U.S. patent application number 14/021988 was filed with the patent office on 2014-06-19 for multimodal particulate formulations.
This patent application is currently assigned to Hale Biopharma Ventures, LLC. The applicant listed for this patent is Hale Biopharma Ventures, LLC. Invention is credited to Steve Cartt, David Medeiros.
Application Number | 20140170220 14/021988 |
Document ID | / |
Family ID | 40642223 |
Filed Date | 2014-06-19 |
United States Patent
Application |
20140170220 |
Kind Code |
A1 |
Cartt; Steve ; et
al. |
June 19, 2014 |
MULTIMODAL PARTICULATE FORMULATIONS
Abstract
Multimodal particulate formulations of medicaments and methods
for their use, e.g. by nasal or pulmonary administration for the
treatment of various medical conditions, are provided.
Inventors: |
Cartt; Steve; (Union City,
CA) ; Medeiros; David; (South San Francisco,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Hale Biopharma Ventures, LLC |
Encinitas |
CA |
US |
|
|
Assignee: |
Hale Biopharma Ventures,
LLC
Encinitas
CA
|
Family ID: |
40642223 |
Appl. No.: |
14/021988 |
Filed: |
September 9, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12266529 |
Nov 6, 2008 |
8530463 |
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14021988 |
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12116842 |
May 7, 2008 |
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12266529 |
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60916550 |
May 7, 2007 |
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Current U.S.
Class: |
424/489 ;
128/200.23; 128/203.12; 128/203.15; 514/221 |
Current CPC
Class: |
A61K 9/0043 20130101;
A61K 9/0073 20130101; A61K 31/5513 20130101; A61M 16/14 20130101;
A61P 11/00 20180101; A61M 2202/064 20130101; A61M 15/009 20130101;
A61M 15/0065 20130101; A61K 31/5517 20130101; A61K 9/14
20130101 |
Class at
Publication: |
424/489 ;
514/221; 128/203.12; 128/203.15; 128/200.23 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61M 16/14 20060101 A61M016/14; A61M 15/00 20060101
A61M015/00; A61K 31/5513 20060101 A61K031/5513 |
Claims
1. A composition for aerosol administration of a medicament,
comprising a first population of particles having a first effective
average particle size and a second population of particles having a
second effective average particle size, wherein the first effective
average particle size is at least 1.5 times that of the second
effective average particle size.
2. The composition of claim 1, wherein the medicament comprises at
least one benzodiazepine.
3. The composition of claim 2, wherein the medicament comprises at
least one benzodiazepine selected from the group consisting of:
alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam,
clorazepam, demoxazepam, flumazenil, flurazepam, halazepam,
midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam,
medazepam, lorazepam, mexazolam, prazepam, quazepam, triazolam,
temazepam, loprazolam, and pharmaceutically acceptable salts and
combinations thereof.
4. The composition of claim 1, wherein the medicament comprises at
least one member of the group consisting of other anticonvulsants
(such as aromatic allylic alcohols, barbiturates, bromides,
carbamates, carboxamides, fatty acids, topiramate, Gaba analogs,
hydantoins, oxazolidinediones, propionates, pyrimidinediones,
pyrrolidines, succinimides, sulfonamides, triazines, ureas,
valproylamides, etc.), insulin, calcitonins, enkephalins, LHRH and
analogs, GHRH (growth hormone releasing hormone), nifedipin, THF
(thymic humoral factor), CGRP (calcitonin gene related peptide),
atrial natriuretic peptide, antibiotics, metoclopramide,
ergotamine, Pizotizin, nasal vaccines (particularly HIV vaccines,
measles, rhinovirus Type 13 and respiratory syncitial virus),
pentamidine, CCK (Cholecystikinine), DDVAP, Interferons, growth
hormone, secretin, bradykinin antagonists, GRF (Growth releasing
factor), THF, TRH (Thyrotropin releasing hormone), ACTH analogues,
IGF (Insulin like growth factors), CGRP (Calcitorin gene related
peptide), Atrial Natriuretic peptide, Vasopressin and analogs
(DDAVP, Lypressin), Metoclopramide, Migraine treatment (e.g.
Dihydroergotamine, Ergometrine, Ergotamine, Pizotizin), Nasal
Vaccines (Particularly AIDS vaccines), FACTOR VIII, Colony
Stimulating factors, G-CSF (granulocyte-colony stimulating factor),
EPO (Erythropoitin) PTH (Parathyroid hormone), antibiotics and
antimicrobial agents (such as tetracyline hydrochloride,
leucomycin, penicillin, penicillin derivatives, erythromycin,
gentamicin, sulphathiazole and nitrofurazone), local anaesthetics,
vasoconstrictors, tetrahydrozoline hydrochloride, naphazoline
nitrate, oxymetazoline hydrochloride and tramazoline hydrochloride,
cardiotonics, vasodilators, antiseptics, enzymes, vitamin D, active
vitamin D, vitamin C, sex hormones, hypotensives, sedatives,
anti-tumor agents, steroidal anti-inflammatory agents,
non-steroidal anti-inflammatory agents, enzymatic anti-inflammatory
agents, anti-allergic agents, antitussive-expectorant agents,
antasthmatic agents, pain medications, antiproliferative or
anticancer chemotherapeutic drugs, insomnia drugs, antibiotics,
drugs for treating spasticity, antiemetics, antipsychotics,
long-acting Beta.sub.2-adrenertic agonists, short-acting
Beta.sub.2-adrenergic agonists, muscarinic antagonists,
corticosteroids, atypical antipsychotics, serotonin reuptake
inhibitors, tricyclic antidepressants, serotonin-norepinephrine
reuptake inhibitors, or pharmaceutically acceptable salts or
combinations thereof.
5. The pharmaceutical composition of claim 1, wherein the first
population of particles has a average size in the range of about 25
to about 7000 nm and the second population of particles has a
average size in the range of about 500 to about 10,000 nm.
6. The pharmaceutical composition of claim 1, wherein the
difference between the average particle size of the first and
second populations is greater than about 100 nm, greater than about
200 nm, greater than about 500 nm, greater than about 1000 nm,
greater than about 2000 nm, greater than about 3000 nm, greater
than about 4000 nm, greater than about 5000 nm, greater than about
6000 nm, greater than about 7000 nm, greater than about 8000 nm,
greater than about 9000 nm or greater than about 10,000 nm.
7. The pharmaceutical composition of claim 1, wherein the
difference between the average particle size of the first and
second particle populations is greater than about 10%, greater than
about 20% or greater than about 30% of the average particle size of
the second population of particles.
8. The pharmaceutical composition of claim 1, wherein the
composition is a dry powder or a suspension of particles in a
liquid carrier or diluent.
9. The pharmaceutical composition of claim 1, comprising at least
first and second populations of particles, wherein the first
population of particles has a particle size distribution having a
first node between about 0.5 .mu.m and about 5.0 .mu.m and the
second population of particles has a particle size distribution
having a second node greater than about 5.0 .mu.m.
10. The pharmaceutical composition of claim 1, comprising at least
first, second and third populations of particles, wherein the first
population of particles has a particle size distribution having a
first node between about 0.5 .mu.m and about 2.0 .mu.m, the second
population of particles has a particle size distribution having a
second node between about 2.0 .mu.m and about 5.0 .mu.m, and the
third population of particles has a particle size distribution
having a third node greater than about 5.0 .mu.m.
11. The pharmaceutical composition of claim 1, adapted for nasal or
pulmonary delivery.
12. A method of using a composition of claim 1, wherein the
medicament is administered to at least one nostril.
13. The method of claim 12, wherein the medicament is an amount of
benzodiazepine effective for acute treatment of seizure, reduction
in the frequency of seizure and or reduction in severity of
seizure.
14. A method of using a composition of claim 1, wherein the
medicament is administered with a pulmonary delivery device.
15. The method of using a composition of claim 14, wherein the
pulmonary delivery device is selected from a nebulizer, a dry
powder inhaler and a metered dose inhaler.
16. A pharmaceutical particulate composition for aerosol delivery
of a medicament comprising particulates having a multimodal
particle size distribution.
17. The pharmaceutical particulate composition of claim 16, wherein
the particulates have a bimodal particle size distribution.
18. The pharmaceutical composition of claim 16, wherein the
medicament comprises at least one benzodiazepine.
19. The pharmaceutical composition of claim 18, wherein the
medicament comprises at least one benzodiazepine selected from the
group consisting of alprazolam, brotizolam, chlordiazepoxide,
clobazam, clonazepam, clorazepam, demoxazepam, flumazenil,
flurazepam, halazepam, midazolam, nordazepam, medazepam, diazepam,
nitrazepam, oxazepam, medazepam, lorazepam, mexazolam, prazepam,
quazepam, triazolam, temazepam, loprazolam, and pharmaceutically
acceptable salts and combinations thereof.
20. The pharmaceutical composition of claim 16, wherein the
medicament comprises at least one member of the group consisting of
other anticonvulsants (such as aromatic allylic alcohols,
barbiturates, bromides, carbamates, carboxamides, fatty acids,
topiramate, Gaba analogs, hydantoins, oxazolidinediones,
propionates, pyrimidinediones, pyrrolidines, succinimides,
sulfonamides, triazines, ureas, valproylamides, etc.), insulin,
calcitonins, enkephalins, LHRH and analogs, GHRH (growth hormone
releasing hormone), nifedipin, THF (thymic humoral factor), CGRP
(calcitonin gene related peptide), atrial natriuretic peptide,
antibiotics, metoclopramide, ergotamine, Pizotizin, nasal vaccines
(particularly HIV vaccines, measles, rhinovirus Type 13 and
respiratory syncitial virus), pentamidine, CCK (Cholecystikinine),
DDVAP, Interferons, growth hormone, secretin, bradykinin
antagonists, GRF (Growth releasing factor), THF, TRH (Thyrotropin
releasing hormone), ACTH analogues, IGF (Insulin like growth
factors), CGRP (Calcitorin gene related peptide), Atrial
Natriuretic peptide, Vasopressin and analogs (DDAVP, Lypressin),
Metoclopramide, Migraine treatment (e.g. Dihydroergotamine,
Ergometrine, Ergotamine, Pizotizin), Nasal Vaccines (Particularly
AIDS vaccines), FACTOR VIII, Colony Stimulating factors, G-CSF
(granulocyte-colony stimulating factor), EPO (Erythropoitin) PTH
(Parathyroid hormone), antibiotics and antimicrobial agents (such
as tetracyline hydrochloride, leucomycin, penicillin, penicillin
derivatives, erythromycin, gentamicin, sulphathiazole and
nitrofurazone), local anaesthetics, vasoconstrictors,
tetrahydrozoline hydrochloride, naphazoline nitrate, oxymetazoline
hydrochloride and tramazoline hydrochloride, cardiotonics,
vasodilators, antiseptics, enzymes, vitamin D, active vitamin D,
vitamin C, sex hormones, hypotensives, sedatives, anti-tumor
agents, steroidal anti-inflammatory agents, non-steroidal
anti-inflammatory agents, enzymatic anti-inflammatory agents,
anti-allergic agents, antitussive-expectorant agents, antasthmatic
agents, pain medications, antiproliferative or anticancer
chemotherapeutic drugs, insomnia drugs, antibiotics, drugs for
treating spasticity, antiemetics, antipsychotics, long-acting
Beta.sub.2-adrenertic agonists, short-acting Beta.sub.2-adrenergic
agonists, muscarinic antagonists, corticosteroids, atypical
antipsychotics, serotonin reuptake inhibitors, tricyclic
antidepressants, serotonin-norepinephrine reuptake inhibitors, or
pharmaceutically acceptable salts or combinations thereof.
21. The pharmaceutical composition of claim 16, wherein the
particles have an effective average size greater than about 500 nm,
1000 nm, greater than about 2000 nm, greater than about 4000 nm or
greater than 5000 nm.
22. The pharmaceutical composition of claim 16, wherein the
composition is a dry powder or a suspension of particles in a
liquid.
23. The composition of claim 22, wherein the composition is a
non-aqueous dispersion or suspension of nanoparticulate
benzodiazepine particles.
24. The pharmaceutical composition of claim 16, comprising at least
first and second populations of particles, wherein the first
population of particles has a particle size distribution having a
first node between about 0.5 .mu.m and about 5.0 .mu.m and the
second population of particles has a particle size distribution
having a second node greater than about 5.0 .mu.m.
25. The pharmaceutical composition of claim 16, comprising at least
first, second and third populations of particles, wherein the first
population of particles has a particle size distribution having a
first node between about 0.5 .mu.m and about 2.0 .mu.m, the second
population of particles has a particle size distribution having a
second node between about 2.0 .mu.m and about 5.0 .mu.m, and the
third population of particles has a particle size distribution
having a third node greater than about 5.0 .mu.m.
26. The pharmaceutical composition of claim 16, adapted for nasal
or pulmonary delivery.
27. A method of using a composition of claim 16, wherein the
medicament is administered to at least one nostril.
28. A method of using a composition of claim 16, wherein the
medicament is administered with a pulmonary delivery device.
29. The method of using a composition of claim 28, wherein the
pulmonary delivery device is selected from a nebulizer, a dry
powder inhaler and a metered dose inhaler.
30. An aerosol composition of an aqueous suspension or dispersion
of nanoparticulate medicament particles, wherein droplets of the
aerosol have a mass median aerodynamic diameter (MMAD) less than or
equal to about 1000 .mu.m and the nanoparticulate particles have an
effective average particle size of less than about 5000 nm.
31. The aerosol composition of claim 30, wherein the nanoparticular
medicament particles comprise at least one benzodiazepine.
32. The aerosol composition of claim 31, wherein the medicament
particles comprise at least one benzodiazepine selected from the
group consisting of: alprazolam, brotizolam, chlordiazepoxide,
clobazam, clonazepam, clorazepam, demoxazepam, flumazenil,
flurazepam, halazepam, midazolam, nordazepam, medazepam, diazepam,
nitrazepam, oxazepam, medazepam, lorazepam, mexazolam, prazepam,
quazepam, triazolam, temazepam, loprazolam, and pharmaceutically
acceptable salts and combinations thereof.
33. A method of using a composition of claim 32, wherein the
medicament is administered to at least one nostril.
34. The method of claim 33, wherein the medicament is an amount of
benzodiazepine effective for acute treatment of seizure, reduction
in the frequency of seizure and or reduction in severity of
seizure
35. A method of using a composition of claim 32, wherein the
medicament is administered with a pulmonary delivery device.
36. The method of using a composition of claim 35, wherein the
pulmonary delivery device is selected from a nebulizer, a dry
powder inhaler and a metered dose inhaler.
37. The aerosol composition of claim 30, wherein the nanoparticular
medicament particles comprise at least one member of the group
consisting of other anticonvulsants (such as aromatic allylic
alcohols, barbiturates, bromides, carbamates, carboxamides, fatty
acids, topiramate, Gaba analogs, hydantoins, oxazolidinediones,
propionates, pyrimidinediones, pyrrolidines, succinimides,
sulfonamides, triazines, ureas, valproylamides, etc.), insulin,
calcitonins, enkephalins, LHRH and analogs, GHRH (growth hormone
releasing hormone), nifedipin, THF (thymic humoral factor), CGRP
(calcitonin gene related peptide), atrial natriuretic peptide,
antibiotics, metoclopramide, ergotamine, Pizotizin, nasal vaccines
(particularly HIV vaccines, measles, rhinovirus Type 13 and
respiratory syncitial virus), pentamidine, CCK (Cholecystikinine),
DDVAP, Interferons, growth hormone, secretin, bradykinin
antagonists, GRF (Growth releasing factor), THF, TRH (Thyrotropin
releasing hormone), ACTH analogues, IGF (Insulin like growth
factors), CGRP (Calcitorin gene related peptide), Atrial
Natriuretic peptide, Vasopressin and analogs (DDAVP, Lypressin),
Metoclopramide, Migraine treatment (e.g. Dihydroergotamine,
Ergometrine, Ergotamine, Pizotizin), Nasal Vaccines (Particularly
AIDS vaccines), FACTOR VIII, Colony Stimulating factors, G-CSF
(granulocyte-colony stimulating factor), EPO (Erythropoitin) PTH
(Parathyroid hormone), antibiotics and antimicrobial agents (such
as tetracyline hydrochloride, leucomycin, penicillin, penicillin
derivatives, erythromycin, gentamicin, sulphathiazole and
nitrofurazone), local anaesthetics, vasoconstrictors,
tetrahydrozoline hydrochloride, naphazoline nitrate, oxymetazoline
hydrochloride and tramazoline hydrochloride, cardiotonics,
vasodilators, antiseptics, enzymes, vitamin D, active vitamin D,
vitamin C, sex hormones, hypotensives, sedatives, anti-tumor
agents, steroidal anti-inflammatory agents, non-steroidal
anti-inflammatory agents, enzymatic anti-inflammatory agents,
anti-allergic agents, antitussive-expectorant agents, antasthmatic
agents, pain medications, antiproliferative or anticancer
chemotherapeutic drugs, insomnia drugs, antibiotics, drugs for
treating spasticity, antiemetics, antipsychotics, long-acting
Beta.sub.2-adrenertic agonists, short-acting Beta.sub.2-adrenergic
agonists, muscarinic antagonists, corticosteroids, atypical
antipsychotics, serotonin reuptake inhibitors, tricyclic
antidepressants, serotonin-norepinephrine reuptake inhibitors, or
pharmaceutically acceptable salts or combinations thereof.
38. A method of using a composition of claim 37, wherein the
medicament is administered to at least one nostril.
39. A method of using a composition of claim 37, wherein the
medicament is administered with a pulmonary delivery device.
40. The method of using a composition of claim 39, wherein the
pulmonary delivery device is selected from a nebulizer, a dry
powder inhaler and a metered dose inhaler.
Description
[0001] This application is a continuation of Ser. No. 12/266,529,
filed Nov. 6, 2008, which is a continuation-in-part of U.S. patent
application Ser. No. 12/116,842, filed May 7, 2008, which claims
benefit of priority of provisional application U.S. Ser. No.
60/916,550, filed on May 7, 2007; the entire contents of each of
these applications are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This application relates to nanoparticulate drug
compositions and to aerosol administration of nanoparticulate
drugs.
BACKGROUND OF THE INVENTION
[0003] Various drugs have been administered orally or parenterally,
e.g. by intravenous (IV), intramuscular (IM) or subcutaneous
(subcu) injection. Injection of a drug can be effective, but is
often characterized by patient discomfort and inconvenience, and
thus poor patient compliance. As a result, it is often considered
desirable to provide a medicament in an oral formulation, as an
alternative to, or substitute for, injection. However, oral
formulations are often characterized by poor absorption, rapid
first-pass metabolism in the liver, slow attainment of effective
blood plasma levels and other problems.
[0004] Intranasal formulations have been used for delivery of some
medicaments. Nasal preparations are generally administered in
metered sprays having volumes of less than 250 .mu.l, preferably
less than 150 .mu.l, and ideally from 25 to 100 .mu.l, since
administration of larger volumes usually exceeds the capacity of
the nasal sinuses and results in volumes in excess of about 250
.mu.l bypassing the sinuses and flowing down the back of the throat
where it is swallowed. As smaller dose volumes are preferred for
nasal administration, poor water solubility of many compounds
limits the dose that may be administered to a patient at any given
time. This in turn limits the clinical effectiveness of
nasally-administered medicaments.
[0005] There is a need for formulations that are capable of
providing to the nasal mucosa sufficient quantity of active
pharmaceutical agents in a small enough volume to provide
therapeutically effective blood plasma concentration of active
pharmaceutical agent within a short period after administration of
the formulation to the nasal mucosa. These and other objects and
advantages are provided by the invention described herein.
SUMMARY OF THE INVENTION
[0006] The foregoing and further needs are met by embodiments of
the present invention, which provide a composition for aerosol
administration of a medicament, comprising a first population of
particles having a first effective mean particle diameter and a
second population of particles having a second effective mean
particle diameter, wherein the first effective mean particle
diameter is at least 1.5 times, at least 1.6 times, at least 1.7
times, at least 1.8 times, at least 1.9 times, at least 2 times, at
least 2.5 times or at least 3 times that of the second effective
mean particle diameter. In some embodiments, the aerosol is adapted
for nasal administration. In some embodiments, the aerosol is
adapted for pulmonary administration. In some embodiments, the
aerosol is a dry powder. In some embodiments, the aerosol is a
particle suspension in a liquid suitable for administration with a
metered dose inhaler. In some embodiments, the aerosol is an
aqueous suspension suitable for administration with a
nebulizer.
[0007] The foregoing and further needs are met by embodiments of
the present invention, which provide a composition for aerosol
administration of a medicament, comprising a first population of
particles having a first effective mean particle diameter and a
second population of particles having a second effective mean
particle diameter, wherein the first effective mean particle
diameter is at least twice that of the second effective mean
particle diameter. In some embodiments, the aerosol is administered
to the nasal mucosa. In some embodiments, the aerosol is
administered by pulmonary inhalation. In some embodiments, the
aerosol is a dry powder and is administered with a dry powder
inhaler. In some embodiments, the aerosol is a particle suspension
in a liquid and is administered with a metered dose inhaler. In
some embodiments, the aerosol is an aqueous suspension administered
with a nebulizer.
[0008] The foregoing and further needs are met by embodiments of
the present invention, which provide a method of using a
composition for aerosol administration of a medicament, comprising
a first population of particles having a first effective mean
particle diameter and a second population of particles having a
second effective mean particle diameter, wherein the first
effective mean particle diameter is at least 1.5 times, at least
1.6 times, at least 1.7 times, at least 1.8 times, at least 1.9
times, at least 2 times, at least 2.5 times or at least 3 times
that of the second effective mean particle diameter. In some
embodiments, the aerosol is administered to the nasal mucosa. In
some embodiments, the method comprises administering an effective
amount of the composition to the nose by administering a
therapeutically effective amount of the composition to at least one
nostril. In some embodiments, the aerosol is administered by
pulmonary inhalation. In some embodiments, the aerosol is a dry
powder and is administered with a dry powder inhaler. In some
embodiments, the aerosol is a particle suspension in a liquid and
is administered with a metered dose inhaler. In some embodiments,
the aerosol is an aqueous suspension administered with a
nebulizer.
[0009] The foregoing and further needs are met by embodiments of
the present invention, which provide a method of using a
composition for aerosol administration of a medicament, comprising
a first population of particles having a first effective mean
particle diameter and a second population of particles having a
second effective mean particle diameter, wherein the first
effective mean particle diameter is at least twice that of the
second effective mean particle diameter. In some embodiments, the
aerosol is administered to the nasal mucosa. In some embodiments,
the method comprises administering an effective amount of the
composition to the nose by administering a therapeutically
effective amount of the composition to at least one nostril. In
some embodiments, the aerosol is administered by pulmonary
inhalation. In some embodiments, the aerosol is a dry powder and is
administered with a dry powder inhaler. In some embodiments, the
aerosol is a particle suspension in a liquid and is administered
with a metered dose inhaler. In some embodiments, the aerosol is an
aqueous suspension administered with a nebulizer.
[0010] The foregoing and further needs are met by embodiments of
the present invention, which provide a pharmaceutical particulate
composition for aerosol delivery of a medicament comprising
particulates having a multimodal particle size distribution. In
some embodiments, the aerosol is adapted for nasal administration.
In some embodiments, the aerosol is adapted for pulmonary
administration. In some embodiments, the aerosol is a dry powder.
In some embodiments, the aerosol is a particle suspension in a
liquid suitable for administration with a metered dose inhaler. In
some embodiments, the aerosol is an aqueous suspension suitable for
administration with a nebulizer.
[0011] The foregoing and further needs are met by embodiments of
the present invention, which provide a method of using a
pharmaceutical particulate composition for nasal delivery of a
medicament comprising particulates having a multimodal particle
size distribution, comprising administering an effective amount of
the composition to the nose by administering a therapeutically
effective amount of the composition to at least one nostril.
[0012] The foregoing and further needs are met by embodiments of
the invention, which provide a method of using a pharmaceutical
particulate composition for pulmonary delivery of a medicament
comprising particulates having a multimodal particle size
distribution, comprising administering an effective amount of the
composition from a suitable pulmonary delivery device. In some
embodiments, the suitable delivery device is a dry powder
inhalation device. In some embodiments, the suitable delivery
device is a metered dose inhaler. In some embodiments, the suitable
delivery device is a nebulizer.
[0013] The foregoing and further needs are further met by
embodiments of the present invention, which provide an aerosol
composition of an aqueous suspension or dispersion of
nanoparticulate medicament particles having a multimodal particle
size distribution, wherein: the droplets of the aerosol have a mass
median aerodynamic diameter (MMAD) less than or equal to about 1000
.mu.m and the nanoparticulate medicament particles have an
effective average particle size of less than about 5000 nm. In some
embodiments, the aerosol composition is adapted for nasal
administration. In some embodiments, the aerosol composition is
adapted for pulmonary administration. In some embodiments, the
droplets have an MMAD of less than or equal to about 5 .mu.m. In
some embodiments, at least one population of particles comprises
medicament particles having an effective average particle size of
less than about 5 .mu.m. In some embodiments, at least one
population of particles comprises medicament particles having an
effective average particle size of about 0.5 .mu.m to about 5.0
.mu.m. In some embodiments, at least one population of particles
has an effective average particle size of about 0.5 .mu.m to about
2.0 .mu.m or about 2.0 .mu.m to about 5.0 .mu.m. In some
embodiments, at least one population of particles has an effective
average particle size of greater than about 5.0 .mu.m. In some
embodiments, at least one population of particles has an effective
average particle size of less than about 5.0 .mu.m and at least one
population of particles has an effective average particle size of
greater than about 5.0 .mu.m. In some embodiments, at least one
population of particles is adapted for administration to the
pulmonary mucosa. In some embodiments, at least one population of
particles is adapted for administration to the nasal, oropharyngeal
and/or gastrointestinal mucosa. In some embodiments, one population
of particles is adapted for penetration into the deep lung and
another population of particles is adapted for penetration into the
upper lung.
[0014] The foregoing and further needs are further met by
embodiments of the present invention, which provide a method of
using an aerosol composition of an aqueous suspension or dispersion
of nanoparticulate medicament particles, wherein: the droplets of
the aerosol have a mass median aerodynamic diameter (MMAD) less
than or equal to about 1000 .mu.m and the nanoparticulate
medicament particles have an effective average particle size of
less than about 5000 nm, the method comprising administering an
effective amount of the composition to a patient by nasal or
pulmonary administration. In some embodiments, the aerosol
composition is adapted for nasal administration. In some
embodiments, the aerosol composition is administered to the nose by
spraying a therapeutically effective amount of the composition into
at least one nostril. In some embodiments, the aerosol composition
is adapted for pulmonary administration.
[0015] The foregoing and further needs are met by embodiments of
the present invention, which provide a method of administering a
medicament drug to a patient, comprising administering to the nose,
nasal cavity or lungs of a patient an effective amount of an
aerosol composition of an aqueous suspension or dispersion of
nanoparticulate medicament particles, wherein: the droplets of the
aerosol have a mass median aerodynamic diameter (MMAD) less than or
equal to about 1000 .mu.m and the nanoparticulate medicament
particles have an effective average particle size of less than
about 5000 nm, the method comprising administering an effective
amount of the composition to a patient by nasal or pulmonary
administration. In some embodiments, the droplets have an MMAD of
less than or equal to about 5 .mu.m. In some embodiments, at least
one population of particles comprises medicament particles having
an effective average particle size of less than about 5 .mu.m. In
some embodiments, at least one population of particles comprises
medicament particles having an effective average particle size of
about 0.5 .mu.m to about 5.0 .mu.m. In some embodiments, at least
one population of particles has an effective average particle size
of about 0.5 .mu.m to about 2.0 .mu.m or about 2.0 .mu.m to about
5.0 .mu.m. In some embodiments, at least one population of
particles has an effective average particle size of greater than
about 5.0 .mu.m. In some embodiments, at least one population of
particles has an effective average particle size of less than about
5.0 .mu.m and at least one population of particles has an effective
average particle size of greater than about 5.0 .mu.m. In some
embodiments, at least one population of particles is adapted for
administration to the pulmonary mucosa. In some embodiments, at
least one population of particles is adapted for administration to
the nasal, oropharyngeal and/or gastrointestinal mucosa. In some
embodiments, one population of particles is adapted for penetration
into the deep lung and another population of particles is adapted
for penetration into the upper lung.
[0016] The foregoing and further needs are met by embodiments of
the present invention, which provide a method of administering a
medicament drug to a patient, comprising administering to the lungs
and/or oropharyngeal mucosa an effective amount of an aerosol
composition of an aqueous suspension or dispersion of
nanoparticulate medicament particles, wherein: the droplets of the
aerosol have a mass median aerodynamic diameter (MMAD) less than or
equal to about 1000 .mu.m and the nanoparticulate medicament
particles have an effective average particle size of less than
about 5000 nm. In some embodiments, the droplets have an MMAD of
less than or equal to about 5 .mu.m. In some embodiments, at least
one population of particles comprises medicament particles having
an effective average particle size of less than about 5 .mu.m. In
some embodiments, at least one population of particles comprises
medicament particles having an effective average particle size of
about 0.5 .mu.m to about 5.0 .mu.m. In some embodiments, at least
one population of particles has an effective average particle size
of about 0.5 .mu.m to about 2.0 .mu.m or about 2.0 .mu.m to about
5.0 .mu.m. In some embodiments, at least one population of
particles has an effective average particle size of greater than
about 5.0 .mu.m. In some embodiments, at least one population of
particles has an effective average particle size of less than about
5.0 .mu.m and at least one population of particles has an effective
average particle size of greater than about 5.0 .mu.m. In some
embodiments, at least one population of particles is adapted for
administration to the pulmonary mucosa. In some embodiments, at
least one population of particles is adapted for administration to
the nasal, oropharyngeal and/or gastrointestinal mucosa. In some
embodiments, one population of particles is adapted for penetration
into the deep lung and another population of particles is adapted
for penetration into the upper lung.
[0017] The foregoing and further needs are additionally met by
embodiments of the present invention, which provide a
pharmaceutical composition for nasal administration of medicament
comprising medicament particles and one or more non-cationic
surface active agents adsorbed to a surface thereof.
[0018] The foregoing and further needs are additionally met by
embodiments of the present invention, which provide a
pharmaceutical composition for pulmonary administration of
medicament comprising medicament particles and one or more
non-cationic surface active agents adsorbed to a surface
thereof.
[0019] The foregoing and further needs are further met by
embodiments of the invention, which provides a method of
administering a pharmaceutical composition for nasal administration
of medicament comprising medicament particles and one or more
non-cationic surface active agents adsorbed to a surface thereof,
the method comprising administering an effective amount of the
composition to the nose by administering a therapeutically
effective amount of the composition to at least one nostril.
[0020] The foregoing and further needs are further met by
embodiments of the invention, which provides a method of
administering a pharmaceutical composition for pulmonary
administration of medicament comprising medicament particles and
one or more non-cationic surface active agents adsorbed to a
surface thereof, the method comprising administering an effective
amount of the composition to the lungs a therapeutically effective
amount of the composition.
[0021] The foregoing and further needs are met by embodiments of
the present invention, which provide a method of administering a
medicament drug to a patient, comprising administering to the
patient's nose or nasal cavity a pharmaceutical composition
comprising particles of a medicament drug having a surface active
agent adsorbed to a surface thereof.
[0022] The foregoing and further needs are met by embodiments of
the present invention, which provide a method of administering a
medicament drug to a patient, comprising administering to the
patient's lungs and/or oropharyngeal mucosa a pharmaceutical
composition comprising particles of a medicament drug having a
surface active agent adsorbed to a surface thereof.
[0023] The foregoing and further needs are met by embodiments of
the present invention, which provide a non-aqueous dispersion or
suspension of nanoparticulate medicament particles. In some
embodiments, the nanoparticulate medicament has a multimodal
particle size distribution. In some embodiments, the
nanoparticulate medicament has a bimodal particle size
distribution. In some embodiments, the nanoparticulate medicament
has a trimodal particle size distribution. In some embodiments, the
nanoparticulate medicament is adapted for nasal administration,
e.g. with a metered dose nasal insufflator. In some embodiments,
the nanoparticulate medicament is adapted for pulmonary
administration, e.g. with a metered dose inhaler. In some
embodiments, at least one population of particles has a mean
particle size of less than about 5 .mu.m. In some embodiments, at
least one population of particles has a mean particle size of about
0.5 .mu.m to about 5 .mu.m. In some embodiments, at least one
population of particles has a mean particle size of about 0.5 .mu.m
to about 2.0 .mu.m. In some embodiments, at least one population of
particles has a mean particle size of about 2.0 .mu.m to about 5.0
.mu.m. In some embodiments, at least one population of particles
has a mean particle size of about 0.5 .mu.m to about 5 .mu.m and at
least one population of particles has a mean particle size of
greater than about 5 .mu.m.
[0024] The foregoing and additional needs are further met by
embodiments of the present invention, which provide a method of
administering a non-aqueous dispersion or suspension of
nanoparticulate medicament particles, the method comprising
administering an effective amount of the dispersion or suspension
to the nose by administering a therapeutically effective amount of
the composition to at least one nostril.
[0025] The foregoing and further needs are additionally met by
embodiments of the present invention, which provide, a method of
administering a medicament drug to a patient, comprising
administering to the patient's nose or nasal cavity a
pharmaceutical composition comprising a non-aqueous dispersion or
suspension of nanoparticulate medicament particles.
[0026] The foregoing and additional needs are further met by
embodiments of the invention, which provide a nanoparticulate
composition comprising: (a) a benzodiazepine having an effective
average particle size of less than about 2000 nm, wherein the
benzodiazepine is selected from the group consisting of alprazolam,
brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam,
demoxazepam, flumazenil, flurazepam, halazepam, midazolam,
nordazepam, medazepam, diazepam, nitrazepam, oxazepam, midazepam,
lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam,
pharmaceutically acceptable salts and esters thereof, and mixtures
thereof; and (b) at least one surface stabilizer. In some
embodiments, the surface stabilizer is selected from the group
consisting of a nonionic surfactant, an ionic surfactant, a
cationic surfactant, an anionic surfactant, and a zwitterionic
surfactant. In some embodiments, the nanoparticulate benzodiazepine
has a multimodal particle size distribution. In some embodiments,
the nanoparticulate benzodiazepine has a bimodal particle size
distribution. In some embodiments, the nanoparticulate
benzodiazepine has a trimodal particle size distribution. In some
embodiments, the nanoparticulate benzodiazepine is adapted for
nasal administration, e.g. with a metered dose nasal insufflator.
In some embodiments, the nanoparticulate benzodiazepine is adapted
for pulmonary administration, e.g. with a metered dose inhaler. In
some embodiments, at least one population of particles has a mean
particle size of less than about 5 .mu.m. In some embodiments, at
least one population of particles has a mean particle size of about
0.5 .mu.m to about 5 .mu.m. In some embodiments, at least one
population of particles has a mean particle size of about 0.5 .mu.m
to about 2.0 .mu.m. In some embodiments, at least one population of
particles has a mean particle size of about 2.0 .mu.m to about 5.0
.mu.m. In some embodiments, at least one population of particles
has a mean particle size of about 0.5 .mu.m to about 5 .mu.m and at
least one population of particles has a mean particle size of
greater than about 5 .mu.m.
