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Патент USA US2100054

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‘. Patented
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12,100,054??? ‘
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. UNITED
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TES- PATENT 1 OFFICE
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2, 2,100,054
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_
opkinsong'andAlexander
'ANESTHETICVTANNATE‘
V. Tolstoouhov,
“
‘ v NewijYork',lN. >Y., assignors to Ostro Research
Laboratoriealna, New York; N. Y., a corpora
tion of‘NewJ/ersey'
1-
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' :No .Dr‘awingJlApplicationOctober 27; 1933,.
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‘.S¢"#1.N0l695,5°6'
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4 Claims. ‘ (Cl. 167-52)
7
p
t This invention relates‘to‘newv compound and 9' [In ‘cases- of painful burns,‘ ulcers,' hemorrhoids, ‘
compositions‘ useful‘iini the“ treatment 'o'ti;,scalds,
burns,- denuded surfaces‘and‘other painful‘lésions
‘
'
‘Y
of the skint‘or mucous membranes,‘ and; to the‘
a‘ j 5 Process of‘producingthe'mo
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‘ H
‘l
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a‘
Y‘
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'3
acid.
This can'be accomplished by combining
tannic. acldand‘local anesthetics, or by making
. ' Picric acid has :been in .use‘ior‘ a long time'as
‘salts thereof. that have all-thesedesirable proper
a disinfectant 'andprotein ‘precipitant in the
treatment of ‘burns?usually in‘ the ‘form of a
ties- Tannates of. local anesthetics generally are
fairly insoluble fat the pH or body ?uids. » This
water solution.
Itr'has some-anesthetic proper-
101 gtieswhich are-of courseioftgreatwbene?t in the
‘ 0‘
etc; it is desirableto add anesthetic action to the
astringent and Jantiseptic ‘properties of tannic
treatment of burnsmI-Iowever, it has-several
drawbacks, the most important .of which is a
relatively high general ‘ toxicity, especially when
used on large areas. It also produces some local
l5“ irritation to the tissue cells due to the fact that
i it is a fairly strong‘ acid.
Furthermore, it pro-
duces an objectionablecyellow color‘to the skin
property? increases
the length‘ of
action
of
I
anesthetics and decreases their general toxicity, 10
so'that. they are safe for use ‘on large areas; _ 1'
_. The salts of anesthetics‘ and 'tannic acid are,
‘soluble in acid media at pH of about 3.0-4.0.‘ The p ‘
pH at which tannates of di?erentzanesthetics are '
soluble varies widely. For the maximum activity 15
of both the tannic acid and anesthetics thé re-v
action of the solutions or ointments ‘containing
which is di?i'cult to remove. j
Local anesthetics in an oily base or carrier
have been used for some time inhthe treatment of
‘,burns principally" for “ the purpose‘ of relieving
them should be-just su?iclent to prevent the
formation Of .a- heavy‘precipitate- This can be
obtained either by adding a. definite excess ‘of.
‘
tannic acid to the Solutions; 01‘ by adding an acid 20
‘pain, and ithas been‘proposed heretofore ‘to com-
Salt Of Phosphoric 61‘ $01118‘ other Weak acidhsuchi
bine these two‘ forms’ ofl'treatment by the use of‘ a5 citric acid, tartaricfblfphthalic acid; ' . i
.
the picrates of certain local anesthetics; ‘(U.' S. ' ‘Tam’lates of ‘anesthetics can 'bQJ’JSOIatGd' only.’ '
1,596,259_)
t
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when the ,pH of the solutions .‘are‘abovecertain - ,
‘Now \we have discovered that the tannates of
certain'local anesthetics'exhibitanumberof prop-
?gures! Usually when‘ Solutions ofjliydrdchlo- 25"
Tides of 19°94 aIlESth?iCS" and ?anmd acid'are ‘
erties which render. them vastly superior to the’
mixed thepH Otthle;s0,1uti0ns\are,it0q10w to give?
. picrates in the treatment of burns or other painful
precipitation Of '
'
Salt 01" htannaté. that .15..
