close

Вход

Забыли?

вход по аккаунту

?

Патент USA US2838453

код для вставки
F
.,
1C6
..
,
2,838,439
passed June 10, 1958, _
2
anesthetic
Another to
substancethat
be ‘administered
has been
by subcutaneous
found useful asinjection
a local
is butethamine, the para-aminobenzoic'acid ester‘of 2
isobutylaminoethanol, usually administeredrin the form’
2,838,439
iNiEcTAnLE LOCAL ANEs'rHErrc SOLUTION§
of an isotonic saline solution of the hydrochloride con
COMPRISING Mrxruans or SOLUBLE Pao
taining 1.0% to 2.0% by weight of butethamine hydro
CAlNE AND BUTETHAMENE SALTS
chloride. This substance is particularly useful in nerve
Samuel D. Goldberg, West Hempstead, N. Y.
block anesthesia, being qualitatively identical in action
No Drawing’. Application October s, 1955
with that of procaine, but producing about one third
greater anesthetic effect, i. e., a butethamine'hydrochlo
ride solution of' three-fourths the concentration of a
Serial No. 538,274
11 Claims. (Cl. 167--52)
procaine hydrochloride solution is of equal effectiveness. -
However, the improvement in the anesthetic power of‘
butethamine over that of procaine is accompanied by the >
This invention relates, generally, to compositions of 15 disadvantage ‘that the toxicity of butethamine, also,,is_
about one third greater than that of procaine. For
dental or other minor surgery, a 1.0% by weight solu
matter useful in medicine and, more particularly, it .re
lates to certain novel compositions useful for producing
local anesthesia.
It is known that certain ‘chemical substances, when
applied or administered parenterally to the human body,
tion of butethamine hydrochloride with epinephrine
(l:75,000) may be injected to obtain nerve block
anesthesia; inrmajor surgery or other procedures requir
are capable of blocking nerve conduction from the area
or region of application or administration and this thus
limited blocking eifect is known as local or regional
ing nerve block anesthesia equivalent to that produced .
anesthesia. Local anesthesia produced by parenterally
(l:lO0,000) may be used.
by 2.0% by Weight procaine solution, a 1.5% by weight
solution of butethamine hydrochloridewith epinephrine ‘ ‘I
administrable substances is designated according to the o
technique employed or the anatomic site of administra
tion: In?ltration anesthesia is injection directly into the
. .
Other anesthetics, such as tetracaine and dibucaine,
have the disadvantage that, when administered with
epinephrine and in suf?cient amounts to produce the de
sired rapid and profound anesthesia, the anesthesia is
area. which is ‘painful or to be subjected to surgical
very prolonged and reactions due to the toxicity of the
trauma; conductive or nerve block anesthesia is injec
tion in proximity to speci?c nerve trunks supplying a 30 anesthetic frequently occur. Moreover, all of the above
particular anatomic site.
All local anesthetic agents are toxic and the tolerance
of individuals varies. Safe dosage is therefore limited
for each drug, and administration must be individualized.
The choice of the drug to be used, its concentration, rate 3‘)
and location of administration, mode of administration,
along with the individual’s age, emotional and physical
'
mentioned anesthetics, when administered subcutaneous
ly, show little tendency to spread into‘ tissues surround
ing the situs of administration; hence, the anesthetic
eifect is substantially limited to the immediate locality
of administration and nerve block anesthesia, rather than
in?ltration anesthesia, generally must be relied on to
achieve the necessary effects.
-
must vbe exercised in parenteral administration of local
One of the objects of this invention is to provide cer-'
tain novel compositions, suitable for subcutaneous ad
anesthetics to assure that merely subcutaneous, not in
travenous, administration is eifected because these sub
stances have profound toxic reactions when administered
intravenously. In general, the smallest amount of the
least toxic drug that will serve the intended purpos
amine but having a materially lesser toxicity.
Another object of this invention is to provide local
anesthetic agents that, in contrast and comparison with
status are a few of the factors involved.
should be employed.
