate pharmacokinetic parameters for each animal. The maximum concentration in plasma (C_max) and the maximum time it occurred (T_max) were determined by examination of the data. The area under the plasma concentration vs. time curve (AUC) was determined. The bioavailability (F) of inhaled fentanyl was determined as:

F=(DIV/DINHAL)*(AUCINHAL/AUCIV)

where D was the dose and AUC was the AUC determined to the last measurable time point.

FIG. 26 plots the data obtained on the blood levels, by dog, for both the IV doses and the inhalation doses using device 1 as described above under Example 1.

The fentanyl aerosol was rapidly absorbed, with the same T_max(2 min, the earliest time point) observed for both routes of administration. The maximum plasma concentration of fentanyl aerosol (11.6±1.9 ng/ml) was nearly two-thirds that of IV fentanyl (17.6±3.6 ng/ml). Plasma concentrations fell below the assay limit of quantitation by 6-8 hr after IV administration and by 3-4 hr after aerosol inhalation. Bioavailability calculations were based on the AUC's observed to the last measurable time point for the inhalation administration. Bioavailability for the inhalation study was 84% based on the nominal (uncorrected) fentanyl dose.

The mean plasma elimination half-life was similar after IV (75.4 min) and inhalation dose. Distribution phase half-lives (3-4 min) were also similar after both routes of administration. The inter-animal variability of pharmacokinetic parameters after the inhalation dose was low, with relative standard deviations (RSD <25%) lower than those observed for IV administration.

Example 2
In vitro Results Using Example 1

Table 2 below summarizes the data collected from use of example 1 for in vitro testing of fentanyl. Particle size was measured with a Moudi cascade impactor.

TABLE 2

Compound Mass (ug)
Mixing air volume (cc)
MMAD (nm)
GSD

20
400
71
1.9

25
400
72-78
1.7-1.8

50
400
77-88
1.7-185

100
400
100-105
1.4-1.8

200
400
103-123
1.6-1.9

300
400
140-160
1.8-2.1

Example 3
Use of Example 1 to Make Fine Aerosol Particles

In this example, example 1 was slightly modified and the flow rate changed, as discussed below, to make a fine aerosol in the 1 to 3 micron particle size range.

Airway section 140 was removed and the air channel heating/vaporization zone 70 was changed. An airway insert (not shown) had a “roof” that was 0.25 inches above the foil. There were no mixing rods as rapid mixing was not desirable in this example. Because of these two device changes, there was much less mixing with the air, thus the vapor/aerosol cloud was mixed with less air and produced a larger particle size aerosol. The airflow rate was reduced 1 liter/minute in this example. Again, this allowed the vapor to be mixed with much less air, resulting in the larger particle size aerosol.

Some operational problems with high compound loading on foil 64 in example 1 were encountered. The compound tested, dioctyl phthalate (DOP), was an oil and during the aerosolization process, a substantial quantity was blown downwind and not aerosolized. Three additional design alternatives were made to address this issue, involving changes to the substrate surface that the compound was deposited on. In the three alternatives, the substrate was made to “hold” the compound through the use of texture They were: a) texturing the foil; b) adding a stainless steel screen on top of the foil; and, c) replacing the foil with a fine stainless steel screen.

The results from this example are set forth below in Table 3 below:

TABLE 3

Substrate Type
MMAD, microns
GSD
Emitted Dose, ug

Textured foil
1.49 microns
1.9
97

Textured foil
2.70 microns
1.95
824

Fine screen alone
1.59 microns
1.8
441

Fine screen alone
1.66 microns
1.8
530

Screen on Foil
2.42 microns
2.2
482

As shown above, a fine particle size can be made with device 1 merely by changing the ratio of the compound to the mixing air.

Example 4
In vitro Results Using Example 700

A tank was partially filled with DOP and placed inside an oven (not shown) having an inlet and an outlet. DOP was used as the test compound. The tank was purged with helium prior to heating the tank and its contents to a temperature of 350° C. Helium was pumped through the tank and used to carry the DOP vapor out of the outlet. The gaseous mixture of helium and vaporized compound 60 was introduced into different size mixing tubes through a nozzle. Each of the tubes bad air moving through them at 14 liters/minute. The nozzle was perpendicular to the flow direction. After this gaseous mixture was mixed with the air, the resulting aerosol was introduced into a parallel flow diffusion battery for particle size analysis. Results are set forth in Table 4 below.

TABLE 4

Mixing tube size (ID)
MMAD
GSD

4.8 mm
65 nm
1.3

14 mm
516 nm
3.3

As can be seen above, as the tube diameter became larger so did the particle size. Additionally, as the diameter became larger, the GSD also became larger. As the tube becomes larger, it is believed that the vaporized gas is introduced into a smaller segment of the mixing gas because the gas is being introduced as a point source leading to uneven mixing, which results in a large GSD.

Example 5
In vitro Results Using Example 800

To demonstrate effectiveness of example 800, a 4-inch long piece of aluminum was fitted with a 150-watt cartridge heater at one end. The heater was powered with a variac AC power transformer. The thickness of the aluminum was designed to ensure that heat would transverse from one end of the aluminum to the other in approximately 30 seconds.

On the topside of the aluminum, an indentation was machined to hold the compound and to hold one of two top covers. The indentation for the compound was approximately 3.5 inches long and 0.4 inches wide. The indentation was 0.025 inches deep, and was filled with 1 mg of DOP.

The first top consisted of a sheet of flat glass placed 0.04 inches above the heated surface, creating an airway. At the exit end an outlet was fitted allowing the air to be drawn into an analytical measurement device. Air was made to flow through the airway at a rate of 15 liters/minute.

In the second configuration, the top was replaced with a half cylinder made of glass. This increased the cross sectional area of the airway by an order of magnitude.

Particle size was measured with both configurations and shown to be affected by the cross sectional area of the airway.

Results from the thermal gradient test are set forth in Table 5 below:

TABLE 5

Cover size and

cross-section
MMAD
GSD

Small
92 nm
1.4

Big
650 nm
unknown

As shown above, the results confirm that as the cross section becomes larger, so does the particle size.

Example 6
In vitro Results Using Example 900

In this example for producing aerosols, airway passage 910 was constructed from 18 mm diameter glass tubing. However, the passage can be made in any shape with a comparable cross-sectional area and out of any suitable material. The screen size, mesh, and the amount of compound were chosen in this example so that a gas could pass through the screen without interference once the compound had been deposited on it.

