U.S. patent application number 13/649336 was filed with the patent office on 2013-04-11 for crystalline microparticles of a beta-agonist coated with a fatty acid.
This patent application is currently assigned to Chiesi Farmaceutici S.p.A.. The applicant listed for this patent is Chiesi Farmaceutici S.p.A.. Invention is credited to Gaetano Brambilla, Francesca Buttini, Paolo Colombo, Michele Miozzi.
Application Number | 20130089617 13/649336 |
Document ID | / |
Family ID | 47115785 |
Filed Date | 2013-04-11 |
United States Patent
Application |
20130089617 |
Kind Code |
A1 |
Brambilla; Gaetano ; et
al. |
April 11, 2013 |
CRYSTALLINE MICROPARTICLES OF A BETA-AGONIST COATED WITH A FATTY
ACID
Abstract
Crystalline microparticles consisting of a phenylalkylamino
beta.sub.2-adrenergic agonist coated with a C12-C20 fatty acid are
useful for the preparation of pharmaceutical aerosol formulations
in form of suspension in a liquefied propellant gas or powder
formulations.
Inventors: |
Brambilla; Gaetano; (Parma,
IT) ; Colombo; Paolo; (Parma, IT) ; Buttini;
Francesca; (Parma, IT) ; Miozzi; Michele;
(Parma, IT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Chiesi Farmaceutici S.p.A.; |
Parma |
|
IT |
|
|
Assignee: |
Chiesi Farmaceutici S.p.A.
Parma
IT
|
Family ID: |
47115785 |
Appl. No.: |
13/649336 |
Filed: |
October 11, 2012 |
Current U.S.
Class: |
424/498 ;
128/203.12; 424/43; 424/45; 427/2.14; 514/554; 514/555 |
Current CPC
Class: |
A61K 9/5015 20130101;
B01J 2/02 20130101; A61K 31/4704 20130101; A61P 11/00 20180101;
A61P 11/08 20180101; A61P 11/06 20180101; A61K 9/008 20130101; A61K
9/5089 20130101; A61K 31/137 20130101; A61M 15/009 20130101; A61K
9/1617 20130101; A61M 15/0068 20140204; A61K 31/167 20130101; A61M
2202/064 20130101; A61M 11/02 20130101 |
Class at
Publication: |
424/498 ;
514/554; 424/43; 424/45; 514/555; 128/203.12; 427/2.14 |
International
Class: |
A61K 9/14 20060101
A61K009/14; A61K 9/12 20060101 A61K009/12; B05D 5/00 20060101
B05D005/00; A61P 11/06 20060101 A61P011/06; A61M 15/00 20060101
A61M015/00; A61K 31/205 20060101 A61K031/205; A61P 11/00 20060101
A61P011/00 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 11, 2011 |
EP |
11184687.9 |
Claims
1. Crystalline microparticles, comprising a phenylalkylamino
beta.sub.2-adrenergic agonist coated with at least one C12-C20
fatty acid in an amount of 0.2 to 2.5% by weight based on the
weight of said microparticles.
2. Crystalline microparticles according to claim 1, which consist
of a phenylalkylamino beta.sub.2-adrenergic agonist coated with at
least one C12-C20 fatty acid in an amount of 0.2 to 2.5% by weight
based on the weight of said microparticles.
3. Crystalline microparticles according to claim 1, wherein said
beta.sub.2-agonist is a compound of formula (I): ##STR00002##
wherein R.sub.1 is CH.sub.2OH or NHCOR.sub.10 with the proviso
that, when R.sub.1 is CH.sub.2OH, R.sub.2 is always hydrogen,
while, when R.sub.1 is NHCOR.sub.10, R.sub.2 and R.sub.10 can be
independently hydrogen or form together a vinylene
(--CH.dbd.CH.mu.) or ethoxy (--CH.sub.2--O--) radical; m is an
integer from 0 to 5; n is an integer from 0 to 4; p is an integer
from 0 to 2; A represents oxygen or a bond; B represents oxygen or
a bond; R.sub.3 and R.sub.4 are hydrogen or methyl; or, when m is
1, n and p are 0, A and B are bonds, and R.sub.3 is hydrogen,
R.sub.4 can form with R.sub.5 a methylene bridge --(CH.sub.2)q-
with q corresponding to 1 or 2, preferably 1; and R.sub.5, R.sub.6,
R.sub.7, R.sub.8, and R.sub.9, which are the same or different, are
each independently hydrogen, hydroxyl, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, SO.sub.2NH.sub.2, or
2-hydroxy-2-phenyl-ethylamino, or a pharmaceutically acceptable
salt thereof.
4. Crystalline microparticles according to claim 3 wherein R.sub.1
is NHCOR.sub.10, and R.sub.2 and R.sub.10 are H.
5. Crystalline microparticles according to claim 1, which are
coated with said C12-C20 fatty acid in an amount of 0.5 to 2.0% by
weight.
6. Crystalline microparticles according to claim 1, wherein said at
least one C12-C20 fatty acid is selected from the group consisting
of lauric acid, myristic acid, palmitic acid, palmitoleic acid,
stearic acid, oleic acid, arachidic acid, and a mixture
thereof.
7. Crystalline microparticles according to claim 6 wherein said at
least one fatty acid is selected from the group consisting of
myristic acid, palmitic acid, stearic acid, arachidic acid, and a
mixture thereof.
8. Crystalline microparticles according to claim 1, which have a
[d(v,0.5)] of 1.5 to 3.0 microns.
9. A pharmaceutical aerosol formulation for a pressurized metered
dose inhaler, comprising microparticles according to claim 1, in
suspension in a liquefied propellant gas.
10. A pharmaceutical formulation according to claim 9, wherein said
liquefied propellant gas is 1,1,1,2,3,3,3-heptafluoro-n-propane
(HFA227) or 1,1,1,2-tetrafluoroethane (HFA 134a), or a mixture
thereof.
11. A pressurized metered dose inhaler, comprising a canister
containing an aerosol pharmaceutical formulation according to claim
9 and a metering valve for delivering a daily therapeutically
effective dose of said phenylalkylamino beta.sub.2-adrenergic
agonist.
12. A dry powder pharmaceutical formulation, comprising
microparticles according to claim 1.
13. A dry powder pharmaceutical formulation, comprising
microparticles according to claim 1 and a carrier.
14. A process for preparing microparticles according to claim 1,
said process comprising: (a) preparing a solution of said C12-C20
fatty acid in a fluorinated model propellant in which said
beta.sub.2-agonist is substantially insoluble, selected from the
group consisting of perfluoropentane, 2H,3H-perfluoropentane
(HPFP), perfluorohexane, and 1H-perfluorohexane; (b) adding said
beta.sub.2-agonist as a micronized powder to said solution of said
fatty acid, to obtain a mixture; (c) mixing said mixture to obtain
a homogeneous suspension; and (d) subjecting said suspension to
spray-drying, to obtain coated microparticles.
15. A process according to claim 14, wherein said fluorinated model
propellant is 2H,3H-perfluoropentane (HPFP).