Great care
~
Of the group of local anesthetic agents suitable for
parenteral administration, probably the most widely used
is the substance procaine, usually in the form of an
isotonic saline solution of procaine hydrochloride at a
concentration of about 2% by weight, i. e., the solution
contains, in each one hundred cubic centimeters, not
less than 1.9 grams and not more than 2.1 grams of pro
caine hydrochloride. Solutions containing greater or
lesser concentrations of procaine hydrochloride, and so
lutions of other procaine salts, such as the borate, which
is readily water soluble, and the butyrate, which is solu
ble both in water and in vegetable oils, have been found
satisfactory for use as local anesthetics.
Procaine
ministration to produce local anesthesia, qualitatively
identical in anesthetic action with procaine and buteth
procaine and butethamine preparations heretofore known,
are suited for use in in?ltration anesthesia and that, when
administered subcutaneously, readily and rapidly spread
into tissue surrounding the situs of administration, pro- ‘
ducing profound anesthesia therein.
A further object of this invention is to provide novel
local anesthetic compositions of the type aforesaid that
are stable, easy to produce, and that can be produced
at costs comparable to those of procaine and butethamine
preparations now in use.
'
Other objects of this invention will be apparent as the
detailed description of the invention proceeds.
Regarded in certain broader aspects, the novel local
anesthetic agents in accordance with this invention are
anesthetics, when administered subcutaneously, induce 60 aqueous solutions containing, in synergistic combination,
a soluble procaine salt and a soluble butethamine salt,
anesthesia approximately equal to thatv produced by
vso proportionated'that there is present in the mixture,
cocaine, While being a mere fraction as toxic as cocaine
per unit weight of butethamine, one to three units of
and virtually free from untoward respiratory and circu
weight of procaine. These novel compositions are re- '
latory effects. The chief disadvantage of procaine’
anesthetics is that the anesthesia, although rapidly vin- 65 markable in that their toxicity is materially less than
that of a solution containing either procaine or buteth
duced, also rapidly disappears; it has been reported that
amine in an amount equal to'the total amount of these
within two minutes following injection, only faint traces
of procaine can be found in the blood. This disadvan
tage, to a limited degree, may be overcome by simul
substances in the new compositions.
For instance, a
composition containing two percent by weight of pro
taneous administration of a vasoconstrictor, such as ‘70 caine and 1.5 percent by weight of ,butethamine has, at
most, about two-thirds the toxicity of a 3.5% by weight
epinephrine, which effectively prolongs the anesthetic
procaine
solution, and ‘even less than two-thirds the
effect.
2,838,439
3
'4
toxicity of a 1.5% by weight solution of butethamine
salt. The term synergistic combination is herein used
in the special and limited signi?cance that it refers to
this unexpected and unpredictable phenomenon where
lethal dose of this product, determined by subcutaneous
injection of white mice, being 325 milligrams per kilo
gram of animal body weight.
It is found, further, that the intravenous toxicity of
by two toxic substances so coact, without loss or im
the novel compositions according to this invention is re
lated to the intravenous toxicity of the components in
pairment of their physiological potencies, that the
toxicity of the combination is materially less than the
aggregated toxicities of the components.
V substantially the same manner as the subcutaneous tox
icities above discussed. Using unanesthetized rabbits as
test animals, the minimum lethal intravenous dose for
toxicity of procaine hydrochloride, administered sub 10 procaine is found to be 45 milligrams per kilogram of
cutaneously in the form of an aqueous solution contain
animal weight; that for butethamine is found to be 32
Using white mice as test animals, it is found that the
ing 2.0% by weight of the salt, is 750 milligrams of the
salt per kilogram of test animal weight; and, when tested
under the same conditions, it is found that the toxicity
milligrams per kilogram; whereas compositions accord
ing to this invention containing 2.0% by weight procaine
hydrochloride and 1.0% to 1.5% by weight of buteth
of butethamine hydrochloride is approximately 550 milli
grams of salt per kilogram of test animal weight. These
values are the minimum lethal dosages of these drugs,
' amine show minimum lethal dose levels of 35 to 40
i. e., the minimum amounts of these drugs that, when
invention may be prepared using any of the water soluble
milligrams per kilogram of test animal weight.
