ES2361908T3 - AN AEROSOL TRAINING DEVICE FOR USE IN INHALATION THERAPY. - Google Patents

Abstract

A device for administering aerosols containing inhalation therapy drug comprising: a housing (10); an air channel (102) in the housing, the air channel comprising a sub-assembly (80), the sub-assembly comprising a metal substrate (64); a composition comprising a drug (60) coated on the substrate; and a heater system (64) for heating the substrate to form a vapor comprising the drug, the air channel further comprising a gas / vapor mixing area for aerosol formation, the device further comprising means for controlling the rate of vaporization of the composition, introduction of carrier gas and mixing of resulting vapors and carrier gas so that stable aerosol particles of a range of selected size are produced from the vapor comprising the drug.

Description

FIELD OF THE INVENTION

[0001] The present invention relates to inhalation administration of aerosols containing small particles. Specifically it refers to a device that forms aerosols that contain drug for use in inhalation therapy.

BACKGROUND OF THE INVENTION

[0002] There are currently several devices authorized for administration by inhalation of drugs that include dry powder inhalers, nebulizers and pressurized metered dose inhalers. However, together with the particular drugs, the devices also administer a wide range of excipients.

[0003] It is desired 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.

[0004] WO 94/09842 refers to a device in which a thin layer of a pharmaceutically active drug is coated on the surface of an electrically conductive metal that heats and converts the drug into a gaseous phase when a current is passed Through the metal.

SUMMARY OF THE INVENTION

[0005] The present invention relates to inhalation administration of aerosols containing small particles. Specifically it refers to a device that forms aerosols containing drug for use in inhalation therapy as defined in claim 1.

[0006] In one aspect of the present invention there is provided a device for administering aerosols containing drug for inhalation therapy. The device includes a housing and an air channel having an area of the gas / steam mixture air channel. The air channel additionally includes a sub-assembly having a metal substrate coated on its surface with a composition comprising a drug.

[0007] Normally, the device additionally includes a heater system. Preferably, the heater system is an inductive heater system. More preferably, it is an inductive heating system that has a ferrite toroid.

[0008] Normally, the air channel contains a restricted cross-sectional area along the gas / steam mixing area. Preferably, the air channel additionally includes means for causing turbulence as the air moves through the air channel.

[0009] Normally, the drug has a decomposition rate of less than 0.15. Preferably, the drug has a decomposition rate of less than 0.10. More preferably, the drug has a decomposition rate of less than 0.05.

[0010] Typically, the drug of the composition is of one of the following classes: antibiotics, anticonvulsants, antidepressants, antiemetics, antihistamines, antiparkinsonian drugs, antipsychotics, anxiolytics, erectile dysfunction drugs, migraine headache drugs, treatment drugs of alcoholism, drugs for the treatment of addiction, muscle relaxants, nonsteroidal anti-inflammatory drugs, opioids, other analgesics and stimulants.

[0011] Normally, if the drug is an antibiotic, it is selected from one of the following compounds: cefmetazole; cefazolin; cephalexin; cefoxitin; cefacetrile; cephaloglycine; cephaloidin; cephalosporins such as cephalosporin C; cephalothin; cephamycins such as cephamycin A, cephamycin B and cephamycin C; cefapirin; cefradine; ampicillin; amoxicillin; hetacillin; carfecillin; carindacillin; carbenicillin; amylpenicillin; azidocillin; benzylpenicillin; clomethocylin; cloxacillin; cyclacillin; methicillin; nafcillin; 2-pentenylpenicillin; penicillins such as penicillin N, penicillin O, penicillin S, penicillin V; chlorobutine-penicillin; dicloxacillin; diphenicillin; heptylpenicillin; and methampicillin.

[0012] Normally, if the drug in an anticonvulsant is selected from one of the following compounds: gabapentin, thiagabine and vigabatrin.

[0013] Normally, if the drug is an antidepressant, it is selected from one of the following compounds: amitriptyline, amoxapine, benmoxine, butriptyline, clomipramine, desipramine, dosulepine, doxepine, imipramine, kitanserin, lofepramine, mediphoxamine, mianserine, maolinaerin, molina serine, molina serine, molina serine, molina serine nortriptyline, protriptyline, trimipramine, viloxazine, citalopram, cotinine, duloxetine, fluoxetine, fluvoxamine, milnacipran, nisoxetine, paroxetine, reboxetine, sertraline, tianeptine, acetafenazina, binedaline, brofaromine, cericlamine, clovoxamine, iproniazid, isocarboxazid, moclobemide, phenylhydrazine, phenelzine, selegiline, sibutramine, tranylcypromine, ademethionine, adrafinyl, amesergida, amisulpride, amperozide, benactizine, bupropion, caroxazone, gepirone, idazoxane, metralindole, milnacipran, ninaprine, nefazodone, nomifensin, rhitansinone Venlafaxine and Zalospirone.

[0014] Normally, if the drug is an antiemetic, it is selected from one of the following compounds: alizapride, azasetron, benzoquinamide, bromoprida, buclizine, chlorpromazine, cynarizine, cleboprida, cycizine, diphenhydramine, diphenidol, dolasetron methanestronate, droperidol, droperidol, hioscin, lorazepam, metoclopramide, metopimazine, ondansetron, perphenazine, promethazine, prochlorperazine, scopolamine, triethylperazine, trifluoperazine, triflupromazine, trimethobenzamide, tropisetron, domeridone and palonosetron.

[0015] Normally, if 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.

[0016] Normally, if the drug is an antiparkinsonian drug, one of the following compounds is selected: amantadine, baclofen, biperidene, benzotropin, orphenadrine, procyclidine, trihexyphenyl, levodopa, carbidopa, selegiline, deprenyl, andropinyrol, apomorphine, apomorphine, apomorphine, apomorphine, apomorphine, apomorphine, apomorphine, apomorphine budipina, cabergoline, dihydroergocriptine, eliprodil, eptastigmine, ergoline pramipexole, galantamine, lazabemide, lisuride, mazindole, memantine, mofegiline, pergolide, pramipexole, propentophilin, rasagiline, remacemide and spinamine, tergpona, tolramine, tergum, entacacaca, tergadine, tolramine, tergum, entacacaca.

[0017] Normally, if the drug is an antipsychotic drug, it is selected from one of the following compounds: acetofenazine, alizapride, amperozide, benperidol, benzoquinamide, bromperidol, buramate, butaperazine, carfenazine, carpipramine, chlorpromazine, chlorprotixen, clocapramine, chlocapramine, chlocapramine, chlocapramine, chlocapramine, chlocapramine, chlocapramine, chlocapramine, chlocapramine, chlocapraminophenol Clospirazine, Clotiapine, Ciamemazine, Droperidol, Flupentixol, Fluphenazine, Fluspirilene, Haloperidol, Mesoridazine, Metofenazate, Molindrona, Penfluridol, Periciazine, Perphenazine, Pimozide, Pipamerona, Piperacetazine, Piploropyriazine, Piploromazine, Piploromazine, Piploromazine, Piploromazine, Piploromazine, Piploromazine, Piploromazine, Piploromazine, Piploromazine, Piploromazine, Piploromazine, Piploromazine, Piploromazine, Piprepyrizinone thiothixen, trifluperidol, triflupromazine, trifluoperazine, ziprasidone, zotepine, zuclopenthixol, amisulpride, butaclamol, clozapine, melperone, olanzapine, quetiapine and risperidone.

[0018] Normally, if the drug is an anxiolytic, it is selected from one of the following compounds: meclocualone, medetomidine, metomidate, adinazolam, chlordiazepoxide, clobenzepam, flurazepam, lorazepam, loprazolam, midazolam, alpidem, alseroxlon, amfenidyl bromide, amphenol, bromide Buspirone, calcium Ncarboamoylaspartate, captodiamine, capuride, carbcloral, carbromal, chloral betaine, enciprazine, flesinoxane, ipsapirone, lesopitron, loxapine, methaqualone, metiprilon, propanolol, tandospirone, trazadone, zopiclone and zopiclone.

[0019] Normally, if the drug is an erectile dysfunction drug, it is selected from one of the following compounds: cialis (IC351), sildenafil, vardenafil, apomorphine, apomorphine diacetate, phentolamine and yohimbine.

[0020] Normally, if the drug is a migraine headache drug, it is selected from one of the following compounds: almotriptan, alperopride, codeine, dihydroergotamine, ergotamine, eletriptan, frovatriptan, isometeptene, lidocaine, lisuride, metocloptamide, naratrodonane, naratrodone propoxyphene, rizatriptan, sumatriptan, tolfenamic acid, zolmitriptan, amitriptyline, atenolol, clonidine, cyproheptadine, diltiazem, doxepine, fluoxetine, lisinopril, methysergide, metoprolol, nadolol, nortriptyline, pyripotin, protriptyl pyrotinol, paroxysphenol, paroxysphenol, paroxysphenol, paroxysphenol, paroxysphenol, paroxysphotamine .

[0021] Normally, if the drug is a drug for the treatment of alcoholism, it is selected from one of the following compounds: naloxone, naltrexone and disulfiram.

