U.S. patent application number 14/323115 was filed with the patent office on 2015-01-08 for novel aerosol formulations of ondansetron and uses thereof.
This patent application is currently assigned to Luxena Pharmaceuticals, Inc.. The applicant listed for this patent is Luxena Pharmaceuticals, Inc.. Invention is credited to Xiaodong LI, George Lu.
Application Number | 20150010633 14/323115 |
Document ID | / |
Family ID | 52132968 |
Filed Date | 2015-01-08 |
United States Patent
Application |
20150010633 |
Kind Code |
A1 |
LI; Xiaodong ; et
al. |
January 8, 2015 |
NOVEL AEROSOL FORMULATIONS OF ONDANSETRON AND USES THEREOF
Abstract
Aerosol formulations of ondansetron useful for pulmonary
delivery are provided. The formulations are useful in the
reduction, elimination or prevention of nausea and vomiting
associated with chemotherapy, radiation therapy, and surgery. Also
provided are novel methods to treat chemotherapy-induced nausea and
vomiting (CINV), radiation-induced nausea and vomiting (RINV), and
post-operative nausea and vomiting (PONV) using the inhalation
formulations.
Inventors: |
LI; Xiaodong; (Sunnyvale,
CA) ; Lu; George; (Palo Alto, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Luxena Pharmaceuticals, Inc. |
Santa Clara |
CA |
US |
|
|
Assignee: |
Luxena Pharmaceuticals,
Inc.
Santa Clara
CA
|
Family ID: |
52132968 |
Appl. No.: |
14/323115 |
Filed: |
July 3, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61842791 |
Jul 3, 2013 |
|
|
|
61909972 |
Nov 27, 2013 |
|
|
|
Current U.S.
Class: |
424/489 ; 424/46;
514/397 |
Current CPC
Class: |
A61K 31/4178 20130101;
A61P 1/08 20180101; A61K 9/1623 20130101; A61K 9/0075 20130101;
A61K 9/16 20130101; A61K 9/008 20130101; A61K 47/26 20130101 |
Class at
Publication: |
424/489 ;
514/397; 424/46 |
International
Class: |
A61K 9/16 20060101
A61K009/16; A61K 9/00 20060101 A61K009/00; A61K 31/4178 20060101
A61K031/4178 |
Claims
1. A formulation, comprising: ondansetron having a mass median
aerodynamic diameter of between 0.05 and 20 microns; and optionally
at least one selected from the group consisting of a
pharmaceutically acceptable excipient and a propellant, wherein the
excipient is selected from the group consisting of a carbohydrate,
an amino acid, a polypeptide, a lipid, a salt, a polyalcohol, an
oleate, a stearate, a myristate, an alkylether, an alkyl arylether,
and a sorbate.
2. The formulation of claim 1, wherein the pharmaceutically
acceptable excipient is present and comprises galactose, mannose,
sorbose, lactose, glucose, trehalose, raffinose, maltodextrins,
dextrans, mannitol, xylitol, or any mixture thereof.
3. The formulation of claim 2, wherein the pharmaceutically
acceptable excipient is lactose, glucose, or a mixture thereof.
4. The formulation of claim 1, wherein the propellant is present
and comprises 1,1,1,2-tetrafluoroethane,
1,1,1,2,3,3,3-heptafluoro-n propane, or a mixture thereof.
5. The formulation of claim 4, wherein the pharmaceutically
acceptable excipient is present and comprises an oleate, a
stearate, a myristate, an alkylether, an alkyl arylether, a
sorbate, or any mixtures thereof.
6. The formulation of claim 5, wherein the pharmaceutically
acceptable excipient is sorbitan trioleate, isopropyl myristate, or
a mixture thereof.
7. The formulation of claim 4, further comprising: a cosolvent,
which is C.sub.2-6 alcohol, polyols, cineole, citral, lactic acid
oligomers, poly(ethylene glycols), or a mixture thereof.
8. The formulation of claim 1, wherein the ondansetron has a mean
geometric diameter between 0.05 and 20 microns.
9. The formulation of claim 1, wherein the mass median aerodynamic
diameter of the ondansetron is from 0.5 to 5 microns.
10. The formulation of claim 9, wherein the proportion of
ondansetron particles with aerodynamic diameters less than 5 .mu.m
is from 70% to 100%.
11. The formulation of claim 9, wherein the proportion of
ondansetron particles with aerodynamic diameters less than 5 .mu.m
is from 10% to 70%.
12. The formulation of claim 2, wherein the pharmaceutically
acceptable excipient comprises a powder having an average particle
size of <5 to 200 microns.
13. The formulation of claim 12, wherein the pharmaceutically
acceptable excipient is a mixture of a first excipient powder
having an average particle size from <5 to 50 microns and a
second excipient powder having an average particles size of 50 to
200 microns.
14. The formulation of claim 13, wherein the first excipient powder
and the second excipient powder are each independently lactose or
glucose.
15. The formulation of claim 14, wherein formulation contains
0.1-40 mg of the powdered ondansetron and from 0.001-2.5 g of the
lactose and/or glucose.
16. The formulation of claim 4, wherein formulation contains
0.1-400 mg of the ondansetron and from 0.5-50 g of the
1,1,1,2-tetrafluoroethane and/or 1,1,1,2,3,3,3-heptafluoro-n
propane.
17. The formulation of claim 1, wherein the amount of the
ondansetron in the formulation is from 0.01 to 100 wt %, based on
the total weight of the formulation.
18. The formulation of claim 17, wherein the formulation is a dry
powder formulation and the amount of the ondansetron in the
formulation is from 0.05 to 100 wt %, based on the total weight of
the formulation.
19. The formulation of claim 17, wherein the formulation is a pMDI
formulation and the amount of the ondansetron in the formulation is
from 0.01 to 20 wt %, based on the total weight of the
formulation.
20. The formulation of claim 1, wherein the ondansetron has
respirable fraction of 15% or more.
21. A method of treating nausea or vomiting, the method comprising:
administering the formulation of claim 1 to a subject in need
thereof, wherein the formulation is administered into the pulmonary
tract of the subject by inhalation.
22. The method of claim 21, wherein from 0.1 mg to 40 mg of
ondansetron are administered.
23. The method of claim 21, wherein a total dosage of ondansetron
is from 0.1 mg to 40 mg per day.
24. The method of claim 21, wherein the administration provides at
least one of the following: a maximum ondansetron concentration
(Cmax) in plasma from 1 ng/mL to 5000 ng/mL; a maximum
concentration in the plasma ondansetron reaches at (Tmax) from 1
minute to 2 hours; and an area under curve (AUC) of ondansetron in
blood plasma from 2 ng*h/mL to 50000 ng*h/mL.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is the utility application based on,
and claiming benefit to, U.S. Provisional Application Ser. No.
61/842,791, filed on Jul. 3, 2013, and U.S. Provisional Application
Ser. No. 61/909,972, filed on Nov. 27, 2013.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not Applicable.
THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT
[0003] Not Applicable.
INCORPORATION-BY-REFERENCE OF THE MATERIAL ON THE COMPACT DISC
[0004] Not Applicable.
BACKGROUND OF THE INVENTION
[0005] 1. Field of the Invention
[0006] Provided herein are novel aerosol inhalation formulations of
ondansetron for pulmonary delivery; and uses thereof in the
reduction, elimination or prevention of nausea and vomiting
associated with chemotherapy, radiation therapy and surgery. Also
provided are methods to treat chemotherapy-induced nausea and
vomiting (CINV), radiation-induced nausea and vomiting (RINV), and
post-operative nausea and vomiting (PONV) using the inhalation
formulations.
[0007] 2. Description of the Related Art Including Information
Disclosed Under 37 CFR 1.97 and 1.98
[0008] Cancer is one of the major causes of death in the modern
world. Major therapies to treat cancers include chemotherapy,
radiation therapy and surgery. Nausea and vomiting are among the
most common side-effects of these treatments. Patients receiving
highly emetogenic agents may postpone, or even refuse, potentially
curative treatments. Increasing of blood level of serotonin and
activation of the 5-HT.sub.3 receptors in the chemoreceptor trigger
zone in the brain are believed to be related to the emetic
responses to cancer treatments [Hornby, 2001].
[0009] Ondansetron is a 5-HT.sub.3 receptor antagonist used mainly
as an antiemetic often following chemotherapy, radiation therapy
and surgery. Ondansetron is believed to block 5-HT.sub.3 receptors
in the chemoreceptor trigger zone [Cooke et al., 1994]. It is
believed to reduce the activity of the vagus nerve, hence the
compound deactivates the vomiting center in the medulla oblongata
[Ye et al., 2001]. FIG. 1 shows the skeletal formula of
ondansetron.
[0010] Currently, ondansetron is administered either through
injection (slow IV or IM) or as oral tablets. Injection of
ondansetron, although effective in reducing or preventing nausea
and vomiting, is inconvenient, invasive and causes pain to the
patients. Existing forms of oral ondansetron tablets can be
difficult to swallow and may be undesirable to some patients
requiring anti-emetic therapy, especially those patients who have
severe nausea or vomiting.
