Aerosol forming device for use in inhalation therapy

Information

  • Patent Grant
  • 11065400
  • Patent Number
    11,065,400
  • Date Filed
    Monday, June 26, 2017
    7 years ago
  • Date Issued
    Tuesday, July 20, 2021
    3 years ago
Abstract
Inhalation delivery of aerosols containing small particles is described. Specifically, it relates to a device that forms drug containing aerosols for use in inhalation therapy. In a device aspect of the present disclosure, a device for delivering drug containing aerosols for inhalation therapy is provided. The device includes a housing and an airway that has a gas/vapor mixing airway. The airway further includes a subassembly, which has a metallic substrate coated on its surface with a composition comprising a drug.
Description
FIELD OF THE INVENTION

The present invention relates to the inhalation delivery of aerosols containing small particles. Specifically, it relates to a device that forms drug containing aerosols 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. Along with particular drugs, however, the devices also deliver a wide range of excipients.


It is desirable to provide a device 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 device that forms drug containing aerosols for use in inhalation therapy.


In a device aspect of the present invention, a device for delivering drug containing aerosols for inhalation therapy is provided. The device includes a housing and an airway that has a gas/vapor mixing airway area. The airway further includes a subassembly, which has a metallic substrate coated on its surface with a composition comprising a drug.


Typically, the device further includes a heater system. Preferably, the heater system is an inductive heater system. More preferably, it is an inductive heating system having a ferrite torroid.


Typically, the airway contains a restricted cross-sectional area along the gas/vapor mixing area. Preferably, the airway further includes means for causing turbulence as air moves through the airway.


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.


In a method aspect of the present invention, a method of forming a drug containing aerosol for use in inhalation therapy is provided. The method includes heating a substrate coated with a composition comprising a drug to form a vapor and mixing the vapor with a volume of air such that an aerosol having particles is formed. The mass median aerodynamic diameter of the formed particles is stable for at least 1 s.


Typically, the substrate is heated by moving it through a heating zone. Preferably, the heating zone is primarily produced by eddy currents induced by an alternating magnetic field.


Typically, the formed aerosol includes about 109 particles/cc of air.


Typically, the drug of the composition is of one of the drugs or classes of drugs described above with respect to a device of the present invention.





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 7. The number is determined by subtracting 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., 56th edition, 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, 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, cannabanoids, 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, 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 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 cannabanoid, it is tetrahydrocannabinol (e.g., delta-8 or delta-9).


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.


“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 turbulence 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, N2 and 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 during 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., between 10μ and 10 nm in thickness). The compound is oftentimes coated as a film between 5μ and 10 nm, 4μ and 10 nm, 3μ and 10 nm, 2μ and 10 nm, or even 1μ 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.


An aerosol of the present invention contains particles having an MMAD between 10 nm and 1μ, preferably 10 nm to 900 nm, 10 nm to 800 nm, 10 nm to 700 nm, 10 nm to 600 nm, 10 nm to 500 nm, 10 nm to 400 nm, 10 nm to 300 nm, 10 nm to 200 nm, or 10 nm to 100 nm. Particles are produced such that their size is stable for several seconds (e.g., 1 to 3 s). The aerosol particle size and subsequent stability is controlled by the rate of compound vaporization, the rate of carrier gas introduction, and the mixing of resultant vapors and the carrier gas. Such control is accomplished using a number of methods, including the following: (a) measuring the quantity and regulating the flow rate of the mixing air; and/or, (b) regulating the vaporization rate of the compound (e.g., by changing the energy transferred to the compound during the heating process or changing the amount of compound introduced into a heating region).


A desired particle size is achieved by mixing a compound in its vapor state into a volume of a carrier gas in a ratio such that, when the number concentration of the mixture reaches approximately 109 particles/mL, a particle that exists in a size range from 10 nm to 100 nm for 1 to 3 seconds results.



