Note: Descriptions are shown in the official language in which they were submitted.
1~.17015
The present invention is directed to new pharmaceutical
products containing cytostatically active alkylating agents
which are detoxified. More in particular, the present-inven-
tion is related to such pharmaceutical preparations o~ cyto-
statically active alkylating agents which are detoxified bycombining these active agent with a pharmacologically accep-
table salt of a mercapto alkane sulfonic acid in order to
overcome the undesired urotoxic side effects caused by such
alkylating agents in the kidneys, urinary tracts and urinary
bladder. The invention is further directed to a process for
producing such pharmaceutical products.
Cytostatically active alkylating agents such as melphalane,
cyclophosphamide, trofosfamide, ifosfamide, sufosfamide,
chlorambucil, busulfane, triethylene thiophosphamide or
triaziquone and in particular the 2-oxo-1,3,2-oxazaphospho-
rinanes cyclophosphamide, trofosfamide, ifosfamide and sufos-
famide produce undesired side effects such as serious irrita-
tions of the kidneys, the urinary tracts and/or the urinary
bladder of the patient treated therewith. ~s is well known,
such undesired side effects occur readily in particular after
such organs have been damaged for the first time. The
undesired side effects are sometimes produced to such a
degree that the cytostatic therapy of the patient suffering
from cancer has to be interrupted temporarily or is rendered
even impossible at all. In view of the fact that malign
tumors readily produce resistency against a particular
cytostatic, such cytostatics are successful in the so-called
li l7~)~ 5
highdosage therapy. In such a treatment, the cytostatic is
administered at first in a dosage which is very high in
comparison to the toxicity of the cytostatic in order to
produce an initial dosage as high as possible of the cytosta-
tic at the tumor tissue. Thereafter, the cytostatics areadministered in several lower dosages over a prolonged period
of time. It is known that such undesired side effects are
caused by metabolites of the cytostatics produced in the body
of the patient treated therewith. These undesired side effects
quite often occur also with alkylating agents such as 2-~N,N-
bis-(2-chloroethyl)-amino~-2-oxo-1,3,2-oxazaphosphorinane (R)
known under the well-known trade names Endoxan or Cytoxan
or un~er the generic name cyclophosphamide, and 2-CN,N-bis-
(2-chloroethyl)-amino~-3-(2-chloroethyl)-2-oxo-1 3,2-oxaza-
phosphorinane known under the trade name Ixoten ~R) or thegeneric name trofosfamide. Of even more importance are these
undesired side effects when using alkylating agents having a
high cytostatic activity at a lower toxicity such as 2-(N-2-
chloroethyl-amino)-3-(2-chloroethyl) 2-o~o~1,3,2-oxazaphGspho-
rinane known under the generic name ifos~amide. The thera-
peutic usefulness of such valuable alkylating agents which
is particularly based upon the low toxicity, is again sub-
stantially limited by these undesired side effects. It has
been observed recently that such irritations of the urinary
bladder may even cause the formation of malign tumors there.
Many experiments have been made in order to avoid or at least
alleviate these detrimetal and undesired side effects of the
cytostatically active alkylating agents since they can no more
be replaced in the treatment of malign tumors, and a premature 30 rupture of the therapy would produce severe damage or prema-
ture death of the patient. One of the attempts consists in
the administration of increased amounts of liquid, possibly
in combination with the administration of agents increasing
the formation of urine in order to obtain a passage of urine
containing metabolites of cytostatics as quick as possible
through the kidneys, the urinary tracts and the urinary bladder
~ 1~7~ ~ ~
and to avoid the formation of high concentrations of meta-
bolites in particular in thc urlnary bladder. This so-called
hydratation in general is combined with an alkalinazation of
the urine for instance by means of the hexapotassium hexa-
sodium pentacitrate hydrate complex known under the registeredtrade name Uralyt-U and in particular by introducing solutions
of mercapto group containing compounds into the urinary bladder
by means of a catheter. With such mercapto group containing
compounds it was supposed that the mercapto group undergoes
reaction with the alkylating agent, thus inactivating the same.
N-Acetyl cysteine and cysteine i.n particular have been used
as such mercapto group containing compounds. However, the
results only where very limited, in particular in cases where
the cytostatics had to be administered in very high dosages.