[0011] Thus, there remains a need for new formulations and for
novel methods to administer ondansetron. The formulations, and
methods described herein are directed toward this end.
BRIEF SUMMARY OF THE INVENTION
[0012] In one aspect, the present invention provides novel aerosol
formulations comprising ondansetron useful for pulmonary delivery
to a subject. In one embodiment, the aerosol formulations are
administered by inhalation. In another embodiment, the aerosol
formulations are delivered into the circulation via the pulmonary
tract. In one embodiment, the subject is a patient such as a cancer
patient.
[0013] In certain aspects, the present invention provides
pharmaceutical aerosol inhalation formulations comprising
ondansetron.
[0014] In certain aspects, the aerosol formulations of the present
invention are useful for the reduction, elimination or prevention
of various medical conditions including chemotherapy-induced nausea
and vomiting (CINV), radiation-induced nausea and vomiting (RINV),
and post-operative nausea and vomiting (PONY).
[0015] In another aspect, the present invention provides methods of
treating a condition of nausea or vomiting, wherein the method
comprises pulmonary administration of a pharmaceutically acceptable
amount of the aerosol formulations of the present invention, and
wherein the aerosol formulations are administered into the
pulmonary tract by inhalation.
[0016] In yet another aspect, the present invention provides
methods for pulmonary delivery of ondansetron to a subject that
comprise having the subject inhale a pharmaceutically acceptable
amount of the aerosol formulation of the present invention through
the subject's mouth into the circulation via the pulmonary tract.
In one embodiment, the subject is a cancer patient.
[0017] In yet another aspect, the present invention provides a
method for pulmonary delivery of ondansetron to a subject, where
the method comprises having the subject inhale a pharmaceutically
acceptable amount of the aerosol formulation of the present
invention through the subject's nose into the circulation via the
pulmonary tract. In one embodiment, the subject is a cancer
patient.
[0018] In yet another aspect, with respect to the aerosol
formulations or methods of the present invention, the pulmonary
administration of the aerosol formulations minimizes the first pass
metabolism before the drug reaches the target receptors since there
is rapid transport from the alveolar epithelium into the
circulation. In addition, the pulmonary administration of the
aerosol formulations of the present invention by inhalation avoids
gastrointestinal intolerance which is typical for nausea and
vomiting sufferers.
[0019] Other objects and advantages will become apparent to those
skilled in the art from a consideration of the ensuing detailed
description.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0020] FIG. 1: Skeletal Formula of Ondansetron
[0021] FIG. 2: A typical particle size distribution of spray dried
ondansetron powder.
[0022] FIG. 3: The aerosol particle size distribution (ASPD) of 5
runs of the spray dried ondansetron under ambient temperature and
humidity conditions of .about.22.degree. C. and 20% RH.
[0023] FIG. 4: The ASPD of 4 runs of the LH201 blend at 60 LPM and
under ambient temperature and humidity conditions of
.about.22.degree. C. and 20% RH.
DETAILED DESCRIPTION OF THE INVENTION
[0024] The present invention provides novel aerosol formulations
comprising ondansetron useful for pulmonary delivery to a subject.
In one embodiment, the aerosol formulations are administered by
inhalation. In another embodiment, the aerosol formulations are
delivered into the circulation via the pulmonary tract. The subject
for whom the aerosol formulations are administered may be a mammal,
such as a human. In one embodiment, the subject is a patient; in
particular, the subject is a cancer patient.
[0025] The present invention also provides pharmaceutical aerosol
inhalation formulations comprising powdered ondansetron. In one
embodiment, with respect to the aerosol inhalation formulation, the
mass median aerodynamic diameter (MMAD) of powdered ondansetron is
between 0.05 and 20 microns, preferably the powdered ondansetron
has an MMAD between 0.5 and 5 microns. In another embodiment, the
aerosol formulations are useful for pulmonary delivery of
ondansetron to a subject. In one embodiment, the subject is a
cancer patient.
[0026] The present invention provides inhalable pharmaceutical
aerosol formulations comprising powdered ondansetron, wherein the
MMAD of powdered ondansetron is between 0.05 and 20 microns; and
wherein the formulations are useful for pulmonary delivery to a
subject, where the subject is a cancer patient. In one embodiment,
the aerosol formulations are delivered into the circulation via
pulmonary tract of the subject and the subject is a cancer
patient.
[0027] In certain aspects, the aerosol formulations of the present
invention are useful for the reduction, elimination, or prevention
of nausea and vomiting associated with various medical conditions
including chemotherapy-induced nausea and vomiting (CINV),
radiation-induced nausea and vomiting (RINV), and post-operative
nausea and vomiting (PONY).
[0028] In certain aspects, the aerosol formulations of the present
invention are administered by subjects via an inhaler allowing
ondansetron to enter the circulation rapidly.
[0029] In certain aspects, the aerosol formulations of the present
invention provide a novel route of administration of ondansetron to
subjects who have severe nausea or vomiting, or to subjects who are
not willing to or not able to swallow or to be injected.
[0030] In certain aspect, the aerosol formulations of the present
invention contains ondansetron that is in a solute form. In certain
aspect, the aerosol formulations of the present invention contains
ondansetron that is in a powdered form.
[0031] In certain aspect, the aerosol formulations of the present
invention contains ondansetron that is in a powdered form, and the
powdered ondansetron is in a dry powder form.
[0032] In certain aspect, the aerosol formulations of the present
invention contains ondansetron that is in a powdered form, and the
powdered ondansetron is in a suspension. In certain aspect, the
powdered ondansetron suspension is in a liquid selected from a
group consisting of propellants, hybrid propellants, propellants
with stabilizers, propellants with surfactants, propellants with
diluents, propellants with cosolvents, water, buffer, and
combinations thereof.
[0033] In certain aspect, the aerosol formulations of the present
invention contains ondansetron that is a solute in a solution, and
the solvent is selected from a group consisting of propellants,
hybrid propellants, cosolvents, cosolvent mixture, organic
solvents, water, buffers, and combinations thereof.
[0034] When the ondansetron in the aerosol formulations is in a
powdered form, the powdered ondansetron is produced by one or more
particle engineering processes [Chow et al., 2007]. For example,
the powdered ondansetron may be produced by a mechanical
micronization operation selected from the group consisting of
crushing, cutting, bashing, milling, and grinding. In another
embodiment, the powdered ondansetron is produced by a precipitation
process, such as spray drying, solution precipitation,
lyophilization, or combinations of the foregoing. Yet in another
embodiment, the powered ondansetron is produced by one of more
precipitation processes followed by one or more mechanical
micronization processes.
[0035] In one embodiment, the powdered ondansetron of the aerosol
formulations is produced by a spray drying process. The spray
drying process may be followed by a cyclone separation/filtering
process.
[0036] In another embodiment, the powdered ondansetron of the
aerosol formulations is produced by a direct controlled
crystallization process. The direct controlled crystallization
process may utilize an antisolvent precipitation technique.
Moreover, the size range of the crystallines may be controlled by
one or more growth-retarding stabilizing additives.
[0037] In yet another embodiment, the powdered ondansetron of the
aerosol formulations is produced by a supercritical fluid process.
The supercritical fluid process is selected from the group
consisting of rapid expansion of supercritical solution (RESS),
solution enhanced diffusion (SEDS), gas-anti solvent (GAS),
supercritical antisolvent (SAS), precipitation from gas-saturated
solution (PGAS), precipitation with compressed antisolvent (PCA)
and aerosol solvent extraction system (ASES).
[0038] In a particular embodiment, with respect to the aerosol
formulations, the powdered ondansetron is produced by supercritical
fluid process, and the process is rapid expansion of supercritical
solution (RESS) process. In another particular embodiment, the
process is solution enhanced diffusion (SEDS) process. In yet
another particular embodiment, the process is gas-anti-solvent
(GAS) process. In yet another particular embodiment, the process is
supercritical-anti-solvent (SAS) process. In yet another particular
embodiment, the process is precipitation from gas-anti-solvent
(PGAS) process. In yet another particular embodiment, the process
is precipitation with compressed anti-solvent (PCA) process. In yet
another particular embodiment, the process is aerosol solvent
extraction system (ASES) process. In yet another particular
embodiment, the process is any combinations of the foregoing.
[0039] In a more particular embodiment, with respect to the aerosol
formulations, the powdered ondansetron is produced by a
supercritical fluid process, and the supercritical fluid process is
rapid expansion of supercritical solution process.
[0040] In one embodiment, with respect to the aerosol formulations,
the mean geometric diameter of powdered ondansetron is at least
0.01 microns, at least 0.05 microns, at least 0.1 microns, at least
0.25 microns, at least 0.5 microns, at least 0.75 microns, at least
0.9 microns, at least 1 microns, at least 1.25 microns, at least
1.5 microns, at least 1.75 microns, or even at least 2.0 microns.
