U.S. patent application number 13/078525 was filed with the patent office on 2011-10-06 for delivery of drug amines through an inhalation route.
This patent application is currently assigned to ALEXZA PHARMACEUTICALS, INC.. Invention is credited to Joshua D. RABINOWITZ, Alejandro C. Zaffaroni.
Application Number | 20110245493 13/078525 |
Document ID | / |
Family ID | 29420630 |
Filed Date | 2011-10-06 |
United States Patent
Application |
20110245493 |
Kind Code |
A1 |
RABINOWITZ; Joshua D. ; et
al. |
October 6, 2011 |
DELIVERY OF DRUG AMINES THROUGH AN INHALATION ROUTE
Abstract
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, h) 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.
Inventors: |
RABINOWITZ; Joshua D.;
(Mountain View, CA) ; Zaffaroni; Alejandro C.;
(Atherton, CA) |
Assignee: |
ALEXZA PHARMACEUTICALS,
INC.
Mountain View
CA
|
Family ID: |
29420630 |
Appl. No.: |
13/078525 |
Filed: |
April 1, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10437643 |
May 13, 2003 |
8003080 |
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13078525 |
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60380819 |
May 13, 2002 |
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Current U.S.
Class: |
540/592 ;
544/295; 544/396; 544/45; 546/279.4; 546/333; 546/39; 546/75;
564/345; 73/23.41 |
Current CPC
Class: |
A61M 11/001 20140204;
A61M 15/00 20130101; A61M 11/041 20130101; Y10S 514/958 20130101;
A61K 9/007 20130101; A61K 9/0073 20130101 |
Class at
Publication: |
540/592 ; 546/75;
546/333; 546/39; 564/345; 544/295; 544/45; 544/396; 546/279.4;
73/23.41 |
International
Class: |
C07D 223/28 20060101
C07D223/28; C07D 215/00 20060101 C07D215/00; C07D 213/38 20060101
C07D213/38; C07D 489/12 20060101 C07D489/12; C07C 225/12 20060101
C07C225/12; C07D 401/14 20060101 C07D401/14; C07D 417/06 20060101
C07D417/06; C07D 241/04 20060101 C07D241/04; C07D 401/04 20060101
C07D401/04; G01N 30/06 20060101 G01N030/06 |
Claims
1. 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.
2. The method of claim 1, wherein said substrate is metallic.
3. The method of claim 2, wherein said metallic substrate is
aluminum foil or stainless steel.
4. The method of claim 2, wherein said heating is on a hot
plate.
5. The method of claim 4, wherein said heating is to a temperature
approximately about 300.degree. C.
6. The method claim 1, wherein said heating is resistance
heating.
7. The method of claim 6, wherein said heating is to a temperature
of approximately about 400.degree. C.
8. The method of claim 1, wherein the amine drug salt is selected
from the group consisting often antibiotic, anticonvulsant,
antidepressant, antiemetic, antihistamine, anti parkinsonian drug,
antipsychotic, anxiolytic, a drug for erectile dysfunction, a drug
for migraine headache, a drug for the treatment of addiction, a
muscle relaxant, a non-steroidal anti-inflammatory, an opioid, or
other analgesic.
9. An aerosol comprising an amine drug from an amine drug salt
selected by the method of claim 2, wherein said amine drug salt is
vaporized and condensed to form amine drug aerosol particles having
a mass median aerodynamic diameter between the range of 1 and 3,
and has less than 10% amine drug decomposition products.
10. The aerosol of claim 9, wherein said amine drug salt has a
molecular weight between 200 to 600.
11. The aerosol of claim 9, wherein said amine drug salt is
selected from the group consisting of antibiotic, anticonvulsant,
antidepressant, antiemetic, antihistamine, antiparkinsonian drug,
antipsychotic, anxiolytic, a drug for erectile dysfunction, a drug
for migraine headache, a drug for the treatment of addiction, a
muscle relaxant, a non-steroidal anti-inflammatory, an opioid, or
other analgesic.
12. A method or delivering an amine drug in an aerosol form,
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,
running a amine drug vapor, and c. during said heating, drawing air
through said device, condensing said vapor to from aerosol
particles containing less than 10% degradation products of the
compound.
13. The method according to claim 12, wherein said coating of amine
drug salt has a thickness between about 0.2 and 20 .mu.m.
14. The method according to claim 13, wherein said aerosol
particles have a mass median aerodynamic diameter between about 1
and 3 microns.
15. The method of claim 14, wherein the amine drug salt is selected
from the group consisting of an antibiotic, anticonvulsant,
antidepressant, antiemetic, antihistamine, antiparkinsonian drug,
antipsychotic, anxiolytic, a drug for erectile dysfunction, a drug
liar migraine headache, a drug for the treatment of addiction, a
muscle relaxant, a non-steroidal anti-inflammatory, an opioid, or
other analgesic.
16. The method according to claim 15, wherein said amine drug salt
has a molecular weight between 200 to 600.
