A product containing a local anesthetic, buffer, and glucosaminoglycan in a syringe with improved stability.

Abstract

The present invention provides a composition comprising a glycosaminoglycan, a local anesthetic, and a buffer solution packaged in a syringe or vial constructed from glass or a plastic selected from the group consisting of cyclic olefin polymer, cyclic olefin copolymer, or high-density non-nuclear polypropylene. The composition unexpectedly has improved storage stability. The composition can be formulated for the treatment of urinary tract diseases or conditions, such as interstitial cystitis, also known as painful bladder syndrome or irritable bladder syndrome.

Description

[Technical Field]

[0001] Cross-references to related applications This application claims the rights of U.S. Provisional Application No. 62 / 484,477, filed on April 12, 2017, entitled “Article of Manufacture Comprising Local Anesthetic, Buffer, and Glycosaminoglycan in Plastic Syringe with Improved Stability,” by Dr. Dan Vickery et al., which is incorporated herein by reference in its entirety.

[0002] Field of Invention The present invention relates to a product having improved stability, comprising a local anesthetic, a buffer, and a glycosaminoglycan in a syringe or vial, typically combined with final sterilization of the product. [Background technology]

[0003] Background of the Invention Interstitial cystitis (IC), often also known as bladder pain syndrome or irritable bladder syndrome, is a chronic, progressive disorder of the lower urinary tract that causes urinary urgency and frequent urination, and / or pelvic pain. The American Urological Association defines IC / BPS as "a perceived unpleasant sensation (pain, pressure, discomfort) associated with the bladder, accompanied by lower urinary tract symptoms lasting more than six weeks, in the absence of infection or other identifiable cause." For many years, urologists considered IC / BPS a rare disease for which there was no widely effective treatment. In reality, the condition is quite common. In 1999, the prevalence in the United States was estimated at 750,000 cases (Curhan et al., J Urol 161(2):549-552 (1999)). However, current estimates from the RAND Interstitial Cystitis Epidemiology (RICE) study suggest that the true prevalence of IC / BPS is estimated to be between 2.7% and 6.53% (approximately 3.3 million to 7.9 million US women aged 18 or older) and between 2.9% and 4.2% (approximately 2 million to 4.6 million US men aged 18 or older) (Berry SH et al., J Urol 2011, Vol. 186, p. 540). And Suskind AM et al., J Urol 2013, vol. 189, p. 141. In addition, overactive bladder, urethral syndrome, prostatitis, and gynecological chronic pelvic pain syndromes, for which there is no effective treatment, also result in bladder symptoms such as urgent, frequent, incontinence, and / or pelvic pain, and involve millions of patients. All of these syndromes share similar symptoms and possibly common pathophysiology to traditionally diagnosed IC (Parsons, CL Int Br J Urol December 2010), but there is no widely effective treatment for these conditions.

[0004] Therefore, there is a need for a treatment that would benefit a larger portion of the patient population, provide immediate symptom relief without requiring significant dietary changes or causing additional pain, and even lead to a reversal of the disease course over time.

[0005] Compositions and methods for treating interstitial cystitis are incorporated herein by whole reference by Parsons U.S. Patent No. 7,414,039, published on 19 August 2008, entitled "Interstitial Therapy for Immediate Symptom Relief and Chronic Therapy in Interstitial Cystitis," and U.S. Patent Application Publication No. 2008 / 0300219, published on 4 December 2008, entitled "Novel Interstitial Therapy for Immediate Symptom Relief and Chronic Therapy in Interstitial Cystitis," both of which are incorporated herein by whole reference by Parsons U.S. Patent Application Publication No. 2008 / 0300219, published on 4 December 2008, entitled "Kits and Improved Compositions for Treating Lower Urinary Tract," published on 20 July 2006. This is described in PCT patent application publication WO2006 / 07663 by Flashner et al., entitled “Disorders”, and PCT patent application publication WO2007 / 073397 by Flashner et al., entitled “Kits and Improved Compositions for Treating Lower Urinary Tract Disorders”, published on June 28, 2007. Generally, the compositions disclosed in these published patents and these published patent applications include a local anesthetic, typically lidocaine; a glycosaminoglycan, typically heparinoid, more typically heparin; and a buffer. The composition is injected into the bladder. The buffer is typically a phosphate buffer, although other buffers, such as bicarbonate buffer or Tris buffer, may be used as described below. A particularly preferred phosphate buffer is sodium phosphate buffer.

[0006] Alkalinated lidocaine and heparin may be used to successfully treat bladder symptoms, including, but not limited to, frequent urination, urgency, incontinence, and pain originating in the bladder. Pain originating in the bladder (viscera) is not always perceived as originating from the bladder. Pain can be thought to originate anywhere from the navel to the knee, or from the lumbar region down the buttocks and into the legs, and is often unrelated to the bladder being full or empty. As a result, the source of pelvic pain may not be recognized as the bladder. These bladder symptoms can be seen in a variety of “clinical syndromes” in which they may all actually stem from a single disease process of dysfunctional epithelium (Parsons, CL Int Br J Urol, December 2010). Nevertheless, all of these syndromes that can cause bladder symptoms that can be successfully treated with this solution include, but are not limited to, overactive bladder, interstitial cystitis, urethral syndrome in women, recurrent lower urinary tract infections, prostatitis (chronic pelvic pain syndrome in men), radiation cystitis, chemical cystitis, and gynecological chronic pelvic pain syndromes (e.g., endometriosis, vulvodynia, vulvovaginitis, yeast vaginitis).

[0007] However, mixing these compounds presents a problem because an imbalance can result in lidocaine precipitation and loss of efficacy. When exposed to a pH of 7.0 or higher, lidocaine deionizes and is absorbed through lipid membranes, such as the bladder epithelium. As a result, absorbed lidocaine can paralyze the bladder nerves and alleviate the bladder symptoms described above. Heparin can "coat" the bladder wall, inhibiting the diffusion of urinary solutes that initially cause bladder symptoms. Therefore, the combination results in prolonged relief of bladder symptoms (Parsons, Urology 2003). However, since lidocaine precipitates at pH values ​​above 7 under certain conditions, the mixing of heparin, lidocaine, and buffers must be carried out in a precise manner to prevent lidocaine precipitation. Lidocaine precipitation reduces its bioavailability and diminishes the efficacy of the composition. However, even if the composition is prepared in a manner that prevents immediate precipitation of lidocaine in the formation of the composition, including a mixture of glycosaminoglycans, buffers, and local anesthetics, the storage and transport of the composition require long-term stability. One factor contributing to the loss of lidocaine stability and the resulting loss of lidocaine from the composition is the interaction between alkalized lidocaine and the syringe components. Lidocaine can adhere to the syringe after sterilization. In the absence of such long-term stability, there is a serious risk that a patient may be administered one or more components of the composition in a dosage that may not produce the desired clinical effect. Therefore, there is a particular need for compositions manufactured to be stable and transportable and storeable in a form that can be immediately administered to a patient. In addition, there is a need for compositions of substances that can withstand sterilization without a significant decrease in stability. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] U.S. Patent No. 7,414,039 [Patent Document 2] U.S. Patent Application Publication No. 2008 / 0300219 [Patent Document 3] International Publication No. 2006 / 07663 [Patent Document 4] International Publication No. 2007 / 073397 [Non-patent literature]

[0009] [Non-Patent Document 1] Curhan et al., J Urol Vol. 161 (No. 2): pp. 549-552 (1999) [Non-Patent Document 2] Berry SH et al., J Urol 2011, Vol. 186, p. 540. [Non-Patent Document 3] Suskind AM et al., J Urol 2013, Vol. 189, p. 141. [Non-Patent Document 4] Parsons, CL Int Br J Urol December 2010 [Overview of the project] [Means for solving the problem]

[0010] Summary of the Invention A product comprising a composition containing glycosaminoglycans, a local anesthetic, and a buffer, packaged in a syringe or vial constructed from a material selected from glass and high-density plastic polymers. Typically, the high-density plastic polymer is selected from the group consisting of cyclic olefin polymers, cyclic olefin copolymers, high-density polyethylene, and high-density nucleus-free polypropylene, and is a plastic that meets these needs and provides improved stability of the composition in the container, making it suitable for administration into the urinary tract of patients suffering from interstitial cystitis (bladder pain syndrome or irritable bladder syndrome) or another urinary tract disease or disorder. Generally, the present invention relates to a product comprising a composition containing a glycosaminoglycan, a local anesthetic, and a buffer, packaged in a syringe or vial constructed from glass or a high-density plastic polymer. Typically, the high-density plastic polymer is selected from the group consisting of cyclic olefin polymers, cyclic olefin copolymers, high-density polyethylene, and high-density nucleus-free polypropylene.

[0011] In one alternative configuration, the inside of the syringe may be coated to reduce the deposition of anesthetic onto the syringe surface.

[0012] Typically, glycosaminoglycans are heparinoids. Preferably, the heparinoid is selected from the group consisting of heparin, chondroitin sulfate, heparan sulfate, hyaluronic acid, keratan sulfate, dermatan sulfate, hyaluronan, pentosan polysulfate sodium, dalteparin, and enoxaparin. Particularly preferred heparinoids include heparin, heparan sulfate, chondroitin sulfate, hyaluronic acid, and pentosan polysulfate sodium. A more particularly preferred heparinoid is heparin, for example, heparin sodium. The heparin may be heparin having a molecular weight of about 2,000 daltons to about 8,000 daltons, or alternatively, heparin having a molecular weight of about 8,000 daltons to about 40,000 daltons.

[0013] Typically, when the glycosaminoglycan is heparin, the unit dose of the composition contained in the product contains about 1,000 to about 250,000 units of heparin per unit dose of the composition. Preferred amounts of heparin per unit dose of the composition include 40,000, 50,000, and 60,000 units of heparin. Typically, when the heparinoid is pentosan polysulfate sodium, the composition contains about 1 mg to about 600 mg of pentosan polysulfate sodium per unit dose of the composition. Typically, when the glycosaminoglycan is heparan sulfate, the composition contains about 1 mg to about 600 mg of pentosan polysulfate sodium per unit dose of the composition. Typically, when the glycosaminoglycan is heparan sulfate, the composition contains about 0.5 mg to about 10,000 mg of heparan sulfate per unit dose of the composition. Typically, when the glycosaminoglycan is hyaluronic acid, the composition contains about 5 mg to about 600 mg of hyaluronic acid per unit dose of the composition. Typically, when the glycosaminoglycan is chondroitin sulfate, the composition contains about 1 mg to about 10,000 mg of chondroitin sulfate per unit dose of the composition.

[0014] Typically, local anesthetics are selected from the group consisting of benzocaine, lidocaine, tetracaine, bupivacaine, etidocaine, mepivacaine, pramoxin, prilocaine, procaine, chloroprocaine, oxyprocaine, propalacaine, ropivacaine, diclonin, dibucaine, propoxycaine, dexivacaine, diamocaine, hexylcaine, levobupivacaine, pirocaine, lysocaine, rhodocaine, and pharmaceutically acceptable derivatives and bioequivalents thereof, as well as combinations thereof. Preferred local anesthetics include lidocaine, bupivacaine, mepivacaine, benzocaine, tetracaine, etidocaine, prilocaine, and dibucaine. More preferred local anesthetics include lidocaine, bupivacaine, and mepivacaine. Particularly preferred local anesthetics are lidocaine, e.g., lidocaine hydrochloride. When the local anesthetic is lidocaine, typically the unit dose of the composition contained in the product contains an amount of lidocaine ranging from about 10 mg to about 400 mg per unit dose of the composition.

[0015] Typically, buffers include phosphate buffer, bicarbonate buffer, Tris(tris(hydroxymethyl)aminomethane) buffer, MOPS buffer (3-(N-morpholino)propanesulfonic acid), HEPES (N-(2-hydroxyethyl)piperazine-N-(2-ethanesulfonic acid) buffer, ACES (2-[(2-amino-2-oxoethyl)amino]ethanesulfonic acid) buffer, ADA (N-(2-acetamide)2-iminodiacetic acid) buffer, AMPSO (3-[(1 ,1-dimethyl-2-hydroxyethyl)amino]-2-propanesulfonic acid) buffer, BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid buffer, bicine (N,N-bis(2-hydroxyethylglycine) buffer, bis-tris (bis-(2-hydroxyethyl)imino-tris(hydroxymethyl)methane buffer, CAPS (3-(cyclohexylamino)-1-propanesulfonic acid) buffer, CAPSO (3-(cyclohexyl a (N-(2-hydroxy-1-propanesulfonic acid) buffer, CHES (2-(N-cyclohexylamino)ethanesulfonic acid) buffer, DIPSO (3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid) buffer, HEPPS (N-(2-hydroxyethylpiperazine)-N'-(3-propanesulfonic acid) buffer, HEPPSO (N-(2-hydroxyethyl)piperazine-N'-(2-hydroxypropanesulfonic acid) ) buffer, MES (2-(N-morpholino)ethanesulfonic acid) buffer, triethanolamine buffer, imidazole buffer, glycine buffer, ethanolamine buffer, MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid) buffer, PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid) buffer), POPSO (piperazine-N,N'-bis(2-hydroxypropanesulfonic acid)) buffer, TAPS (N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid) buffer;The buffer is selected from the group consisting of TAPSO (3-[N-tris(hydroxymethyl)methylamino]-2-hydroxy-propanesulfonic acid) buffer, TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid) buffer, Trisine (N-tris(hydroxymethyl)methylglycine buffer), 2-amino-2-methyl-1,3-propanediol buffer, and 2-amino-2-methyl-1-propanol buffer, as well as combinations thereof. Preferred buffers include phosphate buffer, bicarbonate buffer, Tris buffer, and combinations thereof. A particularly preferred buffer is phosphate buffer. A more particularly preferred buffer is sodium phosphate buffer.