The mean geometric diameter of powdered ondansetron is at most 20
microns, at most 15 microns, at most 12 microns, at most 10
microns, at most 9 microns, at most 8 microns, at most 7.5 microns,
at most 7 microns, at most 6.5 microns, at most 6.0 microns, at
most 5.75 microns, at most 5.5 microns, at most 5.25 microns, at
most 5.0 microns, at most 4.75 microns, at most 4.5 microns, at
most 4.25 microns, at most 4.0 microns, at most 3.75 microns, at
most 3.5 microns, at most 3.25 microns, and even at most 3.0
microns. The mean geometric diameter of powdered ondansetron
generally ranges from between 0.05 and 30 microns, preferably
between 0.1 and 20 microns, between 0.2 and 15 microns, between 0.3
and 10 microns, and more preferably between 0.5 and 5 microns.
Advantageously, the mean geometric diameter of powdered ondansetron
is between 1 and 3 microns.
[0041] In a particular embodiment, with respect to the aerosol
formulations, the mean geometric diameter of powdered ondansetron
is between 0.05 and 20 microns, preferably between 0.5 and 4
microns, more preferably between 1 and 3 microns.
[0042] In one embodiment, with respect to the aerosol formulations,
the powdered ondansetron has an MMAD of at least 0.01 microns, at
least 0.05 microns, at least 0.1 microns, at least 0.25 microns, at
least 0.5 microns, at least 0.75 microns, at least 0.9 microns, at
least 1 microns, at least 1.25 microns, at least 1.5 microns, at
least 1.75 microns, or even at least 2.0 microns. The MMAD of
powdered ondansetron is at most 30 microns, at most 20 microns, at
most 15 microns, at most 10 microns, at most 9 microns, at most 8
microns, at most 7.5 microns, at most 7 microns, at most 6.5
microns, at most 6.0 microns, at most 5.75 microns, at most 5.5
microns, at most 5.25 microns, at most 5.0 microns, at most 4.75
microns, at most 4.5 microns, at most 4.25 microns, at most 4.0
microns, at most 3.75 microns, at most 3.5 microns, at most 3.25
microns, and even at most 3.0 microns. Generally, the MMAD of the
powdered ondansetron is between 0.05 and 30 microns, preferably
between 0.1 and 20 microns, between 0.2 and 15 microns, more
preferably between 0.3 and 10 microns, between 0.5 and 5 microns,
and especially between 1 and 3 microns.
[0043] In a particular embodiment, with respect to the aerosol
formulations, the powdered ondansetron has an MMAD between 0.05 and
20 microns, preferably between 0.5 and 4 microns, and more
preferably between 1 and 3 microns.
[0044] In one embodiment, with respect to the aerosol formulations,
the mean geometric diameter and the MMAD of powdered ondansetron
are similar. Alternatively, in another embodiment, the mean
geometric diameter and the MMAD of powdered ondansetron are
different. In one embodiment, where the mean geometric diameter and
the MMAD of powdered ondansetron are different, the difference is
due to the morphology of the ondansetron particles.
[0045] The powdered ondansetron may be a solvate, hydrate, organic
salt, inorganic salt, ester, or free base. The powdered ondansetron
may also be amorphous, crystalline, or polymorphous. Preferably,
the ondansetron is a chloride, bromide, iodide, mesylate,
methanesulphonate, para-toluenesulphonate, or methyl sulphate salt.
More preferably, the ondansetron is in the form of a hydrochloride,
anhydrous, monohydrate or dihydrate.
[0046] In one embodiment, the ondansetron particles of the aerosol
formulations are amorphous.
[0047] In one embodiment, the ondansetron particles of the aerosol
formulations are crystallines. In another embodiment, the shape of
the ondansetron particles is one of the group consisting of
spherical, ellipsoidal, cubical, diamond, rectangular,
orthorhombic, triangular, hexagonal, needlelike, and porous.
Preferably, the ondansetron particles of the aerosol formulations
are spherical.
[0048] In one embodiment, the ondansetron particles of the aerosol
formulations are polymorphous. In another embodiment, the shapes of
the ondansetron particles are two of more from the group consisting
of spherical, ellipsoidal, cubical, diamond, rectangular,
orthorhombic, triangular, hexagonal, needlelike, and porous.
[0049] In one embodiment, with respect to the aerosol formulations,
the proportion of ondansetron particles with aerodynamic diameters
less than 5 .mu.m is at least 5%, at least 10%, at least 15%, at
least 20%, at least 25%, at least 30%, at least 35%, at least 40%,
at least 45%, at least 50%, at least 55%, at least 60%, at least
70%, and preferably at least 70%. In another embodiment, the
proportion of ondansetron particles with aerodynamic diameters less
than 5 .mu.m is at most 100%, at most 99%, at most 95%, at most
90%, at most 85%, at most 80%, at most 75%, at most 70%, at most
65%, at most 60%, at most 55%, at most 50%, at most 45%, at most
40%, at most 35%, at most 30%, at most 25%, at most 20%, at most
17.5%, at most 15%, and even at most 12.5%.
[0050] In one embodiment, with respect to the aerosol formulations,
the proportion of ondansetron particles with aerodynamic diameters
less than 5 .mu.m is 10% to 100%, preferably from 70% to 100%. In
another embodiment, the proportion of ondansetron particles with
aerodynamic diameters less than 5 .mu.m is from 20 to 80%,
preferably from 30% to 70%. In a further embodiment, the proportion
of ondansetron particles with aerodynamic diameters less than 5
.mu.m is 10% to 30%.
[0051] In one embodiment, with respect to the aerosol formulations,
the fine particle fraction (FPF) of ondansetron is 10% to 100%. In
certain embodiments, the minimum FPF is 50%, for instance, at least
55%, at least 60%, at least 65%, at least 70%, at least 75%, at
least 80%, at least 85%, and even at least 90%. In one embodiment,
the FPF of ondansetron is from 70% to 100%. The FPF of ondansetron
may also range from 30% to 70%. In another embodiment, the maximum
FPF of ondansetron is 50% or less, for instance, the maximum FPF of
ondansetron is at most 40%, at most 35%, at most 30%, at most 25%,
at most 20%, at most 17.5%, at most 15%, at most 12.5%, and even at
most 10%. In one embodiment, the FPF of the ondansetron is 10% to
30%.
[0052] In the aerosol formulations according to the invention, the
ondansetron has respirable fraction of 10% or more, preferably 15%
or more, 20% or more, 25% or more, 35% or more, 40% or more, 45% or
more, 50% or more, more preferably 75% or more, and even 90% or
more.
[0053] In one embodiment, the aerosol formulations do not comprise
an excipient.
[0054] In another embodiment, the aerosol formulations further
comprise a pharmaceutically acceptable excipient. The excipient is
any excipient acceptable for pulmonary delivery. More particularly,
the excipient is any inhalable excipient.
[0055] In aerosol formulations containing an excipient, the
excipient is selected from the group consisting of carbohydrates,
amino acids, polypeptides, lipids, buffers, salts, polyalcohols,
and mixtures thereof. In yet another embodiment, the excipient is
selected from the group consisting of galactose, mannose, sorbose,
lactose, glucose, trehalose, raffinose, maltodextrins, dextrans,
mannitol, xylitol, and mixtures thereof. In yet another embodiment,
the excipient is selected from the group consisting of alanine,
glycine, tryptophan, tyrosine, leucine, phenylalanine, and mixtures
thereof. In yet another embodiment, the excipient is selected from
the group consisting of oleates, stearates, myristates,
alkylethers, alkyl arylethers, sorbates, polyvinylpyrrolidone (PVP)
and mixtures thereof. In yet another embodiment, the excipient is
selected from the group consisting of 1,1,1,2-tetrafluoroethane
(P134a), 1,1,1,2,3,3,3-heptafluoro-n propane (P227), 2H,
3H-perfluoropentane (HPFP) and mixtures thereof. In yet another
embodiment, the excipient is any combinations of the foregoing.
[0056] In certain embodiments, the aerosol formulations are
pressurized metered dose formulations. In certain embodiments, the
aerosol formulations are dry powder formulations. In certain
embodiments, the aerosol formulations are nebulizer
formulations.
[0057] Dry Power Formulations
[0058] In a particular embodiment, the formulation is a dry powder
formulation containing an excipient, where the excipient is
lactose, glucose, or a mixture of lactose and glucose.
[0059] In the dry powder formulations containing a pharmaceutically
acceptable excipient, the excipient consists of powders with an
average particles size of <5 to 200 microns, from 1 to 150
microns, or from 5 to 100 microns. The excipient may consists of
powders of the same substance with an average particle size of
<5 to 200 microns, from 1 to 150 microns, or from 5 to 100
microns. There may also be a mixture of powders in which the
average particle size is from <5 to 200 microns, from 1 to 150
microns, or from 5 to 100 microns.
