EP2459169A1

EP2459169A1 - Bladder instillation compositions for treating bladder cancer

Info

Publication number: EP2459169A1
Application number: EP10744508A
Authority: EP
Inventors: Bernd-W. MÜLLER
Original assignee: Fresenius Kabi Deutschland GmbH
Current assignee: Fresenius Kabi Deutschland GmbH
Priority date: 2009-07-31
Filing date: 2010-07-30
Publication date: 2012-06-06
Also published as: WO2011012312A1; DE102009035586A1

Abstract

The present invention relates to a bladder instillation composition, comprising at least two different glycosaminoglycanes, or the salts thereof, and at least one cytostaticum, a method for the production thereof, and a kit containing separate solutions of the glycosaminoglycanes and the cytostaticum. The compositions are used for treating bladder cancer and are applied intravesically.

Description

Bladder instillation compositions for the treatment of bladder cancer

The present invention relates to bladder instillation compositions containing at least two different glycosaminoglycans or their salts and at least one

Antitumoragens contain, processes for their preparation and kits which the

Components of the glycosaminoglycans and the antitumor agent separately. The compositions are used to treat bladder cancer and are applied intravesically.

About 2% of all malignant cancers are bladder cancer, making it the fifth and tenth of the most common cancers in men and women, respectively. 70 to 80% of bladder cancers are restricted to the bladder surface at the first diagnosis. The treatment of bladder bladder cancer involves endoscopic surgical removal, followed in many cases by adjunctive intravesical chemotherapy or immunotherapy. This has the goal of removing or killing residual tumor cells and avoiding recurrence.

Both chemotherapeutic agents and immunostimulants (such as BCG) are applied intravesically within certain limits with respect to the reduction of the

Recurrence rates, although it is unclear whether the progression of muscle invasive tumors can be prevented. In any case, the one with the mentioned anti-tumor agents

(Chemotherapeutics and immunostimulants) achievable therapeutic success is still insufficient, and there is an urgent need for the development of new improved therapeutic concepts for the successful and sustainable treatment of bladder cancer.

In addition, treating the bladder with antitumor agents as a complication often results in bladder damage (chemocystitis), which results in a weakening of the GAG layer and, consequently, increased permeability of the bladder wall. This makes the bladder wall more susceptible to foreign irritants from the urine, but also to the body's own substances (eg uric acid). Consequences are symptoms such as constant urination and abdominal pain. Consequently, there is also an urgent need for the provision of therapy concepts which have improved tolerability and in particular significantly reduce the occurrence of chemocystitis. Of particular interest in the treatment of bladder cancer is a local bladder treatment. This is done for example by intravesical instillation of the bladder. Such topical treatment is preferable to systemic treatment because the side effects and effects on other organs of the body can be minimized. This also allows a reduction in the required dose of the active ingredient.

Hyaluronic acid and chondroitin sulfate belong to the group of glycosaminoglycans (GAGs). They are composed of disaccharide units of D-glucuronic acid and N-acetyl-D-galactosamine or glucosamine. In the case of chondroitin sulfate, these units are in

sulfated to varying degrees, i. esterified with sulfuric acid. GAGs in the

general and hyaluronic acid and chondroitin sulfate in particular occur naturally in human tissue. They are structural components of the connective tissue and are therefore important for the function of the extracellular matrix, for cell mobility, cell adhesion and cell proliferation.

It is known that cancer cells, inter alia, an increased expression rate of

Hyaluronic acid receptors such as e.g. CD 44 have. Against this background, WO 01/47561 A1 describes a composition for the treatment of various types of cancer, which contains hyaluronic acid in addition to a so-called anti-neoplastic agent, which may be, inter alia, a chemotherapeutic agent. It is described that hyaluronic acid alone has antiproliferative properties for some cancers treated therewith (such as prostate or breast cancer).

However, none of the bladder cancer cell lines tested is inhibited by more than 5% growth by 80 μg / ml hyaluronic acid. In comparison, the growth of other cancer cell lines is inhibited by up to 38%.

