Title:  Remedies for bladder disorders

United States Patent:  6,232,301

Assignee:  Seikagaku Corporation (Tokyo, JP)

Filed:  August 27, 1998

PCT NO:  PCT/JP97/04894

102(e) Date:  August 27, 1998

PCT PUB. Date:  July 9, 1998

Foreign Application Priority Data:  Dec 27, 1996[JP] (8-351609)

In order to provide an agent for treatment of bladder troubles that has vesical mucosa epithelium dilatation promoting action and/or vesical mucosa healing action, and exhibits excellent curative effect for bladder troubles, in particular, non-bacterial intractable bladder troubles, the agent for treatment of bladder troubles is formulated with hyaluronic acid and/or a pharmaceutically acceptable salt thereof, preferably hyaluronic acid and/or a pharmaceutically acceptable salt thereof having the following physicochemical properties: (A) endotoxin content; 0.03 EU (endotoxin unit)/10 mg or less, (B) sulfur content; 0.01% or less as determined by coulometric titration, (C) iron content; 20 ppm or less, (D) protein content; 0.1% or less, and (E) weight average molecular weight; 500,000 or more, in an amount effective for promoting vesical mucosa epithelium dilatation and/or healing vesical mucosa, preferably in an amount of 0.2-0.6% by weight based on total amount of the agent.

DESCRIPTION OF THE INVENTION

The present invention has been completed under the circumstances described above, and its object is to provide an agent for treatment of bladder troubles that has vesical mucosa epithelium dilatation promoting action and/or vesical mucosa healing action, and exhibits excellent curative effect for bladder troubles, in particular, non-bacterial intractable bladder troubles.

The present inventors conducted various studies in order to achieve the above object, and as a result they found that, in the treatment of bladder troubles, the bladder troubles can be effectively treated by administering a solution of hyaluronic acid and/or a pharmaceutically acceptable salt thereof at a specific concentration directly into bladder, thereby promoting dilatation of vesical mucosa epithelium or healing vesical mucosa. The present invention has been completed on the basis of these findings.

That is, the present invention provides an agent for treatment of bladder troubles comprising a solution containing hyaluronic acid and/or a pharmaceutically acceptable salt thereof in an amount effective for promoting vesical mucosa epithelium dilatation and/or healing vesical mucosa.

The present invention also provide an agent for treatment of bladder troubles comprising an aqueous solution containing 0.2-0.6% by weight of hyaluronic acid and/or a pharmaceutically acceptable salt thereof.

The present invention will be explained in detail hereinafter. Hyaluronic acid and/or pharmaceutically acceptable salts thereof contained in the solution constituting the agent for treatment of bladder troubles of the present invention will be explained first.

(1) Hyaluronic acid and/or pharmaceutically acceptable salts thereof

Hyaluronic acid and/or pharmaceutically acceptable salts thereof used for the agent for treatment of bladder troubles of the present invention are not particularly limited, so long as they can effectively treat bladder troubles when used as a solution of a certain concentration. As the hyaluronic acid and/or pharmaceutically acceptable salts thereof used for the agent for treatment of bladder troubles of the present invention, hyaluronic acid and/or a pharmaceutically acceptable salt thereof having action for promoting vesical mucosa epithelium dilatation and/or action for healing vesical mucosa are particularly preferred.

As the hyaluronic acid and/or pharmaceutically acceptable salts thereof used for the agent for treatment of bladder troubles of the present invention, hyaluronic acid and/or pharmaceutically acceptable salts thereof having the following physicochemical properties can be specifically mentioned:

(A) endotoxin content; 0.03 EU (endotoxin unit)/10 mg or less,

(B) sulfur content; 0.01% or less as determined by coulometric titration,

(C) iron content; 20 ppm or less,

(D) protein content; 0.1% or less, and

(E) weight average molecular weight; 500,000 or more.

The properties (A) to (E) mentioned above are determined by methods commonly used by those skilled in the art for determining such physicochemical properties.

