SOLUTIONS STABLES D'ALCALOIDES D'ERGOT HYDROGENES

STABLE SOLUTIONS OF HYDROGENATED ERGOT ALKALOIDS

Abrégé anglais

Abstract of the Disclosure
Stable solutions of a) hydrogenated ergot alkaloids
and b) haparin as well as the salts thereof in a carrier
medium comprising c) water, d) a mono- or poly-alcohol,
e) an acetanilide anaesthetic or salt thereof and f) urea
and/or mono-calcium-bis-sodium ethylenediaminetetraacetic
acid.

Revendications

Case 118-5292
THE EMBODIMENTS OF THE INVENTION IN WHICH AN
EXCLUSIVE PRIVILEGE OR PROPERTY IS CLAIMED ARE
DEFINED AS FOLLOWS:
1. A pharmaceutical composition in stable solution
form comprising as active ingredient a comination of
a) a compound of formula I,
<IMG> I
wherein R is hydrogen or C1-4alkyl,
R1 is methyl, ethyl or isopropyl,
R2 is isopropyl, sec.-butyl, isobutyl or
benzyl, and
X is hydrogen or methoxy,
or a pharmaceutically acceptable acid addition salt thereof;
and
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b) heparin or a pharmaceutically acceptable salt thereof,
and a carrier medium comprising
c) water;
d) a pharmaceutically acceptable mono- or poly-alcohol;
e) an acetanilide anaesthetic or a pharmaceutically
acceptable acid addition salt thereof; and
f) urea and/or mono-calcium-bis-sodium ethylenediamine-
tetraacetic acid.
2. Composition according to Claim 1, having a pH of
from 4 to 6.
3. Composition according to Claim 1, wherein the
compound of formula I is dihydroergotamine.
4. Composition according to Claim 1, wherein the
compound of formula I is dihydroergovaline.
5. Composition according to Claim 1, wherein the
compound of formula I is dihydroergotamine or dihydro-
ergovaline and is in the form of the methane sulphonate.
6. Composition according to Claim 1, wherein the
compound of formula I is 6-nor-6-isopropyl-9,10-dihydro-
2'.beta.-methyl-5'.alpha.-benzyl-ergopeptine.
7. Composition according to Claim 6, wherein the
compound of formula I is in the form of the maleate.
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118-5292
8. Composition according to any one of Clalms
1, 3 or 5, wherein the heparin is in the form of the
sodium salt.
9. Composition according to any one of Claims
1, 3 or 5, wherein the compound of formula I and heparin
are present in a ratio of lmg:500 to 70,000 I.U.
10. Composition according to any one of Claims
1, 3 or 5, wherein the compound of formula I and heparin
are present in a ratio of lmg:2,0o0 to 20,000 I.U.
11. Composition according to any one of Claims
1, 3 or 5, wherein component c) is present in an amount of
from 45 to 72% based on the total volume of the compos-
ition.
12. Composition according to any one of Claims
1, 3 or 5, wherein component d) is present in an amount
of from 28 to 55% based on the total volume of the com-
position.
13. Composition according to any one of Claims
1, 3 or 5, wherein component d) is selected from the group
consisting of ethanol, propylene glycol, polyethylene
glycol of average mol. wt. ca. 400, diethyleneglycol,
glycerol and mixtures thereof.
14. Composition according to Claim 1, wherein
component d) comprises either (i) ethanol and (ii) tri-
ethylene glycol or (iii) glycerol and (iv) propylene glycol.
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15. Composition according to Claim 14 wherein (i)
and (ii) are present in a ratio of from 1:6 to 10 parts by
weight or (iii) and (iv) are present in a ratio of from
1:8 to 12 parts by weight.
16. Composition according to Claim 15 wherein (i)
and (ii) are present in a ratio of from 1:8 parts by
weight or (iii) and (iv) are present in a ratio of from
1:10 parts by weight.
17. Composition according to any one of Claims 1, 3
or 5 wherein the acetanilide anaesthetic is selected from
the group consisting of 2-(diethylamlno)-N-(2,6-dimethyl-
phenyl)-acetamide, 2-(butylamino)-N-(2-chloro-6-methyl-
phenyl0-acetamide and 2-(2-diethylaminoacetamido)-m-toluic
acid methyl ester.
18. Composition according to any one of Claims 1, 3
or 5 wherein the acetanilide anaesthetic is present in an
amount of from 1 to 2% based on the total weight of the
composition.
19. Composition according to any one of Claims 1, 3
or 5 wherein component f) is present in an amount of 2 to
5 mg based on an amount of 5,000 I,U. to 2,500 I.U.
heparin.
20. Composition according to any one of Claims 1, 3
or 5 in unit dosage form.
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21. Composition according to any one of Claims 1, 3
or 5, in ampoule form for injection and containing 0.5 mg
of compound of formula I and/or 2,500 or 5,000 I.U.
heparin.
22. Process for the preparation of a pharmaceutical
composition according to any one of Claims 1, 3 or 5 which
process comprises bringing an active ingredient a) and an
active ingredient b) into solution in a carrier medium
comprising components c), d), e) and f).
23. Process for the preparation of a pharmaceutical
composition according to any one of Claims 1, 3 or 5,
which process comprises the individual steps of
1) preparing a solution of an active ingredient a) in a
solvent medium comprising components d) and e);
2) preparing a solution of an active ingredient b) in a
solvent medium comprising components c) and f);
3) combining the solutions obtained via steps 1) and 2);
and
4) when required adding component c) and/or d).
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Description