[0027] The foregoing and additional needs are further met by a
method of treating a subject in need comprising administering to
the subject a nanoparticulate benzodiazepine composition
comprising: (a) a benzodiazepine having an effective average
particle size of less than about 2000 nm, wherein the
benzodiazepine is selected from the group consisting of alprazolam,
brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam,
demoxazepam, flumazenil, flurazepam, halazepam, midazolam,
nordazepam, medazepam, diazepam, nitrazepam, oxazepam, midazepam,
lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam,
pharmaceutically acceptable salts and esters thereof, and mixtures
thereof; and (b) at least one surface stabilizer. In some
embodiments, the surface stabilizer is selected from the group
consisting of a nonionic surfactant, an ionic surfactant, a
cationic surfactant, an anionic surfactant, and a zwitterionic
surfactant. In some embodiments, the nanoparticulate benzodiazepine
has a multimodal particle size distribution. In some embodiments,
the nanoparticulate benzodiazepine has a bimodal particle size
distribution. In some embodiments, the nanoparticulate
benzodiazepine has a trimodal particle size distribution. In some
embodiments, the nanoparticulate benzodiazepine is adapted for
nasal administration, e.g. with a metered dose nasal insufflator.
In some embodiments, the nanoparticulate benzodiazepine is adapted
for pulmonary administration, e.g. with a metered dose inhaler. In
some embodiments, at least one population of particles has a mean
particle size of less than about 5 .mu.m. In some embodiments, at
least one population of particles has a mean particle size of about
0.5 .mu.m to about 5 .mu.m. In some embodiments, at least one
population of particles has a mean particle size of about 0.5 .mu.m
to about 2.0 .mu.m. In some embodiments, at least one population of
particles has a mean particle size of about 2.0 .mu.m to about 5.0
.mu.m. In some embodiments, at least one population of particles
has a mean particle size of about 0.5 .mu.m to about 5 .mu.m and at
least one population of particles has a mean particle size of
greater than about 5 .mu.m.
[0028] These and further advantages and characteristics of the
present invention will become apparent to the person skilled in the
art upon consideration of the description and claims.
INCORPORATION BY REFERENCE
[0029] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference.
DETAILED DESCRIPTION OF THE INVENTION
[0030] The present invention provides aerosol (e.g. nasal and
pulmonary) formulations for administering various drugs. In some
embodiments, there are provided compositions comprising
nanoparticulates characterized by multimodal (e.g. bimodal or
trimodal) particle size distribution. In particular embodiments,
the compositions are characterized by containing two or more
populations of nanoparticles, each having a particle size
distribution possessing a distinct node. The aerosol compositions
can be used to deliver e.g. benzodiazepine drugs, other
anticonvulsants (such as aromatic allylic alcohols, barbiturates,
bromides, carbamates, carboxamides, fatty acids, topiramate, Gaba
analogs, hydantoins, oxazolidinediones, propionates,
pyrimidinediones, pyrrolidines, succinimides, sulfonamides,
triazines, ureas, valproylamides, etc.), insulin, calcitonins,
enkephalins, LHRH and analogs, GHRH (growth hormone releasing
hormone), nifedipin, THF (thymic humoral factor), CGRP (calcitonin
gene related peptide), atrial natriuretic peptide, antibiotics,
metoclopramide, ergotamine, Pizotizin, nasal vaccines (particularly
HIV vaccines, measles, rhinovirus Type 13 and respiratory syncitial
virus), pentamidine, CCK (Cholecystikinine), DDVAP, Interferons,
growth hormone, secretin, bradykinin antagonists, GRF (Growth
releasing factor), THF, TRH (Thyrotropin releasing hormone), ACTH
analogues, IGF (Insulin like growth factors), CGRP (Calcitorin gene
related peptide), Atrial Natriuretic peptide, Vasopressin and
analogs (DDAVP, Lypressin), Metoclopramide, Migraine treatment
(e.g. Dihydroergotamine, Ergometrine, Ergotamine, Pizotizin), Nasal
Vaccines (Particularly AIDS vaccines), FACTOR VIII, Colony
Stimulating factors, G-CSF (granulocyte-colony stimulating factor),
EPO (Erythropoitin) PTH (Parathyroid hormone), antibiotics and
antimicrobial agents (such as tetracyline hydrochloride,
leucomycin, penicillin, penicillin derivatives, erythromycin,
gentamicin, sulphathiazole and nitrofurazone), local anaesthetics,
vasoconstrictors, tetrahydrozoline hydrochloride, naphazoline
nitrate, oxymetazoline hydrochloride and tramazoline hydrochloride,
cardiotonics, vasodilators, antiseptics, enzymes, vitamin D, active
vitamin D, vitamin C, sex hormones, hypotensives, sedatives,
anti-tumor agents, steroidal anti-inflammatory agents,
non-steroidal anti-inflammatory agents, enzymatic anti-inflammatory
agents, anti-allergic agents, antitussive-expectorant agents,
antasthmatic agents, or pharmaceutically acceptable salts or
combinations thereof.
[0031] As used herein, the terms "average" and "mean" are
synonymous, unless otherwise stated. As used herein, the terms
"particle size" and "particle diameter" are synonymous, unless
otherwise stated. As used herein, the pharase "effective mean
particle diameter" is intended to by synonymous with "effective
average particle size" as used in United States pre-grant
publication number US 2006/0198896, which is incorporated herein by
reference in its entirety. Effective mean particle diameter
(effective average particle size) may be measured by an
art-recognized method, such as by light-scattering methods,
microscopy, or other appropriate methods. Redispersibility can be
tested e.g. as set forth in the examples of U.S. Pat. No.
6,375,986, which is incorporated herein by reference.
[0032] As used herein, "pulmonary" refers to the lungs and
"pulmonary delivery" refers to delivery of a composition, e.g. a
medicament comprising a benzodiazepine drug, to the lungs. The
person of skill in the art will recognize that not all of a dose of
medicament for administration to the lungs will actually be
deposited in the lungs. Different modes of administration to the
lungs are characterized by different degrees of tendency to deposit
the medicament in the lungs. The portion of drug that is not
deposited in the lungs is generally divided between that which is
exhaled, that which is deposited in the oropharyngeal cavity and
that which escapes inhalation altogether, e.g. through leakage
around a nebulization mask, etc. The portion of the drug that is
deposited in the oropharyngeal cavity may be absorbed directly
through the oropharyngeal mucosa and/or may be swallowed and, if
stable in the gastrointestinal tract, absorbed through the
gastrointestinal mucoa. The person of skill in the art will
recognize that, no mode of pulmonary delivery is 100% efficient in
delivering drug to the lungs, and that though some (potentially
large) fraction of the drug is deposited in some other organ or
tissue than the lung, delivery of a medicament to the lungs, e.g.
using a nebulizer, a dry powder inhaler or a metered dose inhaler,
is "pulmonary delivery" for purposes of the invention described in
various embodiments herein.
[0033] In some embodiments, the invention provides for
administration aerosol (e.g. nasal and pulmonary) formulations for
administering one or more benzodiazepine drugs, such as diazepam,
lorazepam or midazolam, to a patient in need of therapeutic
treatment with a benzodiazepine drug. In some embodiments, the
invention further provides methods of administering a
benzodiazepine to a patient, comprising nasally administering an
effective amount of the benzodiazepine to the patient, wherein the
effective amount of the composition is effective to treat seizure,
protect against seizure, reduce or ameliorate the intensity of
seizure, reduce or ameliorate the frequency of seizure, and/or
prevent occurrence or re-occurrence of seizure. In some
embodiments, the invention further provides methods of
administering a benzodiazepine to a patient, comprising nasally
administering an effective amount of the benzodiazepine to the
patient, wherein the effective amount of the composition is
effective to provide a therapeutic effect selected from an
anxiolytic effect, an anticonvulsant effect, a sedative effect, a
skeletal muscle relaxant effect, an amnesic effect or combinations
thereof.
[0034] In some embodiments, the invention provides a composition
for aerosol (e.g. nasal or pulmonary) administration of a
medicament comprising a first population of particles having a
first effective mean particle diameter and a second population of
particles having a second effective mean particle diameter, wherein
the first effective mean particle diameter is at least 1.5 times,
at least 1.6 times, at least 1.7 times, at least 1.8 times, at
least 1.9 times, at least 2 times, at least 2.5 times or at least 3
times that of the second effective mean particle diameter. In some
embodiments, the invention provides a composition for aerosol (e.g.
nasal or pulmonary) administration of a medicament comprising a
first population of particles having a first effective mean
particle diameter and a second population of particles having a
second effective mean particle diameter, wherein the first
effective mean particle diameter is at least twice that of the
second effective mean particle diameter. In some embodiments, the
first population of particles comprises a first active ingredient.
In some embodiments, the first population of particles and the
second population of particles both comprise the first active
ingredient. In some embodiments, the second population of particles
comprises a second active ingredient. In some embodiments, the
first population of particles, the second population of particles
or both the first and second populations of particles comprise a
first active ingredient and a second active ingredient. In some
embodiments, the medicament comprises a benzodiazepine. In some
embodiments, the medicament comprises other anticonvulsants (such
as aromatic allylic alcohols, barbiturates, bromides, carbamates,
carboxamides, fatty acids, topiramate, Gaba analogs, hydantoins,
oxazolidinediones, propionates, pyrimidinediones, pyrrolidines,
succinimides, sulfonamides, triazines, ureas, valproylamides,
etc.), insulin, calcitonins, enkephalins, LHRH and analogs, GHRH
(growth hormone releasing hormone), nifedipin, THF (thymic humoral
factor), CGRP (calcitonin gene related peptide), atrial natriuretic
peptide, antibiotics, metoclopramide, ergotamine, Pizotizin, nasal
vaccines (particularly HIV vaccines, measles, rhinovirus Type 13
and respiratory syncitial virus), pentamidine, CCK
(Cholecystikinine), DDVAP, Interferons, growth hormone, secretin,
bradykinin antagonists, GRF (Growth releasing factor), THF, TRH
(Thyrotropin releasing hormone), ACTH analogues, IGF (Insulin like
growth factors), CGRP (Calcitorin gene related peptide), Atrial
Natriuretic peptide, Vasopressin and analogs (DDAVP, Lypressin),
Metoclopramide, Migraine treatment (e.g. Dihydroergotamine,
Ergometrine, Ergotamine, Pizotizin), Nasal Vaccines (Particularly
AIDS vaccines), FACTOR VIII, Colony Stimulating factors, G-CSF
(granulocyte-colony stimulating factor), EPO (Erythropoitin) PTH
(Parathyroid hormone), antibiotics and antimicrobial agents (such
as tetracyline hydrochloride, leucomycin, penicillin, penicillin
derivatives, erythromycin, gentamicin, sulphathiazole and
nitrofurazone), local anaesthetics, vasoconstrictors,
tetrahydrozoline hydrochloride, naphazoline nitrate, oxymetazoline
hydrochloride and tramazoline hydrochloride, cardiotonics,
vasodilators, antiseptics, enzymes, vitamin D, active vitamin D,
vitamin C, sex hormones, hypotensives, sedatives, anti-tumor
agents, steroidal anti-inflammatory agents, non-steroidal
anti-inflammatory agents, enzymatic anti-inflammatory agents,
anti-allergic agents, antitussive-expectorant agents, antasthmatic
agents, or pharmaceutically acceptable salts or combinations
thereof. In some embodiments, the medicament comprises a
benzodiazepine selected from the group consisting of: alprazolam,
brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam,
demoxazepam, flumazenil, flurazepam, halazepam, midazolam,
nordazepam, medazepam, diazepam, nitrazepam, oxazepam, medazepam,
lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam,
and pharmaceutically acceptable salts and combinations thereof. In
some embodiments, the benzodiazepine comprises at least one member
of the group consisting of alprazolam, diazepam, flurazepam,
lorazepam, medazepam, mexazolam, midazolam, temazepam and
pharmaceutically acceptable salts and combinations thereof. In some
embodiments, the benzodiazepine comprises one or more members of
the group consisting of: diazepam, lorazepam, midazolam and
pharmaceutically acceptable salts thereof. In some embodiments, the
particles in the medicament have a mean diameter of greater than
about 500 nm, greater than about 1000 nm, greater than about 2000
nm, greater than about 4000 nm or greater than about 5000 nm. In
some embodiments, the second population of particles or both are
coated with at least one surface acting agent. In some embodiments,
at least one surface acting agent is a cationic surfactant, a
non-ionic surfactant, an anionic surfactant, a surface active
biological modifier or a zwitterionic surfactant. In some
embodiments, at least one surface acting agent is a cationic
surfactant selected from the group consisting of natural
phospholipids, synthetic phospholipids, quaternary ammonium
compounds, benzalkonium chloride, cetyltrimethylammonium bromide,
chitosans, lauryldimethylbenzylammonium chloride, acyl carnitine
hydrochlorides, dimethyldioctadecylammomium bromide (DDAB),
dioleyoltrimethylammonium propane (DOTAP),
dimyristoyltrimethylammonium propane (DMTAP),
dimethylaminoethanecarbamoyl cholesterol (DC-Chol),
1,2-diacylglycero-3-(O-alkyl)phosphocholine,
O-alkylphosphatidylcholine, alkyl pyridinium halides, and
long-chain alkyl amines such as, for example, n-octylamine and
oleylamine. In some embodiments, at least one surface acting agent
is an anionic surface active agent selected from the group
consisting of natural anionic phospholipids, synthetic anionic
phospholipids and anionic polymers. In some embodiments, the
natural anionic phospholipids, synthetic anionic phospholipids and
anionic polymers are selected from the group consisting of
polyacrylic acid, carrageenan k type II, carbopol 980, carbopol 974
P, carbopol 971 P, polycarbophil, sodium carboxymethylcellulose,
sodium hyaluronate or combinations thereof. In some embodiments, at
least one surface acting agent is selected from the group
consisting of thiolated polymers. In some embodiments, the
thiolated polymer is selected from the group consisting of cysteine
conjugates of polyacrylic acid, polycarbophil (thiomer
polycarbophil-cysteine), thiolated sodium carboxymethylcellulose,
chitosan modified with 2-iminothiolate (e.g.
chitosan-4-thiobutylamidine conjugates, chitosan-thioglycolic acid
conjugates, chitosan-cysteine conjugates). In some embodiments, at
least one surface acting agent is selected from the group
consisting of polymeric mucilaginous polysaccharides. In some
embodiments, the polymeric mucilaginous polysaccharide is from the
aloe vera plant. In some embodiments, at least one surface acting
agent is methylcellulose, ethylcellulose,
hydroxypropylmethylcellulose (HPMC) or a mixture of two or more
thereof. In some embodiments, the composition comprises a third
population of benzodiazepine particles having a third mean particle
size distribution different from the first and second populations
of particles. In some embodiments, the composition further
comprises one or more additional ingredient selected from active
pharmaceutical ingredients and enhancers. In some embodiments, the
first population of particles has a mean diameter in the range of
about 25 to about 4000 nm and the second population of particles
has a mean diameter in the range of about 500 to about 10,000 nm.
In some embodiments, the first population of particles has a mean
diameter in the range of about 50 to about 2000 nm and the second
population of particles has a mean diameter in the range of about
1000 nm to about 10,000 nm. In some embodiments, the first
population of particles has a mean diameter in the range of about
50 to about 1000 nm and the second population of particles has a
mean diameter in the range of about 1000 nm to about 10,000 nm. In
some embodiments, the mean particle diameter of the first
population of particles is smaller than the mean particle diameter
of the second population of particles. In some embodiments, the
first population of particles has a mean diameter in the range of
about 50 to about 500 nm and the second population of particles has
a mean diameter in the range of about 2000 to about 10,000 nm. In
some embodiments, the difference between the mean particle size of
the first and second populations is greater than about 100 nm,
greater than about 200 nm, greater than about 500 nm, greater than
about 1000 nm, greater than about 2000 nm, greater than about 3000
nm, greater than about 4000 nm, greater than about 5000 nm, greater
than about 6000 nm, greater than about 7000 nm, greater than about
8000 nm, greater than about 9000 nm or greater than about 10,000
nm. In some embodiments, the difference between the mean particle
size of the first and second particle populations is greater than
about 10%, greater than about 20% or greater than about 30% of the
mean particle diameter of the second population of particles. In
some embodiments, the benzodiazepine particles do not contain
solvent residues resulting from solvent extraction or solvent
precipitation.
[0035] In some embodiments, the invention provides a method of
using a composition for aerosol (e.g. nasal or pulmonary)
administration of a medicament, the composition comprising a first
population of particles having a first effective mean particle
diameter and a second population of particles having a second
effective mean particle diameter. In some embodiments, the first
effective mean particle diameter is at least 1.5 times, at least
1.6 times, at least 1.7 times, at least 1.8 times, at least 1.9
times, at least 2 times, at least 2.5 times or at least 3 times
that of the second effective mean particle diameter, comprising
administering an effective amount of the composition to the nose by
administering a therapeutically effective amount of the composition
to at least one nostril. In some embodiments, the first effective
mean particle diameter is at least twice that of the second
effective mean particle diameter, comprising administering an
effective amount of the composition to the nose by administering a
therapeutically effective amount of the composition to at least one
nostril. In some embodiments, at least a portion of the
therapeutically effective amount of the composition to each
nostril. In some embodiments, the method comprises administering a
first quantity of the composition to a first nostril, administering
a second quantity of the composition to a second nostril, and
optionally after a pre-selected time delay, administering a third
quantity of the composition to the first nostril. In some
embodiments, the method further comprises optionally after a
pre-selected time delay, administering at least a fourth quantity
of the composition to the second nostril. In some embodiments, the
effective amount of the composition is effective to treat seizure,
protect against seizure, reduce or ameliorate the intensity of
seizure, reduce or ameliorate the frequency of seizure, and/or
prevent occurrence or re-occurrence of seizure. In some
embodiments, the effective amount of the composition is effective
to provide a therapeutic effect selected from an anxiolytic effect,
an anticonvulsant effect, a sedative effect, a skeletal muscle
relaxant effect, an amnesic effect or combinations thereof. In some
embodiments, a therapeutically effective plasma level of
benzodiazepine drug is obtained within about 1 hours of
administration to the patient. In some embodiments, the
therapeutically effective plasma level of the benzodiazepine drug
is obtained within about 30 minutes of administration of the
composition to the patient. In some embodiments, the
therapeutically effective plasma level of the benzodiazepine is
obtained within about 15 minutes of administration of the
composition to the patient. In some embodiments, the
therapeutically effective plasma level of benzodiazepine drug is
obtained within about 10 minutes of administration of the
composition to the patient. In some embodiments, the
therapeutically effective plasma level of benzodiazepine drug is
obtained within about 5 minutes of administration of the
composition to the patient. In some embodiments, a maximum (peak)
plasma concentration (C.sub.max) is obtained for the benzodiazepine
drug at a time (T.sub.max) less than about 1 hour after
administration of the composition to a patient. In some
embodiments, T.sub.max is less than about 30 minutes after
administration of the composition to the patient. In some
embodiments, T.sub.max is less than about 15 minutes after
administration of the composition to the patient. In some
embodiments, T.sub.max, is less than about 12 minutes after
administration of the composition to the patient. In some
embodiments, a benzodiazepine plasma concentration curve having a
first benzodiazepine plasma concentration maximum (Cmax1) and a
second benzodiazepine plasma concentration maximum (Cmax2) is
obtained. In some embodiments, the first benzodiazepine plasma
concentration maximum (Cmax1) is obtained from 1 to 30 minutes
after administration of the composition and the second
benzodiazepine plasma concentration maximum (Cmax2) is obtained
from 5 to 360 minutes after administration of the composition. In
some embodiments, Cmax1 is obtained from 5 to 20 minutes after
administration of the composition and Cmax2 is obtained from 10 to
60 minutes after administration. In some embodiments, Cmax1 and
Cmax2 are obtained at times Tmax1 and Tmax2 that are at least about
5 minutes, at least about 10 minutes, at least about 20 minutes or
at least about 30 minutes apart. In some embodiments, Cmax1 is
obtained at time Tmax1 and Cmax2 is obtained at time Tmax2, wherein
a difference between Tmax1 and Tmax2 is from 5 to 360, from 10 to
240, from 15 to 120 or from 20 to 60 minutes. In some embodiments,
a benzodiazepine plasma concentration curve having a plasma
benzodiazepine concentration maximum (C.sub.max) and a shoulder
(C.sub.shoulder) is obtained. In some embodiments, the shoulder
occurs within about 1 minute, within about 5 minutes, within about
10 minutes, within about 15 minutes or within about 30 minutes of
time (T.sub.max) when the concentration maximum (C.sub.max) occurs.
In some embodiments, a benzodiazepine plasma concentration curve
having a single plasma benzodiazepine concentration maximum
(C.sub.max) is obtained. In some embodiments, Cmax is obtained
within about 5 minutes, within about 10 minutes, within about 20
minutes, within about 30 minutes or within about 60 minutes of
administering the medicament to the patient. in some embodiments,
the plasma benzodiazepine concentration is in the range of 5 to 95%
of C.sub.max from 30 to 720 minutes after the time (T.sub.max) when
C.sub.max is obtained. In some embodiments, the plasma
benzodiazepine concentration is in the range of 5 to 95% of
C.sub.max from 30 to 360 minutes after the time (T.sub.max) when
C.sub.max is obtained. In some embodiments, the plasma
benzodiazepine concentration is in the range of 10 to 90 of
C.sub.max from 30 to 720 minutes after the time (T.sub.max) when
C.sub.max is obtained. In some embodiments, the plasma
benzodiazepine concentration is in the range of 10 to 90 of
C.sub.max from 60 to 360 minutes after the time (T.sub.max) when
C.sub.max is obtained. In some embodiments, the plasma
benzodiazepine concentration is in the range of 15 to 60% of from
30 to 720 minutes after the time (T.sub.max) when C.sub.max is
obtained. In some embodiments, the plasma benzodiazepine
concentration is in the range of 15 to 60% of C.sub.max from 60 to
360 minutes after the time (T.sub.max) when C.sub.max is obtained.
In some embodiments, the plasma benzodiazepine concentration is in
the range of 20 to 55% of C.sub.max from 30 to 720 minutes after
the time (T.sub.max) when C.sub.max is obtained. In some
embodiments, the plasma benzodiazepine concentration is in the
range of 20 to 55% of C.sub.max from 60 to 360 minutes after the
time (T.sub.max) when C.sub.max is obtained.
[0036] In some embodiments, the invention provides a pharmaceutical
particulate composition for nasal delivery of a medicament
comprising particulates having a multimodal particle size
distribution. In some embodiments, the particulates have a bimodal
particle size distribution. In some embodiments, the particulates
have a trimodal or higher order modal particle size distribution.
In some embodiments, the medicament comprises at least one
benzodiazepine. In some embodiments, the medicament comprises at
least one benzodiazepine selected from the group consisting of
alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam,
clorazepam, demoxazepam, flumazenil, flurazepam, halazepam,
midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam,
medazepam, lorazepam, prazepam, quazepam, triazolam, temazepam,
loprazolam, and pharmaceutically acceptable salts and combinations
thereof. In some embodiments, at least one benzodiazepine drug
comprises at least one member of the group consisting of
alprazolam, diazepam, flurazepam, lorazepam, medazepam, mexazolam,
midazolam, temazepam and pharmaceutically acceptable salts and
combinations thereof. In some embodiments, at least one
benzodiazepine drug comprises one or more members of the group
consisting of diazepam, lorazepam, midazolam and pharmaceutically
acceptable salts thereof. In some embodiments, the particles have
an effective mean diameter greater than about 500 nm, 1000 nm,
greater than about 2000 nm, greater than about 4000 nm or greater
than 5000 nm. In some embodiments, the first population of
particles, the second population of particles or both are coated
with surface acting agent. In some embodiments, the surface acting
agent is a cationic surfactant, a non-ionic surfactant, an anionic
surfactant, a surface active biological modifier or a zwitterionic
surfactant. In some embodiments, the second population of particles
or both are coated with at least one surface acting agent. In some
embodiments, at least one surface acting agent is a cationic
surfactant, a non-ionic surfactant, an anionic surfactant, a
surface active biological modifier or a zwitterionic surfactant. In
some embodiments, at least one surface acting agent is a cationic
surfactant selected from the group consisting of natural
phospholipids, synthetic phospholipids, quaternary ammonium
compounds, benzalkonium chloride, cetyltrimethylammonium bromide,
chitosans, lauryldimethylbenzylammonium chloride, acyl carnitine
hydrochlorides, dimethyldioctadecylammomium bromide (DDAB),
dioleyoltrimethylammonium propane (DOTAP),
dimyristoyltrimethylammonium propane (DMTAP),
dimethylaminoethanecarbamoyl cholesterol (DC-Chol),
1,2-diacylglycero-3-(O-alkyl)phosphocholine,
O-alkylphosphatidylcholine, alkyl pyridinium halides, and
long-chain alkyl amines such as, for example, n-octylamine and
oleylamine. In some embodiments, at least one surface acting agent
is an anionic surface active agent selected from the group
consisting of natural anionic phospholipids, synthetic anionic
phospholipids and anionic polymers. In some embodiments, the
natural anionic phospholipids, synthetic anionic phospholipids and
anionic polymers are selected from the group consisting of
polyacrylic acid, carrageenan k type II, carbopol 980, carbopol 974
P, carbopol 971 P, polycarbophil, sodium carboxymethylcellulose,
sodium hyaluronate or combinations thereof. In some embodiments, at
least one surface acting agent is selected from the group
consisting of thiolated polymers. In some embodiments, the
thiolated polymer is selected from the group consisting of cysteine
conjugates of polyacrylic acid, polycarbophil (thiomer
polycarbophil-cysteine), thiolated sodium carboxymethylcellulose,
chitosan modified with 2-iminothiolate (e.g.
chitosan-4-thiobutylamidine conjugates, chitosan-thioglycolic acid
conjugates, chitosan-cysteine conjugates). In some embodiments, at
least one surface acting agent is selected from the group
consisting of polymeric mucilaginous polysaccharides. In some
embodiments, the polymeric mucilaginous polysaccharide is from the
aloe vera plant. In some embodiments, at least one surface agent is
methylcellulose, ethylcellulose, hydroxypropylmethylcellulose
(HPMC) or a mixture of two or more thereof. In some embodiments,
the composition further comprises one or more additional ingredient
selected from active pharmaceutical ingredients and enhancers. In
some embodiments, the multimodal particle size distribution has a
has first mode in the range of about 25 to about 4000 nm and a
second mode in the range of about 500 to about 10,000 nm. In some
embodiments, the multimodal particle size distribution has a first
mode in the range of about 50 to about 2000 nm and a second mode in
the range or about 1000 to about 10000 nm. In some embodiments, the
first mode is greater than the second mode. In some embodiments,
the first mode is in the range of about 50 to about 1000 nm and the
second mode is in the range of about 1000 to about 10,000 nm. In
some embodiments, the difference between the first and second modes
is greater than about 100 nm, greater than about 200 nm, greater
than about 500 nm, greater than about 1000 nm, greater than about
2000 nm, greater than about 3000 nm, greater than about 4000 nm,
greater than about 5000 nm, greater than about 6000 nm, greater
than about 7000 nm, greater than about 8000 nm, greater than about
9000 nm or greater than about 10,000 nm. In some embodiments, the
difference between the mean particle size of the first and second
particle populations is greater than about 10%, greater than about
20% or greater than about 30% of the mean particle diameter of the
second population of particles. In some embodiments, the
benzodiazepine particles do not contain solvent residues resulting
from solvent extraction or solvent precipitation.
[0037] In some embodiments, the invention provides a method of
using a pharmaceutical particulate composition for nasal delivery
of a medicament comprising particulates having a multimodal
particle size distribution, comprising administering an effective
amount of the composition to the nose by administering a
therapeutically effective amount of the composition to at least one
nostril. In some embodiments, at least a portion of the
therapeutically effective amount of the composition to each
nostril. In some embodiments, the method comprises administering a
first quantity of the composition to a first nostril, administering
a second quantity of the composition to a second nostril, and
optionally after a pre-selected time delay, administering a third
quantity of the composition to the first nostril. In some
embodiments, the method further comprises, optionally after a
pre-selected time delay, administering at least a fourth quantity
of the composition to the second nostril. In some embodiments, the
effective amount of the composition is effective to treat seizure,
protect against seizure, reduce or ameliorate the intensity of
seizure, reduce or ameliorate the frequency of seizure, and/or
prevent occurrence or re-occurrence of seizure. In some
embodiments, the effective amount of the composition is effective
to provide a therapeutic effect selected from an anxiolytic effect,
an anticonvulsant effect, a sedative effect, a skeletal muscle
relaxant effect, an amnesic effect or combinations thereof. In some
embodiments, a therapeutically effective plasma level of
benzodiazepine drug is obtained within about 1 hour of
administration of the composition to a patient. In some
embodiments, a therapeutically effective plasma level of the
benzodiazepine drug is obtained within about 30 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of the
benzodiazepine is obtained within about 15 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of
benzodiazepine drug is obtained within about 10 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of
benzodiazepine drug is obtained within about 5 minutes of
administration of the composition to the patient. In some
embodiments, a peak plasma concentration (C.sub.max) is achieved
for the benzodiazepine drug at a time (T.sub.max) less than about 1
hour after administration of the composition to a patient. In some
embodiments, T.sub.max is less than about 30 minutes after
administration of the composition to the patient. In some
embodiments, T.sub.max is less than about 15 minutes after
administration of the composition to the patient. In some
embodiments, T.sub.max is less than about 12 minutes after
administration of the composition to the patient. In some
embodiments, the effective amount of the composition is effective
to treat seizure, protect against seizure, reduce or ameliorate the
intensity of seizure, reduce or ameliorate the frequency of
seizure, and/or prevent occurrence or re-occurrence of seizure. In
some embodiments, the effective amount of the composition is
effective to provide a therapeutic effect selected from an
anxiolytic effect, an anticonvulsant effect, a sedative effect, a
skeletal muscle relaxant effect, an amnesic effect or combinations
thereof. In some embodiments, a first benzodiazepine plasma
concentration maximum (Cmax1) is obtained from 1 to 30 minutes
after administration of the composition and a second benzodiazepine
plasma concentration maximum (Cmax2) is obtained from 5 to 360
minutes after administration of the composition. In some
embodiments, Cmax1 is obtained from 5 to 20 minutes after
administration of the composition and Cmax2 is obtained from 10 to
60 minutes after administration. In some embodiments, Cmax1 and
Cmax2 are obtained at times Tmax1 and Tmax2 that are at least about
5 minutes, at least about 10 minutes, at least about 20 minutes or
at least about 30 minutes apart. In some embodiments, Cmax1 is
obtained at time Tmax1 and Cmax2 is obtained at time Tmax2; and
wherein Tmax1 and Tmax2 are from 5 to 360, from 10 to 240, from 15
to 120 or from 20 to 60 minutes apart. In some embodiments, a
benzodiazepine plasma concentration curve having a concentration
maximum (C.sub.max) and a shoulder (C.sub.shoulder) is obtained. In
some embodiments, the shoulder occurs within about 1 minute, within
about 5 minutes, within about 10 minutes, within about 15 minutes
or within about 30 minutes of time (T.sub.max) when the
concentration maximum (C.sub.max) occurs. In some embodiments, a
benzodiazepine plasma concentration curve having a single plasma
benzodiazepine concentration maximum (C.sub.max) is obtained. In
some embodiments, C.sub.max is obtained within about 5 minutes,
within about 10 minutes, within about 20 minutes, within about 30
minutes or within about 60 minutes of administering the medicament
to the patient. In some embodiments, the plasma benzodiazepine
concentration is in the range of 5 to 95% of C.sub.max from 30 to
720 minutes after the time (T.sub.max) when C.sub.max is obtained.
In some embodiments, the plasma benzodiazepine concentration is in
the range of 5 to 95% of C.sub.max from 30 to 360 minutes after the
time (T.sub.max) when C.sub.max is obtained. In some embodiments,
the plasma benzodiazepine concentration is in the range of 10 to 90
of C.sub.max from 30 to 720 minutes after the time (T.sub.max) when
C.sub.max is obtained. In some embodiments, the plasma
benzodiazepine concentration is in the range of 10 to 90 of
C.sub.max from 60 to 360 minutes after the time (T.sub.max) when
C.sub.max is obtained. In some embodiments, the plasma
benzodiazepine concentration is in the range of 15 to 60% of
C.sub.max from 30 to 720 minutes after the time (T.sub.max) when
C.sub.max is obtained. In some embodiments, the plasma
benzodiazepine concentration is in the range of 15 to 60% of
C.sub.max from 60 to 360 minutes after the time (T.sub.max) when
C.sub.max is obtained. In some embodiments, the plasma
benzodiazepine concentration is in the range of 20 to 55% of
C.sub.max from 30 to 720 minutes after the time (T.sub.max) when
C.sub.max is obtained. In some embodiments, the plasma
benzodiazepine concentration is in the range of 20 to 55% of
C.sub.max from 60 to 360 minutes after the time (T.sub.max) when
C.sub.max is obtained.
[0038] In some embodiments, the invention provides an aerosol
composition of an aqueous suspension or dispersion of
nanoparticulate benzodiazepine particles, wherein: the droplets of
the aerosol have a mass median aerodynamic diameter (MMAD) less
than or equal to about 1000 .mu.m and the nanoparticulate
benzodiazepine particles have an effective average particle size of
less than about 5000 nm. In some embodiments, the nanoparticulate
benzodiazepine particles comprise at least one member of the group
consisting of alprazolam, brotizolam, chlordiazepoxide, clobazam,
clonazepam, clorazepam, demoxazepam, flumazenil, flurazepam,
halazepam, midazolam, nordazepam, medazepam, diazepam, nitrazepam,
oxazepam, medazepam, lorazepam, prazepam, quazepam, triazolam,
temazepam, loprazolam, and pharmaceutically acceptable salts and
combinations thereof. In some embodiments, the nanoparticulate
benzodiazepine particles comprise at least one member of the group
consisting of alprazolam, diazepam, flurazepam, lorazepam,
medazepam, mexazolam, midazolam, temazepam and pharmaceutically
acceptable salts and combinations thereof. In some embodiments, the
nanoparticulate benzodiazepine particles comprise at least one
benzodiazepine selected from the group consisting of diazepam,
lorazepam, midazolam and pharmaceutically acceptable salts thereof.
In some embodiments, the aerosol composition can be administered in
a drug dosage in less than about 60 seconds. In some embodiments,
the aerosol composition can be administered in a drug dosage in
less than about 15 seconds. In some embodiments, the
nanoparticulate benzodiazepine particles have an effective average
particle size of about 50 nm to about 5000 nm. In some embodiments,
the nanoparticulate diazepam benzodiazepine have an effective
average particle size of about 50 nm to about 400 nm. In some
embodiments, the nanoparticulate benzodiazepine particles have an
effective average particle size of about 400 nm to about 5000 nm.
In some embodiments, the droplets of the aerosol have a mass median
aerodynamic diameter (MMAD) of less than or equal to about 1000
.mu.m. In some embodiments, the benzodiazepine or pharmaceutically
acceptable salt thereof is present in a concentration of from about
0.05 mg/mL up to about 600 mg/mL. In some embodiments, essentially
each droplet of the aerosol comprises at least one nanoparticle. In
some embodiments, the nanoparticulate benzodiazepine drug particles
have an effective average particle size of less than about 400 nm.