[0016] In one alternative form, the composition contained in the product is (1) Osmotic components that provide an isotonic or nearly isotonic solution compatible with human cells and blood, (2) A compound that allows the composition to remain on the surface of the bladder epithelium in an amount sufficient to treat, restore, or prevent lower urinary tract disorders. (3) A sufficient amount of antibiotics to treat, treat, or prevent lower urinary tract disorders, (4) An amount of antifungal agent sufficient to treat, treat, or prevent lower urinary tract disorders, (5) A sufficient amount of vasoconstrictor to treat, treat, or prevent lower urinary tract disorders, (6) Preservatives, and (7) Anti-inflammatory drugs It includes an additional component selected from the group consisting of the following.

[0017] Typically, the pH of the composition contained in the product is about 6.8 to about 8.3. Preferably, the pH of the composition contained in the product is about 7.2 to about 7.6. More preferably, the pH of the composition contained in the product is about 7.5.

[0018] Typically, the compositions contained in the product are formulated to treat lower urinary tract disorders selected from the group consisting of bacterial cystitis, fungal / yeast cystitis, vaginitis, vulvovaginitis, dyspareunia, urethral syndrome, and endometriosis in women; prostatitis and chronic pelvic pain syndrome in men; and radiation-induced cystitis, chemotherapy-induced cystitis, interstitial cystitis (bladder pain syndrome or hypersensitive bladder syndrome), and overactive bladder in men or women.

[0019] In one alternative configuration, the syringe or vial is constructed from glass. In another alternative configuration, the syringe or vial is constructed from cyclic olefin polymer (COP) plastic. In yet another alternative configuration, the syringe or vial is constructed from cyclic olefin copolymer (COC) plastic. In yet another alternative configuration, the syringe or vial is constructed from high-density polyethylene. In yet another alternative configuration, the syringe or vial is constructed from high-density nucleus-free polypropylene. In one alternative configuration, if the container is a syringe, the syringe has a capacity of 20 mL, but syringes of other capacities may be used.

[0020] In one alternative form, the composition contained in the product is prepared in purified water having the specified concentrations of its components, as follows: (1) 16.67 g / L heparin sodium, (2) 13.33 g / L of lidocaine hydrochloride, (3) 10.03 g / L of Na2HPO4·12H2O to obtain a concentration of 0.028 M, and (4) 0.02N NaOH to adjust the pH, if necessary.

[0021] These and other features, embodiments, and advantages of the present invention will be better understood by referring to the following description, the appended claims, and the appended drawings. [Brief explanation of the drawing]

[0022] [Figure 1]Figure 1 is a graph showing the results regarding the pH stability of cyclic olefin polymer (COP) syringes (left panel) and polypropylene (PP) syringes (right panel) up to 6 months in Example 2.

[0023] [Figure 2] Figure 2 is a graph showing the results regarding the stability of lidocaine concentrations in COP syringes (left panel) and PP syringes (right panel) up to 6 months in Example 2.

[0024] [Figure 3] Figure 3 shows the results of the storage stability test in Example 2 at 25°C / 60%RH using a COP syringe.

[0025] [Figure 4] Figure 4 shows the results of the storage stability test in Example 2 at 40°C / 75%RH using a COP syringe.

[0026] [Figure 5] Figure 5 shows the results of the storage stability test in Example 2 at 25°C / 60%RH using a PP syringe.

[0027] [Figure 6] Figure 6 shows the results of the storage stability test in Example 2 at 40°C / 75%RH using a PP syringe.

[0028] [Figure 7] Figure 7 is a graph showing the results of pH measurements in a COP syringe at either 25°C / 60%RH or 40°C / 75%RH up to 12 months.

[0029] [Figure 8] Figure 8 is a graph showing the results of pH measurements in PP syringes at either 25°C / 60%RH or 40°C / 75%RH up to 12 months.

[0030] [Figure 9] Figure 9 is a graph showing the loss of lidocaine hydrochloride after sterilization in glass vials and polypropylene plastic syringes at different molar concentrations of phosphate buffer.

[0031] [Figure 10] Figure 10 is a graph showing the loss of lidocaine hydrochloride in plungers and syringe bodies containing Tris buffer (left bar) and phosphate buffer (right bar).

[0032] [Figure 11] Figure 11 is a graph showing the amount of lidocaine hydrochloride extracted from a 10x syringe using a Soxhlet extractor, with tetrahydrofuran (THF) (left bar), ethanol (center bar), and pH 3 water (far right bar).

[0033] [Figure 12] Figure 12 is a graph showing the lidocaine loss after sterilization of samples derived from the samples in Table 14(B), with different phosphate buffer concentrations and pH adjustments.

[0034] [Figure 13] Figure 13 is a graph showing the lidocaine loss as a function of sterilization over multiple cycles, derived from the samples in Table 14(C). [Modes for carrying out the invention]

[0035] Detailed description of the invention Generally, the present invention includes products comprising a composition comprising a glycosaminoglycan, a local anesthetic, and a buffer, packaged in a syringe or vial constructed from glass or a plastic selected from the group consisting of cyclic olefin polymers, cyclic olefin copolymers, high-density polyethylene, and high-density nucleus-free polypropylene. Typically, the glycosaminoglycan is a heparinoid, as detailed below. Preferably, the heparinoid is heparin, as detailed below. Typically, the local anesthetic is lidocaine, as detailed below. Typically, the buffer is a phosphate buffer, particularly a sodium phosphate buffer, as detailed below. However, other buffers, including but not limited to bicarbonate buffer and Tris buffer, may be used as alternatives.

[0036] I. Composition comprising glycosaminoglycans, local anesthetics, and buffers.

[0037] The product's composition includes glycosaminoglycans, local anesthetics, and buffer solutions. Other components may also be included in the composition, as detailed below.

[0038] Glycosaminoglycans are present in the composition in amounts sufficient to treat urinary tract disorders or conditions, such as interstitial cystitis (also known as bladder pain syndrome (BPS) or bladder hypersensitivity syndrome (BHS)). Local anesthetics are also present in the composition in amounts sufficient to treat urinary tract disorders or conditions, such as interstitial cystitis (also known as BPS or BHS). The buffer is present in the composition in such amounts that approximately 2% to approximately 45% of the local anesthetic is present in the composition in a free base (uncharged) form rather than a protonated (charged) form.

[0039] Typically, glycosaminoglycans are heparinoids. As used herein, “heparinoid” includes glycosaminoglycans (e.g., heparin, chondroitin sulfate, heparan sulfate, hyaluronic acid, keratan sulfate, dermatan sulfate, hyaluronan, pentosan polysulfate sodium, etc.) that contain a network of long-branched sugars, and optimally refers to any molecule further containing smaller nitrogen-containing molecules (e.g., low molecular weight molecules). This does not mean that the present invention is limited to any one type of glycosaminoglycan (GAG) or any one type of source of GAGs. Examples of GAG molecules include, but are not limited to, low molecular weight (LMW) GAGs, naturally occurring GAGs, biotechnology-prepared GAGs, chemically modified GAGs, and synthetic GAGs. Heparinoids may also consist of pentoses, such as pentosan polysulfate, instead of hexoses (GAGs are composed of hexoses). This does not mean that the present invention is limited to any one heparinoid molecule or any one source of heparinoid molecules. As used herein, “heparin” refers to a mixed group of linear anionic glycosaminoglycans having molecular weights in the range of 2,000 to 40,000 Da, as described above. In some embodiments, heparin is a high molecular weight species in the range of 8,000 to 40,000 daltons. As used herein, “low molecular weight heparin” refers to a low molecular weight (LMW) species in the range of 2,000 to 8,000 daltons. Pentosan polysulfate sodium may be in the range of 2,000 to 6,000 daltons. Polymers such as dalteparin or enoxaparin are also included within the scope of the present invention. LMW heparin is produced by controlled enzymatic or chemical hydrolysis of unfractionated heparin and has a chemical structure very similar to unfractionated heparin, except for some modifications that may have been introduced for enzymatic or chemical processing. While not intended to limit the mechanism of action of the compositions of the present invention, the mechanism of action of these drugs may be similar to that of full-length heparin. LMW heparin is typically isolated from bulk heparin. In one embodiment, heparin or another heparinoid is a heparin salt.As used herein, the terms “pharmaceutically acceptable salt,” “pharmaceutically acceptable salt thereof,” or “pharmaceutically acceptable complex” are synonymous and refer to derivatives prepared from pharmaceutically acceptable nontoxic acids or bases, including inorganic acids and bases, as well as organic acids and bases.

[0040] These polysaccharides are administered in the form of salts having a suitable cation to neutralize the negative charge of the acidic group due to the negative charge caused by the presence of sulfate and / or carboxylic acid groups. Typically, the cation is sodium. However, salts made from other physiologically acceptable counterions that do not induce urinary tract dysfunction, such as magnesium, aluminum, calcium, ammonium, or physiologically acceptable organic bases, such as but not limited to trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N'-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, dibenzylpiperidine, N-benzyl-p-phenethylamine, dehydroabiethylamine, N,N'-bisdehydroabiethylamine, glucamine, N-methylglucamine, cholidine, kinin, quinoline, and basic amino acids such as lysine and arginine may also be used. These cationic counterions can also be used as counterions for anionic buffers such as bicarbonates. Sodium is typically used as a positively charged counterion, as indicated above. Therefore, the preferred form of heparin is heparin sodium, in which sodium acts as the counterion. These salts can be prepared by methods known to those skilled in the art. However, due to its role in the pathogenesis of the conditions and syndromes being treated, the use of potassium as a counterion is generally undesirable. Other polysaccharides with the required activity include, but are not limited to, dextran sulfate and carrageenan. Other glycosaminoglycans, including low molecular weight (LMW) glycosaminoglycans, naturally derived glycosaminoglycans, biotechnology-prepared glycosaminoglycans, chemically modified glycosaminoglycans, and synthetic glycosaminoglycans, as well as linear anionic polysaccharides composed of pentoses, may be used in the manner of the present invention.References to heparinoids, such as heparin, which have a negative charge at physiological pH, should be understood to include all possible counterions that do not interfere with the physiological activity of heparin or other components of the composition, and do not cause compound changes with any other components of the composition, unless there is a specific reference to counterions.

[0041] In some embodiments, heparinoids include heparin-like molecules (e.g., heparan sulfate). For example, heparin-like molecules such as heparan sulfate are glycosaminoglycans with a structure similar to heparin, the difference being that heparan sulfate is less polymerized than heparin and therefore contains more glucuronic acid and N-acetylglucosamine. Because heparan sulfate contains fewer sulfate groups, it is slightly less acidic. Heparin exists in a variety of forms characterized by different degrees of sulfation. Typically, heparin has a molecular weight ranging from about 2 kDa to about 40 kDa. Both heparin and heparan sulfate are characterized by repeating disaccharide units containing uronic acid (glucuronic acid or iduronic acid) and glucosamine that is either N-sulfated or N-acetylated. The sugar residues may be further O-sulfated at the C-6 and C-3 positions of glucosamine, and at the C-2 position of uronic acid. This type of compound may have at least 32 unique disaccharide units. Five examples of sugars present in heparin are (1) α-L-iduronic acid 2-sulfate, (2) 2-deoxy-2-sulfamino-α-D-glucose 6-sulfate, (3) β-D-glucuronic acid, (4) 2-acetamido-2-deoxy-α-D-glucose, and (5) α-L-iduronic acid.

[0042] In one embodiment, heparin contains at least 130 USP units per 1 mg. Heparin is measured in units according to its specific anticoagulant activity, and when describing the activity of heparin, either USP units or International Units (IU) are specified. As used herein, “USP units” refers to the amount of heparin (defined as units / ml) that prevents coagulation in 1.0 ml of citrated sheep plasma at 20°C for 1 hour after the addition of 0.2 ml of 1% CaCl2, as measured by the USP standard. As used herein, “IU” refers to the amount of active heparin (defined as International Units / ml) in an assay established by the Fifth International standard for Unfractionated Heparin (WHO-5) (Linhardt, RJ and Gunay, NS (1999) Semin Thromb Hemost, Vol. 25, pp. 5-16). However, in some embodiments, it is also possible and preferable to specify the heparin concentration in milligrams. Typically, 1 mg of heparin is equivalent to approximately 200 units.