Because the internal resistance of the screen was low, i.e., between 0.01 and 0.2 ohms, the discharge rate (the RC time constant) of the capacitor was rapid, and on the order of a few milliseconds, i.e. less than 20 milliseconds, preferably in the range of about 2 to about 10 milliseconds. Upon discharge of capacitor 902 and the subsequent heating of screen 902, the deposited compound was rapidly vaporized. Because air moved through screen 902, the vaporized compound rapidly mixed with air and cooled.

The compound was deposited onto the fine stainless steel screen, e.g., 200 mesh, made from 316 stainless steel, having measurements of 2.54 cm.×2.54 cm. The current from the capacitor was passed between one edge and another. It was not necessary to heat the screen to temperatures comparable to the thin foil in Example 1, because the compound vaporized at a lower temperature due to the rapid air movement. Rapid air movement allowed the compound to vaporize at a lower vapor pressure, since airflow constantly removed compound vapors from the surface as soon as they were formed. Thus, the compound vaporized at a lower temperature without decomposition.

Deposition of the compound onto the screen was accomplished by mixing the compound with an organic solvent until the compound dissolved. The resulting solution was then applied to the fine stainless steel screen 902 and the solvent was allowed to evaporate. The screen was then inserted into holder 940 that electrically connected two sides of screen 902 to the power circuit described above.

A 10,000 mF capacitor was discharged while the gas was passing through screen 902. The rapid heat up of the screen resulted in a rapid vaporization of the compound into the gas. Thus the resulting vaporized compound was mixed into a small volume of the gas. Because the ratio of the mass of the compound to the volume of the mixing gas was large, a fine (1-3 micron diameter) particle aerosol was made.

Example 7
Flash Device for Forming Aerosols

A high-power flashcube (GE or Sylvania), which can produce 300-400 J of energy, was inserted into an anodized aluminum tube. The flashcube/tube assembly was dipped into an organic solution containing a drug and quickly removed. Evaporation of residual solvent from the assembly was performed by placing it into a vacuum chamber for 30 min. This left a film of drug coated on the exterior surface of the aluminum tube. The flashbulb assembly was electrically connected to two 1.5 V batteries and a switch using copper wires and then enclosed in a sealed, glass vial. Ignition of the flashbulb was performed by momentarily turning on the switch between the flashbulb and batteries. After ignition, the vial was kept closed for 30 minutes such that particles of volatilized drug coagulated and condensed on the inside surface of the vial. Analysis of the aerosol involved rinsing the vial with 5 mL of acetonitrile and injecting a sample of the organic solution into an HPLC.

Measurement with a fast thermocouple indicated that the aluminum tube heated up to 600° C. in 50 milliseconds. This translates into a heating rate of 12,000°/s.

One of ordinary skill in the art would understand that the experimental device detailed above could be transformed into an inhalation delivery device by excluding the sealed vial and including a housing to contain the assembly and electrical components. The housing would contain an air inlet and a mouthpiece such that, when drug volatilization occurred, an inhaled breath would carry the formed aerosol into the lungs of a subject.

Example 8
Relationship Between Film Thickness and Aerosol Purity

Sildenafil was dissolved in a minimal amount of dichloromethane. The resulting solution was coated onto a piece of pure aluminum foil, and the residual solvent was allowed to evaporate. The coated foil was placed on an aluminum block that had been preheated to 275° using a hot plate. A pyrex beaker was synchronously placed over the foil, and the coated material was allowed to vaporize for 1 min. The beaker was removed, and the adsorbed aerosol was extracted using dichloromethane. HPLC analysis (250 nm) of an aliquot of the extract provided purity data for the aerosol. Using this procedure the following data were obtained: 3.4 μm thickness, 84.8% purity; 3.3 μm thickness 80.1% purity; 1.6 μm thickness, 89.8% purity; 0.8 μm thickness, 93.8% purity; 0.78 μm thickness, 91.6% purity; 0.36 μm thickness, 98.0% purity; 0.34 μm thickness, 98.6% purity; 0.29 μm thickness, 97.6% purity; and, 0.1 μm, 100% purity.

Example 9
General Procedure for Screening Drugs to Determine Aerosolization Preferability

Drug (1 mg) is dissolved or suspended in a minimal amount of solvent (e.g., dichloromethane or methanol). The solution or suspension is pipeted onto the middle portion of a 3 cm by 3 cm piece of aluminum foil. The coated foil is wrapped around the end of a 1½ cm diameter vial and secured with parafilm. A hot plate is preheated to approximately 300° C., and the vial is placed on it foil side down. The vial is left on the hotplate for 10 s after volatilization or decomposition has begun. After removal from the hotplate, the vial is allowed to cool to room temperature. The foil is removed, and the vial is extracted with dichloromethane followed by saturated aqueous NaHCO₃. The organic and aqueous extracts are shaken together, separated, and the organic extract is dried over Na₂SO₄. An aliquot of the organic solution is removed and injected into a reverse-phase HPLC with detection by absorption of 225 nm light. A drug is preferred for aerosolization where the purity of the drug isolated by this method is greater than 85%. Such a drug has a decomposition index less than 0.15. The decomposition index is arrived at by subtracting the percent purity (i.e., 0.85) from 1.

One of ordinary skill in the art can combine the foregoing embodiments or make various other embodiments and aspects of the method and device of the present invention to adapt them to specific usages and conditions. As such, these changes and modifications are properly, equitably, and intended to be, within the full range of equivalents of the following claims.