[0022] Normally, if the drug is a drug for addiction treatment, it is buprenorphine.

[0023] Normally, if the drug is a muscle relaxant, it is selected from one of the following compounds: baclofen, cyclobenzaprine, orphenadrine, quinine and tizanidine.

[0024] Normally, if the drug is a non-steroidal anti-inflammatory drug, it is selected from one of the following compounds: aceclofenac, alminoprofen, amfenac, aminopropylone, amixetrin, benoxaprofen, bromfenac, bufexamaco, carprofen, choline, salicylate, zincofen, chlophene, cinmecoprine clomethacin, diclofenac, etodolac, indoprofen, mazipredone, meclofenamate, piroxicam, pirprofen and tolfenamate.

[0025] Normally, if the drug is an opioid, it is selected from one of the following compounds: alfentanil, allylprodin, alphaprodin, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, carbifen, cipramadol, clonitazene, codeine, dextromopoxide, dextropropoxide, dextropropoxamide dihydrocodeine, diphenoxylate, dipipanone, fentanyl, hydromorphone, L-alpha-acetyl methadol, lofentanil, levorphanol, meperidine, methadone, meptazinol, metopon, morphine, nalbuphine, nalorphine, oxycodone, papaveretum, petidine, pentazole, pentazole, pentazole, pentazole tracinate

[0026] Normally, if the drug is another analgesic, it is selected from one of the following compounds: apazone, benzopiperilone, benzidramine, caffeine, clonixin, ethoheptazine, flupirtine, nefopam, orphenadrine, propacetamol and propoxyphene.

[0027] Normally, if the drug is a stimulant, it is selected from one of the following compounds: amphetamine, brucine, caffeine, dexfenfluramine, dextroamphetamine, ephedrine, fenfluramine, mazindole, methylphenidate, pemoline, phentermine and sibutramine.

[0028] A method of forming an aerosol containing drug for use in inhalation therapy is also described. The process includes heating a substrate coated with a composition comprising a drug to form a vapor and mixing the steam with a volume of air so that an aerosol having particles is formed. The median of the aerodynamic diameter of the mass of the particles formed is stable for at least 1 s.

[0029] Normally, the substrate is heated by moving it through a heating zone. Preferably, the heating zone is mainly produced by eddy currents induced by an alternating magnetic field.

[0030] Normally, the aerosol formed includes approximately 109 particles / cc of air.

[0031] Typically, the drug of the composition is one of the drugs or classes of drugs described above with respect to a device of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Additional features and advantages will be 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 global system for conducting experiments using an example of laboratory of a device of the present invention; FIG. 2 is a perspective view from above, from the right and front end of the example shown in FIG. one; FIG. 3 is a partial cross-sectional and partial schematic side view of the example shown in FIG. 2; FIG. 4 is a view from an end in partial cross-section and partial schematic 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 alternative example of the device of the present invention using a warning device; FIG. 7 is a perspective view from above, from the left and front end of the removable subassembly containing the compound and a sliding mobile element of the example shown in FIG. 2 showing the

subassembly that is mounted inside the sliding element; FIG. 8 is a schematic view of the heating element of the example shown in FIG. 2 What shows the electric drive circuit; FIG. 9 is a schematic side view of a second example of the present invention using a tube of Venturi; FIG. 10 is a schematic side view of a fourth example of the present invention using a tube of thin walls 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 a inductive heating system that generates an alternating magnetic field; FIG. 13 is a schematic side view of an alternative example of that shown in FIG. 10 using a flow reducer inside the thin-walled tube; FIG. 14 is a schematic side view of a fifth example of the present invention using a container expandable 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 recirculation of the inert atmosphere on the surface of the compound; FIG. 17 is a schematic side view of a seventh example of the present invention using a tube that contains particles coated with the compound; FIG. 18 is a schematic side view of the example shown in FIG. 17 using a system of heating to heat the gas that passes over the coated particles; FIG. 19 is a schematic side view of an eighth example of the present invention cited in this document as the "oven device"; FIG. 20 is a schematic side view of a ninth example of the present invention using heating in gradient; FIG. 21 is a schematic side view of a tenth example of the present invention using a screen fine mesh coated with the compound; FIG. 22 is a perspective view from above, from the right and front end of the example shown in FIG. twenty-one; FIG. 23 is a representation of the aggregation rate of smaller particles into larger ones; FIG. 24 is a representation of the coagulation coefficient (K) against the particle size of the compound; FIG. 25 is a representation of the vapor pressure of various compounds, for example, diphenyl ether, hexadecane, geranyl formate and caproic acid, versus temperature; FIG. 26 is a representation 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. one; FIG. 27 is a representation of the median mass diameter (MDM) calculated and experimental versus the mass of compounds in the range of 10 to 310 µg; FIG. 28 is a representation of the calculated and experimental MDM against the mass of compounds in the range of 10 to 310 µg; Y FIG. 29 is a representation of the theoretical size (diameter) of an aerosol as a function of the ratio of vaporized compound with the volume of the mixing gas.

DETAILED DESCRIPTION

Definitions

[0033]

"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 sedimentation rate 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 purity in percentage of the aerosol generated of 1. "Drug" refers to any chemical compound used in the prevention, diagnosis, treatment or cure of disease, for pain relief, or to control or improve any physiological or pathological disorder in humans or animals. Such compounds are frequently listed in the vademecum (Medical Economics Company, Inc. at Montvale, NJ, 56th edition, 2002).

[0034] Exemplary drugs include the following: cannabis cannabinoid extracts, THC, ketorolac, fentanyl, morphine, testosterone, ibuprofen, codeine, nicotine, vitamin A, vitamin E acetate, vitamin E, nitroglycerin, pilocarpine, mescaline , testosterone enanthate, menthol, fencaramide, metsuximide, eptastigmine, promethazine, procaine, retinol, lidocaine, trimeprazine, isosorbide dinitrate, thymolol, methiprilon, etamifilin, propoxyphene, salmetrol, vitamin E succinate, methadone isol, tertolol, methadol, methadol etacualone, vitamin D3, ethambutol, ritodrine, omoconazole, cocaine, lomustine, ketamine, ketoprofen, cilazaprol, propranolol, sufentanil, metaproterenol, pentoxifylline, testosterone propionate, valproic acid, acebutolol, terbutaline, diazentam, peptide, H-diazentam, peptide papaverine, nicergoline, fluconazole, zafirlukast, testosterone acetate, droperidol, atenolol, metoclopramide, enalapril, albuterol, k ethotifen, isoproterenol, amiodarone HCl, zileuton, midazolam, oxycodone, cilostazol, propofol, nabilone, gabapentin, famotidine, lorezepam, naltrexone, acetaminophen, sumatriptan, bitolterol, nifedipine, phenobarmine retinal phenylamine , amlodipine, caffeine, zopiclone, tramadol HCl, pyrbuterol naloxone, meperidine HCl, trimethobenzamide, nalmefene, scopolamine, sildenafil, carbamazepine, procaterol HCl, methysergide, glutathione, olanzapine, zolpidem, leplospirp, same mixtures.

[0035] Normally, the drug of the composition is of one of the following classes: antibiotics, anticonvulsants, antidepressants, antiemetics, antihistamines, antiparkinsonian drugs, antipsychotics, anxiolytics, erectile dysfunction drugs, migraine headache drugs, treatment drugs of alcoholism, drugs for the treatment of addiction, muscle relaxants, nonsteroidal anti-inflammatory drugs, opioids, other analgesics, cannabinoids and stimulants.

[0036] Normally, if the drug is an antibiotic, it is selected from one of the following compounds: cefmetazole; cefazolin; cephalexin; cefoxitin; cefacetrile; cephaloglycine; cephaloidin; cephalosporins such as cephalosporin C; cephalothin; cephamycins such as cephamycin A, cephamycin B and cephamycin C; cefapirin; cefradine; ampicillin; amoxicillin; hetacillin; carfecillin; carindacillin; carbenicillin; amylpenicillin; azidocillin; benzylpenicillin; clomethocylin; cloxacillin; cyclacillin; methicillin; nafcillin; 2-pentenylpenicillin; penicillins such as penicillin N, penicillin O, penicillin S, penicillin V; chlorobutin penicillin; dicloxacillin; diphenicillin; heptylpenicillin; and methampicillin.

[0037] Normally, if the drug in an anticonvulsant is selected from one of the following compounds: gabapentin, thiagabine and vigabatrin.

[0038] Normally, if the drug is an antidepressant, it is selected from one of the following compounds: amitriptyline, amoxapine, benmoxine, butriptyline, clomipramine, desipramine, dosulepine, doxepine, imipramine, ketanserin, lofepramine, mediphoxamine, mianserine, molina serine, molina serine, molina serine, molina serine, molina serine nortriptyline, protriptyline, trimipramine, viloxazine, citalopram, cotinine, duloxetine, fluoxetine, fluvoxamine, milnacipran, nisoxetine, paroxetine, reboxetine, sertraline, tianeptine, acetafenazina, binedaline, brofaromine, cericlamine, clovoxamine, iproniazid, isocarboxazid, moclobemide, phenylhydrazine, phenelzine, selegiline, sibutramine, tranylcypromine, ademethionine, adrafinyl, amesergida, amisulpride, amperozide, benactizine, bupropion, caroxazone, gepirone, idazoxane, metralindole, milnacipran, minaprine, nefazodone, nomifensin, ritansilcinate, triphanedinone, trypthylenedinone Venlafaxine and Zalospirone.