[0060] In particular, where the dry powder formulations further
comprise a pharmaceutically acceptable excipient and the excipient
consists of powders with an average particle size of <5 to 200
microns, the excipient may be a mixture of the same substance with
different particle size distributions. For example, in one
embodiment the pharmaceutically acceptable excipient having an
average particle size of <5 to 200 microns with different
particle size distributions is a mixture of coarser powders and
finer powders of the same substance, where the finer powders have
an average particle size from <5 to 50 microns and the coarser
powders have an average particle size of 50 to 200 microns. The
finer powders may have an average particle size from <5 to 45
microns, from 10 to 40 microns, from 15 to 35 microns, or from 20
to 30 microns, while the coarser powders may have an average
particle size from 60 to 90 microns, from 65 to 85 microns, or from
70 to 80 microns. Alternatively, the finer powders may have an
average particle size from 1 to 10 microns, from 1 to 7.5 microns,
from 1 to 5 microns, or from 2 to 5 microns, while the coarser
powders may have an average particle size from 20 to 60 microns,
from 20 to 25 microns, from 30 to 60 microns, from 40 to 60
microns, or from 50 to 60 microns. In some embodiments, the coarser
powders have an average particle size from 50 to 90 microns, from
65 to 85 microns, or from 70 to 80 microns. The proportion of finer
excipient powders may be 0.1% to 99% of the total amount of
excipient powders.
[0061] In another embodiment, with respect to the dry powder
formulations, the pharmaceutically acceptable excipient having an
average particle size of <5 to 200 microns with different
particle size distributions is a mixture of finer powders, coarser
powders, and much coarser powders of the same substance, where the
finer powders have an average particle size of <5 to 20 microns,
the coarser powders have an average particles size of 20 to 60
microns, and the much coarser powders have an average particles
size of 60 to 200 microns. Preferably, the finer powders have an
average particle size of <5 to 10 microns, the coarser powders
have an average particles size of 25 to 45 microns, and the much
coarser powders have an average particles size of 75 to 90 microns.
The proportion of finer excipient powders may be 0.1% to 99% of the
total amount of excipient powders.
[0062] In addition, in the dry powder formulations, the
pharmaceutically acceptable excipient may be a mixture of different
substances with similar particle size distributions in which the
average particle size is from <5 to 200 microns or from 5 to 100
microns.
[0063] Advantageously, the pharmaceutically acceptable excipient in
the dry powder formulations is a mixture of different substances
with different particle size distributions in which the average
particle sizes are from <5 to 200 microns. Namely, the
pharmaceutically acceptable excipient of the dry powder
formulations is a mixture of finer powders having an average
particle size of <5 to 50 microns and coarser powders with an
average particles size of 50 to 200 microns; the finer powders and
the coarser powders being different substances. The proportion of
finer excipient powders may be 0.1% to 99% of the total amount of
excipient powders.
[0064] In another embodiment, the pharmaceutically acceptable
excipient of the dry powder formulations is a mixture of finer
powders having an average particle size of <5 to 20 microns,
coarser powders having an average particles size of 20 to 60
microns, and much coarser powders having an average particles size
of 60 to 200 microns; the finer powders, the coarser powders, and
the much coarser powders being different substances. Preferably,
the finer powders have an average particle size of <5 to 15
microns, the coarser powders have an average particles size of 30
to 50 microns, and the much coarser powders have an average
particles size of 70 to 90 microns. The proportion of finer
excipient powders may be 0.1% to 99% of the total amount of
excipient powders.
[0065] In embodiments where the pharmaceutically acceptable
excipient of the dry powder formulations is a mixture of finer
powders and coarser powders; the powdered ondansetron may be
blended with the finer excipient powders first, and then the
mixture of the powdered ondansetron and the finer powders are
blended with the coarser excipient powders. Alternatively, the
powdered ondansetron may be blended with the finer excipient
powders and the coarser excipient powders separately, and then each
of the blended excipient mixtures (i.e., finer excipient powders
with powdered ondansetron and coarser excipient powders with
powdered ondansetron) are blended with each other.
[0066] In embodiments were the pharmaceutically acceptable
excipient of the dry powder formulations is a mixture of finer
powders, coarser powders, and much coarser; the powdered
ondansetron may be sequentially blended with the finer excipient
powders, the coarser excipient powders, and the much coarser
excipient powders. Alternatively, the powdered ondansetron is
blended with the finer excipient powders, the coarser excipient
powders, and the much coarser excipient powders separately, and
then the mixtures (i.e., finer excipient powders with powdered
ondansetron, coarser excipient powders with powdered ondansetron,
and much coarser excipient powders with ondansetron) are blended
with each other.
[0067] The content of the powdered ondansetron in the dry powder
formulations ranges from 0.05% to about 100% of the total
composition of formulation, preferably from about 0.05% to about
50%, from about 0.05% to about 45%, from about 0.05% to about 40%,
from about 0.05% to about 35%, from about 0.05% to about 30%, from
about 0.05% to about 25%, from about 0.05% to about 20%, from about
0.05% to about 15%, or from about 0.05% to about 10% of the total
composition of formulation.
[0068] The content of the powdered ondansetron in the dry powder
formulations may also range from about 0.1% to about 100%, from
about 0.1% to about 50%, from about 0.1% to about 45%, from about
0.1% to about 40%, from about 0.1% to about 35%, from about 0.1% to
about 30%, from about 0.1% to about 25% of the total composition of
formulation, from about 0.1% to about 20%, from about 0.1% to about
15%, or from about 0.1% to about 10% of the total composition of
formulation, preferably from about 1% to about 10% of the total
composition of formulation, and more preferably from about 5% to
about 10% of the total composition of formulation. In a particular
embodiment, with respect to the formulations, the powdered
ondansetron is about 10% of the total composition of
formulation.
[0069] Generally, the dry powder formulations contain 0.1-40 mg of
the powdered ondansetron, preferably from 0.5-20 mg, from 5-16.
[0070] In a particular embodiment, the dry powder formulations
comprise ondansetron and lactose. The dry powder formulations
containing lactose comprise ondansetron, finer lactose, and coarser
lactose, or ondansetron, finer lactose, and much coarser lactose
ondansetron, or finer lactose, coarser lactose, and much coarser
lactose. For example, the dry powder formulations may comprise
about 0.5 to about 20 mg of ondansetron, about 0.001 to about 2 g
of finer lactose, and about 0.001 to about 2 g of coarser lactose.
For example, in dry powder formulations containing ondansetron and
lactose or glucose, the amount of the ondansetron is from 0.5-20
mg, and the amount of lactose or glucose is about 0.001 g to about
2.5 g. Preferably, the amount of ondansetron is about 0.5 to about
20 mg and the amount of lactose or glucose is about 1 to about 200
mg.
[0071] In yet another particular embodiment, the dry powder
formulations comprise ondansetron and glucose. The dry powder
formulations containing glucose comprise ondansetron, finer
glucose, and coarser glucose, or ondansetron, finer glucose,
coarser glucose, and much coarser glucose. In yet another
particular embodiment, the dry powder formulations comprise about
0.5 to about 20 mg of ondansetron, about 0.001 to about 2 g of
finer glucose, and about 0.001 to about 2 g of coarser glucose. For
example, the dry powder formulations may comprise about 0.5 to
about 20 mg of ondansetron, about 1 to about 200 mg of finer
glucose, and about 1 to about 200 mg of coarser glucose.
[0072] In yet another particular embodiment, the dry powder
formulations comprise ondansetron, lactose, and glucose. The dry
powder formulations comprising ondansetron, lactose, and glucose
may comprise ondansetron, finer lactose, and coarser glucose or
ondansetron, finer glucose, and coarser lactose. For example, the
dry powder formulations may comprise about 0.5 to about 20 mg of
ondansetron, from about 0.001 to about 2 g of lactose, and from
about 0.001 to about 2 g of glucose. In one particular embodiment,
the dry powder formulations comprise from about 0.5 to about 20 mg
ondansetron, from about 0.001 to 2 g of finer lactose, and from
about 0.001 to about 2 g of coarser glucose. In an alternative
embodiment, the formulation comprises from about 0.5 to about 20 mg
of ondansetron, from about 0.001 to about 2 g of finer glucose, and
from about 0.001 to about 2 g of coarser lactose.
[0073] The aerosol formulations of the present invention are
uniform and homogeneous. The uniformity/homogeneity of the aerosol
formulations is measured by drawing 3 or more samples from the
formulation, dissolving in mobile, and testing for concentration of
the active pharmaceutical ingredient (API, ondansetron) in the
formulation by HPLC. The uniformity of the aerosol formulations is
expressed by the relative standard deviation (% RSD) of the API
concentration. The aerosol formulations have an RSD % less than 5%,
less than 4%, less than 3%, less than 2.5%, less than 2.25%, less
than 2.0%, less than 1.75%, less than 1.5%, less than 1.25%, less
than 1.0%, less than 0.75%, less than 0.5%, less than 0.25%, and
even less than 0.25%.
[0074] The discharge capacity or percent recovery of the aerosol
formulations is measurable with a Next Generation Pharmaceutical
Impactor (NGI). In this device, powders are drawn by vacuum into
different chambers representing the lung, each chamber
corresponding to a different range of aerodynamic particle size.