[0043] Particularly preferred heparinoids for use in the methods according to the present invention and in the compositions prepared by those methods include heparin and sodium pentosan polysulfate. The most particularly preferred heparinoid for use in the methods according to the present invention and in the compositions prepared by those methods is heparin. As described above, other counterions may be used, but a preferred form of heparin is sodium heparin. The amount of heparin in the composition prepared by the method of the present invention may range from about 1,000 units to about 250,000 units per unit dose of the composition; any intermediate amount of heparin, for example, 1,000 units, 5,000 units, 10,000 units, 15,000 units, 20,000 units, 25,000 units, 30,000 units, 35,000 units, 40,000 units, 45,000 units, 50,000 units, 55,000 units, 60,000 units, 65,000 units, 70,000 units per unit dose of the composition. The units are, but are not limited to, 75,000, 80,000, 85,000, 90,000, 95,000, 100,000, 110,000, 120,000, 130,000, 140,000, 150,000, 160,000, 170,000, 180,000, 190,000, 200,000, 210,000, 220,000, 230,000, 240,000, or 250,000 units. As used herein, “unit dose” refers to the amount of heparin or other component of the composition according to the present invention administered in a typical single treatment.When expressed in milligrams, these amounts of heparin range from approximately 0.5 mg to approximately 1250 mg per unit dose, and include, but are not limited to, 1 mg, 5 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, or 1250 mg. A suitable amount of heparinoids other than heparin can be determined by those skilled in the art based on the molecular weight of the heparinoid used. Typically, the concentration of heparin in the composition of a product ranges from approximately 1,000 units of heparin per milliliter of composition to approximately 6,000 units of heparin per milliliter of composition. The concentration of heparin in the composition of a product can be selected from the group consisting of 1,000 units, 1,500 units, 2,000 units, 2,500 units, 3,000 units, 3,500 units, 4,000 units, 4,500 units, 5,000 units, 5,500 units, and 6,000 units per milliliter of composition.

[0044] The amount of heparinoid in a composition may vary depending on the subject, the severity and course of the disease, the subject's health status, response to treatment, pharmacokinetic considerations such as liver and kidney function, and the judgment of the physician administering the treatment. Therefore, several compositions containing different amounts of heparin per unit dose can be prepared by the method according to the present invention.

[0045] According to the embodiment of the present invention, for example, if the heparinoid is sodium pentosan polysulfate, the amount of heparinoid in the composition may be about 1 mg to about 600 mg of sodium pentosan polysulfate per unit dose (for example, about 100 mg to about 600 mg of sodium pentosan polysulfate per unit dose). According to the embodiment of the present invention, for example, if the heparinoid is heparan sulfate, the amount of heparinoid in the composition may be about 0.5 mg to about 10,000 mg of heparan sulfate per unit dose (for example, about 100 mg to about 300 mg of heparan sulfate per unit dose). According to the embodiment of the present invention, for example, if the heparinoid is hyaluronic acid, the amount of heparinoid in the composition may be about 5 mg to about 600 mg of hyaluronic acid per unit dose (for example, about 10 mg to about 100 mg of hyaluronic acid per unit dose). According to the embodiment of the present invention, for example, if the heparinoid is chondroitin sulfate, the amount of heparinoid in the composition may be about 1 mg to about 10,000 mg of chondroitin sulfate per unit dose (for example, about 100 mg to about 300 mg of chondroitin sulfate per unit dose). According to the embodiment of the present invention, for example, if the heparinoid is heparin sodium, the amount of heparinoid in the composition may be about 10 mg to about 1,000 mg of heparin sodium per unit dose.

[0046] Local anesthetics are typically sodium channel blockers, such as, but not limited to, drugs commonly referred to as "caine" drugs, and other sodium channel blockers. The local anesthetics in the compositions prepared by the method of the present invention may be, but are not limited to, benzocaine, lidocaine, tetracaine, bupivacaine, cocaine, etidocaine, mepivacaine, pramoxin, prilocaine, procaine, chloroprocaine, oxyprocaine, propalacaine, ropivacaine, diclonin, dibucaine, propoxycaine, dexivacaine, diamocaine, hexylcaine, levobupivacaine, pirocaine, lysocaine, rhodocaine, and any pharmaceutically acceptable derivatives and bioequivalents thereof, or combinations thereof. Preferably, the anesthetic (e.g., local anesthetic) is selected from the group consisting of lidocaine, bupivacaine, benzocaine, tetracaine, etidocaine, prilocaine, and dibucaine, or combinations thereof. A particularly preferred local anesthetic is lidocaine, preferably in the form of lidocaine hydrochloride, where chloride acts as the counterion. Where used herein, the term "local anesthetic" includes all salts of that local anesthetic that are compatible with the desired pH, the buffer used, and any counterions present; however, the term "local anesthetic" is not intended to limit the salt forms or counterions used beyond these criteria. Specifically, a reference to a positively charged local anesthetic at a physiological or near-physiological pH, such as lidocaine, should be understood to include all possible counterions that do not interfere with the physiological activity of lidocaine or other components of the composition and do not cause compound changes with any other components of the composition, unless there is a specific reference to a counterion.

[0047] The amount of local anesthetic in a composition may vary depending on the subject, the severity and course of the disease, the subject's health status, response to treatment, pharmacokinetic considerations such as liver and kidney function, and the judgment of the physician performing the treatment. Therefore, several compositions containing different amounts of local anesthetic per unit dose can be prepared by the method according to the present invention. For example, if the local anesthetic is lidocaine, such as lidocaine hydrochloride, the amount of lidocaine in the composition may range from about 10 mg to about 400 mg per unit dose, and any intermediate amount of lidocaine, such as 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, or 400 mg per unit dose of the composition, can be used. Typically, the concentration of lidocaine in the composition contained in the product ranges from about 5 mg / mL to about 20 mg / mL. For example, the amount of lidocaine may be 10 mL of 1% lidocaine per unit dose or 16 mL of 2% lidocaine per unit dose. In a preferred embodiment, the composition contains 200 mg of lidocaine as lidocaine hydrochloride. A suitable amount of local anesthetic other than lidocaine can be determined by those skilled in the art based on the molecular weight and anesthetic potency of the local anesthetic used.

[0048] The buffers in the composition of the present invention are phosphate buffer, bicarbonate buffer, Tris(tris(hydroxymethyl)aminomethane) buffer, MOPS buffer (3-(N-morpholino)propanesulfonic acid), HEPES (N-(2-hydroxyethyl)piperazine-N-(2-ethanesulfonic acid) buffer, ACES (2-[(2-amino-2-oxoethyl)amino]ethanesulfonic acid) buffer, ADA (N-(2-acetamide)2-iminodiacetic acid) buffer, AMPSO(3-[ (1,1-dimethyl-2-hydroxyethyl)amino]-2-propanesulfonic acid) buffer, BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid) buffer, Bis(N,N-bis(2-hydroxyethylglycine) buffer, Bis-Tris(bis-(2-hydroxyethyl)imino-Tris(hydroxymethyl)methane buffer, CAPS (3-(cyclohexylamino)-1-propanesulfonic acid) buffer, CAPSO (3-(cyclohexyl (Amino)-2-hydroxy-1-propanesulfonic acid) buffer, CHES (2-(N-cyclohexylamino)ethanesulfonic acid) buffer, DIPSO (3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid) buffer, HEPPS (N-(2-hydroxyethylpiperazine)-N'-(3-propanesulfonic acid) buffer, HEPPSO (N-(2-hydroxyethyl)piperazine-N'-(2-hydroxypropanesulfonic acid) Acid buffer, MES (2-(N-morpholino)ethanesulfonic acid) buffer, triethanolamine buffer, imidazole buffer, glycine buffer, ethanolamine buffer, MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid) buffer, PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid) buffer), POPSO (piperazine-N,N'-bis(2-hydroxypropanesulfonic acid)) buffer, TAPS (N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid) buffer;The buffer may be, but is not limited to, TAPSO (3-[N-tris(hydroxymethyl)methylamino]-2-hydroxy-propanesulfonic acid) buffer, TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid) buffer, Trisine (N-tris(hydroxymethyl)methylglycine buffer), 2-amino-2-methyl-1,3-propanediol buffer, and 2-amino-2-methyl-1-propanol buffer, or a combination thereof. Particularly preferred buffers are bicarbonate buffers, phosphate buffers, Tris buffers, or a combination thereof. The most particularly preferred buffer is a phosphate buffer, especially a sodium phosphate buffer. Specific examples of compositions where the buffer is a phosphate buffer are described below. If the buffer is a bicarbonate buffer, the bicarbonate buffer is preferably sodium bicarbonate.

[0049] Since a phosphate can bind to up to three hydrogen ions, dihydrogen phosphate (H2PO4) - ), monohydrogen phosphate (HPO4 2- ), and the phosphate ion itself (PO4 3- It can exist in several forms, including the pK of the first ionization of phosphate (H3PO4) to produce dihydrogen phosphate. a The pK of the ionization of dihydrogen phosphate to produce monohydrogen phosphate is approximately 2.12. a It is approximately 7.21. The pK of the ionization of monohydrogen phosphate to produce phosphate ions. aThe pH is approximately 12.67. The relative proportions of dihydrogen phosphate, monohydrogen phosphate, and phosphate ions present at a given pH can be easily determined by using the Henderson-Hasselbalch formula. Typically, when phosphate buffer is used, it is used as the dihydrogen phosphate, taking into account the pH range in question. However, it is also possible to use monohydrogen phosphate and raise the pH to the desired value by adding an alkaline agent, such as sodium hydroxide. Alternatively, a combination of monohydrogen phosphate and dihydrogen phosphate may be used. While it is possible to use other hydroxides, such as potassium hydroxide, it is generally preferable to use sodium hydroxide rather than potassium hydroxide, considering the potential role of potassium ions in the pathogenesis of some lower urinary tract conditions. Phosphate buffer is preferred in some alternative forms because it is more physiologically acceptable to the bladder and is normally present in urine.

[0050] Generally, it is preferable to achieve the final pH using an alkaline agent, such as sodium hydroxide, rather than the buffer solution itself. The use of an alkaline agent to achieve the final pH results in greater stability for immediate-acting anesthetics, particularly lidocaine.

[0051] In addition, the composition may contain other additional components. Such additional components include: (1) Osmotic components that provide an isotonic or nearly isotonic solution compatible with human cells and blood, (2) A compound that allows the composition to remain on the surface of the bladder epithelium in an amount sufficient to treat, restore, or prevent lower urinary tract disorders. (3) A sufficient amount of antibiotics to treat, treat, or prevent lower urinary tract disorders, (4) An amount of antifungal agent sufficient to treat, treat, or prevent lower urinary tract disorders, (5) A sufficient amount of vasoconstrictor to treat, treat, or prevent lower urinary tract disorders, (6) Preservatives, and (7) Anti-inflammatory drugs These are some examples.

[0052] If present, the osmotic components, as needed, are salts such as sodium chloride, sugars, or combinations of two or more of these components. Sugars may be monosaccharides such as dextrose, disaccharides such as sucrose or lactose, polysaccharides such as dextran 40, dextran 60, or starch, or sugar alcohols such as mannitol. While all components of a solution contribute to its osmolality, it will be apparent to those skilled in the art that, in order to achieve an isotonic or nearly isotonic solution, the contributions of these components should be taken into account, and care should be taken to ensure that an excessive amount of osmotic components is not added, resulting in a hypertonic solution. Indeed, when a composition as described above contains heparin sodium as a heparinoid, lidocaine hydrochloride as an anesthetic, and sodium bicarbonate as a buffer, the osmolality contributions of sodium ions from heparin sodium and sodium bicarbonate, chloride ions from lidocaine hydrochloride, and carbonic acid / bicarbonate ions from sodium bicarbonate are sufficient to eliminate the need for additional osmotic components. Similarly, when phosphate buffer is used, the osmolar contributions of sodium and phosphate ions are typically sufficient, eliminating the need for additional osmotic components. However, in some alternative formulations, additional osmotic components may be used.

[0053] If an antibacterial agent is present, it can be selected from the group consisting of sulfonamides, penicillins, combinations of trimethoprim and sulfamethoxazole, quinolones, methenamine, nitrofurantoin, cephalosporins, carbapenems, aminoglycosides, tetracyclines, macrolides, and gentamicin. Suitable sulfonamides include, but are not limited to, sulfanilamides, sulfadiazines, sulfamethoxazoles, sulfisoxazoles, sulfamethizols, sulfadoxine, and sulfacetamide. Suitable penicillins include, but are not limited to, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, ampicillin, amoxicillin, bacampicillin, carbenicillin, ticarcillin, mezlocillin, and piperacillin. Suitable quinolones include, but are not limited to, nalidixic acid, levofloxacin, cinoxacin, norfloxacin, ciprofloxacin, orfloxacin, sparfloxacin, lomefloxacin, freloxacin, pefloxacin, and amifloxacin. Suitable cephalosporins include, but are not limited to, cephalothin, cefazolin, cephalexin, cefadroxyl, cephamandol, cefoxathin, cefaclor, cefuroxime, loracalbef, cefonisid, cefotetan, cefolanide, cefotaxime, cefpodoxime proxetil, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, and cefepime. Suitable carbapenems include, but are not limited to, imipenem, meropenem, and aztreonam. Suitable aminoglycosides include, but are not limited to, netylmycin and gentamicin. Suitable tetracyclines include, but are not limited to, tetracycline, oxytetracycline, demeclocycline, minocycline, doxycycline, and chlortetracycline. Suitable macrolides include, but are not limited to, erythromycin, clarithromycin, and azithromycin.