16. A method for the prevention and/or treatment of a respiratory
disease, comprising administering to a subject in need thereof an
effective amount of microcparticles according to claim 1.
17. A method according to claim 16, wherein said disease is asthma
or chronic obstructive pulmonary disease.
18. Crystalline microparticles, comprising of a phenylalkylamino
beta.sub.2-adrenergic agonist coated with a C12-C20 fatty acid in
an amount of 0.2 to 2.0% by weight, based on the weight of said
microparticles, which are produced by a process comprising: (a)
preparing a solution of said C12-C20 fatty acid in a fluorinated
model propellant in which said beta.sub.2-agonist is substantially
insoluble, selected from the group consisting of perfluoropentane,
2H-3H-perfluoropentane (HPFP), perfluorohexane, and
1H-perfluorohexane; (b) adding said beta.sub.2-agonist as a
micronized powder to said solution of said fatty acid, to obtain a
mixture; (c) mixing said mixture to obtain a homogeneous
suspension; and (d) subjecting said suspension to spray-drying, to
obtain coated microparticles.
Description
CROSS REFERENCES TO RELATED APPLICATIONS
[0001] This application claims priority to European Patent
Application No. 11184687.9 filed on Oct. 11, 2011, which is
incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to crystalline microparticles
comprising a beta.sub.2-agonist suitable for use in formulations to
be administered by inhalation for the treatment of respiratory
diseases. The present inventions also relates to pharmaceutical
aerosol formulations comprising said microparticles and to a
process for preparing them. The present invention further relates
to methods of treating/preventing certain diseases and conditions
by administering such microparticles.
[0004] 2. Discussion of the Background
[0005] The administration of pharmacologically active ingredients
by inhalation to the lungs is a widely used technique especially
for the treatment of reversible airway obstruction, inflammation
and hyper-responsiveness. Inhalable preparations include dry
powders formulations, pressurized metered dose (pMDI) formulations
containing propellants such as hydrofluoroalkanes (HFA), or
propellant-free aqueous formulations to be administered by suitable
devices such as nebulizers.
[0006] The drugs present in the formulations can either be
dissolved or suspended. A specific group of drugs administered by
the pulmonary route are bronchodilators having a local therapeutic
action in the lungs and/or a systemic therapeutic action after
absorption in the blood.
[0007] For example, widely used bronchodilators are beta2-agonists
belonging to the class of the phenylalkylamino derivatives such as
rac-(R,R)-N-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamin-
o]ethyl]phenyliformamide, also known as formoterol. However,
formoterol as well as other drugs belonging to said class may
suffer of chemical stability problems due to the susceptibility to
oxidative conditions of the functional groups present on the
molecules such as formamide and hydroxyethyl groups. Some of said
groups such as formamide are also susceptive to solvolysis
reactions.
[0008] On the other hand, molecules belonging to said class may
also incur problems of physical stability of their suspension
formulations. This is because of partial solubility of the drugs in
the liquefied gas propellant. This partial solubility, in turn, may
lead to an undesirable increase in the particle size during storage
and/or the formation of aggregates.
[0009] Moreover, formulations of beta.sub.2-agonists in HFA
propellant might be susceptible to absorption of the drug into the
rubber components of the valves of the administration device. This
may then cause the valves to seize resulting in a reduction of fine
particle mass and/or the aggregates of particles will penetrate
less well into the fine lower respiratory pathways, subsequently
causing problems with dose uniformity.
[0010] To overcome the problems of physical stability and of
adsorption of the drug, it has been proposed in the art to coat the
particles with additives such as surfactants, and to suspend said
coated particles in the HFA propellant. For instance, WO 92/08447
and WO 91/04011 teach coating the active agent by a process
involving the steps of dissolving the surfactant in a solvent in
which the pharmaceutically active agent is substantially insoluble,
mixing a quantity of the pharmaceutically active agent, in
micronized form, into the surfactant solution and isolating
particles of surfactant coated active agent either by filtration
and drying, or by removal of the solvent by evaporation. However,
it has so far not proven possible, to manufacture useful
formulations in this way. For example, it is difficult to achieve a
uniform coating using techniques of this nature because the manner
in which the surfactant agent precipitates from the evaporating
solvent can be unpredictable.
[0011] WO 2006/059152 discloses the preparation of coated particles
with dispersing agents such as surfactants by mechano-fusion
processes. However, it is known that particles obtained in this way
are prevalently amorphous. On the other hand, amorphous or
prevalently amorphous materials tend to absorb water in larger
amounts than crystalline ones, and this could be a pitfall for
active ingredients liable to degradation by hydrolysis.
[0012] WO 00/61108 discloses salmeterol particles coated with a
surfactant and free of any other coating excipient. They are
obtained by a process involving the steps of suspending the active
ingredient in form of particles in a medium, preferably water, then
dispersing the surfactant, and subjecting the suspension to spray
-drying. However, also in this case, it is well known that the use
of water could yield some amorphous material. Moreover, it is
difficult to achieve a uniform coating if the surfactant is
dispersed and not dissolved in said medium.
[0013] WO 2008/152398 discloses particles coated with polymers such
as PVP without any mention of their chemical stability.
[0014] US 2004/101483 discloses suspension aerosol formulations
based on hydrofluoroalkanes comprising micronized particles of
active ingredients and calcium salts, magnesium salts, and zinc
salts of palmitic acid and of stearic acid as solid excipients. The
demonstrated advantage is that said suspensions show a markedly
improved valve accessibility.
[0015] US 2004/013611 discloses suspension aerosol formulations
comprising a therapeutically effective amount of micronized
albuterol sulfate, from about 5 to 15 percent by weight of ethanol,
from about 0.05 to about 0.5 percent by weight of a surfactant
selected from the group consisting of oleic acid and sorbitan
trioleate, and HFC 227 as substantially the only propellant. Said
formulations are characterized in that they exhibit substantially
no growth in particle size or change in crystal morphology of the
drug over a prolonged period, are substantially and readily
redispersible, and upon redispersion do not flocculate so quickly
as to prevent reproducible dosing of the drug. Nothing is said
about their chemical stability.
[0016] In view of the above, there is still a need for particles of
beta.sub.2-agonists of high chemical stability as well as being
capable of giving rise to physically stable suspensions with a slow
sedimentation rate and a reduced adhesion to the components of the
device. These problems are solved by the particles of the present
invention.
SUMMARY OF THE INVENTION
[0017] Accordingly, it is one object of the present invention to
provide novel particles of beta.sub.2-agonists.
[0018] It is another object of the present invention to provide
novel beta.sub.2-agonists which exhibit high chemical
stability.
[0019] It is another object of the present invention to provide
novel beta.sub.2-agonists which are capable of giving rise to
physically stable suspensions with a slow sedimentation rate and a
reduced adhesion to the components of a device in which they are
contained.
[0020] It is another object of the present invention to provide
novel methods of preparing such particles.
[0021] It is another object of the present invention to provide
novel methods of treating and/or preventing certain diseases and
conditions by administering such particles.