In some embodiments, the nanoparticulate benzodiazepine drug
particles have an effective average particle size of less than
about 300 nm, less than about 200 nm, less than about 100 nm or
less than about 50 nm. In some embodiments, the nanoparticulate
benzodiazepine drug particles further comprises at least one
additional ingredient selected from active pharmaceutical
ingredients and enhancers. In some embodiments, the nanoparticulate
benzodiazepine drug particles further comprise at least one
additional active pharmaceutical ingredient. In some embodiments,
the nanoparticulate benzodiazepine drug particles further comprise
at least one enhancer. In some embodiments, the droplets of the
aerosol have a mass median aerodynamic diameter of from about 2
.mu.m to about 10 .mu.m. In some embodiments, the first population
of particles, the second population of particles or both are coated
with at least one surface acting agent. In some embodiments, at
least one surface acting agent is a cationic surfactant, a
non-ionic surfactant, an anionic surfactant, a surface active
biological modifier or a zwitterionic surfactant. In some
embodiments, at least one surface acting agent is a cationic
surfactant selected from the group consisting of natural
phospholipids, synthetic phospholipids, quaternary ammonium
compounds, benzalkonium chloride, cetyltrimethylammonium bromide,
chitosans, lauryldimethylbenzylammonium chloride, acyl carnitine
hydrochlorides, dimethyldioctadecylammomium bromide (DDAB),
dioleyoltrimethylammonium propane (DOTAP),
dimyristoyltrimethylammonium propane (DMTAP),
dimethylaminoethanecarbamoyl cholesterol (DC-Chol),
1,2-diacylglycero-3-(O-alkyl)phosphocholine,
O-alkylphosphatidylcholine, alkyl pyridinium halides, and
long-chain alkyl amines such as, for example, n-octylamine and
oleylamine. In some embodiments, at least one surface acting agent
is an anionic surface active agent selected from the group
consisting of natural anionic phospholipids, synthetic anionic
phospholipids and anionic polymers. In some embodiments, the
natural anionic phospholipids, synthetic anionic phospholipids and
anionic polymers are selected from the group consisting of
polyacrylic acid, carrageenan k type II, carbopol 980, carbopol 974
P, carbopol 971 P, polycarbophil, sodium carboxymethylcellulose,
sodium hyaluronate or combinations thereof. In some embodiments, at
least one surface acting agent is selected from the group
consisting of thiolated polymers. In some embodiments, the
thiolated polymer is selected from the group consisting of cysteine
conjugates of polyacrylic acid, polycarbophil (thiomer
polycarbophil-cysteine), thiolated sodium carboxymethylcellulose,
chitosan modified with 2-iminothiolate (e.g.
chitosan-4-thiobutylamidine conjugates, chitosan-thioglycolic acid
conjugates, chitosan-cysteine conjugates). In some embodiments, at
least one surface acting agent is selected from the group
consisting of polymeric mucilaginous polysaccharides. In some
embodiments, the polymeric mucilaginous polysaccharide is from the
aloe vera plant. In some embodiments, at least one surface acting
agent is methylcellulose, ethylcellulose,
hydroxypropylmethylcellulose (HPMC) or a mixture of two or more
thereof.
[0039] In some embodiments, the invention provides a method using
an aerosol composition of an aqueous suspension or dispersion of
nanoparticulate benzodiazepine particles, wherein: the droplets of
the aerosol have a mass median aerodynamic diameter (MMAD) less
than or equal to about 1000 .mu.m and the nanoparticulate
benzodiazepine particles have an effective average particle size of
less than about 5000 nm, the method comprising administering an
effective amount of the composition to the nose by spraying a
therapeutically effective amount of the composition into at least
one nostril. In some embodiments, the method comprises spraying at
least a portion of the therapeutically effective amount of the
composition into each nostril. In some embodiments, the method
comprises spraying a first quantity of the composition into the
first nostril, spraying a second quantity of the composition into a
second nostril, and optionally after a pre-selected time delay,
spraying a third quantity of the composition into the first
nostril. In some embodiments, the method further comprises,
optionally after a pre-selected time delay, administering at least
a fourth quantity of the composition to the second nostril. In some
embodiments, the effective amount of the composition is effective
to treat seizure, protect against seizure, reduce or ameliorate the
intensity of seizure, reduce or ameliorate the frequency of
seizure, and/or prevent occurrence or re-occurrence of seizure. In
some embodiments, the effective amount of the composition is
effective to provide a therapeutic effect selected from an
anxiolytic effect, an anticonvulsant effect, a sedative effect, a
skeletal muscle relaxant effect, an amnesic effect or combinations
thereof. In some embodiments, a therapeutically effective plasma
level of benzodiazepine drug is obtained within about 1 hour of
administration of the composition to a patient. In some
embodiments, the therapeutically effective plasma level of the
benzodiazepine drug is obtained within about 30 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of the
benzodiazepine is obtained within about 15 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of
benzodiazepine drug is obtained within about 10 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of
benzodiazepine drug is obtained within about 5 minutes of
administration of the composition to the patient. In some
embodiments, peak plasma concentration (C.sub.max) is achieved for
the benzodiazepine drug at a time (T.sub.max) less than about 1
hour after administration of the composition to a patient. In some
embodiments, T.sub.max is less than about 30 minutes after
administration of the composition to the patient. In some
embodiments, T.sub.max is less than about 15 minutes after
administration of the composition to the patient. In some
embodiments, T.sub.max is less than about 12 minutes after
administration of the composition to the patient.
[0040] In some embodiments, the invention provides a method of
administering a benzodiazepine drug to a patient, comprising
administering to the nose or nasal cavity an effective amount of an
aerosol composition of an aqueous suspension or dispersion of
nanoparticulate benzodiazepine particles, wherein: the droplets of
the aerosol have a mass median aerodynamic diameter (MMAD) less
than or equal to about 1000 .mu.m and the nanoparticulate
benzodiazepine particles have an effective average particle size of
less than about 5000 nm. In some embodiments, the nanoparticulate
benzodiazepine particles comprise at least on member of the group
consisting of alprazolam, brotizolam, chlordiazepoxide, clobazam,
clonazepam, clorazepam, demoxazepam, flumazenil, flurazepam,
halazepam, midazolam, nordazepam, medazepam, diazepam, nitrazepam,
oxazepam, medazepam, lorazepam, prazepam, quazepam, triazolam,
temazepam, loprazolam, and pharmaceutically acceptable salts and
combinations thereof. In some embodiments, the nanoparticulate
benzodiazepine particles comprise at least one member of the group
consisting of alprazolam, diazepam, flurazepam, lorazepam,
medazepam, mexazolam, midazolam, temazepam and pharmaceutically
acceptable salts and combinations thereof. In some embodiments, the
nanoparticulate benzodiazepine particles comprise at least one
benzodiazepine selected from the group consisting of diazepam,
lorazepam, midazolam and pharmaceutically acceptable salts thereof.
In some embodiments, the aerosol composition is administered in a
drug dosage in less than about 60 seconds. In some embodiments, the
aerosol composition is administered in a drug dosage in less than
about 15 seconds. In some embodiments, the nanoparticulate
benzodiazepine particles have an effective average particle size of
less than about 5000 nm. In some embodiments, the nanoparticulate
benzodiazepine particles have an effective average particle size of
less than about 1000 nm In some embodiments, the droplets of the
aerosol have a mass median aerodynamic diameter (MMAD) of less than
or equal to about 100 .mu.m. In some embodiments, the
benzodiazepine is present in a concentration of from about 0.05
mg/mL up to about 600 mg/mL. In some embodiments, essentially each
droplet of the aerosol comprises at least one nanoparticle.
[0041] In some embodiments, the nanoparticulate benzodiazepine drug
particles have an effective average particle size of less than
about 400 nm, less than about 300 nm, less than about 200 nm, less
than about 100 nm or less than about 50 nm. In some embodiments,
the droplets of the aerosol have a mass median aerodynamic diameter
of from about 2 to about 10 .mu.m. In some embodiments, the
effective amount of the composition is effective to treat seizure,
protect against seizure, reduce or ameliorate the intensity of
seizure, reduce or ameliorate the frequency of seizure, and/or
prevent occurrence or re-occurrence of seizure. In some
embodiments, the effective amount of the composition is effective
to provide a therapeutic effect selected from an anxiolytic effect,
an anticonvulsant effect, a sedative effect, a skeletal muscle
relaxant effect, an amnesic effect or combinations thereof. In some
embodiments, a therapeutically effective plasma level of
benzodiazepine drug is obtained within about 1 hour of
administration of the composition to a patient. In some
embodiments, the therapeutically effective plasma level of the
benzodiazepine drug is obtained within about 30 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of the
benzodiazepine is obtained within about 15 minutes, within about 10
minutes or within about 5 minutes of administration of the
composition to the patient. In some embodiments, peak plasma
concentration (C.sub.max) is achieved for the benzodiazepine drug
at a time (T.sub.max) less than about 1 hour after administration
of the composition to a patient. In some embodiments, T.sub.max is
less than about 30 minutes after administration of the composition
to the patient. In some embodiments, T.sub.max is less than about
15 minutes after administration of the composition to the patient.
In some embodiments, T.sub.max is less than about 12 minutes after
administration of the composition to the patient.
[0042] In some embodiments, the invention provides a pharmaceutical
composition for aerosol (e.g. nasal or pulmonary) administration of
benzodiazepine comprising benzodiazepine particles and one or more
non-cationic surface active agents adsorbed to a surface thereof.
In some embodiments, the nanoparticulate benzodiazepine particles
comprise at least one member of the group consisting of alprazolam,
brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam,
demoxazepam, flumazenil, flurazepam, halazepam, midazolam,
nordazepam, medazepam, diazepam, nitrazepam, oxazepam, medazepam,
lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam,
and pharmaceutically acceptable salts and combinations thereof. In
some embodiments, the benzodiazepine particles comprise at least
one member of the group consisting of alprazolam, diazepam,
flurazepam, lorazepam, medazepam, mexazolam, midazolam, temazepam
and pharmaceutically acceptable salts and combinations thereof. In
some embodiments, the nanoparticulate comprise at least one
benzodiazepine selected from the group consisting of diazepam,
lorazepam, midazolam and pharmaceutically acceptable salts thereof.
In some embodiments, the pharmaceutical composition is in the form
of an aqueous suspension or dispersion. In some embodiments, the
pharmaceutical composition is in the form of a spray powder. in
some embodiments, the benzodiazepine particles contain crystalline
benzodiazepine, amorphous benzodiazepine, semi-crystalline
benzodiazepine, a mixture of amorphous and crystalline
benzodiazepine, a mixture of amorphous and semi-crystalline
benzodiazepine, a mixture of crystalline and semi-crystalline
benzodiazepine or a mixture of amorphous, crystalline and
semi-crystalline diazepine. In some embodiments, the benzodiazepine
particles contain crystalline diazepam, amorphous diazepam,
semi-crystalline diazepam, a mixture of amorphous and crystalline
diazepam, a mixture of amorphous and semi-crystalline diazepam, a
mixture of crystalline and semi-crystalline diazepam, a mixture of
amorphous, crystalline and semi-crystalline diazepam, crystalline
lorazepam, amorphous lorazepam, semi-crystalline lorazepam, a
mixture of amorphous and crystalline lorazepam, a mixture of
amorphous and semi-crystalline lorazepam, a mixture of crystalline
and semi-crystalline lorazepam, a mixture of amorphous, crystalline
and semi-crystalline lorazepam, crystalline medazepam, amorphous
medazepam, semi-crystalline medazepam, a mixture of amorphous and
crystalline medazepam, a mixture of amorphous and semi-crystalline
medazepam, a mixture of crystalline and semi-crystalline medazepam
and a mixture of amorphous, crystalline and semi-crystalline
medazepam. In some embodiments, the benzodiazepine particles have a
mean particle size of less than about 5000 nm. In some embodiments,
the benzodiazepine particles have a mean particle size of
approximately 1000 nm. In some embodiments, the benzodiazepine
particles have adsorbed to a surface thereof one or more surface
active agents selected from the group consisting of cationic
surfactants, anionic surfactants, zwitterionic surfactants, surface
active biological modifiers and nonionic surfactants. In some
embodiments, the benzodiazepine particles adsorb to a biological
surface. In some embodiments, at least one surface acting agent is
a cationic surfactant selected from the group consisting of natural
phospholipids, synthetic phospholipids, quaternary ammonium
compounds, benzalkonium chloride, cetyltrimethylammonium bromide,
chitosans, lauryldimethylbenzylammonium chloride, acyl carnitine
hydrochlorides, dimethyldioctadecylammonium bromide (DDAB),
dioleyoltrimethylammonium propane (DOTAP),
dimyristoyltrimethylammonium propane (DMTAP),
dimethylaminoethanecarbamoyl cholesterol (DC-Chol),
1,2-diacylglycero-3-(O-alkyl)phosphocholine,
O-alkylphosphatidylcholine, alkyl pyridinium halides, and
long-chain alkyl amines such as, for example, n-octylamine and
oleylamine. In some embodiments, at least one surface active agent
is an anionic surfactant selected from the group consisting of
natural anionic phospholipids, synthetic anionic phospholipids and
anionic polymers. In some embodiments, the natural anionic
phospholipids, synthetic anionic phospholipids and anionic polymers
are selected from the group consisting of polyacrylic acid,
carrageenan k type II, carbopol 980, carbopol 974 P, carbopol 971
P, polycarbophil, sodium carboxymethylcellulose, sodium hyaluronate
or combinations thereof. In some embodiments, at least one surface
active agents is selected from the group consisting of thiolated
polymers. In some embodiments, the thiolated polymer is selected
from the group consisting of cysteine conjugates of polyacrylic
acid, polycarbophil (thiomer polycarbophil-cysteine), thiolated
sodium carboxymethylcellulose, chitosan modified with
2-iminothiolate (e.g. chitosan-4-thiobutylamidine conjugates,
chitosan-thioglycolic acid conjugates, chitosan-cysteine
conjugates). In some embodiments, at least one surface active
agents is selected from the group consisting of polymeric
mucilaginous polysaccharides. In some embodiments, the polymeric
mucilaginous polysaccharide is from the aloe vera plant. In some
embodiments, at least one surface active agents is methylcellulose,
ethylcellulose, hydroxypropylmethyl-cellulose (HPMC) or a mixture
of two or more thereof. In some embodiments, the benzodiazepine
particles do not contain solvent residues resulting from solvent
extraction or solvent precipitation. In some embodiments, the
composition further comprises one or more additional ingredient
selected from active pharmaceutical ingredients and enhancers.
[0043] In some embodiments, the invention provides a method of
administering a pharmaceutical composition for aerosol (e.g. nasal
or pulmonary) administration of benzodiazepine comprising
benzodiazepine particles and one or more non-cationic surface
active agents adsorbed to a surface thereof, the method comprising
administering an effective amount of the composition to a patient
via a suitable administration route (e.g. nasal or pulmonary). In
some embodiments, the method comprises administering the
composition to the nose by administering a therapeutically
effective amount of the composition to at least one nostril. In
some embodiments, at least a portion of the therapeutically
effective amount of the composition to each nostril. In some
embodiments, the method comprises administering a first quantity of
the composition to a first nostril, administering a second quantity
of the composition to a second nostril, and optionally after a
pre-selected time delay, administering a third quantity of the
composition to the first nostril. In some embodiments, the
invention further comprises, optionally after a pre-selected time
delay, administering at least a fourth quantity of the composition
to the second nostril. In some embodiments, the method comprises
administering the composition by a pulmonary route, e.g. with a
nebulizer, a dry powder inhaler (DPI) or a metered dose inhaler
(MDI). In some embodiments, the effective amount of the composition
is effective to treat seizure, protect against seizure, reduce or
ameliorate the intensity of seizure, reduce or ameliorate the
frequency of seizure, and/or prevent occurrence or re-occurrence of
seizure. In some embodiments, the effective amount of the
composition is effective to provide a therapeutic effect selected
from an anxiolytic effect, an anticonvulsant effect, a sedative
effect, a skeletal muscle relaxant effect, an amnesic effect or
combinations thereof. In some embodiments, a therapeutically
effective plasma level of benzodiazepine drug is obtained within
about 1 hour of administration of the composition to a patient. In
some embodiments, the therapeutically effective plasma level of the
benzodiazepine drug is obtained within about 30 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of the
benzodiazepine is obtained within about 15 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of
benzodiazepine drug is obtained within about 10 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of
benzodiazepine drug is obtained within about 5 minutes of
administration of the composition to the patient. In some
embodiments, peak plasma concentration (C.sub.max) is achieved for
the benzodiazepine drug at a time (T.sub.max) less than about 1
hour after administration of the composition to a patient. In some
embodiments, T.sub.max is less than about 30 minutes after
administration of the composition to the patient. In some
embodiments, T.sub.max is less than about 15 minutes after
administration of the composition to the patient. In some
embodiments, T.sub.max is less than about 12 minutes after
administration of the composition to the patient.
[0044] The invention further provides a method of administering a
benzodiazepine drug to a patient, comprising administering to the
patient's nose or nasal cavity a pharmaceutical composition
comprising particles of a benzodiazepine drug having a surface
active agent adsorbed to a surface thereof. In some embodiments, at
least one surface active agent is a cationic surfactant or a
non-cationic surfactant. In some embodiments, at least one surface
active agent is a cationic surfactant selected from the group
consisting of natural phospholipids, synthetic phospholipids,
quaternary ammonium compounds, benzalkonium chloride,
cetyltrimethylammonium bromide, chitosans,
lauryldimethylbenzylammonium chloride, acyl carnitine
hydrochlorides, dimethyldioctadecylammonium bromide (DDAB),
dioleyoltrimethylammonium propane (DOTAP),
dimyristoyltrimethylammonium propane (DMTAP),
dimethylaminoethanecarbamoyl cholesterol (DC-Chol),
1,2-diacylglycero-3-(O-alkyl)phosphocholine,
O-alkylphosphatidylcholine, alkyl pyridinium halides, and
long-chain alkyl amines such as, for example, n-octylamine and
oleylamine. In some embodiments, at least one surface active agent
is a non-cationic surfactant selected from the group consisting of
anionic surfactants, non-ionic surfactants, surface active
biological modifiers and zwitterionic surfactants. In some
embodiments, at least one non-cationic surfactant is anionic
surfactant selected from the group consisting of natural anionic
phospholipids, synthetic anionic phospholipids and anionic
polymers. In some embodiments, the natural anionic phospholipids,
synthetic anionic phospholipids and anionic polymers are selected
from the group consisting of polyacrylic acid, carrageenan k type
II, carbopol 980, carbopol 974 P, carbopol 971 P, polycarbophil,
sodium carboxymethylcellulose, sodium hyaluronate or combinations
thereof. In some embodiments, at least one surface active agents is
selected from the group consisting of thiolated polymers. In some
embodiments, the thiolated polymer is selected from the group
consisting of cysteine conjugates of polyacrylic acid,
polycarbophil (thiomer polycarbophil-cysteine), thiolated sodium
carboxymethylcellulose, chitosan modified with 2-iminothiolate
(e.g. chitosan-4-thiobutylamidine conjugates, chitosan-thioglycolic
acid conjugates, chitosan-cysteine conjugates). In some
embodiments, at least one surface active agents is selected from
the group consisting of polymeric mucilaginous polysaccharides. In
some embodiments, the polymeric mucilaginous polysaccharide is from
the aloe vera plant. In some embodiments, at least one surface
active agents is methylcellulose, ethylcellulose,
hydroxypropylmethylcellulose (HPMC) or a mixture of two or more
thereof. In some embodiments, the nanoparticulate benzodiazepine
particles comprise at least one member of the group consisting of
alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam,
clorazepam, demoxazepam, flumazenil, flurazepam, halazepam,
midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam,
medazepam, lorazepam, prazepam, quazepam, triazolam, temazepam,
loprazolam, and pharmaceutically acceptable salts and combinations
thereof. In some embodiments, the benzodiazepine drug comprises at
least one member of the group consisting of alprazolam, diazepam,
flurazepam, lorazepam, medazepam, mexazolam, midazolam, temazepam
and pharmaceutically acceptable salts and combinations thereof. In
some embodiments, the benzodiazepine drug comprises one or more
members of the group consisting of diazepam, lorazepam, midazolam
and pharmaceutically acceptable salts thereof. In some embodiments,
the benzodiazepine drug is in the form of an aqueous suspension or
dispersion. In some embodiments, the benzodiazepine drug is in the
form of a spray powder. In some embodiments, the benzodiazepine
particles contain crystalline benzodiazepine, amorphous
benzodiazepine, semi-crystalline benzodiazepine, a mixture of
amorphous and crystalline benzodiazepine, a mixture of amorphous
and semi-crystalline benzodiazepine, a mixture of crystalline and
semi-crystalline benzodiazepine and a mixture of amorphous,
crystalline and semi-crystalline benzodiazepine. In some
embodiments, the benzodiazepine particles contain crystalline
diazepam, amorphous diazepam, semi-crystalline diazepam, a mixture
of amorphous and crystalline diazepam, a mixture of amorphous and
semi-crystalline diazepam, a mixture of crystalline and
semi-crystalline diazepam, a mixture of amorphous, crystalline and
semi-crystalline diazepam, crystalline lorazepam, amorphous
lorazepam, semi-crystalline lorazepam, a mixture of amorphous and
crystalline lorazepam, a mixture of amorphous and semi-crystalline
lorazepam, a mixture of crystalline and semi-crystalline lorazepam,
a mixture of amorphous, crystalline and semi-crystalline lorazepam,
crystalline medazepam, amorphous medazepam, semi-crystalline
medazepam, a mixture of amorphous and crystalline medazepam, a
mixture of amorphous and semi-crystalline medazepam, a mixture of
crystalline and semi-crystalline medazepam and a mixture of
amorphous, crystalline and semi-crystalline medazepam. In some
embodiments, the benzodiazepine particles have a mean particle size
of less than about 5000 nm. In some embodiments, the benzodiazepine
particles have a mean particle size of less than about 4000 nm. In
some embodiments, the benzodiazepine particles have a mean particle
size in the range of about 50 to 5000 nm, about 100 to about 2500
nm, about 250 to about 1000 nm or approximately 500 nm. In some
embodiments, the benzodiazepine particles do not contain solvent
residues resulting from solvent extraction or solvent
precipitation. In some embodiments, the benzodiazepine particles
further comprise at least one additional ingredient selected from
active pharmaceutical ingredients and enhancers. In some
embodiments, the effective amount of the composition is effective
to treat seizure, protect against seizure, reduce or ameliorate the
intensity of seizure, reduce or ameliorate the frequency of
seizure, and/or prevent occurrence or re-occurrence of seizure. In
some embodiments, the effective amount of the composition is
effective to provide a therapeutic effect selected from an
anxiolytic effect, an anticonvulsant effect, a sedative effect, a
skeletal muscle relaxant effect, an amnesic effect or combinations
thereof. In some embodiments, a therapeutically effective plasma
level of benzodiazepine drug is obtained within about 1 hour of
administration of the composition to a patient. In some
embodiments, the therapeutically effective plasma level of the
benzodiazepine drug is obtained within about 30 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of the
benzodiazepine is obtained within about 15 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of
benzodiazepine drug is obtained within about 10 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of
benzodiazepine drug is obtained within about 5 minutes of
administration of the composition to the patient. In some
embodiments, peak plasma concentration (C.sub.max) is achieved for
the benzodiazepine drug at a time (T.sub.max) less than about 1
hour after administration of the composition to a patient. In some
embodiments, T.sub.max is less than about 30 minutes after
administration of the composition to the patient. In some
embodiments, T.sub.max is less than about 15 minutes after
administration of the composition to the patient. In some
embodiments, T.sub.max is less than about 12 minutes after
administration of the composition to the patient.
[0045] The invention further provides a method of administering a
benzodiazepine drug to a patient, comprising administering to the
patient's lungs a pharmaceutical composition comprising particles
of a benzodiazepine drug having a surface active agent adsorbed to
a surface thereof. In some embodiments, at least one surface active
agent is a cationic surfactant or a non-cationic surfactant. In
some embodiments, at least one surface active agent is a cationic
surfactant selected from the group consisting of natural
phospholipids, synthetic phospholipids, quaternary ammonium
compounds, benzalkonium chloride, cetyltrimethylammonium bromide,
chitosans, lauryldimethylbenzylammonium chloride, acyl carnitine
hydrochlorides, dimethyldioctadecylammonium bromide (DDAB),
dioleyoltrimethylammonium propane (DOTAP),
dimyristoyltrimethylammonium propane (DMTAP),
dimethylaminoethanecarbamoyl cholesterol (DC-Chol),
1,2-diacylglycero-3-(O-alkyl)phosphocholine,
O-alkylphosphatidylcholine, alkyl pyridinium halides, and
long-chain alkyl amines such as, for example, n-octylamine and
oleylamine. In some embodiments, at least one surface active agent
is a non-cationic surfactant selected from the group consisting of
anionic surfactants, non-ionic surfactants, surface active
biological modifiers and zwitterionic surfactants. In some
embodiments, at least one non-cationic surfactant is anionic
surfactant selected from the group consisting of natural anionic
phospholipids, synthetic anionic phospholipids and anionic
polymers. In some embodiments, the natural anionic phospholipids,
synthetic anionic phospholipids and anionic polymers are selected
from the group consisting of polyacrylic acid, carrageenan k type
II, carbopol 980, carbopol 974 P, carbopol 971 P, polycarbophil,
sodium carboxymethylcellulose, sodium hyaluronate or combinations
thereof. In some embodiments, at least one surface active agents is
selected from the group consisting of thiolated polymers. In some
embodiments, the thiolated polymer is selected from the group
consisting of cysteine conjugates of polyacrylic acid,
polycarbophil (thiomer polycarbophil-cysteine), thiolated sodium
carboxymethylcellulose, chitosan modified with 2-iminothiolate
(e.g. chitosan-4-thiobutylamidine conjugates, chitosan-thioglycolic
acid conjugates, chitosan-cysteine conjugates). In some
embodiments, at least one surface active agents is selected from
the group consisting of polymeric mucilaginous polysaccharides. In
some embodiments, the polymeric mucilaginous polysaccharide is from
the aloe vera plant. In some embodiments, at least one surface
active agents is methylcellulose, ethylcellulose,
hydroxypropylmethylcellulose (HPMC) or a mixture of two or more
thereof. In some embodiments, the nanoparticulate benzodiazepine
particles comprise at least one member of the group consisting of
alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam,
clorazepam, demoxazepam, flumazenil, flurazepam, halazepam,
midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam,
medazepam, lorazepam, prazepam, quazepam, triazolam, temazepam,
loprazolam, and pharmaceutically acceptable salts and combinations
thereof. In some embodiments, the benzodiazepine drug comprises at
least one member of the group consisting of alprazolam, diazepam,
flurazepam, lorazepam, medazepam, mexazolam, midazolam, temazepam
and pharmaceutically acceptable salts and combinations thereof. In
some embodiments, the benzodiazepine drug comprises one or more
members of the group consisting of diazepam, lorazepam, midazolam
and pharmaceutically acceptable salts thereof. In some embodiments,
the benzodiazepine drug is in the form of an aqueous suspension or
dispersion. In some embodiments, the benzodiazepine drug is in the
form of a spray powder. In some embodiments, the benzodiazepine
particles contain crystalline benzodiazepine, amorphous
benzodiazepine, semi-crystalline benzodiazepine, a mixture of
amorphous and crystalline benzodiazepine, a mixture of amorphous
and semi-crystalline benzodiazepine, a mixture of crystalline and
semi-crystalline benzodiazepine and a mixture of amorphous,
crystalline and semi-crystalline benzodiazepine. In some
embodiments, the benzodiazepine particles contain crystalline
diazepam, amorphous diazepam, semi-crystalline diazepam, a mixture
of amorphous and crystalline diazepam, a mixture of amorphous and
semi-crystalline diazepam, a mixture of crystalline and
semi-crystalline diazepam, a mixture of amorphous, crystalline and
semi-crystalline diazepam, crystalline lorazepam, amorphous
lorazepam, semi-crystalline lorazepam, a mixture of amorphous and
crystalline lorazepam, a mixture of amorphous and semi-crystalline
lorazepam, a mixture of crystalline and semi-crystalline lorazepam,
a mixture of amorphous, crystalline and semi-crystalline lorazepam,
crystalline medazepam, amorphous medazepam, semi-crystalline
medazepam, a mixture of amorphous and crystalline medazepam, a
mixture of amorphous and semi-crystalline medazepam, a mixture of
crystalline and semi-crystalline medazepam and a mixture of
amorphous, crystalline and semi-crystalline medazepam. In some
embodiments, the benzodiazepine particles have a mean particle size
of less than about 5000 nm. In some embodiments, the benzodiazepine
particles have a mean particle size of less than about 4000 nm. In
some embodiments, the benzodiazepine particles have a mean particle
size in the range of about 50 to 5000 nm, about 100 to about 2500
nm, about 250 to about 1000 nm or approximately 500 nm. In some
embodiments, the benzodiazepine particles do not contain solvent
residues resulting from solvent extraction or solvent
precipitation. In some embodiments, the benzodiazepine particles
further comprise at least one additional ingredient selected from
active pharmaceutical ingredients and enhancers. In some
embodiments, the effective amount of the composition is effective
to treat seizure, protect against seizure, reduce or ameliorate the
intensity of seizure, reduce or ameliorate the frequency of
seizure, and/or prevent occurrence or re-occurrence of seizure. In
some embodiments, the effective amount of the composition is
effective to provide a therapeutic effect selected from an
anxiolytic effect, an anticonvulsant effect, a sedative effect, a
skeletal muscle relaxant effect, an amnesic effect or combinations
thereof. In some embodiments, a therapeutically effective plasma
level of benzodiazepine drug is obtained within about 1 hour of
administration of the composition to a patient. In some
embodiments, the therapeutically effective plasma level of the
benzodiazepine drug is obtained within about 30 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of the
benzodiazepine is obtained within about 15 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of
benzodiazepine drug is obtained within about 10 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of
benzodiazepine drug is obtained within about 5 minutes of
administration of the composition to the patient. In some
embodiments, peak plasma concentration (C.sub.max) is achieved for
the benzodiazepine drug at a time (T.sub.max) less than about 1
hour after administration of the composition to a patient. In some
embodiments, T.sub.max is less than about 30 minutes after
administration of the composition to the patient. In some
embodiments, T.sub.max is less than about 15 minutes after
administration of the composition to the patient. In some
embodiments, T.sub.max is less than about 12 minutes after
administration of the composition to the patient.
[0046] In some embodiments, the invention provides a non-aqueous
dispersion or suspension of nanoparticulate benzodiazepine
particles. In some embodiments, the nanoparticulate benzodiazepine
particles comprise at least one member of the group consisting of
alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam,
clorazepam, demoxazepam, flumazenil, flurazepam, halazepam,
midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam,
medazepam, lorazepam, prazepam, quazepam, triazolam, temazepam,
loprazolam, and pharmaceutically acceptable salts and combinations
thereof. In some embodiments, the nanoparticulate benzodiazepine
particles comprise at least one member of the group consisting of
alprazolam, diazepam, flurazepam, lorazepam, medazepam, mexazolam,
midazolam, temazepam and pharmaceutically acceptable salts and
combinations thereof. In some embodiments, the nanoparticulate
benzodiazepine particles comprise at least one benzodiazepine
selected from the group consisting of diazepam, lorazepam,
midazolam and pharmaceutically acceptable salts thereof. In some
embodiments, the droplets have a mass median aerodynamic diameter
(MMAD) less than or equal to about 1000 .mu.m and the
nanoparticulate benzodiazepine particles have an effective average
particle size of less than about 5000 nm. In some embodiments, the
nanoparticulate benzodiazepine particles have an effective average
particle size of less than about 1000 nm, less than about 500 nm,
less than about 400 nm, less than about 250 nm, less than about 100
nm or less than about 50 nm. In some embodiments, the
nanoparticulate benzodiazepine particles have an effective average
particle size in the range of about 25 to about 10000 nm In some
embodiments, the nanoparticulate benzodiazepine particles have an
effective average particle size of about 50 to about 5000 nm. In
some embodiments, the nanoparticulate benzodiazepine particles have
an effective average particle size of about 500 nm to about 5000
nm. In some embodiments, the non-aqueous dispersion or suspension
is adapted for nasal administration. In some embodiments, the
non-aqueous dispersion or suspension is adapted for pulmonary
delivery. In some embodiments, the dispersion or suspension further
comprises at least one additional ingredient selected from the
group consisting of active pharmaceutical ingredients and
enhancers. In some embodiments, the composition further comprises a
non-aqueous carrier or propellant. In some embodiments, the
non-aqueous carrier or propellant comprises a hydrocarbon, a
hydrofluorocarbon or a chlorofluorocarbon. In some embodiments, at
least a portion of the particles is coated with at least one
surface acting agent. In some embodiments, at least one surface
acting agent is a cationic surfactant, a non-ionic surfactant, an
anionic surfactant, a surface active biological modifier or a
zwitterionic surfactant. In some embodiments, at least one surface
acting agent is a cationic surfactant selected from the group
consisting of natural phospholipids, synthetic phospholipids,
quaternary ammonium compounds, benzalkonium chloride,
cetyltrimethylammonium bromide, chitosans,
lauryldimethylbenzyl-ammonium chloride, acyl carnitine
hydrochlorides, dimethyldioctadecylammomium bromide (DDAB),
dioleyoltrimethylammonium propane (DOTAP),
dimyristoyltrimethylammonium propane (DMTAP),
dimethylaminoethanecarbamoyl cholesterol (DC-Chol),
1,2-diacylglycero-3-(O-alkyl)phosphocholine,
O-alkylphosphatidylcholine, alkyl pyridinium halides, and
long-chain alkyl amines such as, for example, n-octylamine and
oleylamine. In some embodiments, at least one surface acting agent
is an anionic surface active agent selected from the group
consisting of natural anionic phospholipids, synthetic anionic
phospholipids and anionic polymers. In some embodiments, the
natural anionic phospholipids, synthetic anionic phospholipids and
anionic polymers are selected from the group consisting of
polyacrylic acid, carrageenan k type II, carbopol 980, carbopol 974
P, carbopol 971 P, polycarbophil, sodium carboxymethylcellulose,
sodium hyaluronate or combinations thereof. In some embodiments, at
least one surface acting agent is selected from the group
consisting of thiolated polymers. In some embodiments, the
thiolated polymer is selected from the group consisting of cysteine
conjugates of polyacrylic acid, polycarbophil (thiomer
polycarbophil-cysteine), thiolated sodium carboxymethylcellulose,
chitosan modified with 2-iminothiolate (e.g.
chitosan-4-thiobutylamidine conjugates, chitosan-thioglycolic acid
conjugates, chitosan-cysteine conjugates). In some embodiments, at
least one surface acting agent is selected from the group
consisting of polymeric mucilaginous polysaccharides. In some
embodiments, the polymeric mucilaginous polysaccharide is from the
aloe vera plant. In some embodiments, at least one surface acting
agent is methylcellulose, ethylcellulose,
hydroxypropylmethylcellulose (HPMC) or a mixture of two or more
thereof. In some embodiments, the nanoparticulate benzodiazepine
has a multimodal particle size distribution. In some embodiments,
the nanoparticulate benzodiazepine has a bimodal particle size
distribution. In some embodiments, the nanoparticulate
benzodiazepine has a trimodal or higher order modal particle size
distribution.
[0047] In some embodiments, the invention provides a method of
using a non-aqueous dispersion or suspension of nanoparticulate
benzodiazepine, comprising administering an effective amount of the
dispersion or suspension to a patient. In some embodiments, the
method comprises administering a therapeutically effective amount
of the composition to at least one nostril of the patient. In some
embodiments, the method comprises administering at least a portion
of the therapeutically effective amount of the composition to each
nostril. In some embodiments, the method comprises administering a
first quantity of the composition to a first nostril, administering
a second quantity of the composition to a second nostril, and
optionally after a pre-selected time delay, administering a third
quantity of the composition to the first nostril. In some
embodiments, the method further comprises, optionally after a
pre-selected time delay, administering at least a fourth quantity
of the composition to the second nostril. In some embodiments, the
method comprises pulmonary administration of a therapeutically
effective amount of the composition to a patient. In some
embodiments, the effective amount of the composition is effective
to treat seizure, protect against seizure, reduce or ameliorate the
intensity of seizure, reduce or ameliorate the frequency of
seizure, and/or prevent occurrence or re-occurrence of seizure. In
some embodiments, the effective amount of the composition is
effective to provide a therapeutic effect selected from an
anxiolytic effect, an anticonvulsant effect, a sedative effect, a
skeletal muscle relaxant effect, an amnesic effect or combinations
thereof. In some embodiments, a therapeutically effective plasma
level of benzodiazepine drug is obtained within about 1 hour of
administration of the composition to a patient. In some
embodiments, the therapeutically effective plasma level of the
benzodiazepine drug is obtained within about 30 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of the
benzodiazepine is obtained within about 15 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of
benzodiazepine drug is obtained within about 10 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of
benzodiazepine drug is obtained within about 5 minutes of
administration of the composition to the patient. In some
embodiments, peak plasma concentration (C.sub.max) is achieved for
the benzodiazepine drug at a time (T.sub.max) less than about 1
hour after administration of the composition to a patient. In some
embodiments, T.sub.max is less than about 30 minutes after
administration of the composition to the patient. In some
embodiments, T.sub.max is less than about 15 minutes after
administration of the composition to the patient. In some
embodiments, T.sub.max is less than about 12 minutes after
administration of the composition to the patient.
