Note: Descriptions are shown in the official language in which they were submitted.
wo 92/11236 PCr/US9l/0~1l7 i
1 ~9~
A~ROSOL FORMULATIONS
SCOPI~ OF THE ~NllON
This invention relates to an aerosol formulation comprising a
triester of sorbitan and a salt of an LTD4 antagonist analog of the
5 peptido-leukotriene series, a substituted phenylcarboxy-
alkylthioalkanoic acid. More particularly, this invention relates to an
aerosol formulation made up of a long chain aliphatic triester of
sorbitan and the 1,2-ethanediamine salt of [R-(R*,S*)]-,~-[(2-
carboxyethyl)thio] -a-hydroxy-2-(8-phenyloctyl)benzenepropanoic
1 0 acid.
In a second aspect, this invention relates to the monohydrate
form of the 1,2-ethanediamine salt (1:1) of [R-(R*,S*)]-,~-[(2-
carboxyethyl)thio]-a-hydroxy-2-(8-phenyloctyl)benzenepropanoic
acid, a stable polymorph thereof and methods for making both.
1 5 BACKGROUND
Aerosol technology provides a convenient means for remotely
dispensing and applying a host of different materials. These
formulations are now a commonly used means for dispersing onto a
surface any numbers of solid materials in a powder or liquid form.
2 0 Aerosols are routinely used in the cosmetic industry, for painting, for
dispensing insecticides and herbicides, for foaming materials, for
applying cleaning and preservative agents and for administering
drugs, to.name a few of the various numerous applications of the
aerosol technology.
Aerosols are quickly applied. Small amounts or a thin layer
material can be rapidly applied over a large area in a repetitive
fashion. Aerosol container are sealed. There is no back-aspiration
during application so content contamination is greatly reduced in
comparison with sprays or other forms of airborne application.
The word aerosol is classically defined as a collodial suspension
of finely divided liquids or solid particles dispersed in and
surrounded by a gas. An ae-osol spray is obtained by forcing a
mixture of gas and a liquid, semi-solid or solid material through a
specially designçd valve system resulting in a finely divided liquid
3 5 or solid particles being dispersed in the gas stream.
Aerosol formulations have found use as a means for drug
delivery and drug application. Pharmaceutical-based aerosol
formulations are most frequently used orally or topically. Diseases
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wo 92/11236 PCr/US9l/02177
in the throat and lungs are frequently treated via aerosol
formulations. Topical diseases such as acne or where there is need
for first aid have utilized aerosol preparations. Anesthetics,
antiseptics, germicides, body rubs, dermatological products and foot
5 preparations are often applied via aerosols.
This invention is primarily concerned with the oral delivery of
an anti-allergy agent. It is a particularly useful means for
administering these drugs to prevent or treat asthma and other
allergy^related or induced diseases of the mouth, throat or lungs.
Applicants have discovered that there are two unique
phenomena associated with preparing an aerosol dispersion
formulation of a certain asthma drug. First, a monohydrate of a
polymorph is considerably more stable in the aerosol formulation.
Secondly, applicants have discovered that the 1,2-ethanediamine salt
of [R-(R*,S*)]-,B-[(2-carboxyethyl)thio]-a-hydroxy-2-(8-phenyloctyl)-
benzenepropanoic acid monohydrate is very sparingly soluble in
triester sorbitans as compared with other dispersing agents which
may be used in aerosol formulations.
Summarv of the Tnvention
2 0 In one aspect this invention covers a pharmaceutically
acceptable aerosol formulation comprising a sorbitan tries~er of C1 o
to C20 aliphatic acids, at least one propellant and the 1,2-
ethanediamine salt of [R-(R*,S*)]-~-[(2-carboxyethyl)thio]-a-
hydroxy-2-(8-phenyloctyl)benzenepropanoic acid monohydrate in
2 5 an amount sufficient to deliver a therapeutically effective dose when
inhaled.
Also, this invention covers a method for preparing a stable
aerosol of the 1,2-ethanediamine salt of [R-(R*,S*)]-~-[(2-
carboxyethyl)thio]--hydroxy-2-(8-phenyloctyl)benzenepropanoic
3 0 acid monohydrate which comprises mixing the monohydrate with
about a 10-fold excess of a sorbitan triester of Clo to C20 aliphatic
acids and a propellant.
