Dispersing agents for use with hydrofluoroalkane propellants

Vitamin E acetate, C.sub.3 -linked triesters, glycerin, t-butanol, and transesterified oil/polyethylene glycol are effective dispersing agents for use with hydrofluoroalkanes. Effective amounts of the above are effective in suspending medicaments which are useful in inhalation aerosols, and especially meter-dose inhalers.

BACKGROUND OF THE INVENTION 
1. Field 
The invention relates in general to dispersing agents, and more 
particularly to dispersing agents for suspending medicaments in 
hydrofluoroalkane (HFA) propellants to be used in inhalation aerosols. 
2. Description 
There has long been realized a link between chlorofluorocarbons (CFCs) and 
the depletion of the ozone layer in the earth's atmosphere. Since the 
Montreal Protocol on Substances That Deplete the Ozone Layer, it has been 
agreed by most of the world's industrialized nations that the use of 
chlorofluorocarbons should be eliminated by the year 2000. Recently, 
parties to the Montreal Protocol voted to advance the deadline for phase 
out of CFCs to Jan. 1, 1996. Accordingly, there is an ongoing search for 
non-chlorofluorocarbon propellants. 
Hydrofluoroalkanes (HFAs) are one group of aerosol propellants, and 
ttFA-134a (1,1,1,2-tetrafluoroethane) and HFA-227 
(1,1,1,2,3,3,3-heptafiuoropropane) have been identified for possible use 
as replacement propellants in medicament containing aerosols. 
Unfortunately, neither HFA-134a nor HFA-227 effectively interacts with the 
dispersing agents currently utilized in pressurized meter dose inhalers 
(MDIs). Thus, there exists a chasm in adapting these propellants for use 
in MDIs. 
European Patent Publication Numbers 0 499 344 and 0 372 777, the contents 
of which are herein incorporated by reference, describe aerosol 
formulations comprising a medicament, HFA-134a, a surfactant, and at least 
one compound or a co-solvent having a higher polarity than HFA-134a. 
Surfactants discussed as acceptable in these publications are sorbitan 
trifoliate, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene 
(20) sorbitan monolaurate, polyethylene (20) sorbitan monooleate, natural 
lecithin, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) 
ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene 
and oxypropylene, oleic acid, synthetic lecithin, diethylene glycol 
dioleate, tetrahydrofurfuryl, oleate, ethyloleate, isopropyl myristate, 
glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, 
cetyl alcohol, stearyl alcohol, polyethylene glycol 400, cetyl pyridinium 
chloride, olive oil, glyceryl monolaurate, corn oil, cotton seed oil, and 
sunflower seed oil. Such surfactants are also identified in International 
Publication No. WO 91/04011, the contents of which are herein incorporated 
by reference. 
In another attempt to achieve satisfactory dispersion of a medicament in 
HFA-134a, the medicament was precoated with a surfactant prior to admixing 
with the HFA-134a propellant. In particular, micronized beclomethasone 
dipropionate was coated with Epikuron 200. 
In World Patent Publication No. WO 92/00061, the contents of which are 
herein incorporated by reference, a hydrofluorocarbon propellant was used 
together with a polyethyloxylated surfactant. Using this surfactant, the 
formulation was made sufficiently stable without the need for additional 
solvents. 
The present invention provides dispersing agents suitable for suspending 
medicaments in hydrofluoroalkane compositions. The subject dispersing 
agents are superior in these properties to those known in the art. 
Additionally, these dispersing agents provide the advantage of not 
requiring a co-solvent such as alcohol, thus eliminating the possibility 
of adverse interaction of alcohol with certain classes of medicaments. 
The subject invention fulfills this need through the use of compounds which 
are generally regarded as safe (GRAS). 
SUMMARY OF THE INVENTION 
A composition for use in a medicament-containing aerosol comprises a 
hydrofluoroalkane and a dispersing agent selected from the group 
consisting of C.sub.3 -1inked triesters, vitamin E acetate, glycerin, 
t-butanol, and transesterified oil/polyethylene glycol. The dispersing 
agent is present in an amount effective to suspend the medicament in the 
hydrofluoroalkane.