Case 118- 52 9 2
STABLE SOLUTIONS OF HYDROGENATED.ERGOTALKALOIDS
-
The present invention relates to pharmaceutical
compositions in the ~orm of stable solutions and com-
prising as active ingredients a combination of
5 a) a compound of formula I,
Il~
X ~ ~ O
R ~ }~2
HN.
wherein R is hydrogen or Cl_4alkyl,
Rl is methyl, ethyl or isopropyl,
R2 is isopropyl, sec.-butyl, isobutyl or
benzyl, and
X is hydrogen or methoxy,
or a pharmaceutically acceptable aci~ addition salt
thereof;
and
: ~''

-~ 2
118-52g2
b) heparin or a pharmaceutically acceptable salt thereof.
Previous attempts to prepare pharmaceutical
compositions in solution form comprising mixtures of
active ingredients a) and b) as afforesaid (for example
of dihydroergotamine and dihydroexgovaline or their
salts, e.g. the methane sulfonate, or of 6-nor-6-iso-
propyl-9,10-dihydro-2'~-methyl-5'a-benzyl-ergopeptine
or its salts, e.g. the maleate, and of heparin or its
salts, e.g. the sodium salt) have not met with success.
First the individual ingredients are themselves unstable
in solution. Secondly when combined in solution,
the ingredients a) and b) react to form difficultly
soluble salts which precipitate out of the solution.
The obtained solutions accordingly possess very low
stability. They cannot be kept in reserve fox
periods of more than a few hours and are thus of
little practical value.

~ 3 _ ~5~2
100-5292
Various proposals have been made to surmount this
problem. Thus it has been suggested to use e.g. the
methane sulfonate salt of dihydroergotamine in the form of a
soll~ solution employing polyvinyl-pyrrolidone. Salk formation
5 can be delayed in this manner, but only for a relatively
limited period of time. More recently lyophilised pre-
parations have been developed for use in the preparation
of injectable solutions.
As an alternative, individually stabilized solu-
tions comprising components a) and b) separately, have
been developed. The individually stabilized solutions
are then brought into admixture shortly before admini-
stration.
Clearly none of these proposals provides a satis~
factorv,practical answer to the problem. The develop-
ment of stabilized solution forms comprising ingredients
- a~ and b) in combination, having a prolonged shelf-life,
capable of tran~port and storage and ready for use as
and when required has remained a major objective.
In accordance with the present invention it has
now surprisingly been found that the a~ove problems may
be overcome and clear solutions of components a) and b)
in combination obtained, whlch are stable over prolonaed
periods of time, e.g. for two years and more, employing
a carrier medium comprising

~16S~
c) water;
d) a pharmaceutically accepta~le mono- or poly alcohol;
e~ an acetanilide anaesthetic or a pharmaceutically
acceptable acid addition salt thereof; and
f) urea and/or mono-calcium-bis-sodium ethylene-
diaminetetraacetic acid.
Accordingly the pesent invention provides, in a first
aspect a pharmaceutical composition in stable solution
form comprising as a¢tive ingredients a ~ombination of a
¢omponent a) and a component b) as hereinbefore defined
and a carrier medium comprising components c), d~, e~ and
f) as hereinbef~ore defined.
Preferably the comp~sitions according to the inven~ion
have a pH of from 4 to 6
Suitable pharmaceutically acceptable acid addition
salt forms of the compounds of Formula I, inclu~e e.g.
the methane sulfonates, maleates and tartratesO Suitable
pharmaceu~ically accep~able salts o~ heparin in~lude e.g.
the sodium, pQtaSSiUm and calcium salt.
Pre~erred ingredients a3 are dihydroergotamine o~ a
pharm~ceutically ac~eptable acid addition salts thereof,
in particular the methane sulfonate/ dihydroergovaline or
a pharmaceutically accep~able acid addition salt thereo~,
in particular the methane sulfonate and 6-nor-6-1sopropyl-
. ~ ?3