' ‘I ‘30 lesions. We have also discovered asimple method 'forméd- This‘ may ‘.P9$sib1¥§”eXP1a,1n Why Such '
whereby ‘these tannates, whicliheretofore have Salts'h3V'e<P0t,"DreVi011S1y ‘been. ‘prepared- _
, .30
' not been known, can be prepared in a su?iciently
Tannat'es'bflocal anesthetics may be Prepared ’
. pure state to enable them to be used with safety. in 360011131153 with Fhé‘fpresent inventioneither‘
‘ ‘
Tannic acid has heretofore been'used chie?y as
iv 35 an astringent for ‘ mucous membranes‘ of the;
,iby'mixingan alcohol solutionlof va local anesthetic
‘
in‘the form qfyth'e ‘free, base anda solution of 1- ~ - *
"
and
mouth
disinfectant
and intestinal
in the
tract
preparation
and as‘anofastringent
the skin
‘
of patients or hands of surgeons for Surgiéa] 0p_ ‘ solution 'Of_ tannic acid»; MOther vSCVJIVGDJJS’(Liitl'l. also erations. It has also been usedfor the treat-‘9 be Used instead“ 31cbh°1,..b1‘- Water-I To isolate
, 40“ ment of burns with good results; .
‘t
‘
a‘local
tar'm'ic‘ acid;
anesthetic
or‘by hydrochloride
mixing-‘ah aqueous
and‘an
solution
aqueous‘!
or
i
Tannlc .acid has a .very‘ low general'toxlcity.
It is completely oxidized in the body, whether
the tannates .in dry for‘ ' ,iti'S preferable ‘2,0 use 40
the ‘aqueous solu-tio
_' adjust the pH ‘in'each
particular ‘case,v 'otasto-givethe ‘maximum'pre- .
‘taken by mouth or» intravenously. ‘This vlow ' cipitation oflthe ztannate' consistent with purity
fgeneral toxicity of .tannic acid gives it a very
:
of the.product.i_;_Thepligljis adjusted by adding ‘is 3
+45‘ important advantage in comparison with plcrie . an alkali, such‘astsodiumfhydroxide, for example. 45 '
‘
acid. ‘Picric acid‘ has ‘the disadvantage that ‘it
The. precipitated tann'ate' may be- removed by
‘ is sooner or later absorbed in the body and causes ,' ?lteringand is then ‘ ied.
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vv‘poisoning. . This disadvantage is not present
,In- carrying out‘ his invention it has. been
1 ‘ with tannic acid as it forms protein. tannates found that tannates that are produced by causing
‘ 50 ‘which act as a protection. These vtann'ate's'h’av'e '-tannic acid to react vwith local anestheticsthat
‘
no poisonous propertiea}Tannicaacid has also have basic properties are ‘very e?ective. We
. bactericidal
properties. ' , The "combination
of _.have. also found that tannates produced by caus
astringentand antiseptic properties together with
~
ing tannic acid to react with local anesthetics
negligible toxicity make tannic acid very useful . that have basic properties ‘dueto the factthat'r
' ootforthehuman‘beingh1.1»
" I t
»
a
"
they contain an aminov group or-a, substituted 55
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2
2,100,054
amine are particularly useful in treating vburns
and other skin lesions. More particularly, local
anesthetics that have basic properties and have
an aromatic nucleus, such as a naphthalene
nucleus and others, can be used to form the tan
nate when reacted with tannic acid’, thus produc
ing products veryuseful for the purposes of this
invention.
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i
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The precipitate is a brownish powder that ‘is
very di?icultly soluble in H2O, alcohol, and weak
alkalies, but is soluble in dilute acids. Its melting
point is 107-109" C.
The smallest visible precipitation of salt starts
from N/ 100 solutions of the hydrochloride of this
anesthetic and free tannic acid at about pH
4.38. Maximum precipitation takes place at about
e
The tannates of anesthetics prepared in ac
10 cordance with this invention can be incorporated
into ointments, suppositories, pastes, etc.
We
pH 7.08.
‘
Example 3.——Preparation of cz-blltYlOXYCiil 10
choninic acid diethyl-ethylenediamide tannate:
15
15
coin,
N
20
20
prefer to use 1 to 5% by weight of the tannate
in such vehicles depending on the strength of the
particular local anesthetic that is used in mak
ing the tannate.
25
»
i
- The following are given for illustrative purposes
as speci?c examples for preparing the tannates
of some local anesthetics, but it is to be under
stood that the invention is not restricted to these
examples.
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Example 1.—Preparation of l-ethoxy-‘i-(beta
diethyl-amino-ethyl) -naphthalene tannate:
This tannate can be prepared in a similar way,
i. e., by dissolving 2 mols of a-butyloxycinchoninic
acid diethyl-ethylenediamide hydrochloride and 1
mol. of tannic acid in ‘100 cc. of water and adding
NaOH. The pH of the solution should not be 25
above 5.0. At higher pH the yields ‘are ‘higher,
but the salt is not stable. The salt obtained at
this higher'pI-I turns to a dark brown color.
This tannate is a brown powder. It is *di?i
cultly soluble in water, alcohol, and weak alkalies, 30
and it is soluble in weak‘ acids. Its melting point
is 94—96° C.
.
0 CIH|
35
40
Dissolve 1.5 gm. of tannic acid '(2 mols) in 100.0
cc. of H20 and 0.9 gm. of 1-ethoxy-4-(beta-di
ethyl-amino-ethyl) -*naphthalene - hydrochloride
(1 mol.) in 25.0 cc. of H20. Mix the solutions
and add 25.0 cc. of N/10 NaOH to bring the
45 pH of solution to 4.6. Filter the precipitate that
is formed, wash with H20 and dry in vacuo. As
an alternative, powdered tannic acid and hydro
chlorides of anesthetics can be dissolved together
and-N/lO NaOH can be added to the mixture
50 afterwards. The yield is 92% of the theoretical
yield.
I
The smallest visible precipitate of salt ‘starts
40
from N/ 100 solutions of the hydrochloride of this '
anesthetic and free tannic acid at about pH 3.64.
Maximum precipitation takes place at about pH
6.16.
i
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Example 4.—Preparation of the ‘tannate of
methyl. ethyl dimethylamino-methyl carbinol
benzoate (stovaine).
V
'
CH:
1
50
.
C O O-(f-CHaNGIHzOaHO O C (OIl)2.Caii2.O.0 C.CcH2(OH):
.
The precipitate or tannate is a light, creamy
powder that is di?icultly soluble in H2O, alcohol,
and weak alkalies and is soluble in dilute acids.
55 The melting point is 115-117° C. If the pH of the
solution from which the precipitate is formed by‘
adding the alkalies is above 4.6 the precipitate
Dissolve
gm.
of water.
of stovaine
1.5To
.gm.
precipitate
hydrochloride
of tannicthe
acidtannate
(1(2mol.)
mols)add
mice
and. 0
turns purplish brown soon after it is formed.
The smallest visible precipitation of salt starts
60 from N/100 solutions of the anesthetic hydrochlo
ride and free tannic acid at about ,pH 3.53.
65
N .
i-GNaOH
Maximum precipitation'of the salt takes place
at about pH 4.55.
Example 2.—-Preparation of diethyl-amino
to bring the pH to 5.22. Filter the precipitate
that is formed, wash with water and dry in vacuo.
ethyl ester of p~amino benzoic acid tannate or
very poorly soluble in water, alcohol, and weak
alkalies, but is soluble in dilute acids.
The smallest visible precipitation of the salt
Dissolve 1.5 gm. of tannic acid (‘2 mols) and 0.87
70 gm. of procaine hydrochloride (1 mol.) in 100
cc. of H20, add 20.0 cc. of N / 10 NaOH to'bring the
‘The tannate is a light creamy powder that is
starts from
_li ,
70
100
pH of the solution to 6.0. Filter the precipitate " solutions of the anesthetic hydrochloride and free
which forms, wash a few times with H20 and dry tannic acid at about pH-4.'69. Maximum pre
cipitation of this salt takes place at about pH 75
75 in vacuo.
2,100,054
5.22. The tannate melts vat .959-100° C. with de
composition.
v
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of water. An alternative method is to dissolve
_
one part of the hydrochloride of the local anes
Example 5.—Preparation ‘of the tannate‘ of
thetic and ?ve parts of tannic acid in 200 parts
of water. Part of the tannic acid is immediately
ethenyl-p-diethoxydiphenylamidine v (holocaine). .
/
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CHIC
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V
Nn-O-omm
\
10
.
‘Dissolve 1.5 gr. of tannic acidj(2 mols) plus 0.69
. gmseof ethenyl-p#diethoxydiphenylamidine hy
‘ ,rdrochloride' (1 mol.) in 100 cc.’ 01' water. To pre
cipitate the tannate add
15
N'
.to bring the pH to 4.98.v Filter the precipitate
that is formed, wash with water and dry in
vacuo.
‘
a The tannate is a light creamy powder that is
very poorly soluble in water, alcohol, and weak
alkalies, but is ‘soluble in dilute acids.
The smallest visible precipitation of the salt
.25
starts from ,
.
'
this second method is ease of preparation. This
solution can be applied to the denuded area by 1
.
a In addition to theadvantage which the tan
nates‘ of local anesthetics have over the corre
'
‘
10
used to form' the tannate.‘ ‘The advantage of
means of tampons or swabs.
. ENaOl-I ‘ l
20
3
15
sponding picrates in being non-toxic,‘ colorless
and non-staining, there is another important ad
vantage. Tannic acid is an'oxygen absorbent
‘and therefore acts to prevent the decomposition , 20
of the readily oxidizable local anesthetics when
exposed to air. On the other hand, picric acid
does not prevent this oxidation. The tannates
of local anesthetics have been found to be much
more stable than the corresponding picrates. .25
3!.
Examplesof other local anesthetics, the tan
100
nates of which are useful in the treatment of
solutions of the anesthetic hydrochloride and‘ burns, denuded areas and other painful lesions I
free tannic acid at about pH 4.20. Maximum are:
precipitation of salt takes place at about pH 4.98.
Cocaine
‘l 80
. The tannate melts at 1509-155° with decomposi
tion.
For application to painful lesions, the tan
nates described above, and other similar tan-r
nates, can be dissolved in water that is slightly
1 j acidi?ed; or theymay be incorporated into oint
ments by methods well-known in the art; or they
‘ ‘ may be incorporated in‘ a “areaseless cream”. We
40 prefer to use about 1 to 5% of the tannate in any
of the‘above bases or carriers.
-
r
A particularly ‘useful ointment for ‘serious
~burns, scalds,'etc. can be prepared by mixing 2
‘ parts by weight of 1-.ethoxy-4-(beta-diethyl
‘ 745‘ amino-ethyll-naphthalene
tannate, 90 parts
‘white Vaseline and 10v parts lanolin. 2 parts of
; tannic acid may be added to the above if'desired.
A‘ very satisfactory creainfor the treatment
of ‘sunburn can be prepared by mixing one or
two parts by weight of l-ethoizy-4-‘(beta-diethyl
amino-ethyl),-naphthalene tannate with 20 parts
of glycerol mono stearate and 80 parts of water
at 70° C. and allowing the mixture to cool while
stirring.
This produces a cooling greaseless
cream having a neutral reaction.
Several parts .
of Vaseline, lanolin or petrolatum may be added
to the above if desired.
_
,
Tropacocaine
v
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Trimethyl-benzoxy-piperidine (eucaine)
,
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Occasionally, physicians, prefer in the treat
ment of large burns to use an aqueous solution
60 and to leave the areas uncovered until the nat
ural formation of ‘a protective covering. An ex
cellent wash can be prepared for this purpose by
dissolving one part by weight of 1-ethoxy-4
(beta-diethyl -. amino-ethyl) -naphthalene
tan
V65 nate and two parts of tannic acid in 100 parts
Benzoxy-dimethylamino-methyl dimethyl-amij
no butane (alypine)
p-Amino-benzoyl dimethyl-amino-methyl-bu
tanol (tutocaine)
‘
.p - Amino - benzoyl - gamma -
amino propanol (butyn).
dinormal - butyl
vWe claim:
- 1. A composition for treating'skin lesions hav
ing therein a compound in the list consisting of
1-ethoxy-4-(beta- diethyl - amino-ethyl) - naph
thalene tannate, diethyl-amino-ethyl ‘ester of
p-amino benzoic acid tannate, a-butylox'y cincho
ninic acid diethyl-ethylenediamine tannate,
methyl ethyl dimethylamino-methyl carbinol
benzoate tannate, ethenyl-p-diethoxydiphenyl
tannate, ‘ tropacooaine tannate, tri
methyl-benzoxy-piperidine tannate, benzoxy
dimethyl-amino-methyl dimethyl-amino butane
amidine
tannate,
p - amino - benzoyl
'50
dimethyl - amino
methyl-butanol tannate, and p-amino-benzoyl
gamma-dinormal~butylamino propanol tannate.‘
2. A composition for treating skin lesions hav
ing therein 1-ethoxy-4-(beta-diethyl-amino
55
benzoic acid tannate.
4. A composition for treating skin lesions hav
60
ethyl) -naphthalene tannate.
3. A composition fortreating‘skin lesions hav
ing therein diethyl-amino-ethyl ester of p-amino
ing therein a—butyloxy. cinchoninic acid diethyl
ethylenediamide tannate.
RUSSELL HOPKINSON.
ALEXANDER V. TOLSTOOUHOV.
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