Specific examples of the hyaluronic acid and/or pharmaceutically acceptable salts thereof used for the agent for treatment of bladder troubles of the present invention include, for example, those having the aforementioned properties (A) to (D) and having a weight average molecular weight of around 500,000-4,000,000, preferably around 500,000-2,200,000, more preferably around 600,000-1,200,000, particularly preferably 800,000-1,200,000. If concentration and viscosity of the solution are selected adequately, hyaluronic acid and/or pharmaceutically acceptable salts thereof having a weight average molecular weight of around 1,500,000-2,200,000 or around 1,900,000-3,900,000 can also be used.

As the hyaluronic acid and/or pharmaceutically acceptable salts thereof used for the agent for treatment of bladder troubles of the present invention, hyaluronic acid and/or pharmaceutically acceptable salts thereof having the aforementioned physicochemical properties (A) to (E) and having a limiting viscosity of 11.0-45 (dl/g) can also be mentioned.

As for the agent for treatment of bladder troubles of the present invention, if hyaluronic acid and/or pharmaceutically acceptable salts thereof having an endotoxin content; sulfated glycosaminoglycan content, iron content; protein content; weight average molecular weight; and/or limiting viscosity outside the above-defined ranges are used, it may cause exacerbation of inflammation and hemorrhage, allergic reactions and the like, or the desired effect may not be obtained.

As the pharmaceutically acceptable salts of hyaluronic acid used for the agent for treatment of bladder troubles of the present invention, pharmaceutically acceptable water-soluble metal salts of hyaluronic acid such as sodium hyaluronate, potassium hyaluronate, and calcium hyaluronate are usually used. Among these, sodium hyaluronate, which is used mainly for medical purposes including medicaments, medical devices and the like, is preferred. Origin of hyaluronic acid and/or pharmaceutically acceptable salts thereof, and production method therefor are not particularly limited. For example, they can be produced from chicken crest, animal umbilical cord, skin, vitreous body or the like by extraction using any optional combination of heat treatment, organic solvent treatment, mincing, protease treatment and the like, and purification using any optional combination of salting out with ammonium sulfate, precipitation with organic solvents such as ethanol, fractional precipitation with quaternary ammonium salts, deproteination, absorption of impurities with absorbents (Celite, activated carbon etc.), ultrafiltration, membrane filtration and the like (see, Japanese Published Examined Patent Application Nos. 61-8083, 61-60081, 61-21241, 6-8323, U.S. Pat. Nos. 4,141,973, 5,449,104 etc.). They can also be produced by fermentation technique using microorganisms such as hemolytic streptococcus (genus Streptococcus) (see, U.S. Pat. Nos. 4,946,780, 4,780,414 etc.).

Some of such hyaluronic acid and/or pharmaceutically acceptable salts thereof are commercially available, and hence those made as preparations for medical use such as for medicaments, whose concentration of hyaluronic acid and/or pharmaceutically acceptable salts thereof and the like are adjusted depending on the purpose, can be selected from them and used for the agent for treatment of bladder troubles of the present invention. Preferred examples of such commercially available hyaluronic acid and/or pharmaceutically acceptable salts thereof include, as sodium hyaluronate satisfying the above properties (A) to (D), ARTZ (weight average molecular weight; 600,000-1,200,000), OPEGAN (weight average molecular weight; 600,000-1,200,000), and OPEGAN Hi (weight average molecular weight; 1,900,000-3,900,000) produced by SEIKAGAKU CORPORATION, Hyalein (weight average molecular weight; 600,000-1,200,000) produced by Santen Pharmaceutical Co., Ltd., OPELEAD (weight average molecular weight; 1,530,000-2,130,000) produced by Shiseido Co., Ltd., Healon (weight average molecular weight; 1,900,000-3,900,000) produced by Kabi Pharmacia Inc. and the like.

