US006054488A

Ulllted States Patent [19] [11] Patent Number: 6,054,488

Oliver et al. [45] Date of Patent: Apr. 25, 2000

[54] MEDICINALAEROSOL FORMULATIONS 0F 91/11496 8/1991 WIPO.

FORMOTEROL 92/22286 12/1992 WIPO.
92/22287 12/1992 WIPO.
[75] Inventors: Martin J. Oliver; Simon G. Paling; 93/11745 6/1993 WIPO
Philip A. Jinks; Sukhbinder K. 93/11747 6/1993 WIPO -
WO 9311747 6/1993 WIPO.
J aisWal, all of Leicester, United 94/2128 9/1994 WIPO
Klngdom 94/21229 9/1994 WIPO .
_ _ _ 96/18384 6/1996 WIPO .
[73] Assrgnee: 3M Innovative Properties Company, 96/199653 7/1996 WIPO _
St. Paul, Minn. 97/47286 12/1997 WIPO .

OTHER PUBLICATIONS
[21] Appl. No.: 09/088,871
. _ Kontny, M.J.; Destefano, G.; Jager, P.D.; McNamara, DR;
[22] Flled' Jun' 2’ 1998 Turi, J.S.; and Van Campen, L. “Issues Surrounding MDI
R 1 t d U.S.A 1 - t - D t Formulation Develo P ment With Non—CFC Pro P ellants” ’
ea e pp lea Ion a a Journal of Aerosol Medicine, vol. 4, No. 3, 1991, pp.
[63] Continuation of application No. PCT/US97/09471, Jun. 2, 181_187’ Mary Ann Liebert, Inc” Publishers‘
1997 Tansey, Ian P. “The challenges in the development of
[60] Provisional application No. 60/048,233, Jun. 2, 1997. metered dose inhalation aerosols using oZon—friendly pro
[30] Foreign Application Priority Data gzllgrglts”, Spray Technology & Marketing for Jul. 1994, pp.
Jun. 11, 1996 [GB] United Kingdom ................. .. 9612297 Sharpe, R., “Development of a metered dose inhaler using
one of the neW HFA Pro ellants”,Aerosol and S ra Re ort,
[51] Int. c1.7 ................................................. .. A61K 31/135 VOL 35, N0 3,96, pp‘ 113L129 P y P
[52] US. Cl. ............................................................ .. 514/646 Dalby, Richard N; Byron, Peter R”; Shepherd, HR; and
[58] Field Of Search ............................................. .. 514/646 papadopoulos, Elaine, “CFC propellant Substitution;
_ P—134a as a Potential Replacement for P—12 in MDIs”,
[56] References Clted Pharmaceutical Technology, Mar. 1990, pp.—26—33.
U_S_ PATENT DOCUMENTS Jinks, PA, “A Rapid Technique for Characterisation of the
Suspension Dynamics of Metered Dose Inhaler Formula
3,014,844 12/1961 Thiel
POl’llShetCtal.8.1. .............................
........................... .. 167/82 Hons”,
10_13 (Dec'
Proceedings
1995) printed
of by Delivery
The Aerosol
to the
Society~
Lung,
5’182’O97 1/1993 Byron et a1‘ ' Phillips, Elaine M., “Crystal GroWth—Formulation Depen
5,225,183 7/1993 Purewal et al. .
5 439 670 8/1995 Purewal et a1‘ _ dence and Early Detection”, Journal of Biopharmaceutical
5:605:674 2/1997 Purewal et al. . Sciences» 3(1/2) 1992’ PP-—11—18
576537962 8/1997 Akehurst et a1_ _ Smith, Ian J. “The Challenge of Reformulation”, Journal of
5,658,549 8/1997 Akehurst e] a] _ Aerosol Medicine, vol. 8, Supplement 1, 1995, Mary Ann
5,674,471 10/1997 Akehurst et al. . Liebert, Inc., Publishers, pp.—s—19—s—27.
5,674,473 10/1997 Purewal et al. .
5,676,929 10/1997 Akehurst et 8.1.. Primary EX?mi”@r—Raym0Hd Henley, 111
5,681,545 10/1997 Purewal etal,, Attorney, Agent, or Firm—Ted K. Ringsred; Robert W.
5,683,677 11/1997 Purewal et al. . Sprague; Gary L. Griswold
5,695,743 12/1997 Purewal et al. .
5,720,940 2/1998 Purewal et al. . [57] ABSTRACT
5,736,124 4/1998 Akehurst et al. . _ _ _ _
577447123 4/1998 Akehurst et aL _ Apharmaceutrcal suspension formulation suitable for aero
5’766’573 6/1998 Purewaleta1__ sol administration having from 0.0025 to 0.1% W/W of
5,776,434 7/1998 Purewal et al, _ InicroniZed Formoterol, or an acid addition salt thereof, from
0.1 to 5.0% W/W ethanol, HFA 134a, HFA 227 or a mixture
FOREIGN PATENT DOCUMENTS of HFA 227 and HFA 134a, and optionally a surfactant other
209547131 1/1987 European pat Off _ than a monoacetylated or diacetylated monoglyceride, the
372777B1 6/1990 European Pat, Off, _ formulation being further characterized in that it exhibits
384371B1 8/1990 European Pat. Off. . substantially no groWth in particle siZe or change in crystal
504112A2 9/1992 European Pat- O?- - morphology of the drug over a prolonged period, is sub
61761031 10/1994 European Pat O?- - stantially and readily redispersible, and upon redispersion
656207A1 6/1995 European Pat. Off. . does not ?occulate so quickly as to prevent reproducible
2288978 11/1995 United Kingdom .
91/04011 4/1991 WIPO .
dosing of the drug.
91/11173 8/1991 WIPO .
91/11495 8/1991 WIPO . 19 Claims, N0 Drawings
 6,054,488
1 2
MEDICINAL AEROSOL FORMULATIONS OF essentially of a therapeutically effective amount of a drug
FORMOTEROL and a propellant selected from the group consisting of HFA
