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Патент USA US3079420

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IE
3,079,410
Patented Feb. 26, 1963
2
droxyalkylamines and analogous diamines or polyarnines
3,079,410
such as hexamethylene tetramine. In the case of the
cationic steroid esters, there may be used for the formation
PRQCESS FUR STABlLlZiNG ANEUNIC AND CATE
GNlC ESTER SALTS 0F Zl-l-i‘i’DRtiXY-Zddil??
STERGEDS EN AN AQUEGUS SQL‘UTEGN
of salts for example hydrohalic acids such as hydrochloric
heirn, Tar-nuns, Heirnut Scherer, Bad Sudan, Taunus, and
acid, hydrobromic acid, sulfuric acid, phosphoric acid,
low molecular aliphatic carboxylic acids, acylated amino
Walter Kenipe, Frankfurt am Main, Germany, assign
acids, dicarboxylic acids or hydroxycarboxylic acids and
ors to Farbwerlre Hoechst Alrtieugeseiischaft vornials
hydroxydicarboxylic acids.
Werner Eritsch, Neuen‘iiain, Taunus, Werner Hacde, Hot‘
Meister Lucius & Briining, Frankfurt am Main, Ger
The following examples serve to illustrate the inven
many, a corporation of Germany
10 tion, but they are not intended to limit it thereto.
No Drawing. Filed Mar. 23, 1%}, Ser. No. 93,761
Ciaims priority, application Germany Apr. 2, 1959
Example 1
3 Claims. (Ci. 269~3§7.45}
2 g. of prednisolone-sodium succinate are dissolved in
40 cc. of water and the solution is adjusted to a pH value
‘ The present invention relates to a process- for stabilizing
anionic and cationic ester salts of 2l-hydroxy-20~keto
15 of 6.4, while stirring, under nitrogen and adding 20 mg.
steroids in an aqueous solution.
of prednisolone-hemisuccinate. After ?ltration, 10 g. of
sarcosine anhydride are added to the solution which is
then ?ltered again.
can be esteri?ed with acids containing, in addition to the
Example 2
carboxyl vgroup, another group capable of forming a salt.
The salts thus formed, for example, of succinic acid esters 20
1 g. of prednisolone-sodium-succinate is dissolved in 40
and diethylaminoacetic acid esters, are distinguished by
cc. of water and the solution is adjusted to a pH value of
an increased solubility in Water. Particularly the sodium
6.4 by adding 10 mg. of prednisolone-hemisuccinate under
salts of such steriod-suecinic acid esters are clinically valu
nitrogen and while stirring. After ?ltration, 5 g. of ethyl
able anesthetic and hormone preparations. These esters,
urethane are added to the solution and the solution is
however, hydrolyze in an aqueous solution at room tem 25 made up to 50 cc.
It is already known that 21-hydroxy-20-keto-steroids
perature already and, therefore, possess a limited stability
only.
Example 3
A solution is prepared as described in Example 2 which
According to a known process, solutions of steroid-suc
solution, however contains 5 g. of 1-phenyl-2,3-dimethyl
cinic acid semi-ester salts can be stabilized by adding ascor
bio acid salts. The stabilizing effect of the ascorbates, 30 pyrazolone-(S) instead of ethylurethane.
‘however, is only very poor and only possible at very
Example 4
'low steroid concentrations, i.e. at concentrations of 5 mg.
I
A
solution
is
prepared
as described in Example 2 which
of steroid per cc. At higher concentrations as mostly
solution, however, contains 5 g. of diethylacetarnide in
used in pharmaceutics, for example 5-50 mg. of steroid
stead of ethylurethane.
per cc., these ascorbates have a detrimental effect on the 35
‘stability.
Now we have found a process for stabilizing anionic
and cationic ester salts of 2l-hydroxy-ZO-keto-steroids in
Example 5
A solution is prepared as described in Example 2 which
solution, however, contains 5 g. of polyvinyl pyrrolidone
instead of ethylurethane.
tolerable non-ionic organic hydrotropic solubilizer is added 40
Example 6
to the solutions of these salts at a pH value ranging from
an aqueous solution wherein at least one physiologically
5 to 8.