Furthermore, the washing of the urinary bladder or vesicoc-
lysis is a procedure very burdensome to the patient, and can
only very hardly be practiced in the treatment with cytostatics
over prolonged periods of time. Furthermore, more upward areas
in the urinary tract cannot be reached by vesicoclysis.
The use of mercapto group containing compounds f~r the general
- detoxification in the therapy with alkylating agents has been
first published by T.A. Connors, Eur~p. J. Cancer 2, 393 to
395 (1966). However, these experiments showed no result
because the mercapto group containing compounds there used
at the same time decreased the cytostatic activity of the
alkylating agents (see in particular loc. cit. p. 300 and 303,
last but one sentence).
After introduction of t~e2-oxo-1,3,2-oxazaphosphorinanes as
alkylating agents and after observation of urotoxic side
effects (hemorrhaginal cysto-pyelonephritis), the first
attempts to avoid such undesired side effects where made by
topically applying mercapto group containing compounds in the
urinary bladder itself. This instillation of N-acetylcysteine
up to now represented a standard prophylaxis against urotoxic
side effects when administering cyclophosphamide and ifosfamide
11~ 7~ 15
at very high dosages (see for instance Hoe~er-Janker et al.,
Med. Welt 26, 972 (1975); Drings et al., Verh. Dtsch. Ges.
inn. Med. 78, 166 (1972); Cohen et al., Cancer Chemother.
rep., Part 1, 59, 751 (1975); Creaven et al., Cancer Treatm.
Rep. 60, 445 (1976); and Primack, J. Nat. Cancer Inst. 47,
223 (1971)).
However, the instillation of HS-group containing compounds
into the urinary bladder did not solve the problem of a
general detoxification. The bene~icial effects of the applied
mercapto group containing compound were limited to the urinary
bladder. Furthermore, the application by means of a catheter
was not regarded as most favourable. Finally, the clinical
effectiveness of this burdensome prophylaxis by no means was
sati~factory (see for instance Falkson, Suid-Afrikaanse
Kankerbulletin 15, 97, 1971).
It surprisingly now has been found that the above described
undesired urotoxic side effect produced by cytostatically
active alkylating agents in the kidney, the urinary tract
and the urinary bladder of patient treated therewith may be
overcome in a simple manner and to a substantially complete
degree, and pharmaceutical products of cytostatically active
alkylating agents may be detoxified, by admixing to such
pharmaceutical products a known pharmacologically acceptable
salt of a mercapto alkane sulfonic acid having the general
formula
HS-EIlk-$03H
wherein alk is a straight or branched alkylene group having
from 2 to 6, in particular from 2 to 4 carbon atoms in an
amount of at least 20 % of the weight of the cytostatically
active alkylating agent contained therein up to the highest
dose which is tolerated by the patient. The present invention
therefor is directed to such d~toxified pharmaceutical pro-
ducts containing cytostatically active alkylating agents by
1117~15
combining them and adding thereto a pharmacologically accep-
table salt of a mercapto alkane sulfonic acid having the
general formula
HS-alk-S03H
wherein alk is a straight or branched alkylene group having
from 2 to 6 carbon atoms, and process for producing such
detoxified pharmaceutical products.
Particularely good detoxification results have been obtained
with such salts o~` 2-mercapto ethane sul~onic acid. Thus, the
pharmacologically acceptable salts of 2-mercapto ethane
sulfonic ac~d are preferred according to the present invention.
Particularly preferred among these salts are the alkali metal
salts of 2-mercapto ethane sulfonic acid, in particularly its
sodium salt. This is the most preferably used salt.