[0039] Normally, if the drug is an antiemetic, it is selected from one of the following compounds: alizapride, azasetron, benzoquinamide, bromoprida, buclizine, chlorpromazine, cynarizine, cleboprida, cycizine, diphenhydramine, diphenidol, dolasetron methanesulfonate, dronabolol, dronabolol, dronabolol, dronabolol, dronabolol, dronabolol, dronabolol, dronabolol granisetron, hioscin, lorazepam, metoclopramide, metopimazine, ondansetron, perphenazine, promethazine, prochlorperazine, scopolamine, triethylperazine, trifluoperazine, triflupromazine, trimethobenzamide, tropisetron, domeridone and palonose.

[0040] Normally, if 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.

[0041] Normally, if the drug is an antiparkinsonian drug, it is selected from one of the following compounds: amantadine, baclofen, biperidene, benzotropin, orphenadrine, procyclidine, trihexyphenyl, levodopa, carbidopa, selegiline, deprenyl, andropinyrol, apomorphine, apomorphine, apomorphine, apomorphine, apomorphine , budipina, cabergoline, dihydroergocriptine, eliprodil, eptastigmine, ergoline pramipexole, galantamine, lazabemide, lisuride, mazindole, memantine, mofegiline, pergolide, pramipexole, propentophilin, rasagiline, remacemide and sporminaca, entaminaca, tolramine, tolramine, spiramine, tercamine, tolramine.

[0042] Normally, if the drug is an antipsychotic, it is selected from one of the following compounds: acetofenazine, alizapride, amperozide, benperidol, benzoquinamide, bromperidol, buramate, butaperazine, carfenazine, carpipramine, chlorpromazine, chlorprotixen, clocapramine, chlocapramine, chlocapramine, chlocapramine, chlocapramine, chlocapramine, chlocapramine, chlocapramine, chlocapraminophenol Clospirazine, Clotiapine, Ciamemazine, Droperidol, Flupentixol, Fluphenazine, Fluspirilene, Haloperidol, Mesoridazine, Metofenazate, Molindrona, Penfluridol, Periciazine, Perphenazine, Pimozide, Pipamerona, Piperacetazine, Piploropyriazine, Piploromazine, Piploromazine, Piploromazine, Piploromazine, Piploromazine, Piploromazine, Piploromazine, Piploromazine, Piploromazine, Piploromazine, Piploromazine, Piploromazine, Piploromazine, Piprepyrizinone thiothixen, trifluperidol, triflupromazine, trifluoperazine, ziprasidone, zotepine, zuclopenthixol, amisulpride, butaclamol, clozapine, melperone, olanzapine, quetiapine and risperidone.

[0043] Normally, if the drug is an anxiolytic, it is selected from one of the following compounds: meclocualone, medetomidine, metomidate, adinazolam, chlordiazepoxide, clobenzepam, flurazepam, lorazepam, loprazolam, midazolam, alpidem, alseroxlon, amfenidyl bromide, amphenol, bromide Buspirone, calcium Ncarboamoylaspartate, captodiamine, capuride, carbcloral, carbromal, chloral betaine, enciprazine, flesinoxane, ipsapirone, lesopitron, loxapine, methaqualone, metiprilon, propanolol, tandospirone, trazadone, zopiclone and zopiclone.

[0044] Normally, if the drug is an erectile dysfunction drug, it is selected from one of the following compounds: cialis (IC351), sildenafil, vardenafil, apomorphine, apomorphine diacetate, phentolamine and yohimbine.

[0045] Normally, if the drug is a migraine headache drug, it is selected from one of the following compounds: almotriptan, alperopride, codeine, dihydroergotamine, ergotamine, eletriptan, frovatriptan, isometeptene, lidocaine, lisuride, metocloptamide, naratrodonane, naratrodone propoxyphene, rizatriptan, sumatriptan, tolfenamic acid, zolmitriptan, amitriptyline, atenolol, clonidine, cyproheptadine, diltiazem, doxepine, fluoxetine, lisinopril, methysergide, metoprolol, nadolol, nortriptyline, pyripotin, protriptyl pyrotinol, paroxysphenol, paroxysphenol, paroxysphenol, paroxysphenol, paroxysphenol, paroxysphotamine .

[0046] Normally, if the drug is a drug for the treatment of alcoholism, it is selected from one of the following compounds: naloxone, naltrexone and disulfiram.

[0047] Normally, if the drug is a drug for addiction treatment it is buprenorphine.

[0048] Normally, if the drug is a muscle relaxant, it is selected from one of the following compounds: baclofen, cyclobenzaprine, orphenadrine, quinine and tizanidine.

[0049] Normally, if the drug is a non-steroidal anti-inflammatory drug, it is selected from one of the following compounds: aceclofenac, alminoprofen, amfenac, aminopropylone, amixetrin, benoxaprofen, bromfenac, bufexamaco, carprofen, choline, salicylate, zincofen, chlophene, cinmecoprine clomethacin, diclofenac, etodolac, indoprofen, mazipredone, meclofenamate, piroxicam, pirprofen and tolfenamate.

[0050] Normally, if the drug is an opioid, it is selected from one of the following compounds: alfentanil, allylprodin, alphaprodin, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, carbifen, cipramadol, clonitazene, codeine, dextromopoxide, dextropropoxide, dextropropoxamide dihydrocodeine, diphenoxylate, dipipanone, fentanyl, hydromorphone, L-alpha-acetyl methadol, lofentanil, levorphanol, meperidine, methadone, meptazinol, metopon, morphine, nalbuphine, nalorphine, oxycodone, papaveretum, petidine, pentazole, pentazole, pentazole, pentazole tracinate

[0051] Normally, if the drug is another analgesic, it is selected from one of the following compounds: apazone, benzopiperilone, benzidramine, caffeine, clonixin, ethoheptazine, flupirtine, nefopam, orphenadrine, propacetamol and propoxyphene.

[0052] Normally, if the drug is a cannabinoid it is tetrahydrocannabinol (for example, delta-8 or delta9).

[0053] Normally, if the drug is a stimulant, it is selected from one of the following compounds: amphetamine, brucine, caffeine, dexfenfluramine, dextroamphetamine, ephedrine, fenfluramine, mazindole, methylphenidate, pemoline, phentermine and sibutramine.

[0054] "Drug degradation product" refers to a compound resulting from a chemical modification of a drug. The modification, for example, may be the result of a thermally or photochemically induced reaction. Such reactions include, without limitation, oxidation and hydrolysis.

[0055] "Median of the aerodynamic diameter of the mass" or "MDAM" of an aerosol refers to the aerodynamic diameter for which half of the particulate mass of the aerosol contributes particles with an aerodynamic diameter greater than the MDAM and half with particles with an aerodynamic diameter smaller than MDAM.

[0056] "Stable aerosol" refers to an aerosol in which the MDAM of its constituent particles does not vary more than 50% for a fixed period of time. For example, an aerosol with an MDAM of 100 nm is stable for 1 s if at a time of 1 second later it has an MDAM between 50 nm and 150 nm. Preferably, the MDAM does not vary more than 25% for a fixed period of time. More preferably, the MDAM does not vary more than 20%, 15%, 10% or 5% over time.

Aerosolization device

[0057] Example 1 is described in terms of an in vivo experiment in dogs. However, the example can be easily modified to suit human inhalation, mainly by increasing the flow of air through it.

[0058] With reference 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 operatively connected to a flowmeter 4 (for example, a TSI 4100 flowmeter). The readings of the flowmeter 4 are fed to the electronic system inside the frame 8 shown in FIG. 2. The flowmeter 4 is shown in FIG. 1 within a dotted line to indicate the housing 10. The device controller 20 includes a Chembook laptop model No. N30W that has an activator switch 22 (FIG. 3) and a National Instruments I / O keyboard (model No. SC2345 ) (not shown) that connects to computer 20 to control device 1 and to control the reading of all data collected during the experiments. A software program was developed to carry out these functions using the National Instruments' Labview software program.

[0059] The connection between device 1 and the I / O keyboard is carried out with a cable (for example, DB25, not shown). A standard power supply (for example, Condor F15-15-A +, not shown) supplies power to device 1. Inhalation controller 30 is used to control the rate and volume of inhalation by device 1 in a dog anesthetized by an endotracheal tube 34. The controller 30 has a delay in the containment of programmable breathing at the end of which the exhaust valve 40 is opened on the exhaust line 42 and the dog is allowed to exhale. The filter 50 on line 42 measures the amount of leakage and its composition to monitor any exhaled drug. The air source via the inlet line 54, the inlet valve 58, the flowmeter 4 and the inlet port 59 is from a cylinder of compressed air (not shown).

