Article of manufacture comprising local anesthetic, buffer, and glycosaminoglycan in syringe with improved stability

Abstract

To provide improved articles of manufacture.SOLUTION: An article of manufacture according to the present invention comprises a composition including a glycosaminoglycan, a local anesthetic, and a buffer packaged in a syringe or vial constructed from either glass or a plastic selected from the group consisting of cyclic olefin polymer, cyclic olefin copolymer, or high density non-nucleated polypropylene. The composition has unexpectedly improved stability on storage. The composition can be formulated for treatment of a urinary tract disease or condition, such as interstitial cystitis, also known as bladder pain syndrome or hypersensitive bladder syndrome.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 484,477, entitled "Article of Manufacture Comprising Local Anesthetic, Buffer, and Glycosaminoglycan in Plastic Syringe with Improved Stability," by Dan Vickery, Ph.D., et al., and filed April 12, 2017, the contents of which are incorporated herein by reference in their entirety.

[0002] FIELD OF THE INVENTION The present invention is directed to a product having improved stability, comprising a local anesthetic, a buffer, and a glycosaminoglycan in a syringe or vial, typically combined with terminal sterilization of the product. [Background technology]

[0003] Background of the Invention Interstitial cystitis (IC), often known as bladder pain syndrome or irritable bladder syndrome, is a chronic, progressive disorder of the lower urinary tract that causes urinary urgency and frequency and / or pelvic pain. The American Urological Association defines IC / BPS as "an unpleasant sensation (pain, pressure, or discomfort) perceived as related to the bladder, accompanied by lower urinary tract symptoms of greater than six weeks' duration, in the absence of infection or other identifiable cause." For many years, urologists considered IC / BPS a rare disorder without a widely effective treatment. In fact, 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 2.7% to 6.53% (approximately 3.3 to 7.9 million US women aged 18 years or older) and 2.9% to 4.2% (approximately 2.0 to 4.6 million US men aged 18 years or older) (Berry SH et al., J Urol 2011, 186, 540; and Suskind AM et al., J Urol 2013, 189, 141). In addition, overactive bladder, urethral syndromes, prostatitis, and gynecological chronic pelvic pain syndromes, which also result in bladder symptoms of urgency, frequency, incontinence, and / or pelvic pain for which there are no effective therapies, involve millions of patients, and all of these syndromes share similar symptoms and possibly common pathophysiology with the traditionally diagnosed IC (Parsons, CL Int Br J Urol Dec 2010), but there are no widely effective treatments for these conditions.

[0004] Therefore, there is a need for treatments that can benefit a larger patient population, provide immediate relief of symptoms without requiring significant dietary changes and causing additional pain, and can also result in reversal of the disease process over time.

[0005] Compositions and methods for the treatment of interstitial cystitis are described in "Interstitial Cystitis," published August 19, 2008, both of which are incorporated herein by reference in their entirety. Parsons U.S. Patent No. 7,414,039 entitled "Therapy for Immediate Symptom Relief and Chronic Therapy in Interstitial Cystitis" and the 2008 U.S. Patent No. U.S. Patent Application Publication No. 2008 / 0300219, by Parsons, entitled "Novel Interstitial Therapy for Immediate Symptom Relief and Chronic Therapy in Interstitial Cystitis," published February 4, and U.S. Patent Application Publication No. 2008 / 0300219, by Parsons, entitled "Kits and Improved Compositions for Treating Cystitis," published July 20, 2006, both of which are incorporated herein by reference in their entireties. These compositions are described in PCT Patent Application Publication No. WO 2006 / 07663 by Flashner et al., entitled "Kits and Improved Compositions for Treating Lower Urinary Tract Disorders," and PCT Patent Application Publication No. WO 2007 / 073397 by Flashner et al., published June 28, 2007. Generally, the compositions disclosed in this issued patent and these published patent applications include a local anesthetic, typically lidocaine, a glycosaminoglycan, typically a heparinoid, more typically heparin, and a buffer solution. The composition is instilled into the bladder. The buffer solution is typically a phosphate buffer, although other buffer solutions, such as bicarbonate or Tris buffer, can be used, as described below. A particularly preferred phosphate buffer solution is sodium phosphate buffer.

