HK1171675A - Pharmaceutical composition for the treatment of bladder disorders - Google Patents

Description

Pharmaceutical composition for treating bladder diseases

Technical Field

The present invention relates to a pharmaceutical composition having activity against urogenital diseases in mammals, which comprises a zinc hyaluronate complex as an active ingredient and a pharmaceutically acceptable carrier and/or additive. The preparation method of the pharmaceutical composition, the therapeutic use thereof for treating and preventing diseases related to abnormalities and defects of the glycosaminoglycan (GAG) layer of the urogenital system in mammals, and a kit comprising a zinc hyaluronate solution, a catheter useful for intravesical administration, and optionally a balloon useful for bladder distension are also included within the scope of the present invention.

Background

The Hyaluronic Acid (HA) is a homopolymer of the glycosaminoglycan type, comprising repeating disaccharide units of N-acetylglucosamine-glucuronic acid of formula (I).

In hyaluronic acid, monosaccharides are linked by a β (1 → 3) structure, and disaccharide units are linked by a β (1 → 4) structure, thereby forming a linear glycan in which β (1 → 3) and β (1 → 4) alternate.

In living organisms, hyaluronic acid exists as a cationic salt, usually sodium salt, with a molecular weight in the range of 10-20kDa to several thousand kDa. The presence of carboxyl groups of the glucuronic acid moiety of hyaluronic acid and carbonyl and amino groups in the N-acetyl group of glucosamine, as well as the hydroxyl groups present, promote the formation of several hydrogen bridges. Hyaluronic acid has a complex three-dimensional structure due to the action of these intramolecular hydrogen bonds and hydrogen bridges formed by the interaction between hyaluronic acid and water present in biological systems (C.L.Hew et al, Eur.J.biochem.203,33-42, (1992); Q.Liu et al J.am.chem.Soc 118, 12276-. Relatively dilute aqueous solutions of hyaluronic acid still exhibit high viscosity due to their superior ability to bind water. In aqueous solution, its rheological properties are highly dependent on the molecular size; for example, an aqueous solution of 1% hyaluronic acid of molecular size 1000kDa has a viscosity of 3000mPa, whereas an aqueous solution of hyaluronic acid of molecular size 4000kDa has a viscosity of 400000mPa at similar concentrations (H.B.Wik and O.Wik: Rheology of Hialuronan, chemistry, Biology and Medical Applications of Hialuronan and Derivatives (ed.T.C.laurent) pp.25-32, Portland Press, London, (1998)). Thus, the two most important physical properties of hyaluronic acid are its viscosity and molecular size.

Hyaluronic acid is present in all parts of the body as a major component of the extracellular matrix. Certain organs and tissues (connective tissue, skin, synovial fluid, vitreous humor, and vessel walls) contain relatively greater amounts of hyaluronic acid. The biological effects of hyaluronic acid have long been thought to arise from its physical properties. For example, it may provide mechanical protection to the joint by virtue of its rheological properties. Due to its superior water retention capacity, hyaluronic acid can control water balance by its osmotic pressure and providing flow resistance. Hyaluronic acid also plays an important role in filling interstitial tissue and protecting cells from various physical impacts. Recent studies have shown that the interaction of hyaluronic acid with certain macromolecules present in the body may be associated with several physiological processes. Examples of these macromolecules are proteoglycans (such as aggrecan, versican, and brevican, etc.), which are located in the extracellular matrix and mainly function to fill the gaps between cells and promote substance transport. The macromolecules involved in the interaction with hyaluronic acid may be transmembrane proteins (e.g., CD44, RHAMM) in the cell, and receptor proteins (e.g., C1q, P-32, TSG-6, etc.) present in the cytoplasm. By means of the above mentioned proteinaceous substances, hyaluronic acid plays an important role in some regulatory processes occurring at the cellular or body level.

The molecular size and concentration of hyaluronic acid in aqueous solution, as it is a physical property, has an important influence on its biological effect. Thus, hyaluronic acid may exert a positive or negative effect in the same cellular process, depending on the molecular size. Similar effect changes were also observed when the concentration of hyaluronic acid in the solution was changed. The expected optimum results are more pronounced when considering The influence of both The size and concentration of The molecule (E.A. Bal. zs, The Chemistry, Biology and Medical Applications of high purity and differences, pp.185-204, Portland Press, London (1998)).