[0022] These and other objects, which will become apparent during
the following detailed description, have been achieved by the
inventors' discovery of crystalline microparticles consisting of a
phenylalkylamino beta.sub.2-adrenergic agonist coated with a
C12-C20 fatty acid in an amount comprised between 0.2 and 2.5% by
weight.
[0023] Thus, in a first aspect, the invention is directed to
crystalline microparticles comprising a phenylalkylamino
beta.sub.2-adrenergic agonist coated with a C12-C20 fatty acid in
an amount comprised between 0.2 and 2.5% by weight.
[0024] In a second aspect, the crystalline microparticles
preferably consist of a phenylalkylamino beta.sub.2-adrenergic
agonist coated with a C12-C20 fatty acid in an amount comprised
between 0.2 and 2.5% by weight.
[0025] Advantageously, said beta.sub.2-agonist is selected from a
derivative belonging to the general formula (I):
##STR00001##
wherein
[0026] R.sub.1 is CH.sub.2OH or NHCOR.sub.10
[0027] with the proviso that, when R.sub.1 is CH.sub.2OH, R.sub.2
is hydrogen, while, when R.sub.1 is NHCOR.sub.10, R.sub.2 and
R.sub.10 can be independently hydrogen or form together a vinylene
(--CH.dbd.CH--) or ethoxy (--CH.sub.2--O--) radical;
[0028] m is an integer from 0 to 5, preferably 0 or 5;
[0029] n is an integer from 0 to 4, preferably 0, 2 or 4;
[0030] p is an integer from 0 to 2, preferably 0 or 1;
[0031] A represents oxygen or a bond;
[0032] B represents oxygen or a bond;
[0033] R.sub.3 and R.sub.4 are hydrogen or methyl; otherwise, when
m is 1, n, p are 0, A and B are bonds, and R.sub.3 is hydrogen,
R.sub.4 can form with R.sub.5 a methylene bridge --(CH.sub.2)q-
where q is 1 or 2, preferably 1;
[0034] R.sub.5, R.sub.6, R.sub.7, R.sub.8, and R.sub.9, which are
the same or different, are each independently selected from
hydrogen, hydroxyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen atoms, SO.sub.2NH.sub.2, and 2-hydroxy-2-phenyl-ethylamino;
preferably they are hydrogen, halogen atoms, C.sub.1-C.sub.4 alkyl,
and C.sub.1-C.sub.4 alkoxy,
and pharmaceutically acceptable salts and/or solvates thereof.
[0035] In a third aspect, the invention provides pharmaceutical
aerosol formulations for pressurized metered dose inhalers (pMDIs)
comprising the above microparticles in suspension in a liquefied
propellant gas.
[0036] In a fourth aspect, the invention provides pressurized
metered dose inhalers (pMDI) comprising a canister filled with the
aforementioned aerosol pharmaceutical formulation, and a metering
valve for delivering a daily therapeutically effective dose of the
active ingredient.
[0037] In a fifth aspect, the invention concerns dry powder
pharmaceutical formulations comprising the above microparticles
and, optionally a carrier.
[0038] In a sixth aspect, the invention provides dry powder
inhalers filled with the aforementioned dry powder formulation.
[0039] In a seventh aspect, the present invention is directed to a
process for preparing the microparticles of the invention, said
process comprising the steps of:
[0040] (a) preparing a solution of the C12-C20 fatty acid in a
fluorinated model propellant wherein the beta.sub.2-agonist is
substantially insoluble selected from the group of
perfluoropentane, 2H,3H-perfluoropentane (HPFP), perfluorohexane,
and 1H-perfluorohexane;
[0041] (b) adding the micronized drug powder to the solution of the
fatty acid;
[0042] (c) stirring to give a homogeneous suspension; and
[0043] (d) subjecting the resulting suspension to spray-drying to
obtain the coated microparticles.
[0044] In an eighth aspect, the present invention is also directed
to the microparticles of the invention for use for the prevention
and/or treatment of a respiratory disease.
[0045] In an ninth aspect, the present invention is further
directed to the use of the microparticles of the invention in the
manufacture of a medicament for the prevention and/or treatment of
a respiratory disease.
[0046] In a tenth aspect, the present invention provides methods
for preventing and/or treating a respiratory disease in a patient,
comprising administering a therapeutically effective amount of the
microparticles of the invention.
[0047] In an eleventh aspect, the present invention concerns
crystalline microparticles consisting of a phenylalkylamino
beta.sub.2-adrenergic agonist coated with a C12-C20 fatty acid in
an amount comprised between 0.2 and 2.5% by weight, said
microparticles obtainable by a process comprising the steps of:
[0048] (a) preparing a solution of the C12-C20 fatty acid in a
fluorinated model propellant wherein the beta.sub.2-agonist is
substantially insoluble selected from the group of
perfluoropentane, 2H,3H-perfluoropentane (HPFP), perfluorohexane,
and 1H-perfluorohexane;
[0049] (b) adding the micronized drug powder to the solution of the
fatty acid;
[0050] (c) stirring to give a homogeneous suspension; and
[0051] (d) subjecting the resulting suspension to spray-drying to
obtain the coated microparticles.
[0052] In a further aspect, the present invention provides a
process for preparing crystalline microparticles consisting of a
drug to be administered by inhalation coated with a C12-C20 fatty
acid, said process comprising the steps of:
[0053] (a) preparing a solution of the C12-C20 fatty acid in a
fluorinated model propellant wherein the drug is substantially
insoluble selected from the group of perfluoropentane,
2H,3H-perfluoropentane (HPFP), perfluorohexane, and
1H-perfluorohexane;
[0054] (b) adding the micronized drug powder to the solution of the
fatty acid;
[0055] (c) stirring to give a homogeneous suspension; and
[0056] (d) subjecting the resulting suspension to spray-drying to
obtain the coated microparticles.
[0057] The invention is also directed to the crystalline coated
microparticles obtainable by said process.
BRIEF DESCRIPTION OF THE DRAWINGS
[0058] A more complete appreciation of the invention and many of
the attendant advantages thereof will be readily obtained as the
same become better understood by reference to the following
detailed description when considered in connection with the
accompanying drawings, wherein:
[0059] FIG. 1 is a thermogram of microparticles of the present
invention in comparison to crystalline microparticles of formoterol
fumarate dihydrate (top line).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0060] The term "halogen atoms" as used herein includes fluorine,
chlorine, bromine and iodine.
[0061] The expression "C.sub.1-C.sub.4 alkyl" refers to
straight-chained and branched alkyl groups wherein the number of
carbon atoms is in the range 1 to 4. Particular alkyl groups are
methyl, ethyl, n-propyl, isopropyl and t-butyl, preferably methyl
and ethyl.
[0062] The expression "C.sub.1-C.sub.4 alkoxy" refers to straight
and branched chain alkoxy groups wherein the number of carbon atoms
is in the range 1 to 4. Exemplary groups are methoxy, ethoxy, and
butyloxy.
[0063] The term "coated' refers to microparticles having their
surface covered by a continuous film of the fatty acid.
