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Патент USA US2411631

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2,411,631
Patented Nov. 26, 1946
UNITED ‘STATE S PATENT OFFICE
2,411,631
STABLE, SUPERSATURATED SOLUT
ONS SU
OF
OF THE
SACCHARIDE DERIVATIVES
HORMONE SERIE
PRARENAL CORTICAL
AKING SAME
.
AND PROCESS OF M
Karl Miescher, Riehen, and Charles Meystre,
Basel, Switzerland, assignors to Ciba Pharma
ceutical Products Incorporated, Summit, N. J .,
a corporation of New Jersey
No Drawing. Application June 11, 1943, Serial
No. 490,536. In Switzerland December 24,
1942
9 Claims.
(Cl. 167-77)
2
amongst these physiologically occurring sugars
According to K. Miescher, W. H. Fischer and
Ch. Meystre (Helvetica Chimica Acta, vol. 25,
in particular. The concentration of these sub
page 40, 1942) , the solubility of desoxycorticoster
one in water is increased about ten times to 0.12
exceed in general 20-25%.
percent by converting it into the ?-glucoside.
See also the Miescher et al. Patent No. 2,270,379,
tically.
The following examples illustrate the invention
granted on Jan. 20, 1942. For practical purposes,
however, in particular for injection therapy, often
but are not to be regarded as limiting it in any
renal cortical hormone series can be obtained if
these derivatives are dissolved in aqueous solu
tions of inert, easily water-soluble organic com
one is brought into solution in 100 parts of a 10%
d-glucose solution in water by heating in a boiling
water-bath. The solution obtained is ?lled into
stances is chosen as low as possible and does not
The solutions obtained are to be used therapeu
way, the parts being by weight:
still more concentrated solutions are desired. It
Example 1
10
has now been found that stable, super-saturated
1 part of the ?-d-glucoside of desoxycorticoster
solutions of saccharide derivatives of the supra
pounds containing. oxygen, with exclusion of any 15 ampules. The latter are sealed and sterilized in
the usual way by heat. The ampules prepared in
crystallization nucleus.
this way remain clear and are very stable. No
Such solutions remain surprisingly stable for a
long time even at low temperatures; after the
precipitation occurs on pouring the solution into
addition of a small crystal of the saccharide de
water.
.
rivative, however, crystallization of the super 20 Aqueous solutions of other sugars such as
sucrose, lactose, etc. can also be used with the
saturated solutions soon starts. The latter should
therefore be stored in sealed ampules. If the so
lutions prepared as described in the process are
diluted with water, there is no separation of the
same success.
saccharide derivative contained. This is surpris
ing as it is known that, for example, free desoxy
corticosterone or barbituric acids which are
brought into aqueous solution by means of suit
Example 2
2 parts of the p-d-glucoside of desoxycortico
sterone are dissolved in 100 parts of a 10% solu
tion of glycol in water as in Example 1. The solu
tion is ?lled into ampules andsterilized. Instead
able hydrotropic agents, for example by means of 30 of glycol, other polyalcohols or their derivatives,
urea, are precipitated immediately on dilution
e. g. ethers, and also monoalcohols may be used.
with water.
'
The following saccharide derivatives of the su
prarenal cortical hormone series may, for exam
ple, be used: monosaccharide derivatives, such as
Example 3
0.5 part of the ?-lactoside of desoxycorticoster
one is dissolved in 100 parts of a 20% solution of
the a- and B-glucosides, galactosides, mannosides 35 glycerine in water as described in Example 1.
or arabinosides, polysaccharide derivatives such
as maltosidcs, lactosides, lactosidoglucosides, etc.
of, for example, desoxycorticosterone, corticoster
one, dehydrocorticosterone, anhydrocorticoster
one or corresponding compounds hydroxylated in 40
the l7-position.
As solvents ior the saccharide derivatives
The solution is ?lled into ampules and sterilized.
It is stable even on cooling.
' Example 4
2 parts of the s-d-glucoside of corticosterone
(prepared by reaction of corticosterone and tetra
acetylbromoglucose in the presence of silver car
bonate and saponi?cation of the tetra-acetate ob
named, the following are suitable: aqueous solu
tained) are dissolved hot in 100 parts of a 15%
tions of mono- or poly-alcohols, such as glycol,
glycerine, erythritol or mannitol, of monosac 45 aqueous d-glucose solution. The solution is ?lled
into ampules and sterilized in the usual way
charides and sugar-like polysaccharides, such as
glucose, galactose, fructose, lactose, maltose,
after sealing. It is stable.
In a similar way, solutions of glucosides of
sucrose or ra?inose and ?nally of further inert,
easily water-soluble organic compounds contain 50 other active compounds of the suprarenal cortical
hormone series, such as, for example, dehydrocor
ing oxygen, such as dioxane or polymers of ethyl
ene oxide, or of mixtures of such compounds.
ticosterone, can be prepared. The glucosides
Especially to be recommended on account of their
themselves are obtained analogously to that of
good tolerability are solutions of certain members
corticosterone.
A
of the sugar series, i. e. of polyalcohols, mono
What we claim is:
‘saccharides and sugar-like polysaccharides, and
2,411,631
a physiologically inert proportion of a saccharide,
said hydrotropic agent being present in a concen
tration sui?cient to eifect stabilization of the solu
tion but not exceeding about 20-25%.
»5. A stable, supersaturated aqueous solution of a
monosaccharide derivative of the suprarenal cor
tical hormone series containing, as hydrotropic
agen , a physiologically inert proportion of a sac
10
the solution but not exceeding about 20—25%.
6. A stable, supersaturated aqueous solution ofca
glucose derivative of the suprarenal cortical hor
15 mone series containing, as hydrotropic agent, a
solution but not exceeding about 20-25%.
7. A stable, supersaturated aqueous solution of a I
about 20—_25%.
glucoside of desoxycorticosterone containing, as
hydrotropic agent, a physiologically inert quantity
of glucose, said hydrotropic agent being present
3. A process for the manufacture of
25
30
suprarenal cortical
hydrotropie agent,
I
containing,
hydrotropic agent,
about 10% Of glucose.
as
9. A stable, supersaturated aqueous solution of a
glucoside of desoxycorticosterone containing, as
hydrotropic agent, about 10% of glucose.
‘
KARL MIESCHER.
CHARLES MEYSTRE.
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