The present invention relates to the delivery of drug amines through an inhalation route. Specifically, it relates to aerosols containing drug amines that are used in inhalation therapy. In one aspect of the present invention, a method of delivering an amine drug in an aerosol form is provided. The method comprises: a) heating a coating, which includes an amine drug salt on a substrate contained in a device to a temperature sufficient to volatilize the amine drug from the coating, b) by said heating, forming an amine drug vapor, and c) during said heating, drawing air through said device, condensing said vapor to form aerosol particles containing less than 10% degradation products of the compound.

Description of the Invention

SUMMARY OF THE INVENTION

The present invention provides methods and reagents for selecting and generating novel amine drug condensation aerosols and vapors, as well as methods of delivering amine drug aerosols, novel thermal vapor compositions, and methods for generating therapeutically effective inhalation doses of condensation aerosols.

In one aspect, the invention provides a method for selecting amine drugs salts for use in forming a condensation aerosol comprising: a. dissolving or suspending a salt form of an amine drug in a solvent, b. coating the suspended or dissolved salt form of the amine drug on a substrate, c. heating the coated substrate to form a compound vapor, d. cooling the vapor to form aerosol particles, e. collecting the aerosol particles, f. analyzing the collected particles to determine the purity of the aerosol particles; and g, selecting the amine drug based on a decomposition index less than 0.15.

Other preferred embodiments are those wherein the amine drug salt is selected from the group consisting of an antibiotic, anticonvulsant, antidepressant, antiemetic, antihistamine, antiparkinsonian drug, antipsychotic, anxiolytic, drugs for erectile dysfunction, drugs for migraine headache, drugs for the treatment of addiction, muscle relaxants, non-steroidal anti-inflammatory, opioid, or analgesics.

Amine drug salts selected by the above method can be used to form novel amine drug condensations aerosols having preferably a mass median aerodynamic diameter between the range of 1 and 5, and less than 10% amine drug decomposition products. More preferable embodiments have a mass median aerodynamic diameter between the range of 1 and 3.

In another aspect of the invention, a method of delivering an amine drug in an aerosol form is provided, comprising: a. heating a coating, which includes an amine drug salt on a substrate contained in a device to a temperature sufficient to volatilize the amine drug from the coating, b. by said heating, forming a amine drug vapor, and c. during said heating, drawing air through said device, condensing said vapor to form aerosol particles containing less than 10% degradation products of the compound.

In more preferred embodiments of the method, the coating of the amine drug salt used has a thickness between about 0.5 and 20 .mu.m and the aerosol particles generated have a mass median aerodynamic diameter between about 1 and 5 micrometers. More preferably, the aerosol particles generated have a mass median aerodynamic diameter of about 1 to 3 micrometers with a geometric standard deviation of about 2.5 or less.

In a third aspect of the invention, novel thermal vapors are provided. These thermal vapors comprise gas and amine drug aerosol particles,

a. wherein said gas comprises an acid halide vapor, organic acid vapor, or organic acid decomposition product vapor, and

b. wherein said amine drug aerosol particles i. comprise at least 10 micrograms of an amine drug and less than 10% amine drug decomposition products relative to said total mass of amine drug in the particles, and ii. have a mass median aerodynamic diameter in the range 1 to 5 micrometers.

These thermal vapors typically further contain a supersaturated amine drug vapor. Preferably such vapor is warmer than ambient temperature, and more preferably such vapor is warmer than 100.degree. C., 200.degree. C., 250.degree. C., or 300.degree. C.

In yet another aspect of the invention, a method is provided for forming a therapeutically effective inhalation does of drug amine aerosol particles with less than 10% degradation products, comprising:

a) providing a drug delivery article comprising a body defining an interior flow-through chamber having upstream and down stream chamber ends and a drug supply unit contained within such chamber, wherein said drug supply unit comprises a heat-conductive substrate coated with a composition comprising at least a therapeutic amount of amine drug salt having a decomposition index less than 0.10;

b) heating said heat-conductive substrate to a temperature of greater than 200.degree. C. over a period of less than 5 seconds, thereby producing a vapor of a therapeutic dose of said amine drug salt; and

c) flowing a gas through said chamber thereby cooling said vapor to form drug amine aerosol particles.