Claims

1. A method of forming an aerosol for use in inhalation therapy comprising: (a) heating a substrate coated with a composition comprising a drug for a period of time, thereby forming a vapor, wherein the period is less than 500 milliseconds and wherein the increase in temperature of the substrate over the period is greater than 1000° C./s; and(b) allowing the vapor to cool, thereby forming an aerosol comprising the drug.
2. The method according to claim 1, wherein the increase in temperature of the substrate over the period is greater than 2000° C./s.
3. The method according to claim 1, wherein greater than 0.1 mg of the composition is vaporized in less than 100 milliseconds from the start of heating.
4. The method according to claim 1, wherein the increase in temperature of the substrate over the period is greater than 5,000° C./s.
5. The method according to claim 4, wherein greater than 0.25 mg of the composition is vaporized in less than 100 milliseconds from the start of heating.
6. The method according to claim 5, wherein the increase in temperature of the substrate over the period is greater than 7,500° C./s.
7. A method of forming an aerosol for use in inhalation therapy comprising: (a) heating a substrate coated with a composition comprising a drug to form a vapor in a period of time less than 100 milliseconds, wherein the vapor has a mass greater than 0.1 mg; and(b) allowing the vapor to cool, thereby forming an aerosol comprising the drug.
8. The method according to claim 7, wherein the vapor has a mass greater than 0.25 mg.
9. The method according to claim 7, wherein the vapor is formed in less than 75 milliseconds.
10. The method according to claim 8, wherein the vapor has a mass greater than 0.5 mg.
11. The method according to claim 9, wherein the period of time is less than 50 milliseconds.
12. The method according to claim 3, wherein the formed aerosol is greater than 80 percent by weight of the drug.
13. The method according to claim 3, wherein the formed aerosol contains less than 5 percent by weight of drug decomposition products.
14. The method according to claim 3, wherein the formed aerosol is stable over 1 second.
15. The method according to claim 3, wherein the formed aerosol has an MMAD in the 10 nm to 100 nm range.
16. The method according to claim 3, wherein the formed aerosol has an MMAD in the 1 μm to 3 μm range.
17. The method according to claim 3, wherein the geometric standard deviation of the form aerosol is other than 1.
18. The method according to claim 7, wherein the formed aerosol is greater than 80 percent by weight of the drug.
19. The method according to claim 7, wherein the formed aerosol contains less than 5 percent by weight of drug decomposition products.
20. The method according to claim 7, wherein the formed aerosol is stable over 1 second.
21. The method according to claim 7, wherein the formed aerosol has an MMAD in the 10 nm to 100 nm range.
22. The method according to claim 7, wherein the formed aerosol has an MMAD in the 1 μm to 3 μm range.
23. The method according to claim 7, wherein the geometric standard deviation of the form aerosol is other than 1.
24. The method according to claim 3, wherein the film is less than 10 μm thick.
25. The method according to claim 24, wherein the film is less than 5 μm thick.
26. The method according to claim 24, wherein the film is between 10 nm and 5 μm thick.
27. The method according to claim 25, wherein the film is less than 3 μm thick.
28. The method according to claim 26, wherein the film is between 10 nm and 3 μm thick.
29. The method according to claim 7, wherein the film is less than 10 μm thick.
30. The method according to claim 29, wherein the film is less than 5 μm thick.
31. The method according to claim 29, wherein the film is between 10 nm and 5 μm thick.
32. The method according to claim 30, wherein the film is less than 3 μm thick.
33. The method according to claim 31, wherein the film is between 10 nm and 3 μm thick.

Parent Case Info

This application is a continuation-in-part of U.S. patent application Ser. No. 10/057,198 entitled “Method and Device for Delivering a Physiologically Active Compound,” filed Oct. 26, 2001, Lloyd et al. and of U.S. patent application Ser. No. 10/057,197 entitled “Aerosol Generating Device and Method,” filed Oct. 26, 2001, Wensley et al., both of which are hereby incorporated by reference for all purposes. This application further claims priority to U.S. provisional application Ser. No. 60/296,225 entitled “Aerosol Generating Device and Method,” filed Jun. 5, 2001, Wensley et al., the entire disclosure of which is hereby incorporated by reference.

US Referenced Citations (542)