Compositions embodying the principles of the present
administered subcutaneously, result in death ofvthe test
salts of procaine and butethamine, the term salts here
animal. Likewise, using guinea pigs as thetest animals, 20 signifying the products obtained by treating the free amine
it is found that the subcutaneous toxicity of procaine is
bases with a mineral or simple, water soluble organic
410-430 milligrams of procaine hydrochloride per kilo
carboxylic acid. Although the hydrochlorides are the
gram of test animal body weight; while, under the same
presently preferred salts, it will be understood that other
test conditions, the minimum lethal dose of butethamine
hydrochloride is 210—255 milligrams per kilogram.
Under comparable test conditions, it is found‘ that the
following compositions according to this invention pos
sess the toxicity indicated:
salts may be used as above indicated. The ratio of
butethamine to procaine salt in these products is one part
by weight of the former per one to three parts by weight
of the latter. As a practical matter, it seldom is necessary
or desirable to use either component at a concentration
less than about 0.25% of the total weight of solution;
Minimum
lethal dose
(M L D50)
Using white mice as test animals and subcutaneously ad
ministering to them:
butethamine hydrochloride ____________________ -_
(3) Isotonic saline solution containing 2% by weight of
procaine hydrochloride and 1.5% by weight of
butethamine hydrochloride ____________________ . _
Using guinea pigs as test animals and subcutaneously ad~
ministering to them:
(1) Isotonic saline solution containing.r 2% by weight of
butethamine hydrochloride ____________________ __
(3) Isotonic saline solution containing 2% by weight of
375
400
grccaine hydrochloride and 1.5% by weight of
utethamine hydrochloride _____________________ _ _
350
From these data, especially the studies conducted with
white mice as the test animals, it is evident that the com
bination of 2% procaine hydrochloride with 1% buteth
amine hydrochloride, or with 1.25% butethamine hydro
chloride, results in a product having a toxicity indistin
guishable from that of a 2% procaine solution alone,
although the anesthetic power is increased to that of a ‘
31/a% procaine solution, or a 3.6% procaine solution,
respectively.
These results are the more impressive
when compared with the toxicity data found by studies
of subcutaneous injection of procaine solutions at con
centrations higher than 2.0% by weight: using white
mice as the test animals, it is found that the minimum
lethal dose, using a solution containing 3.0% procaine
hydrochloride, is 700 milligrams per kilogram of animal
body weight and, using a 4.0% solution, the minimum
lethal dose is 550 milligrams per kilogram. This remark
able synergistic action is. limited to combinations of pro
caine and butethamine, so far as now known, and it is not
exhibited in combinations of procaine with other local
anesthetics.
Similar
use of butethamine hydrochloride in amounts within the
range of 1.0% to 1.5% of total weight, and of procaine
hydrochloride in the amount of 2.0% of the total weight
of ?nished solution presently is preferred.
In addition to the improvement in toxicity effected in
the novel compositions according to this invention, com
pared to anesthetic compositions containing the individual
components separately, these new compositions have an
procaine hydrochloride and 1% by weight of
(2) Isotonic saline solution containing 2% by weight of
procaine hydrochloride and 1.25% by weight of
concentration for the individual components.
considerations set 2.0% of total weight as the effective
upper limit of concentration for the butethamine and
6.0% of total weight for the procaine component. The
(1) Isotonic saline solution containing 2% by weight
procaine hydrochloride and 1% by weight of JVIqsn/kilo.
butethamine hydrochloride. ____________________ __
.750
(2) Isotonic saline solution containing 2% by weight of
procaine hydrochloride and 1.25% by weight of
butethamine hydrochloride _____________________ ..