DETAILED DESCRIPTION OF THE INVENTION 
The subject invention will now be described in terms of its preferred 
embodiments. These embodiments are set forth to aid in the understanding 
of the invention, but are not to be construed as limiting. 
The invention relates to a group of generally regarding as safe (GRAS) 
materials that are effective as dispersing agents in hydrofluoroalkane 
(HFA) propellants. 
The term "hydrofluoroalkane" includes all C.sub.1 -C.sub.5 polyfluorinated 
alkane gases which are safe for aerosol administration. Thus far, HFA-134a 
and HFA-227 appear suitable. 
The term "dispersing agents" embraces surfactants and other compositions 
useful for keeping a medicament suspended in a hydrofluoroalkane. Among 
the preferred dispersing agents are "C.sub.3 -linked triesters" having the 
formula: 
##STR1## 
The group R may be hydrogen or hydroxy. In a more preferred embodiment, the 
C.sub.1-18 groups are alkyl groups, typically C.sub.1 to C.sub.10 in 
length. Examples of these C.sub.3 -1inked triesters include C.sub.8 
-C.sub.10 triglycerides, 1,2,3-propanetriol triacetate and trialkyl 
citrates. Other suitable dispersing agents include vitamin E acetate, 
glycerin, t-butanol and transesterified oil/polyethylene glycol (for 
example, PEG-6). 
Preferred C.sub.8 -C.sub.10 triglycerides have the formula: 
##STR2## 
wherein n is 6 or 8. Examples of these triglycerides are Neobee M-5 
manufactured by Stepan, Miglyol 810 and 812 manufactured by Huls America, 
Captex 300 and 355 manufactured by Capital City, Hodag CC-33 manufactured 
by Hodag, Labrafac Lipophile WL 1349 manufactured by Inolex, Liponate GC 
manufactured by Lipo, Octanoic/Decanoic Acid Triglyceride O.D.O. 
manufactured by Nisshin Oil Mill, Protachem CTG manufactured by Protameen, 
and Unitolate 160-K manufactured by UPI. 
Preferred 1,2,3-propanetriol triacetate has the formula: 
##STR3## 
Examples of this compound include ESTOL 1580 manufactured by Unichema and 
Unitolate GTA manufactured by UPI. 
Trialkyl citrates preferrably have the formula: 
##STR4## 
More preferred triaalkyl citrates are triethyl citrate (C.sub.2) and 
tributyl citrate (C.sub.4). An example of triethyl citrate is Citroflex 2 
manufactured by Morflex. 
Transesterified oil/polyethylene glycol is a complex mixture formed from 
the transesterification of an oil and polyethylene glycol (PEG). These 
compositions are exemplified by the Labrafil series of compositions 
manufactured by Gattefosse. For example, Labrafil M 1980 CS (olive oil 
PEG-6 esters), Labrafil M 1969 CS (peanut oil PEG-6 esters), Labrafil 2125 
CS (corn oil PEG-6 esters), Labrafil M 1966 CS (almond oil PEG-6 esters), 
Labrafil M 1944 CS (apricot kernel oil PEG-6 esters), Labrafil M 2130 CS 
and BS (Hydrogenated Palm/palm kernel oil PEG-6 esters), Labrafil M 2735 
CS (triolein PEG-6 esters), Labrafil Isostearique (tristearin PEG-6 
esters) and Labrafil WL 2609 BS (corn oil PEG-8 esters). 
The selection of a medicament is within the purview of one skilled in the 
art. Examples of medicaments include antiallergics, analgesics, 
antihistamines, antitussives, anginal preparations, antibiotics, 
anti-inflammatories, bronchodialators, hormones, sulphonamides, 
therapeutic proteins, peptides, steroids, and mixtures thereof. One 
particularly suitable group of medicaments are the leukotrine antagonists, 
which preferably are micronized. 