[0064] The term "single therapeutically effective dose" means the
quantity of active ingredient administered at one time by
inhalation upon actuation of the pMDI or DPI inhaler.
[0065] Said dose may be delivered in one or more actuations,
preferably one actuation (shot) of the inhaler.
[0066] The term "actuation" refers to the release of active
ingredient from the device by a single activation (e.g. mechanical
or breath).
[0067] For "fluorinated model propellant" it is meant a fluorinated
alkane derivative liquid at room temperature and at atmospheric
pressure in which common beta.sub.2-agonists are insoluble. Typical
members of this class are perfluoropentane, 2H,3H-perfluoropentane,
perfluorohexane, and 1H-perfluorohexane. 2H,3H-perfluoropentane is
also known as HPFP (see Rogueda P. Drug Dev. Ind. Pharm., 2003,
29(1), 39-49, which is incorporated herein by reference in its
entirety).
[0068] "Substantially insoluble" refers to an active ingredient
having a solubility in the desired medium of less than 1.0% w/v,
preferably of less than 0.5%, more preferably less than 0.1%
w/v.
[0069] In general terms, the particle size of the particles is
quantified by measuring a characteristic equivalent sphere
diameter, known as volume diameter, by laser diffraction. The
particle size can also be quantified by measuring the mass diameter
by means of suitable instruments and techniques known to the
skilled person, such as sieving.
[0070] The volume diameter (VD) is related to the mass diameter
(MD) by the density of the particles (assuming the size being
independent from the density of the particles).
[0071] In the present application, the particle size interval is
expressed in terms of mass diameter. Otherwise, the particle size
distribution is expressed in terms of: i) the volume median
diameter (VMD) which corresponds to the diameter of 50 percent by
weight or volume respectively, of the particles, e.g. d(v0.5), and
ii) the volume diameter (VD) in microns of 10% and 90% of the
particles, respectively, e.g. d(v0.1) and d(v0.9).
[0072] Upon aerosolization, the particle size is expressed as mass
aerodynamic diameter (MAD) and the particle size distribution as
mass median aerodynamic diameter (MMAD). The MAD indicates the
capability of the particles of being transported as suspended in an
air stream. The MMAD corresponds to the mass aerodynamic diameter
of 50 percent by weight of the particles.
[0073] The expression "physically stable" refers to formulations
which exhibit substantially no growth in particle size or change in
crystal morphology of the suspended particles over a prolonged
period, are readily redispersible, and upon redispersion, do not
flocculate so quickly as to prevent reproducing dosing of the
active ingredient.
[0074] The expression "chemically stable" refers to a formulation
that, upon storage, meets the requirements of the EMEA Guideline
CPMP/QWP/122/02 referring to "Stability Testing of Existing Active
Substances and Related Finished Products".
[0075] The expression "respirable fraction" refers to an index of
the percentage of active particles which would reach the deep lungs
in a patient.
[0076] The respirable fraction, also termed fine particle fraction
(FPF), is evaluated using a suitable in vitro apparata such as Next
Generation Impactor (NGI), Multistage Cascade Impactor or Multi
Stage Liquid Impinger (MLSI) according to procedures reported in
common Pharmacopoeias. It is calculated by the ratio between the
delivered dose and the fine particle mass (formerly fine particle
dose).
[0077] The delivered dose is calculated from the cumulative
deposition in the apparatus, while the fine particle mass is
calculated from the deposition on Stage N (herein N is an integer
number) to filter (AF) corresponding to particles .ltoreq.5.0
microns.
[0078] The term "therapeutically effective amount" means the amount
of active ingredient that, when delivered to the lungs, provides
the desired biological effect.
[0079] The term "prevention" means an approach for reducing the
risk of onset of a disease.
[0080] The term "treatment" means an approach for obtaining
beneficial or desired results, including clinical results.
Beneficial or desired clinical results can include, but are not
limited to, alleviation or amelioration of one or more symptoms or
conditions, diminishment of extent of disease, stabilized (i.e. not
worsening) state of disease, preventing spread of disease, delay or
slowing of disease progression, amelioration or palliation of the
disease state, and remission (whether partial or total), whether
detectable or undetectable.
[0081] The present invention concerns crystalline microparticles
comprising or consisting of a phenylalkylamino
beta.sub.2-adrenergic agonist and pharmaceutically acceptable salts
and/or solvates thereof.
[0082] Phenylalkylamino beta.sub.2-adrenergic agonists are drugs
having a bronchodilator activity and include for example salbutamol
(albuterol), bambuterol fenoterol, procaterol, salmeterol,
indacaterol, and formoterol.
[0083] Pharmaceutically acceptable salts include those obtained by
reacting the amino group of the compound with an inorganic or
organic acid to form a salt, for example, hydrochloride,
hydrobromide, sulphate, phosphate, methane sulfonate, camphor
sulfonate, oxalate, maleate, fumarate, succinate, citrate,
cinnamate, xinafoate, and trifenatate.
[0084] Advantageously, said beta.sub.2-agonist is selected from a
derivative belonging to the general formula (I).
[0085] The compounds of general formula (I) may contain asymmetric
centers. Therefore the present invention includes all the optical
stereoisomers and mixtures thereof
[0086] A first class of preferred compounds is that wherein
[0087] R.sub.1 is NHCOR.sub.10 with R.sub.10.dbd.H, R.sub.4 is
methyl, m is 1, n, p are 0, A and B are bonds, R.sub.3, R.sub.5,
R.sub.6, R.sub.8 and R.sub.9 are H, and R.sub.7 is methoxy.
[0088] When the phenolic group is adjacent to R.sub.I, the compound
is known as formoterol.
[0089] As it contains two chiral centers, formoterol is preferably
used in the form of 1:1 (R,R), (S,S) racemate or (R,R) enantiomer,
more preferably as the racemate.
[0090] A particularly preferred salt is the fumarate dihydrate.
[0091] A second class of preferred compounds is that wherein:
[0092] R.sub.1 is NHCOR.sub.10 wherein R.sub.10 forms together with
R.sub.2 a vinylene (--CH.dbd.CH--) radical, R.sub.4 is H, R.sub.3
forms with R.sub.5 a methylene bridge --(CH.sub.2)q- with q=1, m is
1, n, p are 0, A and B are bonds, R6 and R.sub.9 are H and R.sub.7
and R.sub.8 are ethyl group.
[0093] When the phenolic group is adjacent to R.sub.1, the compound
is known as indacaterol.
[0094] Since it contains a chiral center, indacaterol is preferably
used in the form of R-enantiomer, more preferably as maleate
salt.
[0095] A third class of preferred compounds is that wherein:
[0096] R.sub.1 is CH.sub.2OH, R.sub.2 R.sub.6, R.sub.7 and R.sub.8
are H, R.sub.5 and R.sub.9 are chlorine atoms, A and B are O, m is
5, n is 2, and p is 1.