NGI data includes mass median aerodynamic diameter (MMAD), and fine
particle fraction (FPF). The FPF is generally assumed to represent
the fraction of particles that would deposit in vivo in the "deep
lungs," or particles that have an aerodynamic diameter of equal to
or less than 5 .mu.m. The discharge capacity or percent recovery of
the aerosol formulations of the present invention is at least 70%,
at least 75%, at least 80%, at least 85%, at least 90%, at least
91%, at least 92%, at least 93%, at least 94%, at least 95%, at
least 96%, at least 97%, at least 98%, and even at least 99%, as
measured by NGI.
[0075] The present inventors have observed that the inclusion of
fine excipient particles increases the FPF while decreasing the
MMAD. The inclusion of coarse excipient powders alone resulted in a
FPF percent delivery of 7 to 8% where the coarse particles were
lactose particles having a D10 of 3.about.6 .mu.m, a D50 of
20<25 .mu.m, and a D90 of 50.about.60 .mu.m (LACTOHALE.RTM. 201
(LH201)), or lactose particles having a D10 of .about.4 .mu.m, a
D50 of .about.55 .mu.m, and D90 a of .about.170 .mu.m
(RESPITOSE.RTM. ML001 (ML001)). However, a combination of the
coarse lactose particles ML001(D10 of .about.4 .mu.m, a D50 of
.about.55 .mu.m, and D90 a of .about.170 .mu.m) with fine lactose
excipient particles having a D50<5 .mu.m and a D90.ltoreq.10
.mu.m increased the FPF percent delivery. The FPF percent delivery
increased further where the coarse particles that were mixed with
the fine particle had a D10 of .about.30 .mu.m, a D50 of .about.60
.mu.m, and a D90 was .about.100 .mu.m (RESPITOSE.RTM. SV003
(SV003)).
[0076] In the present invention, each of the aerosol formulations
containing coarse and fine lactose particles achieved a 3-5%
increase in the delivery of FPF when the humidity of the
environment during the aerodynamic performance testing was
controlled to have a relative humidity (RH) of 50% rather than the
ambient 20% RH. It is believed that the higher-than-ambient
humidity, which is more representative of the environment in the
human inhalation route, further increases the disaggregation by
reducing the surface-energy-induced-aggregation when the
formulation is inhaled into the impactor.
[0077] Typically, the dry powdered formulations are administered by
a dry powder inhaler, a dry powder dispenser, or a dry powder
delivery device. The inhaler may be a single dose or multi-dose
inhaler. Suitable inhalers may include SPINHALER.RTM.,
ROTAHALER.RTM., AEROLIZER.RTM., INHALATOR.RTM., HANDIHALER.RTM.,
DISKHALE.RTM., DISKUS.RTM., ACCUHALER.RTM., AEROHALER.RTM.,
ECLIPSE.RTM., TURBOHALER.RTM., TURBUHALER.RTM., EASYHALER.RTM.,
NOVOLIZER.RTM., CLICKHALER.RTM., PULVINAL.RTM., NOVOLIZER.RTM.,
SKYEHALER.RTM., XCELOVAIR.RTM., PULVINA.RTM., TAIFUN.RTM.,
MAGHALER.RTM., TWISTHALER.RTM., JETHALER.RTM., FLOWCAPS.RTM.,
XCAPS.RTM., TWINCAPS.RTM., CYCLOHALER.RTM., TURBOSPIN.RTM., AIR
DPI.RTM., ORBITAL.RTM., DIRECTHALER.RTM., or an inhaler that is
newly developed.
[0078] Pressurized Metered Dose Formulations (pMDI
Formulations)
[0079] In another particular embodiment, the formulation is a pMDI
formulation containing an excipient, where the excipient selected
from the group consisting of oleates, stearates, myristates,
alkylethers, alkyl arylethers, sorbates, and mixtures thereof. In
the pMDI formulations, the excipient may include sorbitan
trioleate, isopropyl myristate, or lecithin. Additional excipients
for the pMDI formulations include oleic acid or oleic acid esters
and polyvinylpyrrolidone (PVP).
[0080] In certain embodiments, the pMDI formulations do not include
a propellant. However, the pMDI formulations generally include a
propellant, especially a hydrofluoroalkane propellant. The
hydrofluoroalkane propellants for the pMDI formulations are
selected from the group consisting of 1,1,1,2-tetrafluoroethane
(P134a), 1,1,1,2,3,3,3-heptafluoro-n propane (P227), and mixtures
P134a and P227. Another suitable propellant for the pMDI
formulations is 2H, 3H-perfluoropentane (HPFP).
[0081] The pMDI formulations may further include a diluent or a
mixture of diluents. The pMDI formulations may also include a
surfactant or a mixture of surfactants. Exemplary surfactants are
selected from the group consisting of alkylethers, alkyl
arylethers, laurates, myristates, oleates, sorbates, stearates,
propylene glycol, lipids, and combinations thereof. Preferred
surfactants are oleates, sorbates, stearates, propylene glycol, and
combinations thereof.
[0082] In certain embodiments, the pMDI formulations do not
comprise a co-solvent. However, in alternate embodiments, the pMDI
formulations contain a co-solvent or a mixture of co-solvents. The
pMDI formulations may include a co-solvent selected from C.sub.2-6
alcohols, polyols, cineole, citral, lactic acid oligomers, or
poly(ethylene glycols).
[0083] The pMDI formulations may comprises ethanol as a co-solvent.
The content of ethanol in the pMDI formulations is no more than 25%
(w/w), no more than 20% (w/w), no more than 15% (w/w), no more than
10% (w/w), no more than 8% (w/w), preferably no more than 5% (w/w)
of ethanol, no more than 2.5% (w/w), and more preferably no more
than 1% (w/w) of ethanol.
[0084] The content of the ondansetron in the pMDI formulations is
from about 0.01% to about 20%, from about 0.01% to about 10%, from
0.01% to about 5%, from about 0.01% to about 2%, from about 0.01%
to about 1%, or from about 0.01% to about 0.5% of the total
composition of the formulation. In a particular embodiment, with
respect to the pMDI formulations, the content of the ondansetron is
from about 0.1% to about 0.5% of the total composition of the
formulation.
[0085] In a particular embodiment, the pMDI formulations comprise
ondansetron and at least one selected from P134a and P227. In such
pMDI formulations, based on the size of the canister, the amount of
ondansetron is from 0.1-400 mg, and the amount of P134a and/or P227
is about 0.5 g to about 50 g. In certain embodiments, the pMDI
formulation contains ondansetron and P134a, where the amount of
ondansetron is from about 0.1 to about 400 mg, preferably about
1-200 mg, and the amount of P134a is from 0.5 g to about 50 g,
preferably about 10 g to 20 g. Similarly, the pMDI formulation may
contains ondansetron and P227, where the amount of ondansetron is
from about 0.1 to about 400 mg, preferably about 1-200 mg, and the
amount of P227 is from 0.5 g to about 50 g, preferably about 10 g
to 20 g. In pMDI formulations containing ondansetron, P134a, and
P227, the amount of ondansetron is from about 0.1 to about 400 mg,
preferably about 1-200 mg, the amount of P134a about 0.5 g to about
50 g, and the amount of P227 is about 0.5 g to about 50 g.
[0086] In further embodiments, the pMDI formulation comprises
ondansetron, P134a and/or P227, and isopropyl myristate. In certain
embodiments, the pMDI formulations contain ondansetron, P134a
and/or P227, and propylene glycol. In addition, the pMDI
formulations may contain ondansetron, P134a and/or P227, and
isopropyl laurate.
[0087] In certain embodiments, the pMDI formulations of the present
invention contains ondansetron that is a solute in a solution, and
the solvent is selected from a group consisting of propellants,
hybrid propellants, cosolvents, cosolvent mixture, organic
solvents, water, buffers, and combinations thereof.
[0088] In certain embodiments, the pMDI formulations of the present
invention contains ondansetron that is in a powdered form in a
suspension, and the suspension is in a liquid selected from a group
consisting of propellants, hybrid propellants, propellants with
stabilizers, propellants with surfactants, propellants with
diluents, propellants with cosolvents, water, buffer, and
combinations thereof.
[0089] In a particular embodiment, the pMDI formulations of the
present invention contains ondansetron that is a solute in a
solution, wherein the solubility of ondansetron is more than 0.01%
w/w, more than 0.1% w/w, or more than 1%.
[0090] In a particular embodiment, the pMDI formulations of the
present invention contains ondansetron that is in a powdered form
in a suspension, wherein the solubility of ondansetron is less than
0.1% w/w, less than 0.01% w/w, or less than 0.001%.
[0091] Typically, the pMDI formulations are administered by an
actuator, a metered dose inhaler, an aerosol dispenser, or an
aerosol delivery device.