In addition, in conjunction with the cytostatic 5-FU and cisplatin the

antiproliferative effect supposedly potentiated. With regard to a treatment of bladder cancer with a combination of hyaluronic acid and a cytostatic, WO 01/47561 A1 can not provide clear evidence of an alleged synergistic or potentiating effect of hyaluronic acid. Thus, in vitro proliferation of human RT-4

Although bladder cancer cells are inhibited by cisplatin after the addition of hyaluronic acid, potentiation of the effect by hyaluronic acid is not given for 5-FU. In addition, none of the animal experiments described there with a combination of 5-FU or cisplatin with hyaluronic acid is documented. The effectiveness of a combination of cytostatic with hyaluronic acid in bladder cancer is therefore extremely doubtful. WO 03/094 929 A2 describes the effect of so-called blocking agents (eg

Chondroitin sulfate) on the action of covalently bound hyaluronic acid cytostatics (so-called conjugates) in a variety of different cancers. It should

Chondroitin sulfate block the receptors for hyaluronic acid on cancer cells and thus facilitate the uptake of the conjugates of hyaluronic acid with cytostatics in the cancer cell. This approach is based on the so-called EPR effect. It is known that blood vessels in the cancerous tissue are more permeable than in normal healthy tissue, so that even cytostatics that are chemically linked to macromolecules, and thus very large, can penetrate from the bloodstream into the cancerous tissue, while at Normal healthy tissue is due to the size of the molecule only for steric reasons, or only limited possible. This allows a targeted administration (targeting) of the sterically very demanding cytostatic macromolecule conjugate to the cancerous tissue. This has the therapeutic benefit of being through the

Targeting the cytostatic to the cancerous tissue can reduce side effects and reduce the dosage of the cytostatic drug. However, WO 03/094 929 A2 is limited to the administration of the described conjugates. It has not been commented on the effect of unconjugated (i.e., free) cytotoxic agents in association with free GAGs, such as hyaluronic acid or chondroitin sulfate. Furthermore, WO 03/094 929 A2 does not explicitly concern bladder cancer.

Consequently, the compositions known in the prior art are not sufficiently effective in bladder cancer and there is still a need for sustained successful and well-tolerated therapy for the treatment of bladder cancer.

Thus, the object underlying the present invention is in the

Providing a new and improved therapy concept for the successful and sustainable treatment of bladder cancer. In particular, the object is to provide a bladder cancer treatment composition that can be applied topically, highly selectively targeting the bladder tumor tissue, and improved tolerability by reduced side effects, e.g. Chemocystitis, guaranteed.

This object is surprisingly achieved by a bubble instillation composition according to the present invention, which

(a) at least two different glycosaminoglycans or their salts (GAGs) and

(b) contains at least one antitumor agent. The bladder instillation composition of the present invention is incorporated into a pharmaceutically acceptable carrier prior to use.

Surprisingly, it has been found that by the combined use of two different GAGs and at least one antitumor agent, a composition can be provided which can be administered locally into the bladder and is characterized by a high efficacy in the treatment of bladder cancer with improved tolerability and reduced side effects.

In particular, it has been shown that the combination of the antitumor agent with 2 different GAGs delays the elimination of the antitumor agent.

The above-mentioned disadvantages of the prior art could thus be overcome.

The individual constituents of the composition according to the invention are described in more detail as follows:

In the composition according to the invention as component (a) at least two different glycosaminoglycans (GAGs) are included. These are preferably selected from the group consisting of hyaluronic acid, hyaluronan, heparin, keratan, dermatan, chondroitin sulfate, heparin sulfate, heparan sulfate, keratan sulfate and dermatan sulfate. Also included are the salts of said GAGs, especially the alkali metal salts (such as the sodium salts). The mentioned GAGs are with the exception of hyaluronic acid in

(partially) sulfated form. According to the present invention, all

Sulfation levels and positions of the GAGs include. For example, chondroitin sulfate includes chondroitin-4-sulfate and chondroitin-6-sulfate. The GAGs used according to the present invention are naturally occurring substances and are known to the person skilled in the art.