[0097] When the phenolic group is adjacent to R.sub.1, the compound
is known as vilanterol. Vilanterol is preferably used in the form
of R-enantiomer as trifenatate salt
[0098] A fourth class of preferred compounds is that wherein:
[0099] R.sub.1 is NHCOR.sub.10 with R.sub.10 forming together with
R.sub.2 an ethoxy (--CH2--O--) radical, R.sub.3 and R.sub.4 are
methyl, m=1, A d B are bonds, n and p are 0, R.sub.5, R.sub.6,
R.sub.8 and R.sub.9 are H, and R.sub.7 is methoxy. When the
phenolic group is meta to R.sub.1 the compound is known as
olodaterol, that is preferably used as R-enantiomer.
[0100] A fifth class of preferred compounds is that wherein:
[0101] R.sub.1 is NHCOR.sub.10 with R.sub.10.dbd.H, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.8 and R.sub.9 are H, m is
1, A and B are bonds, n and p are 0, and R.sub.7 is
2-hydroxy-2-phenyl-ethylamino.
[0102] When the phenolic group is adjacent to R.sub.1 the compound
is known as milveterol. As it contains two chiral centers,
milveterol is preferably used in the form of (R,R)-enantiomer, more
preferably as the hydrochloride salt.
[0103] A sixth class of preferred compounds is that wherein:
[0104] R.sub.1 is CH.sub.2OH, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.6, R.sub.8 and R.sub.9 are H, m is 5, n is 4, p is 0, A is O,
and B is a bond.
[0105] When the phenolic group is adjacent to R.sub.1 the compound
is known as salmeterol. As it contains one chiral center,
salmeterol is preferably used in the form of racemic form (R,S),
more preferably as a xinafoate salt.
[0106] Preferably, the compound of formula (I) is a long-acting
beta.sub.2-agonist selected from the group consisting of
formoterol, salmeterol, vilanterol, olodaterol, milveterol,
indacaterol, and pharmaceutically acceptable salts and/or solvates
thereof.
[0107] In a particular embodiment, preferred compounds are those
wherein R.sub.1 is NHCOR.sub.10, R.sub.2 and R.sub.10 are H, and
the other substituents and indexes have the meanings reported
above.
[0108] In fact, phenylalkylamino derivatives bearing said group are
particularly sensitive to solvolysis reactions.
[0109] The preferred compound of said class is formoterol,
preferably in the form of fumarate dihydrate salt.
[0110] In another particular embodiment, preferred compounds are
those wherein R.sub.1 CH.sub.2OH, R.sub.2 is H, and the other
substituents and indexes have the meanings reported above.
[0111] The preferred compound of said class is salmeterol,
preferably in the form of a xinafoate salt.
[0112] The particle size of said microparticles is lower than 15
microns, preferably lower than 10 microns. Advantageously, at least
90% of the particles have a volume diameter lower than about 5
micron. More advantageously no more than 10% of the microparticles
have a volume diameter [d(v,0.1)] lower than 0.6 micron, and no
more than 50% of particles have a volume diameter [d(v,0.5)] lower
than 1.5 micron.
[0113] Preferably the [d(v,0.5)] is comprised between 1.5 and 3.0
micron.
[0114] The particle size method could be measured by laser
diffraction according to known methods.
[0115] The microparticles of the compound of general formula (I)
are coated with a C12-C20 fatty acid in an amount comprised between
0.2 and 2.5% by weight of said particles, preferably between 0.5
and 2.0% by weight. In one embodiment, the preferred amount may be
comprised between 1.0 and 2.0% by weight, while in other
embodiment, it may be comprised between 0.5 and 1.0% by weight.
[0116] The C12-C20 fatty acid is advantageously selected from the
group consisting of saturated and monounsaturated compounds such as
lauric acid (C12:0), myristic acid (C14:0), palmitic acid (C16:0),
palmitoleic acid (C16:1), stearic acid (C18:0), oleic acid (C18:1),
and arachidic acid (C20:0) or mixtures thereof.
[0117] More preferably, the fatty acid it is a saturated fatty acid
selected from the group consisting of myristic acid, palmitic acid,
stearic acid, and arachidic acid. In a preferred embodiment, the
fatty acid is myristic acid. In fact, the percentage being equal,
myristic acid is capable of giving rise to higher performances in
terms of respirable fraction (FPF) as it can be appreciated from
the Examples.
[0118] As monounsaturated acid, oleic acid may be preferably
used.
[0119] The fatty acid shall form a continuous film on the surface
of the microparticles.
[0120] Depending on the amount of fatty acid, the coating may cover
part of the microparticles or all of them (complete coating),
preferably all of them.
[0121] The amount of beta.sub.2-adrenergic agonist will depend on
its single therapeutically effective dose, which in turn, depends
on the kind and the severity of the disease and the conditions
(weight, sex, age) of the patient.
[0122] For example, in the case of formoterol, the single
therapeutically effective dose could be 6 or 12 .mu.g, calculated
as fumarate dihydrate salt.
[0123] Once the microparticles of the invention are suspended in a
liquefied propellant gas, the relevant suspensions turned out to be
chemically and physically stable over time and capable of giving
rise to excellent respirable fraction. Unexpectedly, said
formulations show a lower sedimentation speed than the
corresponding formulations comprising uncoated microparticles.
[0124] Accordingly, the present invention provides for pressurized
metered dose inhalers (pMDIs) comprising the above microparticles
in suspension in a liquefied propellant gas.
[0125] Any liquefied propellant gas may be used, preferably a
hydrofluoroalkane (HFA) propellant. Advantageously, the liquefied
propellant gas is 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) or
1,1,1,2-tetrafluoroethane (HFA 134a), and mixtures thereof.
[0126] The formulations of the present invention may also comprise
other pharmaceutically acceptable excipients, for instance
surfactants. Suitable surfactants are known in the art and include:
sorbitan esters such as sorbitan trioleate, sorbitan monolaurate,
sorbitan mono-oleate and their ethoxylated derivates such as
polysorbate 20, polysorbate 80; ethylene oxide/propylene oxide
co-polymers and other agents such as natural or synthetic lecithin,
oleic acid, polyvinylpyrrolidone (PVP), and polyvinyl alcohol.
[0127] The amount of surfactant, which may be present in the pMDI
formulation according to the invention, is usually in the range of
0.001 to 3.0% (w/w), preferably between 0.005 to 1.0% (w/w).
[0128] The formulations according to the present invention may
further comprise other active ingredients useful for the prevention
and/or treatment of respiratory diseases, for instance
corticosteroids or antimuscarinic drugs suspended or dissolved in
the liquefied propellant gas.
[0129] Examples of corticosteroids are beclometasone dipropionate
(BDP), fluticasone propionate, fluticasone furoate, mometasone
furoate, budesonide, and ciclesonide.
[0130] Examples of antimuscarinic drugs are ipratropium bromide,
tiotropium bromide, glycopyrronium bromide, and aclidinium
bromide.
[0131] According to another aspect, the present invention provides
a pMDI comprising a canister filled with the pharmaceutical
formulation of the invention and a metering valve for delivering a
daily therapeutically effective dose of the active ingredient.