[0092] The present invention also provides methods of treating a
condition of nausea or vomiting, wherein the method comprises
pulmonary administration of a pharmaceutically acceptable amount of
the aerosol formulations of the present invention; and wherein the
formulations are administered into the pulmonary tract by
inhalation. The pulmonary delivery of ondansetron to a subject is
carried out by having the subject inhale a pharmaceutically
acceptable amount of the aerosol formulation of the present
invention through the subject's mouth. Additionally or
alternatively, the pulmonary delivery of ondansetron to a subject
is accomplished by having the subject inhale a pharmaceutically
acceptable amount of the aerosol formulation of the present
invention through the subject's nose.
[0093] In one embodiment, the pharmaceutically acceptable amount is
produced by introducing the ondansetron into a gas stream.
Specifically, the pharmaceutically acceptable amount is produced by
introducing the ondansetron into a gas stream, and the gas stream
is the subject's inspiratory breath.
[0094] In one embodiment, with respect to the methods, the
pharmaceutically acceptable amount contains about 0.1 mg to about
40 mg of ondansetron and the total dosage is from about 0.1 mg to
about 40 mg.
[0095] Preferably, the pharmaceutically acceptable amount contains
less than about 40 mg, less than about 30 mg, less than about 25
mg, less than about 20 mg, less than about 15 mg, or less than
about 10 mg of ondansetron. In another embodiment, the
pharmaceutically acceptable amount contains more than about 0.1 mg,
more than about 0.5 mg, more than about 1 mg, more than about 2 mg,
or more than about 5 mg of ondansetron. More preferably, the
pharmaceutically acceptable amount contains about 8 mg of
ondansetron.
[0096] The total dosage of ondansetron per day is about 0.1 mg to
about 40 mg, about 0.5 mg to about 30 mg, about 1 mg to about 25
mg, about 5 mg to about 20 mg, about 8 mg to about 16 mg of
ondansetron per day.
[0097] With the dry powder formulations, the pharmaceutically
acceptable amount of ondansetron is produced by releasing blended
powders containing powdered ondansetron from a container such as a
capsule or a blister by using a device such as a dry powder
inhaler. A device may be loaded with one or more capsules/blisters
at a time. The pharmaceutically acceptable amount is produced
through one, two or multiple actuations. The releasing amount of
one actuation is preferably equal to the formulation stored in one
capsule or blister. Whereas with the pMDI formulations, the
pharmaceutically acceptable amount of ondansetron is produced by
releasing a propellant containing ondansetron from a container such
as a canister by using a device such as a pMDI inhaler. The
canister may be actuated by pressing an actuator or by inhalation.
The pharmaceutically acceptable amount is produced through one, two
or multiple actuations. The releasing amount of one actuation is
preferably less than the formulation stored in one canister. The
releasing amount is metered.
[0098] After administration to a subject, ondansetron in blood
plasma reaches a maximum concentration (Cmax) of 1-5000 ng/mL in
the subject, preferably of 2-2000 ng/mL, and more preferably of
5-1000 ng/mL in a subject.
[0099] Delivery of the aerosol formulations through the pulmonary
tract of a subject provides a Cmax of ondansetron in blood plasma
that is about 0.05 to about 1, about 0.1 to about 0.8, about 0.2 to
about 0.6, or about 0.3 to about 0.4 times of the Cmax achieved
following intravenous bolus delivery of ondansetron. Moreover,
delivery of the aerosol formulations through the pulmonary tract of
a subject to provides a Cmax of ondansetron in blood plasma that is
about 0.1 to about 1.5, about 0.2 to about 1.25, about 0.4 to about
1.1, or about 0.8 to about 1.05 times of the Cmax achieved
following oral delivery of ondansetron.
[0100] In addition, the ondansetron in blood plasma reaches maximum
concentration at (Tmax) 1 minute to 2 hours after dose in a
subject, preferably the Tmax is 2 minutes to 1 hour after dose in a
subject, and even 5 minutes to 30 minutes after dose in a subject.
Delivery of the aerosol formulations through the pulmonary tract of
a subject provides a Tmax of ondansetron in blood plasma that is
about 0.01 to about 1.5, about 0.05 to about 1, about 0.1 to about
0.8, about 0.2 to about 0.6, or about 0.3 to about 0.4 times of the
Tmax achieved following oral delivery of ondansetron.
[0101] The area under curve (AUC) of ondansetron in blood plasma of
a subject ranges from 2-50000 ng*h/mL, preferably from 5-20000
ng*h/mL, and more preferably from 10-10000 ng*h/mL. Delivery of the
aerosol formulations through the pulmonary tract produces a mean
AUC of ondansetron in blood plasma that is about 0.1 to 1.5, about
0.2 to about 1.25, about 0.4 to about 1.1, or about 0.8 to about
1.05 times of the mean AUC achieved following intravenous bolus
delivery of ondansetron. In one embodiment, the AUC is about the
same as that is achieved following intravenous bolus delivery of
ondansetron. Similarly, delivery of the aerosol formulations
through the pulmonary tract produces a mean total AUC of
ondansetron in blood plasma that is about 0.1 to about 1.5, about
0.2 to about 1.25, about 0.4 to about 1.1, or about 0.8 to about
1.05 times of the AUC achieved following oral delivery of
ondansetron. In one embodiment, the AUC is about the same as that
is achieved following oral delivery of ondansetron.
[0102] In one embodiment, the aerosol and dry powder formulations
and the method are useful for the reduction, elimination, or
prevention of nausea and vomiting, where the nausea and vomiting
are chemotherapy-induced nausea and vomiting, radiation-induced
nausea, or vomiting and post-operative nausea and vomiting.
[0103] In one embodiment, the subject is a cancer patient; in
particular, a cancer patient undergoing chemotherapy, radiotherapy,
or a surgery. Additionally, the cancer patient may suffer from
nausea and/or vomiting related to the chemotherapy, radiotherapy,
or surgery.
[0104] The powdered ondansetron of the aerosol formulations may be
prepared by dissolving the bulk ondansetron in distilled water with
co-solvents, to form a solution; spray drying the solution, to
obtain powered ondansetron; separating and filtering the powdered
ondansetron according to their sizes with a cyclone; milling and
grinding the powdered ondansetron to further reduce the size of
powered ondansetron; and collecting and analyzing the precipitated
ondansetron powder. During the milling and grinding, the milling
and grinding forces and timing are optimized so that the particle
size distribution of the processed ondansetron is from about 0.5 to
about 5 .mu.m; and the mean volume diameter is of about 2-3
.mu.m.
[0105] The powdered ondansetron of the aerosol and dry powder
formulations may also be prepared by dissolving the bulk
ondansetron in distilled water, to form a solution; spray drying
the solution with temperature in a drying vessel; separating and
filtering the powdered ondansetron according to their sizes with a
cyclone; and collecting and analyzing the precipitated ondansetron
powder. The flow rate of the solution, the temperature and the flow
rate of the drying air, and other parameters are optimized so that
the ondansetron precipitation is crystalline; and the particle size
distribution is of about 0.5 to about 5 .mu.m; and the mean volume
diameter is of about 2-3 .mu.m.
[0106] Alternatively, the powdered ondansetron of the aerosol and
dry powder formulations may be prepared by dissolving the bulk
ondansetron in supercritical fluid CO.sub.2, to form a solution;
depressuring the solution in a depressurization vessel; and
collecting and analyzing the precipitated ondansetron powder. The
temperature and the pressure of the SCF CO.sub.2 (before the
precipitation) and the depressurization vessel, and other
parameters are optimized so that the ondansetron precipitation is
crystalline; and the particle size distribution is of about 0.5 to
about 5 .mu.m; and the mean volume diameter is of about 2-3
.mu.m.
[0107] For dry powder formulations, the powdered ondansetron may be
mixed with one or more excipients, to form the dry powder
formulation. The obtained dry powder formulation is then loaded
into a dry powder inhaler. Alternatively, for pMDI formulations,
the ondansetron may be mixed with a pressurized propellant or
mixture of propellants, to form the pMDI formulation. The obtained
pMDI formulation is then filled into canisters, which are installed
into a metered-dose inhaler.
[0108] Thus, the present invention also provides pharmaceutical
aerosol inhalation formulations or inhalable pharmaceutical aerosol
formulations for pulmonary administration to a subject, wherein
[0109] the formulation is a dry power formulation and comprises
powdered ondansetron; [0110] the powdered ondansetron is produced
by a particle engineering process; [0111] the MMAD of powdered
ondansetron is between 1 and 3 microns; [0112] the formulation may
comprise excipient(s); [0113] the formulation is administered into
the pulmonary tract by inhalation; and [0114] the subject is a
cancer patient suffering from nausea that is related to
chemotherapy, radiotherapy, or surgery; [0115] or the formulation
is a pMDI formulation comprises ondansetron; [0116] the ondansetron
may be powered ondansetron produced by a particle engineering
process; [0117] the MMAD of powdered ondansetron is between 1 and 3
microns; [0118] the formulation may comprise excipient(s) and at
least a hydrofluoroalkane; [0119] the formulation is administered
into the pulmonary tract by inhalation; and [0120] the subject is a
cancer patient suffering from nausea that is related to
chemotherapy, radiotherapy, or surgery.