In the preferred embodiments, the thickness of the coating of amine drug salt on the substrate is between about 0.2 and 20 .mu.m. The typical amine drug particle mass median aerodynamic diameter of these embodiments is between about 1 and 5 micrometers. More preferably, the amine drug particle mass median aerodynamic diameter of these embodiments is between about 1 and 3 micrometers. In a more preferred embodiment the thermal vapor consists essential of gas and amine drug aerosol particles.

DETAILED DESCRIPTION OF THE INVENTION

Characteristics of The Amine Drug Salts

Preferably, the drug amine salt is a salt of a drug amine freebase, wherein the salt of the freebase has a molecular weight of greater than 200 grams/mole. More preferably, the drug amine salt has a molecular weight greater than 250 grams/mole, 300 grams/mole, or 350 grams/mole.

Preferably, the drug amine salt has a decomposition index less than 0.15. More preferably, the drug amine salt has a decomposition index less than 0.10. Most preferably, the drug amine salt has a decomposition index less than 0.05. Preferably, the composition that is heated comprises at least 10 percent by weight of drug amine salt. More preferably, the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of drug amine salt.

Typically, the drug amine salt is a salt of a drug amine from 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, and other analgesics.

Typically, where the drug amine salt is a salt of an antibiotic, it is selected from a salt of one of the following compounds: cephalexin; cephaloglycin; cephalosporins, such as cephalosporin C; cephradine; amoxicillin; hetacillin; cyclacillin; and penicillins, such as penicillin N.

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

Typically, where the drug amine salt is a salt of an anticonvulsant, it is selected from a salt of tiagabine.

Typically, where the drug amine salt is a salt of an antidepressant, it is selected from a salt of one of the following compounds: amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine, lofepramine, medifoxamine, mianserin, mirtazapine, nortriptyline, protriptyline, trimipramine, viloxazine, citalopram, cotinine, duloxetine, fluoxetine, fluvoxamine, milnacipran, paroxetine, reboxetine, sertraline, tianeptine, iproniazid, isocarboxazid, moclobemide, phenyhydrazine, phenelzine, selegiline, sibutramine, tranylcypromine, ademetionine, amisulpride, amperozide, benactyzine, bupropion, idazoxan, metralindole, milnacipran, minaprine, nefazodone, nomifensine, ritanserin, roxindole, tofenacin, trazodone, tryptophan, and venlafaxine.

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

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

Typically, where the drug amine salt is a salt of an antiparkisonian drug, it is selected from a salt of one of the following compounds: amantadine, baclofen, biperiden, benztropine, orphenadrine, procyclidine, trihexyphenidyl, levodopa, carbidopa, selegiline, deprenyl, apomorphine, benserazide, bromocriptine, budipine, cabergoline, dihydroergokryptine, pramipexole, galanthamine, lazabemide, lisuride, memantine, mofegiline, pergolide, remacemide, and terguride.

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

Typically, where the drug amine salt is a salt of an anxiolytic, it is selected from a salt of one of the following compounds: diazepam, alprazolam, triazolam, indiplon, zaleplon, mecloqualone, medetomidine, metomidate, adinazolam, chlordiazepoxide, clobenzepam, flurazepam, loprazolam, midazolam, azacyclonol, buspirone, captodiamine, enciprazine, flesinoxan, ipsapirone, lesopitron, loxapine, methaqualone, propanolol, tandospirone, trazadone, zopiclone, and zolpidem.

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

Typically, where the drug amine salt is a salt of a drug for migraine headache, it is selected from a salt of one of the following compounds: almotriptan, alpiropride, eletriptan, 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, pizotyline, propanolol, protriptyline, sertraline, timolol, and verapamil.

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

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

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

Typically, where the drug amine salt is a salt of a nonsteroidal anti-inflammatory, it is selected from a salt of one of the following compounds: aceclofenac, alminoprofen, amfenac, bromfenac, carprofen, cinchophen, diclofenac, etodolac, mazipredone, meclofenamate, pirprofen, and tolfenamate.