30 hence, this may be regarded as an eifective minimal
For example,,which serves further to em
phasize the unexpectedncss of this synergistic action, it
is found that the addition of merely 0.15% of tetracaine
hydrochloride to a 2.0% procaine hydrochloride solution
results in a product more'than twice (ca. 2.3><) as toxic
as the procaine hydrochloride solution alone, the minimum
other remarkable property: their ability to migrate into
surrounding tissue near the situs of injection. This prop
erty is of great importance as it permits the anesthetic
to be administered by in?ltration rather than restricting
its use to block anesthesia as has been necessary with
procaine preparations and with butethamine preparations
of types heretofore known. This property may be dem
onstrated by intracutaneous wheal tests on human sub
jects. In these tests, a small amount of the drug under
test is injected below the skin surface between the epi
dermis and the under-lying tissue, whereby a bleb is
produced and the area of this bleb is indicative of the
degree of spread of the injected material from the point
of injection, and, in this instance, it is indicative of the
area of anesthetization. Using a solution containing
1.5% procaine hydrochloride in isotonic saline, no ap~
preciable spreading was observed; using a 1.5% buteth
amine hydrochloridc solution, the area of spreading was
vfound to be 1.25 centimeters in diameter; and, when
epinephrine was included in the butethamine solution, the
area of spreading was found to be 1.50 centimeters in
diameter. A solution according to the present invention,
containing 2.0% by weight procaine hydrochloride and
1.0% to 1.5% by weight of butethamine, but containing
no vasoconstrictor, spread over an area 2.0 centimeters
in diameter; and, after addition of a vasoconstrictor
(epinephrine) to this solution, the area of spread was
found to be 3.0 centimeters in diameter.
This property of spreading is of great importance in
anesthesia as it permits the anesthetist to induce a rapid
and profound anesthesia due to in?ltration of the anes
thetic throughout the area surrounding the situs of admin
istration. In clinical studies of compositions embodying
2,888,439
5
one to three units of weight of procaine.
2. A new composition of matter ‘as de?ned in claim 1
wherein the soluble butethamine salt is present in the aque
thesia was established was observed in 500 cases. It was
found that complete anesthesia was established immedi
ately following injection over a 15-30 second period,
whereas, in block or conductive anesthesia, the injection
requires 45-60 seconds and anesthesia is not established
until about one and one-half minutes thereafter.
ous solution in an amount Within the range of 0.25% to
2.0% by weight, based on the total weight of the solution.
3. A new composition of matter as de?ned in claim 1
wherein the soluble butethamine salt is present in the
It is preferred, in compositions embodying the prin
aqueous solution in an amount within the range of 1.0%
ciples of this invention, to include a suitable vascoconstric
tive sympathomimetic amine, such as epinephrine, phenyl
6
present in the mixture, per unit weight of butethamine,
the principles of this invention, the rate at which anes
10
ephrine, laevoarterenol and the like, for the purpose of
localizing and prolonging the action of the anesthetic.
to 1.5% by weight, based on the total weight of the
solution.
4. A new composition of matter as de?ned in claim 1
wherein the soluble procaine salt is present in the aqueous
solution in an amount substantially equal to 2.0% of the
These substances in amounts of less than 0.02% of the
total weight of the solution are effective for this purpose.
total weight of the solution.
In general, for anesthetics to be used in dentistry, it is pre
ferred to use epinephrine in the proportion of 1:50,000 to
5. As a new composition of matter, useful in medicine
as a local anesthetic agent, an isotonic aqueous saline solu
1:100,000 parts by weight; phenylephrine, 1:2,500 to
tion containing, in synergistic combination, a soluble pro
1:3,500; and laevo-arterenol, 130,000 to 1:60,000. For
caine salt and a soluble butethamine salt, so proportion
anesthetics to be used in surgery, it is preferred to use
somewhat less of the vascoconstrictor, say, for epineph 20 iated that there is present in the solution, per unit weight of
butethamine, one to three units of weight of procaine; and
rine, 1:130,000 to 1:500,000 parts by weight.