In principle, any combination of the GAGs referred to above as preferred is as

suitable according to the invention. Moreover, according to the invention, the use of the following combinations of GAGs is particularly preferred: hyaluronic acid / chondroitin sulfate, hyaluronic acid / heparin, hyaluronic acid / keratan, hyaluronic acid / dermatan,

Hyaluronic acid / heparin sulfate, hyaluronic acid / heparan sulfate, hyaluronic acid / keratan sulfate, hyaluronic acid / dermatan sulfate, chondroitin sulfate / heparin, chondroitin sulfate / keratan, chondroitin sulfate / dermatan, chondroitin sulfate / heparin sulfate,

Chondroitin sulfate / heparan sulfate, chondroitin sulfate / keratan sulfate and chondroitin sulfate / dermatan sulfate, or each salts thereof. The molecular weights of the GAGs are in the known range of 10 ³ to 10 ⁷ Da. In many cases, a distinction is made between a low molecular weight and a high molecular weight variant, such as, for example, between low molecular weight hyaluronic acid (< ⁵ × ^{10 5} Da) and high molecular weight hyaluronic acid (10 ⁶ -10 ⁷ Da). According to the invention, the GAGs can be used over the entire range mentioned.

It has been found that the use of at least two different GAGs leads to an unexpected improvement in the tolerability of antitumor therapy over the use of only one GAG. The typical side effects, such as

Chemocystitis is more rare and less pronounced when the compositions contain at least two GAGs. The best results are obtained with a combination of hyaluronic acid and chondroitin sulfate, in particular sodium hyaluronate and

Chondroitin sulfate, with the use of low molecular weight hyaluronic acid being most preferred.

The composition according to the invention also contains as component (b) at least one antitumor agent which is suitable for the local treatment of bladder cancer. This includes, according to the invention, cytostatic agents and immunostimulants (such as BCG or interferons). According to the invention, component (b) also comprises combinations of two or more cytostatics, combinations of two or more immune stimulants and combinations of one or more cytostatics with one or more

Immune stimulants.

In principle, all cytostatics are suitable according to the invention. Preferred cytostatics are selected from the group consisting of gemcitabine, 5-fluorouracil (5-FU),

Cisplatin, carboplatin, mitomycin C, methotrexate, vinblastine, paclitaxel, vincristine, vinorelbine, vindesine, calicheamicin, neomycin, epirubicin and doxorubicin.

Preferably, the composition contains gemcitabine, epirubicin, doxorubicin or

Mitomycin C, more preferably gemcitabine, most preferably gemcitabine hydrochloride.

As a combination are preferred due to a particularly good effectiveness

Gemcitabine and platinum compounds such as cisplatin or carboplatin used.

The composition according to the invention can also be used as component (b)

Immunostimulant included. In principle, all immune stimulants are suitable according to the invention. The immunostimulant preferred according to the invention is BCG (bacillus calmette-guerin). BCG is an attenuated strain of Mycobacterium bovis, which triggers an immune reaction that subsequently causes an anticancerogenic effect. BCG is well known in the art and commercially available, for example, under the trade names TheraCys® or TICE® BCG.

It is essential to the invention that there is no covalent bond between the antitumor agent (b) and the GAGs (a), i. the antitumor agent should not be covalently bound to the GAGs. It has surprisingly been found that the covalent binding in the local therapy after instillation of the composition in the bladder in contrast to systemic administration (see WO 03/094 929 A2 in the introductory part) leads to no target effect on the tumor tissue. On the contrary, the covalent binding of the antitumor agent to GAG may even lead to a worsened or slowed effect of the antitumor agent on the bladder tumor cells. In addition, the covalent bond is very expensive and costly to ensure, which would only unnecessarily increase the production of the composition according to the invention without showing a positive effect.

The composition of the invention is incorporated into a pharmaceutically acceptable carrier for administration. This is not subject to any restrictions as long as it is suitable for intravesical instillation. Usually, the carrier is suitable for dissolving components (a) and (b) of the composition so that the composition to be applied is an instillation solution. Preferably, the carrier is physiological saline.

In addition, the compositions of the present invention may contain other conventional additives and adjuvants which are readily apparent to those skilled in the art for instillation solutions. Examples include pH buffers, viscosity regulators or mucoadhesive agents. But also additional therapeutic agents such. Anti-inflammatory agents, analgesics or anti-incontinence agents may be included in the compositions of the invention.