[0132] The aerosol formulation according to the invention shall be
filled into pMDIs.
[0133] Said pMDIs comprise a canister fitted with a metering valve.
Actuation of the metering valve allows a small portion of the spray
product to be released.
[0134] Part or all of the internal surfaces of the canister may be
made of glass or of a metal, for example aluminum or stainless
steel or anodized aluminum.
[0135] Alternatively the metal canister may have part or all of the
internal surfaces lined with an inert organic coating. Examples of
preferred coatings are epoxy-phenol resins, perfluorinated polymers
such as perfluoroalkoxyalkanes, perfluoroalkoxyalkylenes,
perfluoroalkylenes such as poly-tetrafluoroethylene (Teflon),
fluorinated-ethylene-propylene, polyether sulfone,
fluorinated-ethylene-propylene (FEP), and
fluorinated-ethylene-propylene polyether sulfone (FEP-PES) mixtures
or combination thereof. Other suitable coatings may be polyamide,
polyimide, polyamideimide, polyphenylene sulfide or their
combinations.
[0136] The canister is closed with a metering valve for delivering
a daily therapeutically effective dose of the active
ingredient.
[0137] Generally, the metering valve assembly comprises a ferrule
having an aperture formed therein, a body molding attached to the
ferrule which houses the metering chamber, a stem constituted of a
core and a core extension, an inner- and an outer seal around the
metering chamber, a spring around the core, and a gasket to prevent
leakage of propellant through the valve.
[0138] The gasket may comprise any suitable elastomeric material
such as, for example, low density polyethylene, chlorobutyl, black
and white butadiene-acrylonitrile rubbers, butyl rubber, neoprene,
EPDM (a polymer of ethylenepropylenediene monomer) and TPE
(thermoplastic elastomer). EPDM rubbers are particularly
preferred.
[0139] Suitable valves are commercially available from
manufacturers well known in the aerosol industry, for example, from
Valois, France, Bespak, plc UK and 3M, Neotechnic Ltd UK.
[0140] The formulation shall be actuated by a metering valve
capable of delivering a volume of between 25 .mu.l and 100 .mu.l,
e.g. 25 .mu.l, 50 .mu.l, 63 .mu.l or 100 .mu.l.
[0141] Advantageously, the MDI device filled with the formulation
may be equipped with a dose counter.
[0142] Surprisingly, when administered as a powder by a suitable
device, the microparticles of the inventions give rise to a
significantly higher respirable fraction than the corresponding
uncoated microparticles.
[0143] Accordingly, the invention also provides a dry powder
pharmaceutical formulation comprising the above microparticles and
optionally a carrier.
[0144] The carrier particles may be made of any physiologically
acceptable, pharmacologically inert material or combination of
materials suitable for inhalatory use. For example, the carrier
particles may be composed of one or more materials selected from
sugar alcohols; polyols, for example sorbitol, mannitol and
xylitol, and crystalline sugars, including monosaccharides and
disaccharides.
[0145] Preferably, the carrier particles are made of lactose, more
preferably of alpha-lactose monohydrate.
[0146] Advantageously, said carrier particles have a mass diameter
(MD) of at least 50 microns, more advantageously greater that 90
microns. Preferably the MD is comprised between 50 microns and 500
microns.
[0147] In certain embodiments of the invention, the MD may be
comprised between 90 and 150 microns.
[0148] In other embodiments, the MD may be comprised between 150
and 400 micron, with a MMD preferably greater than 175 microns, and
more preferably the MD may be comprised between 210 and 355
microns.
[0149] The desired particle size may be obtained by sieving
according to known methods.
[0150] The aforementioned powder formulation may also
advantageously comprise an additive material, preferably bound to
the surface of the carrier particles. Said additive material may be
an amino acid, preferably selected from leucine or isoleucine, or a
water soluble surface active material, for example lecithin, in
particular soya lecithin, or a lubricant selected from the group
consisting of stearic acid and salts thereof such as magnesium
stearate, sodium lauryl sulphate, sodium stearyl fumarate, and
stearyl alcohol.
[0151] The dry powder formulations herein described may be used in
all customary dry powder inhalers, such as unit dose or multidose
inhalers.
[0152] For example, said formulations may be filled in hard
gelatine capsules, in turn loaded in a unit dose inhaler such as
the Aerolizer.TM. or the RS01/7 model available from Plastiape,
Italy.
[0153] Alternatively, it may be filled in a multidose inhaler
comprising a powder reservoir as described in WO 2004/012801, which
is incorporated herein by reference in its entirety.
[0154] The present invention further provides a process for
preparing the microparticles of the invention, said process
comprising the steps of: [0155] (a) preparing a solution of the
C12-C20 fatty acid in a fluorinated model propellant wherein the
beta2-agonist is substantially insoluble selected from the group of
perfluoropentane, 2H,3H-perfluoropentane (HPFP), perfluorohexane,
and 1H-perfluorohexane; [0156] (b) adding the micronized drug
powder to the solution of the fatty acid; [0157] (c) mixing to give
a homogeneous suspension; and [0158] (d) subjecting the resulting
suspension to spray-drying to obtain the coated microparticles.
[0159] It fact, it has been found that, due to the physico-chemical
properties of the utilized model propellant, the solid
characteristic of the particles upon drying are not modified, and
they remain substantially crystalline. Advantageously, the
microparticles of the present invention have a crystalline degree,
expressed as weight % of the crystalline compound with respect to
the total weight of the compound, of at least 90%, preferably of at
least 95%, even more preferably of at least 98%, determined
according to methods know in the art such as differential scanning
calorimetry (DSC), microcalorimetry or X-ray powder
diffractometry.
[0160] Moreover, since the fatty acid is added as a solution, a
uniform and extensive coating of microparticles is achieved. Said
coating with the fatty acid is performed in the absence of any
other coating excipient.
[0161] Without being limited by the theory, said uniform and
extensive coating may contribute to improve the chemical stability
of the active ingredient. Furthermore, it prevents both the partial
solubilization and formation of aggregates of the drug, once
suspended in a liquefied propellant gas, making possible to obtain
formulations characterized by an improved physical stability.
[0162] It is believed that the features of the coating explain the
better inhalatory performances of the microparticles of the
invention, once administered as a powder, in comparison to the
uncoated microparticles.
[0163] The fluorinated model propellant shall be selected depending
on the solubility characteristics of both the active ingredient and
the fatty acid.
[0164] Preferably, said model propellant is perfluoropentane or
2H,3H-perfluoropentane (HPFP), more preferably
2H,3H-perfluoropentane.
[0165] The amount of the fatty acid in the solution will vary
depending on the amount of active ingredient added in stage (b) and
will be selected so as to obtain a percentage in the final coated
microparticles comprised between 0.2 and 2.5% by weight.
[0166] The content of the active ingredient in the suspension
prepared in stage (b) can vary within wide limits, usually within
the range from 1 to 40% w/v, preferably from 2 to 20% w/v, more
preferably from 5 to 10% w/v.