In a further aspect this invention relates to a monohydrate
form of the 1,2-ethanediamine salt (1:1) of [R-(R*,S$)]-~-[(2-
3 5 carboxyethyl)-thio]-a-hydroxy-2-(8-phenyloctyl)benzenepropanoic
acid, a stable polymorph thereof and methods for making both.
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WO 92/11236 PCI`/US91/0217'7
f
3 2~8'~3~
SPECIFlC EMBODIhl~NTS
Pictorially, the acid salt of this invention is represented by the
following formula.
_ _
S' ~CH2)2C2 H ~N
0~ ~CR2)2C2 +
H~N
The di-acid itself is disclosed in U.S. patent No. 4,820,719. That
patent describes a synthetic process for making a racemic mixture of
the acid and a means for recovering the isomer of this invention from
10 that racemic mixture. Several salts of the acid, including the
1,2-ethanediamine salt, are also disclosed in that patent.
This compound is believed to be useful in treating asthma,
especially when administered directly to the lung, a topical
application for all intents and purposes. This indicated an aerosol
15 formulation would be a useful means of administering this drug for
treating asthma, as well as for other allergy-related diseases of the
respiratory tract.
Monohvdrate and Polymorph Formation
During the course of preparing- formulations for various testing
2 0 regimens, the anhydrous 1,2-ethanediamine salt material was used.
It was not stable. It took up water, which in certain inst~nces
changed the characteristics of the formulations in which it was
confected (for example, the aerosol formulation described herein).
Research showed the 1,2-ethanediamine salt would form a
2 5 monohydrate which then remained stable in various formulations,
that is it did not take up more water or lose water as it was being
formulated or during storage.
Further work with the monohydrate form of this 1,2-e;.l~ne-
diamine salt revealed changes were occurring in certain formulations
3 0 during preparation or storage. Two polymorphs were isolated and
characterized. One polymorph was found to be unstable. It
converted to the other, more stable, form under certain conditions
such as when sufficient heat was applied or certain formulating
processes were carried out on the monohydrate.
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WO 92/1 1236 PCI`/US91tO2177
20982~J~ ~.
Additionally, it has been found that certain solvent
combinations used for making the monohydrate will give the desired
polymorph directly, while others provide only the undesired
(unstable) polymorph form. For example methanol- and ethanol-
5 based solvent systems give the stable polymorph directly.
Isopropanol/water and tetrahydrofuran/water mixtures may
produce an unstable polymorph form of the monohydrate which
must then be acted on further to convert it to the stable polymorph.
Solvents and solvent mixtures which produce satisfactory
10 product, the stable polymorph of the monohydrate, are methanol,
methanol containing up to 50% ethyl acetate, methanol/acetonitrile,
and methanol/tetrahydrofuran, all containing about 1% water. The
preferred solvent system is methanol or methanol/ethyl .
acetate/water, particularly this solvent in a 75 :25 :1 ratio. These
15 figures are expressed in terms of volume/volume ratios.
One may vary the order of addition of reagents and the ~ -
temperature of the reaction mixture during the formation of the salt.
Reagents and substrates may be mixed together in any order at
ambient temperature, and then heated to about 60C. Alternatively,
2 0 the substrate may be heated to 60C in the chosen solvent system
followed by the addition of reagents. Once precipitated, it is best to
stir the reaction mixture for a period of time, preferably for about 3-
16 hours, prior to filtering out the precipitate.
The stable polymorph can also be prepared by heating the
2 5 unstable form to about 60C, preferably in a solvent.
The stable polymorph of this invention is characterized by the
differential scanning calorimetry (DSC~ readout shown in Figure 1 and
a crystal habit of thin blades or needles up to 100 microns long and
35 microns wide. By comparison, the unstable polymorph shows a
3 0 crystal habit of rectangular plates approximately 350 microns by '~0
microns. It is possible to distinguish between the two polymorphs
based on powder X-ray diffraction; however, the differences are
much more subtle than those exhibited by DSC.