(2) Agent for treatment of bladder troubles of the present invention

The agent for treatment of bladder troubles of the present invention comprises a solution containing hyaluronic acid and/or a pharmaceutically acceptable salt thereof in an amount effective for promoting vesical mucosa epithelium dilatation and/or healing vesical mucosa. The term amount effective for promoting vesical mucosa epithelium dilatation and/or healing vesical mucosa of hyaluronic acid and/or a pharmaceutically acceptable salt thereof contained in the solution constituting the agent for treatment of bladder troubles of the present invention means an amount sufficient for the solution to act on vesical mucosa epithelium and promote its dilatation, and/or act on vesical mucosa and heal it or reproduce it as an agent for treatment of bladder troubles. Specifically, while it depends on the kinds of hyaluronic acid and/or pharmaceutically acceptable salts thereof contained in the solution, the concentration of hyaluronic acid and/or pharmaceutically acceptable salts thereof in the solution is, for example, around 0.1-0.8% by weight, preferably around 0.2-0.6% by weight, more preferably around 0.3-0.45% by weight, particularly preferably about 0.4% by weight.

As for the agent for treatment of bladder troubles of the present invention, when the content of hyaluronic acid and/or a pharmaceutically acceptable salt thereof in the solution is less than 0.2%, the agent may not be effectively used as the agent for treatment of bladder troubles of the present invention, because, for example, the action for promoting vesical mucosa epithelium dilatation becomes insufficient. When the content exceeds 0.6% by weight, difficulty of urination may be caused because of high viscosity.

Upon administration of the agent at an effective dose within the range defined above, vesical mucosa epithelium dilatation is promoted and the mucosa is healed and reproduced at damaged or excoriated regions of vesical mucosa epithelium caused by bladder troubles.

In non-bacterial intractable bladder troubles, patients suffer from pain when bladder is filled because nerve is usually denuded due to excoriation of vesical mucosa epithelium, and patients suffer from increased urinary frequency because of decreased bladder capacity caused by fibrillation of bladders. The agent for treatment of bladder troubles of the present invention can indirectly ameliorate such pain and prevent progress of vesical fibrillation through the aforementioned actions.

The solution containing hyaluronic acid and/or a pharmaceutically acceptable salt thereof that constitutes the agent for treatment of bladder troubles of the present invention preferably have a pH value of about 6-8, and a relative osmotic pressure to body fluid is around 0.9-1.2 (substantially isotonic as to body fluid or physiological saline).

By adjusting the pH of the solution in the agent for treatment of bladder troubles of the present invention to the aforementioned range of around 6-8, its acrimony for vesical mucosa made sensitive can be reduced. When the pH is less than 6, acrimony for vesical mucosa may become too strong. When the pH is more than 8, acrimony for vesical mucosa may become too strong, healing and reproduction of vesical mucosa may be retarded, and the preventive effect for the vesical fibrillation may be invalidated.

By adjusting the relative osmotic pressure of the solution in the agent for treatment of bladder troubles of the present invention to the aforementioned range of around 0.9-1.2, its acrimony for vesical mucosa can be reduced as in the adjustment of pH. When the relative osmotic pressure is less than 0.9, difficulty of urination may be caused by increased viscosity. When the relative osmotic pressure is more than 1.2, acrimony for vesical mucosa may become too strong.

For the agent for treatment of bladder troubles of the present invention comprising a solution containing hyaluronic acid and/or a pharmaceutically acceptable salt thereof, the solution containing hyaluronic acid and/or a pharmaceutically acceptable salt thereof is preferably an aqueous solution having an apparent viscosity of 10-1500 mPa.cndot.s as determined at a shear rate of 9.6 sec^-1 at 20^oC.

By adjusting the apparent viscosity of the aqueous solution constituting the agent for treatment of bladder troubles of the present invention to around 10-1500 mPa.cndot.s, it becomes possible to obtain appropriate degree of the effect for healing vesical mucosa without causing difficulty of urination. When the apparent viscosity of the aqueous solution is less than 10 mpa.cndot.s, the effect for healing vesical mucosa may become insufficient. When the apparent viscosity of the aqueous solution exceeds 1500 mPa.cndot.s, difficulty of urination may be caused.

