IE47609B1 - Process for producing detoxified pharmaceutical products containing a cytostatically active alkylating agent - Google Patents

Abstract

The present invention is related to a process for producing a pharmaceutical preparation containing a cytostatically active alkylating agent which has been detoxified by adding thereto a a pharmacologically acceptable salt of a mercapto alkane sulfonic acid of the general formula HS-alk-SO3H wherein alk is an alkylene group having from 2 to 6 carbon atoms, in an amount of at least 20 % of the weight of the alkylating agent thereby substantially improving the properties thereof. [CA1117015A]

Description

The present invention is directed to new pharmaceutical products containing cytostatically active alkylating agents which are detoxified. More in particular, the present invention is related to such pharmaceutical preparations of cyto5 statically active alkylating agents which are detoxified by combining these active agentswith a pharmacologically acceptable 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-oxazaphosphorinanes cyclophosphamide, trofosfamide, ifosfamide and sufosfamide produce undesired side effects such as serious irritations of the kidneys, the urinary tracts and/or the urinary bladder of the-patient treated therewith. As is well knovm, 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 - 2 47609 hi$idosage 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 cytostatic at the tumor tissue. Thereafter, the cytostatics are administered 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 effect.3 quite often occur also with alkylating agents such as 2-/N,Nbis-(2-chloroethyl)-aminq7-2-OXO-1,3,2-oxazaphosphorinane known under the well-known trade names Endoxan or Cytoxan^ or under the generic name cyclophosphamide, and 2-/N,N-bis(2-chloroethyl)-amino7-3-(2-chloroethyl)-2-oxo-1,3,2-oxa zaphosphorinane known under the trade name Ixoten or the generic 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-2chloroethyl-amino)-3-(2-chloroethyl)-2-oxo-1,3,2-oxazaphosphorinane known under the generic name ifosfamide. The therapeutic usefulness of such valuable alkylating agents which is particularly based upon the low toxicity, is again substantially 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 rupture of the therapy would produce severe damage or premature 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 - 3 47603 and to avoid, the formation of high concentrations of metabolites in particular in the urinary bladder. This so-called hydratation in general Is combined with an alkalinazation of the urine for instance by means of the hexapotassium hexa5 sodium pentacitrate hydrate complex known under the registered trade name Uralyt-U and in particular by introducing solutions of mercapto group containing compounds into the urinary bladder by means bf 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 in 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 vesicoclysis 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 for the general detoxification in the therapy with alkylating agents has been first published by T.A. Connors, Europ. 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 the 2-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 hy 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 - 4 47609 at very high dosages (see for instance Hoefer-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 beneficial 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 satisfactory (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 hy 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-alk-S0,H wherein alk ic 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 dhtoxified pharmaceutical products containing cytostatically active alkylating agents by - 5 47609 combining them and. adding thereto a pharmacologically acceptable salt of a mercapto alkane sulfonic acid having the general formula HS-alk-SO^H wherein alk is a straight or branched alkylene group having from 2 to 6 carbon atoms, and process for producing such detoxified pharmaceutical products.· Particularly good detoxification results have been obtained with such salts of 2-mercapto ethane sulfonic acid. Thus, the pharmacologically acceptable salts of 2-mercapto ethane sulfonic acid 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 agenis against the urotoxic side effects upon the kidney, 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 he avoided with 30 % of the amount of the alkylating agent. Since the urotoxic side effects in particular occur upon administra25 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 for 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 limit of the amount of salts of mercapto alkane sulfonic anids is of minor importance. It is surprising and important that the cytostatic activity of the alkylating agents is not at all - 6 47609 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-mercapto 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 urotoxic side effects even at high doses of the cytostatic may be substantially completely removed with equal amounts of the salts of the mercapto alkane sulfonics 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 cytostatic.

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 usd 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 2 694 732). These or simular compounds up to now have however never been used to remove the described urotoxic side effects 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 containing 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. - 7 4 7 6 0 9· 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 alky5 lating agents is~ produced just by the metabolites blamed for the urotxic side effects and that, therefor, the mercapto group 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 of 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 however limiting the same thereto.