17-23. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. provisional
application Ser. No. 60/380,819 entitled "Delivery of Drug Amines
Through an Inhalation Route," filed May 13, 2002, Rabinowitz and
Zaffaroni, the entire disclosure of which is hereby incorporated by
reference.
FIELD OF THE INVENTION
[0002] 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.
BACKGROUND OF THE INVENTION
[0003] There are a number of compounds containing amines that are
currently marketed as drugs. In certain circumstances, the presence
of such functionality, however, can prevent effective drug
delivery. This phenomenon could be due to a range of effects,
including poor solubility and instability.
[0004] Inhaled drugs, however, have the potential to enter the
systemic circulation and thereby circumvent a number of the
problems associated with oral and other drug delivery methods.
Moreover, by manipulation of particle size and/or density, delivery
of drugs into the alveoli may be facilitated. Alveoli have a large
surface area for drug absorption and are surrounded by an extensive
capillary network which facilitates rapid passage of drugs into the
pulmonary circulation. Furthermore, because blood returning from
the lungs is pumped directly to the systemic arterial circulation,
drugs inhaled into the alveoli have the potential to reach target
organs very rapidly. Of particular importance is that drugs
delivered in this manner reach their target site without being
exposed to potentially degrading conditions in the gastrointestinal
tract and without undergoing modification by first pass metabolism
in the liver. Thus, it is desirable to provide a new route of
administration for drug amines that rapidly produces peak plasma
concentrations of the compounds. This invention provides a route of
administration to accomplish this goal.
[0005] One type of inhalation aerosol is a condensation aerosol
formed from vaporization of compounds. The use of vaporized drugs,
thus, provides a method of maximizing alveolar delivery and rapidly
delivering drugs to target organs. However, the heat required to
vaporize a drug often also generates degradation products, which
may decrease the efficacy of the thermal vapor and are undesirable
to be delivered to the patient. Particularly, the salt form of a
drug is expected to lower a compound's vapor pressure, and
consequently raise its vaporization temperature and potentially
increase the amount of degradation product that is likely
generated. Thus, a method that enhances drug volatilization without
the formation of a substantial amount of degradation products with
amine drug salts and a method for selected amine drug salts
suitable for use in condensation aerosol is needed. Therefore, one
object of the invention is to provide a thermal vapor of amine drug
salts for inhalation therapy that does not contain a significant
amount of thermal degradation products.
[0006] Furthermore, white many drugs may be delivered in their free
base form using vaporization, such as those, for example, disclosed
in U.S. application Ser. Nos. 10/150,591, 10/150,267, 10/155,705
and 10/152,640, some amine drugs are liquid in their free base form
and thus, are not optimal in a vaporization method that uses films
or coatings to generate the aerosol. In such cases, the physical or
chemical stability of the coating may be enhanced through formation
of the drug amine salt. Thus, another object of the present
invention is to provide amine drugs with desirable properties for
thermal vapor delivery.
[0007] While dry powder formulations and new liquid aerosol devices
are being developed or are available for inhalation therapy. See
for example, U.S. Pat. No. 5,993,805 to Sutton et al.; WO 0000176
to Robinson et al.; WO 9916419 to Tarara et al.; WO 0000215 to Rot
et al.; U.S. Pat. No. 5,855,913 to Hanes et al.; and U.S. Pat. Nos.
6,136,295 and 5,874,064 to Edwards et al.; U.S. Pat. No. 6,131,570
to Schuster et al.; U.S. Pat. No. 5,724,957 to Rubsamen et al.; and
U.S. Pat. No. 6,098,620 to Lloyd et al.; U.S. Pat. Nos. 5,586,550;
5,758,637; and 6,085,740 to Ivri et al.; and U.S. Pat. No.
5,938,117.
[0008] These technologies are limited, however. Dry powders require
excipients to formulate the dry powders for appropriate delivery.
Whereas with liquid aerosols, because the solubility of many drug
compounds in water or other solvents suitable for liquid aerosol
delivery is low, the total quantity of drug that can be delivered
in a single breath is quite small. Thus, there is a need for
condensation aerosol of amine drug salts that overcome these
limitations. This invention provides such a means.
[0009] These and other features of the invention will be described
in detail below. All publications, patents, and patent applications
referred to herein are incorporated herein by reference in their
entirety.
SUMMARY OF THE INVENTION
[0010] 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.
[0011] In one aspect, the invention provides a method for selecting
amine drugs salts for use in forming a condensation aerosol
comprising: [0012] a. dissolving or suspending a salt form of an
amine drug in a solvent, [0013] b. coating the suspended or
dissolved salt form of the amine drug on a substrate, [0014] c.
heating the coated substrate to form a compound vapor, [0015] d.
cooling the vapor to form aerosol particles, [0016] e. collecting
the aerosol particles, [0017] f. analyzing the collected particles
to determine the purity of the aerosol particles; and [0018] g.
selecting the amine drug based on a decomposition index less than
0.15.