The present inventors found that administration of 5% acetic acid to bladders of experimental animals excoriates vesical mucosa epithelium and irreversibly promotes fibrillation of the bladders, and as a result, the bladder capacity is lowered, and that the symptoms of such animals as treated as mentioned above are quite similar to those of non-infectious intractable bladder troubles of humans. Moreover, they also found that, using the aforementioned animal models, medicaments effective for treatment of non-infectious intractable bladder troubles can be screened by evaluating the following parameters: (a) bladder capacity, (b) bladder dry weight or amount of intravesical hydroxyproline (amount of collagen), and (c) amount of intravesical trypan blue adhesion or area of trypan blue adhesion to the excoriation region of vesical mucosa, which reflect (A) degree of vesical expansion, (B) degree of fibrillation of bladder proper muscle coat, and (C) degree of dilatation of vesical mucosa epithelium and/or degree of healing of vesical mucosa, respectively.

The term "5% acetic acid" herein used refers to a solution containing acetic acid at a concentration of 5%.

Specific examples of the solution containing hyaluronic acid and/or a pharmaceutically acceptable salt thereof, which constitutes the agent for treatment of bladder troubles of the present invention, include such a solution prepared so that bladder capacity of a rabbit which has been subjected to vesical mucosa excoriation treatment by introducing 5% acetic acid into bladder and retaining it for 10 minutes, and then a treatment by introducing the solution to the bladder every day for seven days after the excoriation of the vesical mucosa should be 2 to 3 times as large as bladder capacity of a rabbit which has been subjected to the same vesical mucosa excoriation treatment with 5% acetic acid as mentioned above and a treatment by introducing phosphate buffered physiological saline instead of the solution in the same manner; such a solution prepared so that bladder dry weight of a rabbit which has been subjected to the same vesical mucosa excoriation treatment with 5% acetic acid as mentioned above and then the same treatment by introducing the solution as mentioned above should be 0.6 to 0.9 times as large as bladder dry weight of a rabbit which has been subjected to the same vesical mucosa excoriation treatment with 5% acetic acid as mentioned above and the same treatment by introducing phosphate buffered physiological saline instead of the solution as mentioned above; and the like.

Specific examples of the solution containing hyaluronic acid and/or a pharmaceutically acceptable salt thereof, which constitutes the agent for treatment of bladder troubles of the present invention, further include such a solution prepared so that amount of intravesical trypan blue adhesion of a rabbit which has been subjected to vesical mucosa excoriation treatment by introducing 5% acetic acid to bladder and retaining it for 10 minutes, then a treatment by introducing the solution to the bladder every day for seven days after the excoriation of the vesical mucosa, and then a treatment by introducing 0.5% aqueous trypan blue solution to the bladder to obtain trypan blue adhesion should be 0.5 to 0.7 times as large as amount of intravesical trypan blue adhesion of a rabbit which has been subjected to the same vesical mucosa excoriation treatment with 5% acetic acid as mentioned above, then a treatment by introducing phosphate buffered saline instead of the solution in the same manner, and then the same trypan blue adhesion treatment as mentioned above; such a solution prepared so that trypan blue adhesion area in vesical mucosa excoriation region of a rabbit which has been subjected to the same vesical mucosa excoriation treatment with 5% acetic acid as mentioned above, then the same treatment with the solution as mentioned above, and then the same trypan blue adhesion treatment as mentioned above should be 0.25 to 0.45 times as large as trypan blue adhesion area in vesical mucosa excoriation region of a rabbit which has been subjected to the same vesical mucosa excoriation treatment with 5% acetic acid as mentioned above, then a treatment by introducing phosphate buffered saline instead of the solution in the same manner, and then the same trypan blue adhesion treatment as mentioned above; and the like.

