Note: Descriptions are shown in the official language in which they were submitted.
1 328078
AQUEOUS FORMULATIONS CONTAINING A
PIPERIDINYLCYCLOPENTYLHEPTENOIC ACID DERIVATIVE
This invention relate~ to aqueous formulation~ cont~ining as
active ingredient rlR-[la(Z),2~,3~,5a]]-(l)-7-[5-[[(1,1'-biphenyl~-
4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic
acid (hereinafter referred to as 'Compound A'), to processe~ for their
preparation and to their u~e in medicine.
Compound A i8 described in our British ~atent No. 2097397 as one
of a group of aminocyclopentane derivatives ~aving endoperoxide and
thromboxane antagonist activity, and it is reported therein that such
compounds are of interest in the treatment of asthma and
cardiovssdular diaeases. More recently, we discovered thst the
hydrochloride salt of Compound A has edvantages over Compound A and
other sfllts and solvates thereof both in its preparation and iQ its
use in medicine. The hydrochloride salt is described in our British
Patent No. 2127406.
Compound A ia ùnfortunately only sparingly soluble in water and
formulations in water contsining the hydrochloride salt of Compound A
together with standard ex¢ipients and/or carriers have proved to be
unacceptable for intravenous ~dministrstion a8 the hydrochloride salt
of Compound A is converted to the virtually insoluble Compound A at
near to physiological pH.
Wo have now found that the aolubility in water of Compound A or
its hydrochloride salt st around physiologicsl pH is significantly
improved in the pr~sence of an unsubstituted or substituted a~ or
r-cyclodextrin (or a hydrate thereof). We have also found that
aqusous formulations comprising Compound A or the hydrochloride salt
thereof and an unsubstituted or substituted a-, ~- or y-cyclodextrin
(or Q hydrate thereof) are suitable for use in medicine, more
particularly for use in the treatment or prophylaxis of conditions
mediated by thromboxsne A2, when administered either orally, by
inhalstion or parenterally, in particular by injection (eg
intravenously).
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1 328078
Thu~, according to one aspect of the present invention, we
provide an aqueou~ formuletion comprising Compound A or the
hydrochloride sslt thereof with an unsubstituted or substituted -,
~-, or y-cyclodextrin (or a hydrate thereo~).
In another aspect of the invention, we provide an aqueous
formulation as definod herein for u~e in medicine, more particularly
for use in the treatment or prophylaxis of conditiona mediated by
thromboxane A2.
According to anothsr aspect of the invention, we provide a method
of tresting conditions mediated by thromboxane A2 which method
comprise administering to the human or animal patient an effective
amount of Compound A in an aqueous formulstion as defined herein.
Suitable conditions which msy be treated with aqueous
formulations of the present invention include those conditions
described in British Patents Nos. 2097397 and 2127406~treated using
other (e.g. orel) formulation~ of Compound A and the hydrochloride
salt of Compound A respectively. In particular, the aqueous
formulations of the present invention may be used in the treatment or
prophylaxis of occlusive vascular disease, including myocardial
infarction, ¢ardiac fatalities, unstsble angina, transient i~chaemic
attacks and cerebrsl infarction, atherosclerosis and vessel w811
disease, peripheral vascular disease, retinopathy, postoperative
thrombosis and pulmonary embolism. The aqueous formulations msy also
be us0d in the prophylaxis of peri- and postoperative complications
following organ transplantation ~pQrticularly cardiac and renal),
coronary artery bypass, peripheral artery bypass and thrombolysis.
The aqueous formulations are also of potential use in connection with
peptic ulcei disease, more particularly for the prevention of relapse
of healed peptic ulcers.
32807~
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Preferably, in the aqueous formulat~ons of the present
invention Compound A i9 used as its hydrochloride salt.
It will be appreciated by those skilled in the art that the
benefits of the present invention may be achieved by utilising more
th~n one cyclodextrin, ~lthough the use of a single cyclodextrin i8
generally preferred.
