according to the method of the present invention , physiologically active compounds with real or potential physiological activity can be volatilized along with a second , different compound , without medicinally significant degradation of the physiologically active compound . the resulting vapors can be controlled to produce mixed composition aerosols with average particle sizes in the range useful for administration of the aerosolized physiologically active compound to a patient . physiologically active compounds which have been volatilized using the device and method of the present invention typically have a purity level of at least 90 %; preferably , at least 95 %; more preferably , at least 96 %; and most preferably , at least 97 %. in the preferred embodiments of the present invention , compounds are volatilized into vapors , avoiding medicinally significant degradation and thus maintaining acceptable compound purity , by the steps of : ( 1 ) heating a substrate surface onto which a first which has physiological activity and a second compound that is different from the first compound have been coated to an elevated temperature for a limited time ; and ( 2 ) under the conditions of step ( 1 ), simultaneously passing a gas ( typically ambient air ) across the substrate surface . in commonly assigned , issued u . s . pat . no . 7 , 090 , 830 and copending u . s . application ser . no . 11 / 504 , 419 , the disclosures of which are hereby incorporated by reference in their entireties , we disclosed devices and methods for generating and delivering aerosolized drugs by heating the drug to vaporize at least a portion of the drug , followed by mixing the resulting vapor with a gas , in a ratio , to form a desired particle size when a stable concentration of particles in the gas is reached . pure drug was coated onto the surface of a heating unit which was used to heat the drug to the temperature required for volatilization of the drug . pure ( at least 90 %; or preferably , at least 95 %) drug was then delivered to the patient by inhalation of the aerosolized particles . however , as discussed above in the “ background of the invention ”, delivery of certain drugs could benefit from “ on demand ” generation of condensation aerosol particles containing a mixture of drugs and / or additives for the purpose of controlling pharmacokinetic profiles , improving drug palatability , and / or delivering combination therapeutics . the present invention overcomes the manufacturing complexity and shelf - life stability issues encountered with prior mixed particle aerosol compositions , making it possible to generate mixed particle aerosol compositions “ on demand ” using a simple , inexpensive manufacturing method . the present invention is broadly applicable to a wide variety of drugs . typically , the drug belongs to one of the following classes : antibiotics , anticonvulsants , antidepressants , antiemetics , antihistamines , antiparkisonian drugs , antipsychotics , anxiolytics , drugs for erectile dysfunction , drugs for migraine headaches , drugs for the treatment of alcoholism , drugs for the treatment of addiction , muscle relaxants , nonsteroidal anti - inflammatories , opioids , other analgesics , and stimulants . typically , when the drug is an antibiotic , it is selected from one of the following compounds : cefmetazole ; cefazolin ; cephalexin ; cefoxitin ; cephacetrile ; cephaloglycin ; cephaloridine ; cephalosporins , such as cephalosporin c ; cephalotin ; cephamycins , such as cephamycin a , cephamycin b , and cephamycin c ; cepharin ; cephradine ; ampicillin ; amoxicillin ; hetacillin ; carfecillin ; carindacillin ; carbenicillin ; amylpenicillin ; azidocillin ; benzylpenicillin ; clometocillin ; cloxacillin ; cyclacillin ; methicillin ; nafcillin ; 2 - pentenylpenicillin ; penicillins , such as penicillin n , penicillin o , penicillin s , penicillin v ; chlorobutin penicillin ; dicloxacillin ; diphenicillin ; heptylpenicillin ; and metampicillin . typically , when the drug is an anticonvulsant , it is selected from one of the following compounds : gabapentin , tiagabine , and vigabatrin . typically , when the drug is an antidepressant , it is selected from one of the following compounds : amitriptyline , amoxapine , benmoxine , butriptyline , clomipramine , desipramine , dosulepin , doxepin , imipramine , kitanserin , lofepramine , medifoxamine , mianserin , maprotoline , mirtazapine , nortriptyline , protriptyline , trimipramine , viloxazine , citalopram , cotinine , duloxetine , fluoxetine , fluvoxamine , milnacipran , nisoxetine , paroxetine , reboxetine , sertraline , tianeptine , acetaphenazine , binedaline , brofaromine , cericlamine , clovoxamine , iproniazid , isocarboxazid , moclobemide , phenyhydrazine , phenelzine , selegiline , sibutramine , tranylcypromine , ademetionine , adrafinil , amesergide , amisulpride , amperozide , benactyzine , bupropion , caroxazone , gepirone , idazoxan , metralindole , milnacipran , minaprine , nefazodone , nomifensine , ritanserin , roxindole , s - adenosylmethionine , tofenacin , trazodone , tryptophan , venlafaxine , and zalospirone . typically , when the drug is an antiemetic , it is selected from one of the following compounds : alizapride , azasetron , benzquinamide , bromopride , buclizine , chlorpromazine , cinnarizine , clebopride , cyclizine , diphenhydramine , diphenidol , dolasetron methanesulfonate , droperidol , granisetron , hyoscine , lorazepam , metoclopramide , metopimazine , ondansetron , perphenazine , promethazine , prochlorperazine , scopolamine , triethylperazine , trifluoperazine , triflupromazine , trimethobenzamide , tropisetron , domeridone , and palonosetron . typically , when the drug is an antihistamine , it is selected from one of the following compounds : azatadine , brompheniramine , chlorpheniramine , clemastine , cyproheptadine , dexmedetomidine , diphenhydramine , doxylamine , hydroxyzine , cetrizine , fexofenadine , loratidine , and promethazine . typically , when the drug is an antiparkisonian drug , it is selected one of the following compounds : amantadine , baclofen , biperiden , benztropine , orphenadrine , procyclidine , trihexyphenidyl , levodopa , carbidopa , selegiline , deprenyl , andropinirole , apomorphine , benserazide , bromocriptine , budipine , cabergoline , dihydroergokryptine , eliprodil , eptastigmine , ergoline pramipexole , galanthamine , lazabemide , lisuride , mazindol , memantine , mofegiline , pergolike , pramipexole , propentofylline , rasagiline , remacemide , spheramine , terguride , entacapone , and tolcapone . typically , when the drug is an antipsychotic , it is selected from one of the following compounds : acetophenazine , alizapride , amperozide , benperidol , benzquinamide , bromperidol , buramate , butaperazine , carphenazine , carpipramine , chlorpromazine , chlorprothixene , clocapramine , clomacran , clopenthixol , clospirazine , clothiapine , cyamemazine , droperidol , flupenthixol , fluphenazine , fluspirilene , haloperidol , mesoridazine , metofenazate , molindrone , penfluridol , pericyazine , perphenazine , pimozide , pipamerone , piperacetazine , pipotiazine , prochlorperazine , promazine , remoxipride , sertindole , spiperone , sulpiride , thioridazine , thiothixene , trifluperidol , triflupromazine , trifluoperazine , ziprasidone , zotepine , zuclopenthixol , amisulpride , butaclamol , clozapine , melperone , olanzapine , quetiapine , and risperidone . typically , when the drug is an anxiolytic , it is selected from one of the following compounds : mecloqualone , medetomidine , metomidate , adinazolam , chlordiazepoxide , clobenzepam , flurazepam , lorazepam , loprazolam , midazolam , alpidem , alseroxlon , amphenidone , azacyclonol , bromisovalum , buspirone , calcium n - carboamoylaspartate , captodiamine , capuride , carbcloral , carbromal , chloral betaine , enciprazine , flesinoxan , ipsapiraone , lesopitron , loxapine , methaqualone , methprylon , propanolol , tandospirone , trazadone , zopiclone , and zolpidem . typically , when the drug is a drug for erectile dysfunction , it is selected from one of the following compounds : cialis ( ic351 ), sildenafil , vardenafil , apomorphine , apomorphine diacetate , phentolamine , and yohimbine . typically , when the drug is a drug for migraine headache , it is selected from one of the following compounds : almotriptan , alperopride , codeine , dihydroergotamine , ergotamine , eletriptan , frovatriptan , isometheptene , lidocaine , lisuride , metoclopramide , naratriptan , oxycodone , propoxyphene , rizatriptan , sumatriptan , tolfenamic acid , zolmitriptan , amitriptyline , atenolol , clonidine , cyproheptadine , diltiazem , doxepin , fluoxetine , lisinopril , methysergide , metoprolol , nadolol , nortriptyline , paroxetine , pizotifen , pizotyline , propanolol , protriptyline , sertraline , timolol , and verapamil . typically , when the drug is a drug for the treatment of alcoholism , it is selected from one of the following compounds : naloxone , naltrexone , and disulfuram . typically , when the drug is a drug for the treatment of addiction it is buprenorphine . typically , when the drug is a muscle relaxant , it is selected from one of the following compounds : baclofen , cyclobenzaprine , orphenadrine , quinine , and tizanidine . typically , when the drug is a nonsteroidal anti - inflammatory , it is selected from one of the following compounds : aceclofenac , alminoprofen , amfenac , aminopropylon , amixetrine , benoxaprofen , bromfenac , bufexamac , carprofen , choline , salicylate , cinchophen , cinmetacin , clopriac , clometacin , diclofenac , etodolac , indoprofen , mazipredone , meclofenamate , piroxicam , pirprofen , and tolfenamate . typically , when the drug is an opioid , it is selected from one of the following compounds : alfentanil , allylprodine , alphaprodine , anileridine , benzylmorphine , bezitramide , buprenorphine , butorphanol , carbiphene , cipramadol , clonitazene , codeine , dextromoramide , dextropropoxyphene , diamorphine , dihydrocodeine , diphenoxylate , dipipanone , fentanyl , hydromorphone , l - alpha acetyl methadol , lofentanil , levorphanol , meperidine , methadone , meptazinol , metopon , morphine , nalbuphine , nalorphine , oxycodone , papavereturn , pethidine , pentazocine , phenazocine , remifentanil , sufentanil , and tramadol . typically , when the drug is an other analgesic it is selected from one of the following compounds : apazone , benzpiperylon , benzydramine , caffeine , clonixin , ethoheptazine , flupirtine , nefopam , orphenadrine , propacetamol , and propoxyphene . typically , when the drug is a stimulant , it is selected from one of the following compounds : amphetamine , brucine , caffeine , dexfenfluramine , dextroamphetamine , ephedrine , fenfluramine , mazindol , methyphenidate , pemoline , phentermine , and sibutramine . drugs which would particularly benefit from controlled pulmonary delivery according to the present invention include triptans , citalopram , triamterene , isoniazid , and combinations of various respiratory and systemic drugs . the drug may be a triptan selected from the group consisting of rizatriptan , sumatriptan , naratriptan , zolmitriptan , eletriptan , almotriptan , and frovatriptan . for purposes of modulating dissolution and / or pharmacokinetic absorption of the drug , the second compoundis typically selected from the group consisting of long - chain fatty acids , alcohols , amines , and hydrocarbons ; for example and not by way of limitation , palmitic acid , hexadecanol , hexadecyl amine , and / or hexadecane may be used . for purposes of altering vaporization characteristics , high vapor pressure or sublimable second compounds , such as maltol , benzoic acid , caffeine , fumaric acid , norvaline , and / or menthol , for example and not by way of limitation , may be used . for purposes of improving drug palatability of undesirable tasting drugs , taste attenuating agents such as sweeteners ( e . g ., acesulfame , xylitol ), menthol , and / or flavoring agents ( e . g ., strawberry furanone ), for example and not by way of limitation , may be used . the following experimental examples further illustrate the method and various embodiments of the present invention . these examples are for illustrative purposes and are not meant to limit the scope of the claims in any way . an aerosol comprising heterogeneous particles of rizatriptan ( free - based from rizatriptan benzoate salt , obtained from topharman , shanghai , china ) and palmitic acid ( obtained from calbiochem / emd biosciences , san diego , calif .) was generated as follows : a heating substrate ( foil ) was coated with a solution comprising riztariptan free - base and palmitic acid in organic solvent . after the solvent evaporated , a thin film remained on the substrate . upon rapid heating of the heating substrate in the presence of airflow across the substrate , the thin film vaporized and condensed to form an aerosol . brownian motion , flow discontinuities , and chemical attractions all facilitate the mixing of the first ( drug ) compound and the second ( excipient ) compound in the vapor phase so that upon condensation , heterogeneous aerosol particles may be formed . palmitic acid ( chemical formula : c 16 h 32 o 2 ; chemical name : hexadecanoic acid ; other names : hexadecyclic acid , cetylic acid ) is one of the most common saturated fatty acids found in animals and plants . palmitic acid is a major compound of the oil from palm trees ( palm oil and palm kernel oil ). palmitic acid ( which is also found in butter , cheese , milk , and meat ) was selected as the second compound ( excipient ) in this experiment due to its relative physiological abundance . scanning electron microscopy ( sem ) of heterogeneous particles of rizatriptan and palmitic acid ( generated as described in example one , above ) was performed using a philips xl - 30feg scanning electron microscope ( philips electronics , amsterdam ) at a magnification level of 550 ×. fig1 a is an sem photomicrograph of unary ( single - compound ) particles of rizatriptan aerosol ; fig1 b is an sem photomicrograph of unary particles of palmitic acid aerosol ; fig1 c is an sem photomicrograph of heterogeneous particles of rizatriptan and palmitic acid ( 3 : 1 mole ratio of palmitic acid : rizatriptan ) aerosol . from the