A particularly preferred embodiment of the present invention relates to

Combination of chondroitin sulfate and free sodium hyaluronate with gemcitabine hydrochloride in the form of a bladder instillation solution. This is clearly superior in the local treatment of bladder cancer compared to the treatment with gemcitabine alone, ie without the addition of GAGs (Example 2). Further preferred embodiments relate to the combination of chondroitin sulfate and sodium hyaluronate with BCG, epirubicin, doxorubicin or mitomycin C.

Another preferred embodiment relates to the combination of keratan sulfate and sodium hyaluronate with doxorubicin.

Another preferred embodiment relates to the combination of keratan sulfate and heparan sulfate with mitomycin C.

In the compositions of the invention, the concentration of GAGs (a) is 0.05-10 mg / ml, preferably 0.2-2 mg / ml, more preferably 0.5-1 mg / ml, and most preferably 0.6-0 , 9 mg / ml, such as about 0.8 mg / ml (by volume of the incorporated into a pharmaceutically acceptable carrier for administration

Composition).

The concentration of antitumor agent (b) in the case of the cytostatics is 0.1-50 mg / ml, preferably 5-50 mg / ml, more preferably 10-35 mg / ml and most preferably 15-25 mg / ml, e.g. 20 mg / ml (based on the volume of the composition incorporated for administration into a pharmaceutically acceptable carrier). Further preferred cytostatic concentrations are 0.2-1.8 mg / ml, more preferably 0.4-1.6 mg / ml.

The concentration of antitumor agent (b) in the case of BCG is 0.1-3 mg / ml, preferably 0.2-2.5 mg / ml, more preferably 0.4-1.8 mg / ml.

With respect to the said preferred embodiments, the intrinsic viscosity of sodium hyaluronate should be 0.5-3.7 dl / g and the intrinsic viscosity of chondroitin sulfate 0.1-1.5 dl / g.

The present invention relates to a bladder instillation composition comprising at least two different glycosaminoglycans or their salts and at least one antitumor agent, wherein the antitumor agent comprises at least one cytostatic or at least one immunostimulant or combinations thereof, wherein between the

Antitumoragens and the glycosaminoglycans no covalent bond exists.

The present invention preferably relates to a bladder instillation composition comprising at least two different glycosaminoglycans or their salts and at least one antitumor agent, wherein the antitumor agent comprises at least one cytostatic or at least one immunostimulant or combinations thereof, wherein no covalent bond exists between the antitumor agent and the glycosaminoglycans and wherein the glycosaminoglycans in a concentration of 0.2 to 2 mg / ml, based on the incorporated into a pharmaceutically acceptable carrier for use

Composition, present.

The present invention further relates to a bladder instillation composition comprising at least two different glycosaminoglycans or their salts and at least one antitumor agent, as a combined preparation for simultaneous, separate or sequential use in bladder cancer therapy, wherein the antitumor agent comprises at least one cytostatic or at least one immunostimulant or combinations thereof, wherein there is no covalent bond between the antitumor agent and the glycosaminoglycans.

A particularly preferred embodiment of the present invention relates to

Combination of 0.8 mg / ml chondroitin sulfate, 0.8 mg / ml sodium hyaluronate and 20 mg / ml gemcitabine (based on the composition incorporated for administration into a pharmaceutically acceptable carrier).

Another particularly preferred embodiment of the present invention relates to the combination of 0.8 mg / ml chondroitin sulfate, 0.8 mg / ml sodium hyaluronate and 1 mg / ml gemcitabine (based on the composition incorporated for administration into a pharmaceutically acceptable carrier).

Another preferred bladder instillation composition contains 0.8 mg / ml

Chondroitin sulfate, 0.8 mg / ml sodium hyaluronate and 1 mg / ml TICE® BCG (based on those incorporated into a pharmaceutically acceptable carrier for administration

Composition).