Number	Name	Date	Kind
1239634	Stuart	Sep 1917	A
1535486	Lundy	Apr 1925	A
1803334	Lehmann	May 1931	A
1864980	Curran	Jun 1932	A
2084299	Borden	Jun 1937	A
2086140	Ernst	Jul 1937	A
2230753	Klavehn et al.	Feb 1941	A
2230754	Klavehn et al.	Feb 1941	A
2243669	Clyne	May 1941	A
2309846	Einar	Feb 1943	A
2469656	Lienert	May 1949	A
2714649	Critzer	Aug 1955	A
2741812	Andre	Apr 1956	A
2761055	Ike	Aug 1956	A
2887106	Robinson	May 1959	A
2898649	Murray	Aug 1959	A
2902484	Horclois	Sep 1959	A
3043977	Morowitz	Jul 1962	A
3080624	Webber, III	Mar 1963	A
3164600	Janssen et al.	Jan 1965	A
3169095	Thiel et al.	Feb 1965	A
3200819	Gilbert	Aug 1965	A
3219533	Mullins	Nov 1965	A
3282729	Richardson et al.	Nov 1966	A
3296249	Bell	Jan 1967	A
3299185	Oda et al.	Jan 1967	A
3371085	Reeder et al.	Feb 1968	A
3393197	Pachter	Jul 1968	A
3433791	Bentley et al.	Mar 1969	A
3560607	Hartley et al.	Feb 1971	A
3701782	Hester	Oct 1972	A
3749547	Gregory et al.	Jul 1973	A
3763347	Whitaker et al.	Oct 1973	A
3773995	Pachter et al.	Nov 1973	A
3831606	Damani	Aug 1974	A
3847650	Gregory et al.	Nov 1974	A
3864326	Babington	Feb 1975	A
3894040	Buzby, Jr.	Jul 1975	A
3909463	Hartman	Sep 1975	A
3930796	Haensel	Jan 1976	A
3943941	Boyd et al.	Mar 1976	A
3949743	Shanbrom	Apr 1976	A
3971377	Damani	Jul 1976	A
3982095	Robinson	Sep 1976	A
3987052	Hester, Jr.	Oct 1976	A
4008723	Borthwick et al.	Feb 1977	A
4020379	Manning	Apr 1977	A
4045156	Chu et al.	Aug 1977	A
4079742	Rainer et al.	Mar 1978	A
4104210	Coran et al.	Aug 1978	A
4121583	Chen	Oct 1978	A
4141369	Burruss	Feb 1979	A
4160765	Weinstock	Jul 1979	A
4166087	Cline et al.	Aug 1979	A
4183912	Rosenthale	Jan 1980	A
4184099	Lindauer et al.	Jan 1980	A
4190654	Gherardi et al.	Feb 1980	A
4198200	Fonda et al.	Apr 1980	A
RE30285	Babington	May 1980	E
4219031	Rainer et al.	Aug 1980	A
4229447	Porter	Oct 1980	A
4229931	Schlueter et al.	Oct 1980	A
4232002	Nogrady	Nov 1980	A
4236544	Osaka	Dec 1980	A
4251525	Weinstock	Feb 1981	A
4276243	Partus	Jun 1981	A
4280629	Slaughter	Jul 1981	A
4284089	Ray	Aug 1981	A
4286604	Ehretsmann et al.	Sep 1981	A
4303083	Burruss, Jr.	Dec 1981	A
4340072	Bolt et al.	Jul 1982	A
4346059	Spector	Aug 1982	A
4347855	Lanzillotti et al.	Sep 1982	A
4376767	Sloan	Mar 1983	A
4391285	Burnett et al.	Jul 1983	A
4423071	Chignac et al.	Dec 1983	A
4474191	Steiner	Oct 1984	A
4484576	Albarda	Nov 1984	A
4508726	Coleman	Apr 1985	A
4523589	Krauser	Jun 1985	A
4556539	Spector	Dec 1985	A
4566451	Badewien	Jan 1986	A
4588425	Usry et al.	May 1986	A
4588721	Mahan	May 1986	A
4591615	Aldred et al.	May 1986	A
4605552	Fritschi	Aug 1986	A
4627963	Olson	Dec 1986	A
4647428	Gyulay	Mar 1987	A
4647433	Spector	Mar 1987	A
4654370	Marriott, III et al.	Mar 1987	A
4683231	Glassman	Jul 1987	A
4693868	Katsuda et al.	Sep 1987	A
4708151	Shelar	Nov 1987	A
4714082	Banerjee et al.	Dec 1987	A
4722334	Blackmer et al.	Feb 1988	A
4734560	Bowen	Mar 1988	A
4735217	Gerth et al.	Apr 1988	A
4735358	Morita et al.	Apr 1988	A
4753758	Miller	Jun 1988	A
4755508	Bock et al.	Jul 1988	A
4756318	Clearman et al.	Jul 1988	A
4765347	Sensabaugh, Jr. et al.	Aug 1988	A
4771795	White et al.	Sep 1988	A
4774971	Vieten	Oct 1988	A
4793365	Sensabaugh, Jr. et al.	Dec 1988	A
4793366	Hill	Dec 1988	A
4800903	Ray et al.	Jan 1989	A
4801411	Wellinghoff et al.	Jan 1989	A
4814161	Jinks et al.	Mar 1989	A
4819665	Roberts et al.	Apr 1989	A
4848374	Chard et al.	Jul 1989	A
4852561	Sperry	Aug 1989	A
4853517	Bowen et al.	Aug 1989	A
4854331	Banerjee et al.	Aug 1989	A
4858630	Banerjee et al.	Aug 1989	A
4863720	Burghart et al.	Sep 1989	A
4881541	Eger et al.	Nov 1989	A
4881556	Clearman et al.	Nov 1989	A
4889850	Thornfeldt et al.	Dec 1989	A
4892109	Strubel	Jan 1990	A
4895719	Radhakrishnun et al.	Jan 1990	A
4906417	Gentry	Mar 1990	A
4911157	Miller	Mar 1990	A
4917119	Potter et al.	Apr 1990	A
4917120	Hill	Apr 1990	A
4917830	Ortiz et al.	Apr 1990	A
4922901	Brooks et al.	May 1990	A
4924883	Perfetti et al.	May 1990	A
4928714	Shannon	May 1990	A
4935624	Henion et al.	Jun 1990	A
4941483	Ridings et al.	Jul 1990	A
4947874	Brooks et al.	Aug 1990	A
4947875	Brooks et al.	Aug 1990	A
4950664	Goldberg	Aug 1990	A
4955945	Weick	Sep 1990	A
4959380	Wilson	Sep 1990	A
4963289	Ortiz et al.	Oct 1990	A
4968885	Willoughby	Nov 1990	A
4984158	Hillsman	Jan 1991	A
4989619	Clearman et al.	Feb 1991	A
5016425	Weick	May 1991	A
5017575	Golwyn	May 1991	A
5019122	Clearman et al.	May 1991	A
5020548	Farrier et al.	Jun 1991	A
5027836	Shannon et al.	Jul 1991	A
5033483	Clearman et al.	Jul 1991	A
5038769	Krauser	Aug 1991	A
5042509	Banerjee et al.	Aug 1991	A
5049389	Radhakrishnun	Sep 1991	A