morphology of the respective unary aerosol particles , sem imaging showed good mixing of drug and excipient . raman spectroscopy is the collection of light inelastically scattered by a material or compound . when a light of known wavelength strikes a material , the light is shifted according to the chemical functionalities of the material . the intensity of this shifted light depends on both the molecular structure and macrostructure of the material . as a result of these phenomena , the collection of the shifted light gives a raman spectrum that can provide direct information regarding the molecular vibrations of the compound or material . this information can then be interpreted to determine chemical structure , organization and , in some cases , non - covalent intermolecular interactions . in order to confirm that individual particles generated by the present method contain both drug and excipient , raman spectroscopy analysis of heterogeneous particles of rizatriptan and palmitic acid was performed by evans analytical group ( sunnyvale , calif .). the measurements were performed using a “ labram ” j - y spectrometer equipped with a 600 gr / mm grating . a hene laser ( 632 . 817 nm wavelength ) was used as the excitation source . the measurements were performed under an olympus bx40 microscope ( olympus america , center valley , pa .). the particles were gravitationally settled onto glass slides . unary ( single - compound ) particles of rizatriptan , unary particles of palmitic acid , and heterogeneous particles of palmitic acid and rizatriptan ( from vaporization of a 3 : 1 mole ratio of palmitic acid : rizatriptan ) were probed . fig2 compares the reference spectra of single - compound particles of rizatriptan 204 and palmitic acid 206 with the spectrum 202 obtained from heterogeneous particles of palmitic acid and rizatriptan , and clearly demonstrates that such particles contain a mixture of drug and excipient . the rizatriptan spectrum 204 has a peak at 1545 cm − 1 due to ring vibration of the drug , which does not overlap with the bands of palmitic acid and can be used to identify the drug presence in the particles of mixture . the palmitic acid spectrum 206 has the stretching vibration of a long ch 2 chain at 2840 cm − 1 ( symmetric ) and 2878 cm − 1 ( antisymmetric ), which can be used to identify the presence of the palmitic acid . aerodynamic particle sizing and laser desorption / ionization ( ldi ) of heterogeneous particles of palmitic acid and rizatriptan was conducted by tsi incorporated ( shoreview , minn .) using aerosol time - of - flight mass spectrometry ( atofms ). atofms utilizes an aerodynamic time - of - flight sizing technique to size individual particles in near real time . single particle laser desorption / ionization facilitates chemical analysis in a bipolar , time - of - flight mass spectrometer . ( see u . s . pat . nos . 5 , 681 , 752 and 5 , 998 , 215 .) heterogeneous aerosol particles of palmitic acid and rizatriptan , at palmitic acid rizatriptan mole ratios of 1 : 1 and 3 : 1 , and drug loading of 100 μg and 500 μg rizatriptan , were analyzed . vaporization temperature was 350 ° c . for all samples tested . fig3 is a bar graph 300 showing the laser desorption / ionization ( atofms - ldi ) fractions 302 of heterogeneous particles in samples generated from a 1 : 1 mole ratio of palmitic acid : rizatriptan , 100 and 500 μg drug loading ; and a 3 : 1 mole ratio of palmitic acid : rizatriptan , 100 and 500 μg drug loading . fig4 a is a line graph 400 showing the mass - based size distributions of the aerosol particles acquired from atofms 402 for rizatriptan 408 and heterogeneous particles of palmitic acid : rizatriptan 410 ( 1 : 1 mole ratio of palmitic acid : rizatriptan , 100 μg drug loading ), and aps ( total size distribution ) 404 for the heterogeneous particles 412 , as a function of aerodynamic diameter 406 . fig4 b is a line graph 420 showing the mass - based size distributions of the aerosol particles acquired from atofms 422 for rizatriptan 428 and heterogeneous particles of palmitic acid : rizatriptan 430 ( 3 : 1 mole ratio of palmitic acid : rizatriptan , 100 μg drug loading ), and aps ( total size distribution ) 424 for the heterogeneous particles 432 , as a function of aerodynamic diameter 426 . fig5 a is an atofms spectrum 500 generated from a rizatriptan aerosol sample . fig5 b is an atofms spectrum 510 generated from a palmitic acid aerosol sample . fig5 c is an atofms spectrum 520 generated from a 3 : 1 palmitic acid rizatriptan aerosol sample . the ldl data showed that at the higher 3 : 1 mole ratio of palmitic acid to rizatriptan , the fraction ( yield ) of heterogeneous particles increased in comparison to the 1 : 1 mole ratio ( approximately 70 % compared to 35 %, respectively , for the 500 μg drug loading ). the mass distribution of the particle sizes is fairly consistent with modes focusing at approximately 1 μm . acesulfame ( chemical formula : c 4 h 5 no 4 s ) is a common synthetic , normutritive sweetener used in foods and cosmetics . it was selected as an appropriate excipient to attenuate the taste of pcz based on its gras ( generally recognized as safe ) status and evidence that suggests it reduces the throat irritation associated with nicotine ( see , for example , u . s . patent publication no . 