134a, HFA 227, and a mixture thereof, the formulation being
This application claims the bene?t of the ?ling date of further characteriZed in that it exhibits substantially no
US. provisional application No. 60/048,233, ?led Jun. 2, groWth in particle siZe or change in crystal morphology of
1997; also and, is a continuation of international application the drug over a prolonged period, is substantially and readily
PCT/US97/09471, ?led Jun. 2, 1997, Which claims priority redispersible, and upon redispersion does not ?occulate so
to Great Britain application GB 96.12297, ?led Jun. 11,
quickly as to prevent reproducible dosing of the drug. The
application speci?cally discloses formulations of Formot
1996.
10
erol Fumarate in HFA 134a, HFA 227 and 1:1 mixtures of
FIELD OF THE INVENTION HFA 134a and HFA 227. The formulations do not contain
surfactants or ethanol. It is stated that mixtures of HFA 134a
This invention relates to medicinal aerosol formulations and HFA 227 may be adjusted for density matching With the
and in particular to aerosol formulations containing Formot drug.
erol Fumarate Which are suitable for administration to the
W093/11745 discloses pharmaceutical aerosol
respiratory system of a patient. 15
formulations, substantially free of surfactant containing
BACKGROUND ?uorocarbon or hydrogen-containing chloro?uorocarbon
propellants and up to 5% of a polar co-solvent. Preferred
Most pharmaceutical suspension aerosol formulations propellants are HFA 134a and HFA 227 Which are preferably
currently use a mixture of liquid chloro?uorocarbons as the used alone. The preferred polar co-solvent is ethanol and it
propellant. Fluorotrichloromethane, dichlorodi?uo 20
is stated that in general only small quantities e.g. 0.05 to
romethane and dichlorotetra?uoroethane arc the most com
3.0% W/W of polar co-solvent are required to improve the
monly used propellants in aerosol formulations for admin dispersion and the use of quantities in excess of 5% W/W
istration by inhalation. may disadvantageously tend to dissolve the medicament.
Chloro?uorocarbons (CFCs), hoWever, have been impli EP-A-0504112 discloses a pharmaceutical composition
cated in the destruction of the oZone layer and their produc 25
for aerosol use containing:
tion is being phased out. Hydro?uorocarbon 134a (HFA (a) a lique?ed propellant gas or propellant gas mixture
134a, 1,1,1,2-tetra?uoroethane) and hydro?uorocarbon 227 With a vapor pressure exceeding 1 bar but less than 6
(HFA 227, 1,1,1,2,3,3,3-hepta?uoropropane) are vieWed as bar (20° C.) from the unsubstituted or partially to
being more oZone friendly than many chloro?uorocarbon
30 completely ?uorinated hydrocarbon group;
propellants; furthermore, they have loW toxicity and vapor
pressures suitable for use in aerosols.
(b) a non-ionic tensile of the monoacetylated or diacety
lated monoglyceride group;
W091/11495 and W091/11496 disclose pharmaceutical (c) a pharmaceutical active substance or combination of
suspension aerosol formulations comprising a medicinal
agent, a surfactant, and a propellant mixture containing active substances, and, if necessary,
1,1,1,2,3,3,3-hepta?uoropropane and one or more additional (d) other common pharmaceutical accessory substances
suitable for aerosol formulations.
components, eg pentane, butane, propellant 134a , propel
lant 11, propellant 125, or propellant 152a. It is stated the basic purpose of that invention Was to ?nd
a special accessory suspending substance for active sub
EP 0384371 discloses solution aerosols in Which 1,1,1,2,
stances in aerosol formulations, Which dissolves better in
3,3,3-hepta?uoropropane or its mixture With propane,
lique?ed “alternative” propellant gases than the accessory
butane, isobutane, dimethyl ether, or 1,1, di?uoroethane suspending substances hitherto recogniZed and used.
serves as the propellant. The application does not, hoWever,
disclose suspension aerosols or pharmaceutical aerosol for
Surprisingly, it Was discovered, in solving this problem, that
non-ionic tensides of the monoacetylated or diacetylated
mulations.
monoglyceride group are very soluble in the “alternative”
EP 0372777 discloses, inter alia, examples of aerosol 45 propellant gases mentioned, particularly in hepta?uoropro
formulations comprising a medicament, 1,1,1,2 pane (HFA 227), are bene?cial to the production of homog
tetra?uoroethane, a surface active agent, and at least one enous suspensions, and also have outstanding metering
compound having higher polarity than 1,1,1,2 valve lubrication properties. Some of the examples of EP-A
tetra?uoroethane. 0504112 disclose formulations comprising Formoterol