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

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

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

Typically, the drug amine salt is a hydrochloric acid salt, hydrobromic acid salt, formic acid salt, acetic acid salt, maleic acid salt, fumaric acid salt, benzoic acid salt or trifluoroacetic acid salt.

Typically, the drug amine salt is selected from a group of salts consisting of brompheniramine maleate, carbinoxamine maleate, chlorpheniramine maleate, cyproheptadine hydrochloride, pyrilamine maleate, buproprion hydrochloride, trimipramine maleate, tranylcypromine hydrochloride, protriptyline hydrochloride, apomorphine diacetate hydrochloride, buprenorphine hydrochloride, nicotine dihydrochloride, nicotine sulfate, apomorphine hydrochloride, diphenhydramine hydrochloride, mexiletine hydrochloride, and nicotine hydrochloride..

Typically, the drug amine salt is a mono- or di-salt (e.g., monohydrochloride or dihydrochloride).

III. Characteristics of The Thermal Vapor, Aerosol and/or Particles

Typically, the particles comprise at least 5 percent by weight of drug amine. Preferably, the particles comprise at least 10 percent by weight of drug amine. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of drug amine.

Typically, the condensation aerosol particles have a mass of at least 0.01 mg. Preferably, the aerosol particles have a mass of at least 0.05 mg. More preferably, the aerosol particles have a mass of at least 0.10 mg, 0.15 mg, 0.2 g or 0.25 mg.

Typically, the particles comprise less than 10 percent by weight of drug amine degradation products relative to drug amine. Preferably, the particles comprise less than 5 percent by weight of drug amine degradation products relative to drug amine. More preferably, the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of drug amine degradation products relative to drug amine.

Typically, the particles comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water.

Typically, the particles of the delivered condensation aerosol have a mass median aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 micrometers. More preferably, the particles have a mass median aerodynamic diameter between the range of 1-3 micrometers.

Typically, the particles of the delivered condensation aerosol have a mass median aerodynamic diameter of greater than 0.01 micrometers. Preferably, the particles have a mass median aerodynamic diameter of greater than 1 micrometers.

Typically, the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 3. Preferably, the geometric standard deviation is less than 2.5. More preferably, the geometric standard deviation is less than 2.3, 2.0, 2.0 or 1.8.

Typically, the delivered aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 100 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 75 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 50 mg/L.

Typically, the delivered aerosol has an inhalable aerosol particle density greater than 10.sup.6 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 10.sup.7 particles/mL or 10.sup.8 particles/mL.

Typically, the rate of inhalable aerosol particle formation of the delivered condensation aerosol is greater than 10.sup.8 particles per second. Preferably, the aerosol is formed at a rate greater than 10.sup.9 inhalable particles per second. More preferably, the aerosol is formed at a rate greater than 10.sup.10 inhalable particles per second.

Typically, the delivered condensation aerosol is formed at a rate greater than 0.5 mg/second. Preferably, the aerosol is formed at a rate greater than 0.75 mg/second. More preferably, the aerosol is formed at a rate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

Typically, the thermal vapor comprises a gas and amine drug aerosol particles, a. wherein said gas comprises an acid halide vapor, organic acid vapor, or organic acid decomposition product vapor, and b. wherein said amine drug aerosol particles i. comprise at least 10 micrograms of an amine drug and less than 10% amine drug decomposition products relative to said total mass of amine drug in the particles, and ii. have a mass median aerodynamic diameter in the range 1 to 5 micrometers.

Typically, the thermal vapor also includes supersaturated amine drug vapor. Generally, the supersaturated amine drug vapor is at a temperature greater than 200.degree. C. More preferably, the temperature of the supersaturated amine drug vapor is greater than 300.degree. C.

Preferably, the composition that is heated comprises at least 10 percent by weight of drug amine salt. More preferably, the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of drug amine salt.

A number of gases can be used in the invention, including but not limited to air, nitrogen, argon, and carbon dioxide. The preferred embodiment includes air as a gas.