[0019] 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.
[0020] 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.
[0021] In another aspect of the invention, a method of delivering
an amine drug in an aerosol form is provided, comprising: [0022] 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, [0023] b. by said heating, forming a
amine drug vapor, and [0024] 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.
[0025] 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.
[0026] In a third aspect of the invention, novel thermal vapors are
provided. These thermal vapors comprise gas and amine drug aerosol
particles,
[0027] a. wherein said gas comprises an acid halide vapor, organic
acid vapor, or organic acid decomposition product vapor, and
[0028] b. wherein said amine drug aerosol particles [0029] 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 [0030] ii. have a mass median
aerodynamic diameter in the range 1 to 5 micrometers.
[0031] 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.
[0032] 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:
[0033] 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;
[0034] 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
[0035] c) flowing a gas through said chamber thereby cooling said
vapor to form drug amine aerosol particles.
[0036] 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.
BRIEF DESCRIPTION OF THE FIGURES
[0037] FIG. 1 is a side view showing internal details of a device
for vaporizing a drug including an external chamber in accordance
with the present invention for delivery of a drug to a mammal.
DETAILED DESCRIPTION OF THE INVENTION
[0038] The present invention provides methods for screening amine
drug salts for suitability in condensation aerosols; methods to
deliver aerosols, novel vapor compositions, and methods to generate
therapeutically effective amounts of amine aerosols. To facilitate
understanding and the practice of the invention in its many and
diverse applications, this description is organized as shown below.
[0039] I. DEFINITIONS [0040] II. CHARACTERISTICS OF THE AMINE DRUG
SALTS [0041] III. CHARACTERISTICS OF THE THERMAL. VAPOR, AEROSOL
AND/OR PARTICLES [0042] IV. METHODS [0043] V. EXAMPLES
I. DEFINITIONS
[0044] "Acid halide" refers to HE, HCl, HBr, HI, HAt.
[0045] "Aerodynamic diameter" of a given particle refers to the
diameter of a spherical droplet with a density of 1 g/mL (the
density of water) that has the same settling velocity as the given
particle.
[0046] "Aerosol" refers to a suspension of solid or liquid
particles in a gas.
[0047] "Aerosol drug amine mass density" refers to the mass of drug
amine per unit volume of aerosol.
[0048] "Aerosol mass density" refers to the mass of particulate
matter per unit volume of aerosol.
[0049] "Aerosol particle density" refers to the number of particles
per unit volume of aerosol.
[0050] "Condensation aerosol", refers to an aerosol formed by
vaporization of a substance followed by condensation of the
substance into an aerosol.
[0051] "Decomposition index" refers to a number derived from an
assay and described in Example 3 and 4. The number is determined by
substracting the fractional purity of the generated aerosol from
1.
[0052] "Drug" refers to any chemical compound that is used in the
prevention, diagnosis, treatment, or cure of disease, for the
relief of pain, or to control or improve any physiological or
pathological disorder in humans or animals. Such compounds are
oftentimes listed in the Physician's Desk Reference (Medical
Economics Company, Inc. at Montvale, N.J., 56.sup.th edition,
2002), which is herein incorporated by reference. The drugs are
preferably other than recreational drugs. More specifically, the
drugs are preferably other than recreational drugs used for
non-medicinal recreational purposes, e.g., habitual use to solely
alter one's mood, affect, state of consciousness, or to affect a
body function unnecessarily, for recreational purposes. Cocaine,
amphetamine, methamphetamine, and their derivatives are
recreational drugs specifically excluded from the term "drug". The
terms "drug" and "medication" are herein used interchangeably.
[0053] "Drug amine" refers to a drug containing a primary,
secondary, or tertiary amine moiety and not a quaternary amine
moiety.
[0054] "Drug amine" refers to a drug containing an amine moiety.
Drug amine and "amine drug" are terms that mean the same and herein
are used interchangeably.
[0055] "Drug amine salt" refers to a drug amine, where the amine
group is protonated by an acid to form an ammonium salt with a
corresponding counterion derived from the acid. The counterion is a
pharmaceutically acceptable anion (e.g., Cl-- or
CH.sub.3CO.sub.2--). The drug amines from which the salts are
formed come from a variety of drug classes, including, without
limitation, 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. Drug amine salt
and "amine drug salt" are terms that mean the same and herein are
used interchangeably.
[0056] Examples of antibiotics from which drug amine salts are
formed include cephalexin; cephaloglycin; cephalosporins, such as
cephalosporin C; cephradine; amoxicillin; hetacillin; cyclacillin;
and penicillins, such as penicillin N.
[0057] An example of anticonvulsants from which a drug amine salt
is formed is tiagabine.
[0058] Examples of antidepressants from which drug amine salts are
formed include 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, amperozidc,
benactyzine, bupropion, idazoxan, mctralindole, milnacipran,
minaprine, nefazodone, nomifensine, ritanserin, roxindolc,
tofenacin, trazodone, tryptophan, and venlafaxine.