[0060] Now with reference to FIGS. 3-5 and 7, a dose of compound 60 is deposited on a thin sheet 64 of stainless steel so that the thickness of compound 60 is less than 10 micrometers. In most cases, compound 60 is deposited by preparing a solution of the compound with an organic solvent. This mixture is then applied to the sheet substrate with an automatic pumping system. As shown, the size of the entire sheet 64 (for example, 302 or 304 alloy with 0.01 cm (0.004 inches) thick) is 1.78 by 7.37 cm (0.7 by 29 inches) and The area in which compound 60 is deposited is 0.89 by 4.06 cm (0.35 by 1.6 inches). Other sheet materials may be used, but stainless steel has an advantage over other materials such as aluminum, since it has a much lower thermal conductivity value, while not appreciably increasing the thermal mass. A low thermal conductivity is useful since due to the heat generated in the sheet 64 it could remain in the area of interest (i.e. the heating / vaporization zone 70). The sheet 64 should have a constant cross-section because otherwise the electric currents induced by the heater will not be uniform. The sheet 64 is held in the frame 68, made so that the trailing edge of the sheet 64 has no edge on the mobile sliding element 78, and, therefore, the compound 60, once mixed with the air, is free in a subsequent direction as indicated by arrow 127 of FIG. 3. Frame 68 is normally made of a non-conductive material to resist moderate heat (for example, 200 ° C) and not be chemically reactive with the compound (for example, DELRIN AF®, an acetal copolymer and TEFLON®).

[0061] Subassembly 80, shown in FIG. 7, consists of the frame 68 which has the sheet 64 covered with the compound (60) mounted thereon. The subassembly 80 is secured within the mobile sliding element 78 by placing each of the rear narrowed ends of the frame 68 resting on small rods 86 protruding from each rear end of the sliding element 78 as shown in FIG. 7. The sliding element 78 is driven by the gradual speed motor 88 shown in FIG. 3 that moves the subassembly 80 containing the compound 60 along the longitudinal axis of Example 1. This in turn moves the stainless steel sheet 64 by an alternating magnetic field (it is preferred that the magnetic field be confined within the zone 70 heating / vaporization shown in FIG. 5, as in this laboratory example). Ferrite toroid 90 is used to direct the magnetic field and is placed under sheet 64 (for example, approximately 0.13 cm (0.05 inches) below). As shown in FIG. 5, the heated area 70 is approximately 0.38 by 1.02 cm, (0.15 by 0.4 inches), with the smallest dimension along the direction of travel from left to right (i.e., from the front end towards the back of the device 1) and the largest dimension through the direction of travel (i.e., the width of the device 1).

[0062] Sheet 64 functions both as a substrate for the drug to be administered to the subject as a heating element for vaporization of the drug. The heating element 64 is heated mainly by eddy currents induced by an alternating magnetic field. The alternating magnetic field is produced in ferrite toroid 90 (for example, from Fair-Rite Company) with slot 94 (for example, 0.10 inches

- 0.254 cm wide) which was wound with coil 98 of copper magnetic wire. When an alternating current is passed through the coil 98, an alternating magnetic field is produced in the ferrite toroid 90. A magnetic field fills the gap formed by slot 94 and the marginal lines 100 of magnetic field, shown in FIGS. 5 and 6, extend from the toroid 90. The marginal lines 100 of magnetic field cut the heating element 64. If a ferrite core is used, the frequency of the alternating field is limited to below 1 MHz. In this device a frequency between 100 and 300 kHz is normally used.

[0063] The location and geometry of the eddy currents determine whether the sheet 64 will be heated. As the marginal lines 100 of the magnetic field pass twice through the sheet 64, once when it leaves the ferrite toroid 90 and once when it returns, two current rings are produced, and in opposite directions. One of the rings is formed around the magnetic field lines 100 that leave the toroid 90 and the other ring is formed around magnetic field lines 100 that return to the toroid 90. The current rings overlap directly on the center of the slot 94. Since they were in opposite directions, they add together. Therefore, the greatest heating effect occurs on the center of the groove 94.

[0064] The sliding element 78 and its contents are housed in the air channel 102 constituted by the upper section 104 of the air channel and the lower section 108 of the air channel shown in FIG. 3. The upper section 104 of the air channel is removable and allows the insertion of the mobile sliding element 78, the subassembly 80 and the sheet 64. The lower section 108 of the air channel is mounted on the upper part of the frame 8 that houses the electronics (not shown), magnetic field generator 110, stepper motor 88 and position sensors (not shown). With reference again to FIG. 1, in the upper section 104 of the air duct, the passage 120 and the inlet opening 59 that couples the upper section 104 of the air duct to the flowmeter 4 are mounted upstream. The flowmeter reading 4 is fed to the electronics housed in the frame 8. Additionally, at the rear end of the passage 102 of the air channel, the outlet 124 is connected to a nozzle 126. During administration of the compound 60 to the dog, when attached to the system, the air is forced by the line 54 inlet, flowmeter 4, air channel 102 and outlet 124 in the dog.

[0065] Additionally, a pyrometer at the end of line 130 of TC2 is located within the air channel 102 and is used to measure the temperature of the sheet 64. Due to the specific geometry of the examples shown in FIGS. 1-7, the reading of the sheet 64 is taken after the heating zone 70. Calibration of thermal deterioration between heating zone 70 and the measuring 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 line 132 of TC1 at outlet 124 and is used to monitor the temperature of the air supplied to the dog.

[0066] In a preferred example of the experimental device, the removable block 140, mounted on the upper section 104 of the air channel, restricts an area of the cross section of the air channel 102 and provides a specific mixing geometry inside. In this preferred example, the air channel 140 reduces the roof of the upper section 104 of the air channel (for example, up to within 0.1 cm (0.04 inches)) with respect to the sheet 64. Additionally, the Block 140 contains baffles (for example, 31 steel rods of 0.1 cm (0.04 inches) in diameter, not shown). The rods are oriented perpendicular to the sheet and extend from the top of the upper section 104 of the air channel to a small distance from the sheet (for example, 0.01 cm (0.004 inches)). The rods are placed in a staggered pattern and have sharp square-shaped ends that produce turbulence as the air passes around them. This turbulence ensures the complete mixing of the vaporized compounds with the air that passes through the device.

[0067] 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, the Venturi tube 152 inside the housing 10 having the inlet 154 and the outlet 156 includes a throat 158 between the inlet 154 and the outlet 156 that is used to restrict the flow of gas through the tube 152 from Venturi. Additionally, a controller 160 is designed to control the air flow through a valve 164 based on the thermocouple 168 readings of the air temperature that can be controlled by the heater 166.

[0068] Block 140 is located directly on the heating zone 70 and creates a heating / vaporizing / mixing zone. Before starting the aerosol generation, the sliding element 78 is in the rear position. Then, the sliding element 78, with its contents, enters this anterior position in this heating / vaporizing / mixing zone 70 as energy is applied to the sheet 64 by the inductive heater system described in detail below.

[0069] The device of the present invention is optionally equipped with a warning device. One of the many functions of the warning device is to alert the device operator that a compound is not being vaporized or is being improperly vaporized. The warning 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 handheld aerosolization device 180 of the present invention. As shown, the device 180 includes many of the components of the device 150 discussed above and additionally includes a warning device 170. During the use of the device 180 in which the patient's inhalation rate controls the air flow rate, a signal from the warning device 170 would alert the patient to adjust the inhalation rate to the desired interval. In this case, the controller 160 would be connected to the warning device 170 to send the necessary signal that the flow rate was not within the desired range.

[0070] The induction drive circuit 190 shown in FIG. 8 is used to drive the induction heating element of the device 1. The purpose of circuit 190 is to produce an alternating current in the drive coil 98 wound around the ferrite core 90. Circuit 190 consists of two P-channel transistors 200 and two N-channel MOSFET transistors 202 arranged in a bridge configuration. The MOSFET transistors 200 and 202 connected to the clock pulse generator 219 are switched on and off in pairs by flip-flop 208 of type D by the circuit 210 driving the MOSFET transistor. Flip-flop 208 of type D is connected to produce output Q of flip-flop to alternately change the state of the rising edge of the clock generation signal. One pair of the 200 MOSFET transistors is connected to the Q output on flip-flop 208 of type D and the other pair, 202, is connected to the non-Q output of flip-flop 208. If Q is high (5 volts), a Low impedance connection between the DC power supply (not shown) and the series combination of the drive coil 98 and the capacitor by the pair of 200 MOSFET transistors controlled by the Q output. If flip-flop 208 of type D changes the state and not Q is high, the low impedance connection of the power supply to the series combination drive coil 98 and the capacitor 220 is reversed. Since flip-flop 208 changes the state at the rising edge of the signal of clock generation, two flip-flop changes are required for a complete drive cycle of the induction heating element. The clock generation signal is normally set to twice the resonant frequency of the series combination of the drive coil 90 and the capacitor 220. The frequency of the clock signal can be set manually or automatically.