[0054] If an antifungal agent is available, it can be selected from the group consisting of amphotericin B, itraconazole, ketoconazole, fluconazole, miconazole, and flucytosine.

[0055] If a vasoconstrictor is present, it may be epinephrine.

[0056] If a compound is present that allows the composition to persist on the surface of the bladder epithelium, the compound is typically an activatable gelling agent. Activatable gelling agents are typically thermoreversible gelling agents. Thermoreversible gelling agents may be selected from the group consisting of Pluronic F127 gel, Lutrol gel, N-isopropylacrylamide, ethyl methacrylate, N-acrylooxysuccinimide, 1-2% xyloglucan sol, Pluronic graft copolymer with poly(acrylic acid), Pluronic-chitosan hydrogel, and [poly(ethylene glycol)-poly[lactic acid-co-glycolic acid]-poly(ethylene glycol)] (PEG-PLGA-PEG) copolymer.

[0057] If a preservative is present, it can be selected from the group consisting of parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. However, typically, the compositions forming part of the product according to the present invention do not require a preservative component and meet stability requirements without it. However, in some alternative forms, it may be desirable to include a preservative component.

[0058] If an anti-inflammatory agent is present, it may be a steroid or a non-steroidal anti-inflammatory agent. Suitable steroids and non-steroidal anti-inflammatory agents are known in the art. Suitable steroids include, but are not limited to, hydrocortisone, cortisone, beclomethasone dipropionate, betamethasone, dexamethasone, prednisone, methylprednisolone, triamcinolone, fluocinolone acetonide, and fludrocortisone. Suitable steroidal anti-inflammatory agents include, but are not limited to, hydrocortisone, cortisone, beclomethasone dipropionate, betamethasone, dexamethasone, prednisone, methylprednisolone, triamcinolone, fluocinolone acetonide, and fludrocortisone. Suitable nonsteroidal anti-inflammatory agents include acetylsalicylic acid (aspirin), sodium salicylate, magnesium choline trisalicylate, salsalate, diflunisal, sulfasalazine, olsalazine, acetaminophen, indomethacin, sulindac, tolmetin, diclofenac, ketorolac, ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin, mefenamic acid, meclofenamic acid, piroxicam, meloxicam, nabumetone, lofecoxib, celecoxib, etodolac, nimeslide, aceclofenac, alclofenac, aluminoprofen, amfenac, ampiroxicam, apazon, alaprofen, azapropazon, and be Ndazac, benoxaprofen, benzidamine, belmoprofen, benzpiperilone, bromfenac, bucloxic acid, bumazizone, butibufen, carprofen, simicoxib, cinmethacin, cinnoxicam, cridanac, clofezon, clonixin, clopirac, darbuferon, delacoxib, droxicam, ertenac, enfenamic acid, epirizole, esflurbiprofen, ethenzamide, etofenamate, etoricoxib, felbinac, fenbufen, fenclofenac, fenclozic acid, fenclozin, fendosal, fentiazac, feprazon, filenadol, flobufen, floriphenin, floslid, fluvitin methanesulfonate, flufenamic acid, fluphenisal,Flunixin, flunoxaprofen, fluprofen, fluproquazone, flofenac, ibufenac, imurecoxib, indoprofen, isofezolac, isoxepac, isoxicam, lycopheron, lobuprofen, romoxicam, ronazolac, loxoprofen, lumalicoxib, mabuprofen, miroprofen, mofebutazone, mofezolac, morazon, nepafanac, niflumic acid, nitrofenac, nitroflurbiprofen, nitronaproxen, orpanoxin, oxaseprole, oxydanac, oxypinac, oxyfenbutazone, pamicogrel, parcetasar, pare Examples include, but are not limited to, coxib, palsalmid, perbiprofen, pemedlac, phenylbutazone, pyrazolac, pirprofen, pranoprofen, salicin, salicylamide, salicylsalicylic acid, satigrel, sudoxicam, suprofen, talmethacin, talniflumate, tazoferon, tebuferon, tenidap, tenoxicam, tepoxalin, tiaprofenic acid, tiaramide, chilmacoxib, tinoridine, thiopinac, thioxaprofen, tolfenamic acid, triflusar, tropesin, ursolic acid, valdecoxib, xymoprofen, zaltoprofen, didomemethacin, and zomepirac.

[0059] If any of these optional components are present, namely osmotic components, compounds that allow the composition to persist on the surface of the bladder epithelium, antimicrobial components, antifungal compounds, vasoconstrictors, preservatives, or anti-inflammatory agents, they are typically added after a stable solution containing heparinoids, immediate-acting anesthetics, and buffers has been prepared. The amount of these additional optional components, if used, is selected so that the solution of heparinoids, immediate-acting anesthetics, and buffers remains stable, precipitation of the immediate-acting anesthetic is avoided, and the final pH of the solution is achieved. The final pH is typically about 6.8 to about 8.3, as described above. The optimal pH is about 7.3 to about 7.6, preferably about 7.5.

[0060] II. Method for preparing compositions to be incorporated into a product

[0061] Several methods for preparing compositions to be incorporated into the product according to the present invention are described. These methods result in compositions, which, if packaged in syringes or vials, are then used to fill syringes or vials, which constitutes the final step in the preparation of the product according to the present invention. Alternative forms of the methods described below may be used to prepare the compositions.

[0062] The first method is, (1) Providing heparinoids as either a solid or an aqueous liquid in amounts ranging from approximately 100 units to approximately 250,000 units per unit dose, or alternatively, from approximately 0.5 mg to approximately 1250 mg per unit dose. (2) A step of providing a local anesthetic in either solid or aqueous liquid form in an amount of approximately 5 mg to approximately 1000 mg per unit dose. (3) The step of combining heparinoid and local anesthetic, (4) The heparinoid and local anesthetic combination from step (3) is buffered to a pH value higher than approximately 6.8 and up to approximately 8.3 by the possible addition of a buffer suitable for both the heparinoid and the immediate-acting anesthetic, and a base selected from the group consisting of sodium hydroxide and potassium hydroxide, to form a stable solution. Includes.

[0063] Typically, as mentioned above, the base used in step (4) is sodium hydroxide. Typically, the local anesthetic is lidocaine.

[0064] The second method is, (1) Providing heparinoids as either a solid or an aqueous liquid in amounts ranging from approximately 100 units to approximately 250,000 units per unit dose, or alternatively, from approximately 0.5 mg to approximately 1250 mg per unit dose. (2) A step of buffering the heparinoid with a buffer that is compatible with both the heparinoid and the local anesthetic to be added later, to a pH value higher than about 6.8 and up to about 8.3. (3) Adding a local anesthetic, either as a solid or aqueous liquid, in an amount of about 5 mg to about 1000 mg per unit dose to the buffered heparinoid of step (2) to form a solution containing the heparinoid, local anesthetic, and buffer, and (4) If necessary, rebuffer the solution from step (3) to a pH value higher than approximately 6.8 and up to approximately 8.3 to form a stable solution. Includes.

[0065] Typically, the pH of the resulting solution is approximately 7.3 to 7.5.

[0066] In one particularly preferred method for preparing the composition according to the present invention, the composition is prepared in the following steps: (1) A step of mixing a heparinoid and an immediate-acting anesthetic, wherein the heparinoid and the immediate-acting anesthetic are in a liquid form that is slightly more concentrated than in the final product. (2) A step of adding a buffer solution to obtain a pH of approximately 7.0 to 7.3 in the solution of (1), and (3) A step of raising the pH to a value in the range of about 7.1 to about 8.3 using sodium hydroxide and, if necessary, adding water, to achieve the desired final concentration of the heparinoid and the immediate-acting anesthetic. It is prepared by [method].

[0067] In these alternative formulations, the heparinoid and the immediate-acting anesthetic may be provided in either solid (e.g., powder) or aqueous liquid form prior to the mixing step. All possible combinations of solid and aqueous liquid forms are possible in these steps, and it is possible to use (i) both solid heparinoid and immediate-acting anesthetic, (ii) both aqueous liquid heparinoid and immediate-acting anesthetic, (iii) solid heparinoid and aqueous liquid immediate-acting anesthetic, or (iv) aqueous liquid heparinoid and solid immediate-acting anesthetic. However, as detailed below, if the heparinoid is heparin and the immediate-acting anesthetic is lidocaine, the alternative formulations described above require the use of powdered heparin and powdered lidocaine hydrochloride because the available heparin solution and lidocaine hydrochloride solution are not compatible when buffer is added, and lidocaine precipitates despite subsequent attempts to maintain lidocaine in solution to avoid precipitation. The resulting heparinoid-containing solution stabilizes lidocaine at least partially as a free base, typically containing about 2% to 45% lidocaine in its free base form.

[0068] The compositions described above, which are included in the products of the present invention, can be formulated, or are suitable for treating, reversing, or preventing bacterial cystitis, fungal / yeast cystitis, vaginitis, vulvovaginitis, dyspareunia, urethral syndrome, and endometriosis in women; prostatitis and chronic pelvic pain syndrome in men; and lower urinary tract disorders selected from the group consisting of radiation-induced cystitis, chemotherapy-induced cystitis, interstitial cystitis (also known as bladder pain syndrome (BPS) or hypersensitive bladder syndrome (HBS)), and overactive bladder in men or women. The compositions of the present invention are particularly useful for treating interstitial cystitis.

[0069] As used herein, the term “to treat, restore, or prevent” means any detectable improvement, whether subjective or objective, in a lower urinary tract disorder in the subject to which the composition is administered. For example, the term “to treat, restore, or prevent” may mean an improvement determined by the PORIS scale, the PUF scale, or any preferred assessment of those scales; a reduction in pain; a reduction in urination frequency; a reduction in urinary urgency; a reduction in the need for narcotic administration; a reduction in incontinence; a reduction in abnormal potassium permeability of the urothelium; or an improvement in two or more of these parameters. The term “to treat, restore, or prevent” does not describe or imply a cure for the underlying lower urinary tract disorder.

[0070] III. Glass and high-density polyethylene, high-density nucleus-free polypropylene, COP, or COC plastics for syringes and vials

[0071] The products according to the present invention include syringes or vials constructed from (i) glass, or (ii) any plastic selected from the group consisting of COP (cyclic olefin polymer) plastic, COC (cyclic olefin copolymer) plastic, high-density polyethylene plastic, and high-density nucleus-free polypropylene plastic.

[0072] Cyclic olefin polymer plastics are described in U.S. Patent No. 5,008,356 by Ishimaru et al.; U.S. Patent No. 5,087,677 by Brekner et al.; U.S. Patent No. 5,304,596 by Moriya et al.; U.S. Patent No. 5,324,801 by Brekner et al.; U.S. Patent No. 5,331,057 by Brekner et al.; U.S. Patent No. 5,422,409 by Brekner et al.; U.S. Patent No. 5,795,945 by Natori; U.S. Patent No. 6,090,888 by Khananian et al.; U.S. Patent No. 6,197,804 by Sunaga et al.; U.S. Patent No. 6,388,032 by Yamaura et al.; U.S. Patent No. 6,980,970 by Tsunogae et al.; U.S. Patent No. 7,202,312 by Choi et al.; U.S. Patent No. 7,648,937 by Yoon et al.; U.S. Patent No. 7,814,713 by Yoon et al.; U.S. Patent No. 7,838,088 by Suzuki et al.; U.S. Patent No. 7,964,680 by Choi et al.; U.S. Patent No. 7,989,570 by Chun et al.; U.S. Patent No. 8,148,472 by Baugh et al.; U.S. Patent No. 8,158,732 by Wakatsuki et al.; U.S. Patent No. 8,293,674 by Chung et al.; U.S. Patent No. 8,344,070 by Squire et al.; U.S. Patent No. 8,883,925 by Kizu et al.; U.S. Patent No. 8,946,366 by Yoo et al.; U.S. Patent No. 9,056,938 by Sunaga et al.; U.S. Patent No. 9,151,988 by Yoo et al.; U.S. Patent No. 9,163,113 by Choi et al.; U.S. Patent No. 9,206,278 by Yoshida et al.; and U.S. Patent No. 9,359,588 by Smith.