[0059] Examples of antiemetics from which drug amine salts are
formed include alizapride, azasetron, benzquinamide, bromopride,
buclizine, chlorpromazine, cinnarizine, cyclizine, diphenhydramine,
diphenidol, dolasetron, droperidol, granisetron, hyoscine,
metoclopramide, mctopimazine, ondansetron, perphenazine,
promcthazine, prochlorperazine, scopolamine, triethylperazine,
trifluoperazine, trillupromazine, trimethobenzamide, and
tropisctron.
[0060] Examples of antihistamines from which drug amine salts are
formed include azatadine, brompheniramine, carbinoxamine,
chlorpheniramine, clemastine, cyproheptadine, dexmedetomidine,
diphenhydramine, doxylamine, hydroxyzine, cetrizine, fexofenadine,
and promethazine.
[0061] Examples of antiparkisonian drugs from which drug amine
salts are formed include amantadine, baclofen, biperiden,
benztropine, orphenadrine, procyclidine, trihexyphenidyl, levodopa,
carbidopa, selegiline, deprenyl, apomorphine, benserazide,
bromocriptine, budipine, cabergoline, dihydroergokryptine,
pramipexole, galanthamine, lazabemide, lisuride, memantine,
mofegiline, pergolidc, remacemide, and terguride.
[0062] Examples of antipsychotics from which drug amine salts are
formed include 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, melperonc, olanzapine,
quetiapine, and risperidone.
[0063] Examples of anxiolytics from which drug amine salts are
formed include diazepam, alprazolam, triazolam, indiplon, zaleplon,
mecloqualone, mcdetomidine, metomidate, adinazolam,
chlordiazepoxide, clobenzepam, flurazepam, loprazolam, midazolam,
azacyclonol, buspirone, captodiamine, enciprazine, flesinoxan,
ipsapirone, lesopitron, loxapine, methaqualone, propanolol,
tandospirone, trazadone, zopiclone, and zolpidem.
[0064] Examples of drugs for erectile dysfunction from which amine
salts are formed include cialis (IC351), sildenafil, vardenafil,
apomorphine, apomorphine diacetate, phentolamine, and
yohimbine.
[0065] Examples of drugs for migraine headache from which drug
amine salts are formed include almotriptan, eletriptan,
alpiropride, 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.
[0066] Examples of drugs for the treatment of alcoholism from which
drug amine salts are formed include naloxone and naltrexone.
[0067] An example of a drug for the treatment of addiction from
which drug amine salts are formed is buprenorphine.
[0068] Examples of muscle relaxants from which drug amine salts are
formed include baclofen, cyclobenzaprine, orphenadrine, quinine,
and tizanidine.
[0069] Examples of nonsteroidal anti-inflammatories from which drug
amine salts are formed include aceclofenac, alminoprofen, amfenac,
bromfenac, carprofen, cinchophen, diclofenac, etodolac,
mazipredonc, meclofenamate, pirprofen, and tolfenamate.
[0070] Examples of opioids from which drug amine salts are formed
include alfentanil, allylprodine, alphaprodine, anileridine,
henzylmorphine, bezitramide, buprenorphine, butorphanol,
cipramadol, clonitazene, codeine, dextromoramide,
dextropropoxyphene, diamorphine, dihydrocodeine, diphenoxylate,
dipipanone, fentanyl, hydromorphone, lofentanil, levorphanol,
meperidine, methadone, meptazinol, metopon, morphine, nalbuphine,
nalorphine, oxycodone, papavereturn, pethidine, pentazocine,
phenazocine, remifentanil, sufentanil, and tramadol.
[0071] Examples of other analgesics from which drug amine salts are
formed include apazone, benzpiperylon, bcnzydramine, caffeine,
clonixin, ethoheptazine, flupirtine, nefopam, orphenadrine,
propacetamol, and propoxyphene.
[0072] Examples of acids used to form the drug amine salt include,
without limitation, the following: hydrochloric acid; hydrobromic
acid; formic acid; acetic acid; maleic acid; fumaric acid, benzoic
acid, and trifluoroacetic acid.
[0073] "Drug amine degradation product" refers to a compound
resulting from a chemical modification of the amine. The
modification, for example, can be the result of a thermally or
photochemically induced reaction. Such reactions include, without
limitation, oxidation and hydrolysis.
[0074] "Inhalable aerosol drug amine mass density" refers to the
aerosol drug amine mass density produced by an inhalation device
and delivered into a typical patient tidal volume.
[0075] "Inhalable aerosol mass density" refers to the aerosol mass
density produced by an inhalation device and delivered into a
typical patient tidal volume.
[0076] "Inhalable aerosol particle density" refers to the aerosol
particle density of particles of size between 100 nm and 5 microns
produced by an inhalation device and delivered into a typical
patient tidal volume.