Since hyaluronic acid participates in the above-mentioned physiological processes, it can be successfully applied to some medical fields (e.g., wound healing, treatment of chronic inflammation, and ophthalmic surgery).

The applicability of hyaluronic acid in human medicine can be extended, in addition to the above, by chemical modification of its structure. In this respect, two main trends are known. According to one, a hydrogel is formed by using an aliphatic compound (usually a dihydrazide) to establish cross-linking between two distant hyaluronic acid molecules. The cross-linked structure enables the hyaluronic acid after chemical modification to have enhanced viscoelasticity, thereby having stronger resistance to the recession (degradation) effect generated by organisms. This is advantageous for patients in whom it is desired to regain synovial fluid-secreting rheumatoid arthritis and those suffering from post-operative adhesions. In another important strategy, active agents that are difficult to absorb or accurately transport to the site of effect are chemically bonded to hyaluronic acid (e.g., paclitaxel, pilocarpine, and insulin). In these cases, hyaluronic acid improves the absorption of the active agents bound to its structure and facilitates the arrival of these substances at their specific target sites, respectively.

Complexes of hyaluronic acid with zinc and cobalt are described in EP413016 (Burger et al, 1989), and complexes of two zinc hyaluronate are used as active agents in wound treatment compositions. Further studies of this active agent have shown that the potential for therapeutic applications of the active agent can be expanded due to the presence of zinc, since the zinc complex of hyaluronic acid has a new or more pronounced effect compared to the sodium salt of hyaluronic acid (j.ill es et al, Acta pharm. hung.72,15-24 (2002)). Among these effects include enhanced antioxidant activity of zinc hyaluronate (gy. t. balogh et al, Arch, biochem. biophysis, 410,76-82. (2003)); the inhibitory activity against tissue-damaging enzymes (matrix metalloproteinases, in particular MMP-9) secreted excessively by invasive cells, whereas the latter effect is not shown by hyaluronic acid sodium salt (WO 00/53194, Ill. et al, l 999). The gastrointestinal protective effect (in terms of peptic ulcer treatment) of zinc hyaluronate is disclosed in published international patent application No. WO 98/48815, and the antibacterial effect of zinc hyaluronate active agent is disclosed in published international patent application No. WO 98/10773.

A Glycosaminoglycan (GAG) layer containing a large amount of hyaluronic acid was arranged on the inner surface of the bladder. The highly viscous, highly hydrophilic glycosaminoglycan layer protects the urothelial tissue from irritants in the urine, including, but not limited to, microorganisms, pathogens, microcrystals, proteins, calcium, urea, and carcinogens.

When the glycosaminoglycan layer is damaged, irritants from the urine can penetrate the epithelial tissue of the bladder. This causes immediate pain and is also the beginning of a degenerative process. Damage to this protective barrier also increases the risk of infection development and neoplastic disease. Deformation of the glycosaminoglycan layer can be diagnosed by biopsy.

The following diseases may be associated with damage to the glycosaminoglycan layer:

● interstitial cystitis

● Chronic recurrent bacterial and non-bacterial cystitis

● radiation cystitis and chemical cystitis

Interstitial cystitis is a disease that can cause repeated discomfort or pain to the bladder and the nearby pelvic region. Symptoms of interstitial cystitis also include urgency and frequency. At the same time, no bacteria could be detected.

Individuals with interstitial cystitis may have significant physical dysfunction, while individuals with advanced interstitial cystitis may require major surgery to achieve functional recovery. Although the cause of interstitial cystitis is not clear, it is suggested that defects in the glycosaminoglycan layer may be a major defect. Because the symptoms of interstitial cystitis are similar to those of other urinary system diseases, the diagnosis of interstitial cystitis can be very difficult, taking a long time (5-8 years) in most cases.

Radiation cystitis and chemical cystitis may occur following radiation therapy and chemotherapy of tumors of pelvic organs such as the prostate, bladder, uterus, ovary, vagina, colon and rectum. One major effect of radiation therapy is damage to the bladder epithelium. The duration of such disease is typically 3 to 6 months, but may also be 24 months or longer. In the most severe cases, symptoms may occur that cause lifestyle changes. Without adequate treatment, the inflammation within the bladder may become more severe, and the symptoms may worsen.