5060666	Clearman et al.	Oct 1991	A
5060667	Strubel	Oct 1991	A
5060671	Counts et al.	Oct 1991	A
5067499	Banerjee et al.	Nov 1991	A
5072726	Mazloomdoost et al.	Dec 1991	A
5076292	Sensabaugh, Jr. et al.	Dec 1991	A
5093894	Deevi et al.	Mar 1992	A
5095921	Loose et al.	Mar 1992	A
5099861	Clearman et al.	Mar 1992	A
5105831	Banerjee et al.	Apr 1992	A
5109180	Boultinghouse et al.	Apr 1992	A
5112598	Biesalski	May 1992	A
5118494	Schultz et al.	Jun 1992	A
5119834	Shannon et al.	Jun 1992	A
5126123	Johnson	Jun 1992	A
5133368	Neumann et al.	Jul 1992	A
5135009	Muller et al.	Aug 1992	A
5137034	Perfetti et al.	Aug 1992	A
5144962	Counts et al.	Sep 1992	A
5146915	Montgomery	Sep 1992	A
5149538	Granger et al.	Sep 1992	A
5156170	Clearman et al.	Oct 1992	A
5160664	Liu	Nov 1992	A
5164740	Ivri	Nov 1992	A
5166202	Schweizer	Nov 1992	A
5167242	Turner et al.	Dec 1992	A
5177071	Freidinger et al.	Jan 1993	A
5179966	Losee et al.	Jan 1993	A
5186164	Raghuprasad	Feb 1993	A
5192548	Velasquez et al.	Mar 1993	A
5224498	Deevi et al.	Jul 1993	A
5226411	Levine	Jul 1993	A
5229120	DeVincent	Jul 1993	A
5229382	Chakrabarti et al.	Jul 1993	A
5240922	O'Neill	Aug 1993	A
5249586	Morgan et al.	Oct 1993	A
5255674	Oftedal et al.	Oct 1993	A
5261424	Sprin et al.	Nov 1993	A
5264433	Sato et al.	Nov 1993	A
5269327	Counts et al.	Dec 1993	A
5284133	Burns et al.	Feb 1994	A
5285798	Banerjee et al.	Feb 1994	A
5292499	Evans et al.	Mar 1994	A
5322075	Deevi et al.	Jun 1994	A
5333106	Lanpher et al.	Jul 1994	A
5345951	Serrano et al.	Sep 1994	A
5357984	Farrier et al.	Oct 1994	A
5363842	Mishelevich et al.	Nov 1994	A
5364838	Rubsamen	Nov 1994	A
5366770	Wang	Nov 1994	A
5372148	McCafferty et al.	Dec 1994	A
5376386	Ganderton et al.	Dec 1994	A
5388574	Ingebrethsen	Feb 1995	A
5391081	Lampotang et al.	Feb 1995	A
5399574	Robertson et al.	Mar 1995	A
5400808	Turner et al.	Mar 1995	A
5400969	Keene	Mar 1995	A
5402517	Gillett et al.	Mar 1995	A
5408574	Deevi et al.	Apr 1995	A
5436230	Soudant et al.	Jul 1995	A
5451408	Mezei et al.	Sep 1995	A
5455043	Fischel-Ghodsian	Oct 1995	A
5456247	Shilling et al.	Oct 1995	A
5456677	Spector	Oct 1995	A
5457100	Daniel	Oct 1995	A
5457101	Greenwood et al.	Oct 1995	A
5459137	Andrasi et al.	Oct 1995	A
5462740	Evenstad et al.	Oct 1995	A
5468936	Deevi et al.	Nov 1995	A
5479948	Counts et al.	Jan 1996	A
5501236	Hill et al.	Mar 1996	A
5505214	Collins et al.	Apr 1996	A
5507277	Rubsamen et al.	Apr 1996	A
5511726	Greenspan et al.	Apr 1996	A
5519019	Andrasi et al.	May 1996	A
5525329	Snyder et al.	Jun 1996	A
5537507	Mariner et al.	Jul 1996	A
5538020	Farrier et al.	Jul 1996	A
5540959	Wang	Jul 1996	A
5543434	Weg	Aug 1996	A
5544646	Lloyd et al.	Aug 1996	A
5564442	MacDonald et al.	Oct 1996	A
5565148	Pendergrass	Oct 1996	A
5577156	Costello	Nov 1996	A
5584701	Lampotang et al.	Dec 1996	A
5586550	Ivri et al.	Dec 1996	A
5591409	Watkins	Jan 1997	A
5592934	Thwaites	Jan 1997	A
5593792	Farrier et al.	Jan 1997	A
5605146	Sarela	Feb 1997	A
5605897	Beasley, Jr. et al.	Feb 1997	A
5607691	Hale et al.	Mar 1997	A
5613504	Collins et al.	Mar 1997	A
5613505	Campbell et al.	Mar 1997	A
5619984	Hodson et al.	Apr 1997	A
5622944	Hale et al.	Apr 1997	A
5627178	Chakrabarti et al.	May 1997	A
5649554	Sprinkel	Jul 1997	A
5655523	Hodson et al.	Aug 1997	A
5656255	Jones	Aug 1997	A
5660166	Lloyd et al.	Aug 1997	A
5666977	Higgins et al.	Sep 1997	A
5690809	Subramaniam et al.	Nov 1997	A
5694919	Rubsamen et al.	Dec 1997	A
5718222	Lloyd et al.	Feb 1998	A
5724957	Rubsamen et al.	Mar 1998	A
5725756	Subramaniam et al.	Mar 1998	A
5733572	Unger et al.	Mar 1998	A
5735263	Rubsamen et al.	Apr 1998	A
5738865	Baichwal et al.	Apr 1998	A
5743250	Gonda et al.	Apr 1998	A
5743251	Howell et al.	Apr 1998	A
5744469	Tran	Apr 1998	A
5747001	Wiedmann et al.	May 1998	A
5756449	Andersen et al.	May 1998	A
5758637	Ivri et al.	Jun 1998	A
5767117	Moskowitz et al.	Jun 1998	A
5769621	Early et al.	Jun 1998	A
5770222	Unger et al.	Jun 1998	A
5771882	Psaros et al.	Jun 1998	A
5776928	Beasley, Jr.	Jul 1998	A
5804212	Illum	Sep 1998	A
5809997	Wolf	Sep 1998	A
5817656	Beasley, Jr. et al.	Oct 1998	A
5819756	Mielordt	Oct 1998	A
5823178	Lloyd et al.	Oct 1998	A
5829436	Rubsamen et al.	Nov 1998	A
5833891	Subramaniam et al.	Nov 1998	A
5840246	Hammons et al.	Nov 1998	A
5855564	Ruskewicz	Jan 1999	A
5855913	Hanes et al.	Jan 1999	A
5865185	Collins et al.	Feb 1999	A
5874064	Edwards et al.	Feb 1999	A
5874481	Weers et al.	Feb 1999	A
5875776	Vaghefi	Mar 1999	A
5878752	Adams et al.	Mar 1999	A
5884620	Gonda et al.	Mar 1999	A
5890908	Lampotang et al.	Apr 1999	A
5894841	Voges	Apr 1999	A