[0077] "Mass median aerodynamic diameter" or "MMAD" of an aerosol
refers to the aerodynamic diameter for which half the particulate
mass of the aerosol is contributed by particles with an aerodynamic
diameter larger than the MMAD and half by particles with an
aerodynamic diameter smaller than the MMAD.
[0078] "Organic acid" refers to a compound, generally of less than
300 grams/mole of molecular weight, containing one or more
carboxylic acid functional groups.
[0079] "Organic acid decomposition product" refers to products
resulting from a chemical modification of the organic acid. The
modification, for example, can be the result of a thermally or
photochemically induced reaction. Such reactions include, without
limitation, oxidation or decarboxylation.
[0080] "Rate of aerosol formation" refers to the mass of
aerosolized particulate matter produced by an inhalation device per
unit time.
[0081] "Rate of inhalable aerosol particle formation" refers to the
number of particles of size between 100 nm and 5 microns produced
by an inhalation device per unit time.
[0082] "Rate of drug amine aerosol formation" refers to the mass of
aerosolized, drug amine produced by an inhalation device per unit
time.
[0083] "Settling velocity" refers to the terminal velocity of an
aerosol particle undergoing gravitational settling in air.
[0084] "Suitable drug amine salt" refers to a drug amine salt that,
when subjected to the assay described in Example 2, provides a drug
amine aerosol in greater than 85% purity.
[0085] "Thermal vapor" refers to a vapor phase, aerosol phase or
mixture of aerosol-vapor phases, formed preferably by heating. The
thermal vapor may comprise a drug and optionally a carrier, and may
be formed by heating the drug and optionally a carrier.
[0086] "Treatment" refers to an approach for obtaining beneficial
or desired clinical results. For purposes of this invention,
beneficial or desired clinical results include, but are not limited
to, one or more of the following: alleviation of symptoms,
diminishment of extent of a disease; stabilization (i.e., not
worsening) of a state of disease, preventing spread (i.e.,
metastasis) of disease, preventing occurrence or recurrence of
disease, delay or slowing of disease progression, amelioration of
the disease state, and remission (whether partial or total).
[0087] "Typical patient tidal volume" refers to 1 L for an adult
patient and 15 mL/kg for a pediatric patient.
[0088] "Vapor" refers to a gas, and "vapor phase" refers to a gas
phase.
II. CHARACTERISTICS OF THE AMINE DRUG SALTS
[0089] 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 grains/mole.
[0090] 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.
[0091] 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.
[0092] 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.
[0093] 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, tiagahine, and vigabatrin.
[0094] Typically, where the drug amine salt is a salt of an
anticonvulsant, it is selected from a salt of tiagabine.
[0095] 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, adernetionine, amisulpride, amperozide,
benactyzine, bupropion, idazoxan, metralindole, milnacipran,
minaprine, nefazodone, nomifensine, ritanserin, roxindole,
tofenacin, trazodone, tryptophan, and venlafaxine.
[0096] 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.
[0097] 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.
[0098] 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.
[0099] 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.
[0100] 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.
[0101] 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.
[0102] 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.
[0103] 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.
[0104] Typically, where the drug amine salt is a salt of a drug
amine for the treatment of addiction it is buprenorphine.
[0105] 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.
[0106] 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.
[0107] 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, papavereturn, pethidine, pentazocine,
phenazocine, remifentanil, sufentanil, and tramadol.
[0108] 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.
[0109] 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.
[0110] 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.
[0111] 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.
[0112] 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
[0113] 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.
[0114] 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.
[0115] 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.
[0116] 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.
[0117] 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.
[0118] 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.
[0119] 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.
[0120] 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.
[0121] 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.
[0122] 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.
[0123] 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.
[0124] Typically, the thermal vapor comprises a gas and amine drug
aerosol particles,
[0125] a. wherein said gas comprises an acid halide vapor, organic
acid vapor, or organic acid decomposition product vapor, and
[0126] b. wherein said amine drug aerosol particles [0127] 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 [0128] ii. have a mass median
aerodynamic diameter in the range 1 to 5 micrometers.
[0129] 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.
[0130] 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.
[0131] 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.
[0132] 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.
[0133] 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
[0134] In one aspect the present invention provides a method of
selecting an amine drug salt suitable for use in forming a
condensation aerosol, comprising [0135] a. dissolving or suspending
an amine drug salt in a solvent, [0136] b. coating the suspended or
dissolved amine drug salt on a substrate, [0137] c. heating the
coated substrate to form a compound vapor, [0138] d. cooling the
vapor to form aerosol particles, [0139] e. collecting the aerosol
particles, [0140] f. analyzing the collected particles to determine
the purity of the aerosol particles; and [0141] g. selecting the
amine drug based on a decomposition index less than 0.15.
[0142] 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).
[0143] 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).
[0144] 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.
[0145] 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.
[0146] In a preferred embodiment of the invention, the substrate is
metallic. In more preferred embodiments, the substrate is aluminum
foil or stainless steel.
[0147] 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.
[0148] 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.
[0149] 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.
