U.S. patent application number 10/574334 was filed with the patent office on 2007-11-08 for aerosol formulations comprising formoterol fumarate dihydrate.
Invention is credited to Rudi Mueller-Walz.
Application Number | 20070256685 10/574334 |
Document ID | / |
Family ID | 29433594 |
Filed Date | 2007-11-08 |
United States Patent
Application |
20070256685 |
Kind Code |
A1 |
Mueller-Walz; Rudi |
November 8, 2007 |
Aerosol Formulations Comprising Formoterol Fumarate Dihydrate
Abstract
A pharmaceutical aerosol formulation comprising formoterol
fumarate di-hydrate in suspension, and a steroid in suspension, and
a propellant, ethanol, and optionally a surfactant, wherein the
formoterol fumarate di-hydrate has a water content of about 4.8 to
4.28% by weight.
Inventors: |
Mueller-Walz; Rudi;
(Schopfheim, DE) |
Correspondence
Address: |
MINTZ, LEVIN, COHN, FERRIS, GLOVSKY;AND POPEO, P.C.
ONE FINANCIAL CENTER
BOSTON
MA
02111
US
|
Family ID: |
29433594 |
Appl. No.: |
10/574334 |
Filed: |
October 8, 2004 |
PCT Filed: |
October 8, 2004 |
PCT NO: |
PCT/IB04/03481 |
371 Date: |
March 7, 2007 |
Current U.S.
Class: |
128/200.23 ;
424/45; 424/46; 514/169; 514/613 |
Current CPC
Class: |
A61K 9/12 20130101; A61M
15/009 20130101; A61K 9/008 20130101; A61M 16/20 20130101; A61M
11/04 20130101; A61P 11/00 20180101; A61P 11/06 20180101; A61K
31/167 20130101; A61K 9/124 20130101; A61K 31/56 20130101; A61K
31/165 20130101; A61K 31/165 20130101; A61K 2300/00 20130101; A61K
31/56 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
128/200.23 ;
424/045; 424/046; 514/169; 514/613 |
International
Class: |
A61M 11/00 20060101
A61M011/00; A61K 31/167 20060101 A61K031/167; A61K 31/56 20060101
A61K031/56; A61P 11/00 20060101 A61P011/00; A61P 11/06 20060101
A61P011/06; A61K 9/12 20060101 A61K009/12; A61K 9/14 20060101
A61K009/14 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 9, 2003 |
GB |
0323684.1 |
Claims
1. A pharmaceutical aerosol formulation for use in a metered dose
inhaler (MDI) comprising formoterol fumarate di-hydrate in
suspension, a propellant and ethanol, wherein the formoterol
fumarate di-hydrate has a water content of about 4.8 to 4.28% by
weight.
2. The pharmaceutical aerosol formulation according to claim 1
further comprising a steroid in solution.
3. The pharmaceutical aerosol suspension formulation according to
claim 2, wherein the formulation is capable of being dispensed from
an MDI to provide a Delivered dose of formoterol fumarate
di-hydrate that has a variance of no more than +/-25%, of the mean
Delivered dose when the formulation is stored at 40.degree. C. and
75% relative humidity for up to 6 months.
4. The pharmaceutical aerosol suspension formulation according to
claim 2, wherein the formulation is capable of being dispensed from
an MDI to provide a Delivered dose of formoterol fumarate
di-hydrate with a fine particle fraction of 30 to 70%.
5. The pharmaceutical aerosol suspension formulation according to
claim 2, wherein the formoterol fumarate di-hydrate is provided as
particles having a water content of about 4.8 to 4.28% by weight
suspended in the propellant and solvent, and wherein the
formulation is capable of being dispensed from an MDI to provide a
Delivered dose of the steroid that has a variance of no more than
+/-25%, of the mean Delivered dose when the formulation is stored
at 40.degree. C. and 75% relative humidity for up to 6 months.
6. The pharmaceutical aerosol suspension formulation according to
claim 5, wherein the formulation is capable of being dispensed from
an MDI to provide a Delivered dose of steroid containing a fine
particle fraction of 30% to 70%.
7. The formulation according to claim 2, wherein the steroid is
selected from the group consisting of budesonide, ciclesonide,
mometasone, fluticasone, beclomethasone, flunisolide, loteprednol,
triamcinolone, amiloride, rofleponide or a pharmaceutically
acceptable salt or derivative of these active compounds, selected
from mometasone furoate, fluticasone dipropionate, beclomethasone
dipropionate, triamcinolone acetonide and flunisolide acetate.
8. The formulation according to claim 7 wherein the steroid is
fluticasone propionate.
9. The formulation according to claim 8 wherein the fluticasone
proprionate is present in an amount of 0.05 to 2% by weight of the
formulation.
10. The formulation according to claim 1 or claim 2, wherein the
formoterol fumarate di-hydrate is present in an amount of 0.001 to
0.1% by weight of the formulation.
11. The formulation according to according to claim 1 or claim 2
containing a cromone selected from the group consisting of a
pharmaceutically acceptable salt of cromoglycinic acid, nedocromil,
and mixtures thereof.