Specific examples of the solution containing hyaluronic acid and/or a pharmaceutically acceptable salt thereof further include such a solution prepared so that amount of intravesical hydroxyproline of a rabbit which has been subjected to the same vesical mucosa excoriation treatment with 5% acetic acid as mentioned above, and then the same treatment with the solution as mentioned above should be 0.8 to 0.9 times as large as amount of intravesical hydroxyproline of a rabbit which has been subjected to the same vesical mucosa excoriation treatment with 5% acetic acid as mentioned above, and then a treatment by introducing phosphate buffered saline instead of the solution in the same manner; and the like.

The solution containing hyaluronic acid and/or a pharmaceutically acceptable salt thereof, which constitutes the agent for treatment of bladder troubles of the present invention, such as those specifically mentioned above, is a solution selected based on evaluation of the action for promoting vesical mucosa epithelium dilatation and/or action for healing vesical mucosa of the solution in bladders of rabbits whose vesical mucosa has been excoriated by introducing 5% acetic acid into their bladders and retaining it for 10 minutes as a model, more specifically, selected based on the following indexes, action for increasing bladder capacity, action for decreasing bladder dry weight, action for decreasing amount of intravesical trypan blue adhesion or trypan blue adhesion area at vesical mucosa excoriated region, action for decreasing amount of intravesical hydroxyproline and the like of the solution, which indexes are determined by comparing results obtained in the model when the solution is used and result obtained when phosphate buffered saline is used in the same manner instead of the solution. These indexes will be explained hereinafter.

The rabbit model whose vesical mucosa is excoriated, referred to as rabbit vesical mucosa trouble model hereinafter, will be explained first. It has been known that acetic acid has mucosa acrimony, and gastric mucosa trouble models prepared by using acetic acid have widely been used for tests of medicaments and the like. Therefore, in the present invention, a rabbit vesical mucosa trouble model was created in which vesical mucosa is excoriated by applying acetic acid to the vesical mucosa as described above, and factors representing the action for promoting vesical mucosa epithelium dilatation and/or the action for healing vesical mucosa measured in this model were used as indexes for selecting solutions constituting the agent for treatment of bladder troubles of the present invention as described above.

The rabbit vesical mucosa trouble model is prepared, for example, as follows. A bladder catheter is inserted into bladder of rabbit under general anesthesia obtained by a usual method, and then residual urine in the bladder is drained using an infusion pipe of a suitable size. After the drainage of residual urine, the inside of the bladder is washed with sufficient amount of physiological saline. Then, a solution comprising acetic acid diluted with distilled water to a concentration of 5% is introduced into the bladder in an amount sufficiently filling the bladder, and retained for 10 minutes so that vesical mucosa should be excoriated. Subsequently, the acetic acid is drained, and intravesical irrigation is performed with a sufficient amount of physiological saline.

In the present invention, while the rabbit vesical mucosa trouble model treated with 5% acetic acid for ten minutes is used as the standard, any similar models may be used for evaluation tests of various drug substances. In such cases, acetic acid concentration of the acetic acid solution used for excoriation of vesical mucosa is not limited to 5%, and retention time of the acetic acid solution in bladder is not limited to ten minutes. These factors may be appropriately modified as required according to the circumferential conditions. Though kind, age represented by week-basis, and sexuality of rabbits used for the model production are not particularly limited, preferred example of the rabbits include JW male rabbits of 12-14 week old and the like. Animals other than rabbit can also be used.

The factors for evaluating action for promoting vesical mucosa epithelium dilatation and/or action for healing vesical mucosa upon applying the pharmaceutical solution to bladder of the aforementioned vesical mucosa trouble model will be explained hereinafter.