Where a substituted cyclodextrin is employed any suitable
substituted cyclodextrin known in the art may be used according to the
present invention. Suitable substituted cyclodextrins for use
lo a~cording to the present invention will be resdily appreciated by
peraons skilled in the art and will include sulphur-containing
cyclodextrins, nitrogen-containing cyclodextrins, alkylQted (e.g.
methylated) cyclodextrins such as mono-, di- or trimethylated
derivatives o~ a cyclodextrin (e.g. of ~q-cyclodextrin) and
hydroxyalkyl (e.g. hydroxypropyl) cyclode~trins such as hydroxypropyl
,B-cyclodextrin and acylated derivatives thereof. Hydroxyalkyl (e.g.
hydroxypropyl) cyclodextrins such 88 hydroxypropyl ~cyclodextrin hsve
been found to be psrticulsrly suitable for use according to the
present invention.
Conveniently a single unsubstituted cyclodextrin i~ employed
according to the present invention. Psrticulsrly preferred is
,B-cyslodextrin, conveniently used in its hydrsted form.
In order for the squeous formulation to exhibit the desired
properties it is important that the correct molar ratio of Compound A
or its hydrochloride salt to the cyclodextrin(s) is used. We have
found a molar r~tio of Compound A or its hydrochloride salt to the
cyclodextrin(s) within the range 1:1 to 1:4 to be suitable.
It wili be spprecisted by persons skilled in the art that the
squeoua formulstions of the pr~sent invention may, if desired, Qlso
contsin one or more phsrmaceut~ical carIiers or excipients.
Suitable excipients which may be incorporated into the aqueous
formulation include agents to make the preparation isotonic with blood
plasma (e.g. ~odium chloride, dextrose or prefersbly mannitol) and
buffering agents (e.g. phosphQte buffer or a mixture of sodium acid
phosphate and disodium phosphate).
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1 328078
The aqueou~ formulQtions of the present invention are
particularly suitable for parenteral adminiatration in particular by
injection (eg intravenously). When presented for parenteral
admini~tration it is desir~ble that the formulation is at about
physiological pH. It may therefore be appropriate to adjust the pH to
about physiological pH using conventional means, for example using a
suitsble bsse such as a hydroxide (e.g. an alkali metal hydroxide such
as sodium hydroxide ~olution). Conveniently, the pH is edjusted to
about pH 6Ø
For parenteral administration, in particular for administration
by in~ection ~eg intravenously), it is highly desirable for the
formulation to be presented as a cle~r solution. A clear solution
requires no further processing (e.g. constitution of a dry powder)
and may be administer~d without delay. The use of a clear ~olution
al~o enaures that the product C8~ be easily inspected for particulate
or other visible contamination. Furthermore, intravenous in~ection of
an aqueous solution of a drug can produce an immediate physiological
action. We have found that at least one mole of the cyclodextrin must
be used for every one mole of the hydrochloride of Compound A in order
to obtsin a clear solution at near to physiological pH at normal
etorage temperatures, and in th0 case of ~-cyclodextrin at least about
1.2 moles must be used.
In a preferred embodiment of the present invention, therefore, we
provide a clear aqueous formulation comprising the hydrochloride salt
of Compound A and ~-cyclodextrin ~or a hydrate thereof), at about
physiological pH wherein the formulation contains at least about 1.2
moles of ~-cyclodextrin (e.g. 1.2 to 2 moles) for every one mole of
the hydrochloride aalt of Ccmpound A. Preferably the molar ratio will
be about 1:1.4. -
The concentration of Compound A or the hydrochloride salt thereof
in the aforementioned aqueous formulations suitable for parenteral
administration, in perticular for administration by in~ection (eg
intravenously), is conveniently within the range 0.1-lOmg/ml, e.g.
û.l-5mgtml, expressed as the free baae. Preferably, the concentration
is lmgtml expressed a8 the free baae when the aqueous formulation is
edministered by intravenous in~ection. If desired, a higher
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concentration may be used and the solution may be diluted prior to use
with, for example, an isotonic aline solution or dextrose or mannitol
solution. Conveniently, solution~ suitable for injection are
presented in an appropriate dose volume (eg 1 - 100 ml). Dilutions
suitable for continuou~ infusion may have a concentration of Compound
A or its hydrochloride ~alt of 0.01 - 0.2mg/ml expressed ~ the free
base. The ~olution for continuous infusion may be pre~ented in thi~
~orm, for example in packs of 50-lOOml, or may be presented in more
concentrated forms for subsequent dilution before use with, for
example, an isotonic saline solution or dextrose or manniltol
solution. Altern~tively, smsll volumes of ~ more concen~rated
solution (eg û.l - 5 mg/ml) may be utilised for continuo~s infusion
conveniently administered at a rats of 0.5 to 9.9ml/h.