[0048] In some embodiments, the invention provides a method of
administering a benzodiazepine drug to a patient, comprising
administering to the patient a pharmaceutical composition
comprising a non-aqueous dispersion or suspension of
nanoparticulate benzodiazepine particles. In some embodiments, the
composition is administered to the patient's nose or nasal cavity.
In some embodiments, the composition is administered by pulmonary
delivery. In some embodiments, the nanoparticulate benzodiazepine
particles comprise at least one member of the group consisting of
alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam,
clorazepam, demoxazepam, flumazenil, flurazepam, halazepam,
midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam,
medazepam, lorazepam, prazepam, quazepam, triazolam, temazepam,
loprazolam, and pharmaceutically acceptable salts and combinations
thereof. In some embodiments, the benzodiazepine drug comprises at
least one member of the group consisting of alprazolam, diazepam,
flurazepam, lorazepam, medazepam, mexazolam, midazolam, temazepam
and pharmaceutically acceptable salts and combinations thereof. In
some embodiments, the benzodiazepine drug comprises one or more
members of the group consisting of diazepam, lorazepam, midazolam
and pharmaceutically acceptable salts thereof. In some embodiments,
the benzodiazepine particles contain crystalline benzodiazepine,
amorphous benzodiazepine, semi-crystalline benzodiazepine, a
mixture of amorphous and crystalline benzodiazepine, a mixture of
amorphous and semi-crystalline benzodiazepine, a mixture of
crystalline and semi-crystalline benzodiazepine and a mixture of
amorphous, crystalline and semi-crystalline benzodiazepine. In some
embodiments, the benzodiazepine particles contain crystalline
diazepam, amorphous diazepam, semi-crystalline diazepam, a mixture
of amorphous and crystalline diazepam, a mixture of amorphous and
semi-crystalline diazepam, a mixture of crystalline and
semi-crystalline diazepam, a mixture of amorphous, crystalline and
semi-crystalline diazepam, crystalline lorazepam, amorphous
lorazepam, semi-crystalline lorazepam, a mixture of amorphous and
crystalline lorazepam, a mixture of amorphous and semi-crystalline
lorazepam, a mixture of crystalline and semi-crystalline lorazepam,
a mixture of amorphous, crystalline and semi-crystalline lorazepam,
crystalline medazepam, amorphous medazepam, semi-crystalline
medazepam, a mixture of amorphous and crystalline medazepam, a
mixture of amorphous and semi-crystalline medazepam, a mixture of
crystalline and semi-crystalline medazepam and a mixture of
amorphous, crystalline and semi-crystalline medazepam. In some
embodiments, the benzodiazepine particles have a mean particle size
of less than about 5000 nm. In some embodiments, the benzodiazepine
particles have a mean particle size of less than about 4000 nm. In
some embodiments, the benzodiazepine particles have a mean particle
size in the range of about 50 to 5000 nm, about 100 to about 2500
nm, about 250 to about 1000 nm or approximately 500 nm. In some
embodiments, the benzodiazepine particles do not contain solvent
residues resulting from solvent extraction or solvent
precipitation. In some embodiments, the benzodiazepine particles
further comprise at least one additional ingredient selected from
active pharmaceutical ingredients and enhancers. In some
embodiments, the effective amount of the composition is effective
to treat seizure, protect against seizure, reduce or ameliorate the
intensity of seizure, reduce or ameliorate the frequency of
seizure, and/or prevent occurrence or re-occurrence of seizure. In
some embodiments, the effective amount of the composition is
effective to provide a therapeutic effect selected from an
anxiolytic effect, an anticonvulsant effect, a sedative effect, a
skeletal muscle relaxant effect, an amnesic effect or combinations
thereof. In some embodiments, a therapeutically effective plasma
level of benzodiazepine drug is obtained within about 1 hour of
administration of the composition to a patient. In some
embodiments, the therapeutically effective plasma level of the
benzodiazepine drug is obtained within about 30 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of the
benzodiazepine is obtained within about 15 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of
benzodiazepine drug is obtained within about 10 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of
benzodiazepine drug is obtained within about 5 minutes of
administration of the composition to the patient. In some
embodiments, peak plasma concentration (C.sub.max) is achieved for
the benzodiazepine drug at a time (T.sub.max) less than about 1
hour after administration of the composition to a patient. In some
embodiments, T.sub.max is less than about 30 minutes after
administration of the composition to the patient. In some
embodiments, T.sub.max is less than about 15 minutes after
administration of the composition to the patient. In some
embodiments, T.sub.max is less than about 12 minutes after
administration of the composition to the patient.
[0049] In some embodiments, the invention provides an aqueous
dispersion or suspension of nanoparticulate benzodiazepine
particles. In some embodiments, the nanoparticulate benzodiazepine
particles comprise at least one member of the group consisting of
alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam,
clorazepam, demoxazepam, flumazenil, flurazepam, halazepam,
midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam,
medazepam, lorazepam, prazepam, quazepam, triazolam, temazepam,
loprazolam, and pharmaceutically acceptable salts and combinations
thereof. In some embodiments, the nanoparticulate benzodiazepine
particles comprise at least one member of the group consisting of
alprazolam, diazepam, flurazepam, lorazepam, medazepam, mexazolam,
midazolam, temazepam and pharmaceutically acceptable salts and
combinations thereof. In some embodiments, the nanoparticulate
benzodiazepine particles comprise at least one benzodiazepine
selected from the group consisting of diazepam, lorazepam,
midazolam and pharmaceutically acceptable salts thereof. In some
embodiments, the droplets have a mass median aerodynamic diameter
(MMAD) less than or equal to about 1000 .mu.m and the
nanoparticulate benzodiazepine particles have an effective average
particle size of less than about 5000 nm. In some embodiments, the
nanoparticulate benzodiazepine particles have an effective average
particle size of less than about 1000 nm, less than about 500 nm,
less than about 400 nm, less than about 250 nm, less than about 100
nm or less than about 50 nm. In some embodiments, the
nanoparticulate benzodiazepine particles have an effective average
particle size in the range of about 25 to about 10000 nm. In some
embodiments, the nanoparticulate benzodiazepine particles have an
effective average particle size of about 50 to about 5000 nm. In
some embodiments, the aqueous dispersion or suspension is adapted
for nasal administration. In some embodiments, the dispersion or
suspension further comprises at least one additional ingredient
selected from the group consisting of active pharmaceutical
ingredients and enhancers. In some embodiments, the composition
further comprises a non-aqueous carrier or propellant. In some
embodiments, the non-aqueous carrier or propellant comprises a
hydrocarbon, a hydrofluorocarbon or a chlorofluorocarbon. In some
embodiments, at least a portion of the particles is coated with at
least one surface acting agent. In some embodiments, at least one
surface acting agent is a cationic surfactant, a non-ionic
surfactant, an anionic surfactant, a surface active biological
modifier or a zwitterionic surfactant. In some embodiments, at
least one surface acting agent is a cationic surfactant selected
from the group consisting of natural phospholipids, synthetic
phospholipids, quaternary ammonium compounds, benzalkonium
chloride, cetyltrimethylammonium bromide, chitosans,
lauryldimethylbenzyl-ammonium chloride, acyl carnitine
hydrochlorides, dimethyldioctadecylammomium bromide (DDAB),
dioleyoltrimethylammonium propane (DOTAP),
dimyristoyltrimethylammonium propane (DMTAP),
dimethylaminoethanecarbamoyl cholesterol (DC-Chol),
1,2-diacylglycero-3-(O-alkyl)phosphocholine,
O-alkylphosphatidylcholine, alkyl pyridinium halides, and
long-chain alkyl amines such as, for example, n-octylamine and
oleylamine. In some embodiments, at least one surface acting agent
is an anionic surface active agent selected from the group
consisting of natural anionic phospholipids, synthetic anionic
phospholipids and anionic polymers. In some embodiments, the
natural anionic phospholipids, synthetic anionic phospholipids and
anionic polymers are selected from the group consisting of
polyacrylic acid, carrageenan k type II, carbopol 980, carbopol 974
P, carbopol 971 P, polycarbophil, sodium carboxymethylcellulose,
sodium hyaluronate or combinations thereof. In some embodiments, at
least one surface acting agent is selected from the group
consisting of thiolated polymers. In some embodiments, the
thiolated polymer is selected from the group consisting of cysteine
conjugates of polyacrylic acid, polycarbophil (thiomer
polycarbophil-cysteine), thiolated sodium carboxymethylcellulose,
chitosan modified with 2-iminothiolate (e.g.
chitosan-4-thiobutylamidine conjugates, chitosan-thioglycolic acid
conjugates, chitosan-cysteine conjugates). In some embodiments, at
least one surface acting agent is selected from the group
consisting of polymeric mucilaginous polysaccharides. In some
embodiments, the polymeric mucilaginous polysaccharide is from the
aloe vera plant. In some embodiments, at least one surface acting
agent is methylcellulose, ethylcellulose,
hydroxypropylmethylcellulose (HPMC) or a mixture of two or more
thereof. In some embodiments, the nanoparticulate benzodiazepine
has a multimodal particle size distribution. In some embodiments,
the nanoparticulate benzodiazepine has a bimodal particle size
distribution. In some embodiments, the nanoparticulate
benzodiazepine has a trimodal or higher order modal particle size
distribution.
[0050] In some embodiments, the invention provides a method of
using an aqueous dispersion or suspension of nanoparticulate
benzodiazepine, comprising administering an effective amount of the
dispersion or suspension to the nose by administering a
therapeutically effective amount of the composition to at least one
nostril. In some embodiments, the method comprises administering at
least a portion of the therapeutically effective amount of the
composition to each nostril. In some embodiments, the method
comprises administering a first quantity of the composition to a
first nostril, administering a second quantity of the composition
to a second nostril, and optionally after a pre-selected time
delay, administering a third quantity of the composition to the
first nostril. In some embodiments, the method further comprises,
optionally after a pre-selected time delay, administering at least
a fourth quantity of the composition to the second nostril. In some
embodiments, the effective amount of the composition is effective
to treat seizure, protect against seizure, reduce or ameliorate the
intensity of seizure, reduce or ameliorate the frequency of
seizure, and/or prevent occurrence or re-occurrence of seizure. In
some embodiments, the effective amount of the composition is
effective to provide a therapeutic effect selected from an
anxiolytic effect, an anticonvulsant effect, a sedative effect, a
skeletal muscle relaxant effect, an amnesic effect or combinations
thereof. In some embodiments, a therapeutically effective plasma
level of benzodiazepine drug is obtained within about 1 hour of
administration of the composition to a patient. In some
embodiments, the therapeutically effective plasma level of the
benzodiazepine drug is obtained within about 30 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of the
benzodiazepine is obtained within about 15 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of
benzodiazepine drug is obtained within about 10 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of
benzodiazepine drug is obtained within about 5 minutes of
administration of the composition to the patient. In some
embodiments, peak plasma concentration (C.sub.max) is achieved for
the benzodiazepine drug at a time (T.sub.max) less than about 1
hour after administration of the composition to a patient. In some
embodiments, T.sub.max is less than about 30 minutes after
administration of the composition to the patient. In some
embodiments, T.sub.max is less than about 15 minutes after
administration of the composition to the patient. In some
embodiments, T.sub.max is less than about 12 minutes after
administration of the composition to the patient.
[0051] In some embodiments, the invention provides a method of
administering a benzodiazepine drug to a patient, comprising
administering to the patient's nose, nasal cavity or lungs a
pharmaceutical composition comprising an aqueous dispersion or
suspension of nanoparticulate benzodiazepine particles. In some
embodiments, the nanoparticulate benzodiazepine particles comprise
at least one member of the group consisting of alprazolam,
brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam,
demoxazepam, flumazenil, flurazepam, halazepam, midazolam,
nordazepam, medazepam, diazepam, nitrazepam, oxazepam, medazepam,
lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam,
and pharmaceutically acceptable salts and combinations thereof. In
some embodiments, the benzodiazepine drug comprises at least one
member of the group consisting of alprazolam, diazepam, flurazepam,
lorazepam, medazepam, mexazolam, midazolam, temazepam and
pharmaceutically acceptable salts and combinations thereof. In some
embodiments, the benzodiazepine drug comprises one or more members
of the group consisting of diazepam, lorazepam, midazolam and
pharmaceutically acceptable salts thereof. In some embodiments, the
benzodiazepine particles contain crystalline benzodiazepine,
amorphous benzodiazepine, semi-crystalline benzodiazepine, a
mixture of amorphous and crystalline benzodiazepine, a mixture of
amorphous and semi-crystalline benzodiazepine, a mixture of
crystalline and semi-crystalline benzodiazepine and a mixture of
amorphous, crystalline and semi-crystalline benzodiazepine. In some
embodiments, the benzodiazepine particles contain crystalline
diazepam, amorphous diazepam, semi-crystalline diazepam, a mixture
of amorphous and crystalline diazepam, a mixture of amorphous and
semi-crystalline diazepam, a mixture of crystalline and
semi-crystalline diazepam, a mixture of amorphous, crystalline and
semi-crystalline diazepam, crystalline lorazepam, amorphous
lorazepam, semi-crystalline lorazepam, a mixture of amorphous and
crystalline lorazepam, a mixture of amorphous and semi-crystalline
lorazepam, a mixture of crystalline and semi-crystalline lorazepam,
a mixture of amorphous, crystalline and semi-crystalline lorazepam,
crystalline medazepam, amorphous medazepam, semi-crystalline
medazepam, a mixture of amorphous and crystalline medazepam, a
mixture of amorphous and semi-crystalline medazepam, a mixture of
crystalline and semi-crystalline medazepam and a mixture of
amorphous, crystalline and semi-crystalline medazepam. In some
embodiments, the benzodiazepine particles have a mean particle size
of less than about 5000 nm. In some embodiments, the benzodiazepine
particles have a mean particle size of less than about 4000 nm. In
some embodiments, the benzodiazepine particles have a mean particle
size in the range of about 50 to 5000 nm, about 100 to about 2500
nm, about 250 to about 1000 nm or approximately 500 nm. In some
embodiments, the benzodiazepine particles do not contain solvent
residues resulting from solvent extraction or solvent
precipitation. In some embodiments, the benzodiazepine particles
further comprise at least one additional ingredient selected from
active pharmaceutical ingredients and enhancers. In some
embodiments, the effective amount of the composition is effective
to treat seizure, protect against seizure, reduce or ameliorate the
intensity of seizure, reduce or ameliorate the frequency of
seizure, and/or prevent occurrence or re-occurrence of seizure. In
some embodiments, the effective amount of the composition is
effective to provide a therapeutic effect selected from an
anxiolytic effect, an anticonvulsant effect, a sedative effect, a
skeletal muscle relaxant effect, an amnesic effect or combinations
thereof. In some embodiments, a therapeutically effective plasma
level of benzodiazepine drug is obtained within about 1 hour of
administration of the composition to a patient. In some
embodiments, the therapeutically effective plasma level of the
benzodiazepine drug is obtained within about 30 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of the
benzodiazepine is obtained within about 15 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of
benzodiazepine drug is obtained within about 10 minutes of
administration of the composition to the patient. In some
embodiments, the therapeutically effective plasma level of
benzodiazepine drug is obtained within about 5 minutes of
administration of the composition to the patient. In some
embodiments, peak plasma concentration (C.sub.max) is achieved for
the benzodiazepine drug at a time (T.sub.max) less than about 1
hour after administration of the composition to a patient. In some
embodiments, T.sub.max is less than about 30 minutes after
administration of the composition to the patient. In some
embodiments, T.sub.max is less than about 15 minutes after
administration of the composition to the patient. In some
embodiments, T.sub.max is less than about 12 minutes after
administration of the composition to the patient.
[0052] In some embodiments, the invention provides a
nanoparticulate composition comprising: (a) a benzodiazepine having
an effective average particle size of less than about 2000 nm,
wherein the benzodiazepine is selected from the group consisting of
alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam,
clorazepam, demoxazepam, flumazenil, flurazepam, halazepam,
midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam,
midazepam, lorazepam, prazepam, quazepam, triazolam, temazepam,
loprazolam, pharmaceutically acceptable salts and esters thereof,
and mixtures thereof; and (b) at least one surface stabilizer. In
some embodiments, the surface stabilizer is selected from the group
consisting of a nonionic surfactant, an ionic surfactant, a
cationic surfactant, an anionic surfactant, and a zwitterionic
surfactant. In some embodiments, the surface stabilizer is selected
from the group consisting of hypromellose, hydroxypropylcellulose,
polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate,
gelatin, casein, lecithin, dextran, gum acacia, cholesterol,
tragacanth, stearic acid, benzalkonium chloride, calcium stearate,
glycerol monostearate, cetostearyl alcohol, cetomacrogol
emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers,
polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan
fatty acid esters, polyethylene glycols, polyoxyethylene stearates,
colloidal silicon dioxide, phosphates, carboxymethylcellulose
calcium, carboxymethylcellulose sodium, methylcellulose,
hydroxyethylcellulose, hypromellose phthalate, noncrystalline
cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl
alcohol, tyloxapol, poloxamers, poloxamines, Tetronic 1508.RTM., an
alkyl aryl polyether sulfonate, a mixture of sucrose stearate and
sucrose distearate, p-isononylphenoxypoly-(glycidol), Crodestas
SL-40.RTM. (Croda, Inc.); and SA9OHCO, decanoyl-N-methylglucamide;
n-decyl (-D-glucopyranoside; n-decyl (-D-maltopyranoside; n-dodecyl
(-D-glucopyranoside; n-dodecyl (-D-maltoside;
heptanoyl-N-methylglucamide; n-heptyl-(-D-glucopyranoside; n-heptyl
(-D-thioglucoside; n-hexyl (-D-glucopyranoside;
nonanoyl-N-methylglucamide; n-noyl (-D-glucopyranoside;
octanoyl-N-methylglucamide; n-octyl-(-D-glucopyranoside; octyl
(-D-thioglucopyranoside; PEG-phospholipid, PEG-cholesterol,
PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme,
random copolymers of vinyl pyrrolidone and vinyl acetate, cationic
polymers, cationic biopolymers, cationic polysaccharides, cationic
cellulosics, cationic alginates, cationic phospholipids, cationic
nonpolymeric compounds, poly-n-methylpyridinium, anthryul
pyridinium chloride, cationic phospholipids, chitosan, polylysine,
polyvinylimidazole, polybrene, polymethylmethacrylate
trimethylammoniumbromide bromide, hexyldesyltrimethylammonium
bromide, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate
dimethyl sulfate, cationic lipids, sulfonium, phosphonium,
quarternary ammonium compounds, stearyltrimethylammonium chloride,
benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl
ammonium chloride, coconut trimethyl ammonium bromide, coconut
methyl dihydroxyethyl ammonium chloride, coconut methyl
dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride,
decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl
hydroxyethyl ammonium bromide, C.sub.12-15dimethyl hydroxyethyl
ammonium chloride, C.sub.12-15dimethyl hydroxyethyl ammonium
bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut
dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium
methyl sulfate, lauryl dimethyl benzyl ammonium chloride, lauryl
dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy).sub.4
ammonium chloride, lauryl dimethyl (ethenoxy).sub.4 ammonium
bromide, N-alkyl (C.sub.12-18)dimethylbenzyl ammonium chloride,
N-alkyl (C.sub.14-18)dimethyl-benzyl ammonium chloride,
N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl
didecyl ammonium chloride, N-alkyl and (C.sub.12-14) dimethyl
1-napthylmethyl ammonium chloride, trimethylammonium halide,
alkyl-trimethylammonium salts, dialkyl-dimethylammonium salts,
lauryl trimethyl ammonium chloride, ethoxylated
alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl
ammonium salt, dialkylbenzene dialkylammonium chloride,
N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl
ammonium, chloride monohydrate, N-alkyl(C.sub.12-14) dimethyl
1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium
chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl
ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl
benzyl dimethyl ammonium bromide, C.sub.12, C.sub.15, C.sub.17
trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium
chloride, poly-diallyldimethylammonium chloride, dimethyl ammonium
chlorides, alkyldimethylammonium halogenides, tricetyl methyl
ammonium chloride, decyltrimethylammonium bromide,
dodecyltriethylammonium bromide, tetradecyltrimethylammonium
bromide, methyl trioctylammonium chloride, POLYQUAT,
tetrabutylammonium bromide, benzyl trimethylammonium bromide,
choline esters, benzalkonium chloride, stearalkonium chloride
compounds, cetyl pyridinium bromide, cetyl pyridinium chloride,
halide salts of quaternized polyoxyethylalkylamines, MIRAPOL,
ALKAQUAT, alkyl pyridinium salts, amines, alkylamines,
dialkylamines, alkanolamines, polyethylenepolyamines,
N,N-dialkylaminoalkyl acrylates, vinyl pyridine, amine salts,
lauryl amine acetate, stearyl amine acetate, alkylpyridinium salt,
alkylimidazolium salt, amine oxides, imide azolinium salts,
protonated quaternary acrylamides, methylated quaternary polymers,
and cationic guar. In some embodiments, the nanoparticulate
benzodiazepine particles have an effective average particle size
selected from the group consisting of less than about 1900 nm, less
than about 1800 nm, less than about 1700 nm, less than about 1600
nm, less than about 1500 nm, less than about 1400 nm, less than
about 1300 nm, less than about 1200 nm, less than about 1100 nm,
less than about 1000 nm, less than about 900 nm, less than about
800 nm, less than about 700 nm, less than about 650 nm, less than
about 600 nm, less than about 550 nm, less than about 500 nm, less
than about 450 nm, less than about 400 nm, less than about 350 nm,
less than about 300 nm, less than about 250 nm, less than about 200
nm, less than about 150 nm, less than about 100 nm, less than about
75 nm, and less than about 50 mm. In some embodiments, the
composition is formulated into an aerosol of an aqueous dispersion
of the composition described above, wherein essentially each
droplet of the aerosol comprises at least one nanoparticulate
benzodiazepine particle, wherein: (a) the benzodiazepine has a
solubility in the aqueous dispersion of less than about 10 mg/mL;
and (b) the droplets of the aerosol have a mass median aerodynamic
diameter (MMAD) less than or equal to about 100 microns. In some
embodiments, the benzodiazepine is present in a concentration
selected from the group consisting of from about 0.05 mg/mL up to
about 600 mg/mL, about 10 mg/mL or more, about 100 mg/mL or more,
about 200 mg/mL or more, about 400 mg/mL or more, and about 600
mg/mL. In some embodiments, the composition is suitable for
administration of the benzodiazepine dosage in about 15 seconds or
less. In some embodiments, the droplets of the aerosol have a mass
median aerodynamic diameter (MMAD) selected from the group
consisting of about 2 to about 10 microns, about 2 to about 6
microns, less than about 2 microns, about 5 to about 100 microns,
and about 30 to about 60 microns. In some embodiments, the
composition is formulated into an injectable composition. In some
embodiments, the composition comprises povidones as a surface
stabilizer. In some embodiments, the povidone polymer has a
molecular weight of about 40,000 daltons or less. In some
embodiments, the effective average particle size of the
benzodiazepine particles is less than about 600 nm.
[0053] In some embodiments, the invention provides a method of
treating a subject in need comprising administering to the subject
a nanoparticulate benzodiazepine composition comprising: (a) a
benzodiazepine having an effective average particle size of less
than about 2000 nm, wherein the benzodiazepine is selected from the
group consisting of alprazolam, brotizolam, chlordiazepoxide,
clobazam, clonazepam, clorazepam, demoxazepam, flumazenil,
flurazepam, halazepam, midazolam, nordazepam, medazepam, diazepam,
nitrazepam, oxazepam, midazepam, lorazepam, prazepam, quazepam,
triazolam, temazepam, loprazolam, pharmaceutically acceptable salts
and esters thereof, and mixtures thereof; and (b) at least one
surface stabilizer. In some embodiments, the surface stabilizer is
selected from the group consisting of a nonionic surfactant, an
ionic surfactant, a cationic surfactant, an anionic surfactant, and
a zwitterionic surfactant. In some embodiments, the surface
stabilizer is selected from the group consisting of hypromellose,
hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl
sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin, dextran,
gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium
chloride, calcium stearate, glycerol monostearate, cetostearyl
alcohol, cetomacrogol emulsifying wax, sorbitan esters,
polyoxyethylene alkyl ethers, polyoxyethylene castor oil
derivatives, polyoxyethylene sorbitan fatty acid esters,
polyethylene glycols, polyoxyethylene stearates, colloidal silicon
dioxide, phosphates, carboxymethylcellulose calcium,
carboxymethylcellulose sodium, methylcellulose,
hydroxyethylcellulose, hypromellose phthalate, noncrystalline
cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl
alcohol, tyloxapol, poloxamers, poloxamines, Tetronic 1508.RTM., an
alkyl aryl polyether sulfonate, a mixture of sucrose stearate and
sucrose distearate, p-isononylphenoxypoly-(glycidol), Crodestas
SL-40.RTM. (Croda, Inc.); and SA9OHCO, decanoyl-N-methylglucamide;
n-decyl (-D-glucopyranoside; n-decyl (-D-maltopyranoside; n-dodecyl
(-D-glucopyranoside; n-dodecyl (-D-maltoside;
heptanoyl-N-methylglucamide; n-heptyl-(-D-glucopyranoside; n-heptyl
(-D-thioglucoside; n-hexyl (-D-glucopyranoside;
nonanoyl-N-methylglucamide; n-noyl (-D-glucopyranoside;
octanoyl-N-methylglucamide; n-octyl-(-D-glucopyranoside; octyl
(-D-thioglucopyranoside; PEG-phospholipid, PEG-cholesterol,
PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme,
random copolymers of vinyl pyrrolidone and vinyl acetate, cationic
polymers, cationic biopolymers, cationic polysaccharides, cationic
cellulosics, cationic alginates, cationic phospholipids, cationic
nonpolymeric compounds, poly-n-methylpyridinium, anthryul
pyridinium chloride, cationic phospholipids, chitosan, polylysine,
polyvinylimidazole, polybrene, polymethylmethacrylate
trimethylammoniumbromide bromide, hexyldesyltrimethylammonium
bromide, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate
dimethyl sulfate, cationic lipids, sulfonium, phosphonium,
quarternary ammonium compounds, stearyltrimethylammonium chloride,
benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl
ammonium chloride, coconut trimethyl ammonium bromide, coconut
methyl dihydroxyethyl ammonium chloride, coconut methyl
dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride,
decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl
hydroxyethyl ammonium bromide, C.sub.12-15dimethyl hydroxyethyl
ammonium chloride, C.sub.12-15dimethyl hydroxyethyl ammonium
bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut
dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium
methyl sulfate, lauryl dimethyl benzyl ammonium chloride, lauryl
dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy).sub.4
ammonium chloride, lauryl dimethyl (ethenoxy).sub.4 ammonium
bromide, N-alkyl (C.sub.12-18)dimethylbenzyl ammonium chloride,
N-alkyl (C.sub.14-18)dimethyl-benzyl ammonium chloride,
N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl
didecyl ammonium chloride, N-alkyl and (C.sub.12-14) dimethyl
1-napthylmethyl ammonium chloride, trimethylammonium halide,
alkyl-trimethylammonium salts, dialkyl-dimethylammonium salts,
lauryl trimethyl ammonium chloride, ethoxylated
alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl
ammonium salt, dialkylbenzene dialkylammonium chloride,
N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl
ammonium, chloride monohydrate, N-alkyl(C.sub.12-14) dimethyl
1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium
chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl
ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl
benzyl dimethyl ammonium bromide, C.sub.12, C.sub.15, C.sub.17
trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium
chloride, poly-diallyldimethylammonium chloride, dimethyl ammonium
chlorides, alkyldimethylammonium halogenides, tricetyl methyl
ammonium chloride, decyltrimethylammonium bromide,
dodecyltriethylammonium bromide, tetradecyltrimethylammonium
bromide, methyl trioctylammonium chloride, POLYQUAT,
tetrabutylammonium bromide, benzyl trimethylammonium bromide,
choline esters, benzalkonium chloride, stearalkonium chloride
compounds, cetyl pyridinium bromide, cetyl pyridinium chloride,
halide salts of quaternized polyoxyethylalkylamines, MIRAPOL,
ALKAQUAT, alkyl pyridinium salts, amines, alkylamines,
dialkylamines, alkanolamines, polyethylenepolyamines,
N,N-dialkylaminoalkyl acrylates, vinyl pyridine, amine salts,
lauryl amine acetate, stearyl amine acetate, alkylpyridinium salt,
alkylimidazolium salt, amine oxides, imide azolinium salts,
protonated quaternary acrylamides, methylated quaternary polymers,
and cationic guar. In some embodiments, the nanoparticulate
benzodiazepine particles have an effective average particle size
selected from the group consisting of less than about 1900 nm, less
than about 1800 nm, less than about 1700 nm, less than about 1600
nm, less than about 1500 nm, less than about 1400 nm, less than
about 1300 nm, less than about 1200 nm, less than about 1100 nm,
less than about 1000 nm, less than about 900 nm, less than about
800 nm, less than about 700 nm, less than about 650 nm, less than
about 600 nm, less than about 550 nm, less than about 500 nm, less
than about 450 nm, less than about 400 nm, less than about 350 nm,
less than about 300 nm, less than about 250 nm, less than about 200
nm, less than about 150 nm, less than about 100 nm, less than about
75 nm, and less than about 50 nm. In some embodiments, the
composition is formulated into an aerosol of an aqueous dispersion
of the composition described above, wherein essentially each
droplet of the aerosol comprises at least one nanoparticulate
benzodiazepine particle, wherein: (a) the benzodiazepine has a
solubility in the aqueous dispersion of less than about 10 mg/mL;
and (b) the droplets of the aerosol have a mass median aerodynamic
diameter (MMAD) less than or equal to about 100 microns. In some
embodiments, the benzodiazepine is present in a concentration
selected from the group consisting of from about 0.05 mg/mL up to
about 600 mg/mL, about 10 mg/mL or more, about 100 mg/mL or more,
about 200 mg/mL or more, about 400 mg/mL or more, and about 600
mg/mL. In some embodiments, the composition is suitable for
administration of the benzodiazepine dosage in about 15 seconds or
less. In some embodiments, the droplets of the aerosol have a mass
median aerodynamic diameter (MMAD) selected from the group
consisting of about 2 to about 10 microns, about 2 to about 6
microns, less than about 2 microns, about 5 to about 100 microns,
and about 30 to about 60 microns. In some embodiments, the
composition is formulated into an injectable dosage form. In some
embodiments, the composition comprises povidone as a surface
stabilizer. In some embodiments, the povidone polymer has a
molecular weight of about 40,000 daltons or less. In some
embodiments, the effective average particle size of the
benzodiazepine particles is less than about 600 nm.
[0054] As used herein the phrase "therapeutically effective amount"
(or more simply "effective amount") means an amount sufficient to
provide a specific therapeutic response for which the drug is
administered to a patient in need of particular treatment. The
skilled clinician will recognize that the therapeutically effective
amount of drug will depend upon the patient, the indication and the
particular drug administered.
[0055] As used herein the terms "Cmax," and "Tmax" have the
ordinary meaning in the art with respect to pharmacokinetic (PK)
curves. Where more than one C.sub.max occurs, meaning that there is
a local maximum in the PK curve, each C.sub.max may be sequentially
numbered in order of appearance, so that the first local maximum in
the PK curve is numbered Cmax1, the second Cmax2, etc. The times at
which Cmax1, Cmax2, etc. appear are correspondingly sequentially
designated Tmax1, Tmax2, etc.
[0056] As used herein, the modifier "about" is intended to have its
regularly recognized meaning of approximately. In some embodiments,
the term may be more precisely interpreted as meaning within a
particular percentage of the modified value, e.g. "about" may in
some embodiments mean .+-.20%, .+-.10% or .+-.5%.
[0057] Benzodiazepine Drugs
[0058] In the context of the present invention, the term
"benzodiazepine drug" includes any therapeutically effective
benzodiazepine compound, or pharmaceutically acceptable salt or
combinations thereof. In some embodiments, the nanoparticulate
benzodiazepine particles comprise at least one member of the group
consisting of alprazolam, diazepam, flurazepam, lorazepam,
medazepam, mexazolam, midazolam, temazepam and pharmaceutically
acceptable salts and combinations thereof. In some embodiments, the
nanoparticulate benzodiazepine particles comprise at least one
benzodiazepine selected from the group consisting of diazepam,
lorazepam, midazolam and pharmaceutically acceptable salts thereof.
However, it should be recognized by those of skill in the art that
additional benzodiazepine compounds that have heretofore been
considered to have marginal or little therapeutic benefit, either
because of low bioavailability, poor pharmacokinetic properties or
poor pharmacodynamic properties, may find use in the present
invention, which provides for improved bioavailability of
benzodiazepine drugs, delivery of higher concentrations of
benzodiazepine drugs via the nasal route, faster attainment of
therapeutic levels of benzodiazepine in the blood plasma, avoidance
of the liver portal vein and concomitant avoidance of first pass
effects and/or faster presentation of benzodiazepine drug to the
brain. In some embodiments, the invention provides as a preferred
embodiment, diazepam or a therapeutically acceptable salt
thereof.
Alprazolam
(8-chloro-6-phenyl-1-methyl-4H-1,2,4-triazolo[4,3-a][1,4]benzod-
iazepine)
##STR00001##
[0060] Alprazolam is a benzodiazepine drug having sedative,
tranquilizing and muscle relaxing properties. It is classified as
an anxiolytic. Alprazolam has also been shown to be useful in the
treatment of panic disorder. The dosage of Alprazolam varies by
indication, however it is expected that a therapeutic dose will be
in the range of about 0.5 to about 4, preferably about 1 to about 2
mg per dose, from 1 to 8, preferably from 2 to 8, and in some
preferred embodiments about 4 to about 6 times per day. Alprazolam
may be manufactured using the process disclosed in U.S. Pat. No.
3,987,052, which is incorporated herein by reference in its
entirety.
[0061] As a nasal formulation, alprazolam may be administered in 25
to 250 .mu.l metered sprays. In some preferred embodiments,
alprazolam is administered in 50 to 150 .mu.l, especially about 100
.mu.l, metered sprays. In some embodiments, a first metered spray
is applied to a first nostril and if necessary a second metered
spray is applied to a second nostril. In some optional embodiments,
a third metered spray is applied to the first nostril. In some
further embodiments, a fourth metered spray is applied to the
second nostril. In some embodiments, additional metered sprays are
applied to alternating nostrils until the full target therapeutic
dose has been administered to the patient. In some embodiments,
there is a time increment of from several seconds to 5 minutes,
preferably about 10 seconds to about 1 minute, between applications
of benzodiazepine drug to the same nostril. This allows time for
the drug to cross the nasal mucosa and enter the blood stream.
Multiple applications of metered sprays to each nostril, optionally
separated by a time interval, allows administration of a full
therapeutic dose in increments small enough to permit full
absorption of the benzodiazepine drug into the blood stream and
avoid loss of drug down the back of the throat.