It was not obvious to ?nd stabilizers which even at high
steroid concentrations impart to the steroid solutions a
stability 4 to 10 times as high as that of solutions which
are not stabilized or stabilized with ascorbates. ' The solu
tions stabilized according to the invention stand for exam
ple a temperature of 100° C. for several hours.
A solution is prepared as described in Example 2 which
solution, however, contains 2 g. of dextrin instead of ethyl
urethane.
Example 7
A solution is prepared as described in Example 2, which
solution, however, contains 5 g. of 1,2_-propylene-glycol
instead of ethylurethane.
Example 8
A solution is prepared as described in Example 2, which
esters, polyglycols, polyoxyethylene-sorbitoleate, polyoxy
solution, however, contains 5 g. of polyglycol-SOO instead
'e.hylene fatty acid ester, polyoxyethylene fatty acid glycer
of ethylurethane.
ides, polyvinyl pyrrolidone, propylene glycol, pyrazole de
Example 9
rivatives, sarcosine anhydride (N,N’-dimethyl-diketopiper 55
azine), urethanes as well as dextrins, dextrans and water
A solution is prepared as described in Example 2, which
soluble starch preparations. By means of these stabiliz
solution, however, contains 5' g. of lactic acid ethanol
amide instead of ethylurethane.
ers there can be stabilized in aqueous solution anionic
Suitable physiologically tolerable stabilizers for the
present purpose are, for example, alkylamides, alkylphe
nolformaldehyde-ethylene oxide condensates, lactic acid
and cationic steroid ester salts such, for example, as ste
roid-malonates, steroid-succinates or substituted and un 60
substituted amino acid esters of ZI-hydroXy-ZO-keto-ste
roids such as pregnane-Zl-ol-3,20-dione, A4-pregnene-2i
ol-3,20-dione, A1,4-pregnadiene-l7,2l-diol-3,ZO-dione, or
their ll-hydroxy derivatives, 16_hydroxy derivatives, 11
keto-derivatives, 6u-methyl derivatives, 16u-methyl deriva
tives or 9-halogen derivatives, especially ?uorine being
used as halogen atom in position 9.
For the formation of salts with the aforementioned
steroid esters, there may be used in the case of the anionic
esters, in addition to» the sodium cation, for example the
other alkali metal cations or ammonia, alkylamines, hy
Example 10
1 g. of prednisolone-hemisuccinate is ?rst adjusted to a
pH-value of 7 with a 2% aqueous triethanolamine solu
tion, while stirring under nitrogen, and then adjusted to a
pH value of 6.3 by further adding 10 mg. of prednisolone
hemisuccinate. After the addition of 5 g. of sarcosine
anhydride, the solution is made up to 50 cc. and ?ltered.
Example 11
1 g. of prednisolone-hemisuccinate is ?rst adjusted to
a pH-value of 7 with a 2% solution of tetrahydroxyethyl
ethylenediamine, while stirring under nitrogen, and then
adjusted to a pH value of 6.3 by further adding 10 mg.
3,079,410
3
(“Myrj 53”) instead of tertiary-octylphenolformaldehyde
gpof sarcosineanhydride, .theesolution is made up to 50
ethylene oxide condensate.
cc. and ?ltered.
Example 12
1 g._ of‘ prednisolonesdiethylaminoacetate-hydrochloride
4‘.
which‘solution' contains‘ 1.5 g. of polyoxyethylenestearate
of‘prednisolonehemisuccinate; After the additib?‘ofZiS
Example 20
5
and .5"g.,. of ‘sarcosin'e anhydride- are‘ dissolved in150lcc. of
A solution is prepared as described in Example 18 which
solution contains 1.5' g. of polyoxy-ethylene-sorbitane=
water and?lte'red'.
o1eate.(“Tween 80”) instead of tertiary-octylphenolform‘
7
7
aldehyde-ethylene oxide condensate.
Example 13 ‘
Lg; of 6uamethylprednisolone-sodiurmsuccinate .andlO
g::of:sarcosine *anhydride'are dissolvedtin .50 cc. of water
and the solution is adjusted to. a~pH~valuezof 6.4lwhile
stirringsiunder nitrogen and-adding atvery. little“ quantity
of ion exchanger ,“Lewatit S--100,~’? H-form and?ltered...