The aqueous formulationa described herein may conveniently be
lS prepared by mixing Compound A or, more preferably, its hydrochloride
salt with the remeining constituents in water. Prefersbly, Compound A
or its hydrochloride salt sre dissolved in water and the remaining
constituents are added thereto. For parenteral administration, in
particular by in~ection (eg intravenously), the bulk solution is
preferably filtered, then filled into suitable containers and
terminally sterilised, for example by heating. Alternatively, the
solution may be sterilised by filtration and then aseptically filled
into ~uitable containers.
It will b~ appreciated th~t water suitable for in~oction will be
used when the p~renteral formulation is to be administered
intravenoualy or by continuous infusion.
Formulations for in~ection may be presented in unit dose form in
suitable containers such aa ampoules, vials or pre-filled syringes, or
in multi-dose containers with an added prsservative.
As stated hereinbefore, the aqueoua formulations of the present
invention are also suitable for oral administrstion teg a8 a capsule,
syrup or aolution) or for sdmihiatration by inhalation (eg as an
aerosol sproy conveniently presented as a nebuliser). British Patent
Nos. 2097397 and 2127406 provide suitable general methods for the
preparation of oral and inhQlation formulations which may be readily
adapted without undua experimentation for present purposes.
Aqueous formulations may also be prepared by dissolving 8 solid
cyclodextrin complex of Compound A or its hydrochloride salt in water
together, where de~irable, with one or more other constituents as
defined sbove.
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1 328078
Thus, in a further aspect of the present invention, we provide an
aqueous formulation comprî~ing ~ complex of Compound A or the
hydrochloride ~alt thereof and a cyclodextrin.
In another aspect of the invention, we provide a complex of
Compound A or its hydrochloride salt and a cyclodextrin. The ratio of
Compound A or the hydrochloride salt of Compound A with the
cyclodextrin in the said complex will, of course, vary considerably
depending on the cyclodextrin used and the conditions employed for
preparing the complex. However, we have found a molar ratio of
Compound A or its hydrochloride salt with the cyclodsxtrin within the
range 1:1 to 1:3 to be suitable.
The cyclodextrin employed in the solid complex may be
unsubstituted or substituted a-, ~- or r-cyclodextrin as defined
previously or may be a mixture of such cyclodextrins (e.g a mixture of
two such cyclodextrins). Preferably r-cyclodextrin or, more
preferably, ~-cyclodextrin i8 employed.
In a psrticular sspect of the present invention we provide e
complex of Compound A and ~-cyclodextrin in which the molsr ratio of
Compound A to ~-cyclodextrin i8 within the range 1:1 to 1:2, snd is
preferably about 121-
In another perticùlar aspect of the present invention we provide
a complex of Compound A and ~-cyclodrextrin in which the molar ratio
of Compound A to ~-cyclodaxtrin is about 1:1.5.
Complexes of Compound A or the hydrochloride sslt thereof and
cyclodextrin may be prepared by mixing Compound A or its hydrochloride
salt with the cyclodextrin(s) or 8 hydrate thereof in a suitable
solvent under conditions whereby the desired complex is formed. Thus,
for exsmple; the oomplexes may be prepared by dissolving Compound A or
it hydrochloride salt in water or an orgsnic solvent which is miscible
with water (e.g. an alcohol such as methanol) and adding to the
solution a solution of the appropriste cyclodextrin(s) or a hydrste
thereof in water and/or an organic solvent which i8 miscible with
water, The reaction may be effected at a temperature in the range of
0 to 80C; however the mixture is prefersbly kept st around room
temperature and the desired complex obtained by concentrating the
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l 328078
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mixture under reduced pressure or by allowing the mixture to cool.
The mixing ratio of organic solvent with water may vary considerably
according to the solubilities of the starting materials and products.
Preferably 1 to 4 moles of cyclodextrin are used for each mole of
Compound A or its hydrochloric salt.
The resulting complexes msy be obtained a~ white solid with high
thermsl atability and good water solubility. Such physical
characteristics make them particularly suitable for formulation into
pharmaceutic~l p~epar~tions for medical use. In addition to the
aforementioned a~ueou~ formulations of complexes of Compound A or its
hydrochloride sslt and cyclodextrin suitable particularly for
parenteral sdmin~stration, the complexea may also be formulated for
oral or parentersl administration or for administration by inhalation
according to the genersl methods described in British Patent Nos.
