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.
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.
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.
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:
“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
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
Sub-assembly 80, shown in
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
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
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
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
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.
The induction drive circuit 190 shown in
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
A fourth example (300) of an aerosolization device of the present invention will be described in reference to
A fifth example 400 of an aerosolization device of the present invention will be described in reference to
A sixth example 500 of an aerosolization device of the present invention will be described in reference to
A seventh example (600) of an aerosolization device of the present invention will be described in reference to
An eighth example 700 of an aerosolization device of the present invention will be described in reference to
A ninth example 800 of an aerosolization device of the present invention will be described in reference to
A tenth example 900 of an aerosolization device of the present invention will be described in reference to
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.
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
In order to simplify the approach used to predict the resulting particle size, the following assumptions were made:
Consequently, the following variables are taken into consideration in predicting the resulting particle size:
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]
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
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
In the second example of the present invention shown in
In the fourth example of the present invention shown in
The fifth example shown in
In the sixth example shown in
The eighth example shown in
The ninth example shown in
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:
The parameters of the design for one of the examples shown in
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.
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.
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:
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
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.
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.
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.
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:
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.
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.
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.
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:
As shown above, the results confirm that as the cross section becomes larger, so does the particle size.
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.
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.
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.
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 |
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 |
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. |
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