[0073] Monomers that can be used to form cyclic olefin polymer plastics include norbornene; tetracyclododecene; bicyclo[2,2,1]hepta-2-ene; 1-methylbicyclo[2,2,1]hepta-2-ene; hexacyclo[6,6,1,1 3,6 ,1 10,13 ,0 2,7 ,0 9,14]-4-heptadecene; 1,4,5,8-dimetano-1,2,3,4,4a,5,8a-octahydronaphthalene; 2-methyl-1,4,5,8-dimetano-1,2,3,4,4a,5,8,8a-octahydronaphthalene; 2-ethyl-1,4,5,8-dimetano-1,2,3,4,4a,5,8,8a-octahydronaphthalene; 2-propyl-1,4,5,8-dimetano-1,2,3,4,4a,5,8,8a-octahydronaphthalene; 2-hexyl-1,4,5,8-dimetano-1,2,3,4,4a,5,8 ,8a-octahydronaphthalene;2-stearyl-1,4,5,8-dimethano-1,2,3,4,4a,5,8,8a-octahydronaphthalene;2,3-dimethyl-1,4,5,8-dimethano-1,2,3,4,4a,5,8,8a-octahydronaphthalene;2-methyl-3-ethyl-1,4,5,8-dimethano-1,2,3,4,4a,5,8,8a-octahydronaphthalene;2-chloro-1,4,5,8-dimethano-1,2,3,4,4a,5,8,8a-octahydronaphthalene;2-bromo-1,4,5, 8-Dimethano-1,2,3,4,4a,5,8,8a-Octahydronaphthalene; 2,3-Dichloro-1,4,5,8-Dimethano-1,2,3,4,4a,5,8,8a-Octahydronaphthalene; 2-Cyclohexyl-1,4,5,8-Dimethano-1,2,3,4,4a,5,8,8a-Octahydronaphthalene; 2-n-Butyl-1,4,5,8-Dimethano-1,2,3,4,4a,5,8,8a-Octahydronaphthalene; 2-Isobutyl-1,4,5,8-Dimethano-1,2,3,4,4a,5,8,8a-Octahydronaphthalene Tahydronaphthalene; bicyclo[2,2,1]hepta-2-ene; 6-methylbicyclo[2,2,1]hepta-2-ene; 5,6-dimethylbicyclo[2,2,1]hepta-2-ene; 1-methylbicyclo[2,2,1]hepta-2-ene; 6-ethylbicyclo[2,2,1]hepta-2-ene; 6-n-butylbicyclo[2,2,1]hepta-2-ene; 6-i-butylbicyclo[2,2,1]hepta-2-ene; 7-methylbicyclo[2,2,1]hepta-2-ene; 5,10-dimethyltetracyclo[4,4,0,1 2,5 ,1 7,10 ]3-dodecene;2,10-dimethyltetracyclo[4,4,0,12,5 ,1 7,10 ]3-dodecene;11,12-dimethyltetracyclo[4,4,0,1 2,5 ,1 7,10 ]3-dodecene;2,7,9-trimethyltetracyclo[4,4,0,1 2,5 ,1 7,10 ]3-dodecene;9-ethyl-2,7-dimethyltetracyclo[4,4,0,1 2,5 ,1 7,10 ]3-dodecene;9-isobutyl-2,7-dimethyltetracyclo[4,4,0,1 2,5 ,1 7,10 ]3-Dodecene;9,11,12-Trimethyl-tetracyclo[4,4,0,1 2,5 ,1 7,10 ]3-dodecene;9-ethyl-11,12-dimethyltetracyclo[4,4,0,1 2,5 ,1 7,10 ]3-dodecene;9-isobutyl-11,12-dimethyltetracyclo[4,4,0,1 2,5 ,1 7,10 ]3-dodecene;5,8,9-10-tetramethyl-tetracyclo[4,4,0,1 2,5 ,1 7,10 ]3-dodecene;hexacyclo[6,6,1,1 3,6 ,1 10,13 ,0 2,7 ,0 9,14 ]4-Heptadecene;12-Methylhexacyclo[6,6,1,1 3,6 ,1 10,13 ,0 2,7 ,0 9,14 ]4-Heptadecene;12-Ethylhexacyclo[6,6,1,1 3,6 ,1 10,13 ,0 2,7 ,0 9,14 ]4-Heptadecene;12-Isobutyl-Hexacyclo[6,6,1,1 3,6 ,1 10,13 ,0 2,7 ,0 9,14 ]4-Heptadecene;1,6,10-Trimethyl-12-Isobutyl-Hexacyclo[6,6,1,1 3,6 ,1 10,13 ,0 2,7 ,0 9,144-Heptadecene; Octacyclo-[8,8,1 2,9 ,1 4,7 ,1 11,18 ,1 13,16 ,0,0 3,8 ,0 12,17 -5-Docosene; 15-Methyl-octacyclo-[8,8,1 2,9 ,1 4,7 ,1 11,18 ,1 13,16 ,0,0 3,8 ,0 12,17 -5-Docosene; 15-Ethyl-octacyclo-[8,8,1 2,9 ,1 4,7 ,1 11,18 ,1 13,16 ,0,0 3,8 ,0 12,17 -5-Docosene; Tricyclo[4,3,0,1 2,5 -Decene; 2-Methyltricyclo[4,3,0,1 2,5 -Decene; 5-Methyltricyclo[4,3,0,1 2,5 -Decene; Tricyclo[4,4,0,1 2,5 -Decene; 10-Methyltricyclo[4,4,0,1 2,5 -Decene; 1,3-Dimethylpentacyclo-[6,6,1,1[[ID=四十七]] 3,6 ,0 2,7 ,0 9,14 4-Hexadecene; 1,6-Dimethylpentacyclo-[6,6,1,1 3,6 ,0 2,7 ,0 9,14 4-Hexadecene; 15,16-Dimethylpentacyclo-[6,6,1,1 3,6 ,0 2,7 ,0 9,14 4-Hexadecene; Pentacyclo[6,5,1,1 3,6 ,0 2,7 ,0 9,13 -4-Pentadecene; 1,3-Dimethylpentacyclo[6,5,1,1 3,6 ,0 2,7 ,0 9,13 -4-Pentadecene, 1,6-Dimethylpentacyclo[6,5,1,1 3,6 ,0 2,7 ,0 9,13 It should be noted that there may be some inaccuracies in the original text's format and content, especially in the tags and chemical names. This translation is based on the best understanding of the provided text. If possible, it is recommended to double-check with the original source for more accurate information.-4-Pentadecene; 14,15-dimethylpentacyclo[6,5,1,1 3,6 ,0 2,7 ,0 9,13 -4-Pentadecene; pentacyclo[6,6,1,1 3,6 ,0 2,7 ,0 9,14 -4-Hexadecene; heptacyclo[8,7,1 2,9 ,1 4,7 ,1 11,17 ,0,0 3,8 ,0 12,16 -5-Eicosene; and pentacyclo[8,8,1 2,9 ,1 4,7 ,1 11,18 ,0,0 3,8 ,0 12,17 are present. Other suitable monomers are known in the art.

[0074] Suitable catalysts for polymerization to form cyclic olefin polymer plastics are known in the art and include, but are not limited to, catalysts comprising transition metal compounds and aluminoxanes, titanium-containing catalysts comprising titanium compounds and organoaluminum compounds, vanadium-containing catalysts comprising vanadium compounds and organoaluminum compounds, and other catalysts. In one alternative, the transition metal compound is a zirconium compound. Suitable zirconium compounds include ethylenebis(indenyl)zirconium dichloride; ethylenebis(indenyl)zirconium monohydrate monohydride; ethylenebis(indenyl)ethoxyzirconium chloride; ethylenebis(4,5,6,7-tetrahydro-1-indenyl)ethoxyzirconium chloride; ethylenebis(indenyl)dimethylzirconium; ethylenebis(indenyl)diethylzirconium; ethylenebis(indenyl)diphenylzirconium; ethylenebis(indenyl)dibenzylzirconium; ethylenebis(indenyl)methylzirconium monobromide; ethylenebis(indenyl)ethylzirconium monochloride; ethylenebis(indenyl)benzylzirconium monochloride; ethylenebis(indenyl)methylzirconium monochloride; ethylenebis(indenyl)zirconium dichloride; ethylenebis Indenyl zirconium dibromide; ethylenebis(4,5,6,7-tetrahydro-1-indenyl)dimethylzirconium; ethylenebis(4,5,6,7-tetrahydro-1-indenyl)ethylzirconium ethoxide; ethylenebis(4,5,6,7-tetrahydro-1-indenyl)zirconium dichloride; ethylenebis(4,5,6,7-tetrahydro-1-indenyl)zirconium dibromide, ethylenebis (4-methyl-1-indenyl) zirconium dichloride; ethylenebis(5-methyl-1-indenyl) zirconium dichloride; ethylenebis(6-methyl-1-indenyl) zirconium dichloride; ethylenebis(7-methyl-1-indenyl) zirconium dichloride; ethylenebis(5-methoxy-1-indenyl) zirconium dichloride; ethylenebis(2,3-dimethyl-1-indenyl) zirconium dichloride;Ethylenebis(4,7-dimethyl-1-indenyl)zirconium dichloride; Ethylenebis(4,7-dimethoxy-1-indenyl)zirconium dichloride; Ethylenebis(indenyl)zirconium dimethoxide; Ethylenebis(indenyl)zirconium diethoxide; Ethylenebis(indenyl)methoxyzirconium chloride; Ethylenebis(indenyl)ethoxyzirconium chloride; Ethylenebis(indenyl)methylzirconium ethoxide; Ethylenebis(4,5,6,7-tetrahydro-1-indenyl)zirconium dimethoxide; Ethylenebis( Examples include, but are not limited to, 4,5,6,7-tetrahydro-1-indenyl)methoxyzirconium chloride; ethylenebis(4,5,6,7-tetrahydro-1-indenyl)methylenebis(indenyl)methylzirconium ethoxide, methylenebis(indenyl)zirconium dichloride; methylenebis(indenyl)dimethylzirconium; methylenebis(4,5,6,7-tetrahydro-1-indenyl)zirconium dichloride; propylenebis(indenyl)zirconium dichloride; propylenebis(indenyl)dimethylzirconium; and propylenebis(4,5,6,7-tetrahydro-1-indenyl)zirconium dichloride.

[0075] The aluminoxane component of the catalyst is not limited to, but is represented by formula (CI) or formula (C-II): [ka] (wherein R is a hydrocarbon group, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl group, preferably methyl, ethyl, or isobutyl, more preferably methyl, and m is an integer greater than 2, preferably 5.) It may be an organoaluminum compound.

[0076] Other catalysts and catalytic components for the polymerization of cyclic olefin polymers are known in the art.

[0077] Syringes constructed from cyclic olefin polymers are described in U.S. Patent No. 9,381,687 by Felts et al.; U.S. Patent No. 9,220,631 by Sigg et al.; U.S. Patent No. 8,939,940 by Haury et al.; U.S. Patent No. 8,747,726 by Haury et al.; U.S. Patent No. 8,721,603 by Lundquist; U.S. Patent No. 8,679,068 by Young; U.S. Patent No. 8,398,600 by Hirokane et al.; U.S. Patent No. 8,303,540 by Shue et al.; U.S. Patent No. 7,766,882 by Sudo et al.; and U.S. Patent No. 7,740,792 by Haury et al. The syringe barrel may be formed by injection molding or by other techniques known in the art.

[0078] Cyclic olefin polymer plastics are patented by Abe et al. (US Patent No. 5,559,199; Yamamoto et al. (US Patent No. 6,627,714; Oshima et al. (US Patent No. 6,639,021; Oshima et al. (US Patent No. 6,844,403; Oshima et al. (US Patent No. 6,992,154; Bennett et al. (US Patent No. 7,122,239; Rivett et al. (US Patent No. 7,258,930; Jang et al. (US Patent No. 7,258,930)) This is described in U.S. Patent No. 7,468,417 by Nagara et al.; U.S. Patent No. 7,662,445 by Heidari et al.; U.S. Patent No. 7,854,873 by Sakagami et al.; U.S. Patent No. 8,084,563 by Shin et al.; U.S. Patent No. 8,541,621 by Jemelin; U.S. Patent No. 8,637,128 by Yoshida et al.; and U.S. Patent No. 9,206,278 by Smith.

[0079] Suitable cyclic olefins as comonomers in cyclic olefin copolymers, including the cyclic olefins described above, are known in the art. Other olefins useful as comonomers are known in the art and include ethylene, as well as other linear olefins having 3 to 20 carbon atoms, such as propylene, 1-butene, 1-hexene, 4-methyl-1-pentene, 1-octane, 1-decene, 1-dodecene, 1-tetradecene, 1-hexadecene, 1-octadecene, and 1-eicosene.

[0080] Suitable catalysts for the production of these copolymers are described above with respect to the production of cyclic olefin polymers. Other catalysts known in the art include zirconium compounds, nickel compounds, cobalt compounds, palladium compounds, platinum compounds, rhenium compounds, and ruthenium compounds, as well as complexes of tungsten salts and organoaluminum halogen compounds. Additional catalysts are described in U.S. Patent No. 5,559,199 by Abe et al.; U.S. Patent No. 6,639,021 by Oshima et al.; U.S. Patent No. 6,844,403 by Oshima et al.; U.S. Patent No. 7,468,417 by Jang et al.; and U.S. Patent No. 8,084,563 by Sakagami et al.

[0081] Syringes constructed from cyclic olefin polymers are described in U.S. Patent No. 9,381,687 by Felts et al.; U.S. Patent No. 8,721,603 by Lundquist; U.S. Patent No. 8,679,068 by Young; U.S. Patent No. 7,041,087 by Henderson et al.; and U.S. Patent No. 6,065,270 by Reinhard et al.