[0121] The powdered ondansetron may be produced by a spray drying
process that comprises: [0122] i) dissolving the bulk ondansetron
in distilled water, to form a solution; [0123] ii) spray drying the
solution in a spray dryer; [0124] iii) separating and filtering the
ondansetron particles according to their sizes with a cyclone; and
[0125] iv) collecting and analyzing the precipitated ondansetron
powder.
[0126] In another embodiment, the powdered ondansetron is produced
by a supercritical fluid process that comprises: [0127] i)
dissolving the bulk ondansetron in supercritical fluid CO.sub.2, to
form a solution; [0128] ii) depressuring the saturated solution in
a depressurization vessel; and [0129] iii) collecting and analyzing
the precipitated ondansetron powder.
[0130] In one embodiment, the formulation is a pharmaceutical dry
powder inhalation formulation that contains lactose and/or glucose
as an excipient, where the amount of ondansetron is about 0.05 to
100 wt %, about 1 to 50 wt %, about 2 to 20 wt %, or about 5 to 15
wt % of the excipient. In another embodiment, the formulation is a
pharmaceutical pMDI inhalation formulation that contains P134a
and/or P227 as propellants, where the amount of ondansetron is
about 0.01 to 20 wt %, about 0.01 to 1 wt %, or about 0.01 to 0.5
wt % of the propellant.
[0131] Delivery of the pharmaceutical aerosol inhalation
formulations into the pulmonary tract of a subject provides a Cmax
of ondansetron in blood plasma that is about 20-80% of the Cmax
achieved following intravenous bolus delivery of ondansetron. The
Cmax from delivery into the pulmonary tract may be about the same
as the Cmax achieved following oral delivery of ondansetron.
[0132] Delivery of the pharmaceutical aerosol inhalation
formulations into the pulmonary tract of a subject provides Tmax of
ondansetron in blood plasma that is less than the Tmax achieved
following oral delivery of ondansetron.
[0133] Delivery of the pharmaceutical aerosol inhalation
formulations into the pulmonary tract of a subject provides also
provides an AUC of ondansetron in blood plasma that is about the
same as the AUC achieved following intravenous bolus or oral
delivery of ondansetron.
[0134] Additional embodiments within the scope provided herein are
set forth in non-limiting fashion elsewhere herein and in the
examples. It should be understood that these examples are for
illustrative purposes only and are not to be construed as limiting
in any manner.
Pulmonary Aerosol Formulations of the Present Invention
[0135] As described herein, the aerosol formulations of the present
invention comprise ondansetron and the formulations are useful for
pulmonary delivery via inhalation. The active drug ondansetron when
administered by inhalation must penetrate deep into the lungs in
order to show physiological action. In order to achieve this, the
ondansetron inhaled should be in the powdered form. Preferably, the
MMAD of ondansetron drug does not exceed about 5 .mu.m.
Powdered Ondansetron
[0136] The powdered ondansetron can be prepared by processes of
micronization, such as mechanical grinding, attrition by jet
milling, solution precipitation, spray drying, lyophilization, and
supercritical fluid processes.
[0137] Spray dying followed by a cyclone separation/filtering
process may produce respirable particles rapidly and
efficiently.
[0138] Direct controlled crystallization using an antisolvent
precipitation technique may produce respirable particles with
expected shapes. The particle size may be controlled by using one
or more growth-retarding stabilizing additives.
[0139] Supercritical fluid processes may be used to produce
respirable particles of the desired size. The supercritical
processes may be used to prepare powdered ondansetron may include
rapid expansion, solution enhanced diffusion, gas-anti solvent,
supercritical antisolvent, precipitation from gas-saturated
solution, precipitation with compressed antisolvent, aerosol
solvent extraction system, or combinations of the foregoing.
Particularly, the typical process can be rapid expansion of
supercritical solution (RESS).
[0140] The powdered ondansetron prepared by the above processes may
have an MMAD between 0.5 and 5 .mu.m.
[0141] The amount of the powdered ondansetron in the formulation
may be about 0.01% to about 100% of the total composition of
formulation. Particularly, the amount of the powdered ondansetron
may be 0.05% to about 20% of the total composition of
formulation.
Dry Powder Formulations
[0142] Excipients
[0143] The aerosol formulations of the present invention may
comprise pharmaceutically acceptable excipients. The typical
excipients which may be used in the formulation include
carbohydrates, amino acids, polypeptides, lipids, salts,
polyalcohols, galactose, mannose, sorbose, lactose, glucose,
trehalose, raffinose, maltodextrins, dextrans, mannitol, xylitol,
alanine, glycine, tryptophan, tyrosine, leucine, phenylalanine, and
mixtures or combinations thereof
pMDI Formulations
[0144] Propellants
[0145] The pMDI formulations of the present invention may comprise
pharmaceutically acceptable propellants. Typical propellants
include hydrofluoroalkane (HFA) propellants. The hydrofluoroalkane
propellants which may be used in the pMDI formulations include
1,1,1,2-tetrafluoroethane (P134a), 1,1,1,2,3,3,3-heptafluoro-n
propane (P227), and mixtures of P134a and P227.
[0146] Surfactants
[0147] The pMDI formulations of the present invention may comprise
pharmaceutically acceptable surfactants. Typical surfactants
include alkylethers, alkyl arylethers, laurates, myristates,
oleates, sorbates, stearates, propylene glycol, lipids, and
combinations thereof.
[0148] Co-Solvents
[0149] The pMDI formulations of the present invention may comprise
pharmaceutically acceptable co-solvents. Typical co-solvents
include C.sub.2-6 alcohols, polyols, and combinations thereof.
Particularly, the co-solvent may be ethanol.
Exemplary Formulations of the Invention
[0150] The following examples illustrate certain embodiments of the
disclosure and are not intended to be construed in a limiting
manner.
Exemplary Formulations of the Invention
[0151] Formulation 1
TABLE-US-00001 Ingredient Amount Ondansetron Fine Powder 14 mg
[0152] Formulation 2
TABLE-US-00002 Ingredient Amount Ondansetron Fine Powder 5 mg
Lactose Powder 45 mg
[0153] Formulation 3
TABLE-US-00003 Ingredient Amount Ondansetron Fine Powder 5 mg
Glucose Powder 45 mg
[0154] Formulation 4
TABLE-US-00004 Ingredient Amount Ondansetron Fine Powder 14 mg
Lactose Powder 126 mg
[0155] Formulation 5
TABLE-US-00005 Ingredient Amount Ondansetron Fine Powder 5 mg Finer
Lactose Powder 4.5 mg Coarser Lactose Powder 40.5 mg
[0156] Formulation 6
TABLE-US-00006 Ingredient Amount Ondansetron Fine Powder 14 mg
Glucose Powder 126 mg
[0157] Formulation 7
TABLE-US-00007 Ingredient Amount Ondansetron Fine Powder 5 mg Finer
Glucose Powder 4.5 mg Coarser Glucose Powder 40.5 mg
[0158] Formulation 8
TABLE-US-00008 Ingredient Amount Ondansetron Fine Powder 14 mg
Lactose Powder 63 mg Glucose Powder 63 mg
[0159] Formulation 9
TABLE-US-00009 Ingredient Amount Ondansetron 80 mg HFA 134a
Propellant 10 g
[0160] Formulation 10
TABLE-US-00010 Ingredient Amount Ondansetron 80 mg HFA 134a
Propellant 10 g Isopropyl Myristate 0.1 g
[0161] Formulation 11
TABLE-US-00011 Ingredient Amount Ondansetron 80 mg HFA 227
Propellant 10 g
[0162] Formulation 12
TABLE-US-00012 Ingredient Amount Ondansetron 80 mg HFA 227
Propellant 10 g Isopropyl Myristate 0.1 g
[0163] Formulation 13
TABLE-US-00013 Ingredient Amount Ondansetron 80 mg HFA 134a
Propellant 20 g
[0164] Formulation 14
TABLE-US-00014 Ingredient Amount Ondansetron 80 mg HFA 227
Propellant 20 g
[0165] Formulation 15
TABLE-US-00015 Ingredient Amount Ondansetron 80 mg HFA 134a
Propellant 10 g HFA 227 Propellant 10 g
[0166] Formulation 16
TABLE-US-00016 Ingredient Amount Ondansetron 80 mg HFA 134a
Propellant 10 g HFA 227 Propellant 10 g Isopropyl Laurate 0.1 g
[0167] Formulation 17
TABLE-US-00017 Ingredient Amount Ondansetron 8 mg HFA 134a
Propellant 1 g
[0168] Formulation 18
TABLE-US-00018 Ingredient Amount Ondansetron 8 mg HFA 134a
Propellant 1 g Isopropyl Myristate 0.01 g
[0169] Formulation 19
TABLE-US-00019 Ingredient Amount Ondansetron 8 mg HFA 227
Propellant 1 g
[0170] Formulation 20
TABLE-US-00020 Ingredient Amount Ondansetron 8 mg HFA 227
Propellant 1 g Isopropyl Myristate 0.01 g
[0171] Formulation 21
TABLE-US-00021 Ingredient Amount Ondansetron 8 mg HFA 134a
Propellant 2 g
[0172] Formulation 22
TABLE-US-00022 Ingredient Amount Ondansetron 8 mg HFA 227
Propellant 2 g
[0173] Formulation 23
TABLE-US-00023 Ingredient Amount Ondansetron 8 mg HFA 134a
Propellant 1 g HFA 227 Propellant 1 g
[0174] Formulation 24
TABLE-US-00024 Ingredient Amount Ondansetron 8 mg HFA 134a
Propellant 1 g HFA 227 Propellant 1 g Isopropyl Laurate 0.01 g
Example 1
Preparation of Spray Dried Ondansetron Fine Powder
[0175] Powdered ondansetron was prepared by spray drying with SPRAY
DRYER SD-MICRO.TM. (manufactured by GEA Process Engineering, Inc.,
Columbia, Md., USA). The experiments were done at GEA Process
Engineering, Inc., Columbia, Md., USA.
