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Патент USA US3044946

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United States Patent‘ 0 ”
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p
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Another ‘object of the present invention is to provide
a simple and effective process of ‘producing such highly
concentrated chloramphenicol solutions.
A further object of the present invention is to provider ‘
a. method of parenterally administering to patientslarge
3,044,936
PROCESS OF PRODUCING ‘SOLUTIONS OF CHLOR
AMPHENICOIL IN AQUEOUS LIQUIDS, AND
COMPOSITION
3,044,936 ' I
Patented July 17, 19672, ' j
,
Johann Daniel Achelis, Heidelberg, Rndi Gall, Mann
heim-Kae'fertai, Erich Haack, Heidelberg, and Wolf
gang Voemel, -Mannheim, Germany, assignors to C. F.
Boehringer & Soehne G.rn.b.H., Mannheim-Waidhof,
amounts of chloramphenicol in concentrated solutions.
These and other objects of the present invention and
advantageous features thereof will become apparent as
Germany, a corporation of Germany
No Drawing. Filed Dec. 2, 1958, Ser. No. 777,602
the description proceeds.
.
It has ‘been found that the water-solubility of chloram
Claims priority, application Germany Dec. 7, 1957
5 Claims. (Cl. 167-65)
phenicol is increased considerably by the addition of '
lower chloramphenicol esters.
Solutions of chloram
The present invention relates to solutions of chloram
phenicol in aqueous liquids, and to a process of prepar~
phenicol containing such esters can be diluted with water
the body on oral administration.
tration thereof, which, in .many' cases, is highly desira
without precipitation of chloramphenicol. The applica
15 tion of this principle permits parenteral administration
ing such solutions.
The antibiotic chloramphenicol is readily absorbed by
of chloramphenicol, preferably intramuscular adminis
For this reason it is
usually given per os, for instance, in the form of gelatine
capsules or dragees. In some instances, however, oral
biotic eifects without causing damage to the body, such
administration cannot be used or is ineffective because
as necrotic changes of the tissue.
the patient is not able to swallow the drug, respectively,
to absorb it. It is also frequently necessary for medical
reasons to avoid the passage of the drug through the
digestive tract, for instance, during or before an opera
The term “lower” esters indica-ta esters having a
maximum of 10 carbon atoms Within the ester group and
tion. In some cases it is desirable to achieve a rapid in
ble, in an amount sufficient to produce the desired anti
will be used hereinafter and in the claims annexed here
to. With higher “esters a significant decrease in antibiotic
25 e?iciency is observed.
Suitable esters are not only the
mono-esters of chloramphenicol but also the di-esters
crease of the antibiotic level in the blood. Thus, there is
a considerable demand for injectable solution of this
and mixtures thereof. The esters may be esters of mono
or polyvalent organic acids and their substitution products
valuable antibiotic. However, the preparation of such
solutions meets with great dif?culties.
Chloramphen-icol is soluble in water at room tempera
ture only up to 0.4%. This concentration is by far in
su?icient for administration by intramuscular or intra
venous injection. It has been found that non-aqeous sol
vents for chloramphenicol, which have been used for the
preparation of more concentrated solutions, cause severe
as well as of inorganic acids, such as nitric acid, hydro
chloric acid, phosphoric acid, and the like. Especially
effective esters are the ‘following esters of organic acids:
vEsters of lower aliphatic mono- or'polycarboxylic acids
such as the following esters:
35
damage to the tissue in the form of painful swellings and
frequently of serious necroses, even if the solvent as such
is physiologically inert. This disadvantage is especially
encountered on intramuscular injection.
The same ap
plies to aqueous mixtures with said solvents because the 40
solvent content required to‘ provide stable solutions by
far exceeds the limit of compatibility.
.