Another preferred bladder instillation composition contains 0.6 mg / ml doxorubicin, 0.6 mg / ml keratan sulfate, and 2 mg / ml sodium hyaluronate (based on the composition incorporated for administration into a pharmaceutically acceptable carrier).

Another preferred bladder instillation composition contains 0.8 mg / ml mitomycin, 0.4 mg / ml dermatan and 0.2 mg / ml keratan sulfate (based on the composition already incorporated into a pharmaceutically acceptable carrier for administration).

Another preferred bladder instillation composition contains 0.8 mg / ml

Chondroitin sulfate, 0.8 mg / ml sodium hyaluronate and 1 mg / ml epirubicin (based on those incorporated in a pharmaceutically acceptable carrier for administration

Composition). The present invention further preferably relates to a bladder instillation composition comprising at least two different glycosaminoglycans or their salts and at least one antitumor agent, as a combined preparation for simultaneous, separate or sequential use in bladder cancer therapy, wherein the antitumor agent comprises at least one cytostatic or at least one immunostimulant or combinations thereof wherein there is no covalent bond between the antitumor agent and the glycosaminoglycans, and wherein the glycosaminoglycans are present at a concentration of 0.2-2 mg / ml, respectively, relative to the composition incorporated into a pharmaceutically acceptable carrier for use.

All of the above concentration ranges include the respective endpoints of the ranges.

In addition to the reduced incidence of cystitis described above, the use of at least two GAGs has yet another surprising effect. It has been found that their use in combination with anti-tumor agents in the bladder results in improved adhesion or attachment to the bladder wall (Example 3). Thus, the antitumor agent, not only longer at the site of action, i. on the bladder tumor cells, but there are also present in an increased concentration. In addition, many GAGs, such as hyaluronic acid and chondroitin sulfate, themselves have a cancer-inhibiting effect, so that it comes together with the antitumor agent to a synergistic effect. This is particularly pronounced when using the GAG combination of hyaluronic acid and chondroitin sulfate. The best effect was observed with the cytostatic gemcitabine.

The compositions according to the invention are instilled intravesically, ie introduced into the bladder by known medical devices / devices. Suitable are bladder catheters, which can be provided with appropriate syringes and ensure easy and relatively comfortable administration. As an example, the bubble syringes or the Drainjet ^® (Fresenius Kabi) called. Therefore, it is essential to the invention that the

Compositions at ambient temperature (25 ⁰ C) are liquid. By "liquid" it is to be understood that the composition has a viscosity in the range from 0.5 to 100 mPas, more preferably from 0.8 to 25 mPas and in particular from 1.0 to 10 mPas at 25 ⁰ C. according to Ph Eur. 6th edition, chapter 2.2.10., has. In general, it is the compositions are solutions.

In a preferred embodiment, the instillation into the bladder is carried out in several (preferably two) stages, ie the combination of the GAG components (a) and the Antitumor agent component (b) first takes place in situ in the bladder. The sequence of the instillation is arbitrary, but preferably a solution of the antitumor agent component (b) is first instilled into the bladder and allowed to act on the bladder wall.

Subsequently, a solution of the G AG component (a) is instilled into the bladder. In the intervening period a distinction is made between the first postoperative instillation and more generally subsequent therapy. Between first and second instillation the postoperative instillation preferably has a time duration of up to 6 hours, preferably 1 to 6 hours, and in the subsequent therapy a period of 3 to 8 days, preferably 4 to 6 days. In this way, the effect of the composition according to the invention can be further increased.

The residence time of the inventive composition in the bladder, based on the presence of both components (a) and (b), preferably ranges from 0.1 to 5 hours, more preferably from 0.25 to 3 hours, and most preferably from 0, 5 to 2 hours. The instillation is repeated at intervals of about 0.5 to 3 weeks (preferably about 1 week) for a period of 6 to 10 weeks (preferably about 8 weeks), depending on the severity of the disease.

The composition of the invention is typically incorporated into this pharmaceutically acceptable carrier by mixing the individual components (a) and (b) with a pharmaceutically acceptable carrier in any order.

Preferably, separate solutions of components (a) and (b) are first prepared in a pharmaceutically acceptable carrier, which are then mixed together. The remaining ingredients, if any, can be added in for Instillationslösungen usual way.