[0071] 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 with reference to FIG. . 9. In this example, the Venturi tube 152 inside the housing 10 having the inlet 154, the outlet 156 and the throat 158 between the inlet 154 and the outlet 156 is used to restrict the flow of gas through the tube 152 of Venturi Controller 160 is designed to control the air flow through valve 164 based on thermocouple 168 readings of air temperature as a result of heater 166.

[0072] A fourth example (300) of an aerosolization device of the present invention will be described with reference to FIGS. 10 and 11. A stream of gas passes through a thin-walled tube 302 having a coating (310) of the compound 60 therein. The flow rate of the gas stream is controlled by the valve 314. The device of example 300, as with others, allows rapid heating using a resistive heating system (320), while controlling the flow direction of the vaporized compound After the heating system 320 is activated with the actuator 330, the current passes along the tube 302 in the heating / vaporization zone 340 as the carrier gas (eg, air, N2 and the like) passes through the tube 302 and mixed with the resulting steam.

[0073] FIG. 12 shows an alternative heating system for the resistive heating system 320 used in connection with the fourth example. In this case, the inductive heating system 350 consists of a plurality of ferrites 360 to conduct the magnetic flux to vaporize the compound 310.

[0074] FIG. 13 shows a variation of the fourth example in which the flow reducer 370 is mounted inside the thin-walled tube 302 by means of the support 374 inside a housing (not shown) to increase the flow of mixing gas through the surface of compound 310.

[0075] A fifth example 400 of an aerosolization device of the present invention will be described with reference to FIG. 14. For this example, compound 60 is placed inside an expandable container 402 (for example, a foil bag) and is heated by resistance heater 406, which is activated by actuator 410 as shown in FIG. 14. The generated vaporized compound is forced into the container 420 by the outlet passage 440 and mixed with the gas flowing through the tube 404. Additional steps are taken, when necessary, to discard or delay the decomposition of compound 60. One such stage is the removal or reduction of oxygen around 60 during the heating period. This can be done, for example, by sealing the small container housing in an inert atmosphere.

[0076] A sixth example 500 of an aerosolization device of the present invention will be described with reference to FIG. 15. The compound 60 is placed in an inert atmosphere or under a vacuum in the container 502 inside the housing 10 and is heated by the resistance heater 504 after being activated by the actuator 508 as shown in FIG. 15. Once compound 60 has been vaporized, it can then be expelled through the outlet passage 510 in the air stream passing through the tube 520.

[0077] FIG. 16 shows a variation of the device 500 in which the fan 530 recirculates the inert atmosphere on the surface of the compound 60. The inert gas of a cylinder of compressed gas (not shown) enters through the inlet 540 and a one-way valve 550 and exits through the outlet passage 510 in the tube 502.

[0078] A seventh example (600) of an aerosolization device of the present invention will be described with reference to FIG. 17. A compound (not shown), such as compound 60 discussed above, is deposited on a substrate in the form of discrete particles 602 (for example, aluminum oxide (alumina), silica, coated silica, carbon, graphite, earth). diatoms and other packaging materials commonly used in gas chromatography). The coated particles are placed inside the first tube 604, compressed between filters 606 and 608 and heated by the resistance heater 610 which is activated by the actuator 620. The resulting steam from the tube 604 is combined with air or other gas passing through the second tube 625.

[0079] FIG. 18 shows a variation of the device 600 in which the resistance heater 630 heats the air before it passes through the first tube 604 and over the discrete particles 602.

[0080] An eighth example 700 of an aerosolization device of the present invention will be described with reference to FIG. 19. The compound 60 is deposited in the chamber 710 and is heated by the resistance heater 715 which is activated by the actuator 720. After heating, some of the compound 60 vaporizes and is expelled from the chamber 710 by passing an inert gas that enters the housing 10 through the inlet 725 of inert gas and the valve 728 through the surface of the compound. The mixture of inert gas and vaporized compound passes through step 730 and then mixed with a gas passing through tube 735.

[0081] A ninth example 800 of an aerosolization device of the present invention will be described with reference to FIG. 20. The thermally conductive substrate 802 is heated by the resistance heater 810 at the front end of the tube 820, and the thermal energy is allowed to travel along the substrate

802. This produces, when observed at a particular location, a heating rate that is determined from the characteristics of the thermally conductive substrate. By varying the material and the cross-sectional area it was possible to control the heating rate. The resistive heater is incorporated in the substrate 802 at one end. However, it could be incorporated at 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.

[0082] A tenth example 900 of an aerosolization device of the present invention will be described with reference to FIGS. 21 and 22. The air is channeled through a metal screen 902 of fine mesh on which the drug is deposited. The screen 902 is positioned through the passage 910 of the air duct (for example, constructed from an 18 mm glass tube). The two sides of the screen are electrically connected to the capacitor 920 charged by a silicon controlled rectifier 922 (SCR) to make a circuit. The capacitor charge is calculated and set to a value so that when the actuator 930 closes the SCR 922, the energy of the capacitor 920 is converted into a desired temperature increase in the display 902.

General considerations

[0083] The device of the present invention uses a flow of gas (eg, air) through the surface of a compound (60) to sweep vaporized molecules. This procedure triggers vaporization as opposed to condensation and, therefore, allows aerosol formation at relatively moderate temperatures. Nicotine (1 mg, eg 247 ° C / 745 mm), for example, was vaporized in less than 2 s at approximately 130 ° C in a device of the present invention. Similarly, fentanyl (eg> 300 ° C / 760 mm) was evaporated at approximately 190 ° C in amounts up to 2 mg.

[0084] The 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 quickly heating a thin film of the compound to vaporize it. Then, the vapors cool immediately after entering a stream of carrier gas.

[0085] Normally, 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 increase in temperature within the compound is facilitated when it is coated as a thin film (for example, between 10 µ and 10 nm thick). The compound is frequently coated as a film between 5 µ and 10 nm, 4 µ and 10 nm, 3 µ and 10 nm, 2 µ and 10 nm, or even 1 µ at 10 nm thick.

[0086] Rapid increases in temperature and thin coatings ensure that the compounds vaporize substantially in a short time. Normally, more than 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg or 1 mg of a compound vaporizes in less than 100 milliseconds since the onset of heating. Frequently, the same amount of compound is vaporized in less than 75 milliseconds, 50 milliseconds, 25 milliseconds or 10 milliseconds from the start of heating.

[0087] Examples of compounds that have benefited from rapid heating in a device of the present invention include lipophilic substance No. 87 and fentanyl. The lipophilic substance No. 87 decomposed to more than 90% when it was heated at 425 ° C for 5 minutes, but only 20% when the temperature was reduced to 350 ° C. The decomposition of the substance was further reduced to approximately 12% when the heating time was reduced to 30 seconds and to less than 2% to 10-50 milliseconds. A sample of fentanyl completely decomposed when heated at 200 ° C for 30 seconds, and only decomposed 15-30% when heated for 10 milliseconds. Vaporization of fentanyl in device 1 led to less than 0.1% decomposition.

[0088] An aerosol of the present invention contains particles having an MDAM between 10 nm and 1 µ, 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. The particles are produced so that their size is stable for several seconds (for example, 1 to 3 s). The particle size of the aerosol and subsequent stability is controlled by the vaporization rate of the compound, the rate of introduction of carrier gas and the mixing of the resulting vapors and the carrier gas. Such control is carried out using several procedures that include the following: (a) measure the quantity and regulate the flow rate of the mixing air; and / or, (b) regulate the vaporization rate of the compound (for example, by changing the energy transferred to the compound during the heating process or by changing the amount of compound introduced into a heating region).

[0089] A desired particle size is achieved by mixing a compound in its vapor state in a volume of a carrier gas in a ratio so that when the concentration in number of the mixture reaches approximately 109 particles / ml, a particle results which exists in a size range of 10 nm to 100 nm for 1 to 3 seconds.

[0090] FIG. 23 is a representation 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 that the concentration in number of an aerosol needs to be added to half of its original value depending on the concentration of particles. For example, a 1.0 mg vaporized dose of a compound with a molecular weight of 200 that is mixed in 1 liter of air will have approximately 3 x 1018 molecules (particles) in the liter. This produces a concentration in number of 3 x 1015 / cc. Extrapolating from FIG. 23 it can be seen that less than 10 milliseconds is needed for the number of particles to be halved in this example. Therefore, to ensure uniform mixing of a vaporized compound, mixing must occur in a very short period of time. FIG. 23 also shows that when the concentration in number of the mixture reaches

At approximately 109 particles / cc, the particle size is "stable" in order to administer the drug by inhalation.