[0150] 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.
[0151] 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
[0152] 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.
[0153] 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.
[0154] In a particularly preferred embodiment, an amine drug
aerosol is formed and delivered by a method, comprising: [0155] 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, [0156] b. by said heating, forming a
amine drug vapor, and [0157] 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.
[0158] 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.
[0159] 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.
[0160] 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.
[0161] 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.
[0162] 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).
[0163] 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).
[0164] 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.
[0165] 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.
[0166] 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.
[0167] 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.
[0168] One device used to deliver the drug amine containing aerosol
is described in reference to FIG. 1. 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.
[0169] 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.
[0170] 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
[0171] 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.
[0172] 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.
[0173] 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:
[0174] 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;
[0175] 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
[0176] c) flowing a gas through said chamber thereby cooling said
vapor to form drug amine aerosol particles
[0177] A number of drug delivery devices can be used including the
one describe in FIG. 1 and above.
[0178] 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.
[0179] 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
[0180] 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.
[0181] 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 us 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 us 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.
[0182] 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.
[0183] 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.
[0184] 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.
[0185] 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.
[0186] 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).
[0187] 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.
[0188] 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.
[0189] 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.
[0190] 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.
[0191] 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.
EXAMPLES
[0192] The following examples describe specific aspects of the
invention to illustrate the invention and also provide a
description of the methods used to select amine base salts suitable
for forming condensation aerosols, and methods to generate amine
drug aerosols and measure various physical properties of such
aerosols to aid those of skill in the art in understanding and
practicing the invention. The examples should not be construed as
limiting the invention, in any manner.
[0193] Drug amine salts are typically commercially available from
Sigma (www.sigma-aldrich.com), obtained in tablet form from a
pharmacy and extracted, or synthesized using well known methods in
the art.
Example 1
General Procedure A for Volatilizing Drug Amines from Drug Amine
Salts General Procedure for the Preparation of a Coating
Solution
[0194] The concentration of a solution for coating of the substrate
was typically 50-200 mg/ml. The amine drug salt was dissolved in an
appropriate solvent. Common solvent choices included methanol,
dichloromethane, and a 3:1 chloroform:methanol mixture, although
DMF was used for less soluble amine drug salts and deionized water
was used for amine drug salts that were insoluble in organic
solvents. Occasionally sonication or heat was necessary to dissolve
the compound.
Volatilization
[0195] A solution of drug amine salt in a minimal amount of solvent
was typically coated on a piece of aluminum foil (precleaned with
acetone). The solvent was allowed to evaporate. The coated foil was
wrapped around a 300 watt halogen tube (Felt Electric Company, Pico
Rivera, Calif.), which was inserted into a glass tube sealed at one
end with a rubber stopper. Running 60 V of alternating current
(driven by line power controlled by a variac) through the bulb for
5-15 s or 90 V for 3.5-5 s afforded a thermal vapor (including
aerosol), which was collected on the glass tube walls. (When
desired, the system was flushed through with argon prior to
volatilization.) Reverse-phase HPLC analysis with detection by
absorption of UV light, generally at 225 nm, was used to determine
the purity of the aerosol.
Example 2
General Procedure B for Volatilizing Drug Amines from Drug Amine
Salts Dip Coating
[0196] The substrate, consisting of a hollow stainless steel
cylinder with thin walls, typically having a wall thickness of 0.12
mm, diameter 13 mm, and length 36 mm and conducive to resistance
heating, was dip-coated with an amine drug salt coating solution
(prepared as disclosed in Example 1) typically using a computerized
dip-coating machine to produce a thin layer of drug on the outside
of the substrate surface. Prior to using, the substrates were
cleaned in dichloromethane, methanol, and acetone, then dried, and
fired at least once to remove any residual volatile material. The
substrate was lowered into the drug solution and then removed from
the solvent at a rate atypically 5-25 cm/sec. The substrate was
then allowed to dry for 30 minutes inside a fume hood. If either
DMF or a water mixture was used as a dip coating solvent, the
substrate was vacuum dried inside a desiccator for a minimum of one
hour. Once the substrate was solvent free and only the drug
remained, it was ready for volatilization. The drug-coated portion
of the cylinder generally has a surface area of 8.5 cm.sup.2. By
assuming a unit density for the drug, the initial drug coating
thickness were calculated.
Volatilization
[0197] A dip coated substrate was placed in a surrounding glass
tube connected at the exit end via Tygon tubing to a filter holder
fitted with a Savillex Teflon filter and the junction is scaled
with paraffin film. The substrate was placed in a fitting which
connects it to two 1 farad capacitors wired in series and
controlled by a 12-volt relay. The capacitors were charged by a
separate power source to about 16-21 volts and all the power was
channeled to the substrate by closing a switch and allowing the
capacitors to discharge into the substrate. The substrate was
heated to a temperature of .about.400.degree. C. in .about.50
milliseconds. This heating process was done under an airflow of 15
L/min, which swept the vaporized drug aerosol into a 2 micron
Teflon filter. After volatilization, the aerosol captured on the
filter was recovered for analysis. Any material deposited on the
glass sleeve or remaining on the substrate was also recovered. The
recovered materials were analyzed by HPLC UV absorbance, generally
at 225 nm, or alternatively at 250, 275, or 280 nm, using a
gradient method aimed at detection of impurities. The samples were
further analyzed by LC/MS to confirm the molecular weight of the
drug and any degradants.