12. The formulation according to claim 11 wherein the cromone is
present in the formulation in an amount of 0.001 to 1%.
13. The formulation according to claim 1 or claim 2, wherein the
propellant is selected from the group consisting of
fluorochlorocarbons, alkanes, fluorinated alkanes, and
hydrofluoroalkanes.
14. The formulation according to claim 13 wherein the propellant is
a hydrofluoroalkane of the general formula: CxHyFz (I); in which x
is the number 1, 2 or 3, y and z are each an integer greater than
or equal to (.gtoreq.) 1, and y+z=2x+2.
15. The formulation according to claim 32 wherein the propellant is
HFA 134a or HFA 227 or a mixture thereof.
16. The formulation according to claim 1 or claim 2, wherein the
propellant is employed in an amount of greater than 90% by
weight.
17. The formulation according to claim 1 or claim 2, wherein the
ethanol is present in amounts of less than 2.5% by weight.
18. The formulation according to claim 1 or claim 2 comprising a
surfactant selected from the group consisting of oleic acid,
lecithin, sorbitan trioleate, cetylpyridinium chloride,
benzalkonium chloride, polyoxyethylene (20) sorbitan monolaurate,
polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20)
sorbitan monooleate, polyoxypropylene/polyoxyethylene block
copolymers, polyoxypropylene/polyoxyethylene/ethylenediamine block
copolymers, and ethoxylated castor oil.
19. The formulation according to claim 18 wherein the surfactant is
present in an amount of 0.0001 to 1% by weight.
20. A pharmaceutical aerosol formulation for use in a metered dose
inhaler (MDI) comprising formoterol fumarate di-hydrate in
suspension, a propellant and ethanol, wherein the moisture content
of the formulation is in the range of from 50 ppm to 800 ppm.
21. A vial containing the formulation according to claim 1 or claim
2.
22. The vial according to claim 21 in the form of an aluminum,
uncoated container.
23. The vial according to claim 21 adapted to be placed in a
metered dose inhaler, and capable of delivering a dosage of
formoterol fumarate di-hydrate of about 3 to 15 micro-grams.
24. The vial according to claim 21 adapted to be placed in a
metered dose inhaler, and capable of delivering a dosage of a
steroid of about 10 to 1000 micro-grams per puff.
25. The vial according to claim 24 adapted to be placed in a
metered dose inhaler, and capable of delivering a dosage of
fluticasone proprionate of about 50 to 500 micro-grams per
puff.
26. A package comprising the vial according to claim 21 comprising
a label containing a dosage claim, wherein the mean Delivered dose
of the active substances is no more than +/-15% of the dosage
stated on the label.
27. A metered dose inhaler containing the vial according to claim
21.
28. A method of producing a pharmaceutical aerosol formulation
according to claim 1 or claim 2, comprising drying the formoterol
fumarate di-hydrate to a water content of 4.8 to 4.28%.
29. The formulation according to claim 13, wherein the propellant
is a fluorochlorocarbon selected from the group consisting of
trichloro-monofluoromethane (F11), dichlorodifluoromethane (F12),
monochlorotrifluoromethane (F13), dichloro-monofluoromethane (F21),
monochlorodifluoromethane (F22), monochloromonofluoromethane (F31),
1,1,2-trichloro-1,2,2-trifluoroethane (F113),
1,2-dichloro-1,1,2,2-tetrafluoroethane (F114),
1-chloro-1,1,2,2,2-pentafluoroethane (F115),
2,2-dichloro-1,1,1-trifluoroethane (F123),
1,2-dichloro-1,1,2-trifluoroethane (F123a),
2-chloro-1,1,1,2-tetrafluoroethane (F124),
2-chloro-1,1,2,2-tetrafluoroethane (F124a),
1,2-dichloro-1,1-difluoroethane (F132b),
1-chloro-1,2,2-trifluoroethane (F 133),
2-chloro-1,1,1-trifluoroethane (F133a), 1,1-dichloro-1-fluoroethane
(F141b) and 1-chloro-1,1-difluoroethane (F142b).
30. The formulation according to claim 13, wherein the propellant
is an alkane selected from the group consisting of propane, butane
and isobutene.
31. The formulation according to claim 13, wherein the propellant
is octafluoropropane (F218).
32. The formulation according to claim 13, wherein the propellant
is a hydrofluoroalkanes selected from the group consisting of
difluoromethane (HFA 32), pentafluoroethane (HFA 125),
1,1,2,2-tetrafluoroethane (HFA 134), 1,1,1,2-tetrafluoroethane (HFA
134a), 1,1,2-trifluoroethane (HFA 143), 1,1,1-trifluoroethane (HFA
143a), difluoroethane (HFA 152a) and
1,1,1,2,3,3,3-heptafluoropropane (HFA 227).
33. A metered dose inhaler containing the vial according to claim
22.