10-16

[0091] FIG. 23 is for an aerosol that has a coagulation coefficient (K) of 5 x meters3 / second. This value of K corresponds to a particle size of 200 nm. As the

15 particle size, so you can change its value of K. Table 1 below provides the values of K for various particle sizes. As K increases, the time required for the aerosol to be added from a particular particle size to a larger particle size is reduced. As can be seen from Table 1 and FIG. 24, if the particle is in the range of 10 nm to 100 nm, the effect of a change in the value of K tends to accelerate the coagulation process to 100 nm in size.

twenty

Table 1

Particle size (diameter in nm)

Coagulation coefficient (x e-15 meters3 / second)

one

3.11

5

6.93

10

 9.48

twenty

 11.50

fifty

 9.92

100

 7.17

200

 5.09

500

 3.76

1000

 3.35

2000

 3.15

5000

 3.04

10000

 3.00

[0092] In the creation of an aerosol of a particular particle size, the mass ratio of the vaporized compound with respect 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 produce the same particle size distribution (DTP). Other factors must be known in order to accurately predict the resulting particle size. The density, polarity and temperature of a compound are examples of some of these factors. Additionally, if the compound is hydrophilic or hydrophobic, it will affect the eventual particle size because this fact affects the tendency of a

30 spray to grow by drinking water from the surrounding environment.

[0093] In order to simplify the solution used to predict the resulting particle size the following assumptions were made:

35 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 resulting aerosol is at or near the standard temperature and pressure.

Four.

 The coagulation coefficient is constant with respect to the particle size range and, therefore, the number concentration that predicts the stability of the particle size is constant.

[0094] Therefore, the following variables are considered in the prediction of the resulting particle size:

one.

 The amount (in grams) of the vaporized compound.

2.

 The volume of the gas (in cc) in which the vaporized compound is mixed.

3.

 The concentration in "stable" number in number of particles / cc.

Four.

 The geometric standard deviation (SDR) of the spray.

[0095] If the SDR is 1, all particle sizes are the same size and, therefore, the calculation of particle size is a matter of dividing the mass of a compound by the number of particles facilitated by the concentration in number and hence calculate the particle size diameter using the density of the compounds. However, the problem is different if the SDR is different from 1. When an aerosol changes from a SDR of 1 to a SDR of 1.35, the median mass diameter (MDM) will increase. MDM is the equilibrium point where an equal mass of material exists in particles of smaller diameter than they exist in particles of larger diameter. As the total mass is not changing as the SDR changes, and as there are large and small particles, the MDM will be larger as the SDR increases because the mass of a particle increases with the cube of its diameter. Therefore, indeed, larger particles carry more weight and the MDM becomes larger to "compensate" the masses.

[0096] To determine the effect of a change in the SDR, the formula for the mass per unit volume of an aerosol can be started given a known MDM, the SDR, the density and the concentration in number. The formula is from "The Mechanics of Inhaled Pharmaceutical Aerosols" (2001, Academic press) of Finlay. The formula

2.39 states that the mass per unit volume of an aerosol is:

M = (N / 6) (MDM) 3 exp [-9/2 (lng) 2]

in which: ρ = density in g / cc N = concentration in number in particles / cc MDM = median of mass diameter (in cm) σg = SDR M = mass per unit volume of aerosol in g / cc

[0097] If the change in MDM is considered as a change of aerosol from one SDR to another, while the density, concentration in number and mass remain unchanged, the following equality can be established:

N / 6 (MDM1) 3 exp [-9/2 (lng1) 2] = N / 6 (MDM2) 3 exp [-9/2 (lng2) 2]

simplifying:

(MDM1) 3 exp [-9/2 (lng1) 2] = (MDM2) 3 exp [-9/2 (lng2) 2]

or

(MDM1) 3 / (MDM2) 3 = exp [-9/2 (lng2) 2] / exp [-9/2 (lng1) 2]

[0098] If the SDR of case 1 is set to 1.0 then:

exp [-9/2 (lng1) 2] = 1

[0099] and therefore:

(MDM1 / MDM2) 3 = exp [-9/2 (lng2) 2]

or:

MDM1 / MDM2 = exp [-3/2 (lng2) 2]

[0100] It is advantageous to calculate the change in the MDM as the changes in the SDR. Solving for MDM2 based on MDM1 and the new DEG2 gives:

MDM2 = MDM1 / exp [-3/2 (lng2) 2] for g1 = 1

[0101] To calculate the MDM1, divide the mass of the compound by the number of particles and then calculate its diameter using the density of the compound. MDM1 = (6C / ρNV) 1/3 for an aerosol with a SDR of 1 in which: C = the mass of the compound in g ρ = density in g / cc (as before) N = concentration in number in particles / cc (as before) V = volume of mixing gas in cc

[0102] The insertion of MDM1 into the previous equation leads to: MDM2 = (6C / ρNVπ) 1/3 / [exp [-3/2 (lnσg2) 2], measured in centimeters.

[0103] A resulting MDM can be calculated from the concentration in number, the mass of the compound, the density of the compound, the volume of the mixing gas and the SDR of the aerosol.

[0104] The vaporization rate required depends on the particle size that you want to create. If the particle size is in the range of 10 nm to 100 nm, then the compound should be mixed, once vaporized, in most cases, in the largest possible volume of air. This volume of air is determined from the physiology of the lung and can be assumed to have a reasonable upper limit of 2 liters. If the volume of air is limited to below 2 liters (for example, 500 cc), a particle that is too large will result, unless the dose is extremely small (for example, less than 50 µg).

[0105] In the range of 10 nm to 100 nm doses of 1-2 mg are possible. If this dose is mixed in 2 liters of air, which will be inhaled in 1-2 seconds, the desired vaporization rate required is in the range of about 0.5 to about 2 mg / second.

[0106] The first example of the present invention is shown in FIG. 1 and is the basic device by which the principles mentioned above have been demonstrated in the laboratory. This device is described in detail in the examples.

[0107] In the second example of the present invention shown in FIG. 9, the use of a reduced cross section of the air channel increases the air velocity through the surface of the compound to approximately 10 meters / second. If the complete mixture is to be produced within 1 millisecond, then the distance that the gas must travel and the vaporized mixture to achieve the complete mixture must not exceed 10 millimeters. However, it is more desirable that the entire mixture be produced before the compound has been added to a larger size, so that a desirable mixing distance is normally about 1 millimeter or less.

[0108] In the fourth example of the present invention shown in FIGS. 10-13, an aerosol having particles with an MDAM in the range of 10 nm to 100 nm is generated allowing air to sweep a thin film of the compound during the heating process. This allows the compound to vaporize at a lower temperature due to the reduction of the partial pressure of the compound near the surface of the film.

[0109] The fifth example shown in FIG. 14, the sixth example shown in FIGS. 15 and 16 and the eighth example shown in FIG. 19 solve a problem with certain compounds that react quickly 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, for example, 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 gas mixture is maintained at a temperature sufficient to keep the compound in its vaporized state, then the gas mixture is injected into a stream of air. The volume of inert gas can also be recirculated on 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 steam into an air or other gas stream through one or more mixing nozzles.

[0110] In the sixth example shown in FIGS. 17-18, the gas passes through a first tube and over discrete substrate particles, which have 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 gas mixture of the first tube is combined with the gas passing through the second tube to rapidly cool the mixture before administering it to a patient.

[0111] The eighth example shown in FIG. 20 is a thermal gradient device that is similar to device 1 used in laboratory experiments. This example also has a heating zone in motion without moving parts made by establishing a heat gradient that crosses from one end of the device to the other over time. As the heating zone moves, the exposed portions of the compound are heated sequentially and vaporized. In this way, the vaporized compound can be introduced into a gas stream over time.

[0112] The ninth example shown in FIGS. 21-22 is the display device and it is preferred to generate an aerosol containing particles with an MDAM greater than 100 nm. In this example, the air is channeled through a fine mesh screen on which the drug has been deposited to be administered to the patient.

[0113] The above examples can create aerosols without significant drug breakdown. This is carried out while maintaining a vaporization rate required to control the particle size using a short-term heating cycle. An air flow is established on the surface of the compound so that, when the compound is heated and reaches the temperature at which vaporization is first possible, the vapors of the resulting compound will immediately cool in the air. In the preferred examples this is accomplished by extending the speed increase and the mixing region along an area that is larger than the region of the heating zone. As a result, precise temperature control is not necessary, since the compound is vaporized at the moment when its vaporization temperature is reached. Additionally, because mixing is also present at the time of vaporization, cooling takes place rapidly after vaporization.

[0114] The application of the present invention to the human administration of drugs by inhalation should take into account the limitations of the human body and the physiology of respiration. There have been many studies of deposition of particles in the lung in the fields of public health, environmental toxicology and radiation safety. Most of the in vivo models and data collected from these studies refer to the exposure of people to homogeneously distributed aerosols in the air they breathe, in which the subject does nothing actively to minimize or maximize particle deposition. in the lung The models of the International Commission on Radiation Protection (ICRP) are examples of this (see James AC, Stahlhofen W, Rudolph G, Egan MJ, Nixon W, Gehr P, Briant JK, The respiratory tract deposition model proposed by the ICRP Task Group , Radiation Protection Dosimetry, 1991; vol. 38: p. 157-168).