[0198] Table 1, which follows, provides data from drug amines
volatilized using the above-recited general procedures A and B.
TABLE-US-00001 TABLE 1 Mass % Dose Surface Thickness coated Pur-
Generic Name MW (mg) Method Area (.mu.m) (mg) Yield ity Apomorphine
304 2 B 6 1.1 0.68 0.60 98.1 HCl Apomorphine 388 2 A 20 1.0 1.9
1.65 94 HCl Diacetate Bromophenir- 435 2 A 20 2.8 5.60 3.4 99.6
amine Maleate Bromophenir- 435 2 A under 20 3.2 6.40 3.2 100 amine
argon Maleate Buprenor- 504 0.3 A 20 1.1 2.10 1.37 91.4 phine HCl
Buprenor- 504 0.3 A 20 0.05 0.1 0.08 98.0 phine HCl Bupropion 276
100 A 20 1.1 2.30 2.1 98.5 HCl Bupropion 276 100 A under 20 1.1
2.30 1.8 99.1 HCl argon Buspirone 422 15 A 20 4.2 8.30 2.42 97.8
HCl Carbinox- 407 4 A 20 3.9 7.70 4.8 99 amine Maleate Carbinox-
407 4 A under 20 3.4 6.8 3.0 100 amine argon Maleate Chlorphenir-
391 8 A 20 1.6 3.20 2.1 99.6 amine Maleate Chlorphenir- 391 8 A
under 20 2.1 4.2 2.1 100 amine argon Maleate Clemastine 460 1.34 A
20 2.9 5.70 1.8 76.6 Fumarate Cyprohepta- 324 4 A 20 2.2 4.30 2.6
99.6 dine HCl Cyprohepta- 324 4 A under 20 1.8 3.5 2.1 99.6 dine
HCl argon Diphenhydra- 292 25 A 20 2.5 4.9 3.7 90.3 mine HCl
Diphenhydra- 292 25 A under 20 2.6 5.2 3.9 93.3 mine HCl argon
Enalapril 493 5 B 8 1.1 0.85 0.29 61.0 maleate Fluphenazine 510 1 B
8 1.0 0.78 0.33 80.7 2HCl Hydroxyzine 448 50 A 20 13.7 27.30 0.25
41.2 2HCl Hydroxyzine 448 50 A under 20 12.8 25.60 1.4 70.8 2HCl
argon Meclizine 464 25 A 20 9.7 19.40 0.5 75.3 2HCl Meclizine 464
25 A under 20 11.7 23.40 0.4 70.9 2HCl argon Mexiletine 216 200 B 8
0.9 0.75 0.44 99.4 HCl Nicotine HCl 198 1 A 32 3.2 10.3 5.4 99.9
Nicotine 2HCl 235 1 A 32 4.6 14.8 12.9 99.5 Nicotine 260 1 A 32 2.5
8.0 1.8 97.0 Sulfate Prochlorpera- 446 5 B 8 0.8 0.65 0.24 72.4
zine 2HCl Protriptyline 299 15 A 20 1.1 2.20 0.99 99.7 HCl
Protriptyline 299 15 A under 20 1.1 2.1 1.1 99.8 HCl argon
Pyrilamine 401 25 A 20 10.8 21.50 10.5 93.7 Maleate Pyrilamine 401
25 A under 20 10.2 20.4 9.6 90.7 Maleate argon Tranylcypro- 169 30
A 20 1.2 2.30 1.3 97.5 mine HCl Tranylcypro- 169 30 A under 20 1.0
2.0 1.2 97.2 mine HCl argon Trifluopera- 480 7.5 B 8 1.2 0.97 0.52
87.5 zine 2HCl Trimipramine 411 50 A 20 1.2 2.40 1.6 95.9 Maleate
Trimipramine 411 50 A under 20 1.1 2.20 2.1 97.4 Maleate argon
Example 3
General Procedure A for Screening Drug Amine Salts for
Aerosolization Preferability
[0199] Drug amine salt (1 mg) was dissolved or suspended in a
minimal amount of solvent, such as for example, methanol. The
solution or suspension was pipeted onto the middle portion of a 3
cm by 3 cm piece of aluminum foil. The coated foil was wrapped
around the end of a 11/2 cm diameter vial and secured with
parafilm. A hot plate was preheated to approximately 300.degree.