US. Pat. No. 2,868,691 discloses aerosol formulations Fumarate.
comprising a medicament, a halogenated loWer alkane Formoterol Fumarate is a long acting B2 agonist Which
propellant, and a co-solvent Which assists in dissolving the has been developed for delivery to the respiratory system by
medicament in the propellant. The chemical formula for the a metered dose inhaler (MDI). The drug is highly potent and
propellant given in column 2, lines 6 to 16, generically its dosage is considerably less than many other drugs Which
embraces HFA 134a and HFA 227. Examples of co-solvents 55 have been administered by MDIs. Thus, the concentration of
disclosed include ethanol and diethyl ether. Formoterol Fumarate in aerosol formulations is very loW
US. Pat. No. 3,014,844 discloses aerosol formulations and this factor, together With other properties of the drug
comprising a micronised medicament, a halogenated loWer have led to problems in manufacturing and formulating a
alkane propellant and a surface-active agent to assist in the composition Which is stable and provides good dosage
suspension of the medicament in the propellant. The chemi 60 reproducibility When administered by MDIS.
cal formula for the propellant given in column 4, lines 17 to Aerosol formulations consisting of propellant, e.g. HFA
28, generically embraces HFA 134a and HFA 227. 134a, HFA 227 and mixtures thereof, and Formoterol Fuma
W091/04011 discloses aerosol compositions having HFA rate Without additional excipient sometimes encounter prob
134a as the propellant and comprising a medicament coated lems such as caking on manufacturing equipment, high
With a non-per?uorinated surface active dispersing agent. 65 deposition in the vial or valve of inhalers and valve sticking.
W093/11747 discloses a pharmaceutical suspension for Aerosol compositions consisting of Formoterol Fumarate,
mulation suitable for aerosol administration, consisting HFA 134a and ethanol have proved to be extremely sensitive
 6,054,488
3 4
to ethanol concentration. An ethanol concentration of 3.5% Preferably ethanol is present at a concentration in the range
W/W may cause unacceptable crystal groWth. 1.5 to 3.5%, more preferably about 2.5% W/W in formula
tions Which do not employ bulking agent. In formulations
SUMMARY OF THE INVENTION containing bulking agent ethanol is generally present at
It is an object of the present invention to provide stable about 1% W/W as this has been suf?cient to provide the
aerosol compositions containing Formoterol Fumarate. above bene?ts.
The composition of the invention may comprise a surfac
According to one aspect of the present invention there is tant. LoW levels of surfactant, often beloW the levels nor
provided a pharmaceutical suspension formulation suitable mally used for the purposes of stabiliZing suspensions and
for aerosol administration, consisting essentially of: valve lubrication in aerosol formulations, have been shoWn
10
(a) from 0.0025 to 0.1% W/W of microniZed Formoterol, surprisingly to provide a ?occulant effect to produce stable
or an acid addition salt thereof and ?occular dispersions. Levels of oleic acid of 0.002 to 0.01%
(b) from 0.1 to 5.0% W/W ethanol, W/W have provided useful properties, a preferred concentra
(c) HFA 134a, HFA 227 or a mixture of HFA 227 and HFA tion is about 0.005% W/W. Other surfactants and/or larger
134a and optionally levels of surfactant may be used.
15
(d) a surfactant other than a monoacetylated or diacety
The concentration of Formoterol Fumarate depends upon
the dose required and the metering volume of the valve.
lated monoglyceride, the formulation being further Concentrations of 0.01% W/W and 0.02% W/W have proved
characteriZed in that it exhibits substantially no groWth to be suitable, using a 50 microlitre valve.
in particle siZe or change in crystal morphology of the It is conventional practice When preparing aerosol formu
drug over a prolonged period, is substantially and 20 lations to mix the drug With the highest boiling point
readily redispersible, and upon redispersion does not material and thereafter mix With the propellant. HoWever,
?occulate so quickly as to prevent reproducible dosing When making the formulations of the present invention it is
of the drug. important to ensure the Formoterol Fumarate does not come
According to a second aspect of the invention, there is into contact With high concentrations e.g. above 10% W/W,
provided a pharmaceutical suspension formulation suitable 25 of ethanol since the drug Would dissolve leading to insta