2D97397 and 2127406.
An appropriate daily dose regime for Compound A or its
hydrochloride ~alt when employed in one of the formulations of the
present invention will, of course, depend on the specific condition to
be treated, the age and condition of the patient and the route of
administration. However, generally the dosages quoted in British
Patent Nos. 2097397 and 2127406 will be suitable.
The following examples aro included by way of illu~trating the
present invention and should not be construed as a limitation of the
invention. In the following examples the molar ratioa were determined
by 'H N.M.R. ~nalysis ~nd all temperatures are in C.
Example 1
(a) ~lR-~la(Z),23.3B~5a]]-(+)-7-~5-[[(1,1~-Biphenvl)-4-vl]methoxy~-3-
hYdroxv-2~ piPeridinvl)cvclopentvl]-4-heptenoate: ~-cyclodextrin
(1:1) complex
~ -Cyclodextrin hydrate (0.9~49) was nearly completely dissolved
in water (3~ml). The suspension was filtered and the ~iltrate added
to a solution of Compound A (0.29, Example 10 in GB-B-2097397) in
methanol (lOml). The reaction solution was stirred at 21 for 26h to
give a clear solution which was evaporated to a volume of 12ml when
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1 328078
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~light crystallisation beg~n to occur. The suspension was cooled to
5 for lh to produce a thick precipitate which w~ filtered off and
dried to give the title compound (0.2739), m.p. >310, derkens above
230.
(b) The filtr~te from the above experiment began to precipitate more
crystslline m~terial on standing and was thereforè evaporsted to lesve
8 white solid which wa~ dissolved in hot water (3ml), cooled (5) and
sllowed to crystallise to give a white crystslline ~olid (121mg) shown
by lH N.M.R. ~DMS0) snalysis to contain tlR-[la(Z).2~,3~,5a]]-(+)-7-
t5-~ -biPhenvl)-4-vl]methoxv]-3-hvdroxy-2-(l-piperidinyl)
cvclopentvl]-4-heptenoste : ~-cvclodextrin (1:1.5) complex.
Example 2
[lR-[la(Z),2~,33.5]]-(l)-7-~5-t~(l,l'-BiPhenyl)-4-vl]methoxv]-3-
hvdroxv-2-(l-Piperidinyl)cvclopentyl]-4 heptenoete: ~-cvclodextrin
(1:1.5) comPle-x
A solution of r-cyclodextrin (1.099) in wster (25ml) wss sdded to
8 solution of Compour,d A (0.209) in methsnol (lO,ml). The resction
solution wss stirred at 21 for 26h to produca ~ thick white
suepension. The precipitste wss filtered off and dried in vscuo to
lesve the title compound 8a a white solid (0.6129), m.p. >310,
dsrkens sbove 250.
.
PhsrmsceuticRl ex~mPles of parenteral in~ections/infusions
(i) Hydrochloride sslt of Compound A
equivslent to 50 mg bsse
B-Cyclodextrin hydrste 143mg 166mg 238mg
Sodium hydroxide solution to pH7 to pH7 to pH7
Wster suitable for in~ection to 50ml to 50ml to 50ml
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328~78 ~ :~
g
The hydrochloride salt sf Compound A was dissolved in 35ml water
~uitable for injection and the ~-cyclodextrin waa added. This ---
~olution wa~ titrated to pH7 with 0.02M eodium hydroxide solution and
then adjusted to volume with water suitable for injection. -
The solution may then be sterilised by filtration and filled into - j
vials or empoules.
(ii) Hydrochloride salt of Compound A
equivalent to 50mg base
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~-Cyclodextrin hydrate 166mg
Sodium chloride 450mg
pH7.0 phosphate buffer 2.5ml
Sodium hydroxide solution to pH7
W~ter suitable for inJection to 50ml
The hydrochloride salt of Compound A wss dissolved in approximately
25ml water suitsble for in~ection. The ~-cyclodextrin was dissolved
ther~in and the resulting solution was titrated to pH6 with 0.02M
sodium hydroxide solution snd the phosphate buffer sdded. The sodium
chloride wss added to the solution snd the pH ad~usted to pH7 with
sodium hydroxide. The solution was msde up to volume with water
suitable for in~ection. A ssmple of this solution was filled into a
glass vial which wss sealed with a rubber plug snd metal overseal.
This wss then autoclaved.