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 3×1018 molecules (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 109 particles/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 5×10−16 meters3/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(ln σg)2]

    • Where: ρ=density in gm/cc
    • N=Number concentration in particles/cc
    • MMD=mass median diameter (in cm)
    • σg=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:

σgNπ/6(MMD1)3exp[−9/2(ln σg1)2]=ρNπ/6(MMD2)3exp[−9/2(ln σg2)2]
simplifying:
(MMD1)3exp[−9/2(ln σg1)2]=(MMD2)3exp[−9/2(ln σg2)2]
Or
(MMD1)3/(MMD2)3=exp[−−9/2(ln σg2)2]/exp[−9/2(ln σg1)2]


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

exp[−9/2(ln σg1)2=1
And therefore:
(MMD1/MMD2)3=exp[−9/2(ln σg2)2]
Or:
MMD1/MMD2=exp[−3/2(ln σg2)2]


It is advantageous to calculate the change in the MMD as the GSD changes. Solving for MMD2 as a function of MMD1 and the new GSD2 yields:

MMD2=MMD1/exp[−3/2(ln σg2)2] for a σg1=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)1/3 for an aerosol with a GSD of 1

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


Insertion of MMD1 into the above equation leads to:

MMD2=(6C/ρNVπ)1/3/[exp[−3/2(ln σg2)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 nm 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 A C, 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 rate to have a consistent and repeatable particle size.
    • (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 (Cmax, maximum concentration in plasma, 11.6 ng/ml and Tmax, 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 (Cmax) and the maximum time it occurred (Tmax) 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 Tmax (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 had 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
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 pipetted 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 examples or make various other examples 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 device for delivering apomorphine containing aerosols including: a housing; and, an airway including a gas/vapor mixing area, wherein the airway includes a subassembly, and wherein the subassembly includes a metallic substrate, and wherein a composition comprising apomorphine is coated on the substrate.
  • 2. A device for delivering fentanyl containing aerosols including: a housing; and, an airway including a gas/vapor mixing area, wherein the airway includes a subassembly, and wherein the subassembly includes a metallic substrate, and wherein a composition comprising fentanyl is coated on the substrate.
CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 14/078,577, entitled “Aerosol Forming Device For Use In Inhalation Therapy”, filed Nov. 13, 2013, U.S. Pat. No. 9,687,487, issue date Jun. 27, 2017 which is a continuation of U.S. application Ser. No. 13/078,600, entitled “Aerosol Forming Device For Use In Inhalation Therapy”, filed Apr. 1, 2011 which is a continuation of U.S. application Ser. No. 10/146,080, filed May 13, 2002, now U.S. Pat. No. 7,942,147, which 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., now abandoned and of U.S. patent application Ser. No. 10/057,197 entitled “Aerosol Generating Device and Method,” filed Oct. 26, 2001, Wensley et al., now U.S. Pat. No. 7,766,013, each of said application Ser. Nos. 10/146,080, 10/057,198, 10/057,197 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 disclosures of each of the referenced applications are hereby incorporated by reference. Any disclaimer that may have occurred during the prosecution of the above-referenced applications is hereby expressly rescinded, and reconsideration of all relevant art is respectfully requested.