Description
[0001] The present invention relates to aerosol formulations
comprising formoterol fumarate di-hydrate in suspension which
formulations are capable of being dispensed from a metered dose
inhaler device with good delivered dose uniformity and high fine
particle fraction. In particular, the invention relates to such
formulations additionally comprising a steroid in suspension. The
invention also relates to a method of producing such
formulations.
[0002] Metered dose inhaler (MDI) formulations are well known in
the art. They typically consist of suspensions or solutions of an
active substance in a propellant or mixture of propellants, and
contain other optional ingredients such as solvents and surfactants
and preservatives. MDI formulations are stored in suitable
pressurized containers that are equipped with a valve to permit an
active substance to be dispensed on demand. In common with all drug
products, they are subject to regulatory review as to their safety
and efficacy before they can be marketed for use in humans.
However, unlike oral or injectable products, which typically
contain a single dosage form, an aerosol formulation for use in an
MDI may contain multiple doses, e.g. tens or even hundreds of doses
in a single container, and each of these must be delivered with a
uniform delivered dose, and reliable particle size uniformity.
Furthermore, MDI formulations must be capable of delivering doses
uniformly even after long storage periods, e.g. 2 to 3 years, under
harsh conditions of temperature and humidity in order to mimic all
manner of patient-use conditions.
[0003] Formoterol fumarate di-hydrate has proven to be a
particularly recalcitrant material to formulate. When formulated as
suspended particles in aerosol formulations, the particles are
prone to agglomeration, and to form sediments which are not readily
re-dispersible. Furthermore, the particles often adhere to the
inner surface of both canisters and valves. As a result, such
formulations often display irregular dosing.
[0004] U.S. Pat. No. 6,054,488 addresses formulations containing
formoterol fumarate as the sole active substance in suspension
aerosol formulations in MDIs. This reference describes difficulties
in formulating formoterol, in particular the problem of deposition
of the suspended particles on canisters and valves leading to poor
dose reproducibility. Often, surface active agents or other
adjuvants need to be added to such formulations to counteract these
problems. However, because most acceptable propellants are poor
solvents for these surfactants and other adjuvants, one needs to
use polar co-solvents to assist in their dissolution. Various polar
co-solvents have been employed, but ethanol is a particularly
useful co-solvent in this regard. However, as stated in U.S. Pat.
No. 6,054,488 formulations containing an HFA and ethanol are
extremely sensitive to the amount of ethanol employed. In
particular, it is known that ethanol can affect the density of
propellants, which can in turn alter the ability of the drug
substance to be suspended. This may create complications, if one
wishes to formulate additional active substances in suspension,
because an appropriate ethanol level for formoterol may not be an
appropriate level for suspending the other actives.
[0005] EP1152753 ('753) discloses inhalable formulations containing
a combination of formoterol and the steroid-fluticasone. However,
this document merely teaches the desirability of a fixed
combination of the active substances in all manner of orally or
nasally inhalable formulations, from nebulisers to dry powder
formulations to aerosol formulations containing the active agents
in suspension or solution. There is no mention of the difficulties
in formulating formoterol fumarate and consequently no technical
teaching as to how one should formulate this drug in combination
with a steroid in an MDI formulation as an aerosol suspension, to
produce a product that is capable of being delivered with a uniform
delivered dose and high fine particle fraction. '753 states that
ethanol can be employed in amounts of "up to 30% by weight".
However, having regard to the teaching of U.S. Pat. No. 6,054,488,
the disclosure of this range provides no technical teaching of
workable levels of ethanol. In fact, of the 216 examples provided,
only one example refers to a MDI formulation, and it uses 2.5% by
weight of ethanol.
[0006] It conspicuous that despite the disclosure of EP1152753, and
despite the clearly articulated advantages in the art of a fixed
combination in either dry-powder or aerosol form, and despite the
fact that physicians have co-prescribed these active substances for
several years before the priority date of this document, at the
present time, applicant is not aware of any commercial MDI
formulations containing formoterol fumarate di-hydrate in
combination with fluticasone propionate.
[0007] There remains a need to provide means of stabilizing
suspension formulations containing formoterol fumarate di-hydrate,
particularly such formulations that additionally contain a steroid
in suspension.
[0008] The applicant has now found alternative means of stabilising
suspension aerosol formulations containing formoterol fumarate
di-hydrate, such that it is possible to formulate highly stable
aerosol formulations containing this active substance, even in
combination with a steroid in suspension, without the need to
adjust ethanol levels outside those effective for stabilizing a
formoterol suspension formulation as a sole active agent. This is
achieved by carrying out a drying step on the formoterol fumarate
di-hydrate, thereby presenting it in a form with a particularly low
water content, before mixing it together with other ingredients to
form the formulation.
[0009] Accordingly, the invention provides in a first aspect a
pharmaceutical aerosol formulation for use in a metered dose
inhaler (MDI) comprising formoterol fumarate di-hydrate in
suspension, a propellant and ethanol, wherein the formoterol
fumarate di-hydrate is provided as suspended particles having a
water content of about 4.8 to 4.28%, more particularly 4.50 to
4.28% by weight.