It is, therefore, understandable that injection solu
tions of chloramphenicol, as they have been prepared
heretofore, for instance solutions in solvents containing 45
a high percentage of glycols and substituted fatty acid
amides (see, for instance, German Patent No. 852,123)
have not found applicationin therapy. As pharmacologi
cal tests have shown, such solutions cannot be used for
intramuscular administration on account of their damag 50
ing effect on the tissue. The same applies to the known
crystal suspensions of chloramphenicol in water or oil.
These suspensions are highly unsatisfactory for their low
blood levels. Unsatisfactory blood levels are also ob
tained by administering water soluble chloramphenicol
esters which were proposed for injection purposes. Such
esters, for instance, the preferably investigated 3-suc
Os-acetate,
O1,O3-diaceta'te,
Oa-maleate,
03-succin'ate.
Esters of esteri?ed and etheri?ed hydroxy lower fatty
‘acids such as the following esters:
-O1-ethox-y acetate,‘
O3-ethoxy acetate,
O1,O3-di-(’ethoxy acetate),
O3~methoxy ethoxy acetate,
obO3-di-(methoxy ethoxy acetate),
Os-rnethoxy ethoxy ethoxy acetate,
'1O1,O3-di~(methoxy ethoxy ethoxy acetate),
Oa-tetrahydrofurfuryloxy acetate,‘
‘O1,O3edi-(tetrahydrofurfuryloxy acetate),
O3-1,3-dimethoxy isopropoxy acetate, '
O3-methoxy acetate,
O1,‘O3'-di-(methoxy acetate),
O3éacetoxy acetate,
.
IO3-diacetyl tartrate.
55
1
Esters of partly esteri?ed aliphatic polycarboxylic acids,
such as the followingesters:
O3-mono-methyl succinate,
O3-mono-methyl malonate.~
cinate, are water-soluble in the form of their neutral
Esters of lower aliphatic keto carboxylic acids, such as
salts, such as their sodium salts. Their solutions may
‘the ‘following ester: O3-aceto acetate.
be injected almost without causing harmful reactions. 60 Esters of 'monocyclic aromatic v'dicarboxylic esters, such
However, the biological e?iciency test shows that, for
as the following ester: oa-p'hthalate.
instance, the succinate produces a much lower blood
The solubility increasing and stabilizing effect of such
level than the same amount of chloramphenicol. This
is probably due to the poor hydrolysis of the succinate 65 esters lis vapparently not principally connected with their,
own solubility in wateror, respectively, with the solubility
within the body to produce the effective chloramphenicol.
of their salts in water; most of them are, in fact, only’ ‘
It is one object of the present invention to provide
di?iculty soluble therein. However, in carrying out the '
solutions for parenteral administration which contain a
invention it is of advantage or, respectively, necessary
high percentage of chloramphenicol, which may be di
?rst to prepare solutions of such esters in water miscible
luted with water without precipitation of the chloram 70 organic solvents. "It is, of course, understood that the
phenicol, and which have no damaging effect upon the
‘solvents'must be inert ‘to chloramphenicol and its esters.
tissue when injected in therapeutically useful amounts.
They must :also be physiologically inert, at least in the
3,044,936
3
4
.
succinate are added to the starting solution, a clear solu
concentrations in which they are used therapeutically.
tion results on the addition of the same amount of water.
Solvents which meet with these conditions are, among
This solution does not precipitate even after several days.
others, the following:
Polyethylene glycol ethers, such as diethylene glycol di
methyl ether;
Dimethyl sulfoxide;
Example 3
A solution containing 1.89 g. of chloramphenicol, 2.0
g. of dimethyl urea, and 0.15 g. of chloramphencol-O3~
methoxy ethoxy acetate in 2 cc. of dimethyl sulfoxide
remains clear after dilution with water whereas, without
N,N-di-(lower alkyl) lower alkanoic acid amides such as
dimethyl formamide, dimethyl acetamide, diethyl form
amide, diethyl acetamide;
Glycerol methyl ether;
.
10 the addition of the chloramphenicol ester, the chloram
phenicol is precipitated by the addition of water.
Example 4
Tetrahydrofurfuryl methyl ether; and others.