Typically, between 0.1 mg and 100 mg of drug amine are delivered to the mammal in a single inspiration. Preferably, between 0.1 mg and 75 mg of drug amine are delivered to the mammal in a single inspiration. More preferably, between 0.1 mg and 50 mg of drug amine are delivered in a single inspiration.

Typically, the delivered condensation aerosol results in a peak plasma concentration of drug amine in the mammal in less than 1 h. Preferably, the peak plasma concentration is reached in less than 0.5 h. More preferably, the peak plasma concentration is reached in less than 0.2, 0.1, 0.05, 0.02 or 0.01 h.

IV. Methods

Selection of Drug Amine Salts for Condensation Aerosols

In one aspect the present invention provides a method of selecting an amine drug salt suitable for use in forming a condensation aerosol, comprising a. dissolving or suspending an amine drug salt in a solvent, b. coating the suspended or dissolved amine drug salt on a substrate, c. heating the coated substrate to form a compound vapor, d. cooling the vapor to form aerosol particles, e. collecting the aerosol particles, f. analyzing the collected particles to determine the purity of the aerosol particles; and g, selecting the amine drug based on a decomposition index less than 0.15.

Substrates on which the composition is heated are of a variety of shapes. Examples of such shapes include, without limitation, cylinders of less than 1.0 mm in diameter, boxes of less than 1.0 mm thickness and virtually any shape permeated by small (e.g., less than 1.0 mm-sized) pores. Preferably, substrates provide a large surface to volume ratio (e.g., greater than 100 per meter) and a large surface to mass ratio (e.g., greater than 1 cm.sup.2 per gram).

A substrate of one shape can also be transformed into another shape with different properties. For example, a flat sheet of 0.25 mm thickness has a surface to volume ratio of approximately 8,000 per meter. Rolling the sheet into a hollow cylinder of 1 cm diameter produces a support that retains the high surface to mass ratio of the original sheet but has a lower surface to volume ratio (about 400 per meter).

A number of different materials are used to construct the substrates. Classes of such materials include, without limitation, metals, inorganic materials, and polymers. The following are examples of the material classes: aluminum, silver, gold, stainless steel, copper and tungsten; silica, glass, silicon and alumina; graphite; polytetrafluoroethylene and polyethylene glycol. Combinations of materials and coated variants of materials are used as well.

Where aluminum is used as a solid support, aluminum foil is a suitable material. Examples of silica, alumina and silicon based materials include amphorous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (an alumina of defined surface area greater than 2 m.sup.2/g from Aldrich, St. Louis, Mo.) and a silicon wafer as used in the semiconductor industry. Chromatography resins such as octadecyl silane chemically bonded to porous silica are exemplary coated variants of silica.

In a preferred embodiment of the invention, the substrate is metallic. In more preferred embodiments, the substrate is aluminum foil or stainless steel.

The heating of the drug amine salt compositions is performed using any suitable method. Examples of methods by which heat can be generated include the following: passage of current through an electrical resistance element; absorption of electromagnetic radiation, such as microwave or laser light; and, exothermic chemical reactions, such as exothermic solvation, hydration of pyrophoric materials, oxidation of combustible materials and heating on a hot plate.

The substrate is typically heated to a temperature of at least 200.degree. C. to vaporize the amine drug salt. In more preferred embodiments, the substrate is heated to at least 300.degree. C., 350.degree. C., or 400.degree. C.

The particles are collected by means known to those of skill in the art; preferred means include collection in a vial or on a filter.

The resultant particles are analyzed by any technique known by those of skill in the art., including those disclosed below under Analysis of Drug Amine Aerosols. Preferred methods of analyses include reverse-phase HPLC by absorption of UV light, typically at 225 nm and LC/MS.

A drug amine salt was preferred for aerosolization where the purity of the drug isolated by this method was greater than 85%. Such a drug amine salt has a decomposition index less than 0.15. The decomposition index was arrived at by substracting the fractional purity (i.e., 0.85) from 1.