The thermal behavior of the desired polymorph can be
3 5 described and compared with the undesirable form thusly: The
stable (desired) form exhibits a broad endotherm (onset about 100C )
followed by a large sharp endotherm (onset about 148C) followed by
a small sharp endotherm (onset about 165C). This form correspond~
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wo 92/~1236 Pcr/US9t/02177
to the blade/needle form. The other polymorph (undesired form) is
characlerized by a large sharp skewed endotherm (onset about
1 30C) followed by a moderate sharp endotherm (onset about 145C )
followed by a small sharp endotherm (onset about 1 6~C). This form
5 corresponds to the plate form.
~eros .l ~Q~m~latiQns
In early aerosol work, it was discovered that the formulations
containing the anhydrous form of the 1,2-ethanediamine salt were
physically unstable. By that it is meant that this anhydrous salt
10 exhibited crystal growth in a sorbitan monoester-based aerosol
formulation within a short period of time under accelerated storage
conditions. Crystal growth of the type observed and the growth rate
observed indicated such a formulation was essentially unusable
because it would not have an adequate shelf life. Subsequently, a
15 monohydrate was prepared and tested in the same formulation and
under the same conditions. Surprisingly, the monohydrate showed
substantially greater stability as compared with the anhydrous form.
Though this information was useful, an aerosol formulation still
faced the problem of salt solubility in the suspending agent. A
2 0 number of suspending agents were tested, oleyl alcohol, sorbitan
monooleate, and oleic acid. The monohydride 1,2-ethanediamine salt
was soluble in each of these to a degree which caused concern for
product stability. It was projected that over time the fraction of
solubilized monohydrate salt would recrystallize on existing
2 ~ monohydrate salt particles, thereby increasing the size of the
monohydrate salt particles. This would not only affect the deposition
pattern in the lung but could also impair the mechanical function of
the valve. Then sorbitan trioleate was evaluated. It was found that
the salt was very insoluble in this triester, especially as compared to
3 0 the other suspending agents which had been tested. This salt was
found to be about ten times less soluble in sorbitan trioleate as
compared with the monooleate. Based on this novel finding, it was
decided it was feasible to proceed with an aerosol formulation using
a sorbitan triester, particularly a long chain fatty triester.
3 ~ Sorbitan refers to the 1,4-sorbitan. It is made by dehydrating
sorbitol. That process leaves three reactive hydroxyl groups one or
more of which can be esterifed. In this case the triesters are formed
by esterifying all three hydroxyl groups with a C1o-C20 acid.
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W O 92/11236 .~ ~ 9 " i~ P~r/US91/02177
SIandard esterification processes are used to form these esters.
Acids used to form these compounds may be fully saturated or have
one or more double bonds. Preferably they will be mono-
unsaturated or saturated. It is further preferred that each ester be
5 formed using an acid of the same structure. However, it is expected
that mixtures of acids and mixtures of esterified sorbitans could be
used .
A number of these triesters are commercially available in the
U.S. and worldwide. The most common triesters are sorbitan
10 triisosterate and sorbitan trioleate. At least nine United States
companies and three United Kingdom companies market these two
sorbitan triesters under a host of different trade names. A listing of
such companies and the products they produce is available in
Pharmaceutical Excipients published by the American
15 Pharmaceutical Association and the Pharmaceutical Society of Great
Britain, copyright 1986. Information on sorbitan triesters is also
available from Remington's Pharmaceutical Sciences, the Merck
Index and other compendia of pharmaceutical formulations.
The amount of drug used in the aerosol formulation will be
2 0 based on the amount of material delivered each time the device is
used. In this particular instance, it is most preferred to deliver
between 100 llg of anhydrous free acid during each valve actuation.
That means about 117 llg of the monohydrate 1,2-ethanediamine salt
must be delivered each time. This represents what is believed to be
2 5 an effective dose for treating asthma. But the therapeutically
effective amount required to treat any given disease could vary
between about SO and SOO llg per dose depending on the disease, its
response to this drug, how the aerosol container is used, and other
factors affecting the effectiveness of the drug and the efficiency of
30 delivery. Preferably the drug will be present in an amount between
about 0.05 mg and 10.0 mg per gram of formula, most preferably
about 2 mg per gram.