The following examples illustrate the invention. A one-step method for 
preparing an MDI batch is described in Example 1. The amount of meter-dose 
drug was quantified with a high pressure liquid chromatograph (HPLC) assay 
method in Example 2. Particle size and distribution was determined using a 
laser diffraction method (Malvern particle site analyzer) and a 
time-of-flight measurement (Aerosizer) in Example 3. Dispersion of the 
suspension was characterized by image analysis of the particle 
flocculation in Example 4. Valve performance was measured by shot weight 
test in Example 5, and valve lubrication was evaluated with an Insiron 
Materials Tester in Example 6. 
EXAMPLE 1 
A batch of MDI suspension was prepared and pressure filled as follows: 10.0 
g of drug (Ro 24-5913) and 4.0 g of the C.sub.8 -C.sub.10 triglyceride 
dispersing agent (Miglyol 812 Neutral Oil manufactured by Huls America) 
were placed in a i-liter stainless steel pressure vessel. (Ro 24-5913 is a 
micronized leukotrine (LTD.sub.4) receptor antagonist 
(E)-4- 3- 2-(4-cyclobutyl-2-thiazolyl)ethenyl!phenylamino!-2,2-diethyl-4-o 
xobutanoic acid manufactured by Hoffmann La Roche Inc. which has the 
chemical formula C.sub.23 H.sub.28 N.sub.2 O.sub.35). The vessel was 
sealed and then charged with 1000 g HFA-134a propellant. The mixture in 
the vessel was then homogenized at a mixing speed ca. 1,500 rpm for 30 
minutes. The resulting suspension contained 1.0% by weight of the drug and 
0.4% by weight of the dispersing agent. The mixture was then pressurized 
to about 230 psi and the vessel connected to a Pamasol aerosol filler. The 
filler was adjusted so that about 10.0 g of suspension was transferred to 
a canister crimped with a metering valve at each fill. 
EXAMPLE 2 
Using the method described in Example 1, a series of suspension 
formulations containing various amounts of drug and dispersing agent were 
prepared for aerosol use. Table 1 shows four different formulations 
(samples A, B, C and D) which were analyzed with a high pressure liquid 
chromatography HPLC system to determine the uniformity of each dose 
delivered. 
TABLE 1 
______________________________________ 
Ro 24-5913 
Miglyol Vitamin-E 
Micronized 
812 Acetate HFA-134a 
Sample (mg/Can) (mg/Can) (mg/Can) 
(g/Can) 
______________________________________ 
A 100 40 -- q.s. 10.0 g 
B 100 -- 15 q.s. 10.0 g 
C 50 40 -- q.s. 10.0 g 
D 100 40 -- q.s. 10.0 g 
______________________________________ 
(Throughout the specification similar compositions have been assigned the 
same sample letter). The aerosol canister was fitted with an actuator to 
which a collecting device was attached. Total dosage for each can was 
approximately 150 shots. To obtain a representative dose assay, shot 
numbers 10, 30, 50, 70, 90, and 110 were collected and analyzed by HPLC 
assay. Analytical data are shown in Tables 2A, 2B, 2C and 2D. Total dose 
consists of drug accumulated in the collecting device (Emitted Dose) and 
drug deposited in the actuator (Actuator). Data demonstrate that a uniform 
amount of drug was delivered from the beginning through the end stage 
shots. Total variation as reflected by relative standard deviation (RSD) 
was less than 4% and 2% for emitted dose and shot weight, respectively. 
These data indicate the suitability of C.sub.8 -C.sub.10 triglycerides for 
use in aerosol drug delivery. 