Recurrent bacterial cystitis was defined as a significantly recurrent bacterial urine prior to the absence of ascending uropathology. "recurrence" generally refers to the occurrence of more than 3 confirmed diagnoses of bacterial cystitis over the course of a year. Acute bacterial cystitis is a very common infectious disease among women with more frequent sexual lives. From 30% to 50% of women experience bacterial cystitis in their lives, and from 25% to 40% of them will convert to a relapsing form. The conventional medical approach to bacterial cystitis is a long lasting course of antibiotic therapy. When urethral syndrome occurs, no bacteria are detected in the urine. In both cases, damage to the glycosaminoglycan layer may occur.

Recently, sodium hyaluronate has been used for the treatment of urogenital conditions, in particular interstitial cystitis and radiation cystitis by instillation into the bladder using urethral catheters (Binoche WO96/25168 and WO 000/24387). WO96/25168 describes the use of sodium hyaluronate for the treatment of interstitial cystitis. Clinical trials have demonstrated the efficacy of intravesical administration of sodium hyaluronate solutions. The goal of this study was to improve symptoms based on the relief of pain and urgency. Patients received 1 intravesical infusion of sodium hyaluronate per week for 4 weeks, followed by a 20-week treatment period, with a continuous 1 intravesical infusion of sodium hyaluronate every 4 weeks. Each time, the patient received 50ml of an intravesical infusion of 0.08% sodium hyaluronate solution. The hyaluronic acid composition was slowly infused into the bladder through a urethral catheter. The infused hyaluronic acid solution remains in the patient for at least 30 minutes. 14 patients were observed in the trial. At the end of the study, 5 of the observed patients reported significant improvement in their symptoms. Other patients experienced no or only slight improvement in symptoms.

Disclosure of Invention

The invention relates to a pharmaceutical composition with activity against urogenital diseases of mammals, which comprises zinc hyaluronate complex as active ingredient and pharmaceutically acceptable carriers and/or additives. The preparation method of the pharmaceutical composition, and the therapeutic use thereof for treating and preventing diseases related to abnormalities and defects of glucosaminoglycan (GAG) layer of urogenital system in mammals are also included in the scope of the present invention.

Drawings

Figure 1 is a device suitable for administering an active ingredient under pressure with a balloon catheter.

Figure 2 is a graph of the visually simulated pain metric and daily average urine metric scores for a first patient (from example 5) recorded over time.

Figure 3 is a graph of the visually simulated pain metric and daily average urine metric scores for a second patient (from example 5) recorded over time.

Figure 4 is a balloon catheter for bladder dilation.

Detailed Description

The present invention relates to the use of zinc hyaluronate complexes for the preparation of a medicament for the treatment and prevention of diseases associated with abnormalities and defects of the glycosaminoglycan (GAG) layer of the urogenital system in mammals.

We have found that the use of zinc hyaluronate in intravesical therapy can not only regenerate the glycosaminoglycan layer, but can also induce improvement of the deeper layers of the bladder epithelial tissue.

According to our studies, it was found that prior to the use of zinc hyaluronate, the treatment of bacterial infections was unnecessary. In untreated bacterial infected biopsies, a signal for regeneration of the glycosaminoglycan layer was still observed.

The above observations are surprising because treatment of bacterial infections is necessary prior to treatment with sodium hyaluronate, as toxins and harmful metabolites produced by bacteria in the urine may inhibit the regenerative process. The combination therapy of zinc hyaluronate solution and antibiotics may have a synergistic effect, which may shorten the treatment period and prolong the remission period.

In a desired embodiment of the invention, the zinc hyaluronate solution is administered intravesically.

In another desirable embodiment, intravesical administration of the zinc hyaluronate solution is combined with balloon dilation of the bladder, particularly where the patient has interstitial cystitis. The zinc hyaluronate solution was administered into the bladder through a catheter and then the bladder water expansion was performed with a balloon.

Symptoms of interstitial cystitis include a decrease in bladder capacity. As the condition progresses, the bladder wall becomes less and less elastic. Water distension of the bladder is a common form of urology. The method according to the invention comprises the administration of zinc hyaluronate in combination with bladder dilation. After the balloon is filled, the zinc hyaluronate solution in the bladder is subjected to pressure. The solution is held between the bladder wall and the balloon. The pressure within the bladder inhibits the urine from entering the bladder so the concentration of the solution does not decrease. Another advantage of this method is that the surface of the bladder wall is expanded and the mucous membrane is thinned, so that the active ingredient can diffuse to the deeper layers of the mucous membrane. During treatment, the catheter is inserted into the bladder and after the residual urine is excreted, a solution of the active ingredient is introduced into the bladder through the same catheter. The catheter is then removed from the bladder and a balloon, which may be used for bladder dilation, is inserted into the bladder. The filled balloon helps to distribute the active ingredient containing solution evenly over the bladder wall.