To carry out the present invention it is not necessary
to use the solubilizing or, respectively, stabilizing ester
as such. The ester may also be formed-and this is the
500 mg. of chloramphenicol and 635 mg. of chloram
PhBIIlCOl-Og-SUCClHQl? are dissolved in a mixture of 0.4 cc.
preferred method in some cases-when preparing the
chloramphenicol solution, whereby, of course, an excess
of chloramphenicol is used. For this purpose the corre
sponding acid anhydride is added to the mixture of sol
vent and chloramphenicol. If esters of acids are used 20
which contain a salt-forming group, it is the preferred
procedure to form the salt by adding an equivalent
of dimethyl sulfoxide and 0.2 cc. of diethylene glycol
dimethyl ether. Upon addition of 160 mg. of sodium
carbonate and distilled water in an amount su?icient to
yield a volume of 4 cc., a clear solution containing 25%
of chloramphenicol is obtained.
Example 5
10 g. of chloramphenicol and 13.8 g. of the sodium
salt of chloramphenicol-Oa-succinate are dissolved in 16
cc. of tetrahydrofurfuryl methyl ether. In order to ob
tain a 25% chloramphenicol solution, water is added to
amount of an alkali hydroxide or another basic substance,
for instance, of a physiologically inert amine. In certain
special instances it might be advisable to use additionally
a known solubilizing agent to cause further stabilization
of the resulting solution, such as urea or its substitution
a volume of 80 cc.
Example 6
products, or urethanes. This elfect is very surprising
because such known solubilizing aids alone do not pro~
duce any substantial increase in solubility of chloram
A solution containing 2.0 g. of chloramphenicol and
0.206 g. of succinic acid anhydride in 1.4 cc. of N,N
dimethyl methoxy acetamide is heated at 110° C. for 60
minutes. Upon adding 5.1 cc. of a 4.3% sodium car
bonate solution, a clear solution is obtained with a total
phenicol in aqueous liquids.
The process of increasing the solubility of chloram
phenicol in aqueous liquids by means of “lower” chlor
amphenicol esters according to the present invention is,
as stated above, of considerable importance for the prep
aration of injectable solutions of this valuable antibiotic.
chloramphenicol content of 25 %.
Example 7
A solution of 2.0 g. of chloramphenicol in 1.6 cc. of
diethylene glycol dimethyl ether sold under the trade
The resulting injectable solutions which may contain 30%
and more of the effective drug, are well tolerated espe
mark “Diglyme” is mixed with 0.3 g. of succinic acid
cially by the tissue because their content of organic
solvents, if they are used for preparing the initial ester 40 anhydride. The resulting mixture is heated to 110° C.
for 90 minutes. By adding a solution of 350 mg. of
solution, is always within the limit of compatibility,
sodium carbonate in 4.9 cc. of water thereto, a clear solu
whereas the esters of chloramphenicol are physiologically
tion is obtained.
inert and contribute to the desired therapeutieal effect
due to their more or less rapid hydrolysis to chloram
Example 8
phenicol.
The injectable liquids according to the present inven
45
A solution of 2.0 g. of chloramphenicol in 0.9 cc. of
diethylene glycol dimethyl ether and 0.5 cc. of dimethyl
tion are quite stable. However, due to the sensitivity of
acetamide is mixed with 0.25 g. of maleic acid anhydride.
most esters against hydrolysis, it is advisable to ?rst pre
The mixture is heated to 110° C. for 60 minutes. By
pare a solution containing the chloramphenicol and the
ester and, if necessary, the solubilizing aid in an anhy 50 adding a solution of 300 mg. of sodium carbonate in
5.1 cc. of water, a clear solution is obtained.
drous organic solvent of the above mentioned type. This
solution, which can be stored for an unlimited period of
Example 9
time, represents the stock solution. It is diluted with
0.5 g. of chloramphenicol and 0.69 g. of chloramphen
water shortly before its use. The physician may prepare
the ?nal dilution. Further handling of the injectable 55 icol-3-N,N-dimethy1 glycinate hydrochloride correspond‘
solutions according to the present invention, for instance,
adjustment of its pH-value, sterilization, and the like is
ing to 0.5 g. of chloramphenicol, are dissolved in 1.0 cc.
effected with the usual care.
is diluted with water to a volume of 4 cc.
of dimethyl methoxy acetamide. The resulting solution
A clear solu
The following examples serve to illustrate the present
tion with a total chloramphenicol content of 25% is
invention without, however, limiting the same thereto.