US Referenced Citations (597)
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 Holm 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
3773955 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 et al. 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
7402777 Hale et al. Jul 2008 B2
7442368 Rabinowitz et al. Oct 2008 B2
7445768 Rabinowitz et al. Nov 2008 B2
7449172 Rabinowitz et al. Nov 2008 B2
7449173 Rabinowitz et al. Nov 2008 B2
7449174 Rabinowitz et al. Nov 2008 B2
7449175 Rabinowitz et al. Nov 2008 B2
7458374 Hale et al. Dec 2008 B2
7465435 Rabinowitz et al. Dec 2008 B2
7465436 Rabinowitz et al. Dec 2008 B2
7465437 Rabinowitz et al. Dec 2008 B2
7468179 Rabinowitz et al. Dec 2008 B2
7470421 Rabinowitz et al. Dec 2008 B2
7485285 Rabinowitz et al. Feb 2009 B2
7488469 Rabinowitz et al. Feb 2009 B2
7491047 Rabinowitz et al. Feb 2009 B2
7494344 Galauner et al. Feb 2009 B2
7498019 Hale et al. Mar 2009 B2
7507397 Rabinowitz et al. Mar 2009 B2
7507398 Rabinowitz et al. Mar 2009 B2
7510702 Rabinowitz et al. Mar 2009 B2
7513781 Galauner et al. Apr 2009 B2
7524484 Rabinowitz et al. Apr 2009 B2
7537009 Hale et al. May 2009 B2
7540286 Cross et al. Jun 2009 B2
7550133 Hale et al. Jun 2009 B2
7581540 Hale et al. Sep 2009 B2
7585493 Hale et al. Sep 2009 B2
7601337 Rabinowitz et al. Oct 2009 B2
7645442 Hale et al. Jan 2010 B2
7766013 Wensley et al. Aug 2010 B2
7834295 Sharma et al. Nov 2010 B2
7913688 Cross et al. Mar 2011 B2
7923662 Hale et al. Apr 2011 B2
7942147 Hodges et al. May 2011 B2
7981401 Every et al. Jul 2011 B2
7987846 Hale et al. Aug 2011 B2
7988952 Rabinowitz et al. Aug 2011 B2
8003080 Rabinowitz et al. Aug 2011 B2
8074644 Hale et al. Dec 2011 B2
8173107 Rabinowitz et al. May 2012 B2
8235037 Hale et al. Aug 2012 B2
8288372 Hale et al. Oct 2012 B2
8333197 Cross et al. Dec 2012 B2
8387612 Damani et al. Mar 2013 B2
8506935 Hale et al. Aug 2013 B2
8955512 Hales et al. Feb 2015 B2
8991387 Damani et al. Mar 2015 B2
9211382 Hale et al. Dec 2015 B2
9439907 Hale et al. Sep 2016 B2
9440034 Hale et al. Sep 2016 B2
9687487 Hodges et al. Jun 2017 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
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
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
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
20040101481 Hale et al. May 2004 A1
20040105818 Every 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
20060032496 Hale et al. Feb 2006 A1
20060120962 Rabinowitz et al. Jun 2006 A1
20060193788 Hale et al. Aug 2006 A1
20060257329 Rabinowitz et al. Nov 2006 A1
20070122353 Hale et al. May 2007 A1
20070286816 Hale et al. Dec 2007 A1
20080038363 Zaffaroni et al. Feb 2008 A1
20080216828 Wensley Sep 2008 A1
20080299048 Hale et al. Dec 2008 A1
20080306285 Hale et al. Dec 2008 A1
20090062254 Hale et al. Mar 2009 A1
20090180968 Hale et al. Jul 2009 A1
20100006092 Hale et al. Jan 2010 A1
20100055048 Hale et al. Mar 2010 A1
20100065052 Sharma et al. Mar 2010 A1
20100068155 Lei et al. Mar 2010 A1
20100181387 Zaffaroni et al. Jul 2010 A1
20100294268 Wensley et al. Nov 2010 A1
20100300433 Sharma et al. Dec 2010 A1
20110233043 Cross et al. Sep 2011 A1
20110240013 Hale et al. Oct 2011 A1
20110240014 Bennett et al. Oct 2011 A1
20110240022 Hodges et al. Oct 2011 A1
20110244020 Hale et al. Oct 2011 A1
20110245493 Rabinowitz et al. Oct 2011 A1
20110253135 Hale et al. Oct 2011 A1
20120048963 Sharma et al. Mar 2012 A1
20130032139 Hale et al. Feb 2013 A1
20130180525 Cross et al. Jul 2013 A1
20140060525 Hale et al. Mar 2014 A1
20140060532 Hodges et al. Mar 2014 A1
20140066618 Hale et al. Mar 2014 A1
20140072605 Bennett et al. Mar 2014 A1
20150157635 Hale et al. Jun 2015 A1
20150250800 Hale et al. Sep 2015 A1
20150265783 Damani et al. Sep 2015 A1
20160166564 Myers et al. Jun 2016 A1