Formation and Delivery of Drug Amine Containing Aerosols

Any suitable vaporization method is used to form the aerosols of the present invention. A preferred method, however, involves heating a thin coating or film of a composition comprising a drug amine salt to form a vapor, followed by cooling of the vapor such that it condenses to provide a drug amine comprising aerosol (condensation aerosol). The composition is heated in one of two forms: as pure active compound (i.e., pure drug amine salt); or, as a mixture of active compound and a pharmaceutically acceptable excipient.

Typically, upon heating of the composition, in addition to vaporizing the drug amine, the acidic component of the salt or a decomposition product thereof is also vaporized. For example, upon heating of a salt of a drug amine and an acid, wherein there is an equilibrium between the cationic drug amine plus the anionic acid and the neutral form of the drug amine plus the neutral acid, the acid may vaporize leaving behind the freebase (neutral form) of the drug amine which subsequently vaporizes. Such vaporization may occur at a greater rate if the equilibrium results in a comparatively larger amount of the neutral form of the drug amine and acid, and if the neutral form of the acid has a high vapor pressure (e.g,, HCl). As such, in a preferred embodiment of the invention, the acid component of the drug salt is selected to favor such an equilibrium, or is selected for its high vapor pressure. In cases where the acid component of the drug amine salt is an organic acid, an alternative series of events may occur, which involves decarboxylation of the organic acid to form carbon dioxide plus organic acid decomposition products. Such decarboxylation may leave behind the drug amine in its freebase (neutral) form which may subsequently vaporize. In the case where the organic acid is, for example, lactic or tartaric acid or pyruvic acid, the acid may decompose to generate acetaldehyde in addition to carbon dioxide. In preferred embodiments of the invention the counterion degrades to form carbon dioxide. In other preferred embodiments, the counterion boils at less than 50.degree. C., less than 100.degree. C., or less than 200.degree. C.

In a particularly preferred embodiment, an amine drug aerosol is formed and delivered by a method, comprising: a. heating a coating, which includes an amine drug salt on a substrate contained in a device to a temperature sufficient to volatilize the amine drug from the coating, b. by said heating, forming a amine drug vapor, and c. during said heating, drawing air through said device, condensing said vapor to form aerosol particles containing less than 10% degradation products of the compound.

To deliver a compound through the thermal aerosol route without significant thermal decomposition prior to vaporizing, a key component of the invention involves the use of a coating of the drug as a thin film prior to vaporizing it. Such thin film coatings generally result in vaporization of drug salt amines without substantial decomposition, with thinner coatings generally resulting in less decomposition than thicker coatings. In general, coatings in the range of thickness from 0.05 to 50 micrometers are preferred, with coatings in the range of thickness of 0.1 to 30 micrometers more preferred, and 0.2 to 20 micrometers most preferred. Coatings at the thinner end of the ranges are preferred for drug amines with a substantial tendency to decompose upon heating, whereas the thicker coatings can be employed for drug amines with less tendency to decompose upon heating.

In addition, certain drug amines may undergo decomposition reactions that occur substantially more rapidly in the liquid phase than in the solid phase. For such drug amines, it is particularly preferred to form amine drug salts that sublime upon heating. In a preferred embodiment of the invention, the drug salt amine sublimes at greater than 0.001 atm, 0.01 atm, 0.1 atm, or 1 atm of pressure.

Preferably, the drug amine salt used in the methods of the invention has a decomposition index less than 0.10. More preferably, the drug amine salt has a decomposition index less than 0.05. Preferably, the composition that is heated comprises at least 10 percent by weight of drug amine salt. More preferably, the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of drug amine salt.

Pharmaceutically acceptable excipients that are volatile or nonvolatile may be included in compositions of the methods. Volatile excipients, when heated, are concurrently volatilized, aerosolized and inhaled with drug amine. Classes of such excipients are known in the art and include, without limitation, gaseous, liquid and solid solvents. The following is a list of exemplary carriers within the classes: water; terpenes, such as menthol; alcohols, such as ethanol, propylene glycol, glycerol and other similar alcohols; dimethylformamide; dimethylacetamide; wax;; and mixtures thereof.