[0062] Alprazolam may be combined with other pharmaceutically
active ingredients, including other benzodiazepine compounds (such
as diazepam) in a benzodiazepine drug formulation. In some
embodiments, the ratio of alprazolam to the other pharmaceutically
active ingredient is in one of the ranges from about 1:1000 to
about 1000:1, about 1:100 to about 100:1 or about 1:10 to about
10:1. In some embodiments, the other pharmaceutically active
ingredient is a benzodiazepine drug and the ratio of alprazolam to
the other benzodiazepine drug is in one of the ranges from about
1:1000 to about 1000:1, about 1:100 to about 100:1 or about 1:10 to
about 10:1. In some embodiments, the other pharmaceutically active
ingredient is diazepam and the ratio of alprazolam to diazepam is
about 1:1000 to about 1000:1, about 1:100 to about 100:1 or about
1:10 to about 10:1.
[0063] In some embodiments, Alprazolam is used alone or in
combination with other drugs to provide an anxiolytic effect, an
anticonvulsant effect, a sedative effect, a skeletal muscle
relaxant effect, an amnesic effect or combinations of the foregoing
effects.
[0064] In some embodiments, Alprazolam is used alone or in
combination with another anticonvulsant drug to treat seizure,
protect against seizure, reduce or ameliorate the intensity of
seizure, reduce or ameliorate the frequency of seizure, and/or
prevent occurrence or re-occurrence of seizure. Alprazolam may be
administered by the patient or other person (such as a healthcare
professional) while the patient is in a non-seizing state to
protect against seizure. Even where protection against seizure is
not absolute, administration of alprazolam may reduce or ameliorate
the intensity of seizure and/or reduce or ameliorate the frequency
of seizure. In some embodiments, administration of alprazolam may
prevent occurrence of seizure. In some embodiments, especially
where the patient is prone to experiencing serial seizures or
status epilepticus, administration of alprazolam may aid in
interrupting the seizure cycle and may thus prevent the
re-occurrence of seizure. In addition to the benzodiazepines (such
as diazepam), other anti-convulsant drugs may be combined with
alprazolam to provide a synergistic anticonvulsant effect.
[0065] Alprazolam may also be administered by another person (e.g.
an acquaintance or associate, a family member or a health care
professional) to the patient while the patient is in a state of
seizure. Thus, one of the advantages of the nasal formulations
according to the present invention is the ability to administer
them in an acute therapeutic environment to treat the seizure
victim. Among the beneficial therapeutic effects that may be
imparted by acute nasal dosing of benzodiazepine anticonvulsants
are: reduction in the severity of the seizure (e.g. general
relaxation of the muscles, reduction in seizure-induced anxiety
experienced by the patient and a general impartation of a feeling
of well-being to the patient), reduction in the duration of the
seizure, reduction in the probability that the patient will
experience a repeat seizure, an increase in the interval between
the current seizure and the next seizure. Thus the nasal alprazolam
formulations of the invention provide fast onset of therapeutic
benefit--in some instances less than about 30 minutes, less than
about 15 minutes, less than about 10 minutes, and in some cases
less than about 5 minutes. The nasal alprazolam formulations of the
invention also provide convenient administration of a
therapeutically beneficial drug to a patient that does not require
intravenous drug administration or rectal drug administration.
[0066] Often seizures, particularly severe tonic or tonic-clonic
seizures, will be presaged by one or more aura events that will be
familiar to the patient or those familiar with the patient. These
auras are practically sui generis for each patient, but may be
classified as audible, visual, olfactory or tactile sensations that
usually, or at least often, precedes a patient's experiencing a
seizure. In some embodiments of the invention, the method includes
prompt administration of a nasal preparation of a benzodiazepine
drug according to the invention during the aura. In some
embodiments, such intra-aural administration of benzodiazepine drug
by the intra-nasal route will prevent or at least ameliorate the
effects (intensity, duration or both) of the impending seizure.
Thus, in the context of this invention, prevention of seizure
refers to a temporary forestalling of the onset of seizure, either
with or without the benefit of a warning aura.
Diazepam
(7-chloro-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-on-
e)
##STR00002##
[0068] Diazepam is a benzodiazepine drug having sedative,
tranquilizing and muscle relaxing properties. It is classified as
an anxiolytic and skeletal muscle relaxant. It possesses
anxiolytic, anticonvulsant, sedative, skeletal muscle relaxant and
amnesic properties. The dosage of Diazepam may vary by indication,
however it is expected that a therapeutic dose will be in the range
of about 1 to about 20, preferably about 2 to about 10 mg per dose,
from 1 to 8, preferably from 2 to 8, and in some preferred
embodiments about 4 to about 6 times per day. Diazepam may be
manufactured using the process disclosed in one of U.S. Pat. Nos.
3,371,085, 3,109,843, 3,136,815 or 3,102,116, each of which is
incorporated herein by reference in its entirety.
[0069] As a nasal formulation, diazepam may be administered in 25
to 250 .mu.l metered sprays. In some preferred embodiments,
diazepam is administered in 50 to 150 .mu.l, especially about 100
.mu.l, metered sprays. In some embodiments, a first metered spray
is applied to a first nostril and if necessary a second metered
spray is applied to a second nostril. In some optional embodiments,
a third metered spray is applied to the first nostril. In some
further embodiments, a fourth metered spray is applied to the
second nostril. In some embodiments, additional metered sprays are
applied to alternating nostrils until the full target therapeutic
dose has been administered to the patient. In some embodiments,
there is a time increment of from several seconds to 5 minutes,
preferably about 10 seconds to about 1 minute, between applications
of benzodiazepine drug to the same nostril. This allows time for
the drug to cross the nasal mucosa and enter the blood stream.
Multiple applications of metered sprays to each nostril, optionally
separated by a time interval, allows administration of a full
therapeutic dose in increments small enough to permit full
absorption of the benzodiazepine drug into the blood stream and
avoid loss of drug down the back of the throat.
[0070] Diazepam may be combined with other pharmaceutically active
ingredients, including other benzodiazepine compounds in a
benzodiazepine drug formulation. In some embodiments, the ratio of
diazepam to the other pharmaceutically active ingredient is in one
of the range from about 1:1000 to about 1000:1, about 1:100 to
about 100:1 or about 1:10 to about 10:1. In some embodiments, the
other pharmaceutically active ingredient is a benzodiazepine drug
and the ratio of diazepam to the other benzodiazepine drug is in
one of the range from about 1:1000 to about 1000:1, about 1:100 to
about 100:1 or about 1:10 to about 10:1. In some embodiments, the
other pharmaceutically active ingredient is lorazepam. In some
embodiments, the ratio of diazepam to lorazepam is in the range of
about 1:1000 to about 1000:1, especially about 1:10 to about 10:1.
In some embodiments, the other pharmaceutically active ingredient
is medazepam. In some embodiments, the ratio of diazepam to
medazepam is in the range of about 1:1000 to about 1000:1,
especially about 1:10 to about 10:1.
[0071] In some embodiments, Diazepam is used alone or in
combination with other drugs to provide an anxiolytic effect, an
anticonvulsant effect, a sedative effect, a skeletal muscle
relaxant effect, an amnesic effect or combinations of the foregoing
effects.
[0072] In some embodiments, Diazepam is used alone or in
combination with another anticonvulsant drug to treat seizure,
protect against seizure, reduce or ameliorate the intensity of
seizure, reduce or ameliorate the frequency of seizure, and/or
prevent occurrence or re-occurrence of seizure. Diazepam may be
administered by the patient or other person (such as a healthcare
professional) while the patient is in a non-seizing state to
protect against seizure. Even where protection against seizure is
not absolute, administration of diazepam may reduce or ameliorate
the intensity of seizure and/or reduce or ameliorate the frequency
of seizure. In some embodiments, administration of diazepam may
prevent occurrence of seizure. In some embodiments, especially
where the patient is prone to experiencing serial seizures or
status epilepticus, administration of diazepam may aid in
interrupting the seizure cycle and may thus prevent the
re-occurrence of seizure. In addition to the benzodiazepines (such
as diazepam), other anti-convulsant drugs may be combined with
diazepam to provide a synergistic anticonvulsant effect.
[0073] Diazepam may also be administered by another person (e.g. an
acquaintance or associate, a family member or a health care
professional) to the patient while the patient is in a state of
seizure. Thus, one of the advantages of the nasal formulations
according to the present invention is the ability to administer
them in an acute therapeutic environment to treat the seizure
victim. Among the beneficial therapeutic effects that may be
imparted by acute nasal dosing of benzodiazepine anticonvulsants
are: reduction in the severity of the seizure (e.g. general
relaxation of the muscles, reduction in seizure-induced anxiety
experienced by the patient and a general impartation of a feeling
of well-being to the patient), reduction in the duration of the
seizure, reduction in the probability that the patient will
experience a repeat seizure, an increase in the interval between
the current seizure and the next seizure. Thus the nasal diazepam
formulations of the invention provide fast onset of therapeutic
benefit--in some instances less than about 30 minutes, less than
about 15 minutes, less than about 10 minutes, and in some cases
less than about 5 minutes. The nasal diazepam formulations of the
invention also provide convenient administration of a
therapeutically beneficial drug to a patient that does not require
intravenous drug administration or rectal drug administration.
[0074] Often seizures, particularly severe tonic or tonic-clonic
seizures, will be presaged by one or more aura events that will be
familiar to the patient or those familiar with the patient. These
auras are practically sui generis for each patient, but may be
classified as audible, visual, olfactory or tactile sensations that
usually, or at least often, precedes a patient's experiencing a
seizure. In some embodiments of the invention, the method includes
prompt administration of a nasal preparation of a benzodiazepine
drug according to the invention during the aura. In some
embodiments, such intra-aural administration of diazepam drug by
the intra-nasal route will prevent or at least ameliorate the
effects (intensity, duration or both) of the impending seizure.
Thus, in the context of this invention, prevention of seizure
refers to a temporary forestalling of the onset of seizure, either
with or without the benefit of a warning aura.
Flurazepam
(7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1-(2-(diethylamino)eth-
yl)-1H-1,4-benzodiazepin-2-one)
##STR00003##
[0076] Flurazepam is a benzodiazepine drug having sedative
(especially soporific and hypnotic), anxiolytic, anticonvulsant and
muscle relaxing properties. It is classified as an sedative,
hypnotic. Flurazepam has been shown to be useful in the treatment
of insomnia. The dosage of Flurazepam varies by indication, however
it is expected that a therapeutic dose will be in the range of
about 5 to 40, preferably about 20 to about 35 mg per dose, from 1
to 8, preferably from 2 to 8, and in some preferred embodiments
about 4 to about 6 times per day. Flurazepam may be manufactured
using the process disclosed in U.S. Pat. No. 3,567,710 or
3,299,053, each of which is incorporated herein by reference in its
entirety.
[0077] As a nasal formulation, flurazepam may be administered in 25
to 250 .mu.l metered sprays. In some preferred embodiments,
flurazepam is administered in 50 to 150 .mu.l, especially about 100
.mu.l, metered sprays. In some embodiments, a first metered spray
is applied to a first nostril and if necessary a second metered
spray is applied to a second nostril. In some optional embodiments,
a third metered spray is applied to the first nostril. In some
further embodiments, a fourth metered spray is applied to the
second nostril. In some embodiments, additional metered sprays are
applied to alternating nostrils until the full target therapeutic
dose has been administered to the patient. In some embodiments,
there is a time increment of from several seconds to 5 minutes,
preferably about 10 seconds to about 1 minute, between applications
of benzodiazepine drug to the same nostril. This allows time for
the drug to cross the nasal mucosa and enter the blood stream.
Multiple applications of metered sprays to each nostril, optionally
separated by a time interval, allows administration of a full
therapeutic dose in increments small enough to permit full
absorption of the benzodiazepine drug into the blood stream and
avoid loss of drug down the back of the throat.
[0078] Flurazepam may be combined with other pharmaceutically
active ingredients, including other benzodiazepine compounds (such
as diazepam) in a benzodiazepine drug formulation. In some
embodiments, the ratio of flurazepam to the other pharmaceutically
active ingredient is in one of the ranges from about 1:1000 to
about 1000:1, about 1:100 to about 100:1 or about 1:10 to about
10:1. In some embodiments, the other pharmaceutically active
ingredient is a benzodiazepine drug and the ratio of flurazepam to
the other benzodiazepine drug is in one of the ranges from about
1:1000 to about 1000:1, about 1:100 to about 100:1 or about 1:10 to
about 10:1. In some embodiments, the other pharmaceutically active
ingredient is diazepam and the ratio of flurazepam to diazepam is
about 1:1000 to about 1000:1, about 1:100 to about 100:1 or about
1:10 to about 10:1.
[0079] In some embodiments, Flurazepam is used alone or in
combination with other drugs to provide an anxiolytic effect, an
anticonvulsant effect, a sedative effect, a skeletal muscle
relaxant effect, an amnesic effect or combinations of the foregoing
effects.
[0080] In some embodiments, Flurazepam is used alone or in
combination with another anticonvulsant drug to treat seizure,
protect against seizure, reduce or ameliorate the intensity of
seizure, reduce or ameliorate the frequency of seizure, and/or
prevent occurrence or re-occurrence of seizure. Flurazepam may be
administered by the patient or other person (such as a healthcare
professional) while the patient is in a non-seizing state to
protect against seizure. Even where protection against seizure is
not absolute, administration of flurazepam may reduce or ameliorate
the intensity of seizure and/or reduce or ameliorate the frequency
of seizure. In some embodiments, administration of flurazepam may
prevent occurrence of seizure. In some embodiments, especially
where the patient is prone to experiencing serial seizures or
status epilepticus, administration of flurazepam may aid in
interrupting the seizure cycle and may thus prevent the
re-occurrence of seizure. In addition to the benzodiazepines (such
as diazepam), other anti-convulsant drugs may be combined with
flurazepam to provide a synergistic anticonvulsant effect.
[0081] Flurazepam may also be administered by another person (e.g.
an acquaintance or associate, a family member or a health care
professional) to the patient while the patient is in a state of
seizure. Thus, one of the advantages of the nasal formulations
according to the present invention is the ability to administer
them in an acute therapeutic environment to treat the seizure
victim. Among the beneficial therapeutic effects that may be
imparted by acute nasal dosing of benzodiazepine anticonvulsants
are: reduction in the severity of the seizure (e.g. general
relaxation of the muscles, reduction in seizure-induced anxiety
experienced by the patient and a general impartation of a feeling
of well-being to the patient), reduction in the duration of the
seizure, reduction in the probability that the patient will
experience a repeat seizure, an increase in the interval between
the current seizure and the next seizure. Thus the nasal flurazepam
formulations of the invention provide fast onset of therapeutic
benefit--in some instances less than about 30 minutes, less than
about 15 minutes, less than about 10 minutes, and in some cases
less than about 5 minutes. The nasal flurazepam formulations of the
invention also provide convenient administration of a
therapeutically beneficial drug to a patient that does not require
intravenous drug administration or rectal drug administration.
[0082] Often seizures, particularly severe tonic or tonic-clonic
seizures, will be presaged by one or more aura events that will be
familiar to the patient or those familiar with the patient. These
auras are practically sui generis for each patient, but may be
classified as audible, visual, olfactory or tactile sensations that
usually, or at least often, precedes a patient's experiencing a
seizure. In some embodiments of the invention, the method includes
prompt administration of a nasal preparation of a benzodiazepine
drug according to the invention during the aura. In some
embodiments, such intra-aural administration of benzodiazepine drug
by the intra-nasal route will prevent or at least ameliorate the
effects (intensity, duration or both) of the impending seizure.
Thus, in the context of this invention, prevention of seizure
refers to a temporary forestalling of the onset of seizure, either
with or without the benefit of a warning aura.
Lorazepam
(7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-2H-1,4-benzod-
iazepin-2-one)
##STR00004##
[0084] Lorazepam is a benzodiazepine drug having sedative,
tranquilizing, anticonvulsant, amnesic and muscle relaxing
properties. It is classified as an anxiolytic. Lorazepam has also
been shown to be useful in the treatment of nausea. The dosage of
Lorazepam varies by indication, however it is expected that a
therapeutic dose will be in the range of about 0.1 to about 10,
preferably about 0.2 to about 1 mg per dose, from 1 to 8,
preferably from 2 to 8, and in some preferred embodiments about 4
to about 6 times per day. Lorazepam may be manufactured using the
process disclosed in U.S. Pat. No. 3,296,249, which is incorporated
herein by reference in its entirety.
[0085] As a nasal formulation, lorazepam may be administered in 25
to 250 .mu.l metered sprays. In some preferred embodiments,
lorazepam is administered in 50 to 150 .mu.l, especially about 100
.mu.l, metered sprays. In some embodiments, a first metered spray
is applied to a first nostril and if necessary a second metered
spray is applied to a second nostril. In some optional embodiments,
a third metered spray is applied to the first nostril. In some
further embodiments, a fourth metered spray is applied to the
second nostril. In some embodiments, additional metered sprays are
applied to alternating nostrils until the full target therapeutic
dose has been administered to the patient. In some embodiments,
there is a time increment of from several seconds to 5 minutes,
preferably about 10 seconds to about 1 minute, between applications
of benzodiazepine drug to the same nostril. This allows time for
the drug to cross the nasal mucosa and enter the blood stream.
Multiple applications of metered sprays to each nostril, optionally
separated by a time interval, allows administration of a full
therapeutic dose in increments small enough to permit full
absorption of the benzodiazepine drug into the blood stream and
avoid loss of drug down the back of the throat.
[0086] Lorazepam may be combined with other pharmaceutically active
ingredients, including other benzodiazepine compounds (such as
diazepam) in a benzodiazepine drug formulation. In some
embodiments, the ratio of lorazepam to the other pharmaceutically
active ingredient is in one of the ranges from about 1:1000 to
about 1000:1, about 1:100 to about 100:1 or about 1:10 to about
10:1. In some embodiments, the other pharmaceutically active
ingredient is a benzodiazepine drug and the ratio of lorazepam to
the other benzodiazepine drug is in one of the ranges from about
1:1000 to about 1000:1, about 1:100 to about 100:1 or about 1:10 to
about 10:1. In some embodiments, the other pharmaceutically active
ingredient is diazepam and the ratio of lorazepam to diazepam is
about 1:1000 to about 1000:1, about 1:100 to about 100:1 or about
1:10 to about 10:1.
[0087] In some embodiments, Lorazepam is used alone or in
combination with other drugs to provide an anxiolytic effect, an
anticonvulsant effect, a sedative effect, a skeletal muscle
relaxant effect, an amnesic effect or combinations of the foregoing
effects.
[0088] In some embodiments, Lorazepam is used alone or in
combination with another anticonvulsant drug to treat seizure,
protect against seizure, reduce or ameliorate the intensity of
seizure, reduce or ameliorate the frequency of seizure, and/or
prevent occurrence or re-occurrence of seizure. Lorazepam may be
administered by the patient or other person (such as a healthcare
professional) while the patient is in a non-seizing state to
protect against seizure. Even where protection against seizure is
not absolute, administration of lorazepam may reduce or ameliorate
the intensity of seizure and/or reduce or ameliorate the frequency
of seizure. In some embodiments, administration of lorazepam may
prevent occurrence of seizure. In some embodiments, especially
where the patient is prone to experiencing serial seizures or
status epilepticus, administration of lorazepam may aid in
interrupting the seizure cycle and may thus prevent the
re-occurrence of seizure. In addition to the benzodiazepines (such
as diazepam), other anti-convulsant drugs may be combined with
lorazepam to provide a synergistic anticonvulsant effect.
[0089] Lorazepam may also be administered by another person (e.g.
an acquaintance or associate, a family member or a health care
professional) to the patient while the patient is in a state of
seizure. Thus, one of the advantages of the nasal formulations
according to the present invention is the ability to administer
them in an acute therapeutic environment to treat the seizure
victim. Among the beneficial therapeutic effects that may be
imparted by acute nasal dosing of benzodiazepine anticonvulsants
are: reduction in the severity of the seizure (e.g. general
relaxation of the muscles, reduction in seizure-induced anxiety
experienced by the patient and a general impartation of a feeling
of well-being to the patient), reduction in the duration of the
seizure, reduction in the probability that the patient will
experience a repeat seizure, an increase in the interval between
the current seizure and the next seizure. Thus the nasal lorazepam
formulations of the invention provide fast onset of therapeutic
benefit--in some instances less than about 30 minutes, less than
about 15 minutes, less than about 10 minutes, and in some cases
less than about 5 minutes. The nasal lorazepam formulations of the
invention also provide convenient administration of a
therapeutically beneficial drug to a patient that does not require
intravenous drug administration or rectal drug administration.
[0090] Often seizures, particularly severe tonic or tonic-clonic
seizures, will be presaged by one or more aura events that will be
familiar to the patient or those familiar with the patient. These
auras are practically sui generis for each patient, but may be
classified as audible, visual, olfactory or tactile sensations that
usually, or at least often, precedes a patient's experiencing a
seizure. In some embodiments of the invention, the method includes
prompt administration of a nasal preparation of a benzodiazepine
drug according to the invention during the aura. In some
embodiments, such intra-aural administration of benzodiazepine drug
by the intra-nasal route will prevent or at least ameliorate the
effects (intensity, duration or both) of the impending seizure.
Thus, in the context of this invention, prevention of seizure
refers to a temporary forestalling of the onset of seizure, either
with or without the benefit of a warning aura.
Medazepam
((7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine)
##STR00005##
[0092] Medazepam is a benzodiazepine drug having sedative,
tranquilizing, anticonvulsant, amnesic and muscle relaxing
properties. It is classified as an anxiolytic. Medazepam has also
been shown to be useful in the treatment of nausea. The dosage of
Medazepam varies by indication, however it is expected that a
therapeutic dose will be in the range of about 0.1 to about 10,
preferably about 0.2 to about 1 mg per dose, from 1 to 8,
preferably from 2 to 8, and in some preferred embodiments about 4
to about 6 times per day. Medazepam may be manufactured using the
process disclosed in U.S. Pat. No. 3,243,427, which is incorporated
herein by reference in its entirety.
[0093] As a nasal formulation, medazepam may be administered in 25
to 250 .mu.l metered sprays. In some preferred embodiments,
medazepam is administered in 50 to 150 .mu.l, especially about 100
.mu.l, metered sprays. In some embodiments, a first metered spray
is applied to a first nostril and if necessary a second metered
spray is applied to a second nostril. In some optional embodiments,
a third metered spray is applied to the first nostril. In some
further embodiments, a fourth metered spray is applied to the
second nostril. In some embodiments, additional metered sprays are
applied to alternating nostrils until the full target therapeutic
dose has been administered to the patient. In some embodiments,
there is a time increment of from several seconds to 5 minutes,
preferably about 10 seconds to about 1 minute, between applications
of benzodiazepine drug to the same nostril. This allows time for
the drug to cross the nasal mucosa and enter the blood stream.
Multiple applications of metered sprays to each nostril, optionally
separated by a time interval, allows administration of a full
therapeutic dose in increments small enough to permit full
absorption of the benzodiazepine drug into the blood stream and
avoid loss of drug down the back of the throat.
[0094] Medazepam may be combined with other pharmaceutically active
ingredients, including other benzodiazepine compounds (such as
diazepam) in a benzodiazepine drug formulation. In some
embodiments, the ratio of medazepam to the other pharmaceutically
active ingredient is in one of the ranges from about 1:1000 to
about 1000:1, about 1:100 to about 100:1 or about 1:10 to about
10:1. In some embodiments, the other pharmaceutically active
ingredient is a benzodiazepine drug and the ratio of medazepam to
the other benzodiazepine drug is in one of the ranges from about
1:1000 to about 1000:1, about 1:100 to about 100:1 or about 1:10 to
about 10:1. In some embodiments, the other pharmaceutically active
ingredient is diazepam and the ratio of medazepam to diazepam is
about 1:1000 to about 1000:1, about 1:100 to about 100:1 or about
1:10 to about 10:1.
[0095] In some embodiments, Medazepam is used alone or in
combination with other drugs to provide an anxiolytic effect, an
anticonvulsant effect, a sedative effect, a skeletal muscle
relaxant effect, an amnesic effect or combinations of the foregoing
effects.
[0096] In some embodiments, Medazepam is used alone or in
combination with another anticonvulsant drug to treat seizure,
protect against seizure, reduce or ameliorate the intensity of
seizure, reduce or ameliorate the frequency of seizure, and/or
prevent occurrence or re-occurrence of seizure. Medazepam may be
administered by the patient or other person (such as a healthcare
professional) while the patient is in a non-seizing state to
protect against seizure. Even where protection against seizure is
not absolute, administration of medazepam may reduce or ameliorate
the intensity of seizure and/or reduce or ameliorate the frequency
of seizure. In some embodiments, administration of medazepam may
prevent occurrence of seizure. In some embodiments, especially
where the patient is prone to experiencing serial seizures or
status epilepticus, administration of medazepam may aid in
interrupting the seizure cycle and may thus prevent the
re-occurrence of seizure. In addition to the benzodiazepines (such
as diazepam), other anti-convulsant drugs may be combined with
medazepam to provide a synergistic anticonvulsant effect.
[0097] Medazepam may also be administered by another person (e.g.
an acquaintance or associate, a family member or a health care
professional) to the patient while the patient is in a state of
seizure. Thus, one of the advantages of the nasal formulations
according to the present invention is the ability to administer
them in an acute therapeutic environment to treat the seizure
victim. Among the beneficial therapeutic effects that may be
imparted by acute nasal dosing of benzodiazepine anticonvulsants
are: reduction in the severity of the seizure (e.g. general
relaxation of the muscles, reduction in seizure-induced anxiety
experienced by the patient and a general impartation of a feeling
of well-being to the patient), reduction in the duration of the
seizure, reduction in the probability that the patient will
experience a repeat seizure, an increase in the interval between
the current seizure and the next seizure. Thus the nasal medazepam
formulations of the invention provide fast onset of therapeutic
benefit--in some instances less than about 30 minutes, less than
about 15 minutes, less than about 10 minutes, and in some cases
less than about 5 minutes. The nasal medazepam formulations of the
invention also provide convenient administration of a
therapeutically beneficial drug to a patient that does not require
intravenous drug administration or rectal drug administration.
[0098] Often seizures, particularly severe tonic or tonic-clonic
seizures, will be presaged by one or more aura events that will be
familiar to the patient or those familiar with the patient. These
auras are practically sui generis for each patient, but may be
classified as audible, visual, olfactory or tactile sensations that
usually, or at least often, precedes a patient's experiencing a
seizure. In some embodiments of the invention, the method includes
prompt administration of a nasal preparation of a benzodiazepine
drug according to the invention during the aura. In some
embodiments, such intra-aural administration of benzodiazepine drug
by the intra-nasal route will prevent or at least ameliorate the
effects (intensity, duration or both) of the impending seizure.
Thus, in the context of this invention, prevention of seizure
refers to a temporary forestalling of the onset of seizure, either
with or without the benefit of a warning aura.
Mexazolam
(10-Chloro-11b-(2-chlorophenyl)-1,3,7,11b-tetrahydro-3-methyloxa-
zolo[3,2-d][1,4]benzodiazepin-6(5H)-one)
##STR00006##
[0100] Mexazolam is a benzodiazepine drug having sedative,
tranquilizing, anticonvulsant, amnesic and muscle relaxing
properties. It is classified as an anxiolytic. Mexazolam has also
been shown to be useful in the treatment of nausea. The dosage of
Mexazolam varies by indication, however it is expected that a
therapeutic dose will be in the range of about 0.1 to about 10,
preferably about 0.2 to about 1 mg per dose, from 1 to 8,
preferably from 2 to 8, and in some preferred embodiments about 4
to about 6 times per day. Mexazolam may be manufactured using the
process disclosed in U.S. Pat. No. 3,722,371, which is incorporated
herein by reference in its entirety.
[0101] As a nasal formulation, mexazolam may be administered in 25
to 250 .mu.l metered sprays. In some preferred embodiments,
mexazolam is administered in 50 to 150 .mu.l, especially about 100
.mu.l, metered sprays. In some embodiments, a first metered spray
is applied to a first nostril and if necessary a second metered
spray is applied to a second nostril. In some optional embodiments,
a third metered spray is applied to the first nostril. In some
further embodiments, a fourth metered spray is applied to the
second nostril. In some embodiments, additional metered sprays are
applied to alternating nostrils until the full target therapeutic
dose has been administered to the patient. In some embodiments,
there is a time increment of from several seconds to 5 minutes,
preferably about 10 seconds to about 1 minute, between applications
of benzodiazepine drug to the same nostril. This allows time for
the drug to cross the nasal mucosa and enter the blood stream.
Multiple applications of metered sprays to each nostril, optionally
separated by a time interval, allows administration of a full
therapeutic dose in increments small enough to permit full
absorption of the benzodiazepine drug into the blood stream and
avoid loss of drug down the back of the throat.
[0102] Mexazolam may be combined with other pharmaceutically active
ingredients, including other benzodiazepine compounds (such as
diazepam) in a benzodiazepine drug formulation. In some
embodiments, the ratio of mexazolam to the other pharmaceutically
active ingredient is in one of the ranges from about 1:1000 to
about 1000:1, about 1:100 to about 100:1 or about 1:10 to about
10:1. In some embodiments, the other pharmaceutically active
ingredient is a benzodiazepine drug and the ratio of mexazolam to
the other benzodiazepine drug is in one of the ranges from about
1:1000 to about 1000:1, about 1:100 to about 100:1 or about 1:10 to
about 10:1. In some embodiments, the other pharmaceutically active
ingredient is diazepam and the ratio of mexazolam to diazepam is
about 1:1000 to about 1000:1, about 1:100 to about 100:1 or about
1:10 to about 10:1.
[0103] In some embodiments, Mexazolam is used alone or in
combination with other drugs to provide an anxiolytic effect, an
anticonvulsant effect, a sedative effect, a skeletal muscle
relaxant effect, an amnesic effect or combinations of the foregoing
effects.
[0104] In some embodiments, Mexazolam is used alone or in
combination with another anticonvulsant drug to treat seizure,
protect against seizure, reduce or ameliorate the intensity of
seizure, reduce or ameliorate the frequency of seizure, and/or
prevent occurrence or re-occurrence of seizure. Mexazolam may be
administered by the patient or other person (such as a healthcare
professional) while the patient is in a non-seizing state to
protect against seizure. Even where protection against seizure is
not absolute, administration of mexazolam may reduce or ameliorate
the intensity of seizure and/or reduce or ameliorate the frequency
of seizure. In some embodiments, administration of mexazolam may
prevent occurrence of seizure. In some embodiments, especially
where the patient is prone to experiencing serial seizures or
status epilepticus, administration of mexazolam may aid in
interrupting the seizure cycle and may thus prevent the
re-occurrence of seizure. In addition to the benzodiazepines (such
as diazepam), other anti-convulsant drugs may be combined with
mexazolam to provide a synergistic anticonvulsant effect.
[0105] Mexazolam may also be administered by another person (e.g.
an acquaintance or associate, a family member or a health care
professional) to the patient while the patient is in a state of
seizure. Thus, one of the advantages of the nasal formulations
according to the present invention is the ability to administer
them in an acute therapeutic environment to treat the seizure
victim. Among the beneficial therapeutic effects that may be
imparted by acute nasal dosing of benzodiazepine anticonvulsants
are: reduction in the severity of the seizure (e.g. general
relaxation of the muscles, reduction in seizure-induced anxiety
experienced by the patient and a general impartation of a feeling
of well-being to the patient), reduction in the duration of the
seizure, reduction in the probability that the patient will
experience a repeat seizure, an increase in the interval between
the current seizure and the next seizure. Thus the nasal mexazolam
formulations of the invention provide fast onset of therapeutic
benefit--in some instances less than about 30 minutes, less than
about 15 minutes, less than about 10 minutes, and in some cases
less than about 5 minutes. The nasal mexazolam formulations of the
invention also provide convenient administration of a
therapeutically beneficial drug to a patient that does not require
intravenous drug administration or rectal drug administration.
[0106] Often seizures, particularly severe tonic or tonic-clonic
seizures, will be presaged by one or more aura events that will be
familiar to the patient or those familiar with the patient. These
auras are practically sui generis for each patient, but may be
classified as audible, visual, olfactory or tactile sensations that
usually, or at least often, precedes a patient's experiencing a
seizure. In some embodiments of the invention, the method includes
prompt administration of a nasal preparation of a benzodiazepine
drug according to the invention during the aura. In some
embodiments, such intra-aural administration of benzodiazepine drug
by the intra-nasal route will prevent or at least ameliorate the
effects (intensity, duration or both) of the impending seizure.
Thus, in the context of this invention, prevention of seizure
refers to a temporary forestalling of the onset of seizure, either
with or without the benefit of a warning aura.
Midazolam
(8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a]benzodiaz-
epine)
##STR00007##
[0108] Midazolam is a tricyclic benzodiazepine having anxiolytic,
amnesic, hypnotic, anticonvulsant, skeletal muscle relaxant and
sedative properties. Midazolam is considered soluble in water at a
pH lower than about 4, but is relatively insoluble in most aqueous
solutions at neutral pH (e.g. about 6 to 8). Accordingly,
nanoparticulates of midazolam may be formulated at or near neutral
pH. Thus it is desirable in some embodiments for aqueous nasal
preparations of midazolam to have a pH above about 5.5, preferably
above about 6.0, or above about 6.5. In some preferred embodiments,
the pH is between about 6 and 9, between about 6 and 8. It is
considered that nanoparticulate aqueous preparations of midazolam
are particularly suitable for nasal administration as the
lipid-soluble (at approximately neutral pH) midazolam particles are
rapidly absorbed across nasal mucosa, leading to efficient uptake
of midazolam. It is further considered that nanoparticulate
midazolam may be formulated in a non-aqueous delivery vehicle, such
as is known in the aerosol administration art, such as
hydrofluorocarbon propellants, hydrocarbon propellants, etc.
[0109] The dosage of midazolam varies by indication, however it is
expected that a therapeutic dose will be in the range of about 0.1
to about 20, preferably about 0.2 to about 10 mg per dose, from 1
to 8, preferably from 2 to 8, and in some preferred embodiments
about 4 to about 6 times per day. Midazolam may be manufactured
using the process disclosed in one of U.S. Pat. Nos. 4,280,957 or
5,831,089, each of which is incorporated herein by reference in its
entirety.
[0110] As a nasal formulation, midazolam may be administered in 25
to 250 .mu.l metered sprays. In some preferred embodiments,
midazolam is administered in 50 to 150 .mu.l, especially about 100
.mu.l, metered sprays. In some embodiments, a first metered spray
is applied to a first nostril and if necessary a second metered
spray is applied to a second nostril. In some optional embodiments,
a third metered spray is applied to the first nostril. In some
further embodiments, a fourth metered spray is applied to the
second nostril. In some embodiments, additional metered sprays are
applied to alternating nostrils until the full target therapeutic
dose has been administered to the patient. In some embodiments,
there is a time increment of from several seconds to 5 minutes,
preferably about 10 seconds to about 1 minute, between applications
of benzodiazepine drug to the same nostril. This allows time for
the drug to cross the nasal mucosa and enter the blood stream.
Multiple applications of metered sprays to each nostril, optionally
separated by a time interval, allows administration of a full
therapeutic dose in increments small enough to permit full
absorption of the benzodiazepine drug into the blood stream and
avoid loss of drug down the back of the throat.
[0111] Midazolam may be combined with other pharmaceutically active
ingredients, including other benzodiazepine compounds (such as
diazepam) in a benzodiazepine drug formulation. In some
embodiments, the ratio of midazolam to the other pharmaceutically
active ingredient is in one of the ranges from about 1:1000 to
about 1000:1, about 1:100 to about 100:1 or about 1:10 to about
10:1. In some embodiments, the other pharmaceutically active
ingredient is a benzodiazepine drug and the ratio of midazolam to
the other benzodiazepine drug is in one of the ranges from about
1:1000 to about 1000:1, about 1:100 to about 100:1 or about 1:10 to
about 10:1. In some embodiments, the other pharmaceutically active
ingredient is diazepam and the ratio of midazolam to diazepam is
about 1:1000 to about 1000:1, about 1:100 to about 100:1 or about
1:10 to about 10:1.