TABLE 2A 
______________________________________ 
Dose Uniformity Analysis by HPLC 
Ro 24-5913 MDI Suspension, Sample A 
Shot Actuator Emitted Dose Shot 
Number Deposition 
Ro 24-5913 (.mu.g) 
Total Weight (mg) 
______________________________________ 
10 70.2 672.1 742.3 61.8 
30 120.7 662.1 782.8 62.4 
50 122.0 667.3 789.3 61.6 
70 150.3 671.0 821.3 62.4 
90 136.5 665.1 801.6 62.3 
110 111.5 690.9 802.4 61.5 
Average 
-- 671.4 790.0 62.0 
% RSD -- 1.5 3.4 0.7 
______________________________________ 
TABLE 2B 
______________________________________ 
Dose Uniformity Analysis by HPLC, 
Ro 24-5913 MDI Suspension, Sample B 
Shot Actuator Emitted Dose Shot 
Number Deposition 
Ro 24-5913 (.mu.g) 
Total Weight (mg) 
______________________________________ 
10 121.3 562.9 684.2 61.0 
30 116.1 578.3 694.4 62.4 
50 142.2 571.4 713.6 63.5 
70 134.7 605.6 740.3 63.7 
90 158.9 572.0 730.9 63.7 
110 172.0 569.9 741.9 64.3 
Average 
-- 576.7 717.6 63.1 
% RSD -- 2.6 3.4 1.9 
______________________________________ 
TABLE 2C 
______________________________________ 
Dose Uniformity Analysis by HPLC 
Ro 24-5913 MDI Suspension, Sample C 
Shot Actuator Emitted Dose Shot 
Number Deposition 
Ro 24-5913 (.mu.g) 
Total Weight (mg) 
______________________________________ 
10 33.3 229.7 263.0 61.5 
30 42.4 237.5 279.9 62.7 
50 47.0 234.5 281.5 62.2 
70 41.3 238.2 279.5 62.6 
90 36.9 247.3 284.2 62.8 
110 44.7 238.7 283.4 62.0 
Average 
-- 237.7 278.6 62.3 
% RSD -- 2.4 2.8 0.8 
______________________________________ 
TABLE 2D 
______________________________________ 
Dose Uniformity Analysis by HPLC, 
Ro 24-5913 MDI Suspension, Sample D 
Shot Actuator Emitted Dose Shot 
Number Deposition 
Ro 24-5913 (.mu.g) 
Total Weight (mg) 
______________________________________ 
10 69.2 659.4 728.6 61.7 
30 107.9 677.9 785.8 60.9 
50 123.5 717.8 841.3 62.6 
70 138.3 701.0 839.3 62.4 
90 100.8 718.6 819.4 60.5 
110 115.5 683.4 798.6 62.0 
Average 
-- 693.0 802.2 61.7 
% RSD -- 3.4 5.3 1.3 
______________________________________ 
EXAMPLE 3 
Using the method of Example 1, a series of suspension formulations 
containing various amounts of drug and dispersing agent were prepared. 
Table 3 identifies these aerosol formulations. 
TABLE 3 
______________________________________ 
Aerosol Formulation: Samples Prepared for Particle Size Analysis 
Ro 24-5913, 
Vitamin-E HFA-134a, 
mg/Can Acetate, g/Can 
Sample 
(% w/w/) mg/Can (% w/w) 
(% w/w) 
______________________________________ 
E 10.0 (0.1%) 
1.0 (0.01%) q.s. 10.0 g (99.89%) 
F 50 (0.5%) 
50 (0.5%) q.s. 10.0 g (99%) 
G 100 (1.0%) 
50 (0.5%) q.s. 10.0 g (98.5%) 
H 50 (0.5%) 
1.0 (0.01%) q.s. 10.0 g (99.49%) 
______________________________________ 
Samples were analyzed for the particle size and distribution using a laser 
diffraction method (Malvern) and a time-of-flight (Aerosizer) measurement, 
and the results of these measurements are listed in Tables 4A and 4B. All 
formulations showed particle sizes within the desirable range of between 
0.1 and 10 .mu.m. Particles within this size range are desirable because 
they can reach the lower respiratory tract and lung alveolar peripherals 
to maximize the therapeutic effect of the medicine. In Tables 4A and 4B, 
"D" stands for diameter and "V" stands for volume. The "D(V,n)" numbers 
relate to particle size diameter in a ranked volume fraction. For example, 
D(V,0.1) refers to particle diameter at the 10% of the particle size range 
(smaller than the average particle size), D(V,0.5) is the median particle 
size; and D(V,0.9) refers to diameter at the 90% particle size range 
(larger than average particle size). D(4,3) relates to the mean average 
particle size. 