TABLE-US-00025 TABLE 1 Parameters of Spray Drying to Prepare
Ondansetron Fine Powder N.sub.2 Inlet Outlet Spray Nozzle Conc.
(kg/ Temp. Temp. Rate Diameter Run (wt %) hr) (.degree. C.)
(.degree. C.) (g/min) (mm) 1 2.27 30 170 85 5.8 0.5 2 2.27 30 170
85 3.4 0.5 3 2.27 30 195 100 5.0 0.5
Example 2
Particle Size Distribution of Spray Dried Ondansetron Fine
Powder
[0176] The Particle Size Distribution of the Ondansetron Fine
Powder, prepared by Spray Drying using the above parameters was
measured by Malvern Mastersizer (Malvern Instruments, UK) at GEA
Process Engineering, Inc., Columbia, Md., USA.
[0177] The typical Particle Size Distribution:
[0178] Mean Size: 4.80 .mu.m
[0179] Std. Dev.: 1.59 .mu.m
[0180] D10: 3.23 .mu.m
[0181] D50: 5.01 .mu.m
[0182] D90: 7.22 .mu.m
[0183] Cumulative % on <10 .mu.m: 99.5%
[0184] FIG. 2 shows the typical Particle Size Distribution of the
Spray Dried Ondansetron.
Example 3
Fine Particle Fraction by Laser Diffraction
[0185] The Fine Particle Fraction (FPF) of the dry powder
ondansetron aerosol formulations was measured by Laser Diffraction
at Drug Dynamics Institute, College of Pharmacy, The University of
Texas at Austin, Austin, Tex., USA.
[0186] The dry powder formulation measured by NGI included:
[0187] Spray Dried Ondansetron (SDO): 14 mg;
[0188] Excipient: None.
[0189] A Malvern Spraytec equipped with an inhalation cell and
induction port was used for measuring the aerosol emitted from a
HandiHaler.RTM. operated at 60 LPM. Neat SDO was filled into size 3
hypromellose capsules and inserted into the HandiHaler.RTM..
Measurements were carried out over a 4 second duration at 10
measurements/second. The Refractive Index used for SDO was 1.68
with an imaginary index of 0.01. Particles were assumed to be
spherical.
[0190] The results showed that the FPF (defined as %<5.41 .mu.m)
of the dry powder ondansetron formulation was 15.6%.
Example 4
Fine Particle Fraction by Next Generation Impaction
[0191] The fine particle fraction (FPF) of the dry powder
ondansetron aerosol formulations was measured by Next Generation
Impaction (NGI) at Drug Dynamics Institute, College of Pharmacy,
The University of Texas at Austin, Austin, Tex., USA.
[0192] The in vitro aerodynamic performance of the dry powder
ondansetron aerosol formulations were tested by NGI. The results
reflect the in vivo (pulmonary) aerodynamic performance of the
following aerosol formulations. The Next Generation Impactor used
in this embodiment was made by Copley Scientific, GB.
[0193] The Exemplary Formulation 1 (EF1) measured by NGI
included:
[0194] Milled Ondansetron (MG): 14 mg;
[0195] Excipient: None The Exemplary Formulation 2 (EF2) that was
measured by NGI was:
[0196] Milled Ondansetron (MG): 11.5 mg;
[0197] Coarse Lactose (LH201): 100 mg;
[0198] Fine Lactose: N/A.
[0199] The lactose in the EF2 was LACTOHALE' 201 (LH201; D10 was
3.about.6 .mu.m, D50 was 20.about.25 .mu.m, D90 was 50.about.60
.mu.m) made by DFE Pharma, Germany. EF2 (SDO blended with Lactose)
was prepared by a low shear mixing process, adapted for very low
quantities of powder. SDO was incorporated into a LH201 by a three
step dilution and spatchulation. The blend was then added to a
scintillation vial and mixed by vortex mixing (1000 rpm, 15 sec, 5
cycles).
[0200] Handiflaler.RTM. was used as the model Dry Powder Inhaler
Device. The flow rate was 60 LPM (>4 kPa), the duration was 4
seconds, the total volume was 4 L. Testing was performed under
ambient conditions. The ambient conditions were approximately
22.degree. C. and 20% relative humidity (RH).
[0201] The number of NGI runs at ambient conditions were: EF1, n=5;
EF2, n=4.
[0202] All NGI runs under ambient conditions exhibited a percent
recovery greater than 90%. Aerosol particle size distribution
(APSD) of individual NGI runs are given in FIGS. 3 and 4. Mean
aerosol performance data are given in Table 2.
TABLE-US-00026 TABLE 2 The Mean APSD Parameters of EF1 and EF2
Measured by NGI at ~22.degree. C. and 20% RH. Parameter (Unit) EF1
RSD (%, EF1) EF2 RSD (%, EF2) Amount of Drug Loaded (.mu.g) 14613.6
3.6 1114.7 7.3 % Recovered 92.3 3.2 100.4 5.2 Preseparator, % of
Loaded 30.6 2.6 31.5 16.4 Delivered Dose, % of Loaded 89.7 3.9 97.8
5.3 Fine Particle Fraction (.ltoreq.5 .mu.m), % of 17.4 12.0 19.1
11.4 Delivered Mass Median Aerodynamic 4.97 4.3 4.69 2.1
Diameter(.mu.m)
[0203] The FPF of EF1 and EF2 under ambient conditions were 17.4
and 19.1%, respectively. FPF was defined as percent of particles
less than 5 .mu.m. The MMAD of EF1 and EF2-EF4 under ambient
conditions was 4.97 .mu.m, and 4.69 .mu.m, respectively.
Example 5
Solubility of Ondansetron in pMDI Formulations
[0204] The solubility of ondansetron was measured in a pMDI medium
of HFA 134 as well as a mixture of HFA 134 and ethanol.
[0205] The solubility results with HFA 134 alone were as
follows:
TABLE-US-00027 pMDI Medium 8 days HFA 134a (.mu.g/mL) 34.66 35.97
40.27 40.26 Average (RSD) 37.79 (0.077)
As shown above, the solubility of ondansetron in a propellant
alone, HFA 134a, was 37.79 .mu.g/mL after 8 days. Since the gravity
of the HFA 134a is 1.21 g/mL, the above results are equal to
0.00312% w/w.
[0206] The solubility of ondansetron in a mixture of HFA 134 and a
cosolvent, ethanol, was also conducted. As shown in the following
table, the solubility results were ondansetron 201.81 .mu.g/mL
after 8 days. The results are equal to 0.01668% w/w.
ondansetron
TABLE-US-00028 pMDI Medium 8 days HFA 134a with Ethanol (9:1)
199.48 (.mu.g/mL) 196.85 215.75 195.17 Average (RSD) 201.81
(0.047)
[0207] From the foregoing description, various modifications and
changes in the compositions and methods provided herein will occur
to those skilled in the art. All such modifications coming within
the scope of the appended claims are intended to be included
therein.
[0208] All publications, including but not limited to patents and
patent applications, cited in this specification are herein
incorporated by reference as if each individual publication were
specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
REFERENCES
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11749934 [0210] Cooke, C. E.; Mehra, I. V. (1994). "Oral
ondansetron for preventing nausea and vomiting". American Journal
of Hospital Pharmacy 51 (6): 762-771. PMID 8010314 [0211] Ye,
J.-H.; Ponnudurai, R.; Schaefer, R. (2001). "Ondansetron: a
selective 5-HT3 receptor antagonist and its applications in
CNS-related disorders". CNS Drug Reviews 7 (2): 199-213. PMID
11474424 [0212] Chow, A. H.; Tong, H. H.; Chattopadhyay, P.;
Shekunov, B. Y. (2007). "Particle engineering for pulmonary drug
delivery". Pharmaceutical Research 24 (3): 411-437. PMID
17245651
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