[0010] The present invention represents a considerable
simplification in the formulation of formoterol fumarate
di-hydrate, and permits of its combination in suspension with a
number of steroids. The applicant has shown that such formulations
can deliver the active substances with good delivered dose
uniformity and high fine particle fraction,
[0011] The invention provides in a second aspect a pharmaceutical
aerosol formulation for use in a metered dose inhaler (WI)
comprising formoterol fumarate di-hydrate in suspension, and a
steroid in suspension, a propellant and ethanol, wherein the
formoterol fumarate di-hydrate is provided as suspended particles
having a water content of about 4.8 to 4.28%, more particularly
4.50 to 4.28% by weight.
[0012] Formulations according to the present invention can be
filled into canisters to form highly stable suspensions for use in
MDI devices. Formulations exhibit substantially no particle growth
or change of morphology of the suspended particles. There is also
no, or substantially no, problem of deposition of the suspended
particles on the surface of either canisters or valves, and so the
formulations can be discharged from a suitable MDI device with high
Delivered dose uniformity.
[0013] Formulations of the present invention meet Compendial
requirements as to Delivered dose uniformity as set forth, for
example in the United States and European Pharmacopoeae. For
example, formulations of the present invention meet the requirement
set out in the USP26-NF21 chapter <601> "Delivered dose
Uniformity". Indeed, the formulations appear to be so stable that
they may even meet the relatively more stringent Delivered dose
uniformity requirements set forth in the current Draft Guidance
from the FDA, published by the CDER in October 1998.
[0014] Accordingly, the invention provides in a third aspect a
pharmaceutical aerosol suspension formulation for use in a metered
dose inhaler (MDI) comprising formoterol fumarate di-hydrate in
suspension, and optionally a steroid in suspension, a propellant
and ethanol, wherein the formoterol fumarate di-hydrate is provided
as suspended particles having a water content of about 4.8 to
4.28%, more particularly 4.50 to 4.28% by weight, and wherein the
formulation is capable of being dispensed from an MDI to provide a
Delivered dose of formoterol fumarate di-hydrate that has a
variance of no more than +/-25%, of the mean Delivered dose when
the formulation is stored at, 25 degrees centigrade and 60 relative
humidity (rh), more particularly 40 degrees centigrade and 75% rh
for up to 6 months, e.g. 1, 3 and 6 months.
[0015] Still further, the Delivered dose of the formulations
contains a high fraction of fine particles, i.e. particles that are
capable of penetrating the deep lung, e.g. having a diameter of
less than about 5.8, more preferably less than about 4.7
microns.
[0016] Accordingly, in a fourth aspect, the invention provides a
pharmaceutical aerosol suspension formulation for use in a metered
dose inhaler (MDI) comprising formoterol fumarate di-hydrate in
suspension, and optionally a steroid in suspension, a propellant
and ethanol, wherein the formoterol fumarate di-hydrate has a water
content of about 4.8 to 4.28%, more particularly 4.50 to 4.28% by
weight, and wherein the formulation is capable of being dispensed
from a MDI to provide a Delivered dose of formoterol fumarate
di-hydrate with a fine particle fraction of about 30 to 70%.
[0017] When a steroid is present in a formulation according to the
invention, applicant has found that the Delivered dose of steroid
also meets with Compendial requirements, and the Draft FDA Guidance
referred to above.
[0018] Thus, the invention provides in a fifth aspect a
pharmaceutical aerosol suspension formulation for use in a metered
dose inhaler (MDI) comprising formoterol fumarate di-hydrate in
suspension, and a steroid in suspension, a propellant and ethanol,
wherein the formoterol fumarate di-hydrate is provided as particles
having a water content of about 4.8 to 4.28%, more particularly
4.50 to 4.28% by weight, suspended in the propellant and ethanol,
and wherein the formulation is capable of being dispensed from a
MDI to provide an Delivered dose of the steroid that has a variance
of no more than +/-25%, of the mean Delivered dose when the
formulation is stored at, 25 degrees centigrade and 60% rh, more
particularly 40 degrees centigrade and 75% rh for up to 6 months,
e.g. 1, 3 and 6 months.
[0019] In a sixth aspect of the invention there is provided a
pharmaceutical aerosol suspension formulation for use in a metered
dose inhaler (MDI) comprising formoterol fumarate di-hydrate in
suspension, and a steroid in suspension, a propellant and ethanol,
wherein the formoterol fumarate di-hydrate has a water content of
about 4.8 to 4.28%, more particularly 4.5 to 4.28% by weight,
wherein the formulation is capable of being dispensed from a MDI to
provide an Delivered dose of steroid containing a fine particle
fraction of about 30 to 70%.
[0020] Formulations of the present invention may be made by a
process, which forms a seventh aspect of the invention, and
comprises the step of drying the formoterol fumarate di-hydrate to
a water content of about 4.8 to 4.28%, more particularly 4.50 to
4.28% by weight, before mixing the active ingredients with
propellant and ethanol in a container according to techniques
generally known in the art.