100-5292
5 9,10-dihydro-2'~-methyl-5'a-benzyl-ergotpeptine and the
pharmaceutically acceptable acid addition salts thereof,
in particular the maleate. When b) is present in pharma-
ceutically acceptable salt form this is preferably the
sodium salt.
The ingredients a) and b~ are preferably present
in a ratio of 1 mg compound of formula I: 500 to 70,000
I.U., more preferably 2,000 to 20,000 I~U. hepaxin.
When ingredient a) and/or b) is present in pharmaceuci-
cally acceptable salt form the equivalent amount of
15 salt form giving the stated ratios for the free compound
is employed.
Components c) and d~ are preferably present in an
amount of 45 to 72~ and 28 to 55~ respectively based on
20 the total volume o the composition.
Preferred components d) are ethanol, propylene gly-
col; polyethylene glycol having an average molecular
weight of 400, diethylene glycol and glycerol, as well as
mixtures thereo. More preferably component d~ comprises
25 a mixture o ~i) ethanol and (ii) triethylene glycol or
o (iii) glycerol and (iv) propylene glycol. In such mix-
tures (i) and (ii) are preferably present in a ratlo of
from 1 : 6 to 10, more preferably 1 : 8 parts by ~Jeight
and (iii) and (iv) are preferably present in a ratio of
30 rom 1 : 8 to 12, more preferably 1 : }0 parts by weight.

. 100~529~
By the term "acetanilide anaesthetic" as used in
respect sf component e) is meant any member of the class
of physiologically acceptable acetanilide derivatives
having anaesthetic activityJincluding-the various known
5 anaesthetically active 2-amino~N-phenyl acetanilide deri
va.ives. Pre~erred acetanilide anaesthetics are 2-(di-
ethylamino)-N-(2,6-dimethyl-phenyl)-acetami~e (also
known as ~idocaine),2-(butylamino)-N-~2-chloro-6-methyl-
phenyl)-acetamide (also known as Hostacain) and 2-(2-di-
10 ethvlaminoacetamido)-m--toluic acid methyl ester (also
~g) . .
known as Baycain). Apart from their clearly advantageous
anaesthetic ~ro~erties e.a. when the compositions are ad-
ministered by injection, it has surprisingly been found
that the presence of ingredient e) is essential in con-
15 tributing to the long-tenm stability ~roperties of the
inventive com~ositions.
Preferably ingredient ej is present in an amount
o 1 to 2% by ~elght based on the total weight of the
composition. Ingred1ent r~ is prefe~ably present in an
20 amount of 2 to 5 mg based ~n an amount o 5,000 I.U. to
2,500 I.U. heparin.
The compositions according to the invention may
contain further additives, e.g. stabilizing agents, pre-
25 serving agents, colvuring ager.ts and suracta~ts, as

100-5~92
known in the art. Suitable preserving agents include e.g.
chlorocresol or trichloro-tert.-butanol, suitably present
in an amount of from 0.2 to 1% based on the total weight
of the composition.
The compositions of the invention axe suitabl~ put
up in unit dosage form, e.g. in the form of ampoules for
injection, including e.g. throw-away syringes containing
a predetermined amo~mt of the composition. Such unit
dosage forms preferably contain 0~5 mg of the compound of
10 formula I and/or 2,500 or 5,000 I.U. heparin per unit
dosage.
In addition to the foregoing the present invention
also provides a process for the preparation of pharmaceu-
tical compositions in accordance with the invention,
15 which process comprises bringing an active ingredient a)
and an active ingredient b) as hereinbefore defined into
solution in a carrier medium comprising components c), d),
e) and f) as hereinbefore defined.
Preferably the process is carried out step-wise
20 in a procedure comprising
1) preparing a solution of an active ingredient a) in a
solvent medium comprising components d) and e);
2) preparing a solution of an active ingredient b) in a
solvent medium comprising components c) and f);
25 3) co~bining the solutions obtained via steps 1) and 2)