Example~14
Example 21
10
A solution is prepared as described in Example 18 which
solution contains. 1.5 g. of polyglycol 4000 (polyethylene
glycol) instead‘ of tertiary-octylphen'olformaldehydeeth
15 yleneoxide condensate.
Example 22
A, solution is preparedas described in Example 18 which
1 g. of .6a=rnethylprednisoloneesodium-succinate,7 5- g.
ofsarcosine anhydri'deandl g. of dextrin aredissolyed-in
501cc‘. ofwater and the: solution ViS.-QdjHStBd--tOTE-‘PH ‘value
solution contains'itl g: of polygl'ycol 4000: instead of ter
of 6.4,.by'addingi a ,very littleaquantity of. ion» exchanger 20
“Lewatit S:—100’i~ H-‘formIwhile'stirr-ingg under ‘nitrogen,
and ?ltered.
Example-=15
tiaryLoctylphenolforrn aldehydesethylene. oxide "condensate.
.
Example‘ 23'
A-rsolut'ionfis prepared as described inExaniple -18:which
solution containsit). g. of-polyvinyl .pyrrolidone instead-of
tertiarxhoctylphenolformaldehyde-ethylene 1 oxide- conden
1' g; of 6a-me‘thylp'rednisolone!sodiurnssuccinate, 420 g.
of 'sarcosine anhydride and‘. 2.51 giofoxyethylated castor 25
sate. '
oil a1‘6ldlSSO1V€d‘iHI5O'CC. of-water andthe solution is ad:
ju'sted'itoa pHof .6 by-adding ,ion exchanger: “Lewatit S
100,’."H-form1while stirringwundernitrogen- and ?ltered. >
Example 16
We- claim:
1. A compositionofmatter-comprising ‘an organic ester
salt selected'frorn the-group consisting of 2l-hydroxy-20
keto A4- and’ A114 steroids of the pregnene' series‘in an
30 aqueous solution and-at least one physiologically tolerable
non-ionic organic hydrotropic solubilizer as a stabilizer
A solution is. prepared as described in Example 15
for said'solu‘tion at 21V pH ranging from 5 to 8.‘
which solution, jhoweve'r,‘ contains 2.5‘ g: of‘tertiary-octyl
2; A, composition of matter as claimed in‘claim ‘1
‘phenolformaldehyde-ethylene oxide‘ condensate instead of
wherein
the stabilizer is a member of the group consist"
oxyethylated castor oil.
35 ingro?sarcosine anhydride, ethyl urethane, diethyl acet
Example '1 7
amide, oxethylated eastor oil, tertiary octylphenol-form
aldehyde-ethylene oxide condensate, polyoxyethylene sor
1. g. of I61aémethylprednisolone-diethylaminoacetate-hy
b-itane cleate and polyethylene glycol.
drochloride and 5 ‘g. of sarcos-ine anhydride'are dissolved
3; A’ process for. stabilizing; an anionic and cationicor
in 50 cc. of water.
40' ganic ester salt selected from the group consisting of ‘21.
Examp'le‘18
hyd'roxy-ZO-keto A4 and AM steroids of the pr‘egnene series
l g. of '6a-methylprednisolone=sodium1succinate; 7.5 g.
in an aqueousv solutionwhich comprises adding at least
of sarcosine’anh'ydride' and 3175 g. of‘tertiary-octylphenol
one physiologically tolerable non-ionic organic hydro~
formaldehyde-ethylene oxide condensate‘are'dissolved'in tropic :solubilizer to'the aqueous solution thereof ata pH
50 cc. of water and the-‘solution is adjusted to a pH value
valuerangingfrom S to;8'.
of 6.4 by adding ion exchanger “LewatitS-lOO,” I-Lform,
whilerstirring, under-nitrogen, and ‘?ltered.’ -
References Cited in the ?le of’ this‘. patent
Example '19
50 " 2,970,944‘
A solution 18 prepared ‘as described in Example 18
UNITED STATES ‘ PATENTS "
Charnicki et al.i_ _______ __ Feb. 7, 1961
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