The balloon catheter of the invention, which may be used for bladder dilation, may comprise a plastic catheter and a thin, suitably 5cm long, spherical (when filled) balloon at the end of the catheter.

The pharmaceutical composition of the present invention is preferably in the form of a solution and the concentration of zinc hyaluronate is 0.01-5 mg/ml. Zinc hyaluronate solutions can be prepared by a variety of methods.

The solution can be prepared by dissolving solid zinc hyaluronate in sterile water. Other agents (isotonic, preservative agents) may also be added to the above solution.

The zinc hyaluronate solution can also be prepared in situ from an aqueous solution of sodium hyaluronate.

When the appropriate zinc compound is added to an aqueous solution of sodium hyaluronate, the zinc ions replace the sodium ions, producing a zinc hyaluronate solution. The above-mentioned agents may also be added to the zinc hyaluronate solution obtained by this method.

The pharmaceutical compositions of the present invention comprise a zinc hyaluronate complex active ingredient dissolved in a suitable liquid carrier, such as a sterile aqueous solvent. It may also contain water-soluble isotonic agents, such as sodium chloride or sorbitol; and other additives, for example, preservatives such as sodium hydrogen sulfite, sodium hydrogen sulfate, sodium thiosulfate, potassium sorbate, methylparaben, polyvinyl alcohol, phenyl ethanol; and buffering agents such as sodium carbonate, sodium borate, sodium phosphate, sodium acetate, and sodium bicarbonate.

The concentration of the inactive agent in the solution may be 0.001% to 5% by mass.

Examples

The following examples are intended only to illustrate the present invention and should not be construed as limiting the scope of the invention in any way. It will be apparent to those skilled in the art from this disclosure that many modifications and equivalents are possible within the scope of the invention.

Example 1

In a 100ml flask, 0.20mg of sodium hyaluronate (read. ph. eur.) was weighed, then 5.0ml of a 0.10mol/l zinc chloride solution prepared with double distilled water (water for injection, pyrogen-free, sterile) was added, and then the volume was filled up to 50ml with double distilled water. 23.5ml of a 1.00mol/l sorbitol solution (prepared with double distilled water) were added. Then, the volume was filled up to 100ml with double distilled water. Finally, the solution was filtered through a membrane filter.

Animal model test

Two series of experiments were designed to evaluate the efficacy of zinc hyaluronate solution in bladder wall regeneration. In the first series of tests, the experimental pathological course served as a model for the appearance of changes in the bladder wall in interstitial cystitis. The second series of tests simulates the acute inflammatory process of the bladder.

Example 2

Interstitial cystitis model

The experiment was performed with 20 white female rats. Mimicking an experimental pathological process similar to that occurring on the bladder wall in interstitial cystitis. Impaired bladder freezing (cryostructural). A cotton swab soaked with liquid nitrogen was introduced into the bladder and left for 20 seconds to induce interstitial cystitis. Then, the animals were individually selected into 3 test groups.

Trial group 1: after 48 hours of freezing impairment, the rats received only one treatment, and 1ml of zinc hyaluronate solution (according to example 1) was introduced into the rat bladder and left for 30 minutes.

Trial group 2: animals received the same treatment as group 1 animals, but 3 times (completed within 3 consecutive days).

Trial group 3: 3 control animals received no treatment after freezing damage.

Subsequently, the rats were sacrificed and the bladder was excised with excess thiopentone sodium. For histological studies, the bladder samples were fixed with 10% buffered formalin and processed by standard techniques. The samples were stained with toluidine blue. Toluidine blue stains the damaged mucosal wall, the degree of staining depending on the degree of tissue damage. Histological studies in control animals revealed mucosal ulceration, polymorphonuclear leukocyte-containing lymphoid tissue cell exudate in the perilesional area and significant vasodilation of the microcirculation vasculature. Toluidine blue stained specimens exhibit staining of connective tissue. Electron microscopy studies showed that the collagen fibers were destructively destroyed in a striated structure. The above morphological changes are very consistent with photographs of interstitial cystitis.