About 25 to 150 111 of aerosol should be delivered per
actuation. This amount can be varied by modifying the valve design
35 and by other means. But in any case, this volume should be such
that it delivers a therapeutically effective amount of the drug.
The components from which aerosols are formed require a
source of gas to act as the propellant and a solid, semi-solid or a
WO 92/11236 PCI`/US91/02~ 77
7 2~2~
liquid which becomes dispersed in the gas as it is being dispensed
through a valve system.
Aerosols can be classified as liquid-gas systems, compressed
gas syslems, and a third catch-all category which usually involves
S some type of piston or flexible bag device which assist in expelling
the gas/solid dispersion through the valve system. A general
discussion of the several aerosol systems routinely employed with
pharmaceutical formulations can be found in Remington's
Pharmaceutical Sciences, 17th edition, Mac Publishing Company~
10 Easton, Pennsylvania, USA (1985).
One means of the mode of operation of aerosol systems is to
use a liquified gas as the propellant source for forming the aerosol.
This method introduces a liquified gas into a container. There an
equilibrium is set up between a gaseous and liquid phase. The
15 gaseous phase or vapor phase exerts a pressure on the system which
is sufficient to dispel any portion of the liquified gas, it also contains
the active ingredient, through a specially designed nozzle which
forms the aerosol spray.
Liquified gas systems usually are two phase systems. A
2 0 solution or suspension of an active ingredient is combined with a
liquified gas and introduced into a sealed container with the
appropriate aerosol valve system. As the name implies, a two-phase
system once formulated in a can contains only a gas and a liquid
propellant. The active ingredient can either be miscible, in solution~
2 5 or immiscible; solid particles.
Compressed gas aerosol systems utilize an inert gas such as
nitrogen, carbon dioxide or nitrous oxide, for example. Compressed
gas is placed in a container and expands through the valve when the
valve is opened providing the means for dispensing or expelling the
3 0 container contents.
Valve structures and container forms and structures are
known in 'ne art. Remington's Pharmaceutical Sciences 17th Ed.
illustrates a number of oral devices. Specialized aerosol applicators
have been developed for oral administration of medicaments. These
3 5 devices take into consideration the anatomical and physiological
parameters and structure of the respiratory pathway. Most devices
deliver an accurately metered dose of material in order to control
the amount of medicament which is administered per use.
wo 92/l 1~36 J U 9 ~ 2 r~ ~3 PCI`/~1591/07 1 7 /
The propellants used in ~his invention may be liquified gases
or compressed gases. Liquified gases are preferred. This class is , -
made up of the halocarbons and hydrocarbons. Halocarbons have
found greater use as ~hey are inflammable as contrasted with
5 hydrocarbons, Halocarbons are normally chloro or fluoro-subs~i~u~ed
alkanes, most often of one or two carbons.
Fluorochlorocarbons are identified by two or three digit ',
numbers which represent the number of fluoro, chloro, and
hydrogen atoms in a particular propellant. The simplest of the~e
10 fluorochlorocarbons, and two gases which can be used in the pracaice
of this invention, are Pl1 and P12. Pl1 is trichlorofluoromethane.
P 12 is dichlorodifluoromethane. Mixtures of these simple
fluorochlorocarbons, that is the methane forms, are useful in the
practice of this invention. But other combinations of these methane-
15 based gases as well as other fluorochlorocarbons can be used.
Hydrocarbon gases are now also successfully used inpharmaceutical aerosols. Propanes, butanes and pentanes are
frequently used in pharmaceutical aerosols. Dimethyl ether is also
useful as a propellant in certain formulations, particularly because of
2 0 its high water solubility as compared with the alkane-based
propellants.
Compressed gases have at times been used in pharmaceutical
formulations. However, depending on the nature of the formula~ion
and the valve design, the dispensed product may be a mist, foam or
25 semisolid. Only the mist form will be of real utility in this invention.