for aerosol administration, consisting essentially of: bility and crystal groWth problems in the ?nal formulation.
(a) from 0.0025 to 0.1% W/W of micronised Formoterol, Preferably the maximum concentration of ethanol during
or an acid addition salt thereof, formulation is less than 5%. A suitable method for manu
(b) from 0.1 to 5.0% W/W ethanol, facturing formulations on a pilot scale is as folloWs.
30 The ingredients arc divided into those for making the
(c) a propellant consisting of HFA 134a, HFA 227 or a
concentrate and those for including in the bulk.
mixture of HFA 227 and HFA 134a,
The concentrate contains the drug and optional bulking
(d) a micronised bulking agent in a Weight ratio in the agent, suf?cient propellant to disperse them and ethanol,
range from 1:3 to 1:100 of Formoterol: bulking agent, preferably not in excess of 5 percent of the Weight of the
and optionally 35 concentrate, more preferably about 2.5% The bulk contains
(e) a surfactant, the formulation being further character most of the propellant, the balance of the ethanol and
iZed in that it exhibits substantially no groWth in optional surfactant.
particle siZe or change in crystal morphology of the The bulk ingredients are fed into a batching vessel, Which
drug over a prolonged period, is substantially and is either chilled to approximately —55° C. for the purposes
readily redispersible, and upon redispersion does not 40 of cold ?lling, or is pressure resistant for pressure ?lling.
?occulate so quickly as to prevent reproducible dosing In a glove box purged With dried air, a small quantity of
of the drug. propellant is added to a prechilled stainless steel concentrate
vessel. Prechilled ethanol is added. A homogeniZer is
DETAILED DESCRIPTION
inserted into the concentrate vessel. PreWeighed drug and
It has been found that improved aerosol formulations 45 optional bulking agent are added sloWly to disperse. This
comprising Formoterol Fumarate may be obtained by uti forms the concentrate.
liZing loW concentrations of ethanol. The combination of After dispersing, the concentrate is added to the bulk
HFA 134a and HFA 227 in a Weight ratio of HFA 134a: 227 propellant in the batching vessel and mixed continuously
from 50:50 to 30:70 provides a propellant system in Which until all of the formulation has been dispensed.
the drug has good stability. The preferred ratio is about 50 The bulk formulation is either dispensed chilled into open
37.5 :62.5. aluminum cans, Which are immediately sealed With a meter
Alternatively, stable formulations may be obtained by the ing valve on each can, or pressure ?lled into cans Which have
incorporation of a micronised bulking agent Which Will previously been sealed With metering valves.
sediment in the propellant e.g. lactose, DL-Alanine, ascorbic The invention Will be illustrated by the folloWing
acid, glucose and D+ trehalose dehydrate. The micronised 55 Examples.
bulking agent may prevent the drug from creaming by In the Examples, unless otherWise stated, the folloWing
co-?occulating With the drug, the resultant ?oes are denser preparation technique Was employed.
than the propellant and Will sediment leaving no creamed The formulations Were prepared in the laboratory by
layer upon prolonged standing. The Weight ratio of drug to dispensing the active and if required the bulking agent into
bulking agent is in the range 1:3 to 1:100, generally from 1:3 60 a preWeighed vial. This Was then sealed With a non-metering
to 1:20. If the concentration of bulking agent is too loW, not valve and the premixed ethanol/propellant and optional
all of the drug Will sediment and a small amount Will cream. surfactant injected into the vial. The vial Was then subjected
If the concentration is too high, the formulation may ?oc to ultrasonic energy to disperse the solid particles.
culate and either sediment or cream too quickly for accept
able use as an aerosol formulation. 65 EXAMPLES 1 to 5
The presence of ethanol assists in the stability, the general The folloWing formulations Were prepared (FF denotes
performance and in the manufacturing of the formulation. Formoterol Fumarate):
 6,054,488
5 6
The above formulations Were designed such that the
density of the liquid component Was fairly close to that of
Formoterol Fumarate.
Example 1 Example 2 Example 3 Example 4 Example 5
% W/W % W/W % W/W % W/W % W/W
5
FF 0.010 0010 0010 0010 0010 These formulations had the folloWing creaming and sedi
Ethanol 2.500 2.500 2.500 2.500 2.500 menting Characteristics at 20° C_
HFA 227 48.745 65.806 63.368 60.931 56.057
HFA 134a 48.745 31.684 34.121 36.559 41.433