[0167] In said stage, the micronized drug powder may be added to
the solution of the fatty acid and then mixed with techniques known
in the art, e.g. sonicating or stirring, to give a homogeneous
suspension (stage (c).
[0168] In stage (d), the obtained suspension, maintained under
stirring, is subjected to spray drying in an appropriate
apparatus.
[0169] The operating parameters of the apparatus, such as the flow
rate of the suspension arriving in the drying chamber, the size of
the nozzle, the inlet and outlet temperature, the atomizing
pressure and the flow rate of the atomizing air, may be adjusted by
any skilled person according to the recommendations of the
manufacturer.
[0170] A suitable spray dryer is, for example, the Buchi 191 Mini
Spray Dryer (Buchi Company, Switzerland).
[0171] Typical parameters are the following:
[0172] inlet air temperature: 60 to 150.degree. C., preferably 95
to 105.degree. C., more preferably 100.degree. C.;
[0173] outlet temperature: 40 to 110.degree. C., preferably 55 to
65.degree. C., more preferably 60.degree. C.;
[0174] air flow rate: 600 l/h;
[0175] feed flow: 4 ml/min; and
[0176] nozzle diameter: 0.7 mm.
[0177] Once collected, the microparticles have a diameter less than
15 micron.
[0178] Optionally, they may be subjected to conventional milling
techniques to adjust their size.
[0179] Administration of the microparticles of the invention may be
indicated for prevention and/or the treatment of mild, moderate or
severe acute or chronic symptoms or for prophylactic treatment of
an inflammatory or obstructive airways disease such as asthma and
chronic obstructive pulmonary disease (COPD).
[0180] Other features of the invention will become apparent in the
course of the following descriptions of exemplary embodiments which
are given for illustration of the invention and are not intended to
be limiting thereof.
EXAMPLES
Example 1
Preparation of Microparticles of Formoterol Fumarate According to
the Invention
[0181] 5 mg of myristic acid were dissolved in 100 ml of
2H,3H-perfluoropentane at 30-35.degree. C. in a water bath. 995 mg
of formoterol fumarate dihydrate as micronized particles were added
and dispersed, the suspension was sonicated and then kept under
stirring. The suspension thus obtained contained 99.5% formoterol
fumarate dihydrate and 0.5% myristic acid by weight.
[0182] This suspension was spray-dried in a Biichi 191 Mini Spray
Dryer using the following parameters:
[0183] inlet air temperature: 100.degree. C.;
[0184] outlet temperature: 60.degree. C.;
[0185] air flow rate: 600 l/h;
[0186] feed flow: 4 ml/min; and
[0187] nozzle diameter: 0.7 mm.
The yield of the process was 69.0%.
[0188] Analogously, formoterol fumarate dehydrate (FF)
microparticles having the following compositions were obtained:
TABLE-US-00001 FF Additive Yield Sample (w/w %) (w/w %) (%) FF-myr
1.0% 99.0 Myristic acid 1.0 70.3 FF-myr 2.0% 98.0 Myristic acid 2.0
68.1 FF-lau 0.5% 99.5 Lauric acid 0.5 68.4 FF-pal 0.5% 99.5
Palmitic acid 0.5 69.3 FF-ole 0.5% 99.5 Oleic acid 0.5 69.3
Example 2
Characterization of the Microparticles of Example 1
[0189] The microparticles as obtained in Example 1 were subjected
to the following analysis.
[0190] Scanning electron microscopy (SEM). Morphological properties
were investigated using a scanning electron microscope (SEM, Zeiss
SUPRA 40, Oberkochen, Germany). Each sample was carefully mounted
on a sample holder, so as to ensure representative images, and
analyzed without coating sputter. SEM micrographs were taken using
in-built image capture software. The obtained images demonstrate
that the microparticles of the invention do not change their
morphological aspect in comparison to the uncoated FF
microparticles.
[0191] Differential scanning calorimetry (DSC). The crystalline
properties were further investigated by differential scanning
calorimetry (DSC). The data were obtained on a Mettler Toledo
Instrument DSC821c, software STARe. The calibration standard used
is indium. Approximately 2 to 5 mg of a sample is placed into a DSC
pan, and the weight is accurately measured and recorded. The pan is
hermetically sealed. The sample is heated under nitrogen at a rate
of 20.degree. C./min, from 25.degree. C. to a final temperature of
200.degree. C. The thermogram reported in FIG. 1 shows that the
characteristic endothermic transition ending at about 160.degree.
C., typical of crystalline formoterol fumarate dihydrate, is still
present in the microparticles of the invention, indicating that the
spray-drying process has not modified the solid characteristics of
the drug.
[0192] The microparticles coated with amounts of additive ranging
from 1.0 to 2.0% w/v are more crystalline than microparticles
coated with a lower amount, i.e. 0.5% w/v.
[0193] Particle size via laser diffraction. Particle size
distributions were measured by laser diffraction (Spraytec.RTM. S,
Malvern Instruments, Worcestershire, UK). The powders were
dispersed in Span85:cyclohexane 0.1% w/v. The results are reported
in Table 1.
[0194] After spray-drying, the particle size of the microparticles
of the invention does not substantially change in comparison to
that of raw formoterol fumarate dihydrate.
TABLE-US-00002 TABLE 1 Particle size. d(v0.1) d(v0.5) d(v0.9)
Sample (.mu.m) (.mu.m) (.mu.m) FF raw material 0.62 1.69 3.27
FF-lau 0.5 0.86 1.96 3.60 FF-myr 0.5 0.96 1.65 2.46 FF-pal 0.5 0.85
1.84 3.48 FF-ole 0.5 0.82 1.78 3.56
Example 3
pMDI Formulation Comprising the Microparticles of Example 1
[0195] To prepare pMDI aerosol suspension formulations with a
nominal dose of the active ingredient of 12 the aluminum canisters
were filled in a controlled atmosphere room, by successively
introducing 2.4 mg the microparticles of Example 1 and then 10 ml
pressurized HFA134a gas. The devices were fitted with a 50 .mu.l
APTAR valve and a Bespak actuator of 0.3 mm. For comparative
purposes, a pMDI aerosol suspension formulations comprising
micronized formoterol fumarate dihydrate was also prepared. The
sedimentation rate was determined using a Turbiscan apparatus
(Formulaction SA, France).
[0196] The pMDI formulations obtained with microparticles of the
invention exhibit a good homogenous distribution of the suspended
particles as well as a higher level of physical stability than the
comparative formulation, as the particles sediment more slowly and
are less liable to form agglomerates.
[0197] The pMDI formulations were also characterized in terms of
aerosol performances. They were assessed using a Next Generation
Impactor to according to the procedure described in the European
Pharmacopoeia 7.sup.th edition, 2011, part 2.9.18.