2004 / 0173224 ). fig6 a - 6c show three different coating configurations that can be used to co - vaporize a first compound ( drug ) and a second compound from a heating substrate . fig6 a shows a drug and a second compound coated on the same surface of a heating substrate , with the drug at the trailing edge of airflow across the substrate . fig6 b shows a drug and a second compound coated on the same surface of a heating substrate , with the drug at the leading edge of airflow across the substrate . fig6 c shows a drug coated onto the top surface of the substrate and a second compound coated onto the bottom surface of the substrate . an aerosol composition comprising prochlorperazine ( pcz ) and acesulfame ( ace , free acid obtained from the potassium salt of acesulfame ) was generated as follows : a portion of a heating substrate ( foil ) was coated with a solution of pcz dissolved in acetone . after the solvent evaporated , a different portion of the same substrate was coated with a solution of ace dissolved in 3 : 1 dichloromethane : acetone . after all of the solvent evaporated , a thin film remained on the substrate . upon rapid heating of the heating substrate in the presence of airflow across the substrate , the thin film vaporized and condensed to form an aerosol . brownian motion , flow discontinuities , and chemical attractions all facilitate the mixing of the drug compound and the excipient in the vapor phase so that upon condensation , heterogeneous aerosol particles may be formed . fig7 is a bar graph 700 showing aerosol purity 702 of prochlorperazine ( pcz ) and acesulfame ( ace ) when vaporized from a heating substrate in three different coating configurations 704 , as follows : a : pcz coated on the top surface of the substrate and ace coated on the bottom surface of the substrate ( illustrated in fig6 c ); b : pcz and ace coated on the same surface of the substrate , with pcz at the leading edge of airflow across the substrate ( illustrated in fig6 b ); c : pcz and ace coated on the same surface of the substrate , with pcz at the trailing edge of airflow across the substrate ( illustrated in fig6 c ). fig7 illustrates that pcz can be co - vaporized in the presence of ace without significantly affecting the purity of the aerosolized pcz . scanning electron microscopy ( sem ) of single - compound particles of ace and pcz , and heterogeneous particles of pcz and ace ( generated as described above ) was performed using a philips xl - 30feg scanning electron microscope ( philips electronics , amsterdam ) at a magnification level of 1000 ×. fig8 a is an sem photomicrograph of unary ( single - compound ) particles of ace . fig8 b is an sem photomicrograph of unary ( single - compound ) particles of pcz . fig8 c is an sem photomicrograph of heterogeneous particles of pcz and ace ( 1 : 1 mole ratio ) vaporized from a heating substrate with the coating configuration shown in fig6 c . the morphologies of the pcz particles and the ace particles are shown in fig8 a and 8b . fig8 c showed good mixing of pcz and ace . heterogeneous particles potentially allow the modification of a drug &# 39 ; s pharmacokinetic profile and taste . the characterization techniques described in the above examples facilitate the study of new formulation approaches directed toward taste attenuation and improving the vaporizability of aerosolized drug formulations , as well as the development of combination drug therapies . one of ordinary skill in the art can combine the foregoing embodiments or make various other embodiments and aspects of the method and device of the present invention to adapt them to specific usages and conditions . as such , these changes and modifications are properly , equitably , and intended to be within the full range of equivalents of the following claims .
the present invention pertains to aerosols which comprise a first compound which is physiologically active and a second compound which is different from the first compound . such aerosols may be produced “ on demand ” and can be used to control drug release , to improve vaporizability , or to reduce , modify or eliminate undesirable taste associated with a drug aerosol . the present invention also pertains to methods for producing such aerosols .