In order to obtain an effective protection of the patient to
be treated with cytostatically active alkylating agen~sagainst
the urotoxic side effects upon the kldney, the urinary tracts
and the urinary bladder it is sufficient to admix to the
pharmaceutical product so small amounts as 20 % of the amount
of cytostatic contained therein. This is particularly true at
low doses of the cytostatic. If the alkylating agent is to be
administered in higher doses, the urotoxic side effect may be
avoided with ~0 % of the amo~mt of the alkylating agent. Since
the uroto~ic side effects in particular occur upon administra-
tion of the cytostatic at high doses, the lower limit of 30 %of the amount of cytostatic is the preferred lower limit for
the amount of the salt of the mercapto alkane sulfonic acid
admixed ~or detoxification of the cytostatics. In view of the
known very low toxicity of the pharmacologically acceptable
salts of the mercapto alkane sulfonic acids, the upper limi~
of the amount of salts of mercapto alkane sulfonic a~ids is
of minor importance. It is surprising and important that the
cytostatic activit~ of the alkylating agents is not at all
al~
decreased or otherwise affected by the use of the salts of
mercapto alkane sulfonic acids in accordance with the present
invention. Even when administering the sodium salt of 2-mer-
capto ethane sulfonic acid in a dose amounting to 100 times
the dose of ifosfamide there was observed no decrease in the
cytostatic activity in test animals. Since the undesired uro-
toxic side effects even at high doses of the cytostatic may
be substantially completely removed with equal arnounts of the
salts of the mercapto alkane sulfon~cs acids, it is preferred
to use the salt of the mercapto alkane sulfonic acids in
amounts corresponding to 30 to 100 % of the amount of cyto-
static.
While the salts of the mercapto alkane sulfonic acids may be
used in combination with all of the cytostatically active
alkylating agents to overcome the above described urotoxic
and in particular undesired side effects these salts of
mercapto alkane sulfonic acids are of particular importance
in combination with the 2-oxo-1,3,2--oxazaphosphorinanes
cyclophosphamide, ifosfamide, trofosfamide and sufosfamide
us~ to a great extent in the treatment of humans suffering
from many kinds of cancer diseases.
The pharmacologically acceptable salts of mercapto alkane
sulfonic acids used in accordance to the present invention
are known compounds (see USP 2 69L~ 732). These or simular
compounds up to now have however never been used to remove
the described urotoxic side e~fects of cytostatically active
alkylating agents. Up to now the medical profession was of
the opinion that the alkylating agents or, respectively,
metabolites thereof causing these undesired side effects
have to be detoxified topically at the place where they
produce the injury and damage and that mercapto group con-
taining compounds have to be applied in these damaged areas
(for instance by instillation into the urinary bladder of
the cytostatically treated patient) so that they produce
their beneficial detoxifying activity at the place of damage.
Furthermore, the mercapto group containing compounds used
up to now showed to be ineffective with this respect when
applied orally. Still furthermore, it was -the opinion of the
medical profession that the cytostatic activity of the alky-
lating agents is produced just by the metabolites blamedfor the urotxic side effects and that, therefor, the mercapto
grovp containing compounds have to be administered as late
as possible in the passage through the human body in order
to avoid a negative influence upon the cytostatic activity
of the alkylating agents and their metabolites. However,
even with the mercapto group containing compounds used up to
now the degree o~ detoxification only was quite limited. The
undesired side effects described hereinabove can be overcome
only to a very limited degree.
The following examples serve to further illustrate the present
invention without howe~er limiting the same thereto.
EXAMPLE 1
-
One part by weight of ifosfamide 2-~N-(2-chloroethyl)-amino~-
3-(2-chloroethyl)-2-oxo-1,3,2-oxazaphosphorinane) and 0.63
parts by weight of the sodium salt of 2-mercapto ethane
sulfonic acid, both in pure sterile form, are homogenously
mixed under sterile conditions in a sterile mixer and filled
into injection ampoules such that each ampoule contains 500 mg.
of ifosfamide and 315 mg. of the sodium salt of 2-mercapto
ethane sulfonic acid per 10 ml. of injection solution.
EXAMPL~. 2
Example 1 was repeated using for each part by weight of ifos-
famide 0.20, 0.50 or, respectively, 1.00 paPts by weight of
the sodium salt of 2-mercapto ethane sulfonic acid.
- 8 -
~ 17`~15
EXAMPLE 3
Injec-tion solutions are prepared as described in Example i
above, containing for each part by welght of ifosfamide 1.3
parts by weight of the sodium salt of 3-mercapto-1-propane
sulfonic acid, 3-mercapto-2-methyl-1-propane sulfonic acid
and, respectively, 6-mercapto hexane-1-sulfonic acid.
EXAMPLE 4
Injection solutions are prepared as described in Example 1
above, containlng for each part by weight of cyclophosphamide
0.63 parts by weight of the sodium salt of 2-mercapto ethane
sulfonic acid.