[0006] Alkaline lidocaine and heparin can be used successfully to treat bladder symptoms, including, but not limited to, urinary frequency, urgency, incontinence, and bladder-generated pain. Pain generated by the bladder (visceral organs) is not always perceived as originating from the bladder. Pain can originate anywhere from the navel to the knee, or from the lower back down the buttocks to the legs, and is often unrelated to bladder filling or emptying. As a result, pelvic pain may not be recognized as originating from the bladder. These bladder symptoms can be seen in a variety of "clinical syndromes," all of which may actually stem from a single disease process: dysfunctional epithelium (Parsons, CL Int Br J Urol, December 2010). Nevertheless, all of these syndromes that can produce bladder symptoms that can be successfully treated with the present 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, gynecological chronic pelvic pain syndromes (e.g., endometriosis, vulvodynia, vulvovaginitis, yeast vaginitis).

[0007] However, mixing these compounds can be problematic 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, the absorbed lidocaine can paralyze bladder nerves and relieve the bladder symptoms described above. Heparin can "coat" the bladder wall and inhibit the diffusion of urinary solutes that initially cause bladder symptoms. Therefore, the combination provides prolonged relief of bladder symptoms (Parsons, Urology 2003). However, because lidocaine precipitates at pH levels above 7 under certain conditions, the mixing of heparin, lidocaine, and buffering agents must be performed in a precise manner to prevent lidocaine precipitation. Lidocaine precipitation reduces its bioavailability and reduces the efficacy of the composition. However, even if the composition is prepared in a manner that prevents immediate precipitation of lidocaine upon composition formation, including mixing of glycosaminoglycan, buffer, and local anesthetic, the storage and transportation of the composition requires long-term stability. One factor that contributes to the loss of lidocaine stability and thus its loss from the composition is the interaction of alkalized lidocaine with syringe components. Lidocaine becomes attached to the syringe after sterilization. In the absence of such long-term stability, one of the compositions may be administered in a dosage that does not have the desired clinical effect on the patient. There is a significant risk that multiple components may be administered simultaneously. Therefore, there is a particular need for a composition of manufacture that contains the composition and that can be shipped and stored in a stable, ready-to-administer form to a patient. Additionally, there is a need for such compositions of matter 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 161(2):549-552 (1999) [Non-patent document 2] Berry SH et al., J Urol 2011, 186, 540 [Non-patent document 3] Suskind AM et al., J Urol 2013, 189, 141 [Non-patent document 4] Parsons, CL Int Br J Urol December 2010 Summary of the Invention [Means for solving the problem]

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

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

[0012] Typically, the glycosaminoglycan is a heparinoid. Preferably, the heparinoid is selected from the group consisting of heparin, chondroitin sulfate, heparan sulfate, hyaluronic acid, keratan sulfate, dermatan sulfate, hyaluronan, sodium pentosan polysulfate, dalteparin, and enoxaparin. Particularly preferred heparinoids include heparin, heparan sulfate, chondroitin sulfate, hyaluronic acid, and sodium pentosan polysulfate. More particularly preferred heparinoids are heparins, such as sodium heparin. The heparin may have a molecular weight of about 2,000 to about 8,000 daltons, or alternatively, the heparin may have a molecular weight of about 8,000 to about 40 daltons. It may also be heparin having a molecular weight of 1,000 daltons.