a vascoconstrictive sympathomimetic amine in an amount
It is to be understood that the term butethamine, as
less than 0.02% by weight, based on the total weight of
the solution.
herein employed, signi?es not only the 2-isobutylamino
ethanol ester of para-aminobenzoic acid, but also its iso
mer, the 2-isobutylaminoethanol ester of meta-amino
lbenzoic acid, which, too, is a potent local anesthetic. The
para-isomer is the preferred member of this group for the
purposes of this invention.
6. A new composition of matter ‘as de?ned in claim 5
wherein the soluble butethamine salt is present in the
aqueous saline solution in an amount within the range of
To facilitate a fuller and more complete understanding
0.25% to 2.0% by weight, based on the total weight of
the solution.
examples follow, provided by way of illustration merely,
aqueous saline solution in an amount within the range of
of the principles of this invention and of how the products 30 7. A new composition of matter as de?ned in claim 5‘
wherein the soluble butethamine salt is present in the
in accordance therewith best may be made, several speci?c
1.0% to 1.5 % by weight, based on the total weight of the
not by way of limitation upon the invention de?ned by the
subjoined claims.
solution.
EXAMPLE 1
35
chloride, and the vasoconstrictive sympathomimetic amine
is epinephrine.
procaine hydrochloride, 2.0% by weight; p-butethamine
40
EXAMPLE 2
A solution is prepared as described in Example 1 ex
9. A new composition of matter as de?ned in claim 8
wherein the butethamine hydrochloride is present in the
aqueous saline solution in an amount within the range of
0.25% to 2.0% by weight, based on the total weight of the
solution.
to produce a concentration of one part per 75,000 parts by
weight of ?nished solution. The product has the proper
ties hereinabove described.
wherein the soluble butethamine salt is butethamine hy~
drochloride, the soluble procaine salt is procaine hydro-'
An aqueous solution is prepared containing the follow-'
ing substances in substantially the proportions indicated:
hydrochloride, 1.25% by weight; sodium chloride, 0.45%
by weight; sodium bisul?te, 0.02% by weight; methyl
para-hydroxybenzoate, 0.01%; and epinephrine, su?‘icient
>
8. A new composition of matter as de?ned in claim 5
45
10. A new composition of matter as de?ned in claim 8
wherein the butethamine hydrochloride is present in the
aqueous saline solution in an amount within the range of
1.0% to 1.5% by weight, based on the total weight of the
solution.
11. A new composition of matter as de?ned in claim 8
is increased to 1.5% by weight. The product so obtained 50
cept that the proportion of p-butethamine hydrochloride
has the properties hereinabove described.
EXAMPLE 3
wherein the procaine hydrochloride is present in the aque
ous saline solution in an amount substantially equal to
2.0% of the total weight of the solution.
A solution is prepared as described in Example 1 except
that the proportion of p-butetharnine hydrochloride is de
, References Cited in the ?le of this patent
creased to 1.0% by weight. The product so obtained has
FOREIGN PATENTS
the properties hereinabove described.
Great Britain _________ __ Mar. 19, 1952
668,502
Having thus described the subject matter of this inven
tion, what it is desired to secure [by Letters Patent of the
OTHER REFERENCES
United States is:
60
Goodman et al.: Pharmacological Basis of Therapeu
1. As a new composition of matter, useful in medicine
tics, 2nd ed., 1955, Macmillan Co., New York city, p. 365.
as a local anesthetic agent, an aqueous solution containing,
Gray et al., Jour. Pharm. and Pharmacol, February
in synergistic combination, a soluble procaine salt and a
soluble butethamine salt, so proportionated that there is
1954, vol. 6, No. 2, pp. 89-114.
Документ
Категория
Без категории
Просмотров
0
Размер файла
548 Кб
Теги
1/--страниц
Пожаловаться на содержимое документа