If the bladder treated with acetic acid as described above is not given any appropriate therapeutic treatment, severe inflammation should be induced after the excoriation of vesical mucosa epithelium, and fibrillation of vesical proper muscle coat should be caused after a few days, which makes bladder expansion very difficult. In contrast, if any effective curative treatment is given, dilatation of vesical mucosa epithelium should be promoted, and fibrillation of vesical proper muscle coat should be prevented because of healing of vesical mucosa, thereby the expansion function of bladder should be improved.

Therefore, degree of expansion function of bladder can be evaluated by measuring bladder capacity. In other words, the larger the bladder capacity of the aforementioned rabbit vesical mucosa trouble model after the bladder of the model is applied with a solution of various agents, the more the bladder function is recovered. Further, degree of fibrillation of vesical proper muscle coat can be evaluated by measuring bladder dry weight and intravesical amount of hydroxyproline (collagen). That is, the larger the bladder dry weight or the smaller the intravesical amount of hydroxyproline of the aforementioned rabbit vesical mucosa trouble model after the bladder of the model is applied with a solution of various agents, the stronger the ability of preventing fibrillation of vesical proper muscle coat of the solution.

Furthermore, because it has been known that trypan blue, an acidic living tissue staining agent, can stain damaged mucosa well, degree of dilatation of vesical mucosa epithelium or degree of healing of vesical mucosa can be evaluated by measuring amount of intravesical trypan blue adhesion or trypan blue adhesion area at excoriation region of vesical mucosa. That is, the smaller the amount of intravesical trypan blue adhesion, or the trypan blue adhesion area at excoriation region of vesical mucosa after the bladder of the model is applied with a solution of various agents, the more the solution can promote dilatation of vesical mucosa epithelium or healing of vesical mucosa.

In the present invention, results obtained by daily irrigation of a solution containing hyaluronic acid and/or a pharmaceutically acceptable salt thereof for 7 days to a bladder of the aforementioned rabbit vesical mucosa trouble model and results obtained by daily irrigation of phosphate buffered saline (PBS) to the same for 7 days are compared, and solutions of hyaluronic acid and/or a pharmaceutically acceptable salt thereof resulting a bladder capacity within 2 to 3 times of that obtained with PBS, bladder dry weight within 0.6-0.9 times of that obtained with PBS, amount of intravesical trypan blue adhesion within 0.5-0.7 times of that obtained with PBS, trypan blue adhesion area at vesical mucosa excoriation region within 0.25-0.45 times of that obtained with PBS, and/or amount of intravesical hydroxyproline within 0.8-0.9 times of that obtained with PBS are selected as a preferred solution for the agent for treatment of bladder troubles of the present invention.

Those solutions of hyaluronic acid and/or a pharmaceutically acceptable salt thereof not resulting, when those solutions of hyaluronic acid and/or a pharmaceutically acceptable salt thereof are administered to bladder of the aforementioned vesical mucosa trouble model, a bladder capacity within 2 to 3 times of that obtained with PBS, bladder dry weight within 0.6-0.9 times of that obtained with PBS, amount of intravesical trypan blue adhesion within 0.5-0.7 times of that obtained with PBS, trypan blue adhesion area at vesical mucosa excoriation region within 0.25-0.45 times of that obtained with PBS, and/or amount of intravesical hydroxyproline within 0.8-0.9 times of that obtained with PBS may not be effectively used as the agent for treatment of bladder troubles of the present invention. Therefore, solutions resulting the values of the evaluation factors within the ranges defined above are preferred for the agent for treatment of bladder troubles of the present invention.

The agent for treatment of bladder troubles of the present invention can be produced by dissolving hyaluronic acid and/or a pharmaceutically acceptable salt thereof in a suitable solvent so that a content within the aforementioned range can be obtained. Examples of the solvent include water, buffers, physiological saline, water containing a water-soluble organic solvent such as dimethyl sulfoxide and the like. In the present invention, water or physiological saline is preferably used. The agent for treatment of bladder troubles of the present invention may also be provided as powder of hyaluronic acid and/or a pharmaceutically acceptable salt thereof or the like, so that it can be prepared upon use into a solution having a concentration, apparent viscosity, pH, relative osmotic pressure and the like within the ranges defined above.