10000 10000 10000 10000 10000 10 Formulation 1 just sedimented. Formulation 2 creamed.
Formulation 4 gradually creamed at 20° C. but gradually
settled at 30° C. When observed over a 12 hour period.
Measured Density of Formulations (g/ml)
15 Each formulation Was tested for uniformity of drug
dosing, after storage periods of up to 24 hours at ambient
Tern stature [De _ C: propellant radio (W/W) temperature in order to simulate patient use. Formulation 4
gave the most consistent performance in these tests.
Example 20 25 30 HFA 227:HFA 134a

1 1'285 1266 1'247 SO'OISO'O 2O Formulations containin oleic acid

5 1.298 1.279 1.259 57.5:42.5 g
4 1.307 1.288 1.269 62.5:37.5
3 1.312 1.293 1.272 65.0:35 _ _
2 1317 1198 1177 675325 The following formulations Were prepared:

Example 4 Example 6 Example 7 Example 8 Example 9

% W/W % W/W % W/W % W/W % W/W

FF 0.010 0.010 0.010 0.010 0.010

Oleic Acid 0 0.0001 0.0003 0.0005 0.001
Ethanol 2.500 2.500 2.2500 2.500 2.500
HA 227 60.931 60.931 60.931 60.931 60.931
HFA 134a 36.559 36.559 36.559 36.559 36.558