[0112] In some embodiments, Midazolam is used alone or in
combination with other drugs to provide an anxiolytic effect, an
anticonvulsant effect, a sedative effect, a skeletal muscle
relaxant effect, an amnesic effect or combinations of the foregoing
effects.
[0113] In some embodiments, Midazolam is used alone or in
combination with another anticonvulsant drug to treat seizure,
protect against seizure, reduce or ameliorate the intensity of
seizure, reduce or ameliorate the frequency of seizure, and/or
prevent occurrence or re-occurrence of seizure. Midazolam may be
administered by the patient or other person (such as a healthcare
professional) while the patient is in a non-seizing state to
protect against seizure. Even where protection against seizure is
not absolute, administration of midazolam may reduce or ameliorate
the intensity of seizure and/or reduce or ameliorate the frequency
of seizure. In some embodiments, administration of midazolam may
prevent occurrence of seizure. In some embodiments, especially
where the patient is prone to experiencing serial seizures or
status epilepticus, administration of midazolam may aid in
interrupting the seizure cycle and may thus prevent the
re-occurrence of seizure. In addition to the benzodiazepines (such
as diazepam), other anti-convulsant drugs may be combined with
midazolam to provide a synergistic anticonvulsant effect.
[0114] Midazolam may also be administered by another person (e.g.
an acquaintance or associate, a family member or a health care
professional) to the patient while the patient is in a state of
seizure. Thus, one of the advantages of the nasal formulations
according to the present invention is the ability to administer
them in an acute therapeutic environment to treat the seizure
victim. Among the beneficial therapeutic effects that may be
imparted by acute nasal dosing of benzodiazepine anticonvulsants
are: reduction in the severity of the seizure (e.g. general
relaxation of the muscles, reduction in seizure-induced anxiety
experienced by the patient and a general impartation of a feeling
of well-being to the patient), reduction in the duration of the
seizure, reduction in the probability that the patient will
experience a repeat seizure, an increase in the interval between
the current seizure and the next seizure. Thus the nasal midazolam
formulations of the invention provide fast onset of therapeutic
benefit--in some instances less than about 30 minutes, less than
about 15 minutes, less than about 10 minutes, and in some cases
less than about 5 minutes. The nasal midazolam formulations of the
invention also provide convenient administration of a
therapeutically beneficial drug to a patient that does not require
intravenous drug administration or rectal drug administration.
[0115] Often seizures, particularly severe tonic or tonic-clonic
seizures, will be presaged by one or more aura events that will be
familiar to the patient or those familiar with the patient. These
auras are practically sui generis for each patient, but may be
classified as audible, visual, olfactory or tactile sensations that
usually, or at least often, precede a patient's experiencing a
seizure. In some embodiments of the invention, the method includes
prompt administration of a nasal preparation of a benzodiazepine
drug according to the invention during the aura. In some
embodiments, such intra-aural administration of benzodiazepine drug
by the intra-nasal route will prevent or at least ameliorate the
effects (intensity, duration or both) of the impending seizure.
Thus, in the context of this invention, prevention of seizure
refers to a temporary forestalling of the onset of seizure, either
with or without the benefit of a warning aura.
Temazepam
(7-chloro-1-methyl-5-phenyl-3-hydroxy-1,3-dihydro-2H-1,4-benzodi-
azepin-2-one)
##STR00008##
[0117] Temazepam is a benzodiazepine drug having sedative,
tranquilizing, anticonvulsant, amnesic and muscle relaxing
properties. It is classified as an anxiolytic. Temazepam has also
been shown to be useful in the treatment of nausea. The dosage of
Temazepam varies by indication, however it is expected that a
therapeutic dose will be in the range of about 1 to about 50,
preferably about 5 to about 30 mg per dose, from 1 to 8, preferably
from 2 to 8, and in some preferred embodiments about 4 to about 6
times per day. Temazepam may be manufactured using the process
disclosed in U.S. Pat. No. 3,340,253 or 3,374,225, each of which is
incorporated herein by reference in its entirety.
[0118] As a nasal formulation, temazepam may be administered in 25
to 250 .mu.l metered sprays. In some preferred embodiments,
temazepam is administered in 50 to 150 .mu.l, especially about 100
.mu.l, metered sprays. In some embodiments, a first metered spray
is applied to a first nostril and if necessary a second metered
spray is applied to a second nostril. In some optional embodiments,
a third metered spray is applied to the first nostril. In some
further embodiments, a fourth metered spray is applied to the
second nostril. In some embodiments, additional metered sprays are
applied to alternating nostrils until the full target therapeutic
dose has been administered to the patient. In some embodiments,
there is a time increment of from several seconds to 5 minutes,
preferably about 10 seconds to about 1 minute, between applications
of benzodiazepine drug to the same nostril. This allows time for
the drug to cross the nasal mucosa and enter the blood stream.
Multiple applications of metered sprays to each nostril, optionally
separated by a time interval, allows administration of a full
therapeutic dose in increments small enough to permit full
absorption of the benzodiazepine drug into the blood stream and
avoid loss of drug down the back of the throat.
[0119] Temazepam may be combined with other pharmaceutically active
ingredients, including other benzodiazepine compounds (such as
diazepam) in a benzodiazepine drug formulation. In some
embodiments, the ratio of temazepam to the other pharmaceutically
active ingredient is in one of the ranges from about 1:1000 to
about 1000:1, about 1:100 to about 100:1 or about 1:10 to about
10:1. In some embodiments, the other pharmaceutically active
ingredient is a benzodiazepine drug and the ratio of temazepam to
the other benzodiazepine drug is in one of the ranges from about
1:1000 to about 1000:1, about 1:100 to about 100:1 or about 1:10 to
about 10:1. In some embodiments, the other pharmaceutically active
ingredient is diazepam and the ratio of temazepam to diazepam is
about 1:1000 to about 1000:1, about 1:100 to about 100:1 or about
1:10 to about 10:1.
[0120] In some embodiments, Temazepam is used alone or in
combination with other drugs to provide an anxiolytic effect, an
anticonvulsant effect, a sedative effect, a skeletal muscle
relaxant effect, an amnesic effect or combinations of the foregoing
effects.
[0121] In some embodiments, Temazepam is used alone or in
combination with another anticonvulsant drug to treat seizure,
protect against seizure, reduce or ameliorate the intensity of
seizure, reduce or ameliorate the frequency of seizure, and/or
prevent occurrence or re-occurrence of seizure. Temazepam may be
administered by the patient or other person (such as a healthcare
professional) while the patient is in a non-seizing state to
protect against seizure. Even where protection against seizure is
not absolute, administration of temazepam may reduce or ameliorate
the intensity of seizure and/or reduce or ameliorate the frequency
of seizure. In some embodiments, administration of temazepam may
prevent occurrence of seizure. In some embodiments, especially
where the patient is prone to experiencing serial seizures or
status epilepticus, administration of temazepam may aid in
interrupting the seizure cycle and may thus prevent the
re-occurrence of seizure. In addition to the benzodiazepines (such
as diazepam), other anti-convulsant drugs may be combined with
temazepam to provide a synergistic anticonvulsant effect.
[0122] Temazepam may also be administered by another person (e.g.
an acquaintance or associate, a family member or a health care
professional) to the patient while the patient is in a state of
seizure. Thus, one of the advantages of the nasal formulations
according to the present invention is the ability to administer
them in an acute therapeutic environment to treat the seizure
victim. Among the beneficial therapeutic effects that may be
imparted by acute nasal dosing of benzodiazepine anticonvulsants
are: reduction in the severity of the seizure (e.g. general
relaxation of the muscles, reduction in seizure-induced anxiety
experienced by the patient and a general impartation of a feeling
of well-being to the patient), reduction in the duration of the
seizure, reduction in the probability that the patient will
experience a repeat seizure, an increase in the interval between
the current seizure and the next seizure. Thus the nasal temazepam
formulations of the invention provide fast onset of therapeutic
benefit--in some instances less than about 30 minutes, less than
about 15 minutes, less than about 10 minutes, and in some cases
less than about 5 minutes. The nasal temazepam formulations of the
invention also provide convenient administration of a
therapeutically beneficial drug to a patient that does not require
intravenous drug administration or rectal drug administration.
[0123] Often seizures, particularly severe tonic or tonic-clonic
seizures, will be presaged by one or more aura events that will be
familiar to the patient or those familiar with the patient. These
auras are practically sui generis for each patient, but may be
classified as audible, visual, olfactory or tactile sensations that
usually, or at least often, precedes a patient's experiencing a
seizure. In some embodiments of the invention, the method includes
prompt administration of a nasal preparation of a benzodiazepine
drug according to the invention during the aura. In some
embodiments, such intra-aural administration of benzodiazepine drug
by the intra-nasal route will prevent or at least ameliorate the
effects (intensity, duration or both) of the impending seizure.
Thus, in the context of this invention, prevention of seizure
refers to a temporary forestalling of the onset of seizure, either
with or without the benefit of a warning aura.
[0124] In some embodiments, other drugs may be included in the
aerosol (nasal or pulmonary) formulations of the invention. For
example in the multimodal particulate compositions (e.g. the
bimodal particulate compositions), in addition to the herein
recited benzodiazepines (e.g. diazepam) that may be used, either
alone or in combination with one or more diazepines, include other
anticonvulsants, such as: paraldehyde; aromatic allylic alcohols
(such as stiripentol); barbiturates (e.g. phenobarbital, primidone,
methylphenobarbital, metharbital and barbexaclone); bromides (such
as potassium bromide); carbamates (such as felbamate); carboxamides
(such as carbamazepine and oxcarbazepine); fatty acids (such as
valproic acid, sodium valproate, and divalproex sodium, vigabatrin,
progabide, tiagabine); fructose, topiramate, Gaba analogs (e.g.
gabapentin and pregabalin); hydantoins (e.g. ethotoin, phenyloin,
mephenyloin and fosphenyloin); oxazolidinediones (such as
paramethadione, trimethadione, ethadione); propionates (e.g.
beclamide), pyrimidinediones (e.g. primidone); pyrrolidines (e.g.
brivaracetam, levetiracetam and seletracetam); succinimides (e.g.
ethosuximide, phensuximide and mesuximide); sulfonamides (e.g.
acetazolamide, sulthiame, methazolamide and zonisamide); triazines
(such as lamotrigine); ureas (such as pheneturide, phenacemide);
valproylamides (such as valpromide and valnoctamide); as well as
other anticonvulsants or pharmaceutically acceptable salts or
combinations thereof.
[0125] In some embodiments, other pharmaceutically active
ingredients that can be administered intranasally or pulmonarily
(especially as multimodal, e.g. bimodal particulate compositions)
either alone or in combination with one or more benzodiazepines
(such as diazepam) or other active pharmaceutical ingredient
include: insulin, calcitonins (for example porcine, human, salmon,
chicken, or eel) and synthetic modifications thereof, enkephalins,
LHRH and analogues (Nafarelin, Buserelin, Zolidex), GHRH (growth
hormone releasing hormone), nifedipin, THF (thymic humoral factor),
CGRP (calcitonin gene related peptide), atrial natriuretic peptide,
antibiotics, metoclopramide, ergotamine, Pizotizin, nasal vaccines
(particularly HIV vaccines, measles, rhinovirus Type 13 and
respiratory syncitial virus), pentamidine, CCK (Cholecystikinine),
DDVAP, Interferons, growth hormone (solatotropir polypeptides or
their derivatives (preferably with a molecular weight from 1000 to
300000), secretin, bradykinin antagonists, GRF (Growth releasing
factor), THF, TRH (Thyrotropin releasing hormone), ACTH analogues,
IGF (Insulin like growth factors), CGRP (Calcitorin gene related
peptide) Atrial Natriuretic peptide, Vasopressin and analogues
(DDAVP, Lypressin), Metoclopramide, Migraine treatment
(Dihydroergotamine, Ergometrine, Ergotamine, Pizotizin), Nasal
Vaccines (Particularly AIDS vaccines) FACTOR VIII, Colony
Stimulating factors, G-CSF (granulocyte-colony stimulating factor),
EPO (Erythropoitin) PTH (Parathyroid hormone) or pharmaceutically
acceptable salts or combinations thereof.
[0126] In some embodiments, other pharmaceutically active
ingredients that can be administered intranasally or pulmonarily
(especially as multimodal, e.g. bimodal particulate compositions)
either alone or in combination with one or more benzodiazepines
(such as diazepam) or other active pharmaceutical ingredient
include: antibiotics and antimicrobial agents such as tetracyline
hydrochloride, leucomycin, penicillin, penicillin derivatives,
erythromycin, gentamicin, sulphathiazole and nitrofurazone; local
anaesthetics such as benzocaine; vasoconstrictors such as
phenylephrine hydrochloride, tetrahydrozoline hydrochloride,
naphazoline nitrate, oxymetazoline hydrochloride and tramazoline
hydrochloride; cardiotonics such as digitalis and digoxin;
vasodilators such as nitroglycerine and papaverine hydrochloride;
antiseptics such as chlorhexidine hydrochloride, hexylresorcinol,
dequaliniumchloride and ethacridine; enzymes such as lysozyme
chloride, dextranase; bone metabolism controlling agents such as
vitamin D, active vitamin D and vitamin C; sex hormones;
hypotensives; sedatives; anti-tumor agents; steroidal
anti-inflammatory agents such as hydrocortisone, prednisone,
fluticasone, prednisolone, triamcinolone, triamcinolone acetonide,
dexamethasone, betamethasone, beclomethasone, and beclomethasone
dipropionate; non-steroidal anti-inflammatory agents such as
acetaminophen, aspirin, aminopyrine, phenylbutazone, medanamic
acid, ibuprofen, diclofenac sodium, indomethacine, colchicine, and
probenocid; enzymatic anti-inflammatory agents such as chymotrypsin
and bromelain seratiopeptidase; anti-histaminic agents such as
diphenhydramine hydrochloride, chloropheniramine maleate and
clemastine; anti-allergic agents and antitussive-expectorant
antasthmatic agents such as sodium chromoglycate, codeine
phosphate, and isoproterenol hydrochloride or pharmaceutically
acceptable salts or combinations thereof.
[0127] In some embodiments, the molecular weight of the drug is
preferably in the range 100 to 300,000, although drugs with other
molecular weights may be employed in some embodiments.
[0128] In order to improve the properties, appearance or odor of
the pharmaceutical composition, it may, in some embodiments,
contain any of known additives such as coloring agents,
preservatives, antiseptics, etc. Examples of coloring agents
include .beta.-carotene, Red No. 2 and Blue No. 1; examples of
preservatives include stearic acid, ascorbyl stearate and ascorbic
acid; examples of antiseptics include p-hydroxy-benzoate, phenol,
chlorobutanol, benzylkonium chloride etc.; and examples of
corrigents include menthol and citrus perfume.
[0129] In some embodiments, the drug delivery system of the
invention may advantageously comprise an absorption enhancer. The
term "enhancer", means any material which acts to increase
absorption across the mucosa and/or increases bioavailability. In
some embodiments, such materials include mucolytic agents,
degradative enzyme inhibitors and compounds which increase
permeability of the mucosal cell membranes. Whether a given
compound is an "enhancer" can be determined by comparing two
formulations comprising a non-associated, small polar molecule as
the drug, with or without the enhancer, in an in vivo or good model
test and determining whether the uptake of the drug is enhanced to
a clinically significant degree. The enhancer should not produce
any problems in terms of chronic toxicity because in vivo the
enhancer should be non-irritant and/or rapidly metabolized to a
normal cell constituent that does not have any significant irritant
effect.
[0130] In some embodiments, preferred enhancing materials
lysophospholipids, for example lysophosphatidylcholine obtainable
from egg or soy lecithin. Other lysophosphatidylcholines that have
different acyl groups as well as lyso compounds produced from
phosphatidylethanolamines and phosphatidic acid which have similar
membrane modifying properties may be used. Acyl carnitines (e.g.
palmitoyl-dl-carnitine-chloride) is an alternative. In some
embodiments, a suitable concentration is from 0.02 to 20% w/v.
[0131] In some embodiments, enhancing agents that are appropriate
include chelating agents (EGTA, EDTA, alginates), surface active
agents (especially non-ionic materials), acyl glycerols, fatty
acids and salts, tyloxapol and biological detergents listed in the
SIGMA Catalog, 1988, page 316-321 (which is incorporated herein by
reference). Also agents that modify the membrane fluidity and
permeability are appropriate such as enamines (e.g. phenylalanine
enamine of ethylacetoacetate), malonates (e.g.
diethyleneoxymethylene malonate), salicylates, bile salts and
analogues and fusidates. Suitable concentrations are up to 20%
w/v.
[0132] In some embodiments, the invention takes advantage of
delivery of a drug incorporated into or onto a bioadhesive
microsphere with an added pharmaceutical adjuvant applies to
systems that contain active drug and mucolytic agent, peptidase
inhibitors or non-drug polypeptide substrate singly or in
combination. Suitably mucolytic agents are thiol-containing
compounds such as N-acetylcysteine and derivatives thereof. Peptide
inhibitors include actinonin, amastatin, bestatin,
chloroacetyl-HOLeu-Ala-Gly-NH.sub.2, diprotin A and B, ebelactone A
and B, E-64, leupeptin, pepstatin A, phisphoramidon,
H-Thr-(tBu)-Phe-Pro-OH, aprotinin, kallikrein, chymostatin,
benzamidine, chymotrypsin and trypsin. Suitable concentrations are
from 0.01 to 10% w/v. The person skilled in the art will readily be
able to determine whether an enhancer should be included.
[0133] Other Active Pharmaceutical Ingredients
[0134] Other active pharmaceutical ingredients that may be
formulated as multimodal nanoparticulate formulations, surface
active agent-coated nanoparticulate formulations and non-aqueous
nanoparticulate suspension according to embodiments of the
invention include those active pharmaceutical ingredients that
penetrate the mucosa of the lungs, nasal cavity, oropharyngeal
surfaces and/or the gastrointestinal tract. Especially suitable are
those active pharmaceutical ingredients that are subject to rapid
degradation in the liver, as absorption of active ingredient across
the nasal and pulmonary mucosa permits the active ingredient to
avoid the portal vein, thereby greatly reducing the first-pass
effect. Suitable active pharmaceutical ingredients include: other
anticonvulsants, such as: paraldehyde; aromatic allylic alcohols
(such as stiripentol); barbiturates (e.g. phenobarbital, primidone,
methylphenobarbital, metharbital and barbexaclone); bromides (such
as potassium bromide); carbamates (such as felbamate); carboxamides
(such as carbamazepine and oxcarbazepine); fatty acids (such as
valproic acid, sodium valproate, and divalproex sodium, vigabatrin,
progabide, tiagabine); topiramate, Gaba analogs (e.g. gabapentin
and pregabalin); hydantoins (e.g. ethotoin, phenyloin, mephenyloin
and fosphenyloin); oxazolidinediones (such as paramethadione,
trimethadione, ethadione); propionates (e.g. beclamide),
pyrimidinediones (e.g. primidone); pyrrolidines (e.g. brivaracetam,
levetiracetam and seletracetam); succinimides (e.g. ethosuximide,
phensuximide and mesuximide); sulfonamides (e.g. acetazolamide,
sulthiame, methazolamide and zonisamide); triazines (such as
lamotrigine); ureas (such as pheneturide, phenacemide);
valproylamides (such as valpromide and valnoctamide); as well as
other anticonvulsants or pharmaceutically acceptable salts or
combinations thereof.
[0135] In some embodiments, other pharmaceutically active
ingredients that can be administered intranasally or pulmonarily
(especially as multimodal, e.g. bimodal particulate compositions)
either alone or in combination with one or more benzodiazepines
(such as diazepam) or other active pharmaceutical ingredient
include: insulin, calcitonins (for example porcine, human, salmon,
chicken, or eel) and synthetic modifications thereof, enkephalins,
LHRH and analogues (Nafarelin, Buserelin, Zolidex), GHRH (growth
hormone releasing hormone), nifedipin, THF (thymic humoral factor),
CGRP (calcitonin gene related peptide), atrial natriuretic peptide,
antibiotics, metoclopramide, ergotamine, Pizotizin, nasal vaccines
(particularly HIV vaccines, measles, rhinovirus Type 13 and
respiratory syncitial virus), pentamidine, CCK (Cholecystikinine),
DDVAP, Interferons, growth hormone (solatotropir polypeptides or
their derivatives (preferably with a molecular weight from 1000 to
300000), secretin, bradykinin antagonists, GRF (Growth releasing
factor), THF, TRH (Thyrotropin releasing hormone), ACTH analogues,
IGF (Insulin like growth factors), CGRP (Calcitorin gene related
peptide) Atrial Natriuretic peptide, Vasopressin and analogues
(DDAVP, Lypressin), Metoclopramide, Migraine treatment
(Dihydroergotamine, Ergometrine, Ergotamine, Pizotizin), Nasal
Vaccines (Particularly AIDS vaccines) FACTOR VIII, Colony
Stimulating factors, G-CSF (granulocyte-colony stimulating factor),
EPO (Erythropoitin) PTH (Parathyroid hormone) or pharmaceutically
acceptable salts or combinations thereof.
[0136] In some embodiments, other pharmaceutically active
ingredients that can be administered intranasally or pulmonarily
(especially as multimodal, e.g. bimodal particulate compositions)
either alone or in combination with one or more benzodiazepines
(such as diazepam) or other active pharmaceutical ingredient
include: pain medications, such as prochloroperazine,
acetaminophen, fentanyl, hydrocodone, etodolac, oxycodone, naproxen
sodium, butorphanol, ketoprofen, nalbuphine, pentazocine,
ibuprofen, diclofenac, meperidine, oxymorphone, butalbital,
propoxyphene, gabapentin, and/or indomethacine; barbiturates, such
as mephobarbitol, and/or pentobarbital; antiinsomnia drugs, such as
zolpidem, zaleplon, eszopiclone, doxepine; drugs for treating
addiction, such as methadone, buprenorphine, naltrexone, naloxone;
antibiotics and antimicrobial agents such as tetracyline
hydrochloride, leucomycin, penicillin, penicillin derivatives,
erythromycin, gentamicin, sulphathiazole and nitrofurazone; local
anaesthetics such as benzocaine; vasoconstrictors such as
phenylephrine hydrochloride, tetrahydrozoline hydrochloride,
naphazoline nitrate, oxymetazoline hydrochloride and tramazoline
hydrochloride; cardiotonics such as digitalis and digoxin;
vasodilators such as nitroglycerine and papaverine hydrochloride;
antiseptics such as chlorhexidine hydrochloride, hexylresorcinol,
dequaliniumchloride and ethacridine; enzymes such as lysozyme
chloride, dextranase; bone metabolism controlling agents such as
vitamin D, active vitamin D and vitamin C; sex hormones;
hypotensives; sedatives; anti-tumor agents; steroidal
anti-inflammatory agents such as hydrocortisone, prednisone,
fluticasone, prednisolone, triamcinolone, triamcinolone acetonide,
dexamethasone, betamethasone, beclomethasone, and beclomethasone
dipropionate; non-steroidal anti-inflammatory agents such as
acetaminophen, aspirin, aminopyrine, phenylbutazone, medanamic
acid, ibuprofen, diclofenac sodium, indomethacine, colchicine, and
probenocid; enzymatic anti-inflammatory agents such as chymotrypsin
and bromelain seratiopeptidase; anti-histaminic agents such as
diphenhydramine hydrochloride, chloropheniramine maleate and
clemastine; anti-allergic agents and antitussive-expectorant
antasthmatic agents such as sodium chromoglycate, codeine
phosphate, and isoproterenol hydrochloride; drugs for treating
spasticity, such as baclofen, dantrolene, tizanidine, phenol,
clonidine, gabapentin and/or acamprosate; antiemetics, such as
dolasetron, granisetron, ondansetron, tropisetron, palonosetron,
domperidone, droperidol, haloperidol, chlorpromazine, promethazine,
prochlorperazine, metoclopramide, alizapride, cyclizine,
diphenhydramine, dimenhydrinate, meclizine, promethazine,
hydroxyzine, and/or one or more cannabinoids; antipsychotics, such
as haloperidol, chlorpromazine, fluphenazine, perphenazine,
prochlorperazine, thioridazine, trifluoperazine, mesoridazine,
promazine, triflupromazine, levomepromazine, promethazine,
chlorprothixene, flupenthixol, thiothixene, zuclopenthixol,
clozapine, olanzapine, risperidone, quetiapine, ziprasidone,
amisulpride, and/or asenapine; short-acting Beta.sub.2-adrenergic
agonists, such as salbutamol (albuterol), levosalbutamol,
terbutaline, pirbuterol, procaterol, metaproerenol, fenoterol,
and/or bitolterol mesylate, long-acting Beta.sub.2-adrenergic
agonists, such as salmeterol, formoterol, bambuterol, clenbuterol,
and/or indacaterol; muscarinic antagonists, such as atropine,
scopolamine, ipratropium, tropicamide, pirenzepine,
diphenhydramine, dimenhydrinate, dicyclomine, flavoxate,
tiotropium, cyclopentolate, atropine methonitrate,
trihexylphenidyl, tolterodine, solifenacin, darifenacin,
benatropine, and/or mebeverine; corticosteroids, such as
beclomethasone, budesonide, flunisolide, fluticasone, mometasone,
and/or triamcinolone; atypical antipsychotic medications, such as
clozapine, risperidone, olanzapine, quetiapine, ziprasidone,
aripiprazole, paliperidone, asenapine, iloperidone, sertindole,
zotepine, amisulpride, bifenprunox, and/or melperone; selective
serotonin reuptake inhibitors (SSRIs), such as citalopram,
dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine,
sertraline; tricyclic antidepressants, such as amitriptyline,
amoxapine, clomipramine, desipramine, dosulepin hydrochloride,
doxepin, imipramine, iprindole, lofepramine, nortriptyline,
opipramol, protriptyline, and/or trimipramine; serotonin
norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine,
desvenlafaxine, sibutramine, nefazodone, milnacipran, desipramine,
duloxetine, and/or bicifadine; zimelidine; or pharmaceutically
acceptable salts or combinations thereof.
[0137] In some embodiments, other pharmaceutically active
ingredients that can be administered intranasally or pulmonarily
(especially as multimodal, e.g. bimodal particulate compositions)
either alone or in combination with one or more benzodiazepines
(such as diazepam) or other active pharmaceutical ingredient
include anticancer or antiproliferative chemotherapeutic agents
such as: aminoglutethimide, amsacrine, anastrozole, asparaginase,
bcg, bicalutamide, bleomycin, buserelin, busulfan, campothecin,
capecitabine, carboplatin, carmustine, chlorambucil, cisplatin,
cladribine, clodronate, colchicine, cyclophosphamide, cyproterone,
cytarabine, dacarbazine, dactinomycin, daunorubicin, dienestrol,
diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol,
estramustine, etoposide, exemestane, filgrastim, fludarabine,
fludrocortisone, fluorouracil, fluoxymesterone, flutamide,
gemcitabine, genistein, goserelin, hydroxyurea, idarubicin,
ifosfamide, imatinib, interferon, irinotecan, ironotecan,
letrozole, leucovorin, leuprolide, levamisole, lomustine,
mechlorethamine, medroxyprogesterone, megestrol, melphalan,
mercaptopurine, mesna, methotrexate, mitomycin, mitotane,
mitoxantrone, nilutamide, nocodazole, octreotide, oxaliplatin,
paclitaxel, pamidronate, pentostatin, plicamycin, porfimer,
procarbazine, raltitrexed, rituximab, streptozocin, suramin,
tamoxifen, temozolomide, teniposide, testosterone, thioguanine,
thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin,
vinblastine, vincristine, vindesine, and vinorelbine.
[0138] In some embodiments, other pharmaceutically active
ingredients that can be administered intranasally or pulmonarily
(especially as multimodal, e.g. bimodal particulate compositions)
either alone or in combination with one or more benzodiazepines
(such as diazepam) or other active pharmaceutical ingredient
include: Anti-angiogenesis agents, such as MMP-2
(matrix-metalloprotienase 2) inhibitors, MMP-9
(matrix-metalloprotienase 9) inhibitors, and COX-11 (cyclooxygenase
11) inhibitors, can be used in conjunction with the compound of the
present invention and pharmaceutical compositions described herein.
Examples of useful COX-II inhibitors include CELEBREX.TM.
(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrix
metalloproteinase inhibitors are described in WO 96/33172
(published Oct. 24, 1996), WO 96/27583 (published Mar. 7, 1996),
European Patent Application No. 97304971.1 (filed Jul. 8, 1997),
European Patent Application No. 99308617.2 (filed Oct. 29, 1999),
WO 98/07697 (published Feb. 26, 1998), WO 98/03516 (published Jan.
29, 1998), WO 98/34918 (published Aug. 13, 1998), WO 98/34915
(published Aug. 13, 1998), WO 98/33768 (published Aug. 6, 1998), WO
98/30566 (published Jul. 16, 1998), European Patent Publication
606,046 (published Jul. 13, 1994), European Patent Publication 931,
788 (published Jul. 28, 1999), WO 90/05719 (published May 31,
1990), WO 99/52910 (published Oct. 21, 1999), WO 99/52889
(published Oct. 21, 1999), WO 99/29667 (published Jun. 17, 1999),
PCT International Application No. PCT/IB98/01113 (filed Jul. 21,
1998), European Patent Application No. 99302232.1 (filed Mar. 25,
1999), Great Britain Patent Application No. 9912961.1 (filed Jun.
3, 1999), U.S. Provisional Application No. 60/148,464 (filed Aug.
12, 1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S.
Pat. No. 5,861,510 (issued Jan. 19, 1999), and European Patent
Publication 780,386 (published Jun. 25, 1997), all of which are
incorporated herein in their entireties by reference. Preferred
MMP-2 and MMP-9 inhibitors are those that have little or no
activity inhibiting MMP-1. More preferred, are those that
selectively inhibit MMP-2 and/or AMP-9 relative to the other
matrix-metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6,
MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific
examples of MMP inhibitors useful in the present invention are
AG-3340, RO 32-3555, and RS 13-0830.
[0139] In some embodiments, the molecular weight of the drug is
preferably in the range 100 to 300,000, although drugs with other
molecular weights may be employed in some embodiments.
Surface Active Agents (Surface Stabilizers; Surface Modifiers;
Surfactants)
[0140] In some embodiments, surface active agents, which can also
be referred to as surface stabilizers, surface modifiers or
surfactants, can preferably be selected from known organic and
inorganic pharmaceutical excipients. Such excipients may include
polymers, low molecular weight oligomers, natural products, and
surfactants. In some embodiments, surface active agents include
nonionic or ionic surfactants.
[0141] In some embodiments, surface active agents include gelatin,
casein, lecithin (phosphatides), dextran, gum acacia, cholesterol,
tragacanth, stearic acid, benzalkonium chloride, calcium stearate,
glycerol monostearate, cetostearyl alcohol, cetomacrogol
emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers
(e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene
castor oil derivatives, polyoxyethylene sorbitan fatty acid esters
(e.g., the commercially available Tweens.RTM. such as e.g., TWEEN
20.RTM. and TWEEN 80.RTM. (ICI Specialty Chemicals)); polyethylene
glycols (e.g., Carbowaxes 3550.RTM. and 934.RTM. (Union Carbide)),
polyoxyethylene stearates, colloidal silicon dioxide, phosphates,
sodium dodecylsulfate, carboxymethylcellulose calcium,
carboxymethylcellulose sodium, methylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose phthalate, noncrystalline cellulose,
magnesium aluminum silicate, triethanolamine, polyvinyl alcohol
(PVA), polyvinylpyrrolidone (PVP),
4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and
formaldehyde (also known as tyloxapol, superione, and triton),
poloxamers (e.g., Pluronics F68.RTM. and F108.RTM., which are block
copolymers of ethylene oxide and propylene oxide); poloxamines
(e.g., Tetronic 908.RTM., also known as Poloxamine 908.RTM., which
is a tetrafunctional block copolymer derived from sequential
addition of propylene oxide and ethylene oxide to ethylenediamine
(BASF Wyandotte Corporation, Parsippany, N.J.)); Tetronic 1508.RTM.
(T-1508) (BASF Wyandotte Corporation), dialkylesters of sodium
sulfosuccinic acid (e.g., Aerosol OT.RTM., which is a dioctyl ester
of sodium sulfosuccinic acid (American Cyanamid)); Duponol P.RTM.,
which is a sodium lauryl sulfate (DuPont); Tritons X-200.RTM.,
which is an alkyl aryl polyether sulfonate (Rohm and Haas);
Crodestas F-110.RTM., which is a mixture of sucrose stearate and
sucrose distearate (Croda Inc.); p-isononylphenoxypoly-(glycidol),
also known as Olin-10G.RTM. or Surfactant 10-G.RTM. (Olin
Chemicals, Stamford, Conn.); Crodestas SL-40.RTM. (Croda, Inc.);
and SA9OHCO, which is
C.sub.18H.sub.37CH.sub.2(CON(CH.sub.3)--CH.sub.2(CHOH).sub.4(CH.sub.2OH).-
sub.2 (Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl
.beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside;
n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside;
heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside;
n-heptyl .beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside;
nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside;
octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl
.beta.-D-thioglucopyranoside; etc.
[0142] In some embodiments, surface active agents include one or
more of: hypromellose, hydroxypropylcellulose,
polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate,
gelatin, casein, lecithin, dextran, gum acacia, cholesterol,
tragacanth, stearic acid, benzalkonium chloride, calcium stearate,
glycerol monostearate, cetostearyl alcohol, cetomacrogol
emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers,
polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan
fatty acid esters, polyethylene glycols, polyoxyethylene stearates,
colloidal silicon dioxide, phosphates, carboxymethylcellulose
calcium, carboxymethylcellulose sodium, methylcellulose,
hydroxyethylcellulose, hypromellose phthalate, noncrystalline
cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl
alcohol, tyloxapol, poloxamers, poloxamines, Tetronic 1508.RTM., an
alkyl aryl polyether sulfonate, a mixture of sucrose stearate and
sucrose distearate, p-isononylphenoxypoly-(glycidol), Crodestas
SL-40.RTM. (Croda, Inc.); and SA9OHCO, decanoyl-N-methylglucamide;
n-decyl (-D-glucopyranoside; n-decyl (-D-maltopyranoside; n-dodecyl
(-D-glucopyranoside; n-dodecyl (-D-maltoside;
heptanoyl-N-methylglucamide; n-heptyl-(-D-glucopyranoside; n-heptyl
(-D-thioglucoside; n-hexyl (-D-glucopyranoside;
nonanoyl-N-methylglucamide; n-noyl (-D-glucopyranoside;
octanoyl-N-methylglucamide; n-octyl-(-D-glucopyranoside; octyl
(-D-thioglucopyranoside; PEG-phospholipid, PEG-cholesterol,
PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme,
random copolymers of vinyl pyrrolidone and vinyl acetate, cationic
polymers, cationic biopolymers, cationic polysaccharides, cationic
cellulosics, cationic alginates, cationic phospholipids, cationic
nonpolymeric compounds, poly-n-methylpyridinium, anthryul
pyridinium chloride, cationic phospholipids, chitosan, polylysine,
polyvinylimidazole, polybrene, polymethylmethacrylate
trimethylammoniumbromide bromide, hexyldesyltrimethylammonium
bromide, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate
dimethyl sulfate, cationic lipids, sulfonium, phosphonium,
quarternary ammonium compounds, stearyltrimethylammonium chloride,
benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl
ammonium chloride, coconut trimethyl ammonium bromide, coconut
methyl dihydroxyethyl ammonium chloride, coconut methyl
dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride,
decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl
hydroxyethyl ammonium bromide, C.sub.12-15dimethyl hydroxyethyl
ammonium chloride, C1.sub.2-15dimethyl hydroxyethyl ammonium
bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut
dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium
methyl sulfate, lauryl dimethyl benzyl ammonium chloride, lauryl
dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy).sub.4
ammonium chloride, lauryl dimethyl (ethenoxy).sub.4 ammonium
bromide, N-alkyl (C.sub.12-18)dimethylbenzyl ammonium chloride,
N-alkyl (C.sub.14-10)dimethyl-benzyl ammonium chloride,
N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl
didecyl ammonium chloride, N-alkyl and (C.sub.12-14) dimethyl
1-napthylmethyl ammonium chloride, trimethylammonium halide,
alkyl-trimethylammonium salts, dialkyl-dimethylammonium salts,
lauryl trimethyl ammonium chloride, ethoxylated
alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl
ammonium salt, dialkylbenzene dialkylammonium chloride,
N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl
ammonium, chloride monohydrate, N-alkyl(C.sub.12-14) dimethyl
1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium
chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl
ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl
benzyl dimethyl ammonium bromide, C.sub.12, C.sub.15, C.sub.17
trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium
chloride, poly-diallyldimethylammonium chloride, dimethyl ammonium
chlorides, alkyldimethylammonium halogenides, tricetyl methyl
ammonium chloride, decyltrimethylammonium bromide,
dodecyltriethylammonium bromide, tetradecyltrimethylammonium
bromide, methyl trioctylammonium chloride, POLYQUAT,
tetrabutylammonium bromide, benzyl trimethylammonium bromide,
choline esters, benzalkonium chloride, stearalkonium chloride
compounds, cetyl pyridinium bromide, cetyl pyridinium chloride,
halide salts of quaternized polyoxyethylalkylamines, MIRAPOL,
ALKAQUAT, alkyl pyridinium salts, amines, alkylamines,
dialkylamines, alkanolamines, polyethylenepolyamines,
N,N-dialkylaminoalkyl acrylates, vinyl pyridine, amine salts,
lauryl amine acetate, stearyl amine acetate, alkylpyridinium salt,
alkylimidazolium salt, amine oxides, imide azolinium salts,
protonated quaternary acrylamides, methylated quaternary polymers,
and cationic guar.