The agent for treatment of bladder troubles of the present invention may contain, in addition to the above-explained hyaluronic acid and/or a pharmaceutically acceptable salt thereof and a solvent, optional ingredients as required. Examples of the optional ingredients include, for example, pharmaceutically acceptable known antiinflammatory agents, analgesics, vitamins, antibacterial agents, growth factors, adhesion factors, buffers, stabilizers, inorganic salts and the like. Because the concentration of hyaluronic acid and/or a salt thereof in the solution is relatively low (e.g., 0.1-0.8% by weight, preferably 0.2-0.6% by weight), the hyaluronic acid and the like may be degraded into lower molecular weight compounds when they are subjected to heat sterilization or stored for a long term. In such a case, it is necessary to use a means for preventing the degradation of hyaluronic acid and the like into lower molecular weight compounds, which may be a known one. Examples of such means include, for example, lowering metal ion (e.g., iron ions) content in hyaluronic acid and or salts thereof to be used to 20 ppm or less, preferably 10 ppm or less (see, U.S. Pat. No. 5,559,104), adding known stabilizers capable of preventing the degradation of hyaluronic acid and the like such as citric acid, citric acid salts, and glycerin (see, Japanese Patent Application Laid-open Nos. 8-104642 and 9-176020) and the like.

The agent for treatment of bladder troubles of the present invention is an agent to be directly administered to bladders, and it can be administered by a method usually used for medicaments usually administered directly to bladders. For example, administration method using a intravesical catheter may be used.

As for doses of the agent for treatment of bladder troubles of the present invention, for example, when a phosphate buffered physiological saline containing 0.2-0.6% by weigh of sodium hyaluronate having an endotoxin content of 0.03 EU (endotoxin unit)/10 mg or less, sulfur content of 0.01% or less as determined by coulometric titration, iron content of 20 ppm or less, protein content of 0.1% or less, and weight average molecular weight of 600,000-1,200,000 is used as the agent for treatment of bladder troubles, it may be administered once to seven times a week at a dose of 50 ml per single administration.

The agent for treatment of bladder troubles of the present invention can be widely used for bladder troubles in generic sense so long as the troubles are those whose symptoms can be improved by dilatation of vesical mucosa epithelium and/or healing of vesical mucosa. It is particularly effective for treatment of non-bacterial intractable bladder troubles, for example, hemorrhagic cystitis such as radiation cystitis caused by radiotherapy of uterine cancer, rectal cancer, cystocarcinoma, prostate cancer and the like and drug cystitis caused by chemotherapeutants for treatment of malignancy, e.g., cyclophosphamide, mitomycin, platinum chelates such as cisplatin, methotrexate, bleomycin hydrochloride, and bleomycin sulfate, stimulation therapy agents for treatment of rheumatism such as auranofin; interstitial cystitis; eosinophilic cystitis; neurogenic increased urinary frequency, and the like.

Because the agent for treatment of bladder troubles of the present invention has action for promoting vesical mucosa epithelium dilatation, and heals vesical mucosa damaged by cystitis, thereby exhibiting excellent action for inhibiting fibrillation of bladder, bladder troubles can be effectively treated by the agent. Further, because the agent for treatment of bladder troubles of the present invention does not show anti-thrombogenic activity, it can be used without causing adverse drug reactions such as becoming easy to bleed.

Claim 1 of 22 Claims

What is claimed is:

1. A method for promoting vesical mucosa epithelium dilatation and/or healing vesical mucosa of a patient's bladder, comprising: administering to the inside of the patient's bladder a solution comprising hyaluronic acid and/or a pharmaceutically acceptable salt thereof in an amount of around 0.4% inclusive of 0.45% by weight until promotion of vesical mucosa epithelium dilatation and/or healing vesical mucosa is observed.

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