60 obtained.
Example 1
A suspension containing 4 g. of chloramphenicol in a
solution of 5.5 g. of chloramphenicol-Ownccinate in the
The same results are obtained When chloramphenicol
3-glycinate sulfate or chloramphenicol-3-betainate hydro
chloride are used in place of chloramphenicol-LEN
dimethyl glycinate hydrochloride.
form of its sodium salt in 100 ‘cc. of water is caused to 65
Of course, other lower esters of chloramphenicol may
dissolve by heating for a short period of time. The re
be employed for solubilizing chloramphenicol and sta
sulting solution remains clear after cooling whereas a
bilizing its aqueous solutions as they have been mentioned
solution of 0.6 g. of chloramphenicol in 100 cc. of warm
hereinabove, may be used by those skilled in the art in
water shows immediate precipitation of crystals when
accordance with the principles set forth herein and in the
cooled.
claims annexed hereto.
70
Example 2
If esters of acids are used which contain a salt-forming
group, it is preferred to form the salts by addition of a
When a solution containing 1.0 g. of chloramphenicol
basic substance. In that case, not only alkali hydroxides
in 2.0 cc. of dimethyl sulfoxide is diluted with 10 cc. of
or carbonates can be used but also ammonia or organic
water, chloramphenicol precipitates immediately. How
ever, if 1.4 g. of the sodium salt of chloramphenicol-O3 75 amines, e.g. butyl amine, methoxy propyl amine etc;
3,044,936
5
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We claim:
1. The stable solution of chloramphenicol in an aque
one liquid containing dissolved therein chloramphenicol
ous liquid containing dissolved therein choramphenicol
and, as solubilizing agent, the sodium saltv of chlor
arnphenico1-3-succinate, the molar ratio of chlorarnphen
icol to sodium salt being between about 1:1 and about 2: l. ,
and, as solubilizing agent, a salt of chloramphenicol-3
succinate selected from the group consisting of its alkali ,
metal salts and its ammonium salt, the molar ratio of 1
chloramphenicol to salt being between about 1:1 and '
about 2:1.
5. The solution of chloramphenicol in a water miscible
2. The solution of chloramphenicol in dimethyl sulf
organic solvent containing a salt of chlorarnphenicol~3
oxide containing dissolved therein the sodium salt of
succinate selected from the group consisting of its alkali
chloramphenicol-3-succinate, the molar ratio of chlor
amphenicol to sodium salt being between about 1:1 and 10 metal salts and its ammonium salt, the molar ratio of
chloramphenicol to salt being between about 1:1 and
about 2: 1, said solution being miscible with water to yield
about 2:1.
a highly concentrated, stable, aqueous chloramphenicol
solution.
References Cited in the ?le of this patent
3. The solution of chloramphenicol in tetrahydrofur
furyl methyl ether containing dissolved therein the sodium
UNITED STATES PATENTS
salt of chloramphenicol-3-succinate, the molar ratio of
2,586,661
Jacob ___l_ __________ __ Feb. 19, 1952
chloramphenicol to sodium salt being between about 1:1
2,838,552
Gansau ____________ __ June 10, 1958
and about 2:1, said solution being miscible with water
2,852,430
Goebel ____________ __ Sept. 16, 1958
to yield a highly concentrated, stable, aqueous chlor
20
FOREIGN PATENTS
amphenicol solution.
. 4. The stable solution of chloramphenicol in an aque
HwR’
852,123
Germany ____________ _._ Oct. 13, 1952
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