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2,408,289
Patented Sept. 24, 1946
UNITED STATES PATENT orrlcs
BARBITURIC ACID COMPOSITIONS
Milton '1‘. Bush, Nashville, Tenn., assi'gnor to
Mallinckrodt. Chemical Works, St. Louis, Mo.,
a corporation of Missouri
-
No Drawing. Application‘ July 17, 1942,.
Serial No. 451,311
4' Claims. (Cl. 167-52)
.
1
2
,
,
the desired hypnosis or anaesthesia without irri
This invention relates to. barbituric acid com
tation. They can be sterilized and kept for long
positions, and more particularlyto non-aqueous
periods of time without loss of activity.
_
solutions of barbituric acids suitable .for paren
The solutions of the present invention comprise
terai administration.
barbituric acids dissolved in a non-aqueous sol;
Among the. objects of this. invention arev the
vent. The organic solvents employed must act
provisionv of barbituric acid solutions of the type
as such for the barbituric acid. or acids utilized‘;
indicated which are stable, non-alkaline and non‘
that- is, the barbituric acids must be soluble to
irritating; the provision of barbituric acid- solu
produce the required concentration of hypnotic
tions which. may be. utilized for intramuscular
injections; and the provision of stable barbituric 10 or anaesthetic component in the organic solvent;
The solubility of the barbituric acid in the or
acid solutions which may be administered orally
ganic solvent must not be substantially less than
or intravenously, as well as intramuscularly.
10% and preferably is at least 30%. The-re isno
Other objectswill be in part obvious and in part
upper
limit for this solubility.
pointed out hereinafter.
The invention accordingly comprises the in 15 Moreover, the solvent itself must not be too
soluble in or be miscible with water. Solubilities
gredients and combinations of ingredients, the
of the organic solvents in water of the order of
proportions thereof, and features of composition,
10% are, for example, satisfactory, and may be
which will be exempli?ed in the products herein
even higher without unduly detracting from the
after described, and the scope of the application
of which will be indicated in the following claims. 20 effectiveness ,of the barbituric acid. Zero is the
lower limit for this solubility.
If the solvent possesses too great a solubility
in water the effectiveness of the resulting barbi
they are customarily employed in the form of
turic acid composition is markedly decreased.
strongly alkaline aqueous solutions of their so
dium or other salts. These solutions are gen 25 Solubilities as high as 15% of the organic solvent
in water are permissible. The preferred type of
erally unstable, must be prepared fresh from
solvent, however, has a solubility in water of
previously sterilized components and decompose
approximately 10% or less.
rapidly on heating- Moreover, they are very
Typical of the solvents which may be em
irritating to human tissue due both to their alka-‘
ployed are paraldehyde, triacetin, and olive oil,
linity and the osmotic effect that such hypertonic
although other organic solvents possessing the
solutions produce and consequently their use is
requisite low solubility in water and having a pH
strictly limited to oral or intravenous adminis
value in aqueous solution of substantially 7 may
tration.
a be substituted.
1
In many instances it is impossible to admin
A wide range of barbituric acids may be uti
ister these barbituric acids either orally or intra
lized. as the active hypnotic or anaesthetic agent
venously. For example, where the patient is suf
in the instant compositions. For example:
fering from shock, or where there is little time
to carry out the operation, it may be difficult to
1-methyl-5-allyl-5-isopropyl
?nd the patient’s veins. The veins collapse in
5-ethyl-5-n-butyl
40
shock and are, therefore, difficult to locate, while
K 5-.allyl-5-isopropyl
Barbituric acids are useful as hypnotics and
anaesthetics.
When administered by injection
if the administration is to be carried out on a
battle?eld or under other difficult conditions, it
5-ethyl-5 -sec-butyl
may likewise be hard to quickly determine the
position of the patient’s veins. It may be impos
sible to attempt oral administration due to the
failure of the patient to cooperate or to many.
other conditions. On the other hand, the intra
muscular route is always available and it would
be possible to utilize these barbituric acids if
1 -methyl-5-ethyl-5- ( l-methylbutyl)
5-allyl-5- ( l -methylbutyl)
Barbituric acids have been utilized either alone
solutions suitable for intramuscular injection '
were obtainable.
According to the present invention, solutions
of the barbituric acids are provided. These solu
tions can be injected intramuscularly without
detrimental effect upon the patient, producing
5-ethyl-5 - ( l-methylbutyl)
or in combination with each other or with other
hypnotics. All of the compositions listed above
possess suf?cient solubility in paraldehyde and
triacetin, for example, to enable the injection
intramuscularly of effective hypnotic and/0r
anaesthetic doses without the utilization of det
rimentally large quantities of solution.
In general it is desirable to inject only a small
volume of solution so the solubility and neces~
2,408,289
3
sary dosage will usually as a practical matter de—,
termine suitable combinations for use. Likewise,
where the solution is injected intramuscularly, a
barbituric acid is preferably selected which is
not too rapidly inactivated in vivo so that there
may be the required time for absorption before
inactivation. The preferred barbituric acids are
5-al1yl-5-(l-methyl-butyl) barbituric acid, 1
methyl-57allyl-5-isopropyl barbituric acid, and
N-methyl-5 -ethyl-5- (1 -methylbuty1) barbituric
4
Although the barbituric acid solutions of the
present invention are of especial value for intra
muscular injection, they may also be injected
intravenously. If such an injection is made with
the usual slowness, no detrimental symptoms are
encountered.
As indicated above, two or more of the barbi
turic acids may be used in the same solution or
one or more of such acids may be used in a so
10 lution with another narcotic, hynotic or anaes
acid.
thetic, such as morphine, dilaudid, etc.
It has been found that the median fatal dose
In view of the above, it will be seen that the
and the median anaesthetic dose on intramuscu
several objects of the invention are achieved and
lar or intravenous injection of the solutions of
other advantageous results attained.
the present invention in concentrations of the‘ 15
As many changes could be made in the above
order of, for example, 250 mg./m1. are very close
products without‘ departing from the scope of
to the corresponding doses required of the cus
the invention, it is intended that all matter con
tomarily employed 10% aqueous solutions of the
'tained in the above description shall be inter
sodium salt of the corresponding barbituric acid.
preted as illustrative and not in a limiting sense.
The organic solvent employed must not itself 20 I claim:
be toxic or irritating to human beings. Paral
1. A hypnotic composition for intramuscular
injection comprising a solution of a barbituric acid
dehyde is an instance of a solvent which is not
in paraldehyde.
toxic and has even been employed as a hypnotic.
2. A hypnotic composition for intramuscular
However, its hypnotic activity is only a fraction
' (about 1&0 or 1a,) that of allyl-(l-methylbutyl) 25 injection comprising a solution of 5-allyl-5-(l
methylbutyl) barbituric acid in paraldehyde.
barbituric acid, for example, so that this solvent
3. A hypnotic composition for intramuscular
plays only a negligible part in the activity of
injection comprising a solution of 1-methyl-5
such a solution. A 30% solution of allyl-(l
ally1-5-isopropyl barbituric acid in paraldehyde.
methylbutyl) bar-bituric acid in paraldehyde is
‘ 4. A hypnotic composition for intramuscular
stable. This is true even when such a solution 30 injection comprising a solution of N-methyl-5
is heated to 120° C. for as long as four hours.
ethy1-5-(1-methylbuty1) barbituric acid in par
Such stability makes it possible to sterilize the
solution with heat.
aldehyde.
MILTON T. BUSH.
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