[0143] Thus, in some embodiments, the invention provides a
pharmaceutical composition of an anticonvulsant agent comprising
solid particles of the agent coated with one or more surface
modifiers, wherein the particles have an average effective particle
size of less than about 50 nm to less than about 1000 nm. In some
embodiments, the surface modifier is selected from the group
consisting of: anionic surfactants, cationic surfactants,
zwitterionic surfactants, nonionic surfactants, surface active
biological modifiers, and combinations thereof. In some
embodiments, the anionic surfactant is selected from the group
consisting of: alkyl sulfonates, alkyl phosphates, triethanolamine
stearate, sodium lauryl sulfate, sodium dodecylsulfate, alkyl
polyoxyethylene sulfates, sodium alginate, dioctyl sodium
sulfosuccinate, sodium carboxymethylcellulose, and calcium
carboxymethylcellulose. In some embodiments, the cationic
surfactant is selected from the group consisting of quaternary
ammonium compounds, benzalkonium chloride,
dimethylaminoethanecarbamoyl cholesterol, alkyl pyridinium halides,
n-octylamine and oleylamine. In some embodiments, the anionic
surfactant is a natural or synthetic phospholipid. In some
embodiments, the cationic surfactant is a natural or synthetic
phospholipid. In some embodiments, the zwitterionic surfactant is a
phospholipid, and wherein the phospholipid is natural or synthetic.
In some embodiments, the nonionic surfactant is selected from the
group consisting of: polyoxyethylene fatty alcohol ethers,
polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty
acid esters, sorbitan esters, glycerol monostearate, polyethylene
glycols, polypropylene glycols, cetyl alcohol, cetostearyl alcohol,
aryl alkyl polyether alcohols, polyoxyethylene-polyoxypropylene
copolymers, poloxamines, methylcellulose, hydroxycellulose, hydroxy
propylcellulose, hydroxy propylmethylcellulose, noncrystalline
cellulose, polysaccharides, starch, starch derivatives,
hydroxyethylstarch, polyvinyl alcohol, and polyvinylpyrrolidone. In
some embodiments, the surface active biological modifier is
selected from the group consisting of proteins, polysaccharides,
and combinations thereof. In some embodiments, the polysaccharide
is selected from the group consisting of starches, heparin and
chitosans. In some embodiments, the protein is selected from the
group consisting of albumin and casein. In some embodiments, the
surface modifier comprises a copolymer of oxyethylene and
oxypropylene. In some embodiments, the copolymer of oxyethylene and
oxypropylene is a block copolymerize, the anticonvulsant agent is a
tricyclic anticonvulsant agent. In some embodiments, the tricyclic
anticonvulsant agent is carbamazepine, diazepam, lorazepam,
midazolam or clonazepam. In some embodiments, the anticonvulsant
agent is a phenyltriazine. In some embodiments, the anticonvulsant
agent is lamotrigine. In some embodiments, the antidementia agent
alprazolam. In some embodiments, the anticonvulsant is the
antidementia agent risperidone. In some embodiments, the
anticonvulsant is the antidementia agent sertraline.
Pharmaceutically Acceptable Salts
[0144] Benzodiazepines have the generally basic structure:
##STR00009##
wherein R.sub.1-R.sub.5 are substituents. In particular
embodiments, R.sub.1 is an optionally substituted alkyl or forms a
ring with R.sub.4, R.sub.2 is a halogen (e.g. Cl, Br), R.sub.3 is
optionally substituted aryl (e.g. 2-Chloro or 2-Fluorophenyl),
R.sub.5 is H or OH, R.sub.4 and R.sub.4' together form a carbonyl
(C.dbd.O) with the carbon to which they are attached or R.sub.4 and
R.sub.1 form an optionally substituted heterocyclic ring with the
diazepine ring atoms to which they are respectively attached;
R.sub.3' and R.sub.6 together form a double bond or may be combined
to form an optionally substituted heterocyclic ring along with the
diazepine ring atoms to which they are respectively attached. Such
basic compounds may form acid addition salts with pharmaceutically
acceptable acids, such as pharmaceutically acceptable mineral acids
and pharmaceutically acceptable organic acids.
[0145] Pharmaceutically acceptable mineral acids include HCl,
H.sub.2SO.sub.4, H.sub.2SO.sub.3, H.sub.3PO.sub.4, H.sub.3PO.sub.3,
etc. Pharmaceutically acceptable organic acids include acetic acid,
benzoic acid, tartaric acid, citric acid, oxalic acid, maleic acid,
malonic acid, etc. Thus, in some embodiments, the pharmaceutically
acceptable acid may be selected from the group consisting of:
1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,
2-hydroxyethanesulfonic acid, 2-oxoglutaric acid,
4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic
acidascorbic acid (L), aspartic acid (L), benzenesulfonic acid,
benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+),
capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic
acid (octanoic acid), carbonic acid, cinnamic acid, citric acid,
cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid,
ethanesulfonic acid, formic acidfumaric acid, galactaric acid,
gentisic acid, glucoheptonic acid (D), gluconic acid (D),
glucuronic acid (D), glutamic acid, glutaric acid,
glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic
acid, hydrochloric acid, isobutyric acid, lactic acid (DL),
lactobionic acid, lauric acid, maleic acid, malic acid (-L),
malonic acid, mandelic acid (DL), methanesulfonic acid,
benzenesulfonic acid (besylic acid), naphthalene-1,5-disulfonic
acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid,
oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric
acid, proprionic acid, pyroglutamic acid (-L), salicylic acid,
sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric
acid (+L), thiocyanic acid, toluenesulfonic acid (p) and
undecylenic acid. Other pharmaceutically acceptable acids may be
pharmaceutically acceptable acidic (anionic) polymers or
pharmaceutically acceptable amphoteric polymers. One skilled in the
art will recognize that other basic active pharmaceutical
ingredients may be combined with the foregoing acids to produce
acid addition salts. Likewise the person skilled in the art will
recognize that in some embodiments it may be advantageous that some
or all of the added acid be an active pharmaceutical ingredient in
its own right.
[0146] In some embodiments, the invention provides nanoparticulate
nasal compositions comprising one or more acidic pharmaceutically
active ingredients. It is considered well within the ordinary skill
in the art to determine which of the compounds set for the above
are acidic. Such compounds may be prepared as base addition salts,
e.g. by the addition of one or more mineral bases (e.g. NaOH, KOH,
NaHCO.sub.3, Na.sub.2CO.sub.3, NH.sub.3) or organic bases. It is
considered within the skill in the art to choose a pharmaceutically
acceptable base.
[0147] Known benzodiazepine compounds have anxiolytic,
anticonvulsant, sedative and/or skeletal muscle relaxant effect.
The term "anticonvulsant" includes treatment of seizures,
protection against seizure, reduction or amelioration of the
intensity of seizure, reduction or amelioration of the frequency of
seizure, and/or prevention of the occurrence or re-occurrence of
seizure. In this regard, treatment of seizure includes cessation of
an ongoing seizure, reduction in the severity of an ongoing
seizure, reduction in the duration of an ongoing seizure.
Protection against seizure includes forestalling an oncoming
seizure.
[0148] The term "seizure" includes commonly recognized types of
seizures, including absence seizures, myoclonic seizures, clonic
seizures, tonic seizures, tonic-clonic seizures, and atonic
seizures. Often seizures, particularly severe tonic or tonic-clonic
seizures, will be presaged by one or more aura that will be
familiar to the patient or those familiar with the patient. Each
patient will generally experience a different type of aura, which
is unique to the patient; however auras may be classified as
audible, visual, olfactory or tactile sensations that usually, or
at least often, precedes a patient's experiencing a seizure. (Not
all patients who suffer seizures experience aura; however aura are
not uncommon amongst those who suffer the worst type of seizures,
especially tonic-clonic seizures.) In some embodiments of the
invention, the method includes prompt administration of a nasal
preparation of a benzodiazepine drug according to the invention
during a period when a patient is experiencing an aura. In some
embodiments, such intra-aural administration of benzodiazepine drug
by the intra-nasal route will prevent onset of the seizure or may
at least ameliorate the effects--e.g. intensity, duration or
both--of the seizure. In other embodiments, a patient who has a
history of seizure may administer the intranasal drug periodically,
and in particular at periodic intervals, to prevent the onset of
seizures, to lessen the frequency of seizures, to reduce the
severity of seizures, or to provide a combined reduction in
severity and frequency of seizures. Thus, in the context of this
invention, prevention of seizure refers to a temporary forestalling
of the onset of seizure, either with or without the benefit of a
warning aura. Treatment of seizure refers to the reduction of
seizure intensity, duration or both.
Modes of Administration
[0149] Medicaments comprising a pharmaceutical particulate
composition having a multimodal particle size distribution can be
administered by various modes of delivery, including nasal and
pulmonary modes of delivery. In some embodiments, the invention
provides methods of using a pharmaceutical particulate composition
for nasal delivery of a medicament comprising particulates having a
multimodal particle size distribution. In some embodiments, some
embodiments, the invention provides methods of using a
pharmaceutical particulate composition for pulmonary delivery of a
medicament comprising particulates having a multimodal particle
size distribution.
[0150] Nasal Administration
[0151] In some embodiments, there are provided nasal drug dosages.
Nasal dosages according to the invention can be administered as a
nasal spray or nasal drop, although presently preferred embodiments
are nasal sprays. Nasal sprays may be liquid or solid nasal sprays.
The nasal sprays may be aerosol or non-aerosol nasal sprays. There
are three currently preferred types of nasal delivery system: 1)
aerosolized metered dose pumps, 2) manual metered dose pumps, and
3) metered dose spray-producing squeeze bottles. Each of these is
effective in providing for the rapid absorption of medicinal
compounds into the blood stream. In some embodiments, e.g. in the
case of an unconscious patient experiencing a seizure, the
aerosolized metered dose pump connected to a close fitting plastic
mask covering the nose and mouth (such as is commonly used to
administer oxygen) can be an especially effective delivery system.
However, in other embodiments, one of the other two methods may be
equally effective.
[0152] The term aerosol may refer to a suspension or dispersion of
either liquid droplets or solid powder in air. In this context,
liquid droplets may be formed from solutions, suspensions and
dispersions of drug in a liquid medium, such as water or a
non-aqueous medium. The liquid medium may also contain one or more
diluents, excipients, enhancers or additional active pharmaceutical
ingredients. Where the aerosol is a suspension of liquid in air, it
is possible, and in some embodiments of the invention preferred,
that the liquid contain particles of a drug compound that are
insoluble or slightly soluble in the liquid. It is also possible
for the drug to be fully soluble in the liquid.
[0153] Solid powder includes solid particulates comprising solid
drug and optionally one or more non-liquid diluents, excipients,
additional solid active ingredients, etc.
[0154] An aerosol according to the invention may be insufflated
using a suitable mechanical apparatus. In some embodiments, the
apparatus may include a reservoir and sprayer, which is a device
adapted to expel the pharmaceutical dose in the form of a spray. A
number of doses of the drug to be administered may be contained
within the reservoir, optionally in a liquid solution or suspension
or in a solid particulate formulation, such as a solid particulate
mixture.
[0155] In some embodiments, the apparatus is a pump sprayer that
includes a metering pump. In some embodiments, the apparatus
includes a pressurized spray device, in which the sprayer includes
a metering valve and the pharmaceutical composition further
comprises a pharmaceutically acceptable propellant. Exemplary
propellants include one or mixture of chlorofluorocarbons, such as
dichlorodifluoromethane, as well as the currently preferred
hydrofluorocarbons, such as 1,1,1,2-tetrafluoroethane (HFC-134a)
and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227). Suitable
pressurized spray devices are well known and will be familiar to
those of skill in the art.
[0156] In some embodiments, powders can be administered using a
nasal insufflator. In some embodiments, powders may be contained
within a capsule, which is inserted into an insufflation device.
The capsule is punctured by a needle, which makes apertures at the
top and bottom of the capsule. Air or other pharmaceutically
acceptable propellant is then sent through the needle to blow out
powder particles. In some embodiments, pharmaceutically acceptable
propellants include ethyl chloride, butane, propane,
dichlorodifluoromethane, dichlorotetrafluoroethane, and
trichloromonofluoromethane.
[0157] Many benzodiazepines, including diazepam, are so slightly
soluble in water that a therapeutically effective amount cannot be
dissolved in a volume of aqueous solvent that is amenable to nasal
insufflation as an aerosol or non-aerosol spray. It is considered
that the volume of insufflate that is suitable for nasal
administration is in the range of about 25 to about 250 .mu.L per
nostril, preferably about 50 to about 150 .mu.L per nostril, and
particularly about 50 to about 100 .mu.L per nostril. The solid or
liquid particles may be suspended in an air stream by the action of
a micronizing pump, a stream of aerosolizing inert gas, etc.
[0158] Thus, in some embodiments, the invention provides aerosols
comprising aqueous suspensions or dispersions of drug particles in
a liquid medium. The aqueous suspension or dispersion of the
invention is suspended or dispersed in air to form an aerosol. It
is this aerosol that is insufflated or inhaled through the nose.
The droplets or particles are deposited on the surface of the nasal
mucosa, where the drug particles suspended in the aerosol particles
are absorbed across the mucosal epithelium and into the blood
stream.
[0159] In some embodiments, the invention provides aerosols
comprising dry solid particulates, which are suspended or dispersed
in air.
[0160] Metered-dose spray pumps for aqueous formulations, pMDIs,
and DPIs for nasal delivery are available from, for example, Valois
of America or Pfeiffer of America.
[0161] A propellant driven inhaler (pMDI) releases a metered dose
of drug upon each actuation. The medicine is formulated as a
suspension or solution of a drug substance in a suitable propellant
such as a halogenated hydrocarbon.
[0162] Dry powder inhalers (DPIs), which involve deaggregation and
aerosolization of dry powders, normally rely upon a burst of
inspired air that is drawn through the unit to deliver a drug
dosage. Such devices are known in the art.
[0163] Pulmonary Administration
[0164] Pulmonary drug delivery requires aerosolization of a solid
or liquid and delivery of the aerosol to the lungs via the mouth
and throat. Particles that have aerodynamic diameters greater than
about 5 .mu.m tend to impact surfaces within the oropharyngeal
cavity, and to not reach the lung. Though such particles may
ultimately be absorbed, ingestion generally results in slower
bioabsorption of the medicament than is available through the
pulmonary route. It is generally accepted that 5 .mu.m is the
cutoff for pulmonary availability. Indeed, the portion of particles
in the aerosol that are smaller than 5 .mu.m is referred to as the
respirable dose. (The dose actually deposited in the lungs is
referred to as the deposited dose). Particles having diameters of
about 2 .mu.m to about 5 .mu.m are generally small enough to reach
the upper- to mid-pulmonary region (conducting airways), but are
too large to reach the alveolae. Particles having diameters of
about 0.5 .mu.m to about 2 .mu.m are considered small enough to
reach the alveolae. Particles having diameters smaller than about
0.5 microns can also be deposited in the alveolar region by
sedimentation, although very small particles may be exhaled.
[0165] In some embodiments, the absorption of particles from the
upper- and mid-pulmonary region occurs at a different rate than
absorption via the alveolae. In some embodiments, the larger
particles deposited in the upper regions of the lung take longer to
dissolve in mucosal fluid, and thus take longer to cross the
pulmonary mucosa and epithelium. Accordingly, in some embodiments
of the invention, a bimodal rate of absorption can be obtained by
providing a multimodal distribution of particulates, with at least
one mode occurring between about 0.5 .mu.m and about 2 .mu.m and at
least one mode occurring between about 2 .mu.m and about 5 .mu.m.
In some embodiments, the first mode occurs within the range of
about 0.7 .mu.m to about 1.7 .mu.m; and the second mode occurs
within the range of about 2.2 .mu.m to about 4.0 .mu.m. In such
embodiments, it is considered that one population of particles will
be absorbed at a faster rate and will produce a first maximum
plasma blood concentration Cmax.sub.1 at time Tmax.sub.1, while the
other population of particles will be absorbed more slowly, and
will cause a second maximum plasma blood concentration Cmax.sub.2
(which may appear in a graph of medicament plasma blood
concentration verus time as a second peak or as a "shoulder" on the
blood plasma concentration curve) at time Tmax.sub.2
(Tmax.sub.2>Tmax.sub.1). It is considered that such a bimodal
distribution of particles will preserve the benefits of each
population of particles separately--fast onset of action due to
rapid attainment of an effective blood plasma concentration of the
medicament from the first population of particles and long duration
of effect due to later absorption of the second population of
particles.
[0166] It is also possible to formulate a trimodal pulmonary
medicament, wherein one population of particles has a particle size
distribution characterized by a mode greater than about 5 .mu.m. As
discussed above, such particles will generally impact the
oropharyngeal surfaces and be absorbed through the oropharyngeal
mucosa or swallowed. It is considered that a trimodal pulmonary
medicament having a first population of particles having a particle
size distribution mode in the range of about 0.5 .mu.m to about 2
.mu.m, a second population of particles having a particle size
distribution mode in the range of about 2 .mu.m to about 5 .mu.m,
and a third population of particles having a particle size
distribution mode of greater than about 5 .mu.m, will exhibit a
first blood plasma concentration maximum (Cmax.sub.1) at time
Tmax.sub.1, a second blood plasma concentration maximum
(Cmax.sub.2), which may be visualized as a separate peak or as a
shoulder on the blood plasma concentration versus time curve, at
time Tmax.sub.2 (Tmax.sub.2>Tmax.sub.1), and a third blood
plasma concentration maximum (Cmax.sub.3), which may be visualized
as a separate peak or may appear as a shoulder on the first or
second peak, at at time Tmax.sub.3 (Tmax.sub.3>Tmax.sub.2). In
some embodiments, Cmax.sub.3 may be attributable to
gastrointestinal absorption, oropharyngeal absorption, or a
combination of oropharyngeal and gastrointestinal absorption, of
the medicament. The amount of medicament in each population of
particles can be adjusted through suitable means, as discussed in
more detail herein, to ensure that the fastest-absorbed population
of particles will provide rapid attainment of an effective blood
plasma concentration of the medicament (e.g. within about 1 to
about 30 minutes, especially about 1 to about 10 minutes), while
the later-absorbed population of particles will continue to provide
effective blood plasma concentrations of the medicament over a
prolonged period of (e.g. for about 1 to about 30 hr, especially
about 2 to about 24 hours, about 4 to about 24 hours, about 4 to
about 12 hours or about 4 to about 8 hours.) Where absorption of
medicament from one population of particles is characterized by
significant first pass effects, a higher relative amount of the
population of particles is used in order to compensate for liver
metabolism.
[0167] In some embodiments, the pulmonary aerosol may be
characterized by a bimodal particle size distribution, with a first
mode being between about 0.5 .mu.m and about 5 .mu.m and a second
mode being above about 5 .mu.m. In some embodiments, the first mode
occurs between about 0.5 .mu.m and about 2 .mu.m. In some
embodiments, the first mode occurs between about 2 .mu.m and about
5 .mu.m. In some embodiments, the first mode is between about 1.0
.mu.m and about 4.0 .mu.m. It is considered that the first
population of particles will be absorbed in the lung and will enter
the blood stream at a faster rate than the second population of
particles, having a particle size distribution with a mode greater
than about 5 .mu.m, which will be absorbed via the oropharyngeal
mucosa, the gastrointestinal system, or both. Thus, the first
population of particles will produce a first maximum plasma blood
concentration Cmax.sub.1 at time Tmax.sub.1, while the second
population of particles will be absorbed more slowly, and will
cause a second maximum plasma blood concentration Cmax.sub.2 (which
may appear in a graph of medicament plasma blood concentration
verus time as a second peak or as a "shoulder" on the blood plasma
concentration curve) at time Tmax.sub.2 (Tmax.sub.2>Tmax.sub.1).
It is considered that such a bimodal distribution of particles will
preserve the benefits of each population of particles
separately--fast onset of action due to rapid attainment of an
effective blood plasma concentration of the medicament through
pulmonary absorption of the first population of particles and long
duration of effect due to slower absorption of the second
population of particles via oropharyngeal and/or gastrointestinal
absorption.
[0168] The person skilled in the art will recognize the need to
adjust the relative proportion of a population of particles that is
absorbed primarily through the gastrointestinal tract when the
medicament is subject to so-called first pass effects. First pass
effects generally occur when a drug is absorbed from the
gastrointestinal tract, and are generally avoided when the drug is
absorbed from the mucosa of the nasal cavities, lungs, and/or
oropharyngeal cavity. Absorption of a drug from the
gastrointestinal (GI) tract leads to first-pass metabolism, as the
portal vein carries GI blood directly to the liver, where many
drugs are metabolized. Liver metabolism thus lowers the effective
oral bioavailability of many drugs--even many drugs that are
otherwise well-absorbed from the GI tract. In some embodiments,
such first pass effects are avoided by delivering particles to the
lung and minimizing the delivery of drug particles to the
oropharyngeal mucosa. In other embodiments, especially where a
population of particles comprises a medicament that is quickly
metabolized by the liver, and where gastrointestinal absorption is
contemplated as a desired route for e.g. longer-term absorption of
drug, it is essential to compensate for the first pass effects by
adjusting upward the relative proportion of the population of
particles having an average particle size of greater than about 5
.mu.m. Of course, where long-term absorption can be obtained by
pulmonary absorption, e.g. in the mid- to upper-level lung
(particle sizes of about 2.0 .mu.m to about 5.0 .mu.m), in some
embodiments it will suffice to increase the proportion of particles
having particle sizes in the 2.0 .mu.m to 5.0 .mu.m particle size
range, thereby enhancing longer term absorption of the medicament
from these particles, while minimizing GI absorption, thereby
achieving longer term absorption while minimizing the
bioavailability-reducing first pass effects.
[0169] Particles of medicament may be administered to the lungs as
dry powder aerosols or liquid aerosols. Dry powder aerosols are
generally administered to the lungs with dry powder inhaler (DPI)
inhalation devices. Dry powder inhalers can include breath actuated
dry powder inhalers, such as are described in U.S. Pat. No.
7,434,579. Metered-dose inhalers contain medicament suspended in a
propellant, a mixture of propellants, or a mixture of solvents,
propellants, and/or other excipients in compact pressurized aerosol
dispensers. An MDI product may discharge up to several hundred
metered doses of medicament. Each actuation may contain from a few
micrograms (mcg) up to milligrams (mg) of the active ingredients
delivered in a volume typically between 25 and 100 microliters. In
some embodiments, an MDI will contain suitable proportions of a
first population of particles, a second population of particles and
optionally a third population of particles, each population of
particles having a distinct particle size mode.
[0170] Another type of liquid aerosol dispersion device is
nebulizer, which uses a jet, a vibrating mesh or other means to
aerolsolize a suspension containing particles of medicament. In
some embodiments, a nebulizer is used to prepare an aerosol
containing suitable proportions of a first population of particles,
a second population of particles and optionally a third population
of particles, each population of particles having a distinct
particle size mode.
Preparation of Benzodiazepine Particulate Compositions
[0171] Processes for preparing the particles used in the present
invention can be accomplished through numerous techniques known to
those skilled in the art. A representative, but non-exhaustive,
discussion of techniques for preparing particle dispersions of
pharmaceutical compositions follows.
[0172] In some embodiments, the preparation of small particle
dispersions employs energy addition techniques, including adding
pharmaceutically active compound to a suitable vehicle, such as
water or aqueous solution containing one or more of the surfactants
set forth herein, or other pharmaceutically acceptable liquid in
which the pharmaceutical compound is relatively insoluble, to form
a first suspension. Energy is added to the first suspension to form
a particle dispersion, which is physically more stable than the
first suspension. Energy is added by mechanical grinding (e.g.,
pearl milling, ball milling, hammer milling, fluid energy milling,
jet milling, or wet grinding). Some suitable methods are described
in U.S. Pat. No. 5,145,684, which is incorporated herein by
reference.
[0173] In some embodiments, such methods further include subjecting
the first suspension to high shear conditions, including
cavitation, shearing or impact forces utilizing a microfluidizer.
In some embodiments, the methods include adding energy to the first
suspension using a piston gap homogenizer or counter current flow
homogenizer such as those disclosed in U.S. Pat. No. 5,091,188,
which is incorporated herein by reference. Suitable piston gap
homogenizers are commercially available under the product name
EMULSIFLEX by Avestin, and French Pressure Cells sold by Spectronic
Instruments. Suitable microfluidizers are available from
Microfluidics Corp.
[0174] In some embodiments, addition of energy can also be
accomplished using sonication techniques. The step of sonicating
can be carried out with any suitable sonication device such as the
Branson Model S-450A or Cole-Parmer 500/750 Watt Model. Such
devices are well known in the industry. In some embodiments, the
sonication device may have a sonication horn or probe that is
inserted into the first suspension to emit sonic energy into the
solution. The sonicating device, in a preferred form of the
invention, is operated at a frequency of from about 1 kHz to about
90 kHz and more preferably from about 20 kHz to about 40 kHz or any
range or combination of ranges therein. The probe sizes can vary
and preferably is in distinct sizes such as 1/2 inch or 1/4 inch or
the like.
[0175] In some preferred embodiments, the dispersion of small
particles will be sterilized prior to use. Sterilization can be
accomplished by heat sterilization, gamma irradiation, filtration
(either directly as a dispersion having particle sizes under 200
nm, or by sterile filtration of the solutions used in the
precipitation process, prior to forming the solid dispersion), and
by application of very high pressure (greater than 2000
atmospheres), or by a combination of high pressure and elevated
temperature.
[0176] Small particle dispersions can also be prepared by
precipitation techniques. In some embodiments, the small particle
dispersions are formed by a microprecipitation method, which
includes: (i) dissolving the organic compound in a water-miscible
first solvent; (ii) preparing a solution of polymer and an
amphiphile in an aqueous second solvent and in which second solvent
the organic compound is substantially insoluble whereby a
polymer/amphiphile complex is formed; and (iii) mixing the
solutions from steps (i) and (ii) so as to cause precipitation of
an aggregate of the organic compound and the polymer/amphiphile
complex.
[0177] In some embodiments, the precipitation process is one
described in U.S. Pat. No. 6,607,784 and co-pending and commonly
assigned U.S. Ser. Nos. 09/874,499; 09/874,637; 10/021,692, which
are incorporated herein by reference. In some embodiments, such
methods comprise: (1) dissolving an organic compound in a water
miscible first organic solvent to create a first solution; (2)
mixing the first solution with a second solvent or water to
precipitate the organic compound to create a first suspension; and
(3) adding energy to the first suspension in the form of high-shear
mixing or heat to provide a dispersion of small particles. In some
embodiments, the first organic solvent is removed from the mixture
by any suitable means such as centrifugation or filtration methods.
In some embodiments, the continuous phase of the dispersion can be
optionally replaced by another continuous phase by removing the
first continuous phase using methods such as centrifugation and
filtration, adding a second continuous phase and subsequently
re-dispersing the solid material in the second continuous phase.
One or more optional surface modifiers set forth herein can be
added to the first organic solvent or the second aqueous
solution.
[0178] In some embodiments, particulates according to the invention
are formed by an emulsion precipitation technique, including: (1)
providing a multiphase system having an organic phase and an
aqueous phase, the organic phase having a pharmaceutically active
compound therein; and (2) sonicating the system to evaporate a
portion of the organic phase to cause precipitation of the compound
in the aqueous phase to form a dispersion of small particles. The
step of providing a multiphase system includes the steps of: (1)
mixing a water immiscible solvent with the pharmaceutically active
compound to define an organic solution, (2) preparing an aqueous
based solution with one or more surface active compounds, and (3)
mixing the organic solution with the aqueous solution to form the
multiphase system. The step of mixing the organic phase and the
aqueous phase can include the use of piston gap homogenizers,
colloidal mills, high speed stirring equipment, extrusion
equipment, manual agitation or shaking equipment, microfluidizer,
or other equipment or techniques for providing high shear
conditions. The crude emulsion will have oil droplets in the water
of a size of approximately less than 1 .mu.m in diameter. The crude
emulsion is sonicated to define a microemulsion and eventually to
provide a dispersion of small particles.
[0179] In some embodiments, a dispersion of small particles may
include: (1) providing a crude dispersion of a multiphase system
having an organic phase and an aqueous phase, the organic phase
having a pharmaceutical compound therein; (2) providing energy to
the crude dispersion to form a fine dispersion; (3) freezing the
fine dispersion; and (4) lyophilizing the fine dispersion to obtain
small particles of the pharmaceutical compound. The small particles
can be sterilized by the techniques set forth herein or the small
particles can be reconstituted in an aqueous medium and
sterilized.
[0180] In some embodiments, a multiphase system is provided by: (1)
mixing a water immiscible solvent with the pharmaceutically
effective compound to define an organic solution; (2) preparing an
aqueous based solution with one or more surface active compounds;
and (3) mixing the organic solution with the aqueous solution to
form the multiphase system. The step of mixing the organic phase
and the aqueous phase may include the use of piston gap
homogenizers, colloidal mills, high speed stirring equipment,
extrusion equipment, manual agitation or shaking equipment,
microfluidizer, or other equipment or techniques for providing high
shear conditions.
[0181] In some embodiments, small particle dispersions can be
prepared using solvent anti-solvent precipitation as described in
U.S. Pat. No. 5,118,528 and U.S. Pat. No. 5,100,591, each of which
is incorporated herein by reference. In some embodiments, the
process includes: (1) preparing a liquid phase of a biologically
active substance in a solvent or a mixture of solvents to which may
be added one or more surfactants; (2) preparing a second liquid
phase of a non-solvent or a mixture of non-solvents, the
non-solvent is miscible with the solvent or mixture of solvents for
the substance; (3) adding together the solutions of (1) and (2)
with stirring; and (4) removing of unwanted solvents to produce a
dispersion of small particles. These methods are distinguished from
those described under the above section, "Microprecipitation
Methods", in that they do not provide for a last step of adding
energy to the suspension in the form of high-shear mixing or
heat.
[0182] In some embodiments, small particle dispersions can be
formed using phase inversion precipitation as disclosed in U.S.
Pat. Nos. 6,235,224, 6,143,211 and U.S. Pre-Grant Publication No.
2001/0042932, each of which is incorporated herein by reference.
Phase inversion is a term used to describe the physical phenomena
by which a polymer dissolved in a continuous phase solvent system
inverts into a solid macromolecular network in which the polymer is
the continuous phase. One method to induce phase inversion is by
the addition of a non-solvent to the continuous phase. The polymer
undergoes a transition from a single phase to an unstable two phase
mixture: polymer rich and polymer poor fractions. Micellar droplets
of non-solvent in the polymer rich phase serve as nucleation sites
and become coated with polymer. The '224 patent discloses that
phase inversion of polymer solutions under certain conditions can
bring about spontaneous formation of discrete microparticles,
including nanoparticles. The '224 patent discloses dissolving or
dispersing a polymer in a solvent. A pharmaceutical agent is also
dissolved or dispersed in the solvent. For the crystal seeding step
to be effective in this process it is desirable the agent is
dissolved in the solvent. The polymer, the agent and the solvent
together form a mixture having a continuous phase, wherein the
solvent is the continuous phase. The mixture is then introduced
into at least tenfold excess of a miscible non-solvent to cause the
spontaneous formation of the microencapsulated microparticles of
the agent having an average particle size of between 10 nm and 10
.mu.m. The particle size is influenced by the solvent: non-solvent
volume ratio, polymer concentration, the viscosity of the
polymer-solvent solution, the molecular weight of the polymer, and
the characteristics of the solvent-non-solvent pair.
[0183] In some embodiments, small particle dispersions can be
formed by pH shift precipitation techniques. In some embodiments,
such processes include dissolving a drug in a solution having a pH
in which the drug is soluble, followed by changing the pH to a
point where the drug is no-longer soluble. The pH can be acidic or
basic, depending on the particular pharmaceutical compound. The
solution may then be neutralized to form a dispersion of small
particles. One suitable pH shifting precipitation process is
disclosed in U.S. Pat. No. 5,665,331, which is incorporated herein
by reference. The process includes the step of dissolving of the
pharmaceutical agent together with a crystal growth modifier (CGM)
in an alkaline solution and then neutralizing the solution with an
acid in the presence of suitable surface-modifying surface-active
agent or agents to form a small particle dispersion of the
pharmaceutical agent. The precipitation step can be followed by
steps of diafiltration clean-up of the dispersion and then
adjusting the concentration of the dispersion to a desired
level.
[0184] Other examples of pH shifting precipitation methods are
disclosed in U.S. Pat. Nos. 5,716,642; 5,662,883; 5,560,932; and
4,608,278, which are incorporated herein by reference and are made
a part hereof.
[0185] In some embodiments, infusion precipitation techniques are
used to form small particle dispersions as described in U.S. Pat.
Nos. 4,997,454 and 4,826,689, which are incorporated herein by
reference. First, a suitable solid compound is dissolved in a
suitable organic solvent to form a solvent mixture. Then, a
precipitating non-solvent miscible with the organic solvent is
infused into the solvent mixture at a temperature between about
-10.degree. C. and about 100.degree. C. and at an infusion rate of
from about 0.01 ml per minute to about 1000 ml per minute per
volume of 50 ml to produce a suspension of precipitated
non-aggregated solid particles of the compound with a substantially
uniform mean diameter of less than 10 .mu.m. Agitation (e.g., by
stirring) of the solution being infused with the precipitating
non-solvent is preferred. The non-solvent may contain a surfactant
to stabilize the particles against aggregation. The particles are
then separated from the solvent. Depending on the solid compound
and the desired particle size, the parameters of temperature, ratio
of non-solvent to solvent, infusion rate, stir rate, and volume can
be varied according to the invention. The particle size is
proportional to the ratio of non-solvent: solvent volumes and the
temperature of infusion and is inversely proportional to the
infusion rate and the stirring rate. The precipitating non-solvent
may be aqueous or non-aqueous, depending upon the relative
solubility of the compound and the desired suspending vehicle.