[0021] Formoterol fumarate di-hydrate raw material typically
contains a certain amount of water in addition to the water of
crystallization. Typically, the raw material is used directly in
formulations. However, applicant found that by subjecting the raw
material to a drying step that is designed to drive off all, or
substantially all, of the residual water but not the water of
crystallisation, formulations of very high stability can be
achieved. Applicant found that drying to a water content of about
4.8 to 4.28%, more particularly 4.5 to 4.28% enabled the
preparation of suspension formulations with good stability. The
drying step is carried out under conditions of pressure and
temperature to achieve the desired water content within a time that
is both practical and economical. The skilled person will
appreciate that the inventive concept resides in the realization
that the material should be subjected to a drying step, to achieve
the above stated preferred level of dryness, and not in the means
or conditions by which the drying is achieved. Accordingly,
consistent with the economic consideration, and the need to dry in
a reasonably practical period of time, and consistent with the
requirement of preserving the integrity of the active substance's
water of crystallization, virtually any conditions of temperature
and pressure can be employed.
[0022] Preferably however, the material can be dried at a
temperature of between 10 and 70.degree. C. Preferably, also, the
material can be dried at a pressure of 10 to 400 mbar.
[0023] Water content is measured according to the Karl Fischer
Method. The Karl Fischer method is a well known analytical tool for
the measurement, specifically, of a sample's water content. It is a
titrimetric method that involves the reaction between water
contained in a sample and a Karl Fischer Reagent, which is a
mixture of sulphur dioxide, iodine, pyridine and methanol. The
preferred reagent is Hydranal Composite 1 or 5, wherein 1 is
preferred. The reagent reacts with suspended and dissolved
water.
[0024] Furthermore, because the sample is dissolved during this
method, it is also measures water of crystallization of a
sample.
[0025] The Delivered dose of a formulation is the amount of active
agent to achieve a therapeutic effect or prophylactic effect that
is emitted from a MDI device upon actuation. Depending on the drug
substance to be emitted, and the nature of the valve, the Delivered
dose may be the amount of active material emitted upon a single
actuation of the MDI, or it may be the amount emitted from two or
more actuations. It is not a measure of the total amount of
material (actives and excipients) that is emitted upon actuation.
This is often referred to as the Shot Weight.
[0026] Whilst every precaution is taken to keep formulations dry,
due to residual moisture from excipients and moisture ingress that
might occur during conditions of storage and use, formulations of
the present invention may contain small amounts of moisture.
Preferably formulations of the present invention contain levels of
moisture of 50 ppm to 800 ppm, more particularly 100 to 600 pm.
[0027] The Delivered dose may not only vary between different
formulations of a batch; it may also vary within a given
formulation when that formulation contains a plurality, e.g. 10 or
even 100 or more doses of the active substance. Accordingly, the
variance of the Delivered dose is typically measured for a
formulation in a given container by taking measurements at the
beginning, middle and end of that formulation's life. In this way,
a measure of the in-use variability in the dosing is obtained.
Further, batches of formulations may be tested to obtain a picture
of the inter-batch variability of a formulation after determined
periods of storage. The variance of formulations according to the
present invention is discussed further in the Examples. Variance,
in both cases, must fall within limits set by regulatory
authorities if a product is to gain market authorisation. As stated
herein above, formulations of the present invention fall within all
the Compendial requirements for variance of Delivered dose, and can
even meet the more stringent requirements referred to in the FDA
Draft Guidance for Industry published in October 1998.
[0028] The fraction of active agent contained in the total
Delivered dose that is of small enough aerodynamic diameter to
reach the deep lung upon inhalation is often referred to as the
fine particle fraction (or FPM) of the Delivered dose, and the
absolute amount of fine particles emitted is often referred to as
the Fine Particle Dose (or FPD). As stated herein above,
formulations of the present invention are capable of being
delivered with good Delivered dose uniformity and with a high FPF,
both in relation to the formoterol fumarate di-hydrate, and the
steroid.
[0029] The Delivered dose and its variance can be measured using
the Dosage Unit Sampling Apparatus (DUSA). The FPF can be measured
using an Andersen Cascade Impactor (ACI). The measurement
methodology and the apparatus therefor are well known in the art,
and are described in the United States Pharmacopoeia Chapter
<601>, or in the inhalants monograph of the European
Pharmacopoeia, both of which documents are hereby incorporated by
reference. The USP states that the Apparatus 1 should be used for
the measurement of FPF. The USP also states that Delivered dose
Uniformity should be measured with DUSA or its equivalent. However,
the Delivered dose and Delivered dose uniformity are preferably
measured using the so-called Funnel Method. The Funnel Method is
described in Drug Delivery to the Lungs, VIII p 116 to 119, which
is hereby incorporated by reference. In summary, the Funnel Method
consists of discharging a formulation from a MDI into a Funnel
Apparatus, which basically consists of a standard Buchner Funnel.
The discharged dose is captured on the glass sinter of the Funnel,
and can be washed off, and the dose determined using HPLC analysis.