100.000 100.000 100.000 100.000 100.000

Example Example Example Example Example Example

10 11 12 13 14 15
% W/W % W/W % W/W % W/W % W/W % W/W

FF 0.010 0.010 0.010 0.010 0.010 0.010

Oleic Acid 0.002 0.003 0.004 0.005 0.007 0.009
Ethanol 2.500 2.500 2.500 2.500 2.500 2.500
HFA 227 60.930 60.929 60.929 60.928 60.927 60.926
HFA 134a 36.558 36.558 36.557 36.557 36.556 36.555

100.000 100.000 100.000 100.000 100.000 100.000

The formulations had the folloWing characteristics:

LoW levels of oleic acid have been shoWn surprisingly to
impart a ?occulant effect to produce stable ?occular
dispersions, Which may alloW less migration of drug to and
from the metering chamber of the valve than surfactant-free
55 formulations. This is because the ?oe siZe of the formula
tions is larger. visual differences Were apparent for surfactant
levels When comparing 0% oleic acid With 0.005 to 0.009%
oleic acid. Formulations containing 0.0001 to 0.001% oleic
acid shoWed no difference from the 0% oleic acid
aO
formulation, When examined either visually or by using an
optical measuring technique such as that described in the
Proceedings of Drug Delivery to the Lung VI p. 10—13
(December 1995) printed by The Aerosol Society. Examples
65 9 to 13 having 0.001% to 0.005% in steps of 0.001% oleic
acid shoWed increasing effect, Which Was measurable at the
0.002% level in Example 10.
 6,054 ,488
7
EXAMPLES 16 to 22
Use of Bulking Agent
In order to study the suspension characteristics of lactose
bulked formulations a range of units Was prepared. The ratio
of Formoterol Fumarate to lactose (L) Was varied 5
betWeen 1:1 and 1:7 and suspended in a mixture of Ethanol:
HFA 227, 1:99 using the folloWing formulations:

F amnle

16 17 18 19 20 21 22
FF:L

1:1 1:2 1:3 1:4 1:5 1:6 1:7

% W/W % W/W % W/W % W/W % W/W % W/W % W/W
FF 0.009 0.009 0.009 0.009 0.009 0.009 0.009
Lactose 0.009 0.019 0.028 0.038 0.047 0.056 0.066

All formulations Were made up to 100% With Ethanol

:HFA 227 at 1:99 by Weight.
The folloWing method Was used to prepare the formula- 25 F amnle
lions? 22 23 24
Percentage of ethanol
i) The propellant miX Was made up in a 500 ml can by ?rst 10] 217 317
~ ~ ~ ~ ~ 0 0 O

Weighing out 1 g of ethanol and crimping on a 1 inch

continuous valve. 99 g of HFA 227 Was then injected 30 % W/W
into the can through the valve. FF 0009 0009 00009
ii) The Formoterol Fumarate and the lactose Were Lactose 0066 0066 0066
_ _ _ _ Ethanol 1.000 2.000 3.000
Weighed directly into transparent vials. HFA 227 98925 97925 96924
111) A non-metering valve Was cr1mped onto each v1al. 35 100000 100000 100000
iv) The vials Were ?lled With the prescribed amount of
propellant miX from the 500 ml can using a transfer
button, to transfer some propellant miX via the valves Results
of the can and the vial. 40
V) The Vials Were placed in an ultrasonic bath for four No visual difference Was observed in the siZe of the ?ocs
- - - the ?oc settlin rate obtained With the three concentra
minutes to homo en1Ze the formulation. of g _ _
g tions of ethanol used. Thus the bene?cial effects of adding
Result ethanol Were realiZed by including the minimum amount
45 (i.e. 1% ethanol).
The resulting suspensions Were examined visually.
They Were found to form fairly coarse ?ocs, Which tended EXAMPLE 25
to sediment. The sedimentation rate increased With lactose
concentration. For Weight ratios of greater lactose content 50
than 1:7, more rapid sedimentation Would occur Which could Use of Different Bulking Agents With Formoterol Fuma
lead to a general loss of dosing reproducibility. rate Suspension