[0198] Quantification of formoterol fumarate dihydrate (FF) was
performed using a HPLC method. The following parameters were
determined: [0199] i) delivered dose (DD) is calculated from the
cumulative deposition in the ACI, divided by the number of
actuations per experiment; [0200] ii) fine particle mass (FPM) is
obtained by interpolation of the cumulative percentage undersize of
drug mass deposition versus cut off diameter. The FPM corresponds
to particles of diameter .ltoreq.5.0 microns, divided by the number
of actuations per experiment. [0201] iii) respirable fraction (fine
particle fraction=FPF) which is the percent ratio between the fine
particle mass and the delivered dose. [0202] iv) mass median
aerodynamic diameter (MMAD) which is the diameter around which the
mass aerodynamic diameters of the emitted particles are distributed
equally;
[0203] The results (as a mean.+-.S.D.) are summarized in Table 2.
It is evident that the PMDI formulations comprising the
microparticles of the invention give rise to an excellent
respirable fraction, comparable to that of the formulation
comprising uncoated micronized FF.
TABLE-US-00003 TABLE 2 Aerosol performances of the pMDI
formulations. DD MMAD FPM FPF Sample (.mu.g) (.mu.m) (.mu.g) (%)
FF-Raw 8.34 .+-. 0.32 1.92 .+-. 0.00 6.84 .+-. 0.51 81.9 .+-. 2.9
FF-Lau 0.5 7.10 .+-. 0.22 2.07 .+-. 0.13 5.35 .+-. 0.11 75.4 .+-.
0.8 FF-Pal 0.5 8.12 .+-. 0.35 2.20 .+-. 0.01 6.30 .+-. 0.14 77.7
.+-. 1.6 FF-Ole 0.5 8.56 .+-. 0.33 2.10 .+-. 0.10 6.85 .+-. 0.42
80.1 .+-. 1.8 FF-Mir 0.5 8.23 .+-. 0.23 2.45 .+-. 0.01 5.12 .+-.
0.21 62.2 .+-. 0.7 FF- Mir 1 8.21 .+-. 0.25 2.18 .+-. 0.08 6.46
.+-. 0.39 78.7 .+-. 2.3 FF-Mir 2 8.69 .+-. 0.07 2.05 .+-. 0.03 7.31
.+-. 0.02 84.1 .+-. 0.5
Example 4
Powder Formulation Comprising Formoterol Fumarate Microparticles
According to the Invention
[0204] To prepare powder formulations, the microparticles of
Example 1 FF-myr 0.5 and Ff-myr 2.0 were mixed in a Turbula mixer
with alpha-lactose monohydrate having a mass diameter comprised
between 90 and 150 .mu.m as a carrier, to obtain a ratio of 6 .mu.g
of drug to 10 mg of carrier. For comparative purposes, a powder
formulation comprising micronized formoterol fumarate dihydrate was
also prepared. Each powder was filled in hard HMPC gelatine
capsules, in turn loaded in a RS01/7unit dose inhaler (Plastiape,
Italy).
[0205] The aerosol performances were evaluated using a Next
Generation Impactor (NGI) according to the procedure described in
European Pharmacopoeia 7.sup.th edition, 2011, part 2.9.18, pages
281-285. The results (mean.+-.S.D.) in terms of delivered dose
(DD), fine particle mass (FPM), fine particle fraction (FPF) and
mass median aerodynamic diameter (MMAD), are reported in Table 3.
The data demonstrate that the powder formulations comprising the
microparticles of the invention give rise to significantly higher
respirable fractions than that comprising uncoated micronized
FF.
TABLE-US-00004 TABLE 3 Aerosol performances of the powder
formulations. DD FPM FPF MMAD Sample .mu.g .mu.g % .mu.m FF raw 4.
73 .+-. 0.02 0.71 .+-. 0.04 14.03 .+-. 0.82 2.36 .+-. 0.05 FF-myr
0.5 4.41 .+-. 0.01 1.17 .+-. 0.04 26.47 .+-. 1.02 1.85 .+-. 0.03
FF-myr 2.0 4.69 .+-. 0.30 1.09 .+-. 0.06 23.35 .+-. 0.25 1.65 .+-.
0.02
Example 5
Preparation of Microparticles of Salmeterol Xinafoate According to
the Invention
[0206] 10 mg of myristic acid were dissolved in 100 ml of
2H,3H-perfluoropentane at 30-35.degree. C. in a water bath. 990 mg
of salmeterol xinafoate (SX) as micronized particles were added and
dispersed, the suspension was sonicated and then kept under
stirring. The suspension thus obtained contained 99% formoterol
fumarate dihydrate and 1.0% myristic acid by weight. This
suspension was spray-dried in a Michi 191 Mini Spray Dryer with the
following parameters:
[0207] inlet air temperature: 100.degree. C.;
[0208] outlet temperature: 64.degree. C.;
[0209] air flow rate: 600 l/h;
[0210] feed flow: 4 ml/min; and
[0211] nozzle diameter: 0.7 mm.
Analogously, SX microparticles with oleic acid were prepared. The
microparticles have the following composition:
TABLE-US-00005 FF Additive Yield Sample (w/w %) (w/w %) (%) SX-myr
1.0% 99.0 Myristic acid 1.0 75.0 SX-ole 2.0% 98.0 Oleic acid 1.0
85.0
Example 6
pMDI Formulation Comprising the Microparticles of Example 5
[0212] To prepare pMDI aerosol suspension formulations with a
nominal dose of the active ingredient of 25 .mu.g, canisters coated
with FEP were filled in a controlled atmosphere room, by
successively introducing 3.0 mg the microparticles of Example 5 and
then 6 ml pressurized HFA134a gas. The devices were fitted with a
50 .mu.l APTAR valve and a Bespak actuator of 0.3 mm. For
comparative purposes, a pMDI aerosol suspension formulations
comprising micronized salmeterol xinafoate was also prepared. The
pMDI formulations were characterized in terms of aerosol
performances. They were assessed as described in Example 3. The
results (as a mean.+-.S.D.) are summarized in Table 4.
[0213] It is evident that the PMDI formulations comprising the
microparticles of the invention give rise to a satisfactory
respirable fraction, slightly better to that of the formulation
comprising uncoated micronized.
TABLE-US-00006 TABLE 4 Aerosol performances of the pMDI
formulations. DD FPM FPF MMAD Sample .mu.g .mu.g % .mu.m SX raw
14.28 .+-. 1.72 4.23 .+-. 0.25 29.74 .+-. 1.75 2.79 .+-. 0.39
SX-ole 1.0 16.73 .+-. 2.09 5.82 .+-. 0.83 34.77 .+-. 2.32 3.02 .+-.
0.06 SX-myr 1.0 22.43 .+-. .76 6.77 .+-. 0.57 39.55 .+-. 4.06 2.46
.+-. 0.07.
[0214] Where a numerical limit or range is stated herein, the
endpoints are included. Also, all values and subranges within a
numerical limit or range are specifically included as if explicitly
written out.
[0215] Obviously, numerous modifications and variations of the
present invention are possible in light of the above teachings. It
is therefore to be understood that, within the scope of the
appended claims, the invention may be practiced otherwise than as
specifically described herein.
[0216] All patents and other references mentioned above are
incorporated in full herein by this reference, the same as if set
forth at length.
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