TABLE 4A 
______________________________________ 
Particle Size Analysis Results 
Malvern Results (Microns) 
Sample* D(4,3) D(V,0.5) D(V,0.9) 
D(V,0.1) 
______________________________________ 
E 6.1 1.5 8.0 0.5 
F 4.8 3.0 7.1 0.8 
G 7.4 4.5 12.7 1.2 
H 6.5 3.8 12.1 1.0 
______________________________________ 
*Storage Condition: Initial, Inverted. 
TABLE 4B 
______________________________________ 
Aerosizer Diameter (Microns) 
Sample* D(4,3) D(V,0.5) D(V,0.9) 
D(V,0.1) 
______________________________________ 
E 1.9 1.3 3.8 0.8 
F 3.4 3.1 5.2 1.8 
G 2.8 2.5 4.4 1.6 
H 1.9 1.6 3.3 1.0 
______________________________________ 
*Storage Condition: Initial, Inverted. 
These data indicate that vitamin-E acetate is effective in dispersing the 
drug in suspension for aerosol drug delivery. 
EXAMPLE 4 
A sample was prepared as follows: 40 mg of micronized drug (Ro 24-5913) and 
10 mg of Neobee M-5 were placed in a 15-mL glass vial, which was then 
crimped with a continuous valve and filled with 10.0 g of HFA-134a 
propellant under pressure. The vial containing the formulation was then 
sonicated for 10 minutes. The resulting suspension (designated Sample I) 
contained 0.4% by weight of the drug, 0.1% by weight of the dispersing 
agent, and 99.5% of propellant. Similarly, other formulations were 
prepared: 
______________________________________ 
Sample 
Ro 24-5913 
Surfactant Propellant 
______________________________________ 
I 0.4% Neobee M-5, 0.1% 
P134a, q.s. 100% 
J 0.4% Triacetin, 0.1% P134a, q.s. 100% 
K 0.4% Oleic Acid, 0.1% 
P134a, q.s. 100% 
L 0.4% Sorbitan Trioleate, 0.1% 
P134a, q.s. 100% 
______________________________________ 
Each sample was swirled for 5 seconds before being placed in front of a 
video camera. Image analysis software was used to capture a frame of image 
at various time points. FIG. 1 shows the images of Sample A at time 
intervals of 0, 15, 30 and 45 seconds, 1 and 2 minutes. FIGS. 2, 3, and 4 
show the images of Samples J, K, and L at the same time points. 
These images showed that at a given time interval, formulations containing 
Neobee M-5 or triacetin were more stable than the formulation containing 
oleic acid and sorbitan trioleate (STO). Oleic acid and sorbitan trioleate 
were used extensively as surfactants in CFC suspension formulations. Gross 
particle agglomeration occurred almost immediately after mixing in the 
oleic acid and STO formulations. The last two figures graphically 
illustrate that known surfactants used in CFC propellants can not be 
effectively used in HFA propellants to sustain a stable suspension. 
Using a dispersion index scale from 1 to 4, with 1 being the best dispersed 
system and 4 being the worst dispersed system, a wide range of 
formulations containing various agents were screened and ranked. For a 
formulation to be ranked as having disperion index 1, it must be remained 
fully dispersed for at least one minute after swirling. Similarly, for a 
formulation to be ranked as having dispersion index of 2, 3 or 4, it must 
be remained fully dispersed after swirling for at least 40, 20 and 5 
seconds, respectively. Table 5 lists the results and observations. 
TABLE 5 
______________________________________ 
Ranking of Dispersion Index for MDI 
Formulations Containing Various Surfactants 
at the Same Drug Concentration 
Surfactant Dispersion Index 
______________________________________ 
Neobee M5* 1 
Vitamin-E Acetate 
1 
Triacetin* 1 
Triethyl Citrate* 
1 
Tributyl Citrate* 
1 
Glycerin 1 
t-Butanol 2 
Labrafil 2 
Propylene Glycol 2 
Glyceryl Monooleate 
3 
Oleyl Alcohol 3 
Oleic Acid 4 
Sorbitan Trioleate 
4 
Lecithin 4 
Pluronic 62 4 
Tween 60 4 
Span 40 4 
______________________________________ 
*C.sub.3linked triester 
These data indicate that the dispersing agents of the present invention are 
more effective than known surfactants for keeping a drug suspended in a 
hydrofluoroalkane propellant. 