[0082] High-density polyethylene typically has a density of 0.93 g / cm³. 3 From 0.97 g / cm³ 3It has a density of . High-density polyethylene has almost no branching, which is ensured by the appropriate selection of catalysts such as Ziegler-Natta catalysts and reaction conditions. Syringes constructed from high-density polyethylene are disclosed in Okihara's U.S. Patent No. 9,533,103, Felts et al.'s U.S. Patent No. 9,381,687, and Creatro et al.'s U.S. Patent No. 9,302,050.

[0083] High-density polypropylene typically has a density of 0.895 g / cm³. 3 From 0.92 g / cm³ 3 It has a density of . Such polypropylene can be produced using metallocene catalysts. Particularly useful forms of polypropylene are nucleate-free polypropylene, e.g., Eltex® MED 100-MG03 (INEOS Olefins and Polymers). A syringe constructed from high-density polypropylene is disclosed in U.S. Patent No. 5,820,605 by Zdeb et al.

[0084] If sterilization of the composition is required before filling the syringe with the composition, sterilization is typically carried out by heat sterilization or steam sterilization, which are generally preferred by the FDA and EMA. A preferred method of final sterilization is autoclaving, which is known in the art. Other sterilization methods, including filtration sterilization, are known in the art and may be used as alternatives. In another alternative, the syringe may be sterilized alone and then aseptically filled with the solution. The final product may be produced by final sterilization or aseptically. Final sterilization is generally preferred.

[0085] A particularly preferred syringe is a 20 mL capacity syringe constructed from glass or plastic polymer, as described above.

[0086] In one alternative configuration, the inside of the syringe is coated to reduce the adhesion of local anesthetic to the syringe surface. Preferred coatings are siloxane coatings applied by plasma deposition, such as those disclosed in U.S. Patent No. 7,985,188 by Felts et al. and U.S. Patent No. 8,627,970 by Macy et al.

[0087] An alternative form for the preferred composition is prepared in purified water as follows: (1) 16.67 g / L heparin sodium, (2) 13.33 g / L of lidocaine hydrochloride, (3) 10.03 g / L of Na2HPO4·12H2O to obtain a concentration of 0.028 M, and (4) 0.02N NaOH to adjust the pH, if necessary.

[0088] Modified forms of this particularly preferred composition can also be prepared and are within the scope of the present invention. For example, the amount of heparin may be 16 g / L or another amount. The amount of lidocaine may also vary. Even if the heparinoid is a heparinoid other than heparin, the amount of that heparinoid may also vary. Similarly, even if the local anesthetic is a local anesthetic other than lidocaine, the amount of that local anesthetic may also vary.

[0089] This composition can then be loaded into a syringe or vial constructed from glass or plastic as described above.

[0090] The present invention is illustrated by the following embodiments. These embodiments are included for illustrative purposes only and are not intended to limit the present invention. [Examples]

[0091] (Example 1) (Comparative example) Example 1 demonstrates the stability of a solution containing 200 mg of lidocaine, 50,000 USP units of heparin, and phosphate buffer when stored in a glass vial equipped with a stopper and an overseal.

[0092] Table 1 shows the stability of a solution containing 200 mg of lidocaine, 50,000 USP units of heparin, and phosphate buffer when stored upright in a glass vial at 5°C ± 3°C and ambient relative humidity for 12 months. [Table 1]

[0093] Table 2 shows the stability of a solution containing 200 mg of lidocaine, 50,000 USP units of heparin, and phosphate buffer when stored upright in a glass vial at 25°C ± 2°C and 60% ± 5% relative humidity for 12 months. [Table 2]

[0094] Table 3 shows the stability of a solution containing 200 mg of lidocaine, 50,000 USP units of heparin, and phosphate buffer when stored upright in a glass vial at 40°C ± 2°C and 60% ± 5% relative humidity for 12 months. [Table 3]

[0095] In all three cases (data shown in Tables 1, 2, and 3), the solution was stable, the heparin and lidocaine assays showed no substantial change from the initial values, no impurities were detected, and no biological growth was detected when biological growth tests were performed. (Example 2) Stability of compositions containing heparin, lidocaine, and phosphate buffer in cyclic olefin polymer syringes and polypropylene syringes, as well as in glass.

[0096] This exam includes (1) 1.6 g of heparin sodium, (2) 1.42 g of lidocaine hydrochloride, (3) 1.003 g of Na2HPO4·12H2O, (4) 1.0 mL of 2N NaOH, and (5) Purified water to make a total volume of 100 mL A composition containing the following was used. This composition (1) 16 g / L heparin sodium, (2) 14.2 g / L of lidocaine hydrochloride, (3) 10.03 g / L of Na2HPO4·12H2O to obtain a concentration of 0.028 M, and (4) If necessary, 0.02N NaOH to adjust the pH. Includes.

[0097] This composition was packaged in 20 mL cyclic olefin polymer (COP) and polypropylene (PP) syringes. The polypropylene was not nucleate. Storage conditions were either 25°C / 60% relative humidity (RH) or 40°C / 75% RH, as indicated below.

[0098] The test points were as follows: at the beginning of the stability test, after 1 month, 2 months, 3 months, 6 months, and 12 months.

[0099] The test parameters were as follows: appearance, pH value, heparin sodium assay, lidocaine hydrochloride assay, and DMA (2,6-dimethylaniline) and other impurities assay.

[0100] Table 4 shows the results of the heparin sodium assay after 3 months. [Table 4]

[0101] Table 5 shows more detailed results regarding the sterility, appearance, pH value, lidocaine assay, DMA (2,6-dimethylaniline) assay, and overall impurities of compositions stored in COP syringes at initial (pre- and post-sterilization), 1 month, 2 months, 3 months, 6 months, and 12 months under storage conditions of 25°C ± 2°C and 60% ± 5% relative humidity. [Table 5-1] [Table 5-2]

[0102] Table 6 shows more detailed results regarding the sterility, appearance, pH value, lidocaine assay, DMA (2,6-dimethylaniline) assay, and overall impurities of compositions stored in COP syringes at initial (pre- and post-sterilization), 1 month, 2 months, 3 months, 6 months, and 12 months under storage conditions of 40°C ± 2°C and 75% ± 5% relative humidity. [Table 6-1] [Table 6-2]

[0103] Table 7 shows more detailed results regarding the sterility, appearance, pH value, lidocaine assay, DMA assay, and overall impurities of compositions stored in PP syringes at initial (pre- and post-sterilization), 1 month, 2 months, 3 months, 6 months, and 12 months under storage conditions of 25°C ± 2°C and 60% ± 5% relative humidity; polypropylene was not nucleate-free. [Table 7-1] [Table 7-2]

[0104] Table 8 shows more detailed results regarding the sterility, appearance, pH value, lidocaine assay, DMA assay, and overall impurities of compositions stored in PP syringes at initial (pre- and post-sterilization), 1 month, 2 months, 3 months, 6 months, and 12 months under storage conditions of 40°C ± 2°C and 75% ± 5% relative humidity; polypropylene was not nucleate-free. [Table 8-1] [Table 8-2]

[0105] Figure 1 shows the results regarding the pH stability of COP syringes (left panel) and PP syringes (right panel) at 25°C / 60%RH and 40°C / 75%RH up to 6 months. Polypropylene was not nucleate-free.

[0106] In storage stability tests, the pH value is stable in COP syringes. The pH value at the test point conforms to the standard of 7.2 to 7.6. However, when stored in PP syringes, the pH value decreases after sterilization in PP syringes (polypropylene is not nucleate). The pH value conforms to the standard at 25°C / 60%RH, but becomes outside the standard after 6 months at 40°C / 75%RH.

[0107] Figure 2 shows the results regarding the stability of lidocaine concentrations in COP syringes (left panel) and PP syringes (right panel) at 25°C / 60%RH and 40°C / 75%RH up to 6 months. Polypropylene was not nucleated.

[0108] In storage stability tests, the lidocaine concentration assay was stable in the COP syringe, meeting the specification of 1.26–1.40 g / 100g at all test points. However, in the PP syringe, the lidocaine assay decreased after sterilization but remained stable during further storage. The lidocaine assay continued to decrease under accelerated conditions such as high temperature. In the PP syringe (polypropylene was not nucleated), all post-sterilization time points were outside the specification.

[0109] Regarding impurities, 2,6-dimethylaniline and other impurities increased slightly during the storage stability test, increasing more significantly at 40°C / 75%RH than at 25°C / 60%RH. However, the same impurity profile and similar amounts of impurities were observed in both COP and PP syringes, and the impurities were unrelated to the loss of lidocaine. Nevertheless, impurity levels were below the threshold in both COP and PP under both storage conditions and at all test points.

[0110] Figure 3 shows the results of a storage stability test using a COP syringe at 25°C / 60%RH.

[0111] Figure 4 shows the results of a storage stability test using a COP syringe at 40°C / 75%RH.

[0112] Figure 5 shows the results of a storage stability test using PP syringes at 25°C / 60%RH. The polypropylene syringes were not nucleate.

[0113] Figure 6 shows the results of a storage stability test using PP syringes at 40°C / 75%RH. The polypropylene syringes were not nucleate.

[0114] Figure 7 shows the results of pH measurements in a COP syringe at either 25°C / 60%RH or 40°C / 75%RH up to 12 months.

[0115] Figure 8 shows the results of pH measurements in PP syringes at either 25°C / 60%RH or 40°C / 75%RH up to 12 months. The polypropylene syringes were not nucleate.

[0116] In conclusion, storage in COP syringes results in the stability of the composition containing heparin, lidocaine, and phosphate buffer throughout the storage period, including the stability of pH value, heparin concentration, lidocaine concentration, and the presence of impurities, both at 25°C / 60%RH and 40°C / 75%RH, although there is a slight loss of lidocaine during storage at 40°C / 75%RH. This slight loss of lidocaine is not clinically significant for the use of the composition stored in COP syringes for the treatment of urinary tract diseases and conditions, such as interstitial cystitis. However, storage in non-nucleated PP syringes resulted in a considerable loss of lidocaine. The loss of lidocaine was much greater at 40°C / 75%RH, but occurred at both 25°C / 60%RH and 40°C / 75%RH.

[0117] This difference in stability between storage in COP syringes and storage in non-nucleated PP syringes is both unexpected and clinically significant. The increased stability of such compositions in COP syringes is important for the manufacture, storage, sale, and use of these compositions, particularly for the treatment of urinary tract diseases and conditions, such as interstitial cystitis. The increased stability of the compositions enables more accurate dosing and administration of the compositions to patients with such urinary tract diseases or conditions without the risk of administering doses below the effective dose.

[0118] Table 9 shows the loss of lidocaine and the change in pH value after steam sterilization and subsequent transfer to plastic syringes. [Table 9]

[0119] Figure 9 shows the loss of sterilized lidocaine hydrochloride in glass vials and plastic syringes at different molar concentrations of phosphate buffer. Except for a small loss in 80 mM phosphate buffer, there is no loss in glass vials, but significant loss is observed in plastic syringes, increasing with increasing molar concentration of phosphate buffer.

[0120] Furthermore, syringe components (plunger and syringe body) were analyzed for leachate. Rubber and plastic components (corresponding to the actual contact surface size) in glass containers holding 11 mL of solution (no loss was observed) were tested with 18 mL of Tris and phosphate buffer preparations. The results are presented in Table 10. Table 10 shows that lidocaine hydrochloride loss occurs in both the rubber plunger and the plastic syringe body. Greater lidocaine hydrochloride loss and greater pH decrease are observed in the syringe body than in the plunger. Also, greater lidocaine loss is observed with the phosphate buffer preparation than with the Tris buffer preparation. [Table 10]

[0121] Furthermore, different extraction procedures were attempted to isolate lidocaine from the plastic or rubber components of syringes. These procedures used samples of 10 sterile phosphate-buffered preparations, resulting in a loss of >50% (>110 mg) of lidocaine hydrochloride. The syringe body and plunger were crushed and washed with a solvent (55% acetonitrile, 45% water, pH 11, pH adjusted with NaOH). Using this procedure, less than 0.02 mg of lidocaine hydrochloride could be isolated. Other extractants (tetrahydrofuran, ethanol, and water at pH 3) were tested for the syringe body using extraction with a Soxhlet extractor. The results are shown in Table 11. The best extraction solvent was tetrahydrofuran (polypropylene syringes are unstable in tetrahydrofuran). However, only one-third (112 mg) of the lost lidocaine hydrochloride could be isolated. [Table 11]

[0122] Figure 10 shows the loss of lidocaine hydrochloride in plungers and syringe bodies containing Tris buffer (left bar) and phosphate buffer (right bar).

[0123] Figure 11 shows the amount of lidocaine hydrochloride extracted from a 10× syringe using a Soxhlet extractor, with tetrahydrofuran (THF) (left bar), ethanol (center bar), and pH 3 water (far right bar).

[0124]

[0125]

[0126] Table 12 shows the pH dependence of lidocaine loss in the absence of buffer (A) and with buffer (B); and that repeated sterilization causes additional effects (C). [Table 12-1] [Table 12-2] [Table 12-3]

[0127] Figure 12 shows the loss of lidocaine after sterilization of pH-adjusted samples with different phosphate buffer concentrations, derived from the samples in Table 14(B).

[0128] Figure 13 shows the lidocaine loss from the samples in Table 14(C) as a function of sterilization after multiple cycles.