The Funnel Method gives comparable results to the standard USP
apparatus, and is generally considered to be an equivalent of the
DUSA apparatus.
[0030] Formoterol fumarate di-hydrate is a long acting, selective
B-2-adrenoceptor agonist. It is well known in the literature and is
the active substance in the commercially available
product--Foradil.TM.. The skilled person will be fully apprised of
its properties and uses, and no further discussion needs to be had
here.
[0031] Formulations of the present invention may contain from 0.001
to 0.1%, more particularly 0.003 to 0.05%, still more particularly
0.005 to 0.02% by weight of formoterol fumarate di-hydrate.
[0032] Formoterol fumarate di-hydrate is a very potent material.
The typical therapeutic or prophylactic dose of this material to be
emitted from an MDI device will depend upon the patient, and the
type and severity of the condition to be treated. The dose may vary
from about 3 to 15 micro-grams, more particularly 6 to 12
micro-grams, e.g. 10 micrograms. In a finished form, a formulation
will be packaged, and will be accompanied by labeling. The dose
presented on the packaging and/or labeling of a finished form is
often referred to as its Label Claim. In order to ensure
inter-batch quality and reproducibility, the mean dose of
formulation emitted from a MDI, should not vary considerably from
the Label Claim. In this regard, given the good stability of the
formulation of the present invention, the mean Delivered dose of
formoterol fumarate di-hydrate does not fall outside a range of
+/-15% of the Label Claim.
[0033] Steroids for use in the present invention include any of the
materials selected from the group consisting of budesonide,
ciclesonide, mometasone, fluticasone, beclomethasone, flunisolide,
loteprednol, triamcinolone, amiloride, rofleponide or a
pharmaceutically acceptable salt or derivative of these active
compounds, such as mometasone furoate, fluticasone dipropionate,
beclomethasone dipropionate, triamcinolone acetonide or flunisolide
acetate, where optically active, these materials can be used in the
form of their active isomer or as an isomer mixture.
[0034] A particularly preferred steroid for use in the present
invention is fluticasone propionate.
[0035] An appropriate therapeutic or prophylactic Delivered dose
for the steroids will depend upon the steroid selected, the patient
and the type and severity of the condition to be treated. It may
vary within a range of about 10 to 2000, more particularly 100 to
1600 micro-grams daily dose.
[0036] Taking fluticasone as an example, this material is typically
administered in 50, 125 and 250 micro-grams per puff (two puffs per
dose). The recommended daily dose is 1000 micro-grams per day.
[0037] In respect of the steroid, the mean Delivered dose of
formulations of the present invention does not fall outside a range
of +/-15% of the Label Claim of the steroid.
[0038] In a preferred embodiment of the present invention, a
formulation as herein above defined additionally contains a cromone
selected from the group consisting of a pharmaceutically acceptable
salt of cromoglycinic acid, e.g. di-sodium cromoglycate and/or
nedocromil. Both of these materials are pharmaceutically active
substances, and so their use in the present invention is limited to
sub-therapeutic or sub-prophylactic levels, e.g. from about 5 to
250 micrograms per puff of a MDI inhaler. The materials may be
employed to afford the formulations protection against moisture.
The use of these materials to protect moisture sensitive active
substances is reported in U.S. Pat. No. 6,475,467.
[0039] Preferably, formulations of the present invention contain
from 0.001 to 1%, more particularly 0.005 to 0.2%, still more
particularly 0.01 to 0.1% by weight cromone, e.g. disodium
cromoglycate.
[0040] Suitable propellants for use in the aerosol formulations
according to the invention may be any of the pressure-liquefied
propellants which customarily may find use in metered-dose
aerosols, for example fluorochlorocarbons such as
trichloro-monofluoromethane (F11), dichlorodifluoromethane (F12),
monochlorotrifluoromethane (F13), dichloro-monofluoromethane (F21),
monochlorodifluoromethane (F22), monochloromonofluoromethane (F31),
1,1,2-trichloro-1,2,2-trifluoroethane (F113),
1,2-dichloro-1,1,2,2-tetrafluoroethane (F114),
1-chloro-1,1,2,2,2-pentafluoroethane (F115),
2,2-dichloro-1,1,1-trifluoroethane (F123),
1,2-dichloro-1,1,2-trifluoroethane (F123a),
2-chloro-1,1,1,2-tetrafluoroethane (P124),
2-chloro-1,1,2,2-tetrafluoroethane (F124a),
1,2-dichloro-1,1-difluoroethane (F132b),
1-chloro-1,2,2-trifluoroethane (F133),
2-chloro-1,1,1-trifluoroethane (F133a), 1,1-dichloro-1-fluoroethane
(F141b) and 1-chloro-1,1-difluoroethane (F142b), alkanes such as
propane, butane and isobutane, fluorinated alkanes such as
octafluoropropane (218) and in particular hydrofluoroalkanes such
as difluoromethane (HFA 32), pentafluoroethane (HFA 125),
1,1,2,2-tetrafluoroethane (HFA 134), 1,1,1,2-5 tetrafluoroethane
(HFA 134a), 1,1,2-trifluoroethane (HFA 143), 1,1,1-trifluoroethane
(HFA 143a), difluoroethane (HFA 152a),
1,1,1,2,3,3,3-heptafluoropropane (HFA 227) and the like.