5904900	Bleuse et al.	May 1999	A
5906811	Hersh	May 1999	A
5907075	Subramaniam et al.	May 1999	A
5910301	Farr et al.	Jun 1999	A
5915378	Lloyd et al.	Jun 1999	A
5918595	Olsson	Jul 1999	A
5928520	Haumesser	Jul 1999	A
5929093	Pang et al.	Jul 1999	A
5934272	Lloyd et al.	Aug 1999	A
5934289	Watkins et al.	Aug 1999	A
5935604	Illum	Aug 1999	A
5938117	Ivri	Aug 1999	A
5939100	Albrechtsen et al.	Aug 1999	A
5941240	Gonda et al.	Aug 1999	A
5944012	Pera	Aug 1999	A
5957124	Lloyd et al.	Sep 1999	A
5960792	Lloyd et al.	Oct 1999	A
5970973	Gonda et al.	Oct 1999	A
5971951	Ruskewicz	Oct 1999	A
5985309	Edwards et al.	Nov 1999	A
5993805	Sutton et al.	Nov 1999	A
6004516	Rasouli et al.	Dec 1999	A
6004970	O'Malley et al.	Dec 1999	A
6008214	Kwon et al.	Dec 1999	A
6008216	Chakrabarti et al.	Dec 1999	A
6013050	Bellhouse et al.	Jan 2000	A
6014969	Lloyd et al.	Jan 2000	A
6014970	Ivri et al.	Jan 2000	A
6041777	Faithfull et al.	Mar 2000	A
6044777	Walsh	Apr 2000	A
6048550	Chan et al.	Apr 2000	A
6048857	Ellinwood, Jr. et al.	Apr 2000	A
6050260	Daniell et al.	Apr 2000	A
6051257	Kodas et al.	Apr 2000	A
6051566	Bianco	Apr 2000	A
6053176	Adams et al.	Apr 2000	A
RE36744	Goldberg	Jun 2000	E
6085026	Hammons et al.	Jul 2000	A
6089857	Matsuura et al.	Jul 2000	A
6090212	Mahawili	Jul 2000	A
6090403	Block et al.	Jul 2000	A
6095134	Sievers et al.	Aug 2000	A
6095153	Kessler et al.	Aug 2000	A
6098620	Lloyd et al.	Aug 2000	A
6102036	Slutsky et al.	Aug 2000	A
6113795	Subramaniam et al.	Sep 2000	A
6117866	Bondinell et al.	Sep 2000	A
6125853	Susa et al.	Oct 2000	A
6126919	Stefely et al.	Oct 2000	A
6131566	Ashurst et al.	Oct 2000	A
6131570	Schuster et al.	Oct 2000	A
6133327	Kimura et al.	Oct 2000	A
6135369	Prendergast et al.	Oct 2000	A
6136295	Edwards et al.	Oct 2000	A
6138683	Hersh et al.	Oct 2000	A
6140323	Ellinwood, Jr. et al.	Oct 2000	A
6143277	Ashurst et al.	Nov 2000	A
6143746	Daugan et al.	Nov 2000	A
6149892	Britto	Nov 2000	A
6155268	Takeuchi	Dec 2000	A
6158431	Poole	Dec 2000	A
6167880	Gonda et al.	Jan 2001	B1
6178969	St. Charles	Jan 2001	B1
6234167	Cox et al.	May 2001	B1
6241969	Saidi et al.	Jun 2001	B1
6250301	Pate	Jun 2001	B1
6255334	Sands	Jul 2001	B1
6263872	Schuster et al.	Jul 2001	B1
6264922	Wood et al.	Jul 2001	B1
6284287	Sarlikiotis et al.	Sep 2001	B1
6299900	Reed et al.	Oct 2001	B1
6300710	Nakamori	Oct 2001	B1
6306431	Zhang et al.	Oct 2001	B1
6309668	Bastin et al.	Oct 2001	B1
6309986	Flashinski et al.	Oct 2001	B1
6313176	Ellinwood, Jr. et al.	Nov 2001	B1
6325475	Hayes et al.	Dec 2001	B1
6376550	Raber et al.	Apr 2002	B1
6390453	Frederickson et al.	May 2002	B1
6408854	Gonda et al.	Jun 2002	B1
6413930	Ratti et al.	Jul 2002	B1
6420351	Tsai et al.	Jul 2002	B1
6431166	Gonda et al.	Aug 2002	B2
6443152	Lockhart et al.	Sep 2002	B1
6461591	Keller et al.	Oct 2002	B1
6491233	Nichols	Dec 2002	B2
6501052	Cox et al.	Dec 2002	B2
6506762	Horvath et al.	Jan 2003	B1
6514482	Bartus et al.	Feb 2003	B1
6516796	Cox et al.	Feb 2003	B1
6557552	Cox et al.	May 2003	B1
6561186	Casper et al.	May 2003	B2
6568390	Nichols et al.	May 2003	B2
6591839	Meyer et al.	Jul 2003	B2
6632047	Vinegar et al.	Oct 2003	B2
6648950	Lee et al.	Nov 2003	B2
6671945	Gerber et al.	Jan 2004	B2
6680668	Gerber et al.	Jan 2004	B2
6681769	Sprinkel et al.	Jan 2004	B2
6681998	Sharpe et al.	Jan 2004	B2
6682716	Hodges et al.	Jan 2004	B2
6688313	Wrenn et al.	Feb 2004	B2
6694975	Schuster et al.	Feb 2004	B2
6701921	Sprinkel et al.	Mar 2004	B2
6701922	Hindle et al.	Mar 2004	B2
6715487	Nichols et al.	Apr 2004	B2
6716415	Rabinowitz et al.	Apr 2004	B2
6716416	Rabinowitz et al.	Apr 2004	B2
6716417	Rabinowitz et al.	Apr 2004	B2
6728478	Cox et al.	Apr 2004	B2
6737042	Rabinowitz et al.	May 2004	B2
6737043	Rabinowitz et al.	May 2004	B2
6740307	Rabinowitz et al.	May 2004	B2
6740308	Rabinowitz et al.	May 2004	B2
6740309	Rabinowitz et al.	May 2004	B2
6743415	Rabinowitz et al.	Jun 2004	B2
6759029	Hale et al.	Jul 2004	B2
6772756	Shayan	Aug 2004	B2
6772757	Sprinkel, Jr. et al.	Aug 2004	B2
6776978	Rabinowitz et al.	Aug 2004	B2
6779520	Genova et al.	Aug 2004	B2
6780399	Rabinowitz et al.	Aug 2004	B2
6780400	Rabinowitz et al.	Aug 2004	B2
6783753	Rabinowitz et al.	Aug 2004	B2
6797259	Rabinowitz et al.	Sep 2004	B2
6803031	Rabinowitz et al.	Oct 2004	B2
6805853	Rabinowitz et al.	Oct 2004	B2
6805854	Hale et al.	Oct 2004	B2
6814954	Rabinowitz et al.	Nov 2004	B2
6814955	Rabinowitz et al.	Nov 2004	B2
6855310	Rabinowitz et al.	Feb 2005	B2
6884408	Rabinowitz et al.	Apr 2005	B2
6994843	Rabinowitz et al.	Feb 2006	B2
7005121	Rabinowitz et al.	Feb 2006	B2
7005122	Hale et al.	Feb 2006	B2