C., and the vial was placed on it foil side down. The vial was left
on the hotplate for 10 s after volatilization or decomposition had
begun. After removal from the hotplate, the vial was allowed to
cool to room temperature. The foil was removed, and the vial was
extracted with dichloromethane followed by saturated aqueous
NaHCO.sub.3. The organic and aqueous extracts were shaken together,
separated, and the organic extract is dried over Na.sub.2SO.sub.4.
An aliquot of the organic solution was removed and injected into a
reverse-phase HPLC with detection by absorption of UV light,
generally at 225 nm. 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.
Example 4
General Procedure B for Screening Drug Amine Salts for
Aerosolization Preferability
[0200] Volatilizations were done using a setup which consists of
two 1 farad capacitors wired in series and controlled by a 12-volt
relay. A dip coated substrate (prepared as described in Example 2)
was placed in a surrounding tube connected at the exit end via
Tygon tubing to a filter holder fitted with a'Savillex Teflon
filter and the junction is sealed with paraffin film. The substrate
was placed in a fitting which connects it to the capacitors. The
capacitors were charged by a separate power source to about 16-21
volts and all the power was channeled to the substrate by closing a
switch and allowing the capacitors to discharge into the substrate.
The substrate was heated to a temperature of .about.400.degree. C.
in .about.50 milliseconds. This heating process was done under an
airflow of 15 L/min, which swept the vaporized drug aerosol into a
2 micron Teflon filter. After volatilization, the aerosol captured
on the filter was recovered for analysis. Any material deposited on
the glass sleeve or remaining on the substrate was also recovered.
The recovered materials were analyzed by HPLC UV absorbance,
generally at 225 nm, or alternatively at 250, 275, or 280 nm, using
a gradient method aimed at detection of impurities. The samples
were further analyzed by LC/MS to confirm the molecular weight of
the drug and any degradants. 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.
Example 5
Particle Size, Particle Density, and Rate of Inhalable Particle
Formation of Amine Drug Aerosol
[0201] A solution of 50-200 mg of amine drug salt per mL of solvent
was spread out in a thin layer on the central portion of a 3.5
cm.times.7 cm sheet of aluminum foil. The solvent was allowed to
evaporate. The aluminum foil was wrapped around a 300 watt halogen
tube, which was inserted into a T-shaped glass tube. Both of the
openings of the tube were sealed with parafilm, which was punctured
with fifteen needles for air flow. The third opening was connected
to a 1 liter, 3-neck glass flask. The glass flask was further
connected to a large piston capable of drawing 1.1 liters of air
through the flask. Alternating current was run through the halogen
bulb by application of 90 V using a variac connected to 110 V line
power. Within Is, an aerosol appeared and was drawn into the 1 L
flask by use of the piston, with collection of the aerosol
terminated after 3.5-6 s. The aerosol was analyzed by connecting
the 1 L flask to an eight-stage Andersen non-viable cascade
impactor. MMAD of the collected aerosol ranged between 1 and 3
microns with a geometric standard deviation of less than 3. The
number of particles collected on the various stages of the cascade
impactor was given by the mass collected on the stage divided by
the mass of a typical particle trapped on that stage. The mass of a
single particle of diameter D is given by the volume of the
particle, .pi.D.sup.3/6, multiplied by the density of the drug
(taken to be 1 g/cm.sup.3). The inhalable aerosol particle density
is the sum of the numbers of particles collected on impactor stages
3 to 8 divided by the collection volume of 1 L. The rate of
inhalable aerosol particle formation is the sum of the numbers of
particles collected on impactor stages 3 through 8 divided by the
formation time.
Example 6
Drug Mass Density of Amine Drug Aerosol from Amine Drug Salts
[0202] A solution of 50-200 mg of amine drug salt per mL of solvent
was spread out in a thin layer on the central portion of a 3.5
cm.times.7 cm sheet of aluminum foil. The solvent was allowed to
evaporate. The aluminum foil was wrapped around a 300 watt halogen
tube, which was inserted into a T-shaped glass tube. Both of the
openings of the tube were sealed with parafilm, which was punctured
with fifteen needles for air flow. The third opening was connected
to a 1 liter, 3-neck glass flask. The glass flask was further
connected to a large piston capable of drawing 1.1 liters of air
through the flask. Alternating current was run through the halogen
bulb by application of 90 V using a variac connected to 110 V line
power. Within seconds, an aerosol appeared and was drawn into the 1
L flask by use of the piston, with formation of the aerosol
terminated after about 3.5-5 s. The aerosol was allowed to sediment
onto the walls of the 1 L flask for approximately 30 minutes. The
flask was then extracted with acetonitrile and the extract analyzed
by HPLC with detection by light absorption at 225 nm. Comparison
with standards containing known amounts of the amine drug revealed
the purity of the amine drug that had been collected in the flask,
resulting in a calculatable aerosol drug mass density.
[0203] Although certain embodiments and examples have been used to
describe the present invention, it will be apparent to those of
skill in the art that changes may be made to those described
embodiments and examples without departing from the scope or spirit
of the invention of the following claims.
* * * * *