Substrates on which the composition is heated are of a variety of shapes. Examples of such shapes include, without limitation, cylinders of less than 1.0 mm in diameter, boxes of less than 1.0 mm thickness and virtually any shape permeated by small (e.g., less than 1.0 mm-sized) pores. Preferably, substrates provide a large surface to volume ratio (e.g., greater than 100 per meter) and a large surface to mass ratio (e.g., greater than 1 cm.sup.2 per gram).

A substrate of one shape can also be transformed into another shape with different properties. For example, a flat sheet of 0.25 mm thickness has a surface to volume ratio of approximately 8,000 per meter. Rolling the sheet into a hollow cylinder of 1 cm diameter produces a support that retains the high surface to mass ratio of the original sheet but has a lower surface to volume ratio (about 400 per meter).

A number of different materials are used to construct the substrates. Classes of such materials include, without limitation, metals, inorganic materials, carbonaceous materials and polymers. The following are examples of the material classes: aluminum, silver, gold, stainless steel, copper and tungsten; silica, glass, silicon and alumina; graphite; polytetrafluoroethylene and polyethylene glycol. Combinations of materials and coated variants of materials are used as well.

Where aluminum is used as a solid support, aluminum foil is a suitable material. Examples of silica, alumina and silicon based materials include amphorous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (an alumina of defined surface area greater than 2 m.sup.2/g from Aldrich, St. Louis, Mo.) and a silicon wafer as used in the semiconductor industry. Chromatography resins such as octadecyl silane chemically bonded to porous silica are exemplary coated variants of silica.

The heating of the drug amine salt compositions is performed using any suitable method. Examples of methods by which heat can be generated include the following: passage of current through an electrical resistance element; absorption of electromagnetic radiation, such as microwave or laser light; and, exothermic chemical reactions, such as exothermic solvation, hydration of pyrophoric materials and oxidation of combustible materials.

Drug amine containing aerosols of the present invention are delivered using an inhalation device. Where the aerosol is a condensation aerosol, the device has at least three elements: an element for heating a drug amine salt containing composition to form a vapor; an element allowing the vapor to cool, thereby providing a condensation aerosol; and, an element permitting inhalation of the aerosol. Various suitable heating methods are described above. The element that allows cooling is, in it simplest form, an inert passageway linking the heating means to the inhalation means. The element permitting inhalation is an aerosol exit portal that forms a connection between the cooling element and the mammal's respiratory system.

One device used to deliver the drug amine containing aerosol is described in reference to FIG. 1 (see Original Patent). Delivery device 100 has a down stream chamber end 102 and a upstream chamber end 104, a drug supply unit 106, a power source 108, and a mouthpiece 110.

A drug amine salt composition is deposited on a surface 112 of the drug supply unit 106. Upon activation of a user activated switch 114, power source 108 initiates heating of the drug supply unit 106 (e.g., through ignition of combustible fuel or passage of current through a resistive heating element). The drug amine composition volatilizes due to the heating of the drug supply unit 106 and condenses to form a condensation aerosol prior to reaching the mouthpiece 110 at the downstream chamber end of the device 102. Air flow traveling from the device upstream chamber end 104 to the mouthpiece 110 carries the condensation aerosol to the mouthpiece 110, where it is inhaled.

Devices, if desired, contain a variety of components to facilitate the delivery of drug amine containing aerosols. For instance, the device may include any component known in the art to control the timing of drug aerosolization relative to inhalation (e.g., breath-actuation), to provide feedback to patients on the rate and/or volume of inhalation, to prevent excessive use (i.e., "lock-out" feature), to prevent use by unauthorized individuals, and/or to record dosing histories.

Dosage of Drug Amine Containing Aerosols

A typical dosage of a drug amine aerosol is either administered as a single inhalation or as a series of inhalations taken within an hour or less (dosage equals sum of inhaled amounts). Where the drug amine is administered as a series of inhalations, a different amount may be delivered in each inhalation. The dosage amount of drug amine in aerosol form is generally no greater than twice the standard dose of the drug amine given orally.