Formulations 19 and 22 Were tested for uniformity of drug

dosing, after storage periods up to 24 hours, in order to 55
Formulation % W/W
simulate patient use. Formulation 22 gave the most consis
tent performance in these tests. FF 0.009
Bulking agent 0.066
Ethanol 1.000
HFA 227 98.925
EXAMPLES 23 and 24 60
HFA 134.a
Effect of Different Ethanol Concentration With Bulking 100.000
Agent
The formulation of EXample 22 (1% ethanol) Was com- 65
pared With formulations containing 2 and 3% ethanol. The The bulking agent Was selected from the folloWing list,
folloWing formulations Were prepared: Which also gives densities determined by Pycnometry.
 6,054,488
10
EXAMPLES 29 to 33
The folloWing formulations Were prepared:
Sample Density, g/ml
DL-Alanine 1.3963
Ascorbic acid 1.6955 F amnle
Glucose (dextrose) 1.5264
Lactose, monohydrate 1.5379 29 30 31 32 33
D(+) Trehalose dihydrate 1.5036 % W/W % W/W % W/W % W/W % W/W

10 FF 0.011 0.011 0.011 0.009 0.009

Oleic acid 0.000 0.000 0.010 0.000 0.000
The Alanine bulked formulation formed ?ocs more slowly Ethanol 1.000 2.000 2.499 1.000 2.000
than either of the tWo Lactose bulked formulations Which HFA 134a 98.989 97.989 97.480
HFA 227 98.991 97.991
could improve dosing characteristics. The ?ocs Were sus
pended in the vial, and appeared to be density matched at the 100.000 100.000 100.000 100.000 100.000
15
laboratory temperature of 22° C.
All of the other bulking agents examined formed rapidly The formulations of Examples 29 to 31 produced Well
?occulating suspensions, Which then sedimented. dispersed, sloWly ?occulating suspensions Which gradually
sedimented. The presence of surfactant increased the ?oc
EXAMPLES 26 to 28 20 size.
The formulations of Examples 32 and 33 produced Well
to Alanine bulking agent With propellant mixtures. dispersed, sloWly ?occulating suspensions Which gradually
creamed.
The folloWing formulations Were prepared: We claim:
25 1. A pharmaceutical suspension formulation suitable for
aerosol administration, consisting essentially of:
F amnle (a) from 0.0025 to 0.1% W/W of micronized formoterol, or
an acid addition salt thereof and
26 27 28 (b) from 0.1 to 5.0% W/W ethanol,
Propellant ratio 62.5% HFA 227 75% HFA 227 100% HFA 227 30
(w/w) 37.5% HFA 134a 25% HFA 134a (c) HFA 134a, HFA 227 or a mixture of HFA 227 and HFA
134a and optionally
% W/W (d) a surfactant other than a monoacetylated or diacety
FF 0.10 0.10 0.009 lated monoglyceride,
bulking agent 0.069 0.068 0.066 35
the formulation being further characterized in that it exhibits
Ethanol 1.000 1.000 1.000 substantially no groWth in particle size or change in crystal
HFA 227 61.826 74.192 98.925
HFA 134a 37.095 24.731
morphology of the drug over a prolonged period, is sub
stantially and readily redispersible, and upon redispersion
100.000 100.000 100.000 does not ?occulate so quickly as to prevent reproducible
40
dosing of the drug.
2. An aerosol formulation as claimed in claim 1 Which
Visual Assessment comprises HFA 134a and HFA 227 in a Weight ratio of HFA
The resultant suspensions Were examined visually. As 134a:HFA 227 in the range 50:50 to 30:70.
before, the Alanine suspensions formed smaller ?ocs, Which 3. An aerosol formulation as claimed in claim 2 in Which
formed more sloWly than those of the Lactose bulked 45
the Weight ratio of HFA 134a:HFA 227 is about 37.5:62.5.
suspensions. At the laboratory temperature of 25° C., the 4. An aerosol formulation as claimed in claim 1 Which
suspensions in Example 28 appeared to rise toWards the comprises about 1 to 5% W/W ethanol.
surface of the liquid, although a creamed layer Was not 5. An aerosol formulation as claimed in claim 1 Which
observed. comprises about 0.01% W/W formoterol fumarate.
50
6. An aerosol formulation as claimed in claim 1 Which
Example 27 appeared to be density matched, With the comprises oleic acid.