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1 328078
-- 10
Hydrochloride salt of Compound A
equivalent to 50 mg base
Hydroxypropyl-~-cyclodsxtrin 170mg
Mannitol 2.59
pH 6.0 phosphate buffer 5.0ml
Sodium hydroxide solution to pH 6
Water suitable for in~ection to 50ml
;The hydrochloride salt of Compound A was dissolved in
spproximately 25ml weter suitable for in~ection and the
hydroxypropyl-~-cyclodextrin was added. The msnnitol wss then added
and the solution titrated to pH 6 with 0.02M aodium hydroxide
solution. The phosphate buf,fer solution wes edded and the solution
ad~usted to volume with water suitable for in~ection. The solution
wes then filtered and filled into glass vials which were sealed with
rubber plugs and metal overseals. These were then autoclaved.
(iv) Hydrochloride salt of Compound A
equivalent to 50mg base
~-Cyclodextrin hydrste 166mg
Mennitol 2.59
Sodium acid phosphate ` 46mg
Disodium phosphate, anhydrous 5mg
Sodium hydroxide solution to pH 6
Water suitable for injection to 50n1
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- 11 1 328078
The hydrochloride salt of Compound A w~s dissolved in
spproximately 25ml water suitable for injection. The ~-cyclodextrin
snd mannitol were dissolved therein and the solution titrated to pH 6
with 0.02M ~odium hydroxide solution. The sodium acid phosphate and
~nhydrous disodium phosphate were dissolved in water suitsble for
injection. This solution was added to the bulk solution which was
msde up to volume with water suitsble for injection. The solution wa~
filtered and filled into 91888 ampoules which were sealed and then
~utoclaved.
(v) Cvclodextrin
Mixture
a ~ ~ + r
.:
Hydrochloride sslt of Compound A
equivalent to 5ûmg bsse
Cyclodextrin 143mg 190mg ll9mg 136mg
Msnnitol 2.59 2.59 2.59
pH 6.0 Phosphste buffer 5.0ml 5.0ml 5.0ml
Sodium hydroxide solution to pH 6 to pH 6 to pH6
Water suitsble for injection to 50ml to 5û ml to 50ml
' '
The hydrochloride sslt of Compound A was dissolved in
spproximately 25ml wster suitable for injection snd the
cyclodextrin(s) W~8 (were) edded. The mannitol wss then sdded snd the
solution titrsted to pH 6 with 0.02M sodium hydroxide solution. The
phosphate buffer 301ution was added and the solution was sdjusted to
volume with wster suit~ble for in~ection. The solution wss then
filtered and filled into gla~s visls which were sesled with rubber
plugs snd metal oversesls.
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1 328078
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Pharmaceutical example of oral syrup
Hydrochloride ~alt of Compound A
equiv~lent to 2.5mg base
~-cyclodextrin hydrate 9mg
Citric acid to pH 4.5
lo Methyl hydroxybenzoQte sodium 5mg
Propyl hydroxybenzoate sodium 2mg
Liquid orange flsvour qs
Sucroae 3.259
Purifie,d water to 5.0ml
Dissolve the sucrose in a minimum quantity of water. Add the
hydrochloride aalt of Compound A and then the ~-cyclodextrin with
stirring; ad~ust the pH to 4.5 with citric acid. With continued
atirring add a solution of the hydroxybenzoates and lsstly the
flavour. Ad~u~t almost to volume with weter and stir. Check the pH
and ad~ust to 4.5 with citric acid if nece~ssry. Meke up to volume
with water.
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1 328078
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Pharmaceutical example of solution for inhalation
Per 2ml doQe
Hydrochloride salt of Compound A
equivslent to 2mg bace
~-cyclodextrin hydrate 7mg
Sodium chloride 18mg
10 Sodium hydroxide solution to pH 7.2
pH 7.2 phosphste buffer 0.2ml
:
Wster suitable for injection to 2ml
Dissolve the hydrochloride salt of Compound A in water ~uitsble
for in~e¢tion. Dissolve the ~-cyclodextrin therein and titrate the
resulting solution to pH6 with sodium hydroxide solution; add the
phoaphate buffer solution. Add the sodium chloride end sd~ust to
Z0 pH7.2 with sodlum hydroxide solution. Make the solution up to volume
with water suitable for in~ection and sterilize the solution by
~iltration. F111 assptically into containers suitable ~or inhalation
by nebulising.
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