[0041] Preferred propellants are the hydrofluoroalkanes of the
general formula. CxHyFz (I) in which x is the number 1, 2 or 3, y
and z are each an integer >==1 and y+z=2x+2.
[0042] Those hydrofluoroalkanes of the formula I in which x is the
number 2 or 3 are particularly suitable.
[0043] Particularly preferred aerosol formulations are those which
contain HFA 134 or HFA 227 or mixtures of these two propellants.
HFA 134a and HFA 227 have a vapor pressure of about 6 bar and about
4.2 bar respectively at 20[deg.] C. Both propellants differ with
respect to their density (about 1.2 g/ml for HPA 134a and about 1.4
g/ml for HFA 227), which is important insofar as it is possible by
suitable choice of the propellant or propellant mixture to match
its density better to the density of the suspended substances and
thus to keep the latter better in suspension. If desired, the
density of the propellant can be further reduced by addition of
cosolvents or other propellants, such as ethanol, diethyl ether,
propane, n-butane or isobutane.
[0044] The aerosol formulations according to the invention can
preferably contain one or more hydrofluoroalkanes of the formula I,
particularly preferably 1,1,1,2-tetrafluoroethane (HFA 134a) and/or
1,1,1,2,3,3,3-heptafluoropropane (HFA 227), and their proportion in
the total formulation can preferably be at least about 50% by
weight and particularly preferably at least about 80% by weight. As
a rule, it is advantageous to employ these propellants in an amount
of 90% by weight or more.
[0045] Ethanol is employed in the present invention in anhydrous
form. It is preferred to use ethanol in as low a concentration as
possible. In particular, it is preferred to use it in amounts of
less than 2.5% by weight to about 1% by weight, e.g. 1 to 1.5% by
weight, more particularly 1 to about 1.45% by weight.
[0046] In a particular embodiment of the invention, when using
fluticasone propionate in combination with formoterol fumarate
di-hydrate, it is preferred to use ethanol in an amount of 1.5% or
less, e.g. 1 to 1.5% by weight.
[0047] The aerosol formulations according to the invention can
contain no, or substantially no surfactant, i.e. contain less than
approximately 0.0001% by weight of surface-active agents. This is
particularly the case if one employs a cromone as described above.
If desired, however, the formulations can contain surface-active
agents conventionally employed in aerosol formulations, such as
oleic acid, lecithin, sorbitan trioleate, cetylpyridinium chloride,
benzalkonium chloride, polyoxyethylene (20) sorbitan monolaurate,
polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20)
sorbitan monooleate, polyoxypropylene/polyoxyethylene block
copolymers, polyoxypropylene/polyoxyethylene/ethylenediamine block
copolymers, ethoxylated castor oil and the like, where the
proportion of surface-active agents, if present, can preferably be
about 0.0001 to 1% by weight, in particular about 0.001 to 0.1% by
weight, based on the total formulation.
[0048] Other optional adjuvants can be employed in formulations
according to the present invention. For example, if desired, they
can contain buffer substances or stabilizers such as citric acid,
ascorbic acid, sodium EDTA, vitamin E, N-acetylcysteine and the
like. In general, such substances, if present, are used in amounts
of not more than approximately 1% by weight, for example in an
amount of from approximately 0.0001 to 1% by weight, based on the
total formulation.
[0049] Formulations according to the present invention are prepared
by a process comprising a first step of drying formoterol fumarate
di-hydrate raw material to a water content as described above. If a
cromone is to be employed in the formulation, preferably it too is
subjected to a similar drying step. After drying, these components
can be weighed and mixed with a steroid in an aerosol vial.
[0050] A valve can then be crimped onto the vial, and a pre-mix of
propellant and ethanol can be introduced through the valve under
pressure. The whole mixture can then be placed in an ultra-sonic
bath to form a suspension of formoterol fumarate di-hydrate, and
optionally the steroid.
[0051] The vials may be filled with sufficient formulation to
provide a plurality of dosages. Typically formulations may contain
50 to 150 dosages, more particularly 100 to 150 dosages. The
formulations are typically filled with an overage of doses to avoid
a situation where a patient could, under the proper conditions of
use, actuate its MDI and find that there are no remaining doses to
be delivered.
[0052] The vials or canisters used to contain the formulations
according to the invention may be of plastics, metal or glass
construction. It is a feature of the stability of the formoterol
suspension of the inventive formulations that they exhibit no, or
substantially no, tendency to deposit on the surface of the
containers into which they are filled. This gives the formulator
the latitude to choose from any of the commercially available
alternatives, which can be advantageous from an economic view
point. It is often the case with suspension aerosol formulations
that special containers must be used in order to avoid stability
problems, for example, those coated internally with special low
surface energy coating materials, see for example U.S. Pat. No.