[0129] Table 13 shows the stability of a lidocaine hydrochloride and heparin preparation containing 200 mg of lidocaine hydrochloride and 50,000 units of heparin, stored in a glass vial at 5°C ± 3°C and ambient relative humidity, up to 24 months (without prior sterilization). [Table 13]

[0130] Table 14 shows the stability of a lidocaine hydrochloride and heparin preparation containing 200 mg of lidocaine hydrochloride and 50,000 units of heparin, stored in a glass vial, up to 21 months (without prior sterilization) at 25°C ± 2°C and 60% ± 5% relative humidity. [Table 14]

[0131] Table 15 shows the stability of a lidocaine hydrochloride and heparin preparation containing 200 mg of lidocaine hydrochloride and 50,000 units of heparin, stored in a glass vial, up to 21 months (without prior sterilization) at 40°C ± 2°C and 75% ± 5% relative humidity. [Table 15]

[0132] Table 16 shows the lidocaine loss and pH values ​​for several preparations of heparin and lidocaine hydrochloride in glass syringes, polypropylene syringes, and high-density polyethylene syringes. [Table 16] Advantages of the present invention

[0133] The present invention provides improved products comprising a composition containing a glycosaminoglycan, a local anesthetic, and a buffer, packaged in a syringe, the syringe of which can be constructed from glass, a cyclic olefin polymer (COP), or a cyclic olefin copolymer (COC), or alternatively, high-density nucleated polypropylene. These improved products have unexpectedly improved stability after final heat sterilization and long-term storage, and this improved stability is important for the manufacture, storage, sale, and use of these compositions, particularly for the treatment of urinary tract diseases and conditions, such as interstitial cystitis. The increased stability of the compositions enables more accurate dosing and administration of the compositions to patients with such urinary tract diseases or conditions without the risk of administering doses that may be less than the effective dose.

[0134] The products according to the present invention have industrial applicability as packaged compositions for the treatment of urinary tract diseases, such as, but not limited to, interstitial cystitis.

[0135] The inventions described herein exemplary can be suitably implemented in the absence of any one or more elements or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be interpreted broadly and without limitation. Furthermore, the transitional phrase “comprising” is intended to encompass the terms “essentially consisting of” and “consisting of” unless those terms are explicitly or clearly excluded by context. Moreover, the terms and expressions used herein are descriptive rather than restrictive, and in using such terms and expressions, there is no intention to exclude any equivalents or any part thereof that may be shown or described in the future, and it should be recognized that various modifications are possible within the scope of the claimed invention. Therefore, although the invention is specifically disclosed by preferred embodiments and features as needed, it should be understood that modifications and variations of the invention disclosed herein can be reclassified by those skilled in the art, and such modifications and variations are considered to be within the scope of the invention disclosed herein. The invention is described herein broadly and comprehensively. Each of the more limited species and the more comprehensive group, which fall within the scope of the comprehensive disclosure, also forms part of these inventions. This includes the comprehensive description of each invention, subject to the condition or negative limitation of removing any subject matter from the genus, regardless of whether the subject matter to be deleted is specifically present in the genus.

[0136] In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also described in terms of any individual element or subgroup of elements of the Markush groups. It should also be understood that the above description is intended to be illustrative and not restrictive. Many embodiments will be obvious to those skilled in the art upon reviewing the above description. Therefore, the scope of the invention should not be determined by the above description, but by the appended claims, along with the entire scope of equivalents to which the appended claims are entitled. All disclosures of papers and references, including patent publications, are incorporated herein by reference. According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) A product comprising a composition containing a glycosaminoglycan, a local anesthetic, and a buffer, packaged in a syringe or vial constructed from (i) glass, or (ii) a plastic selected from the group consisting of cyclic high-density polyethylene, high-density nucleus-free polypropylene, cyclic olefin polymers, and cyclic olefin copolymers. (Section 2) The product according to item 1 above, wherein the glycosaminoglycan is a heparinoid. (Section 3) The product according to item 2 above, wherein the heparinoid is selected from the group consisting of heparin, chondroitin sulfate, heparan sulfate, hyaluronic acid, keratan sulfate, dermatan sulfate, hyaluronan, pentosan polysulfate sodium, dalteparin, and enoxaparin. (Section 4) The product according to item 3 above, wherein the heparinoid is heparin. (Section 5) The product according to item 4 above, wherein the heparin is heparin sodium. (Section 6) The product according to item 4 above, wherein the heparin is heparin having a molecular weight of approximately 2,000 daltons to approximately 8,000 daltons. (Section 7) The product according to item 4 above, wherein the heparin is heparin having a molecular weight of approximately 8,000 daltons to approximately 40,000 daltons. (Section 8) The product according to item 4, wherein the heparin contains at least 130 USP units per milligram of heparin. (Section 9) The product according to item 4, wherein the unit dose of the composition contained in the product contains approximately 1,000 units of heparin to approximately 250,000 units of heparin per unit dose of the composition. (Section 10) The product according to item 4, wherein the concentration of heparin in the composition contained in the product is from about 1,000 units of heparin per milliliter of the composition to about 6,000 units of heparin per milliliter. (Section 11) The unit dose of the composition contained in the product is 1,000 units, 5,000 units, 10,000 units, 15,000 units, 20,000 units, 25,000 units, 30,000 units, 35,000 units, 40,000 units, 45,000 units, 50,000 units, 55,000 units, 60,000 units, 65,000 units, 70,000 units, 75,000 units, 80,000 units, 85,000 units, 90,000 units, The product according to item 9 above, comprising an amount of heparin selected from the group consisting of 95,000 units, 100,000 units, 110,000 units, 120,000 units, 130,000 units, 140,000 units, 150,000 units, 160,000 units, 170,000 units, 180,000 units, 190,000 units, 200,000 units, 210,000 units, 220,000 units, 230,000 units, 240,000 units, and 250,000 units. (Section 12) The product according to item 10, wherein the concentration of heparin in the composition contained in the product is selected from the group consisting of 1,000 units, 1,500 units, 2,000 units, 2,500 units, 3,000 units, 3,500 units, 4,000 units, 4,500 units, 5,000 units, 5,500 units, and 6,000 units per milliliter of the composition. (Section 13) The product according to item 9, wherein the unit dose of the composition contained in the product contains approximately 40,000 units of heparin. (Section 14) The product according to item 9, wherein the unit dose of the composition contained in the product contains approximately 50,000 units of heparin. (Section 15) The product according to item 9, wherein the unit dose of the composition contained in the product contains approximately 60,000 units of heparin. (Section 16) The product according to item 4, wherein the unit dose of the composition contained in the product contains heparin in an amount of about 0.5 mg to about 1250 mg per unit dose of the composition. (Section 17) The product according to item 16, wherein the unit dose of the composition contained in the product contains an amount of heparin selected from the group consisting of 1 mg, 5 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, and 1250 mg per unit dose of the composition. (Section 18) The product according to item 3, wherein the heparinoid is pentosan polysulfate sodium, and the composition contains about 1 mg to about 600 mg of pentosan polysulfate sodium per unit dose of the composition. (Section 19) The product according to item 3, wherein the heparinoid is heparan sulfate, and the composition contains about 0.5 mg to about 10,000 mg of heparan sulfate per unit dose of the composition. (Section 20) The product according to item 3, wherein the heparinoid is hyaluronic acid, and the composition contains about 5 mg to about 600 mg of hyaluronic acid per unit dose of the composition. (Section 21) The product according to item 3, wherein the heparinoid is chondroitin sulfate, and the composition contains about 1 mg to about 10,000 mg of chondroitin sulfate per unit dose of the composition. (Section 22) The product according to item 1 above, wherein the local anesthetic is selected from the group consisting of benzocaine, lidocaine, tetracaine, bupivacaine, cocaine, etidocaine, mepivacaine, pramoxin, prilocaine, procaine, chloroprocaine, oxyprocaine, propalacaine, ropivacaine, diclonin, dibucaine, propoxycaine, dexivacaine, diamocaine, hexylcaine, levobupivacaine, pirocaine, lysocaine, rhodocaine, and pharmaceutically acceptable derivatives and bioequivalents thereof, as well as combinations thereof. (Section 23) The product according to item 22 above, wherein the local anesthetic is selected from the group consisting of lidocaine, bupivacaine, mepivacaine, benzocaine, tetracaine, etidocaine, prilocaine, and dibucaine, and combinations thereof. (Section 24) The product according to item 23 above, wherein the local anesthetic is lidocaine. (Section 25) The product according to item 24 above, wherein the lidocaine is lidocaine hydrochloride. (Section 26) The product according to item 24, wherein the unit dose of the composition contained in the product contains lidocaine in an amount of about 10 mg to about 400 mg per unit dose of the composition. (Section 27) The product according to item 26, wherein the unit dose of the composition contained in the product contains an amount of lidocaine selected from the group consisting of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, and 400 mg per unit dose of the composition. (Section 28) The product according to item 24, wherein the concentration of lidocaine in the composition contained in the product is approximately 5 mg / mL to approximately 20 mg / mL. (Section 29) The product according to item 24, wherein the unit dose of the composition contained in the product is 10 mL of 1% lidocaine. (Section 30) The product according to item 24, wherein the unit dose of the composition contained in the product is 16 mL of 2% lidocaine. (Section 31) The buffers mentioned above include phosphate buffer, bicarbonate buffer, Tris(tris(hydroxymethyl)aminomethane) buffer, MOPS buffer (3-(N-morpholino)propanesulfonic acid), HEPES (N-(2-hydroxyethyl)piperazine-N-(2-ethanesulfonic acid) buffer, ACES (2-[(2-amino-2-oxoethyl)amino]ethanesulfonic acid) buffer, ADA (N-(2-acetamide)2-iminodiacetic acid) buffer, AMPSO (3-[(1,1- Dimethyl-2-hydroxyethyl)amino-2-propanesulfonic acid buffer, BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid buffer, Bis(N,N-bis(2-hydroxyethylglycine) buffer, Bis-Tris(bis-(2-hydroxyethyl)imino-Tris(hydroxymethyl)methane buffer, CAPS(3-(cyclohexylamino)-1-propanesulfonic acid) buffer, CAPSO(3-(cyclohexylamino) (N-(2-hydroxy-1-propanesulfonic acid) buffer, CHES (2-(N-cyclohexylamino)ethanesulfonic acid) buffer, DIPSO (3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid) buffer, HEPPS (N-(2-hydroxyethylpiperazine)-N'-(3-propanesulfonic acid) buffer, HEPPSO (N-(2-hydroxyethyl)piperazine-N'-(2-hydroxypropanesulfonic acid)) buffer Buffers, MES (2-(N-morpholino)ethanesulfonic acid) buffer, triethanolamine buffer, imidazole buffer, glycine buffer, ethanolamine buffer, MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid) buffer, PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid) buffer), POPSO (piperazine-N,N'-bis(2-hydroxypropanesulfonic acid)) buffer, TAPS (N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid) buffer;The product described in item 1 above, selected from the group consisting of TAPSO (3-[N-tris(hydroxymethyl)methylamino]-2-hydroxy-propanesulfonic acid) buffer, TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid) buffer, Trisine (N-tris(hydroxymethyl)methylglycine buffer), 2-amino-2-methyl-1,3-propanediol buffer, and 2-amino-2-methyl-1-propanol buffer, and combinations thereof. (Section 32) The product according to item 31, wherein the buffer is selected from the group consisting of phosphate buffer, bicarbonate buffer, Tris buffer, and combinations thereof. (Section 33) The product according to item 32 above, wherein the buffer solution is a phosphate buffer solution. (Section 34) The product according to item 33 above, wherein the phosphate buffer is a sodium phosphate buffer. (Section 35) The product according to item 32 above, wherein the buffer solution is a bicarbonate buffer solution. (Section 36) The product according to item 35 above, wherein the bicarbonate buffer solution is sodium bicarbonate. (Section 37) The product according to item 32 above, wherein the buffer solution is Tris buffer solution. (Section 38) The composition included in the product (a) an osmotic component that provides an isotonic or nearly isotonic solution compatible with human cells and blood; (b) a compound that allows the composition to persist on the surface of the bladder epithelium in an amount sufficient to treat, restore, or prevent lower urinary tract disorders; (c) an amount sufficient to treat, treat, or prevent lower urinary tract disorders, (d) an amount of antifungal agent sufficient to treat, treat, or prevent lower urinary tract disorders, (e) A sufficient amount of vasoconstrictor to treat, treat, or prevent lower urinary tract disorders. (f) Preservatives, and (g) Anti-inflammatory agents The product according to item 1 above, comprising an additional component selected from the group consisting of the following: (Section 39) The product according to item 38, wherein the additional component is an osmotic component selected from the group consisting of sodium chloride, dextrose, sucrose, lactose, dextran 40, dextran 60, starch, and mannitol. (Section 40) The product according to item 38, wherein the additional component is an antimicrobial agent selected from the group consisting of sulfonamide, penicillin, a combination of trimethoprim and sulfamethoxazole, quinolone, methenamine, nitrofurantoin, cephalosporin, carbapenem, aminoglycoside, tetracycline, macrolide, and gentamicin. (Section 41) The product according to item 38, wherein the additional component is an antifungal agent selected from the group consisting of amphotericin B, itraconazole, ketoconazole, fluconazole, miconazole, and flucytosine. (Section 42) The product according to item 38, wherein the additional component is a vasoconstrictor, and the vasoconstrictor is epinephrine. (Section 43) The product according to item 38, wherein the additional component is a compound that enables the persistence of the composition on the surface of the bladder epithelium, and the compound that enables the persistence of the composition on the surface of the bladder epithelium is a thermoreversible gelling agent selected from the group consisting of Pluronic F127 gel, Lutrol gel, N-isopropylacrylamide, ethyl methacrylate, N-acrylooxysuccinimide, 1-2% xyloglucan sol, Pluronic graft copolymer of poly(acrylic acid), Pluronic-chitosan hydrogel, and [poly(ethylene glycol)-poly[lactic acid-co-glycolic acid]-poly(ethylene glycol)] (PEG-PLGA-PEG) copolymer. (Section 44) The product according to item 38, wherein the additional component is a preservative selected from the group consisting of parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. (Section 45) The product according to item 38 above, wherein the additional component is an anti-inflammatory agent. (Section 46) The product according to item 45 above, wherein the anti-inflammatory agent is a steroid selected from the group consisting of hydrocortisone, cortisone, beclomethasone dipropionate, betamethasone, dexamethasone, prednisone, methylprednisolone, triamcinolone, fluocinolone acetonide, and fludrocortisone. (Section 47) The aforementioned anti-inflammatory agents include acetylsalicylic acid (aspirin), sodium salicylate, magnesium choline trisalicylate, salsalate, diflunisal, sulfasalazine, olsalazine, acetaminophen, indomethacin, sulindac, tolmetin, diclofenac, ketorolac, ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin, mefenamic acid, meclofenamic acid, piroxicam, meloxicam, nabumetone, rofecoxib, celecoxib, etodolac, and nimes. Lido, aceclofenac, alclofenac, aluminoprofen, amfenac, ampiroxicam, apazon, alabrefen, azapropazon, bendazac, benoxaprofen, benzydamine, belmoprofen, benzpiperilone, bromfenac, bucloxic acid, bumazizone, butibufen, carprofen, simicoxib, cinmethacin, cinnoxicam, cridanac, clofezon, clonixin, clopirac, darbuferon, delacoxib, droxicam, ertenac, enfenamic acid, epirizole, esflurbiprofen Ethenzamide, etofenamate, etoricoxib, felbinac, fenbufen, fenclofenac, fenclozic acid, fenclozine, fendosal, fentiazac, feprazon, filenadol, flobufen, floriphenin, floslid, fluvitin methanesulfonate, flufenamic acid, fluphenisal, flunixin, flunoxaprofen, fluprofen, fluproquazon, flofenac, ibufenac, imurecoxib, indoprofen, isofezolac, isoxepac, isoxicam, lycopheron, robuprof Romoxicam, lonazolac, loxoprofen, lumalicoxib, mabuprofen, miroprofen, mofebutazone, mofezolac, morazon, nepafanac, niflumic acid, nitrofenac, nitroflurbiprofen, nitronaproxen, orpanoxine, oxaseprole, oxydanac, oxypinac, oxyfenbutazone, pamicogrel, parecosarc, parecoxib, palsalmid, perbiprofen, pemedrac, phenylbutazone, pyrazolac, pirprofen, pranoprofen, salicin,The product described in item 45 above is a nonsteroidal anti-inflammatory agent selected from the group consisting of salicylamide, salicylsalicylic acid, satigrel, sudoxicam, suprofen, talmethacin, tarniflumate, tazoferon, tebuferon, tenidap, tenoxicam, tepoxaline, tiaprofenic acid, tiaramide, chilmacoxib, tinoridine, thiopinac, thioxaprofen, tolfenamic acid, triflusar, tropesin, ursolic acid, valdecoxib, xymoprofen, zaltoprofen, didomethacin, and zomepirac. (Section 48) The product according to item 1, wherein the pH of the composition contained in the product is approximately 6.8 to approximately 8.3. (Section 49) The product according to item 48, wherein the pH of the composition contained in the product is approximately 7.2 to approximately 7.6. (Section 50) The product according to item 49, wherein the pH of the composition contained in the product is approximately 7.5. (Section 51) The composition contained in the aforementioned product is used to treat bacterial cystitis, fungal / yeast cystitis, in women. The product described in item 1 above is formulated for the treatment of lower urinary tract disorders selected from the group consisting of vulvar pain, vulvodynia, dyspareunia, urethral syndrome, and endometriosis; prostatitis and chronic pelvic pain syndrome in men; and radiation-induced cystitis, chemotherapy-induced cystitis, interstitial cystitis (bladder pain syndrome or hypersensitive bladder syndrome), and overactive bladder in men or women. (Section 52) The product according to item 51, wherein the composition contained in the product is formulated for the treatment of interstitial cystitis (bladder pain syndrome or hypersensitive bladder syndrome). (Section 53) The product according to item 1 above, wherein the syringe or vial is constructed from glass. (Section 54) The product according to item 1 above, wherein the syringe or vial is constructed from a cyclic olefin polymer plastic. (Section 55) The product according to item 1 above, wherein the syringe or vial is constructed from a cyclic olefin copolymer plastic. (Section 56) The product according to item 1 above, wherein the syringe or vial is constructed from high-density polyethylene. (Section 57) The product according to item 1 above, wherein the syringe or vial is constructed from high-density nucleus-free polypropylene. (Section 58) The product described in item 1 above, wherein the syringe or vial is a syringe. (Section 59) The product according to item 58, wherein the syringe has a capacity of 20 mL. (Section 60) The product according to item 58, wherein the inside of the syringe barrel is coated to reduce the adhesion of the local anesthetic to the syringe. (Section 61) The product according to item 60, wherein the coating is a siloxane coating deposited by plasma deposition. (Section 62) The product described in item 1 above, after final sterilization. (Section 63) The product according to item 62 above, wherein the final sterilization is sterilization by heating. (Section 64) The product described in item 63 above, wherein the sterilization by heating is carried out by an autoclave.