Connective tissue showed the most significant beneficial changes according to histological studies in treated animals. These beneficial changes are evident after only one treatment with the zinc hyaluronate solution. The change of the connective tissue was deepened in the case of 3 times of administration of the zinc hyaluronate solution.

Electron microscopy of animals receiving only one treatment showed that the collagen fiber structure was stable and its partial streak structure was restored. After 3 times of treatment, the stability of the collagen fibers is more obvious, and the recovery of the stripe structure is more complete.

Example 3

Acute bacterial cystitis model

The experiment was performed with 16 white female rats. Acute inflammation of the bladder was measured by injecting (under pressure) 1.0ml of E.coli culture (10 bacteria solution concentration) into the test animals⁶CFU/ml).

Next, animals were selected into 3 experimental groups:

trial group 1: after 48 hours of injection of the E.coli culture, the rats received only one treatment, and 1ml of zinc hyaluronate solution (according to example 1) was introduced into the rat bladder and left for 30 minutes.

Trial group 2: rats received the same treatment as group 1 animals, but 3 times (completed within 3 consecutive days).

Trial group 3: 3 control animals received no treatment after injection of E.coli culture.

Subsequently, 3 groups of test rats were sacrificed and the bladder was excised with excess thiopentone sodium. For histological studies, the bladder samples were fixed with 10% buffered formalin and processed by standard techniques. The samples were stained with toluidine blue.

Histological studies of control animals showed the following changes:

● all layers of the bladder wall show significant exudates

● microcirculation vasodilation

● edema

● focal destruction of the urothelium and its connective tissue

Microscopic observation of toluidine blue stained samples showed: the connective tissue was visibly stained.

Electron microscopy observations of the animals of the treatment groups confirmed: the treatment with zinc hyaluronate can significantly stabilize collagen fibers, reduce edema and weaken the metachromatism, which indicates the stability of glycosaminoglycan.

In both models, the treatment with zinc hyaluronate also had a beneficial effect on the epithelialization process. After dose treatment, the expression of limbal epithelialization was 14.35% higher than in control animals. Repeated treatments increased the above difference to 21.51%.

Clinical research

Inclusion criteria for this clinical study included:

1. female with a view to preventing the formation of wrinkles

2. The age is greater than 18 years old

3. Urgency, increasing frequency or pelvic pain for at least 6 months

4. Urination at least 7 times per day, foreign body sensation of urination or pelvic pain (measured by visual simulated pain Scale)

5. Under anesthesia, 60-80 cm water column (H) is used₂O) pressure for cystocele with glomerular hemorrhage

6. Sterile urine culture

Exclusion criteria for this clinical study included:

1. average urine volume of over 150ml

2. Tuberculosis of urogenital system

3. Having benign or malignant bladder tumors

4. Within 30 days of clinical study, patients had been treated with any drug or direct therapy for interstitial cystitis

5. Patients use any drug that affects the bladder within 1 week

6. Pregnancy and lactation

7. Has ovarian cancer, cervical cancer or vaginal cancer

8. Vaginal infection

9. Bacterial cystitis in 3 months

10. Active herpes is infected within 3 months

11. Cyclophosphamide treatment history in the previous case history

12. Suffering from radiation cystitis

13. Neurological bladder disease

14. Has suffered from cystitis within 3 months

15. Performing bladder dilating or excising operation

The therapeutic efficacy of zinc hyaluronate was evaluated by using a visual simulated pain scale and measuring the amount of urine.

Example 4

Intravesical administration of zinc hyaluronate solutions

8 patients received treatment.

The bladder catheter was inserted into the bladder, the residual urine in the bladder was drained, and then 10ml of zinc hyaluronate solution (as described in example 1) was introduced into the bladder and left for 1-1.5 hours. This treatment is repeated once a week for a cumulative period of 3-5 weeks depending on the patient's condition. 2 patients reflected no improvement in their symptoms. The other 6 patients reflect an improvement in the symptoms of urgency, frequency and incontinence, such as pelvic pain, after a few hours of the first treatment. This means that the score on the visual simulated pain scale is reduced by 2-3 points. 2 of 6 patients reflected a further reduction in the pain scale score by 2-3 points after subsequent treatment, and this improvement in symptoms was maintained for 1 to 2 months. The symptoms were improved by 100% as reflected by 4 of 6 patients. The patient's condition was stabilized by monthly treatments.