?ocs gradually settling to the bottom of the vial. Example 26 7. An aerosol formulation as claimed in claim 6 in Which
settled to the bottom of the vial more rapidly. the oleic acid is present in an amount of from 0.002 to
On standing overnight, Example 28 had creamed and 0.010% W/W.
formed a layer occupying approximately the top third of the 55
8. An aerosol formulation as claimed in claim 6 in Which
liquid layer. In the tWo suspensions With loWer HFA 227 the oleic acid is present in an amount of about 0.005% W/W.
ratios, the ?ocs had settled to the bottom of the vial. 9. An aerosol composition as claimed in claim 1 consist
Thus, the use of Alanine alloWs the preparation of for ing of:
mulations in Which the density of the suspended solids is a
close match to that of the liquid component. Furthermore, 60
the volume of sedimented or creamed solids is found to be Formoterol fumarate 0.010
advantageously larger than for formulations Without such a Ethanol 2.500
density match. HFA 227 60.931
HFA 134a 36.559
The sloWer ?occulation rate of suspended Alanine permits
higher levels of it to be used as a bulking agent Without 65
causing undesirably rapid ?occulation of the drug 10. An aerosol composition as claimed in claim 1 con
formulation, for example in a ratio of 1:100 drug: Alanine. sisting of:
 6,054,488
11 12
13. A pharmaceutical suspension formulation as claimed
in claim 11 in Which said Weight ratio of formoterol fumarate
to bulking agent is in the range 1:4 to 1:20.
Formoterol fumarate 0.020 14. A pharmaceutical suspension formulation as claimed
Oleic Acid 0.005
Ethanol 2.500
in claim 13 in Which said Weight ratio of formoterol fuma
HFA 227 60.928 rate to bulking agent is about 1:7.
HFA 134a 36.557 15. A pharmaceutical suspension formulation as claimed
in claim 11 in Which the bulking agent is selected from
lactose, DL-Alanine, ascorbic acid, glucose and D+ treha
11. Apharmaceutical suspension formulation suitable for lose dehydrate.
aerosol administration, consisting essentially of: 10
16. A pharmaceutical suspension formulation as claimed
(a) from 0.0025 to 0.1% W/W of microniZed formoterol, or in claim 15 in Which the bulking agent is lactose or
an acid addition salt thereof, DL-Alanine.
(b) from 0.1 to 5.0% W/W ethanol, 17. A pharmaceutical suspension formulation as claimed
in claim 11 in Which the propellant is HFA 227.
(c) a propellant consisting of HFA 134a, HFA 227 or a 15 18. A pharmaceutical suspension formulation as claimed
mixture of HFA 227 and HFA 134a,
in claim 11 consisting of:
(d) a microniZed bulking agent in a Weight ratio in the
range from 1:3 to 1:100 of Formoterol bulking agent,
and optionally
20 Formoterol fumarate 0.132
(e) a surfactant, Lactose 0.924
the formulation being further characterized in that it exhibits Ethanol 14.058
substantially no groWth in particle siZe or change in crystal HFA 227 1390.686
morphology of the drug over a prolonged period, is sub
stantially and readily redispersible, and upon redispersion 19. An aerosol dispensing device comprising a container
does not ?occulate so quickly as to prevent reproducible 25
equipped With a metered dose dispensing valve and con
dosing of the drug. taining an aerosol formulation as claimed in claim 1.
12. A pharmaceutical suspension formulation as claimed
in claim 11 comprising about 1% ethanol. * * * * *
 UNITED STATES PATENT AND TRADEMARK OFFICE
CERTIFICATE OF CORRECTION
PATENT NO. : 6,054,488 Page 1 of l
DATED : April 25, 2000
INVENTOR(S) : Martin J. Oliver, Simon G. Paling, Philip A. Jinks, and Sukhbinder K. Jaiswal

It is certified that error appears in the above-identified patent and that said Letters Patent is
hereby corrected as shown below:

Column 11
Line 3, please change "Formoterol fumarate 0.020" to -- Formoterol fumarate 0.010 --.

Signed and Sealed this

Fifth Day of March, 2002

Attest:

JAMES E. ROGAN
Arresting Officer Director of the United States Patent and Trademark O?lce