Claims

1. below: (a) Anionic polysaccharides selected from the group consisting of chondroitin sulfate, pentosan polysulfate, dermatan sulfate, heparin, heparan sulfate, and keratan sulfate; (b) Local anesthetics selected from the group consisting of benzocaine, lidocaine, etidocaine, flecainide, tetracaine, bupivacaine, mepivacaine, pramoxin, prilocaine, procaine, chloroprocaine, oxyprocaine, propalacaine, ropivacaine, diclonin, dibucaine, propoxycaine, cincocaine, dexivacaine, diamocaine, hexylcaine, levobupivacaine, pirocaine, lysocaine, rhodocaine, and combinations thereof; and (c) Phosphate buffer, bicarbonate buffer, Tris(tris(hydroxymethyl)aminomethane) buffer, MOPS buffer (3-(N-morpholino)propanesulfonic acid), HEPES(N-(2-hydroxyethyl)piperazine-N-(2-ethanesulfonic acid)) buffer, ACES(2-[(2-amino-2-oxoethyl)amino]ethanesulfonic acid) buffer, ADA(N-(2-acetamide)2-iminodiacetic acid) buffer, AMPSO(3-[(1,1-dimethyl-2 N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid) buffer, BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid) buffer, Bis(N,N-bis(2-hydroxyethylglycine)) buffer, Bis-Tris(bis-(2-hydroxyethyl)imino-tris(hydroxymethyl)methane) buffer, CAPS (3-(cyclohexylamino)-1-propanesulfonic acid) buffer, CAPSO (3-(cyclohexylamino)-2 (N-hydroxy-1-propanesulfonic acid) buffer, CHES (2-(N-cyclohexylamino)ethanesulfonic acid) buffer, DIPSO (3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid) buffer, HEPPS (N-(2-hydroxyethylpiperazine)-N'-(3-propanesulfonic acid)) buffer, HEPPSO (N-(2-hydroxyethyl)piperazine-N'-(2-hydroxypropanesulfonic acid)) buffer Combolic acid, MES (2-(N-morpholino)ethanesulfonic acid) buffer, triethanolamine buffer, imidazole buffer, glycine buffer, ethanolamine buffer, MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid) buffer, PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid)) buffer, POPSO (piperazine-N,N'-bis(2-hydroxypropanesulfonic acid))) buffer, TAPS (N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid) buffer;Buffers selected from the group consisting of TAPSO (3-[N-tris(hydroxymethyl)methylamino]-2-hydroxy-propanesulfonic acid) buffer, TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid) buffer, Trisine (N-tris(hydroxymethyl)methylglycine buffer), 2-amino-2-methyl-1,3-propanediol buffer, and 2-amino-2-methyl-1-propanol buffer, and combinations thereof; A product comprising a heat-sterilized aqueous liquid composition containing, Herein, the product is packaged in a syringe or vial constructed from (i) glass; or (ii) a plastic selected from the group consisting of cyclic olefin polymers and cyclic olefin copolymers, wherein the syringe or vial is suitable for heat sterilization or autoclaving of the composition, wherein the pH of the composition is between 6.8 and 8.2, and the local anesthetic is stable through the sterilization process and after 12 months of storage, such that at least 95% of the local anesthetic originally present in the composition is present after 12 months of storage; and Herein, the composition contained in the product is formulated to treat lower urinary tract disorders selected from the group consisting of bacterial cystitis, fungal / yeast cystitis, vaginitis, vulvovaginitis, dyspareunia, urethral syndrome, and endometriosis in women; prostatitis and chronic pelvic pain syndrome in men; and radiation-induced cystitis, chemotherapy-induced cystitis, interstitial cystitis (bladder pain syndrome or hypersensitive bladder syndrome), and overactive bladder in men or women. product.

2. The product according to claim 1, wherein the anionic polysaccharide is heparin, preferably heparin sodium.

3. The product according to claim 2, wherein the unit dose of the composition contained in the product contains approximately 1,000 units of heparin to approximately 250,000 units of heparin per unit dose of the composition.

4. The product according to claim 3, wherein the unit dose of the composition contained in the product comprises about 40,000 units of heparin, about 50,000 units of heparin, or about 60,000 units of heparin.

5. The product according to claim 1, wherein the local anesthetic is selected from the group consisting of lidocaine, mepivacaine, benzocaine, tetracaine, etidocaine, prilocaine, dibucaine, and combinations thereof.

6. The product according to claim 5, wherein the local anesthetic is lidocaine, preferably lidocaine hydrochloride.

7. The product according to claim 6, wherein the unit dose of the composition contained in the product contains lidocaine in an amount of about 10 mg to about 400 mg per unit dose of the composition.

8. The product according to claim 7, wherein the unit dose of the composition contained in the product comprises 10 mL of 1% lidocaine or 16 mL of 2% lidocaine.

9. The buffer may be a phosphate buffer, a bicarbonate buffer, a Tris buffer, or a combination thereof. A product according to claim 1, selected from the group.

10. The product according to claim 9, wherein the buffer solution is a phosphate buffer solution, preferably a sodium phosphate buffer solution.

11. The product according to claim 9, wherein the buffer solution is a bicarbonate buffer solution, preferably a sodium bicarbonate buffer solution.

12. The product according to claim 9, wherein the buffer solution is Tris buffer solution.

13. The composition included in the product (a) an osmotic component that provides an isotonic or nearly isotonic solution compatible with human cells and blood; (b) a compound that allows the composition to persist on the surface of the bladder epithelium in an amount sufficient to treat, restore, or prevent lower urinary tract disorders; (c) an amount sufficient to treat, treat, or prevent lower urinary tract disorders, (d) an amount of antifungal agent sufficient to treat, treat, or prevent lower urinary tract disorders, (e) A sufficient amount of vasoconstrictor to treat, treat, or prevent lower urinary tract disorders, (f) Preservatives, and (g) Anti-inflammatory agents The product according to claim 1, comprising an additional component selected from the group consisting of the following.

14. The product according to claim 1, wherein the pH of the composition contained in the product is about 7.2 to about 7.

6.

15. The product according to claim 14, wherein the pH of the composition contained in the product is approximately 7.

5.

16. The product according to claim 1, wherein the composition contained in the product is formulated for the treatment of interstitial cystitis (bladder pain syndrome or irritable bladder syndrome).

17. The product according to claim 1, wherein the syringe or vial is constructed from glass.

18. The product according to claim 1, wherein the syringe or vial is a syringe.

19. The product according to claim 18, wherein the inside of the syringe barrel is coated to reduce the adhesion of the local anesthetic to the syringe.

20. The product according to claim 19, wherein the coating is a siloxane coating deposited by plasma deposition.

21. The product according to claim 1, wherein the syringe or vial is a vial.

22. The product according to claim 1, wherein the inside of the syringe barrel is coated to reduce the adhesion of the local anesthetic to the syringe.

23. The product according to claim 22, wherein the coating is a siloxane coating deposited by plasma deposition.

24. The product according to claim 1, wherein the syringe or vial is constructed from a cyclic olefin polymer plastic.

25. The product according to claim 1, wherein the syringe or vial is constructed from a cyclic olefin copolymer plastic.

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