One can determine the appropriate dose of drug amine containing aerosols to treat a particular condition using methods such as animal experiments and a dose-finding (Phase I/II) clinical trial. One animal experiment involves measuring plasma concentrations of drug amine in an animal after its exposure to the aerosol. Mammals such as dogs or primates are typically used in such studies, since their respiratory systems are similar to that of a human. Initial dose levels for testing in humans is generally less than or equal to the dose in the mammal model that resulted in plasma drug levels associated with a therapeutic effect in humans. Dose escalation in humans is then performed, until either an optimal therapeutic response is obtained or a dose-limiting toxicity is encountered.

In another aspect of the invention, a method is provided for forming an effective human therapeutic inhalation dose of drug amine aerosol particles having less than 10% degradation products and a drug amine particle mass median aerodynamic diameter between about 1 and 5 micrometers, comprising: a) providing a drug delivery article comprising a body defining an interior flow-through chamber having upstream and down stream chamber ends and a drug supply unit contained within such chamber, wherein said drug supply unit comprises a heat-conductive substrate coated with a composition comprising at least a therapeutic amount of amine drug salt having a decomposition index less than 0.10; b) heating said heat-conductive substrate to a temperature of greater than 200.degree. C. over a period of less than 5 seconds, thereby producing a vapor of a therapeutic dose of said amine drug salt; and c) flowing a gas through said chamber thereby cooling said vapor to form drug amine aerosol particles

A number of drug delivery devices can be used including the one describe in FIG. 1 and above (see Original Patent).

Preferably, the drug amine salt used in the method of the invention has a decomposition index less than 0.10. More preferably, the drug amine salt has a decomposition index less than 0.05. Preferably, the composition that is heated comprises at least 10 percent by weight of drug amine salt. More preferably, the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of drug amine salt.

The preferred coatings are those that result in vaporization of drug salt amines without substantial decomposition and are in the range of thickness from 0.05 to 50 micrometers. More preferred coatings are in the range of thickness of 0.1 to 30 micrometers, and the most preferred thickness is in the range 0.2 to 20 micrometers.

Analysis of Drug Amine Containing Aerosols

Purity of a drug amine containing aerosol is determined using a number of methods, examples of which are described in Sekine et al., Journal of Forensic Science 32:1271-1280 (1987) and Martin et al., Journal of Analytic Toxicology 13:158-162 (1989). One method involves forming the aerosol in a device through which a gas flow (e.g., air flow) is maintained, generally at a rate between 0.4 and 60 L/min. The gas flow carries the aerosol into one or more traps. After isolation from the trap, the aerosol is subjected to an analytical technique, such as gas or liquid chromatography, that permits a determination of composition purity.

A variety of different traps are used for aerosol collection. The following list contains examples of such traps: filters; glass wool; impingers; solvent traps, such as dry ice-cooled ethanol, methanol, acetone and dichloromethane traps at various pH values; syringes that sample the aerosol; empty, low-pressure (e.g., vacuum) containers into which the aerosol is drawn; and, empty containers that fully surround and enclose the aerosol generating device. Where a solid such as glass wool is used, it is typically extracted with a solvent such as ethanol. The solvent extract is subjected to analysis rather than the solid (i.e., glass wool) itself. Where a syringe or container is used, the container is similarly extracted with a solvent.

The gas or liquid chromatograph discussed above contains a detection system (i.e., detector). Such detection systems are well known in the art and include, for example, flame ionization, photon absorption and mass spectrometry detectors. An advantage of a mass spectrometry detector is that it can be used to determine the structure of drug amine degradation products.

Particle size distribution of a drug amine containing aerosol is determined using any suitable method in the art (e.g., cascade impaction). An Andersen Eight Stage Non-viable Cascade Impactor (Andersen Instruments, Smyrna, Ga.) linked to a furnace tube by a mock throat (USP throat, Andersen Instruments, Smyrna, Ga.) is one system used for cascade impaction studies.

Inhalable aerosol mass density is determined, for example, by delivering a drug-containing aerosol into a confined chamber via an inhalation device and measuring the mass collected in the chamber. Typically, the aerosol is drawn into the chamber by having a pressure gradient between the device and the chamber, wherein the chamber is at lower pressure than the device. The volume of the chamber should approximate the tidal volume of an inhaling patient.