Example 5

Combination therapy: zinc hyaluronate solution for intravesical administration and bladder dilation

Zinc hyaluronate administration was used in combination with bladder balloon dilatation. Before or after receiving treatment, the patient received several intravesical administrations of the zinc hyaluronate solution according to the above examples. The bladder catheter was inserted into the bladder, the residual urine in the bladder was drained, and then 20ml of zinc hyaluronate solution (according to example 1) was introduced into the bladder. The catheter is then removed from the bladder and the balloon catheter is inserted into the bladder. Subsequently, the airbag is filled using the apparatus shown in fig. 1.

After the balloon is filled, the zinc hyaluronate solution in the bladder is subjected to pressure. Because of the expansion of the bladder, the epidermis of the bladder expands and the active ingredient can passively diffuse to the deep layers of the mucosa. To avoid side effects (e.g., bladder wall damage), the pressure of the bladder wall is monitored throughout the treatment. The pressure was raised to 80cm of water and held for 10 minutes.

10 patients received the above treatment. Several days after the combination treatment, the patient reflected a 100% improvement in pain sensation. From day 8 to 9 after receiving bladder distension, bladder capacity increased significantly and remained unchanged.

Figures 2 and 3 show the improvement in symptoms in two patients. One of the curves shows pain improvement and the other shows changes in urine volume. The graphs are labeled for the date of combination treatment and for the date of administration of the zinc hyaluronate solution alone. As can be seen from the graph, zinc hyaluronate treatment alone reduced pain but failed to increase bladder capacity. After 3 months, patient 2 (fig. 3) received additional combination therapy. We found that the results are reproducible.

Treatment of chemical cystitis induced by intravesical administration of cytostatic drugs

Example 6

The treatment method was the same as described in example 5. Two patients who had undergone cystectomy for malignant tumors were treated with this treatment. After surgery, they received treatment with cystostatic drugs. After treatment with cytostatic drugs, their symptoms closely resemble those of interstitial cystitis.

After the first treatment (as described in example 5), the patient reflects an almost 100% improvement in symptoms. The visual simulated pain scale score decreased by 80% while the average urine volume increased by 40% to 50%.

The therapeutic effect remained stable for the following 4 to 6 months.

Claims (16)

1. A pharmaceutical composition comprising a zinc hyaluronate complex for the treatment and prevention of diseases associated with abnormalities and defects of the glycosaminoglycan (GAG) layer of the urogenital system in mammals.

2. The pharmaceutical composition of claim 1, for use in the treatment of cystitis.

3. The pharmaceutical composition of any one of claims 1-2 for use in the treatment of interstitial cystitis.

4. The pharmaceutical composition of any one of claims 1-3, in the form of a solution.

5. The pharmaceutical composition of claim 4, wherein the concentration of the solution is 0.01-5 mg/ml.

6. The pharmaceutical composition of any one of claims 4-5, wherein the internal pressure of the solution is 50-80H₂Ocm。

7. Use of a zinc hyaluronate complex for the preparation of a medicament for the treatment and prevention of diseases associated with abnormalities and defects of the glycosaminoglycan (GAG) layer of the urogenital system in a mammal.

8. Use according to claim 1, characterized in that the disease is cystitis.

9. Use according to any one of claims 1 to 2, wherein the disease is interstitial cystitis.

10. A method of treating and preventing diseases associated with abnormalities and deficiencies of the glycosaminoglycan (GAG) layer of the urogenital system in mammals comprising administering a pharmaceutical composition comprising a zinc hyaluronate complex.

11. The method of claim 10, wherein the composition is administered intravesically into the bladder, optionally followed by balloon dilatation of the bladder.

12. The method of any one of claims 10-11, wherein the pharmaceutical composition is in the form of a solution.

13. The method of claim 12, wherein the concentration of the solution is 0.01-5 mg/ml.

14. The method of any one of claims 12-13, wherein the internal pressure of the solution is 50-80H₂Ocm。

15. A kit comprising the pharmaceutical composition of claim 1, a catheter useful for intravesical administration, and optionally a balloon useful for bladder distension.

16. The kit of claim 15, comprising a balloon that can be used for bladder distension.