7008615	Rabinowitz et al.	Mar 2006	B2
7008616	Rabinowitz et al.	Mar 2006	B2
7011819	Hale et al.	Mar 2006	B2
7011820	Rabinowitz et al.	Mar 2006	B2
7014840	Hale et al.	Mar 2006	B2
7014841	Rabinowitz et al.	Mar 2006	B2
7018619	Rabinowitz et al.	Mar 2006	B2
7018620	Rabinowitz et al.	Mar 2006	B2
7018621	Hale et al.	Mar 2006	B2
7022312	Rabinowitz et al.	Apr 2006	B2
7029658	Rabinowitz et al.	Apr 2006	B2
7033575	Rabinowitz et al.	Apr 2006	B2
7045118	Rabinowitz et al.	May 2006	B2
7045119	Rabinowitz et al.	May 2006	B2
7048909	Rabinowitz et al.	May 2006	B2
7052679	Rabinowitz et al.	May 2006	B2
7052680	Rabinowitz et al.	May 2006	B2
7060254	Rabinowitz et al.	Jun 2006	B2
7060255	Rabinowitz et al.	Jun 2006	B2
7063830	Rabinowitz et al.	Jun 2006	B2
7063831	Rabinowitz et al.	Jun 2006	B2
7063832	Rabinowitz et al.	Jun 2006	B2
7067114	Rabinowitz et al.	Jun 2006	B2
7070761	Rabinowitz et al.	Jul 2006	B2
7070762	Rabinowitz et al.	Jul 2006	B2
7070763	Rabinowitz et al.	Jul 2006	B2
7070764	Rabinowitz et al.	Jul 2006	B2
7070765	Rabinowitz et al.	Jul 2006	B2
7070766	Rabinowitz et al.	Jul 2006	B2
7078016	Rabinowitz	Jul 2006	B2
7078017	Rabinowitz et al.	Jul 2006	B2
7078018	Rabinowitz et al.	Jul 2006	B2
7078019	Rabinowitz et al.	Jul 2006	B2
7078020	Rabinowitz et al.	Jul 2006	B2
7087216	Rabinowitz et al.	Aug 2006	B2
7087217	Rabinowitz et al.	Aug 2006	B2
7087218	Rabinowitz et al.	Aug 2006	B2
7090830	Hale et al.	Aug 2006	B2
7094392	Rabinowitz et al.	Aug 2006	B2
7108847	Rabinowitz et al.	Sep 2006	B2
7115250	Rabinowitz et al.	Oct 2006	B2
7169378	Rabinowitz et al.	Jan 2007	B2
20010020147	Staniforth et al.	Sep 2001	A1
20010042546	Umeda et al.	Nov 2001	A1
20020031480	Peart et al.	Mar 2002	A1
20020037828	Wilson et al.	Mar 2002	A1
20020058009	Bartus et al.	May 2002	A1
20020061281	Osbakken et al.	May 2002	A1
20020078955	Nichols et al.	Jun 2002	A1
20020086852	Cantor	Jul 2002	A1
20020097139	Gerber et al.	Jul 2002	A1
20020112723	Schuster et al.	Aug 2002	A1
20020117175	Kottayil et al.	Aug 2002	A1
20020176841	Barker et al.	Nov 2002	A1
20030004142	Prior et al.	Jan 2003	A1
20030015196	Hodges et al.	Jan 2003	A1
20030032638	Kim et al.	Feb 2003	A1
20030033055	McRae et al.	Feb 2003	A1
20030049025	Neumann et al.	Mar 2003	A1
20030051728	Lloyd et al.	Mar 2003	A1
20030062042	Wensley et al.	Apr 2003	A1
20030106551	Sprinkel et al.	Jun 2003	A1
20030118512	Shen	Jun 2003	A1
20030121906	Abbott et al.	Jul 2003	A1
20030131843	Lu	Jul 2003	A1
20030132219	Cox et al.	Jul 2003	A1
20030138508	Novack et al.	Jul 2003	A1
20030156829	Cox et al.	Aug 2003	A1
20030209240	Hale et al.	Nov 2003	A1
20040009128	Rabinowitz et al.	Jan 2004	A1
20040016427	Byron et al.	Jan 2004	A1
20040035409	Harwig et al.	Feb 2004	A1
20040055504	Lee et al.	Mar 2004	A1
20040081624	Nguyen et al.	Apr 2004	A1
20040096402	Hodges et al.	May 2004	A1
20040099266	Cross et al.	May 2004	A1
20040101481	Hale et al.	May 2004	A1
20040102434	Hale et al.	May 2004	A1
20040105818	Every et al.	Jun 2004	A1
20040105819	Hale et al.	Jun 2004	A1
20040234699	Hale et al.	Nov 2004	A1
20040234914	Hale et al.	Nov 2004	A1
20040234916	Hale et al.	Nov 2004	A1
20050034723	Bennett et al.	Feb 2005	A1
20050037506	Hale et al.	Feb 2005	A1
20050079166	Damani et al.	Apr 2005	A1
20050126562	Rabinowitz et al.	Jun 2005	A1
20050131739	Rabinowitz et al.	Jun 2005	A1
20050258159	Hale et al.	Nov 2005	A1
20050268911	Cross et al.	Dec 2005	A1
20060032496	Hale et al.	Feb 2006	A1
20060032501	Hale et al.	Feb 2006	A1
20060120962	Rabinowitz et al.	Jun 2006	A1
20060153779	Rabinowitz et al.	Jul 2006	A1
20060177382	Rabinowitz et al.	Aug 2006	A1
20060193788	Hale et al.	Aug 2006	A1
20060216243	Rabinowitz et al.	Sep 2006	A1
20060216244	Rabinowitz et al.	Sep 2006	A1
20060233717	Rabinowitz et al.	Oct 2006	A1
20060233718	Rabinowitz et al.	Oct 2006	A1
20060233719	Rabinowitz et al.	Oct 2006	A1
20060239936	Rabinowitz et al.	Oct 2006	A1
20060246011	Rabinowitz et al.	Nov 2006	A1
20060246012	Rabinowitz et al.	Nov 2006	A1
20060251587	Rabinowitz et al.	Nov 2006	A1
20060251588	Rabinowitz et al.	Nov 2006	A1
20060257328	Rabinowitz et al.	Nov 2006	A1
20060257329	Rabinowitz et al.	Nov 2006	A1
20060269486	Rabinowitz et al.	Nov 2006	A1
20060269487	Rabinowitz et al.	Nov 2006	A1
20060280692	Rabinowitz et al.	Dec 2006	A1
20060286042	Rabinowitz et al.	Dec 2006	A1
20060286043	Rabinowitz et al.	Dec 2006	A1
20070014737	Rabinowitz et al.	Jan 2007	A1
20070028916	Hale et al.	Feb 2007	A1
20070031340	Hale et al.	Feb 2007	A1
20070122353	Hale et al.	May 2007	A1
20070140982	Every et al.	Jun 2007	A1
20070178052	Rabinowitz et al.	Aug 2007	A1