[0013] Typically, when the glycosaminoglycan is heparin, the unit dose of the composition contained in the product contains about 1,000 units 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 units, 50,000 units, and 60,000 units of heparin. Typically, when the heparinoid is sodium pentosan polysulfate, the composition contains about 1 mg to about 600 mg of sodium pentosan polysulfate per unit dose of the composition. Typically, when the glycosaminoglycan is heparan sulfate, the composition contains about 1 mg to about 600 mg of sodium pentosan polysulfate 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, the local anesthetic is selected from the group consisting of benzocaine, lidocaine, tetracaine, bupivacaine, etidocaine, mepivacaine, pramoxine, prilocaine, procaine, chloroprocaine, oxyprocaine, proparacaine, ropivacaine, dyclonine, dibucaine, propoxycaine, dexivacaine, diamocaine, hexylcaine, levobupivacaine, pyrocaine, lisocaine, rhodocaine, and their pharmaceutically acceptable derivatives and bioequivalents, 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. A particularly preferred local anesthetic is lidocaine, e.g., lidocaine hydrochloride. When the local anesthetic is lidocaine, typically the unit dose of the composition included in the product contains lidocaine in an amount of about 10 mg to about 400 mg per unit dose of the composition.

[0015] Typically, the buffer solution is a phosphate buffer, a bicarbonate buffer, a Tris (tris(hydroxymethyl)aminomethane) buffer, a MOPS buffer (3-(N-morpholino)propanesulfonic acid), a HEPES (N-(2-hydroxyethyl)piperazine-N-(2-ethanesulfonic acid) buffer, an ACES (2-[(2-amino-2-oxoethyl)amino]ethanesulfonic acid) buffer, an ADA (N-(2-acetamido)2-iminodiacetic acid) buffer, an AM PSO (3-[(1,1-dimethyl-2-hydroxyethyl)amino]-2-propanesulfonic acid) buffer solution, BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid) buffer solution, Bicine (N,N-bis(2-hydroxyethylglycine) buffer solution, Bis-Tris (bis-(2-hydroxyethyl)imino-tris(hydroxymethyl)methane) buffer solution, CAPS (3-(cyclohexylamino)-1-propanesulfonic acid) buffer solution , CAPSO (3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid) buffer solution, CHES (2-(N-cyclohexylamino)ethanesulfonic acid) buffer solution, DIPSO (3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid) buffer solution, HEPPS (N-(2-hydroxyethylpiperazine)-N'-(3-propanesulfonic acid) buffer solution, HEPPSO (N-(2-hydroxyethyl ) piperazine-N'-(2-hydroxypropanesulfonic acid) buffer solution, MES (2-(N-morpholino)ethanesulfonic acid) buffer solution, triethanolamine buffer solution, imidazole buffer solution, glycine buffer solution, ethanolamine buffer solution, MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid) buffer solution, PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid) buffer solution, POPSO (piperazine-N,N'-bis(2- The buffer is selected from the group consisting of hydroxypropanesulfonic acid buffer, TAPS (N-tris[hydroxymethyl)methyl-3-aminopropanesulfonic acid) buffer; TAPSO (3-[N-tris(hydroxymethyl)methylamino]-2-hydroxy-propanesulfonic acid) buffer, TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid) buffer, Tricine (N-tris(hydroxymethyl)methylglycine buffer), 2-amino-2-methyl-1,3-propanediol buffer, and 2-amino-2-methyl-1-propanol buffer, and 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, the composition included in the product comprises: (1) an osmotic component that provides an isotonic or near-isotonic solution that is compatible with human cells and blood; (2) a compound that allows the composition to persist on the surface of the bladder epithelium in an amount sufficient to treat, ameliorate, or prevent lower urinary tract disorders; (3) an antibacterial agent in an amount sufficient to treat, ameliorate, or prevent lower urinary tract disorders; (4) an antifungal agent in an amount sufficient to treat, ameliorate, or prevent a lower urinary tract disorder; (5) a vasoconstrictor in an amount sufficient to treat, ameliorate, or prevent lower urinary tract disorders; (6) preservatives, and (7) Anti-inflammatory agents and an additional component selected from the group consisting of:

[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 products are formulated to treat a lower urinary tract disorder selected from the group consisting of bacterial cystitis, fungal / yeast cystitis, vestibulitis, vulvodynia, dyspareunia, urethral syndrome, and endometriosis in women; prostatitis and chronic pelvic pain syndrome in men; and radiation-induced cystitis, chemotherapy-induced cystitis, interstitial cystitis (painful bladder syndrome or irritable bladder syndrome), and overactive bladder in men or women.