6,596,260.
[0053] Valves used with vials may by any of the standard metered
dose valves available in the art. Typically, metered dose valves of
20 to 150 micro-litres can be employed. Often the Delivered dose of
one or more active substance cannot be achieved with a single
actuation of an MDI. It is preferred that, having regard to the
active ingredients that are contained in the formulation, and
having regard to the respective Label Claims, one chooses a valve
that is capable of metering the dose within only one or two
actuations, or puffs.
[0054] Formulations of the present invention find use as medicinal
aerosol preparations for the treatment of disease states of the
lung, for example asthma, e.g. mild, exercise-induced, moderate and
severe bronchial-induced asthmas, cold air-induced asthma, COPD,
and interstitial lung disease sarcoidosis.
[0055] In an embodiment of the present invention, formulations are
provided containing a plurality of doses of fomoterol fumarate
di-hydrate, each dose containing 3 to 15 micro-grams, and a
plurality of doses of fluticasone each dose containing 250 to 1000
micro-grams. Said formulations are suitable for the treatment of
any of the aforementioned conditions.
[0056] Preferred features of the second and subsequent aspects of
the invention are as for the first aspect mutatis mutandis.
[0057] There now follows as series of examples that serve to
illustrate the invention.
EXAMPLE 1
[0058] The following formulation was prepared (FP denotes
formoterol fumarate di-hydrate; FP represents fluticasone
propionate; and DSCG represents disodium cromoglycate).
TABLE-US-00001 % by weight FF 0.009 FP 0.179 Abs. Ethanol 1.429 HFA
227 98.350 DSCG 0.034
[0059] Formoterol Fumarate Di-hydrate is dried at 20 to 40.degree.
C. and at a maximum of 100 mbar reduced air pressure.
[0060] DSCG is dried at 80.degree. C. and a maximum 100 mbar to a
water content of less than 4%.
[0061] The dried materials are deposited along with the fluticasone
propionate in a filling vessel and the vessel is evacuated to less
than 100 mbar air pressure.
[0062] Absolute ethanol (anhydrous) and pharmaceutical grade HFA
227 are pre-blended in another container. The blending container is
then connected to the filling vessel and the blend is fed into the
vessel. The resultant filled vessel is homogenised for 30 minutes
at 300 rpm.
[0063] A 14 mm plain aluminium container (Presspart Manufacturing,
Blackburn, England), is crimped around a 50 micro-litre valve
(Valois Pharm SA, France).
[0064] An aliquot from the filling vessel is pressure-filled into
the aluminium can in a quantity sufficient for a one month
medication. Filled aluminium cans formed in this fashion are
weight-checked and allowed to rest for an equilibration period
before testing.
EXAMPLE 2
(Measurement of Particle Size Distribution and Fine Particle
Fraction)
[0065] The formulations employed are those formed according to
Example 1 above. The aerodynamic particle size distribution is
determined using an Andersen Scale Impactor (ACI) fitted with the
universal induction port (as set forth in the USP) at 28.3
L/minute. 20 shots (equivalent to 10 doses) of a formulation formed
according to Example 1, are discharged into the ACI. Fractions of
the dose are deposited at different stages of the ACI, in
accordance with the particle size of the fraction. Each fraction is
washed from the stage and analysed using HPLC.
[0066] HPLC analysis showed that the fine particle fraction of the
dose delivered to the ACI apparatus is greater than 50% both for
the formoterol fumarate di-hydrate and the fluticasone
propionate.
EXAMPLE 3
[0067] Formulations of Example 1 are tested for Delivered dose
Uniformity according to the following method.
[0068] Cannisters containing formulations are stored at 40.degree.
C. and 75% rh for 6 months.
[0069] After the appropriate storage period, MDI devices containing
formulations of Example 1 are connected with the Funnel Apparatus
described herein above.
[0070] 3 doses (6 shots) are discharged into the apparatus at the
beginning of the life of the container; 4 doses (8 shots) are
discharged in the middle life of the container; and 3 doses (6
shots) are discharged at the end of the container life. The
intermediate doses/shots are discharged to waste. The delivered
dose is collected by washing the glass scinter, and the dose is
analysed by HPLC.
[0071] Analysis shows that after the storage period, variance of
the delivered dose does not exceed +/-25% of the mean delivered
dose, +/-20% of the mean delivered dose.
EXAMPLE 4
[0072] Formulations of Example 1 are tested for Delivered dose
Uniformity according to the following method.
[0073] Canisters containing formulations are stored at 40.degree.
C. and 75% rh for 1, 3 and 6 months.
[0074] After the appropriate storage period, MDI devices containing
formulations of Example 1 are connected with the Funnel Apparatus
described herein above.
[0075] For each container, 1 dose (two shots) are discharged into
the Funnel Apparatus. This is repeated for 10 containers. After
washing the Funnel Apparatus and analysing using HPLC, results show
that no delivered dose varies by more than +/-25% of the mean
delivered dose, and more particularly +/-20% of the mean delivered
dose.
* * * * *