[0115] However, in the field of aerosol drug administration, a patient is ordered to breathe in a way that maximizes the deposition of the drug in the lung. This type of breathing normally involves a complete exhalation, followed by a deep inhalation, sometimes at a prescribed inhalation flow rate range, for example, 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 that is inhaled, but is charged in the early part of the breath as an aerosol bolus, followed by a volume of clean air so that the aerosol enters the alveoli and be washed of the conductive airways, bronchial tubes and trachea by the volume of clean air that follows. A typical deep adult human breath has a volume of approximately 2 to 5 liters. In order to ensure constant administration in the entire population of adult patients, administration of the drug bolus will be completed in the first 1-1½ liters or so of the inhaled air.

[0116] As a result of the limitations of human administration of drugs by inhalation, a compound should be vaporized in a minimum amount of time, preferably not more than 1 to 2 seconds. As discussed above, it is also advantageous to keep the vaporization temperature to a minimum. In order to vaporize a compound in 2 seconds or less and for the temperature to be kept to a minimum, the rapid movement of air, in the range of about 10 to about 120 liters / minute, must flow through the surface of the compound.

[0117] The following parameters are optimal in the use of a device of the present invention due to the physiology of the human lung, the physics of particle growth and the physicochemistry of desirable compounds:

(one)

 The compound should be vaporized for approximately 1 to 2 seconds for the creation of particles in the ultrafine range.

(2)

 The compound should rise to the vaporization temperature as quickly as possible.

(3)

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

(4)

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

(5)

 The air or other gas must move quickly through the surface of the compound to achieve the maximum vaporization rate.

(6)

 The heating of the air or other gas should be kept to a minimum, that is, a temperature rise of no more than about 15 ° C over the environment.

(7)

 The compound must be mixed in the air or other gas at a constant rate to have a constant and repeatable particle size.

(8)

 As the velocity of the gas through the vaporized compound increases, the cross-sectional area by the device should decrease. In addition, as the surface area of the compound increases, the heating of the gas increases.

[0118] The design parameters for one of the examples shown in FIGS. 2-5, 7 and 8 are the result of meeting and balancing the competence requirements listed above. An especially important requirement for an aerosol containing particles with an MDAM between 10 nm and 100 nm is that a compound, while it needs to be vaporized within at least a period of 1 second, also needs each portion of the compound to be exposed to a warm-up period that is as short as possible. In this example, the compound is deposited on a sheet substrate and an alternating magnetic field sweeps along a sheet substrate by heating the substrate so that the compound vaporizes sequentially for no more than about a period of time of a second. . Due to the magnetic field scanning action, each segment of the compound has a heating time that is much less than one second.

[0119] In the example observed directly above, the compound is spread on a thin metal sheet. In one of the examples set forth below, stainless steel (302, 304 or 316 alloy) was used in which the surface was treated to produce a rough texture. Other sheet materials may be used, but it is important that the surface and texture of the material is such that it is "moistened" by the compound when the compound is in its liquid phase, otherwise it is possible that the liquid compound is "bothered" , which would frustrate the design of the device and significantly change the volatilization parameters. If the liquid compound "bothers", the compound can be blown in and collected by the air flow without vaporizing. This leads to the administration of a particle size that is uncontrolled and undesirable.

[0120] Stainless steel has advantages over materials such as aluminum because it has a lower thermal conductivity value, without an appreciable increase in thermal mass. The low thermal conductivity is useful because the heat generated by the process needs to be maintained in the immediate area of interest.

EXAMPLES

[0121] The following examples further illustrate various examples of the present invention. These examples are for illustrative purposes and are not intended to limit the scope of the claims in any way.

EXAMPLE 1

In vivo results using Example 1

[0122] This example, Example 1, was designed to administer an experimental dose of fentanyl between 20 µg and 500 µg, in a range of ultrafine particle sizes, in approximately 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. Due to the value of these parameters, the device 1 in this experiment can be considered a ¼ scale device for administering a dose to a human being. It is believed that scaling the device to work with human subjects mainly involves increasing the air flow through the device. The time of introduction of the compound into the heating / vaporization / mixing zone was set so that the compound was vaporized in a volume of air that was adequate for both the volume required by the anatomy of the dog's lung (600700cc) as for the volume necessary to control the ratio of the compound to the air.

[0123] The following was the sequence of events that took place during each operation:

one.

 At the beginning of the execution, the operator started the inhalation controller 30 to start monitoring the data of the pressure transducer 240 and the inlet flowmeter 4.

2.

 Controller 30 sent signals to controller 20 to start Example 1 and to start collecting data from the two temperature sensors and the flowmeter 4.

3.

 After a previously scheduled delay, Example 1 started aerosol generation. (Note: there was a delay of approximately 0.4 seconds between the start of controller 30 and the start of aerosol generation.)

Four.

 After a previously programmed independent delay (of the original trigger signal), the controller 30 opened the inlet valve 58 to begin the forced inhalation of an experimental dog.

5.

 Example 1 completed the aerosol generation during inhalation.

6.

 The controller 30 monitored the flowmeter 4 and the pressure transducer 240 throughout the inhalation and closed the flow in the inlet valve 58 when a previously specified volume or pressure was met. (Note: the previously specified pressure is a safety feature to prevent injury to the object animal. The termination of respiration at the previously specified volume is the desirable event of the experiment.)

7.

 After a delay in breathing containment (5 seconds), the exhaust valve 40 opened and the dog was allowed to exhale.

8.

 The exhaled aerosol was trapped in the exhaust filter 40 for further analysis. Controller 30 recorded values of the following: volume dispensed, terminal pressure, duration of the air set and average flow rate. The controller 20 continuously recorded the resolution in milliseconds, the inlet flow rate, the exhaust flow rate, the blade temperature, the temperature of the nozzle, the position of the sliding element, the on / off time of the heater and other electrical parameters of internal diagnosis.

[0124] Three female Beagle dogs of the same weight received fentanyl at an intravenous bolus dose of 100 µg. 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 (MDAM). The aerosol was administered to dogs anesthetized by the system schematically represented in FIG. 1 with a target administered volume of 600-700 ml of air, followed by a breath containment of 5 seconds. After dosing, plasma samples were obtained for pharmacokinetic analysis at various times from 2 min to 24 h. The rest of the fentanyl in device 1 was recovered and measured. Fentanyl concentrations were measured using a validated GC procedure with a detection limit of 0.2 ng / ml.

[0125] The plasma pharmacokinetics of this example were compared with intravenous (IV) fentanyl (100 µg) in the same dogs. Inhalation of fentanyl produced rapid absorption (Cmax, maximum plasma concentration, 11.6 ng / ml and tmax, maximum time, 2 min) and high bioavailability (84%). The time course of inhaled fentanyl was almost identical to that of fentanyl IV. Therefore, fentanyl UF for inhalation had an exposure profile that was similar to that of an IV injection.

[0126] Standard non-compartmental pharmacokinetic procedures were used to calculate the pharmacokinetic parameters for each animal. The maximum plasma concentration (Cmax) and the maximum time in which it occurred (tmax) were determined by examining the data. The area under the curve (ABC) of plasma concentration versus time was determined. The bioavailability (F) of the inhaled fentanyl was determined as:

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

in which D was the dose and ABC was the ABC determined at the last moment of measurable time.

[0127] FIG. 26 represents the data obtained in blood levels, per dog, for both the IV dose and the inhalation dose using the device 1 as described above in Example 1.

[0128] The fentanyl aerosol was rapidly absorbed, observing the same Tmax (2 min, the earliest time) for both routes of administration. The maximum plasma concentration of the fentanyl aerosol (11.6 ± 1.9 ng / ml) was almost two thirds that of fentanyl IV (17.6 ± 3.6 ng / ml). Plasma concentrations

5 were below the limit of quantification of the assay 6-8 h after IV administration and 3-4 h after aerosol inhalation. Bioavailability calculations were based on the ABC observed at the last measurable time for administration by inhalation. The bioavailability for the inhalation study was 84% based on the nominal fentanyl dose (uncorrected).

10 [0129] The mean elimination half-life in plasma was similar after dose IV (75.4 min) and by inhalation. Half-lives in the distribution phase (3-4 min) were also similar after both routes of administration. Animal variability of pharmacokinetic parameters after inhalation dose was low, with standard deviations (DER <25%) lower than those observed for IV administration.

15 EXAMPLE 2

In vitro results using Example 1

[0130] Table 2 below summarizes the data collected from the use of Example 1 for in vitro tests of fentanyl. The particle size was measured with a Moudi cascade impactor.

Table 2

Compound mass (ug)

Mixing air volume (cc) MDAM (nm) SDR

twenty

 400 71 1.9

25

 400 72-78 1.7-1.8

fifty

 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

25

Use of Example 1 to prepare fine aerosol particles

[0131] In this example, Example 1 was modified slightly and the flow rate was changed as discussed below to prepare a fine aerosol in the particle size range of 1 to 3 micrometers.

[0132] Section 140 of the air channel was removed and the heating / vaporization zone 70 of the air channel was changed. An air channel insert (not shown) had a "roof" that was 0.635 cm (0.25 inches) above the sheet. There were no mixing rods since rapid mixing was not desirable in this example. Due to the changes of these two devices there was much less mixing with the air, therefore, the vapor / aerosol cloud

35 mixed with less air and a larger particle aerosol was produced. The air flow rate was reduced to 1 liter / minute in this example. Again, this allowed the vapor to mix with much less air, producing the largest particle aerosol.