EXAMPLE 5 
Using the method of Example 1, several suspension formulations containing 
various amounts of drug and dispersing agents were prepared. Table 6 shows 
the mount (percent by weight based on total weight of the formulation) and 
type of surface-active dispersing agent used. 
TABLE 6 
______________________________________ 
Aerosol Formulation 
Vitamin-E 
Ro 24-5913 
Miglyol 812 
Acetate, 
HFA-134a, 
Sample (mg/Can) (mg/Can) mg/Can g/Can 
______________________________________ 
1 A 100 40 -- q.s. 10.0 g 
2 C 50 40 -- q.s. 10.0 g 
3 M 50 -- 40 q.s. 10.0 g 
4 N 50 10 -- q.s. 10.0 g 
______________________________________ 
The above samples were tested for shot weight consistency using a 
laboratory robotics system. The shot weight testing schedule was as 
follows in Table 7: 
TABLE 7 
______________________________________ 
Actuation Number 
______________________________________ 
0-5 Waste 
6-15 Each Shot was Weighed 
16-66 Waste 
68-77 Each Shot was Weighed 
78-127 Waste 
129-138 Each Shot was Weighed 
______________________________________ 
A total of 30 shots representing beginning doses (Shot Numbers 6-16), 
middle doses (Shot Numbers 68-77), and end doses (Shot Numbers 129-138) 
for each can were weighed and recorded. The average of the 30 shot weights 
and relative standard deviation (RSD) for each sample were plotted in FIG. 
5. The relative standard deviations of all lots were below 5%, showing a 
satisfactory valve performance and shot weight consistency. These data 
indicate that vitamin-E acetate and the C.sub.3 -linked triesters are 
effective for use in generating uniform shot weights during aerosol drug 
delivery. 
EXAMPLE 6 
Using the method of Example 1, several suspension formulations were 
prepared. Table 8 shows the amount (percent by weight based on total 
weight of formulation) and type of surface-active dispersing agent used. 
TABLE 8 
______________________________________ 
Formulation Data Sheet 
Sample O G Control 
______________________________________ 
Ro 24-5913 (% w/w) 
1.0% 1.0% -- 
Vitamin-E (% w/w) 
-- 0.5% -- 
HFA-134a q.s. 100% q.s. 100% 100% 
Energy for Actuation 
1.05 (1.9%) 
0.895 (3.4%) 
0.758 (0.7%) 
(1b-Inch) (RSD %) 
______________________________________ 
The samples prepared above were analyzed by an Inswon Materials Tester to 
measure the effect of the dispersing agent (here acting more as a metering 
valve lubricant) on the valve actuation force. FIG. 6 shows the plots of 
load force versus valve stem displacement. The results indicate that the 
compressing force increases as the valve is filled with the suspension 
fluid, largely due to the increase in friction resulting from movement of 
the stem. By adding the dispersing agent, the compression force is 
substantially reduced. This advantage is supplemental to increased 
dispersion of the medicament into the propellant. 
Load versus displacement curves of three Bespak BK356 50 mcL inverted 
metering valves are shown. Curve A represents an empty valve containing no 
fluid. Curve C represents the same valve containing a suspension HFC-p134a 
propellant and 1% micronized medicament. Curve B represents the valve 
containing a suspension identical to that represented in Curve C, except 
an additional 0.1% Neobee M-5 was added to the suspension. 
FIG. 7 compares total energy required to actuate the valves in different 
formulations. As is shown by these data, the dispersing agents of the 
present invention are effective in reducing friction and facilitating 
aerosol drug delivery. 
As shown and exemplified, the dispersing agents of the present invention 
are useful for dispersing medicaments in hydrofluoroalkanes, and are 
effective in lubricating the stem to facilitate actuation of the valve. 
The invention has been described in terms of its preferred embodiment. 
However, upon reading the above description, various alternative 
embodiments will become obvious to those skilled in the art. These 
variations are to be considered within the scope and spirit of the subject 
invention, which is only to be limited by the claims which follow and 
their equivalents.