The invention also relates to a kit which comprises at least 2 GAGs and at least one

Contains antitumor agent separately.

The invention further relates to a kit which contains separately at least 2 GAGs and / or at least one antitumor agent in ready-to-use manner.

The kit preferably comprises as separate components a solution of the glycosaminoglycans (a) in a pharmaceutically acceptable carrier; and the antitumor agent

Anti-tumor agent mixture (b), wherein the anti-tumor or anti-tumor agent mixture is particularly preferably also dissolved in a preferably aqueous pharmaceutically acceptable carrier. The invention is further illustrated by the following examples.

Example 1a

Gemzar 1 g (EII Lilly) containing 1 g Gemcitabine was charged with 25 ml_ Thelosan ^® (Fresenius Kabi) and added to 25 ml Thelosan ^® given in Faltenblagflasche. 1000 ml Thelosan ^® contain at:

Sodium Hyaluronate 800 mg Chondroitin Sulfate 800 mg Sodium Chloride 8.3 g

Water for injections ad 1000 ml_

This solution was tested for physicochemical stability and found to be stable for 24 hours storage at room temperature plus 2 hours at 37 ^° C. The content of gemcitabine and its degradation products as well as pH value, discoloration, turbidity as well as visual and subvisual particles were tested according to Ph.Eur.

Examples 1 b to 1 i

The procedure of Example 1a was used in an analogous manner and with comparable

Repeated results for the following antitumor agent GAG combinations. The

Active ingredient and GAG amounts are in Examples 1 b) to 1j) based on the

ready to use instillation solution. The carrier is physiological saline in all examples.

1 b) 0.4 mg / ml cisplatin with 0.2 mg / ml chondroitin sulfate and 1.2 mg / ml dermatan sulfate

1c) 0.6 mg / ml vinorelbine with 1 mg / ml hyaluronic acid and 0.2 mg / ml heparin

1d) 0.6 mg / ml doxorubicin with 0.6 mg / ml keratan sulfate and 2 mg / ml sodium hyaluronate

1e) 1 mg / ml paclitaxel with 1 mg / ml chondroitin sulfate and 0.2 mg / ml heparan sulfate

1f) 0.8 mg / ml mitomycin C with 0.4 mg / ml dermatan and 0.2 mg / ml keratan sulfate

1g) 1 mg / ml methotrexate with 0.4 mg / ml sodium hyaluronate and 1 mg / ml chondroitin sulfate

1h) 1, 6 mg / ml 5-FU with 2 mg / ml hyaluronic acid and 1 mg / ml keratan 1 i) 1 mg / ml epirubicin with 0.8 mg / ml sodium hyaluronate and 0.8 mg / ml chondroitin sulfate

1j) 1 mg / ml TICE® BCG lyophilisate with 0.8 mg / mg sodium hyaluronate and 0.8 mg / ml chondroitin sulfate

Example 2a

The test specimen prepared according to Example 1a was instilled in a pilot study on 10 patients with recurrent superficial bladder carcinoma for 1.5 hours. The

Tolerability was better in all patients subjectively compared to previous courses of therapy. The recurrence results over a 1-year period showed even better results than the treatment results in previous instillation cycles. Overall, a better compatibility with improved efficacy could thus be shown.

Examples 2b to 2h

The procedure of Example 2a was used in an analogous manner and with comparable

Results were carried out with the test samples of Examples 1 b to 1j.

Example 3a

The residence time of gemcitabine in the bladder was studied in rats. 5 rats received gemcitabine in Thelosan ^® and 5 rats gemcitabine in physiological

Saline. The animals were each instilled with 500 μL of the test solutions and then urine samples were taken every 15 minutes for which the gemcitabine content was determined.

The Gemcitabinausscheidung in the animals, which the cytostatic was administered in Thelosan ^®, was more than half lower than the

Gemcitabine excretion in the animals to which the cytostatic agent was applied in saline.

Examples 3b to 3i

The procedure of Example 3a was used in an analogous manner and with comparable

Results were carried out with the antitumoragen GAG combinations of Examples 1 b to 1j.