Liquified gas formulations are of most interest in this
invention. Bulk concentrates are prepared by dispersing a known
quantity of the 1,2-ethanediamine salt in a known quantity of a
sorbitan triester/trichlorofluoromethane mixture by homogenization.
3 0 This process should be carried out below room temperature (5-8C).
Preferably, it will be carried out under sterile conditions. Thereafter
this dispersion is filled int~ an appropriate container for
administering an aerosol orally. The system is pressurized with a
propellant in a such a manner as to provide the desired amount for
3 5 metering at a particular dose size per use.
Because the 1,2-ethanediamine salt is to be delivered to the
lungs, these aerosols will be delivered via an inhaler of some sort
adapted to use by mouth. A number of these devices have been
wo 92/11236 Pcr/usg1/o2l 77
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developed and are in use with different drugs. Several devices are
illustrated in Remington's Pharmaceutical Sciences. These devices
are readily available from a number of manufacturers or can be
made by reference to published drawings and descriptions.
The following examples are set out to illustrate, but not limit,
this invention. Reference is made to the claims for what has been
reserved to the inventors.
~x~m~plç I
Pre~aration of the monohvdrate of the 1.2-ethanediamine salt (1 :1)
Qf
~R-(R*.S*)l-B-~(2-carboxyethyl)thiol-a-hvdroxv-2-(8-phenvloctvl)-
benzenepropanoic acid as the stable polvmorph
This example illustrates how to make the salt, the monohydrate
and the desired polymorphic form.
1 5 To a stirred solution of [R-(R*,S*)]-~-[(2-carboxyethyl)thio]-a-
hydroxy-2-(8-phenyloctyl)benzenepropanoic acid (2.275 mol) in
absolute methanol (lOL) heated to 60C, was added a solution of 1,2-
ethanediamine (141.2g, 2.33 mol) in absolute methanol (2L) over a
30 minute period. After stirring at 60C for 5 minutes, deionized
20 water (120 mL) was added over a period of 0.5 minutes. After
stirring this solution for 5 minutes, the solution was cooled slowly to
approximately 50C. When the internal temperature reached 45C,
the solution was seeded with 0.30 g of authentic monohydrate of the
1,2-ethanediamine salt (1 :1) of [R-(R*,S*)]-~-[(2-carboxyethyl)thio]-a-
2 5 hydroxy-2-(8-phenyloctyl)benzenepropanoic acid and then slowly
cooled to ambient temperature over a period of 3 hours. After
stirring at ambient temperature for approximately 16 hours, the
mixture was filtered and washed two times with 1.5L of cold
methanol containing 1% of deionized water. The product was air
3 0 dried on the filter for 1 hour, then dried in vacuo (high vacuum) at
ambient temperature until a constant weight was obtained (36
hours). The title product was obtained as a ~ ~hite powder.
IH NMR (DMSO-d6, 400MHz) ~ 7.61 (br s, lH), 7.27-7.23 (m, 2H),
7.17-7.13 (m, 3H), 7.05-7.02 (3H), 6.25 (br s, 6H), 4.46 (m, IH), 4.02
35 (m, lH), 2.83 (s, 4H), 2.65-2.59 (m, lH), 2.56-2.46 (m, SH), 2.38-2.21
(m, 2H), 1.53 (m, 4H), 1.29 (m, 8H); IR (KBr) 3512, 3014, 2926, 2853,
1557, 1403, 1097, 758 cm-l
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WO 92/1 1236 PCr/US91~02177
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The polymorph m~de by this procedure produced a DSC of:
broad endotherm onset at 97.9C (25.2 cal/g) followed by a sharp
endotherm onset at 147.7C (20.8 callg) and a small sharp endotherm ',
onset at 163.1C (1.6 cal/g). Mimima were recorded at 115.4C, ',
5 150.0C, and 164.4C. This scan was generated on a 2.17 mg sample at
a scan rate of 20.00 degrees per minute. (See Figure 1)
This procedure can be carried out by stirring the solution with
all ingredients for 3 hours instead of 16 and still achieve acceptable
results.
I 0 The foregoing procedure was repeated using a methanol/ethyl
acetate solvent system (75:25) containing 1% water. Equivalent
results were obtained.