[0133] Some operational problems with high compound loading on sheet 64 were found in

Example 1. The tested compound, dioctyl phthalate (DOP), was an oil and during the aerosolization process, a substantial amount was blown 36 in the direction of the wind and not aerosolized. Three additional design alternatives were made to address this issue that involved changes in the surface of the substrate on which the compound was deposited. In all three alternatives, the substrate was prepared to "hold" the compound by using texture. They were: a) texturing the sheet; b) add a stainless steel screen on the part

45 upper blade; and, c) replace the sheet with a thin stainless steel screen.

[0134] The results of this example are set forth below in Table 3 below:

Table 3

Type of substrate

MDAM, micrometers SDR Dose issued, ug

Textured foil

1.49 micrometers 1.9 97

Textured foil

2.70 micrometers 1.95 824

Thin screen only

1.59 micrometers 1.8 441

Thin screen only

1.66 micrometers 1.8 530

Screen on the sheet

2.42 micrometers 2.2 482

[0135] As shown above, a fine particle size can be prepared with the device 1 5 only by changing the ratio of the compound to the mixing air.

EXAMPLE 4

In vitro results using Example 700

10 [0136] A tank was partially filled with PDO and placed inside an oven (not shown) that had an inlet and outlet. PDO was used as test compound. The tank was purged with helium before heating the tank and its contents at a temperature of 350 ° C. Helium was pumped through the tank and used to bring DOP steam to the exit. The gaseous mixture of helium and the vaporized compound 60 was introduced into mixing tubes of

15 different sizes per nozzle. Each of the tubes had air that moved through them at 14 liters / minute. The nozzle was perpendicular to the flow direction. After this gas mixture was mixed with the air, the resulting aerosol was introduced into a parallel flow diffusion battery for particle size analysis. The results are presented in Table 4 below.

20 Table 4

Mixing tube size (DI)

MDAM SDR

4.8 mm

65 nm 1.3

14 mm

516 nm 3.3

[0137] As can be seen above, as the diameter of the tube became longer, so did the particle size. Additionally, as the diameter became longer, the SDR also became larger. As the tube becomes longer, it is believed that the vaporized gas is introduced into a

The smallest segment of the mixing gas because the gas is being introduced as a point source that leads to an uneven mixing that produces a higher SDR.

EXAMPLE 5

30 In vitro results using Example 800

[0138] To demonstrate the effectiveness of Example 800, a piece of 10.16 cm (4 inches) long of aluminum was equipped with a 150-watt cartridge heater at one end. The heater was fed with a Variac AC power transformer. The thickness of the aluminum was designed to ensure that heat passed through one end

35 from aluminum to another in about 30 seconds.

[0139] In the upper part of the aluminum, an indentation was machined to support the compound and to support one of the two upper covers. The indentation for the compound was approximately 8.89 cm (3.5 inches) long and 1.02 cm (0.4 inches) wide. The indentation had 0.06 cm (0.025 inches) of

40 depth and filled with 1 mg of PDO.

[0140] The first upper part consisted of a flat glass sheet located 0.1 cm (0.04 inches) above the heated surface, creating an air channel. An outlet was fitted at the outlet end that allowed the air to be extracted in an analytical measuring device. The air was circulated through the

45 air at a rate of 15 liters / minute.

[0141] In the second configuration, the upper part was replaced with a half cylinder made of glass. This increased the order of magnitude the cross-sectional area of the air channel.

[0142] The particle size was measured with both configurations and showed that it is affected by the cross-sectional area of the air channel. [0143] The results of the thermal gradient test are set forth in Table 5 below: Table 5

Size and cross section of the roof

MDAM SDR

Little

 92 nm 1.4

Big

 650 nm unknown

[0144] 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

[0145] In this example to produce aerosols, the passage 910 of the air channel was constructed from an 18 mm diameter glass tube. However, the passage can be made in any way with a comparable cross-sectional area and any suitable material. The screen size, the mesh and the amount of compound were chosen in this example so that a gas could pass through the screen without ever interfering with the compound that had been deposited on it.

[0146] Because the internal resistance of the screen was low, that is, between 0.01 and 0.2 ohms, the discharge rate (the RC time constant) of the capacitor was fast and of the order of a few milliseconds, that is, less than 20 milliseconds, preferably in the range of about 2 to about 10 milliseconds. After the discharge of the condenser 902 and the subsequent heating of the screen 902, the deposited compound quickly vaporized. Because the air moved through the screen 902, the vaporized compound quickly mixed with the air and cooled.

[0147] The compound was deposited on the thin stainless steel screen, for example, 200 mesh, made of 316 stainless steel that had measurements of 2.54 cm x 2.54 cm. The capacitor current was passed between one edge and the other. It was not necessary to heat the screen at temperatures comparable to those of the thin sheet in Example 1 because the compound vaporized at a lower temperature due to rapid air movement. The rapid movement of the air allowed the compound to vaporize at a lower vapor pressure, since the air flow constantly removed the compound vapors from the surface as soon as they formed. Therefore, the compound was vaporized at a lower temperature without decomposition.

[0148] Deposition of the compound on the screen was carried out by mixing the compound with an organic solvent until the compound dissolved. The resulting solution was then applied to the thin stainless steel screen 902 and the solvent was allowed to evaporate. Then, the screen was inserted into the support 940 which electrically connected two sides of the screen 902 to the power circuit described above.

[0149] A 10,000 mF condenser was discharged while the gas was passing through screen 902. The rapid heating of the screen resulted in rapid vaporization of the compound in the gas. Therefore, the resulting vaporized compound was mixed in a small volume of the gas. Because the ratio of the compound's mass to the volume of the mixing gas was large, a fine particle aerosol (1-3 micrometer diameter) was made.

EXAMPLE 7

General procedure to screen drugs to determine the profitability of aerosolization

[0150] The drug (1 mg) is dissolved or suspended in a minimum amount of solvent (for example, dichloromethane or methanol). The solution or suspension is pipetted onto the middle portion of a piece of 3 cm by 3 cm of aluminum foil. The coated sheet 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 with the sheet facing down. The vial is left on the hot plate for 10 s after volatilization or decomposition begins. After removing from the hot plate, the vial is allowed to cool to room temperature.

The sheet is removed and the vial is extracted with dichloromethane followed by saturated aqueous NaHCO3. The organic and aqueous extracts are stirred 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 at 225 nm of light. A drug for aerosolization is preferred when the purity of the drug isolated by this procedure is higher

5 to 85%. Such a drug has a decomposition rate of less than 0.15. The decomposition index is reached by subtracting the purity in percentage (ie 0.85) of 1.

Claims (17)

one.

A device for administering aerosols containing inhalation therapy drug that

comprises: a housing (10); an air channel (102) in the housing, the air channel comprising a sub-assembly (80), the sub-assembly comprising a metal substrate (64); a composition comprising a drug (60) coated on the substrate; and a heater system (64) for heating the substrate to form a vapor comprising the drug, the air channel further comprising a gas / vapor mixing area for aerosol formation, the device further comprising means for controlling the rate of vaporization of the composition, introduction of carrier gas and mixing of resulting vapors and carrier gas so that stable aerosol particles of a range of selected size are produced from the vapor comprising the drug.

2.

The device according to claim 1, wherein the device comprises a valve (164) for controlling the flow of gas in said air channel.

3.

The device according to claims 1 or 2, wherein the air channel has an inlet

(54) and an exit (124).

Four.

The device according to claim 3, wherein the air channel extends through the device between said inlet (54) and outlet (124).

5.

The device according to claim 3 or 4, wherein the air channel is arranged to allow a gas to flow from the inlet, through the surface of the composition, to the outlet.

6.

The device according to any one of claims 1 to 5, wherein the heater system is a resistive heater system.

7.

The device according to any one of claims 1 to 5, wherein the heater system is an inductive heater system.

8.

The device according to any one of claims 1 to 6, wherein the air channel contains a restricted cross-sectional area (158) along the gas / steam mixing area.

9.

The device according to claim 8, wherein the air channel includes means for causing turbulence as the air moves through the air channel.

10.

The device according to any one of claims 1 to 9, wherein the metal substrate comprises stainless steel.

eleven.

The device according to any one of claims 1 to 10, wherein the metal substrate is heated at a rate of at least 1000 ° C / s.

12.

The device according to any one of claims 1 to 11, wherein the composition coated on the substrate has a thickness between 10 nm and 10 µm.

13.

The device according to claim 12, wherein the drug has a decomposition rate of less than 0.15.

14.

The device according to claim 13, wherein the drug has a decomposition rate of less than 0.05.

fifteen.

The device according to any one of claims 1 to 14, wherein the air channel contains aerosols containing drug.

16.

The device according to any one of claims 1 to 15, wherein the metal substrate is a sheet that functions as a heating element.

17.

The device of claim 16, wherein the sheet is a stainless steel sheet.