EXAMPLE 1 One part by weight of ifosfamide 2-/N-(2-chloroethyl)-amino73-(2-chloroethyl)-2-oxo-1,3,2-oxazaphosphorinane) and 0.63 .20 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.

EXAMPLE 2 Example 1 was repeated using for each part by weight of ifosfamide 0.20, 0.50 or, respectively, 1.00 parts by weight of the sodium salt of 2-mercapto ethane sulfonic acid. - 8 47609 EXAMPLE 3 Injection solutions are prepared as described in Example 1 above, containing for each part by weight 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, containing for each part by weight of cyclophosphamide 0.63 parts by weight of the sodium salt of 2-meroapto ethane sulfonic acid.

Claims (12)

CLAIMS:

1. A detoxified pharmaceutical composition containing a cytostatically active alkylating agent, having toxic side effects, as therapeutically active ingredient, and a pharmaceutically acceptable salt of a mercapto alkane sulfonic acid as detoxifying ingredient, the salt being present in the composition in a proportion of not less than 205 by weight of the alkylating agent, and the mercapto alkane sulfonic acid having the general formula HS-alk-SO 3 H wherein alk is a straight or branched chain alkylene group having 2 to 6 carbon atoms.

2. A detoxified pharmaceutical composition as claimed in claim 1 wherein the salt is a salt of 2-mercapto ethane sulfonic acid.

3. A detoxified pharmaceutical composition as claimed in claim 1 or 2 wherein the salt is an alkali metal salt.

4. A detoxified pharmaceutical composition as claimed in claim 3 wherein the alkali metal salt is a sodium salt.

5. A detoxified pharmaceutical composition as claimed in any of claims 1-4 wherein the alkylating agent is selected from 2-(N,N-bis-(2-chloroethyl)-amino)-3-(2chloroethyl)*-2-oxo-l,3,2-oxazaphosphorinane (trofosfamide) , 2-(N-(2-chloroethyl)-amino)-3-(2-chloroethyl)-2-oxo-l,3,2oxazaphosphorinane (ifosfamide) and 2-(N,N-bis-(2-chloroethyl) -amino)-mesyloxyethylamino)-3-(2-chloroethyl)-2oxo-l,3,2-oxazaphosphorinane (sufosfamide).

6. A process for producing a detoxified pharmaceutical composition containing a cytostatically active alkylating agent, having toxic side effects, as therapeutically active ingredient, which comprises incorporating in the composition a pharmaceutically acceptable salt of a mercapto alkane sulfonic acid as detoxifying ingredient, in a proportion of not less than 205 by weight of the -|0 47609 alkylating agent, the mercapto alkane sulfonic acid having the general formula HS-alk-SO-jH wherein alk is a straight or branched chain alkylene group having 2 to 6 carbon atoms.

7. A process as claimed in claim 6 wherein the salt is a salt of 2-mercapto ethane sulfonic acid.

8. A process as claimed in claim 6 or 7 wherein the salt is an alkali metal salt.

9. A process as claimed in claim 8 wherein the alkali metal salt is a sodium salt.

10. A process as claimed in any of claims 6-9 wherein the alkylating agent is selected from 2-(Ν,Ν-bis-(2chloroethyl)-amino)-3-(2-chloroethyl)-2-oxo-l,3,2oxazaphosphorinane (trofosfamide), 2-(N-(2-chloroethyl)amino)-3-(2-chloroethyl) -2-oxo-1,3,2-oxazaphosphorinane (ifosfamide) and 2-(Ν,Ν-bis-(2-chloroethyl)-amino)-mesyloxyethylamino)-3-(2-chloroethyl)-2-oxo-l,3,2-oxazaphosphorinane (sufosfamide).

11. A process for producing a detoxified pharmaceutical composition, substantially as herein described with reference to any of the examples.

12. A detoxified pharmaceutical composition whenever prepared by a process claimed in a preceding claim.