Inhalable aerosol drug amine mass density is determined, for example, by delivering a drug amine-containing aerosol into a confined chamber via an inhalation device and measuring the amount of non-degraded drug collected in the chamber. Typically, the aerosol is drawn into the chamber by having a pressure gradient between the device and the chamber, wherein the chamber is at lower pressure than the device. The volume of the chamber should approximate the tidal volume of an inhaling patient. The amount of non-degraded drug amine collected in the chamber is determined by extracting the chamber, conducting chromatographic analysis of the extract and comparing the results of the chromatographic analysis to those of a standard containing known amounts of drug amine.

Inhalable aerosol particle density is determined, for example, by delivering aerosol phase drug amine into a confined chamber via an inhalation device and measuring the number of particles of given size collected in the chamber. The number of particles of a given size may be directly measured based on the light-scattering properties of the particles. Alternatively, the number of particles of a given size is determined by measuring the mass of particles within the given size range and calculating the number of particles based on the mass as follows: Total number of particles=Sum (from size range 1 to size range N) of number of particles in each size range. Number of particles in a given size range = Mass in the size range/Mass of a typical particle in the size range. Mass of a typical particle in a given size range=.pi.*D.sup.3*.phi./6, where D is a typical particle diameter in the size range (generally, the mean boundary MMADs defining the size range) in microns, .phi. is the particle density (in g/mL) and mass is given in units of picograms (g.sup.-12).

Rate of inhalable aerosol particle formation is determined, for example, by delivering aerosol phase drug amine into a confined chamber via an inhalation device. The delivery is for a set period of time (e.g., 3 s), and the number of particles of a given size collected in the chamber is determined as outlined above. The rate of particle formation is equal to the number of 100 nm to 5 micron particles collected divided by the duration of the collection time.

Rate of aerosol formation is determined, for example, by delivering aerosol phase drug amine into a confined chamber via an inhalation device. The delivery is for a set period of time (e.g., 3 s), and the mass of particulate matter collected is determined by weighing the confined chamber before and after the delivery of the particulate matter. The rate of aerosol formation is equal to the increase in mass in the chamber divided by the duration of the collection time. Alternatively, where a change in mass of the delivery device or component thereof can only occur through release of the aerosol phase particulate matter, the mass of particulate matter may be equated with the mass lost from the device or component during the delivery of the aerosol. In this case, the rate of aerosol formation is equal to the decrease in mass of the device or component during the delivery event divided by the duration of the delivery event.

Rate of drug amine aerosol formation is determined, for example, by delivering a drug amine containing aerosol into a confined chamber via an inhalation device over a set period of time (e.g., 3 s). Where the aerosol is pure drug amine, the amount of drug collected in the chamber is measured as described above. The rate of drug amine aerosol formation is equal to the amount of drug ester aerosol collected in the chamber divided by the duration of the collection time. Where the drug amine containing aerosol comprises a pharmaceutically acceptable excipient, multiplying the rate of aerosol formation by the percentage of drug ester in the aerosol provides the rate of drug aerosol formation.

The drug amine containing aerosols of the present invention are typically used for the same indication for which they are given orally. For instance, baclofen would be used to treat parkinsons disease and fexofenadine would be used to treat allergy symptoms.

As will be apparent to those of skill in the art upon reading of this disclosure, the present invention provides valuable methods relating to amine drug aerosols. The above description of necessity provides a limited and merely illustrative sampling of the specific compounds, substrates, and devices features and should not be construed as limiting the scope of the invention. Other features and advantages of the invention will be apparent from the following examples and claims.
 

Claim 1 of 54 Claims

1. A condensation aerosol for delivery of a drug amine formed by heating a coating of a composition comprising a salt of the drug amine on a substrate, to produce a vapor, and cooling the vapor to form a condensation aerosol comprising particles, wherein the particles comprise at least 10 percent by weight of the drug amine and less than 10 percent by weight of drug amine degradation products, wherein the condensation aerosol has a mass median aerodynamic diameter of less than 5 .mu.m, and wherein the salt of the drug amine has a decomposition index of less than 0.10.
 

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