Example 2
Preparation of the Monohvdrate
I S To a stirred solution of lR-(R*,S*)]-B-[(2-carboxy- ethyl)thio]-a-
hydroxy-2-(8-phenyloctyl)benzenepropanoic acid (2.275 mol) in
absolute methanol (10 L) heated to 50C, was added a solution of
1,2-ethanediamine (141.2 g, 2.33 mol) in absolute methanol (2 L)
over a 30 minute period. After stirring at 60C for 5 minutes,
2 0deionized water (120 mL) was added over a period of 0.5 minutes.
After stirring at 60C for 5 minutes, the r~eaction solution was cooled
slowly to approximately 50C. When the internal temperature
reached 45C, the solution was seeded with 0.30 g of authentic title
compound and then slowly cooled to ambient temperature over a
2 5period of 3 hours. After stirring at ambient temperature for
approximately 16 hours, the product was isolated by filtration and
washed two times with 1.5 L of methanol containing 1 % of deionized
water. The product was air dried in the filter for I hour, then dried
in vacuo (hi-vacuum) at ambient temperature for 36 hours to a
3 0constant weight. This afforded [R-(R*,S*)]-B-[(2-carboxyethyl)thio]-
a-hydroxy-2-(8-phenyloctyl)benzenepropanoic acid, 1,2- -
ethanediamine (1:1), monohydrate as a white powder. The particle
size was reduced by fluid energy grinding in a stainless steel mill to
afford the title compound as a fine white powder: lH NMR (DMSO-
d6, 400 MHz) w 7.61 (br s, lH), 7.27-7.23 (m, 2H), 7.17-7.13 (m, 3H),
7.05-7.02 (3H), 6.25 (br s, 6H), 4.46 (m, IH), 4.02 (m, IH), 2.83 (s,
4H), 2.65-2.59 (m, IH), 2.56-2.46 (m, SH), 2.38-2.21 (m, 2H), 1.53 (m,
WO92/11236 Pcr/lJs~J~ i77
3 J3
1 1
4H), 1.29 (m, 8H); IR (KBr) 3512, 3014, 2926, 2853, 1557, 1403,
1097, 758 cm-l.
Example 3
Salt Solubilitv
The anhydrous form of the entylenediamine salt, when
formulated with sorbitan trioleate, demonstrated crystal grow~h
after two weeks at 50C and 40C at 75% relative humidity
The monohydrate form of the 1,2-ethanediamine salt, when
1 0 formulated with sorbitan trioleate, did not demonstrated crystal
growth after six months storage at 30C and three months storage at
50C and 40C at 75% relative humidity.
Example 4
1 5Testing of the monohvdrate in Sorbitans
The solubility of the 1,2-ethanediamine salt of [R-(R*,S*)]-,B-
[(2-carboxyethyl)thio]--hydroxy-2-(8-phenylocty])benzene-
propanoic acid monohydrate in sorbitan mono-oleate and sorbitan
trioleate was determined. Sorbitan trioleate was determined by
2 0 HPLC analysis. The following results were obtained:
Sorbitan trioleate 0.6 ~lg/ml
Sorbitan mono-oleate 6.2 llg/ml.
2 5 As crystal growth is a function of solubility the trioleate was deemed
to be a superior suspending agent for use in making an aerosol
formulation of this salt.
Example 5
3 0 Aerosol Formulation
An aerosol formulation was prepared by mixing the following
ingredients and amounts.
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wo 92/11236 RCr~U~ J0~77
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Ingredient Amount
Drug 36.0 mg
Sorbitan Trioleate 3.6 mg
Trichlorofluoromethane5.4 g
Dichlorodifluoromethane 12.6 g
Eighteen grams of this mixture were filled into 19 ml, anodized
aluminum "cut-edge", 20 mm neck, aerosol canisters (Presspart
10 C128) crimped with 50 ~I metering valve (Bespak BK356). The
rubber components of the valve had been pre-extracted by the
manufacturer utilizing a total immersion method. An alterna~ive
valve system M3652, produced by 3M Health Care Specialities valve
of Saint Paul, Minnesota, USA.
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