20160324845 Myers et al. Nov 2016 A1
20160374937 Hale et al. Dec 2016 A1
20170049974 Wensley et al. Feb 2017 A1
20170105246 Cross et al. Apr 2017 A1
Foreign Referenced Citations (121)
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 Feb 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
200105 Apr 1990 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 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 9716181 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 9911311 Mar 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 0028844 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 0129011 Apr 2001 WO
WO 0132144 May 2001 WO
WO 01041732 Jun 2001 WO
WO 01043801 Jun 2001 WO
WO 0195903 Dec 2001 WO
WO 0200198 Jan 2002 WO
WO 0224158 Mar 2002 WO
WO 0251466 Jul 2002 WO
WO 0256866 Jul 2002 WO
WO 02094234 Nov 2002 WO
WO 02098389 Dec 2002 WO
WO 0337412 May 2003 WO
Non-Patent Literature Citations (70)
Entry
U.S. Appl. No. 13/311,660, filed Dec. 6, 2011, Bennett et al.
U.S. Appl. No. 13/597,865, filed Aug. 29, 2012, Bennett et al.
Office Action dated Jan. 26, 2007 with respect to U.S. Appl. No. 10/057,198.
Office Action dated Jul. 3, 2006 with respect to U.S. Appl. No. 10/057,198.
Office Action dated Sep. 20, 2005 with respect to U.S. Appl. No. 10/057,198.
Office Action dated Dec. 4, 2003 with respect to U.S. Appl. No. 10/057,198.
Office Action dated Jan. 12, 2005 with respect to U.S. Appl. No. 10/057,197.
Office Action dated Jun. 3, 2004 with respect to U.S. Appl. No. 10/057,197.
Office Action dated Jun. 5, 2007 with respect to U.S. Appl. No. 10/057,197.
Office Action dated Sep. 21, 2006 with respect to U.S. Appl. No. 10/057,197.
Office Action dated Dec. 15, 2003 with respect to U.S. Appl. No. 10/057,197.
Office Action dated Feb. 12, 2007 with respect to U.S. Appl. No. 10/146,086.
Office Action dated Oct. 30, 2007 with respect to U.S. Appl. No. 10/146,086.
Office Action dated Dec. 13, 2005 with respect to U.S. Appl. No. 10/146,086.
Office Action dated Feb. 16, 2007 with respect to U.S. Appl. No. 10/146,088.
Office Action dated Sep. 28, 2007 with respect to U.S. Appl. No. 10/146,088.
Office Action dated Nov. 21, 2007 with respect to U.S. Appl. No. 10/146,088.
Office Action dated Aug. 13, 2003 with respect to U.S. Appl. No. 10/153,313.
Office Action dated Mar. 8, 2005 with respect to U.S. Appl. No. 10/718,982.
Anderson, M.E. (1982). “Recent Advances in Methodology and Concepts for Characterizing Inhalation Pharmacokinetic Parameters in Animals and Man,” Drug Metabolism Reviews. 13(5):799-826.
Anonymous, (Jun. 1998) Guidance for Industry: Stability testing of drug substances and products, U.S. Department of Health and Human Services, FDA, CDER, CBER , pp. 1-110.
Bennett, R. L. et al. (1981). “Patient-Controlled Analgesia: A New Concept of Postoperative Pain Relief,” Annual Surg. 195(6):700-705.
Benowitz (1994). “Individual Differences in Nicotine Kinetics and Metabolism in Humans,” NIDA Research Monography, 2 pages.
BP: Chemicals Products-Barrier Resins (1999). located at <http://www.bp.com/chemicals/products/product.asp> (visited on Aug. 2, 2001), 8 pages.
Brand, P. et al. (Jun. 2000). “Total Deposition of Therapeutic Particles During Spontaneous and Controlled Inhalations,” Journal of Pharmaceutical Sciences. 89(6):724-731.
Campbell, Fiona A. et al. (2001) “Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systemic review,” BMJ, 323 pp. 1-6.
Carroll, M.E. et al. (1990), “Cocaine-Base Smoking in Rhesus Monkey: Reinforcing and Physiological Effects,” Psychopharmacology (Berl) 102:443-450.
Cichewicz, Diana L. et al. (May 1999) “Enhancement of mu opioid antinociception by oral DELTA 9-tetrahydrocannabinol: Dose response analysis and receptor identification” Journal of Pharmacology and Experimental Therapeutics vol. 289 (2): 859-867.