Foreign Referenced Citations (120)

Number	Date	Country
2152684	Jan 1996	CA
1082365	Feb 1994	CN
1176075	Mar 1998	CN
198 54 007	May 2000	DE
0 039 369	Nov 1981	EP
0 274 431	Jul 1988	EP
0 277 519	Aug 1988	EP
0 358 114	Mar 1990	EP
0 430 559	Jun 1991	EP
0 492 485	Jul 1992	EP
0 606 486	Jul 1994	EP
0 734 719	Oct 1996	EP
0 967 214	Dec 1999	EP
1 080 720	Mar 2001	EP
1 177 793	Feb 2002	EP
0 808 635	Jul 2003	EP
921 852	May 1947	FR
2 428 068	Jan 1980	FR
502 761	Jan 1938	GB
903 866	Aug 1962	GB
1 366 041	Sep 1974	GB
2 108 390	May 1983	GB
2 122 903	Jan 1984	GB
HU 200105	Apr 1990	HU
HU 219392	Jun 1996	HU
WO 8500520	Feb 1985	WO
WO 8808304	Nov 1988	WO
WO 9002737	Mar 1990	WO
WO 9007333	Jul 1990	WO
WO 9107947	Jun 1991	WO
WO 9118525	Dec 1991	WO
WO 9205781	Apr 1992	WO
WO 9215353	Sep 1992	WO
WO 9219303	Nov 1992	WO
WO 9312823	Jul 1993	WO
WO 9409842	May 1994	WO
WO 9409842	May 1994	WO
WO 9416717	Aug 1994	WO
WO 9416757	Aug 1994	WO
WO 9416759	Aug 1994	WO
WO 9417369	Aug 1994	WO
WO 9417370	Aug 1994	WO
WO 9427576	Dec 1994	WO
WO 9427653	Dec 1994	WO
WO 9531182	Nov 1995	WO
WO 9600069	Jan 1996	WO
WO 9600070	Jan 1996	WO
WO 9600071	Jan 1996	WO
WO 9609846	Apr 1996	WO
WO 9610663	Apr 1996	WO
WO 9613161	May 1996	WO
WO 9613290	May 1996	WO
WO 9613291	May 1996	WO
WO 9613292	May 1996	WO
WO 9630068	Oct 1996	WO
WO 9631198	Oct 1996	WO
WO 9637198	Nov 1996	WO
WO 9616181	May 1997	WO
WO 9717948	May 1997	WO
WO 9723221	Jul 1997	WO
WO 9727804	Aug 1997	WO
WO 9731691	Sep 1997	WO
WO 9735562	Oct 1997	WO
WO 9736574	Oct 1997	WO
WO 9740819	Nov 1997	WO
WO 9749690	Dec 1997	WO
WO 9802186	Jan 1998	WO
WO 9816205	Apr 1998	WO
WO 9822170	May 1998	WO
WO 9829110	Jul 1998	WO
WO 9831346	Jul 1998	WO
WO 9834595	Aug 1998	WO
WO 9836651	Aug 1998	WO
WO 9837896	Sep 1998	WO
WO 9904797	Feb 1999	WO
WO 9916419	Apr 1999	WO
WO 9924433	May 1999	WO
WO 9937347	Jul 1999	WO
WO 9937625	Jul 1999	WO
WO 9944664	Sep 1999	WO
WO 9955362	Nov 1999	WO
WO 9959710	Nov 1999	WO
WO 9964094	Dec 1999	WO
WO 0000176	Jan 2000	WO
WO 0000215	Jan 2000	WO
WO 0000244	Jan 2000	WO
WO 0019991	Apr 2000	WO
WO 0027359	May 2000	WO
WO 0027363	May 2000	WO
WO 0028979	May 2000	WO
WO 0029053	May 2000	WO
WO 0029167	May 2000	WO
WO 0035417	Jun 2000	WO
WO 0038618	Jul 2000	WO
WO 0044350	Aug 2000	WO
WO 0044730	Aug 2000	WO
WO 0047203	Sep 2000	WO
WO 0051491	Sep 2000	WO
WO 0064940	Nov 2000	WO
WO 0066084	Nov 2000	WO
WO 0066106	Nov 2000	WO
WO 0066206	Nov 2000	WO
WO 0072827	Dec 2000	WO
WO 0076673	Dec 2000	WO
WO 0105459	Jan 2001	WO
WO 0113957	Mar 2001	WO
WO 0117568	Mar 2001	WO
WO 0119528	Mar 2001	WO
WO 0102911	Apr 2001	WO
WO 0132144	May 2001	WO
WO 0143801	Jun 2001	WO
WO 9141732	Jun 2001	WO
WO 0195903	Dec 2001	WO
WO 0200198	Jan 2002	WO
WO 0224158	Mar 2002	WO
WO 02051466	Jul 2002	WO
WO 02056866	Jul 2002	WO
WO 02094234	Nov 2002	WO
WO 02098389	Dec 2002	WO
WO 03037412	May 2003	WO

Related Publications (1)

	Number	Date	Country
	20030015197 A1	Jan 2003	US

Provisional Applications (1)

	Number	Date	Country
	60296225	Jun 2001	US

Continuation in Parts (2)

	Number	Date	Country
Parent	10057198	Oct 2001	US
Child	10146088		US
Parent	10057197	Oct 2001	US
Child	10057198		US

Method of forming an aerosol for inhalation delivery

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

US Classifications

Field of Search

US

International Classifications

Term Extension

Abstract

Description

Claims

Parent Case Info

US Referenced Citations (542)

Foreign Referenced Citations (120)

Related Publications (1)

Provisional Applications (1)

Continuation in Parts (2)