[0186] In some embodiments, temperature shift precipitation
techniques may also be used to form small particle dispersions.
This technique is disclosed in U.S. Pat. No. 5,188,837, which is
incorporated herein by reference. In some embodiments, lipospheres
are prepared by the steps of: (1) melting or dissolving a substance
such as a drug to be delivered in a molten vehicle to form a liquid
of the substance to be delivered; (2) adding a phospholipid along
with an aqueous medium to the melted substance or vehicle at a
temperature higher than the melting temperature of the substance or
vehicle; (3) mixing the suspension at a temperature above the
melting temperature of the vehicle until a homogenous fine
preparation is obtained; and then (4) rapidly cooling the
preparation to room temperature or below.
[0187] In some embodiments, the invention makes use of solvent
evaporation precipitation techniques, as described in U.S. Pat. No.
4,973,465, which is incorporated herein by reference. In some
embodiments, microcrystals are prepared by: (1) providing a
solution of a pharmaceutical composition and a phospholipid
dissolved in a common organic solvent or combination of solvents;
(2) evaporating the solvent or solvents; and (3) suspending the
film obtained by evaporation of the solvent or solvents in an
aqueous solution by vigorous stirring to form a dispersion of small
particles. The solvent can be removed by evaporating a sufficient
quantity of the solvent to cause precipitation of the compound. The
solvent can also be removed by other well known techniques such as
applying a vacuum to the solution or blowing nitrogen over the
solution.
[0188] In some embodiments, reaction precipitation is employed. In
some embodiments, reaction precipitation includes dissolving the
pharmaceutical compound, and optionally other excipients, into a
suitable solvent to form a solution. The compound may be added in
an amount at or below the saturation point of the compound in the
solvent. The compound or any of the excipients is precipitated from
solution by reacting with a chemical agent or by modification in
response to adding energy such as heat or UV light or the like such
that the modified compound has a lower solubility in the solvent
and precipitates from the solution to form a small particle
dispersion. Precipitation of excipient provides a solid matrix into
which the drug is sorbed.
[0189] In some embodiments, a suitable technique for precipitating
is by compressed fluid precipitation. In some embodiments, a
suitable method is described in WO 97/14407, which is incorporated
herein by reference. The method includes the steps of dissolving a
water-insoluble drug in a solvent to form a solution. The solution
is then sprayed into a compressed fluid, which can be a gas, liquid
or supercritical fluid. The addition of the compressed fluid to a
solution of a solute in a solvent causes the solute to attain or
approach supersaturated state and to precipitate out as fine
particles. The compressed fluid acts as an anti-solvent which
lowers the cohesive energy density of the solvent in which the drug
is dissolved. In some embodiments, the drug can be dissolved in the
compressed fluid which is then sprayed into an aqueous phase. The
rapid expansion of the compressed fluid reduces the solvent power
of the fluid, which in turn causes the solute to precipitate out as
small particles in the aqueous phase. In this case, the compressed
fluid acts as a solvent. In order to stabilize the particles
against aggregation, a surface modifier, such as a surfactant, may
be employed within certain embodiments of the invention. In some
embodiments, a suitable technique for precipitating by compressed
fluid is one wherein the active ingredient is mixed with water, one
or more solvents, or a combination thereof, and the resulting
mixture sprayed at or below the surface of a cryogenic fluid.
Frozen particles are thereby provided. Materials for encapsulating
the solid particles may also be added so that frozen particles are
generated wherein the encapsulating agent surrounds the active
agent.
[0190] In some embodiments, methods according to the invention
include protein microsphere precipitation. Microspheres or
microparticles utilized in this invention can also be produced from
a process involving mixing or dissolving macromolecules such as
proteins with a water soluble polymer. In some embodiments, a
suitable method is disclosed in U.S. Pat. Nos. 5,849,884,
5,981,719, 6,090,925, 6,268,053, 6,458,387, which are incorporated
herein by reference. In some embodiments, microspheres may be
prepared by mixing a macromolecule in solution with a polymer or a
mixture of polymers in solution at a pH near the isoelectric point
of the macromolecule. The mixture is incubated in the presence of
an energy source, such as heat, radiation, or ionization, for a
predetermined amount of time. The resulting microspheres can be
removed from any unincorporated components present in the solution
by physical separation methods.
[0191] In some embodiments, other processes for preparing particles
of pharmaceutical compositions (i.e. organic compound) used in the
present invention can be separated into four general categories.
Each of the categories of processes share the steps of: (1)
dissolving an organic compound in a water miscible first solvent to
create a first solution, (2) mixing the first solution with a
second solvent of water to precipitate the organic compound to
create a pre-suspension, and (3) adding energy to the first
suspension in the form of high-shear mixing or heat, or a
combination of both, to provide a stable form of the organic
compound having the desired size ranges defined above. The mixing
steps and the energy adding step can be carried out in consecutive
steps or simultaneously.
[0192] Some categories of processes are distinguished based upon
the physical properties of the organic compound as determined
through x-ray diffraction studies, differential scanning
calorimetry (DSC) studies, or other suitable study conducted prior
to the energy-addition step and after the energy-addition step. In
the first process category, prior to the energy-addition step the
organic compound in the first suspension takes an amorphous form, a
semi-crystalline form or a supercooled liquid form and has an
average effective particle size. After the energy-addition step the
organic compound is in a crystalline form having an average
effective particle size essentially the same or less than that of
the first suspension.
[0193] In another process category, prior to the energy-addition
step the organic compound is in a crystalline form and has an
average effective particle size. After the energy-addition step the
organic compound is in a crystalline form having essentially the
same average effective particle size as prior to the
energy-addition step but the crystals after the energy-addition
step are less likely to aggregate or form large crystals. The
reduced tendency of the organic compound to aggregate or form large
crystals is observed by laser dynamic light scattering and light
microscopy.
[0194] In another process category, prior to the energy-addition
step, the organic compound is in a crystalline form that is friable
and has an average effective particle size. After the
energy-addition step the organic compound is in a crystalline form
having an average effective particle size smaller than the crystals
of the pre-suspension. By taking the steps necessary to place the
organic compound in a crystalline form that is friable, the
subsequent energy-addition step can be carried out more quickly and
efficiently when compared to an organic compound in a less friable
crystalline morphology.
[0195] In another process category, the first solution and second
solvent are simultaneously subjected to the energy-addition step.
Thus, the physical properties of the organic compound before and
after the energy addition step were not measured. The
energy-addition step can be carried out in any fashion wherein the
first suspension or the first solution and second solvent are
exposed to cavitation, shearing or impact forces. In some
embodiments, the energy-addition step is an annealing step.
Annealing is defined in this invention as the process of converting
matter that is thermodynamically unstable into a more stable form
by single or repeated application of energy (direct heat or
mechanical stress), followed by thermal relaxation. This lowering
of energy may be achieved by conversion of the solid form from a
less ordered to a more ordered lattice structure. Alternatively,
this stabilization may occur by a reordering of the surfactant
molecules at the solid-liquid interface.
[0196] It should be understood that the process conditions such as
choice of surfactants or combination of surfactants, amount of
surfactant used, temperature of reaction, rate of mixing of
solutions, rate of precipitation and the like can be selected to
allow for any drug to be processed under any one of the categories
discussed in the following paragraphs.
[0197] The foregoing process categories, can be further divided
into two subcategories: Methods A and B.
[0198] In some embodiments, the first solvent according to the
following processes is a solvent or mixture of solvents in which
the organic compound of interest is relatively soluble and which is
miscible with the second solvent. Such solvents include, but are
not limited to water-miscible protic compounds, in which a hydrogen
atom in the molecule is bound to an electronegative atom such as
oxygen, nitrogen, or other Group VA, VIA and VII A in the Periodic
Table of elements. Examples of such solvents include, but are not
limited to, alcohols, amines (primary or secondary), oximes,
hydroxamic acids, carboxylic acids, sulfonic acids, phosphonic
acids, phosphoric acids, amides and ureas.
[0199] Other examples of the first solvent also include aprotic
organic solvents. Some of these aprotic solvents can form hydrogen
bonds with water, but can only act as proton acceptors because they
lack effective proton donating groups. One class of aprotic
solvents is a dipolar aprotic solvent, as defined by the
International Union of Pure and Applied Chemistry (IUPAC Compendium
of Chemical Terminology, 2nd Ed., 1997): [0071] A solvent with a
comparatively high relative permittivity (or dielectric constant),
greater than ca. 15, and a sizable permanent dipole moment, that
cannot donate suitably labile hydrogen atoms to form strong
hydrogen bonds, e.g. dimethyl sulfoxide.
[0200] In some embodiments, dipolar aprotic solvents can be
selected from the group consisting of: amides (fully substituted,
with nitrogen lacking attached hydrogen atoms), ureas (fully
substituted, with no hydrogen atoms attached to nitrogen), ethers,
cyclic ethers, nitriles, ketones, sulfones, sulfoxides, fully
substituted phosphates, phosphonate esters, phosphoramides, nitro
compounds, and the like. Dimethylsulfoxide (DMSO),
N-methyl-2-pyrrolidinone (NMP), 2-pyrrolidinone,
1,3-dimethylimidazolidinone (DMI), dimethylacetamide (DMA),
dimethylformamide (DMF), dioxane, acetone, tetrahydrofuran (THF),
tetramethylenesulfone (sulfolane), acetonitrile, and
hexamethylphosphoramide (HMPA), nitromethane, among others, are
members of this class.
[0201] In some embodiments, solvents may also be chosen that are
generally water-immiscible, but have sufficient water solubility at
low volumes (less than 10%) to act as a water-miscible first
solvent at these reduced volumes. Examples include aromatic
hydrocarbons, alkenes, alkanes, and halogenated aromatics,
halogenated alkenes and halogenated alkanes. Aromatics include, but
are not limited to, benzene (substituted or unsubstituted), and
monocyclic or polycyclic arenes. Examples of substituted benzenes
include, but are not limited to, xylenes (ortho, meta, or para),
and toluene. Examples of alkanes include but are not limited to
hexane, neopentane, heptane, isooctane, and cyclohexane. Examples
of halogenated aromatics include, but are not restricted to,
chlorobenzene, bromobenzene, and chlorotoluene. Examples of
halogenated alkanes and alkenes include, but are not restricted to,
trichloroethane, methylene chloride, ethylenedichloride (EDC), and
the like.
[0202] In some embodiments, solvent classes include but are not
limited to: N-methyl-2-pyrrolidinone (also called
N-methyl-2-pyrrolidone), 2-pyrrolidinone (also called
2-pyrrolidone), 1,3-dimethyl-2-imidazolidinone (DMI),
dimethylsulfoxide, dimethylacetamide, acetic acid, lactic acid,
methanol, ethanol, isopropanol, 3-pentanol, n-propanol, benzyl
alcohol, glycerol, butylene glycol (butanediol), ethylene glycol,
propylene glycol, mono- and diacylated monoglycerides (such as
glyceryl caprylate), dimethyl isosorbide, acetone, dimethylsulfone,
dimethylformamide, 1,4-dioxane, tetramethylenesulfone (sulfolane),
acetonitrile, nitromethane, tetramethylurea,
hexamethylphosphoramide (HMPA), tetrahydrofuran (THF), dioxane,
diethylether, tert-butylmethyl ether (TBME), aromatic hydrocarbons,
alkenes, alkanes, halogenated aromatics, halogenated alkenes,
halogenated alkanes, xylene, toluene, benzene, substituted benzene,
ethyl acetate, methyl acetate, butyl acetate, chlorobenzene,
bromobenzene, chlorotoluene, trichloroethane, methylene chloride,
ethylenedichloride (EDC), hexane, neopentane, heptane, isooctane,
cyclohexane, polyethylene glycol (PEG, for example, PEG-4, PEG-8,
PEG-9, PEG-12, PEG-14, PEG-16, PEG-120, PEG-75, PEG-150),
polyethylene glycol esters (examples such as PEG-4 dilaurate,
PEG-20 dilaurate, PEG-6 isostearate, PEG-8 palmitostearate, PEG-150
palmitostearate), polyethylene glycol sorbitans (such as PEG-20
sorbitan isostearate), polyethylene glycol monoalkyl ethers
(examples such as PEG-3 dimethyl ether, PEG-4 dimethyl ether),
polypropylene glycol (PPG), polypropylene alginate, PPG-10
butanediol, PPG-10 methyl glucose ether, PPG-20 methyl glucose
ether, PPG-15 stearyl ether, propylene glycol
dicaprylate/dicaprate, propylene glycol laurate, and glycofurol
(tetrahydrofurfuryl alcohol polyethylene glycol ether). A preferred
first solvent is N-methyl-2-pyrrolidinone. In some embodiments,
another preferred first solvent is lactic acid.
[0203] In some embodiments, the second solvent is an aqueous
solvent. This aqueous solvent may be water by itself. This solvent
may also contain buffers, salts, surfactant(s), water-soluble
polymers, and combinations of these excipients.
[0204] In Method A, the organic compound ("drug") is first
dissolved in the first solvent to create a first solution. The
organic compound can be added from about 0.1% (w/v) to about 50%
(w/v) depending on the solubility of the organic compound in the
first solvent. Heating of the concentrate from about 30.degree. C.
to about 100.degree. C. may be necessary to ensure total
dissolution of the compound in the first solvent.
[0205] A second aqueous solvent is provided with one or more
optional surface modifiers such as an anionic surfactant, a
cationic surfactant, a zwitterionic surfactant, a nonionic
surfactant or a biologically surface active molecule added thereto.
Suitable anionic surfactants include but are not limited to alkyl
sulfonates, alkyl phosphates, alkyl phosphonates, potassium
laurate, triethanolamine stearate, sodium lauryl sulfate, sodium
dodecylsulfate, alkyl polyoxyethylene sulfates, sodium alginate,
dioctyl sodium sulfosuccinate, phosphatidyl glycerol, phosphatidyl
inosine, phosphatidylinositol, diphosphatidylglycerol,
phosphatidylserine, phosphatidic acid and their salts, sodium
carboxymethylcellulose, cholic acid and other bile acids (e.g.,
cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid,
glycodeoxycholic acid) and salts thereof (e.g., sodium
deoxycholate, etc.).
[0206] Zwitterionic surfactants are electrically neutral but
possess local positive and negative charges within the same
molecule. Suitable zwitterionic surfactants include but are not
limited to zwitterionic phospholipids. Suitable phospholipids
include phosphatidylcholine, phosphatidylethanolamine,
diacyl-glycero-phosphoethanolamine (such as
dimyristoyl-glycero-phosphoethanolamine (DMPE),
dipalmitoyl-glycero-phosphoethanolamine (DPPE),
distearoyl-glycero-phosphoethanolamine (DSPE), and
dioleolyl-glycero-phosphoethanolamine (DOPE)). Mixtures of
phospholipids that include anionic and zwitterionic phospholipids
may be employed in this invention. Such mixtures include but are
not limited to lysophospholipids, egg or soybean phospholipid or
any combination thereof. The phospholipid, whether anionic,
zwitterionic or a mixture of phospholipids, may be salted or
desalted, hydrogenated or partially hydrogenated or natural
semi-synthetic or synthetic. The phospholipid may also be
conjugated with a water-soluble or hydrophilic polymer to
specifically target the delivery to macrophages in the present
invention. However, conjugated phospholipids may be used to target
other cells or tissue in other applications. A preferred polymer is
polyethylene glycol (PEG), which is also known as the monomethoxy
polyethyleneglycol (mPEG). The molecule weights of the PEG can
vary, for example, from 200 to 50,000. Some commonly used PEG's
that are commercially available include PEG 350, PEG 550, PEG 750,
PEG 1000, PEG 2000, PEG 3000, and PEG 5000. The phospholipid or the
PEG-phospholipid conjugate may also incorporate a functional group
which can covalently attach to a ligand including but not limited
to proteins, peptides, carbohydrates, glycoproteins, antibodies, or
pharmaceutically active agents. These functional groups may
conjugate with the ligands through, for example, amide bond
formation, disulfide or thioether formation, or biotin/streptavidin
binding. Examples of the ligand-binding functional groups include
but are not limited to hexanoylamine, dodecanylamine,
1,12-dodecanedicarboxylate, thioethanol,
4-(p-maleimidophenyl)butyramide (MPB),
4-(p-maleimidomethyl)cyclohexane-carboxamide (MCC),
3-(2-pyridyldithio)propionate (PDP), succinate, glutarate,
dodecanoate, and biotin.
[0207] In some embodiments, suitable cationic surfactants may
include, but are not limited to, natural phospholipids, synthetic
phospholipids, quaternary ammonium compounds, benzalkonium
chloride, cetyltrimethylammonium bromide, chitosans,
lauryldimethylbenzylammonium chloride, acyl carnitine
hydrochlorides, dimethyldioctadecylammomium bromide (DDAB),
dioleyoltrimethylammonium propane (DOTAP),
dimyristoyltrimethylammonium propane (DMTAP),
dimethylaminoethanecarbamoyl cholesterol (DC-Chol),
1,2-diacylglycero-3-(O-alkyl)phosphocholine,
O-alkylphosphatidylcholine, alkyl pyridinium halides, or long-chain
alkyl amines such as, for example, n-octylamine and oleylamine.
[0208] In some embodiments, suitable nonionic surfactants include:
glyceryl esters, polyoxyethylene fatty alcohol ethers (Macrogol and
Brij), polyoxyethylene sorbitan fatty acid esters (Polysorbates),
polyoxyethylene fatty acid esters (Myrj), sorbitan esters (Span),
glycerol monostearate, polyethylene glycols, polypropylene glycols,
cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl
polyether alcohols, polyoxyethylene-polyoxypropylene copolymers
(poloxamers), poloxamines, methylcellulose, hydroxymethylcellulose,
hydroxypropylcellulose, hydroxypropylmethylcellulose,
noncrystalline cellulose, polysaccharides including starch and
starch derivatives such as hydroxyethylstarch (HES), polyvinyl
alcohol, and polyvinylpyrrolidone. In a preferred form, the
nonionic surfactant is a polyoxyethylene and polyoxypropylene
copolymer and preferably a block copolymer of propylene glycol and
ethylene glycol. Such polymers are sold under the tradename
POLOXAMER also sometimes referred to as PLURONIC.RTM., and sold by
several suppliers including Spectrum Chemical and Ruger. Among
polyoxyethylene fatty acid esters is included those having short
alkyl chains. One example of such a surfactant is SOLUTOL.RTM. HS
15, polyethylene-660-hydroxystearate, manufactured by BASF
Aktiengesellschaft. Surface-active biological molecules include
such molecules as albumin, casein, hirudin or other appropriate
proteins. Polysaccharide biologics are also included, and consist
of but are not limited to, starches, heparins, and chitosans. Other
suitable surfactants include any amino acids such as leucine,
alanine, valine, isoleucine, lysine, aspartic acid, glutamic acid,
methionine, phenylalanine, or any derivatives of these amino acids
such as, for example, amide or ester derivatives and polypeptides
formed from these amino acids.
[0209] In some embodiments, it may also be desirable to add a pH
adjusting agent to the second solvent. Suitable pH adjusting agents
include, but are not limited to, hydrochloric acid, sulfuric acid,
phosphoric acid, monocarboxylic acids (such as, for example, acetic
acid and lactic acid), dicarboxylic acids (such as, for example,
succinic acid), tricarboxylic acids (such as, for example, citric
acid), THAM (tris(hydroxymethyl)aminomethane), meglumine
(N-methylglucosamine), sodium hydroxide, and amino acids such as
glycine, arginine, lysine, alanine, histidine and leucine. The
second solvent should have a pH within the range of from about 3 to
about 11. The aqueous medium may additionally include an osmotic
pressure adjusting agent, such as but not limited to glycerin, a
monosaccharide such as dextrose, a disaccharide such as sucrose, a
trisaccharide such as raffinose, and sugar alcohols such as
mannitol, xylitol and sorbitol.
[0210] Method B differs from Method A in the following respects:
The first difference is a surfactant or combination of surfactants
is added to the first solution. The surfactants may be selected
from the groups of anionic, nonionic, cationic surfactants, and
surface-active biological modifiers set forth above.
[0211] U.S. Pat. No. 5,780,062 discloses a process for preparing
small particles of an organic compound by first dissolving the
compound in a suitable water-miscible first solvent. A second
solution is prepared by dissolving a polymer and an amphiphile in
aqueous solvent. The first solution is then added to the second
solution to form a precipitate that consists of the organic
compound and a polymer-amphiphile complex. The '062 patent does not
disclose utilizing the energy-addition step of this process in
Methods A and B. Lack of stability is typically evidenced by rapid
aggregation and particle growth. In some instances, amorphous
particles recrystallize as large crystals. Adding energy to the
pre-suspension in the manner disclosed above typically affords
particles that show decreased rates of particle aggregation and
growth, as well as the absence of recrystallization upon product
storage.
[0212] In some embodiments, the invention provides multimodal
(polymodal) mixtures of particulates for nasal administration. In
some embodiments, such a multimodal mixture is a bimodal mixture in
a suitable carrier, such as an aqueous carrier or a non-aqueous
carrier (e.g. a non-aqueous propellant) as described herein. In
general, a multimodal mixture comprises two or more populations of
particles having distinct mean particle diameters. In addition to
differing in mean particle size, the two or more populations of
particles may differ in terms of the active pharmaceutical
ingredient or ingredients in each, the presence or absence of one
or more surface active agents (surfactants) on one or other of the
populations of particles, etc. In some embodiments, the two or more
populations of particles are formed separately and then mixed
together, optionally in the presence of a suitable carrier, in
appropriate proportions. In some embodiments, the multimodal
mixture is a bimodal mixture comprising about 1 to 50% of a first
population of particles and about 50 to about 99% of the second
population of particles, wherein the percentages refer to the
percent by weight of the one population of particles in relation to
the total weight of all particles prior to mixing the two
populations of particles together. In some embodiments, the
multimodal mixture comprises about 2 to about 48% of the first
population of particles and about 52 to about 98% of the second
population of particles. In some particular embodiments, the
multimodal mixture comprises about 5 to about 45% of the first
population of particles and about 55 to about 95% of the second
population of particles.
[0213] A mixture of two or more different sized particles results
in modified pharmacokinetic properties as compared to a monomodal
composition, as the smaller sized particles generally are absorbed
across the nasal mucosal at a more rapid rate, while the larger
sized particles tend to be absorbed more slowly. Thus, mixture
comprising two or more populations of particles will tend to
exhibit a plasma concentration curve for the active pharmaceutical
ingredient having a shape characteristic of modified release:
either a multimodal plasma concentration curve, a plasma
concentration curve having a single mode (local maximum
concentration on the concentration curve) and one or more shoulders
(leading, trailing or both) or a single mode and a more pronounced
tail. In comparison to a composition comprising a population of
particles having as single particle diameter mode, a multimodal
composition may have a lower peak concentration (Cmax). In some
embodiments, the time required to reach Cmax (Tmax) may be
prolonged, as Cmaxmay not be achieved until after the second
population of particles begins to contribute significantly to the
plasma concentration. In some embodiments, a first Cmax (Cmax1) may
be obtained in a relatively short period of time (Tmax1), and a
second, distinct Cmax (Cmax2), may be obtained at a later time
(Tmax2). Such distinctly bimodal release curves may have the
benefit of providing a first "burst" of activity (especially
anticonvulsant activity), and a later, more gradual release of
active pharmaceutical ingredient for maintenance purposes (e.g.
prevention of relapse into convulsion after the "burst" has begun
to dissipate.) Thus, in some embodiments, the invention provides a
first bolus of active ingredient, e.g. for the purposes of
terminating or palliating the effects of a convulsion, and a longer
period during which an effective concentration of the active
pharmaceutical ingredient remains in the plasma. In some
embodiments, the concentration of active pharmaceutical ingredient
provided by the initial bolus is sufficient to terminate a
convulsion or reduce the duration, severity or both of the
convulsion. In some embodiments, the effective concentration
present in the plasma after the initial bolus is a prophylactic
dose of the active pharmaceutical ingredient. It is to be
understood that prophylaxis is intended to mean reduction in the
likelihood that another convulsion will occur, or if one does
occur, that it will be of shorter duration, lesser severity or
both, than if the patient were not treated.
[0214] In some embodiments, the invention provides extended release
of active pharmaceutical ingredient as compared to a monomodal
composition, especially one comprising only smaller diameter
particles (e.g. less than about 1000 nm).
[0215] In some embodiments, two or more active pharmaceutical
ingredients may be combined in a single formulation. In some
embodiments, the first population of particles may comprise a first
active pharmaceutical ingredient and the second population of
particles a second active pharmaceutical ingredient. In some
embodiments, the first population of particles may comprise a first
active pharmaceutical ingredient and a second active pharmaceutical
ingredient, and the second population of particles may comprise a
second active pharmaceutical ingredient, and optionally either the
first active pharmaceutical ingredient, a third active
pharmaceutical ingredient or a combination thereof. In such cases,
it is considered that at least two distinct plasma concentration
curves will be obtained--one for the first active pharmaceutical
ingredient, one for the second active pharmaceutical ingredient and
optionally (where present), a third active pharmaceutical
ingredient. It is furthermore considered that each distinct plasma
concentration curve, considered by itself, may appear to be a
normal monomodal plasma concentration curve. (Such would especially
be the case in a bimodal mixture in which the first population of
particles contained a first active pharmaceutical ingredient only
and the second population of particles contained a second active
pharmaceutical ingredient only.) However, in such cases, it is
considered that overlaying the two or more concentration curves (or
summing them) would produce one of the characteristic curves
above--i.e. pure bimodal, monomodal with a shoulder or monomodal
with a pronounced tail. It is also considered that one or more of
the plasma concentration curves may itself be of one of the
characteristic shapes for a multimodal mixture of particles. (Such
may be the case in a bimodal mixture in which both of the
populations of particles comprises a the same active pharmaceutical
ingredient.) It is considered that overlaying the two or more
concentration curves (or summing them) would produce one of the
characteristic curves above--i.e. pure bimodal, monomodal with a
shoulder or monomodal with a pronounced tail.
[0216] The two or more populations of particles may also differ
from each other regarding coatings applied to the particles. In
some embodiments, one population of particles may be uncoated and
one or more additional populations may be coated with one or more
coatings comprising enhancers, surface active agents, or both. In
some embodiments, one population of particles may be coated with
one type of coating and one or more additional populations of
particles may be coated with a different type of coating. In some
embodiments, for example, a small population of particles (e.g.
about 25 to about 500 nm in diameter) may be coated uncoated, while
a second, larger population of particles (e.g. about 1000 to about
10,000 nm) may be coated with an enhancer, a surface active agent
that aids in adherence of the particles to the mucosa, or both. In
some embodiments, the smaller population of particles (e.g. about
25 to about 500 nm in diameter) may be coated with a thin layer of
enhancer and the second, larger population of particles (e.g. about
1000 to about 10,000 nm) may be coated with a layer of enhancer
overlayed with a layer of surface active agent or with a layer of
enhancer combined with surface active agent. The person skilled in
the art will recognize that other combinations are possible. For
example, in some embodiments both smaller (e.g. about 25 to 500 nm
diameter) particles and larger (e.g. about 1000 to about 10,000 nm)
particles may be coated with enhancer, surface active agent or
both.
EXAMPLES
[0217] The invention will now be illustrated with reference to the
following illustrative, non-limiting examples.
Example 1
[0218] Compositions comprising diazepam, lorazepam and/or midazolam
(or pharmaceutically acceptable salts thereof) are prepared. The
compositions are bimodal, comprising a first population of
particles having a mean particle diameter of about 100 nm to about
300 nm and a second population of particles having a mean particle
diameter of about 2500 to about 3500 nm (about 2.5 to about 3.5
.mu.m). The first population of particles is prepared as described
herein. The second population is then prepared as described herein.
The two populations of particles are then combined in the weight
proportions indicated in the Table below, mixed with a suitable
delivery vehicle and dispensed into a suitable container for nasal
installation. Compositions according this example are set forth in
the following table.
TABLE-US-00001 TABLE Pop. 1 Pop. 1 Pop. 2 Pop. 2 Pop. 1 Mean
Percent Pop. 2 Mean Percent Active Particle weight Active Particle
weight of Pharmaceutical Diameter of total Pharmaceutical Diameter
total Ingredient (nm) particles Ingredient (.mu.m) particles
Carrier Diazepam 100 nm 50 Diazepam 2.5 50 Saline Diazepam 100 nm
45 Diazepam 2.5 55 Saline Lorazepam 100 nm 50 Lorazepam 2.5 50
Saline Lorazepam 100 nm 45 Lorazepam 2.5 55 Saline Midazolam 100 nm
50 Midazolam 2.5 50 Saline Midazolam 100 nm 45 Midazolam 2.5 55
Saline Diazepam 100 nm 50 Diazepam 3.5 50 Saline Diazepam 100 nm 45
Diazepam 3.5 55 Saline Lorazepam 100 nm 50 Lorazepam 3.5 50 Saline
Lorazepam 100 nm 45 Lorazepam 3.5 55 Saline Midazolam 100 nm 50
Midazolam 3.5 50 Saline Midazolam 100 nm 45 Midazolam 3.5 55 Saline
Diazepam 300 nm 50 Diazepam 2.5 50 Saline Diazepam 300 nm 45
Diazepam 2.5 55 Saline Lorazepam 300 nm 50 Lorazepam 2.5 50 Saline
Lorazepam 300 nm 45 Lorazepam 2.5 55 Saline Midazolam 300 nm 50
Midazolam 2.5 50 Saline Midazolam 300 nm 45 Midazolam 2.5 55 Saline
Diazepam 300 nm 50 Diazepam 3.5 50 Saline Diazepam 300 nm 45
Diazepam 3.5 55 Saline Lorazepam 300 nm 50 Lorazepam 3.5 50 Saline
Lorazepam 300 nm 45 Lorazepam 3.5 55 Saline Midazolam 300 nm 50
Midazolam 3.5 50 Saline Midazolam 300 nm 45 Midazolam 3.5 55 Saline
Midazolam 100 nm 50 Diazepam 3.5 50 Saline Diazepam 100 nm 15
Diazepam 2.5 25 Saline Diazepam 100 nm 50 Lorazepam 2.5 50 Saline
Midazolam 100 nm 45 Lorazepam 2.5 55 Saline Lorazepam 100 nm 50
Midazolam 2.5 50 Saline Midazolam 100 nm 30 Diazepam 2.5 70 Saline
Diazepam 100 nm 50 Lorazepam 3.5 50 Saline Diazepam 100 nm 45
Diazepam 3 55 Saline Lorazepam 100 nm 50 Lorazepam 3.5 50 Saline
Lorazepam 100 nm 45 Midazolam 3.5 55 Saline Midazolam 100 nm 50
Midazolam 3.5 50 Saline Midazolam 100 nm 45 Diazepam 3.5 55 Saline
Diazepam 300 nm 50 Diazepam 2.5 50 HFC Diazepam 300 nm 45 Midazolam
2.5 55 HC Lorazepam 300 nm 50 Midazolam 2.5 50 HFC Lorazepam 300 nm
45 Lorazepam 2.5 55 HC Midazolam 300 nm 20 Lorazepam 2.5 80 HFC
Midazolam 300 nm 45 Diazepam 2.5 55 HC Diazepam 300 nm 50 Diazepam
3.5 50 Saline Diazepam 300 nm 45 Diazepam 3.5 55 Saline Lorazepam
300 nm 50 Lorazepam 3.5 50 Saline Lorazepam 300 nm 45 Lorazepam 3.5
55 Saline Midazolam 300 nm 50 Midazolam 3.5 50 Saline Midazolam 300
nm 45 Midazolam 3.5 55 Saline Saline: 0.9% NaCl, optionally pH
adjusted to 6 to 7.5 with NaOH or H.sub.2SO.sub.4 HFC:
Hydrofluorocarbon propellant HC: Hydrocarbon propellant
Example 2
[0219] Compositions comprising diazepam, lorazepam and/or midazolam
(or pharmaceutically acceptable salts thereof) are prepared. The
compositions are bimodal, comprising a first population of
particles having a mean particle diameter of about 100 nm and a
second population of particles having a mean particle diameter of
about 3000 nm (about 3 .mu.m). The first population of particles is
prepared as described herein. The second population is then
prepared as described herein. The two populations of particles are
then combined in the weight proportions indicated below, mixed with
a suitable delivery vehicle and dispensed into a suitable container
for nasal installation. Compositions according this example are set
forth in the following table.
TABLE-US-00002 TABLE Pop. 1 Pop. 1 Pop. 2 Pop. 2 Active Percent
Active Percent Pharma- weight Pharma- weight of Composition
ceutical of total ceutical total No. Ingredient particles
Ingredient particles Carrier 1 Diazepam 50 Diazepam 50 Saline 2
Diazepam 45 Diazepam 55 Saline 3 Lorazepam 50 Lorazepam 50 Saline 4
Lorazepam 45 Lorazepam 55 Saline 5 Midazolam 50 Midazolam 50 Saline
6 Midazolam 45 Midazolam 55 Saline 7 Diazepam 50 Diazepam 50 HFC 8
Diazepam 45 Diazepam 55 HC 9 Lorazepam 50 Lorazepam 50 HC 10
Lorazepam 45 Lorazepam 55 HFC 11 Midazolam 50 Midazolam 50 HFC 12
Midazolam 15 Midazolam 85 HFC 13 Diazepam 15 Diazepam 85 Saline 14
Diazepam 85 Diazepam 15 Saline 15 Lorazepam 15 Lorazepam 85 Saline
16 Lorazepam 75 Lorazepam 25 Saline 17 Midazolam 60 Midazolam 40
Saline 18 Midazolam 25 Midazolam 75 Saline 19 Diazepam 15 Midazolam
85 Saline 20 Diazepam 15 Diazepam 85 HFC 21 Lorazepam 15 Lorazepam
85 HFC 22 Lorazepam 45 Lorazepam 55 HC 23 Midazolam 50 Diazepam 50
Saline 24 Midazolam 45 Lorazepam 55 Saline 25 Midazolam 80
Lorazepam 20 Saline 26 Midazolam 15 Diazepam 75 Saline 27 Diazepam
50 Lorazepam 50 Saline 28 Midazolam 45 Lorazepam 55 HFC 29
Lorazepam 50 Midazolam 50 Saline 30 Midazolam 30 Diazepam 70 Saline
31 Diazepam 50 Lorazepam 50 HFC 32 Diazepam 45 Midazolam 55 Saline
33 Lorazepam 20 Midazolam 80 HC 34 Lorazepam 45 Midazolam 55 Saline
35 Midazolam 35 Midazolam 65 Saline 36 Midazolam 65 Diazepam 35
Saline 37 Diazepam 50 Diazepam 50 HC 38 Diazepam 45 Midazolam 55 HC
39 Lorazepam 50 Midazolam 50 HFC 40 Lorazepam 20 Lorazepam 80 HC 41
Midazolam 20 Lorazepam 80 HFC 42 Midazolam 45 Diazepam 55 HC 43
Diazepam 50 Lorazepam 50 Saline 44 Diazepam 45 Lorazepam 55 Saline
45 Lorazepam 20 Lorazepam 80 Saline 46 Lorazepam 45 Lorazepam 55
Saline 47 Midazolam 50 Midazolam 50 Saline 48 Midazolam 45
Midazolam 55 Saline Saline: 0.9% NaCl, optionally pH adjusted to 6
to 7.5 with NaOH or H.sub.2SO.sub.4 HFC: Hydrofluorocarbon
propellant HC: Hydrocarbon propellant
[0220] While preferred embodiments of the present invention have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
invention. It should be understood that various alternatives to the
embodiments of the invention described herein may be employed in
practicing the invention. It is intended that the following claims
define the scope of the invention and that methods and structures
within the scope of these claims and their equivalents be covered
thereby.
* * * * *