Clark, A. and Byron, P. (1986). “Dependence of Pulmonary Absorption Kinetics on Aerosol Particle Size,” Z. Erkrank. 166:13-24.
Dallas, C. et al. (1983). “A Small Animal Model for Direct Respiratory and Hemodynamic Measurements in Toxicokinetic Studies of Volatile Chemicals,” Devlopments in the Science and Practice of Toxicology. Hayes, A. W. et al. eds., Elsevier Science Publishers, New York. pp. 419-422.
Darquenne, C. et al. (1997). “Aerosol Dispersion in Human Lung: Comparison Between Numerical Simulations and Experiments for Bolus Tests,” American Physiological Society. 966-974.
Database Biosis “Online!” Biosciences Information Service, Philadelphia, PA 1979, Knight, V. et al., “Amantadine aerosol in humans”, database accession No. PREV 198069035552 abstract, &Antimicrobial Agents and Chemotherapy 16(5):572-578.
Database Biosis “Online!” Biosciences Information Service, Philadelphia, PA 1979, Wilson. S.Z. et al., “Amatadine Aerosol Particle A.erosol Generation and Delivery to Man” Database accession No. PREV198069008137, abstract & Proceedings of the Society for Experimental Biology and Medicine 161(3):350-354.
Database WPI, Section CH, Week 198941, Derwent Publications Ltd., London, GB; Class B07, AN 1989-297792 AP002230849 & JP 01 221313 (Nippon Create 1(K), Sep. 4, 1989, abstract.
Davies, C. N. et al. (May 1972). “Breathing of Half-Micron Aerosols,” Journal of Applied Physiology. 32(5):591-600.
Dershwitz, M., M.D., et al. (Sep. 2000). “Pharmacokinetics and Pharmacodynamics of Inhaled versus Intravenous Morphine in Healthy Volunteers,” Anesthesiology. 93(3): 619-628.
Drugs Approved by the FDA—Drug Name: Nicotrol Inhaler (2000) located at <http://www.centerwatch.com/patient/drugs/dru202.html> (Visited on Aug. 2, 2001), 2 pages.
Feynman, R.P. et al. (1964). “Chapter 32: Refractive Index of Dense Materials” The Feyman Lectures on Physics: Mainly Electromagnetism and Matter. Addison-Wesley: Publishing Company, Inc., Reading, Massachusetts: pp. 32-1-32-13.
Finlay, W. H. (2001). “The Mechanics of Inhaled Pharmaceutical Aerosols”, Academic Press: San Diego Formula 2.39. pp. 3-14 (Table of Contents). pp. v-viii.
Gonda, I. (1991). “Particle Deposition in the Human Respiratory Tract,”Chapter 176, The Lung: Scientific Foundations. Crystal R.G.and West, J.B. (eds.), Raven Publishers, New York. pp. 2289-2294.
Graves, D. A. et al. (1983). “Patient-Controlled Analgesia” Annals of Internal Medicine. 99:360-366.
Hatsukami D., et al. (May 1990) “A Method for Delivery of Precise Doses of Smoked Cocaine-Base to Human.” Pharmacology Biochemistry & Behavior. 36(1):1-7.
Heyder, J. et al. (1986). “Deposition of Particles in the Human Respiratory Tract in the Size Range 0.005-15 μm,” J. Aerosol Sci. 17(5):811-822.
Huizer, H. (1987). “Analytical Studies on Illicit Heron. V. Efficacy of Volitization During Heroin Smoking.” Pharmaceutisch Weekblad Scientific Edition. 9(4):203-211.
Hurt, R. D., MD and Robertson, C. R., PhD, (Oct. 1998). “Prying Open the Door to the Tobacco Industry's Secrets About Nicotine: The Minnesota Tobacco Trial,” JAMA 280(13):1173-1181.
Hwang, S. L. (Jun. 1999). “Artificial Nicotine Studied: R. J. Reynolds Seeks to Develop Drugs that Mimic Tobacco's Potent Effects on Brain,” Wall Street Journal, 3 pages.
James, A.C. et al., (1991). “The Respiratory Tract Deposition Model Proposed by the ICRP Task Group,” Radiation Protection Dosimetry, 38(1/3):159-165.
Kim, M. H. and Patel, D.V. (1994). “‘BOP’ As a Reagent for Mild and Efficient Preparation of Esters,” Tet. Letters 35:5603-5606.
Lichtman, A. H. et al. (1996). “Inhalation Exposure to Volatilized Opioids Produces Antinociception in Mice,” Journal of Pharmacology and Experimental Therapeutics. 279(1):69-76 XP-001118649.