- - J
-- 8 --
lO0-529
and
4) optionally adding additional component c~ and/or d~.
The process of the invention is preferably carried
out with protective gassing, e.g. CO2-gassing, of the so-
lutions. If the pH of the obtained solution is outsidethe range pH 4 to 6 r it is preferably adjusted to within
this range e.g. by the addition of an appropriate quan-
tity of a pharmaceutically acceptable acid e.g. an or~anic
acid. When an acid addition salt of a compound of formula
lO I is employed as ingredient a), the added acid will pre-
ferably correspond to the salt form employed. Thus when
ingredient a) is in methane sulfonate salt form, any ad-
justment of the pH necessary will preferably be effected
by addition of methane sulphonic acid.
The obtained composition may be put-up in unit
~osage form as hereinbefore described, e.g. by filling
into ampoules after filtration, preerably with protecti.ve,
e.g. CO2, gassin~.
The solutions according to the invention may be
20 used ror therapeu~ic treatment or prophylaxis as known
in the art; for example as anti-thrombolic agents parti-
cularly in the prophylaxis o post-operati~e thrombosis
as described in e.g. U.K. Patent Specification No.
l,557,331 (- MZ Patent Specification No. 182797).
The following examples are illustrative of the
present inventioll:

-
- 9 -
Preparation of a 5~000 I.U. heParin / O.S mg
ution:
1~ 18.4 kg o propylene glycol and 1.84 kg o~ anhydrous
glycerol are poured into a 50 litre stirring vessel,
and the mixture stirred for 10 minutes with C02
gassingO 0.0286 kg of dihydroergotamine methane
sulphonate and 0.426 kg of lidocain hydrochloride are
dissolved in the mixture with stirring and CO~-
gassing over a period of a further 30 minutes.
2) 18.4 kg of water (suitable for injec~ion) are poured
into a 30 litre stirring ves~el and stirred for 10
minutes with CO2-gassing. 1.896 kg of heparin
sodium salt (= circa 285.7 million IoU~) and 0.114 kg
of mono-calcium-bis-sodium EDTA hexahydrate (commer-
cially available under the name CALCXUM TITRIPLEX ~ )
and then dissolved in the water with stirring and
CO2-passing over a further 30 minutes.
3) The solution obtained via step 2) above is added with
stirring and CO2-gassing to the solution obtained
via step 1~. The vessel in which solution 2) is
obtained is then washed out with 1 kg of water (suit-
able for injection) and is also added to the step 1)
solution. The combined solutions are stirred for a
further 10

-- 10 -
100-52~2
minutes with CO2 gassing. The pH of the solution is ca.
5.7.
4) The solution is made up to a weight of 42.810 kg
(= 40 litres) by t~e addition o-water (suitab~ ~or in-
jection).
5) The obtained solution is pre-filtered using a membrane-
filter (0.2 ~m: Ultipor nm. Pall) and then passed via
a sterilized pressure-filtration apparatus having a
membrane filter (0.2 ~m: Ultipor nm. Pall) at 1.7 bar
with CO2 directly into an ampoule-filling machine. The
solution is filled in 0.7 ml ~osages into 1 ml ampoules
under sterile conditions.
Example II
Steps 1) - 4) of example I are repeated precisely
15 using the following quantities of ingredients:
Step 1) Propylene glycol 15.30 kg
Anhydrous glycerol l.S3 kg
Dihydroergotamine-
methane sulphonate 0.03 kg
Lidocain - HCl-H2O 0.32 kg
Step 2) Water (for injection) 12.00 kg
Heparin-Na salt 0.997 kg (- 150 ,
million I,~.)
Ethylenediamine-
tetraacetic acid-Ca salt
(hexahydrate) 0.12 kg
,

100-52g2
Step 3) No change
Step 4) The solution is made up to a weight OL 32.040 ~g
(;. 3~ litres) by the addition of-water (for injec-
~ion).
Step 5) The resultant solution is filled into 1 ml
ampou].es in 0.~ ml dosages.
Example III
. .
i) The method of example I is repeated using an equi-
valent quantity of a 1 : 10 (parts by weight) mix-
ture of ethanol and triethylene glycol in place of
pro~lene glycol and glycerol in step 1).
ii) The method of example I is-repeated usin~ an equi-
valent quantity of hostacain in place of liclocain
,.. .
in step 2).
5 iii) The method of example I is repeated using an equi-
valent quantity of ~.aycain in place of lidocain in
step 2).
: