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Патент USA US3091579

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United States Patent 0
1CC
,7
3,091,569
Patented May 28, 1963
1
2
3,091,569
toxic substance, such as sodium hydroxide, ammonium
hydroxide or the like, and thus the nontoxic salts of the
sulfhydryl compounds, such as the salts of sodium, am
MUCOLYTIC-N-ACYLATED SULFHYDRYL COM
POSITIONS AND PROCESS FOR TREATING
ANIIVIAL MUCUS
Aaron Leonard She?'ner, Evansville, Ind., assignor to
Mead Johnson & Company, Evansville, 111th, a corpo
ration of Indiana
No Drawing. Filed Aug. 26, 1960, Ser. No. 52,040
12 Claims. (Cl. 167-58)
This invention relates to a therapeutic composition
and process and has for an object the provision of a com
monium, calcium, magnesium and the like, together with
the nontoxic acid addition salts thereof, are included with
in the scope of this invention.
This invention ?nds particular applicability in the treat
ment of the mucous membrane in animals with the stated
compound in order to reduce the viscosity of the mucus
10 on the membrane. As will be apparent from the follow
ing description, the invention is particularly useful for
deeongesting the respiratory and vaginal tracts of animals.
position and process for treating animal mucus.
The sulfhydryl compounds of this invention may be
The treatment of pathological disorders in the respira
prepared by conventional procedures. The following
tory system is a well developed medical practice and a 15 methods may be used:
number of compositions have been suggested ‘for the treat
N-propionyl~L-cysteine.—-To 35.1 gm. (0.2 mole) L
ment of such respiratory diseases as the common cold,
cysteine hydrochloride (monohydrate in 100 ml. 4 N
allergies, severe bronchitis, and the like. Certain of the
sodium hydroxide at 0° C. is added, with ellicient stir
heretofore proposed compositions have met with some
ring and under a nitrogen atmosphere, 22.2 gm. propionyl
success, but there is still a wide recognition that the ideal 20 chloride and 60 cc. 4 N sodium hydroxide over a two
preparation has not been found. For example, it has
hour period. The mixture is stirred in the cold an ad
been discovered in accordance with one embodiment of
this invention that an ideal decongestant suitable for use
ditional two hours and at room temperature for three
which includes the step of contacting the mucus with an
mixture a material is obtained which is contaminated with
hours. The mixture is stored in the refrigerator over
in treating the respiratory system is one which should
night, acid?ed with 33.3 ml. 6 N hydrochloric acid and
25
have marked mucolytic properties. Secondly, the com
concentrated under reduced pressure at room tempera
position should be compatible with other therapeutic
ture until solids begin to appear. Ethanol is added and
agents that may be used in connection therewith, such
the mixture ?ltered to remove the insoluble salts. The
as vasoconstrictors, vasodilators, antibiotics, sulfa drugs,
?ltrate is evaporated to an oil which is redissolved in
antihistaminics, enzymes, surfactants and antiseptics. In
40 ml. water and passed through a 24" x 2" Dowex
30
addition, such agents should be capable of convenient
ill-X8 (200-400 mesh) column (H+ cycle). The col
administration as a powder by insuiilation, or in solution
umn is eluated with water and that volume giving a posi
as in nose drops or as sprays or aerosols.
tive nitroprusside reaction is collected. The eluate is
Accordingly, it is an object of this invention to provide
concentrated under reduced pressure to an oil which after
a therapeutic agent which may be readily administered
refrigeration for three months gives a crystalline product
which has a high degree of mucolytic activity and which 35 melting inde?nitely (hydroscopic) at 7 5-80".
is compatible with other types of therapeutic agents that
N-acetyl-L-cysteina-A process may be used for the
may be used in connection therewith.
preparation of this compound which is essentially the same
A further object of this invention is the provision of
as that for the preparation of N-propionyl-L-cysteine de
a process for treating mucus whereby viscosity of the 40 scribed above except that acetic anhydride or acetyl chlo
mucus is quickly and markedly reduced.
ride may be substituted for the propionyl chloride. The
A still further object of this invention is the provision
method of Pirie et al., Biochemical Journal, 27, 1716-18
of a process for contacting mucus on a mucous mem
(1933) may also be used.
brane in an animal whereby the viscosity ‘of the mucus
N-caproyI-L-cysteine.-—This product may be employed
is markedly reduced and decongestion in the treated area 45 by the same general method indicated above except that
is attained.
n-caproyl chloride is used as the acylating agent.
Further and additional objects will appear from the
N - benzoyl - L - cysteine.—-L - cysteine hydrochloride
following description and the accompanying claims.
(monohydrate) is reacted with benzoyl chloride and
In accordance with one embodiment of this invention,
sodium hydroxide under general Schotten-Baumann re
a process is provided for the treatment of animal mucus 50 action conditions. Upon acidi?cation of the reaction
N-acylated sulfhydryl compound having the formula
benzoic acid.
Washing with benzene and ether and re
crystallization from these solvents gives a ?nal product
melting at 105-110".
N -acetyl~DL-penicillamine.-—N - acetyl - DL - penicilla
mine is prepared according to the procedure described
by Leach and Hunter, Biochemical Preparations, 3, 111
(195 3) by reacting 4-isopropylidiene-Z-methyl-S(4)- oxa
zalone (prepared from N-chloroacetyl-DL-valine) with
wherein R1 and R2 are each selected from the group con 60 hydrogen sul?de followed by hydrolysis.
sisting of hydrogen and lower alkyl (up to four carbon
N - acetyl‘pt-mercapto-DL-is0leucine.—N-chloroacetyl
atoms) and R3 is selected from the group consisting of
DL-isoleucine is converted to the azlactone with acetic
lower alkyl and phenyl. Speci?c compounds that are
anhydride. Reaction of hydrogen sul?de in sodium meth
included within the scope of this invention are N-ace
oxide with azlactone followed by hydrolysis gives the
tylcysteine, N-propionylcysteine, N-caproylcysteine, N 65 N-acetyl-?unercapto-DL-isoleucine. This is essentially
benzoylcysteine, N-acetylpenicillamine, and N-acetyl-?
the procedure described by Clark ct al., The Chemistry
mercaptoisoleucine. These compounds all contain a sulf~ ' of Penicillin, Princeton University Press, 1949, page 469.
hydryl group and a carboxyl group. It will be apparent
The product is probably a mixture of the two racemic
that the carboxyl group may be partially or completely
pairs. M.P. 143-149.
neutralized by adjustment of pH of the solution to be 70 In order to demonstrate the mncolytic properties of
used for application to the mucous membrane. This pH
N~acetylcysteine, ‘small globules of clots of viscous pul
adjustment is effected by a suitable alkaline-reacting non
monary secretions were placed on glass slides inclined at
3,091,569
4
Example 1
an angle of 53°. At this angle the clots did not move
on the slide. One half of the globules were contacted
with drops of Water and one half with drops of aqueous
An aqueous solution for use in the treatment of the
respiratory tract by inhalation has the following com
0.25 M N-acetylcysteine. The globules treated with wa
ter retained their rigidity while those treated with the N
position:
N-acctylcysteine _____________________ __gm_3.0
Distilled water q.s. ad __________________ __ml__ 100.0
acetylcysteine solution immediately collapsed due to loss
of viscosity and ran down the slides.
Sodium hydroxide in an amount sufficient to impart
pH 7.5 to the solution.
Drops of N-acetylcysteine solution (0.25 M, pH 7.5)
were administered intranasally to a young woman with
Example 2
congested sinuses (chronic condition), a young man 10
with congested sinuses and nostrils from a common cold,
An aqueous solution for use in the treatment of the
and a seven-month-old baby girl with severe bronchitis.
respiratory tract by inhalation containing a chelating
Immediate clearing of the nostrils and sinuses took place
in each instance. In the case of the child, the bronchitis
agent to increase the stability of the mucolytic agent has
the following composition:
was severe enough to warrant placing her in an oxygen 15
tent; also, the administration of an aerosol containing a
N-acetylcysteine
commercially available surface active agent had been
unsuccessful. The bene?cial effect of the N-acetyl
Sodium EDTA _______________________ __gm__
0.1
Distilled water q.s. ad __________________ __ml__ 100.0
Sodium hydroxide in an amount to impart pH 7.5
cysteine solution lasted 21/2 to 3 hours in the adults and
20
approximately 45 minutes in the child.
_____________________ __gm__ } 20.0
to the solution.
Tests have been made on the other sulfhydryl com
pounds as de?ned above and it has been found that they
Example 3
the beta substituted compounds (i.e. R1 and/or R2 equal
‘lower alkyl).
cants and excipicnts and has the following composition:
A composition suitable for inhalation as a powder
also have mucolytic properties. The N-acylated cysteine
aerosol from a pressurized container in which the mu
compounds which are not substituted in the beta position
colytic agent is present ‘as a micronized powder suspension
(i.e. R1=R2=hydnogen) appear to be more effective than 25 and in which the aerosol contains the conventional lubri
N-acetylcysteine, sodium salt _____________ .__igrn__ 1.0
Also in accordance with this invention, a therapeutic
Freon 12 _____________________________ _._ml__ 23.0
composition has been provided which comprises the N
acylated sulfhydryl compound and a pharmaceutical car 30 Freon l4 _____________________________ __rnl__ 77.0
rier, thereby resulting in a composition which may be
Example 4
used readily in the above indicated process. The phar
A composition suitable for intranasal instillation has
maceutical carrier may comprise water, or in the event
the following composition:
that it is to be sprayed, may comprise a suitable aerosol
propellant, as is well known. Other inert pharmaceutical 35 N-acetylcysteine _____________________ __gm__
10.0
carriers may be employed, such as lactose, starch, calcium
Sodium EDTA _______________________ __gm__.
0.1
carbonate, cream or jelly base carriers, talc, hydrated
Cetyl pyridinium chloride (a bacteriological pre
alumina or the like, the type of carrier being dependent
servative) _________________________ "gm-.. 0.02
at least in part upon the type of composition desired and
Distilled water q.s. ad __________________ "ml-.. 100.0
the place and method of its application to ‘the mucus. If 40 Sodium hydroxide in an amount to impart pH 7.5
desired, the N-acylated compound can be combined with
to the solution.
various therapeutic agents which may include (1) vaso
constrictors for reducing mucosa] swelling and diminish
ing the secretion of viscous mucus in the respiratory tract,
(2) bronchodilators to aid in the passage of air to the
The above preparation may be instilled as drops or spray
or by use of nitrogen pressure (nitrosol).
45
lungs, (3) antibiotics, antiseptics and chemotherapeutic
agents to prevent infection and the resultant secretion of
purulent ?uids, (4) antihistaminics ‘or steroids to reduce
allergic and other in?ammatory reactions, (5) surfactants, 60
Examples 5 and 6
N-propionylcysteine or N-caproyl-L‘cysteine may be
substituted for N-acetylcysteine in Example 4.
Example 7
A suitable composition for inhalation containing a
and (6) various enzymes, such as deoxyribonuclease
and/or protcolytic enzymes which under certain condi
tions may supplement the action of the N-acylcysteine.
N-acetylcysteine ______________________ __gm__
3.0
The N-acylcysteines, and particularly N-acetylcysteine,
Epinephrine hydrochloride _____________ __igm__
0.1
bronchodilator has the following composition:
are particularly useful as mucolytic agents in accordance 55 Sodium EDTA _______________________ __gm__
0.1
with this invention since these compounds do not have
Distilled water q.s. ad __________________ _ml__ 100.0
Sodium hydroxide in an amount to impart pH 7.5
an obnoxious odor. They do not have a nauseating taste
to the solution.
and they are relatively stable to oxidation in aqueous
Examples 8 and 9
solution. Because of this stability the mucolytic proper
ties of the compounds are retained in compositions con 60
N-propionylcysteine or N-caproyl-L-cysteine may be
taining water, especially in the presence of sodium
substituted for N-acetylcysteine in Example 7.
ethylenediarnine tetraacetic acid (EDTA) or other chelat
Example 10
ing agents, and the compounds do not form a precipitate
A_ suitable composition containing an antihistaminic
on standing which could produce irritation in the respira 65
‘for intranasal instillation has the following composition:
tory tract upon use. The compositions are relatively in.
nocuous and are nontoxic.
They can be used as often
as required to remove mucus from the respiratory tract
or other areas of the body where the presence of the
_____________________ -_gm__
3.00
Chlorpheniramine maleate _____________ __gm__
N-acetylcysteine
0.02
Sodium EDTA _______________________ __gm__
1.10
70 Distilled water q.s. ad _________________ __ml__ 100.0
Sodium hydroxide in an amount to impart pH 7.5
plete understanding of this invention, reference will now
to the solution.
be made to a number of speci?c examples showing com
Examples 11 and 12
positions which may be prepared and used in accordance
N - benzoyl - L-cysteine or N-acetyl-DL-penioillamine
with this invention but applied to the animal by the usual
75 may be substituted for N-acetylcysteine in Example 10.
‘techniques, as will be understood in the art.
viscous mucus is a clinical problem.
For a more oom
3,091,569
6
Example 13
has the following composition in grams for each four
grams of powder:
Gm.
A composition containing a vasoconstriotor for intra
nasal installation has the following composition:
N-acetylwsteine
N-acetylcysteine ____________________ __gm__
3.00
Phenylephrine hydrochloride __________ "gin"
0.25
Sodium EDTA ______________________ __gm__
0.10
Distilled water qs. ad ________________ .._ml__ 100.00
Sodium hydroxide in an amount to impart pH
7.5 to the solution.
Tyrothricin ______________________________ __ 0.015
Cetylpyridinium chloride ___________________ __ 0.010
Sodium
10
N-acetyl-DL-penieillarnine may be substituted for N
acetylcysteine in Example 13.
Example 15
EDTA
_
__..__
_ 0.020
4.0
As a vaginal cleansing agent, dissolve ‘four grams of
the above composition in 1000 milliliters of water and
use as a douche.
15
A composition containing an antibiotic for intranasal
instillation has the following composition:
Example 26
N-propionylcysteine may be substituted for N-acetyl
cysteine in Example 25.
In the case of aqueous solutions, the concentration of
the active N-acylated compound therein is preferably
between about 0.05 and 25 percent by weight. Also, the
Gm.
N-acetylcysteine ____________________________ __ 3.0
Sodium
1.0
0.75
Lactose (powder) q.s ______________________ __
Example 14
Neomycin
_________________________ __
gbicarbonate _______________________ __
sulfate ___________________________ __ 0.3
EDTA ___________________ -i ________ __ 0.1
20 aqueous solution prepared for administration should
have a pH between about 4- and about 9 and the pH is
adjusted as desired by the use of a suitable alkaline-re
‘Prepare the above as a concentrate, add a bacteriologi
acting material.
cal preservative and lyophilize. At the time of use the
In the foregoing description, particular reference has
composition is reconstituted with a sufficient quantity of 25 ‘been
made to the treatment of the respiratory and vaginal
water
liters. to bring the solution to a total volume of 100
tracts in order to e?ect the desired decongestion by the
above de?ned compounds. However, it will be apparent
Examples 16, I7 and 18
that they may be used for the treatment of the mucous
membranes in animals in other types of disorders, such
N-propionylcysteine, N-caproylcysteine or DL-N-ace
tyl-beta-mercaptoisoleucine may be substituted for N 30 as various topical ulcerations accompanied by muco
purulent discharge, such as occur in bedsores and drain~
acetylcysteine in Example 15.
ing sinuses, debridement, and otitis media serosa.
Example 19
This application is a continuation-in-part of my ap
plication
Serial No. 832,158, ?led August 7, 1959, now
A composition containing an anti-in?ammatory agent 35
abandoned.
for intranasal instillation has the ‘following composition:
While several particular embodiments of this inven
N-acetylcysteine _____________________ __‘gn1__
3.0
Prednisolone-Z 1 phosphate
0. 1
____________ _ -gm- _
tion are shown above, it will be understood, of course,
that the invention is not to be limited thereto, since many
modi?cations may be made, and it is contemplated, there
fore, by ‘the ‘appended claims, to cover any such modi?ca
tions as fall within the true spirit and scope of this in
Sodium EDTA _______________________ __gm__
0.1
Distilled water q.s. ad _________________ "ml-.. 100.0
Sodium hydroxide in an amount to impart pH
6.5 to the solution.
vention.
Example 20
I claim:
1. A mucolytic process which includes the step of con
A suitable solution for vaginal application either by 45 tasting
animal mucus with an N-acylated sulfhydryl com
swab or nitrogen-propelled spray has the following com
pound having the formula
position:
N-aoetylcysteine _____________________ __gm__
3.0
Sodium EDTA ________________________ __gm_._
0.1 50
Distilled Water q.s. ad __________________ __ml_- 100.0
Sodium hydroxide in an amount to impart pH 6.5
to the solution.
Examples 21 and 22
N - benzoyl-L-cysteine
or
N-acetyLDL-penicillamiue 55
may be substituted for N-acetylcysteine in Example 20.
wherein R1 and R2 are each selected from the group con
sisting of hydrogen and lower alkyl and R3 is selected
from the group consisting of lower alkyl and phenyl.
2. The process recited in claim 1 in which said com
' pound is contacted with said mucus in the form of a
Example 23
An e?ervescent vaginal insert tablet having the follow 60 composition having a pH between about 4 and about 9.
3. A mucolytic process which includes the step of con
tacting animal mucus with N-acetylcysteine.
4. A decongcsting process which comprises contacting
N~aoetylcysteine _____________________ __m-g__ 100.0
ing composition per tablet is as follows:
chloride ______________ __mg__
4.0
mucus on a mucous membrane in an animal with an N
_________________________ .. _mg_ _
5.0
acylated sulfhydryl compound having the formula
Cetylpyridinium
Tyroth ricin
Sodium bicarbonate ___________________ __mg__
Sodium EDTA _______________________ __mg__
Lactose (powdered) q.s ________________ __gm__
50.0 65
1.0
1.0
Example 24
N-propionylcysteine may be substituted for N-acetyl
cysteine in Example 23.
wherein R1 and R3 are each selected from the group con
sisting of hydrogen and lower alkyl and R3 is selected irom
Example 25
the group consisting of lower alkyl and phenyl.
A powder ‘for preparing a vaginal cleansing solution 76 5. A decongesting process which comprises contacting
8,091,569
7
cysteine, sodium ethylenediarnine tetraacetic acid and a
mucus on a mucous membrane in an animal with N-acetyl
pharmaceutical carrier.
12. A therapeutic solution comprising water having dis
cysteine.
6. A process for decongesting the respiratory tract of
an animal which comprises introducing into said tract and
into contact with the mucus therein, N-acetylcysteine.
7. The process of claim 6 wherein said N-acetylcysteine
solved therein between about 0.05 and 25 percent by
weight of N-acetylcysteine and sodium ethylenediamine
tetraacetic acid in an amount from about 0.002 to 1.1 per
cent by weight.
is introduced in the form of an aqueous solution.
8. The process of claim 6 wherein said N-acetylcysteine
is introduced in the form of an aerosol.
9. A process for decongesting the mucous membrane in 10
2,283,817
2,666,012
2,666,013
the vaginal tract of an animal which comprises contact
ing the mucus therein with N-aeetylcysteine.
10. A therapeutic composition comp-rising a pharma
ceutical carrier, sodium ethylenediamine tetraacetic acid
and an N-acylated sulfhydryl compound having the for
References Cited in the ?le of this patent
UNITED STATES PATENTS
15
mula
20
2,796,378
2,888,380
2,904,468
2,937,974
3,014,026
3,016,334
3,061,512
Martin et al __________ __
Ferguson ___________ __
Ferguson ___________ __
Ferguson ____________ __
Browne et al. ________ __
Davis et al. _________ __
Ferguson ____________ __
Kroll et a1 ___________ __
May
Jan.
Ian.
June
May
Sept.
May
Dec.
19,
12,
12,
18,
26,
15,
24,
19,
1942
1954
1954
1957
1959
1959
1960
1961
Lewis _______________ __ Jan. 9, 1962
Anderson et a1. ______ __ Oct. 30, 1962
OTHER REFERENCES
Pirie et al., Biochemical 1., vol. 27, 1933, pp. 1716
1718.
Van Scott et al., Arch. of Dermatology and Syphilology,
wherein R1 and R2 are each selected from the group con- 25
70:2, 1954, pp. 141-454.
sisting of hydrogen and lower alkyl and R3 is selected
Edwards, Biochemical 1., 57:4, 1954, pp. 542-7.
from the group consisting of lower alkyl and phenyl.
Kawasaki, Chem. Abst., vol. 50, 1956, col. 2550, 1 p.
11. A therapeutic composition comprising N-acetyl
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