Lichtman, A. H. et al. (2000). “Pharmacological Evaluation of Aerosolized Cannabinoids in Mice” European Journal of Pharmacology, vol. 399, No. 2-3: 141-149.
Lopez, K. (Jul. 1999). “UK Researcher Develops Nicotinic Drugs with R. J. Reynolds,” located at <http://www.eurekalert.org/pub_releases/1999-07/UoKM-Urdn-260799.php> (visited on Oct. 1, 2002), 1 page.
Martin, B. R. and Lue, L. P. (May/Jun. 1989). “Pyrolysis and Volatilization of Cocaine,” Journal of Analytical Toxicology 13:158-162.
Mattox, A.J. and Carroll, M.E. (1996). “Smoked Heroin Self-Administration in Rhesus Monkeys,” Psychoparmacology 125:195-201.
McCormick, A.S.M., et al., “Bronchospasm During Inhalation of Nebulized Midazolam,” British Journal of Anesthesia, vol. 80 (4), Apr. 1988, pp. 564-565 XP001119488.
Meng, Y. et al. (1997). “Inhalation Studies with Drugs of Abuse”, NIDA Research Monogragh 173:201-224.
Meng, Y., et al. (1999). “Pharmacological effects of methamphetamine and other stimulants via inhalation exposure,” Drug and Alcohol Dependence. 53:111-120.
Pankow, J. (Mar. 2000). ACS Conference—San Francisco—Mar. 26, 2000. Chemistry of Tobacco Smoke. pp. 1-8.
Pankow, J. F. et al. (1997). “Conversion of Nicotine in Tobacco Smoke to Its Volatile and Available Free-Base Form through the Action of Gaseous Ammonia,” Environ. Sci. Technol. 31:2428-2433.
Poochikian, G. and Bertha, C.M. (2000). “Inhalation Drug Product Excipient Controls: Significance and Pitfalls,” Resp. Drug Deliv. VII: 109-115.
ScienceDaily Magazine, (Jul. 1999). “University of Kentucky Researcher Develops Nicotinic Drugs with R. J. Reynolds,” located at <http://www.sciencedaily.com/releases/1999/07/990728073542.htm.> (visited on Sep. 23, 2002), 2 pages.
Seeman, J. et al. (1999). “The Form of Nicotine in Tobacco. Thermal Transfer of Nicotine and Nicotine Acid Salts to Nicotine in the Gas Phase,” J. Agric. Food Chem. 47(12):5133-5145.
Sekine, H. and Nakahara, Y. (1987). “Abuse of Smoking Methamphetamine Mixed with Tobacco: 1. Inhalation Efficiency and Pyrolysis Products of Methamphetamine,” Journal of Forensic Science 32(5):1271-1280.
Streitwieser, A. and Heathcock, C. H. eds., (1981). Introduction to Organic Chemistry. Second edition, Macmillan Publishing Co., Inc., New York, pp. ix-xvi. (Table of Contents).
Tsantilis, S. et al. (2001). “Sintering Time for Silica Particle Growth,” Aerosol Science and Technology 34:237-246.
Vapotronics, Inc. (1998) located at http://www.vapotronics.com.au/banner.htm., 11 pages, (visited on Jun. 5, 2000).
Vaughan, N. P. (1990). “The Generation of Monodisperse Fibres of Caffeine” J. Aerosol Sci. 21(3): 453-462.
Ward, M. E. MD, et al. (Dec. 1997). “Morphine Pharmacokinetics after Pulmonary Administration from a Novel Aerosol Delivery System,” Clinical Pharmocology & Therapeutics 62(6):596-609.
Williams, S. (Feb. 1999). “Rhone-Poulenc Rorer Inc. and Targacept Inc. Announce Alliance to Develop New Drugs to Treat Alzheimer's and Parkinson's Diseases” located at http://www.rpr.rpna.com/ABOUT_RPR/pressrels/1999/990209-targa.html (last visited on Jan. 28, 2000) 1 page.
Wood, R.W. et al. (1996). “Methylecgonidine Coats the Crack Particle.” Pharmacology Biochemistry & Behavior. 53(1):57-66.
Wood, R.W. et al. (1996). “Generation of Stable Test Atmospheres of Cocaine Base and Its Pyrolyzate, Methylecgonidine, and Demonstration of Their Biological Activity.” Pharmacology Biochemistry & Behavior. 55(2):237-248.
Related Publications (1)
Number Date Country
20170281884 A1 Oct 2017 US
Provisional Applications (1)
Number Date Country
60296225 Jun 2001 US
Continuations (3)
Number Date Country
Parent 14078577 Nov 2013 US
Child 15633508 US
Parent 13078600 Apr 2011 US
Child 14078577 US
Parent 10146080 May 2002 US
Child 13078600 US
Continuation in Parts (2)
Number Date Country
Parent 10057198 Oct 2001 US
Child 10146080 US
Parent 10057197 Oct 2001 US
Child 10057198 US