Claims

claims

A bladder instillation composition comprising:

(a) at least two different glycosaminoglycans or their salts and

(b) at least one antitumor agent, wherein the antitumor agent comprises at least one cytostatic or at least one

Immunostimulant or combinations thereof, and no covalent bond exists between the antitumor agent (b) and the glycosaminoglycans (a) and wherein the

Glycosaminoglycans at a concentration of 0.2-2 mg / ml, based on the composition incorporated for use in a pharmaceutically acceptable carrier.

2. The composition of claim 1, wherein the glycosaminoglycans (a) are selected from the group consisting of hyaluronic acid, hyaluronan, heparin, keratan,

Dermatan, chondroitin sulfate, heparin sulfate, heparan sulfate, keratan sulfate and

Dermatan sulfate, or salts thereof.

A composition according to claim 1 or 2, wherein the glycosaminoglycans (a) comprise the following combinations:

Hyaluronic acid / chondroitin sulfate, hyaluronic acid / heparin, hyaluronic acid / keratan,

Hyaluronic acid / dermatan, hyaluronic acid / heparin sulfate, hyaluronic acid / heparan sulfate, hyaluronic acid / keratan sulfate, hyaluronic acid / dermatan sulfate, chondroitin sulfate / heparin, chondroitin sulfate / keratan, chondroitin sulfate / dermatan, chondroitin sulfate / heparin sulfate, chondroitin sulfate / heparan sulfate, chondroitin sulfate / keratan sulfate and chondroitin sulfate / dermatan sulfate, or respectively Salts of it.

The composition of any one of claims 1 to 3, wherein the antitumor agent (b) is selected from the group consisting of gemcitabine, 5-fluorouracil (5-FU), cisplatin, carboplatin, mitomycin C, methotrexate, epirubicin, vinblastine, paclitaxel , Vincristine,

Vinorelbine, vindesine, calicheamicin, neomycin, doxorubicin and BCG.

A composition according to any one of claims 1 to 4, wherein the antitumor agent (b) comprises gemcitabine, BCG, mitomycin, doxorubicin or epirubicin.

A composition according to any one of claims 1 to 5, wherein the antitumor agent (b) comprises gemcitabine.

7. The composition according to any one of claims 1 to 6, wherein the

Glycosaminoglycans (a) include the combination of hyaluronic acid and chondroitin sulfate.

A composition according to any one of claims 1 to 7, wherein the concentration of the antitumor agent (b) is 0.1-50 mg / ml.

9. The composition according to any one of claims 1 to 8, wherein the concentration of glycosaminoglycans contained is 0.5 to 1 mg / ml.

10. Blister instillation composition according to any one of claims 1 to 9 as

Combination preparation for simultaneous, separate or sequential use in bladder cancer therapy.

11. Bladder instillation composition according to claim 10 as a combined preparation for simultaneous, separate or sequential use in bladder cancer therapy, this application comprising a first instillation of a solution of glycosaminoglycans (b) in a preferably aqueous pharmaceutically acceptable carrier into the bladder and a second instillation of a solution of the Antitumor agent (a) in a preferably aqueous pharmaceutically acceptable carrier into the bladder, wherein between first and second instillation a period of time of up to 6 hours postoperatively and in the subsequent therapy a period of 3 to 8 days.

12. A process for the preparation of a ready-bladder instillation composition, which comprises mixing the individual components (a) and (b) with a

pharmaceutically acceptable carrier in any order.

The method of claim 12, wherein first separate solutions of the antitumor agent (b) in a pharmaceutically acceptable carrier and the glycosaminoglycans (a) are prepared in a pharmaceutically acceptable carrier and then mixed together.

14. Kit comprising as separate components at least 2 GAGs according to any one of claims 1, 2, 3, 7 and 9 and at least one antitumor agent according to any one of claims 1, 4, 5, 6 and 8.

15. Kit comprising as separate components:

a solution of the glycosaminoglycans (a) according to any one of claims 1, 2, 3, 7 and 9 in a pharmaceutically acceptable carrier; and - Antitumoragens (b) according to any one of claims 1, 4, 5, 6 and 8.