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

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

[0021] These and other features, aspects, and advantages of the present invention are set forth in the following description, appended claims, and accompanying drawings. The scope of the present invention is better understood with reference to the accompanying drawings. [Brief explanation of the drawings]

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

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

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

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

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

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

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

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

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

[0031] [Figure 10] FIG. 10 is a graph showing the loss of lidocaine hydrochloride in the plunger and syringe body with a Tris buffer formulation (left bar) and a phosphate buffer formulation (right bar).

[0032] [Figure 11] FIG. 11 is a graph showing the amount of lidocaine hydrochloride extracted from a 10× syringe body using tetrahydrofuran (THF) (left bar), ethanol (middle bar), and pH 3 water (right-most bar) using a Soxhlet extractor.

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

[0034] [Figure 13] FIG. 13 is a graph showing lidocaine loss as a function of repeated sterilizations from the samples in Table 14(C). DETAILED DESCRIPTION OF THE INVENTION

[0035] Detailed Description of the Invention Generally, the present invention relates to a glass or a polymer selected from the group consisting of cyclic olefin polymers, cyclic olefin copolymers, high density polyethylene, and high density non-nuclear polypropylene. The present invention also includes a product comprising a composition comprising a glycosaminoglycan, a local anesthetic, and a buffer solution packaged in a syringe or vial constructed from plastic. Typically, the glycosaminoglycan is a heparinoid, as described in more detail below. Preferably, the heparinoid is heparin, as described in more detail below. Typically, the local anesthetic is lidocaine, as described in more detail below. Typically, the buffer solution is a phosphate buffer solution, particularly a sodium phosphate buffer solution, as described in more detail below. However, other buffer solutions, including but not limited to bicarbonate buffer and Tris buffer, may alternatively be used.

[0036] I. Compositions Comprising a Glycosaminoglycan, a Local Anesthetic, and a Buffer

[0037] The composition included in the product comprises a glycosaminoglycan, a local anesthetic, and a buffer. Other components may also be included in the composition, as described in more detail below.

[0038] The glycosaminoglycan is present in the composition in an amount sufficient to treat a urinary tract disease or condition, such as interstitial cystitis (also known as bladder pain syndrome (BPS) or bladder hypersensitivity syndrome (BHS)). The local anesthetic is also present in the composition in an amount sufficient to treat a urinary tract disease or condition, such as interstitial cystitis (also known as BPS or BHS). The buffer is present in the composition in an amount such that about 2% to about 45% of the local anesthetic is present in the composition in its free base (uncharged) form rather than its protonated (charged) form.

[0039] Typically, the glycosaminoglycan is a heparinoid. As used herein, "heparinoid" refers to any molecule, including glycosaminoglycans (e.g., heparin, chondroitin sulfate, heparan sulfate, hyaluronic acid, keratan sulfate, dermatan sulfate, hyaluronan, sodium pentosan polysulfate, etc.), which refer to molecules containing long, branched chain sugar networks, and optimally, further comprising 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 source of GAG. GAG molecules include, but are not limited to, low-molecular-weight (LMW) GAGs, naturally occurring GAGs, GAGs prepared by biotechnology, chemically modified GAGs, synthetic GAGs, etc. Heparinoids may also be composed of pentoses, such as pentosan polysulfate, instead of hexoses (GAGs are composed of hexoses). This is not intended to limit the present invention to any one type of heparinoid molecule or to any one source of heparinoid molecules. As used herein, "heparin" refers to a mixed group of linear anionic glycosaminoglycans, as described above, having molecular weights ranging from 2,000 to 40,000 Da. In some embodiments, heparin is a high molecular weight species ranging from 8,000 to 40,000 Da. As used herein, "low molecular weight heparin" refers to a low molecular weight (LMW) species ranging from 2,000 to 8,000 Da. Sodium pentosan polysulfate may range from 2,000 to 6,000 Da. Polymers such as dalteparin or enoxaparin are also 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 that of unfractionated heparin, except for some changes that may have been introduced due to the enzymatic or chemical treatment. Although the mechanism of action of the composition of the present invention is not intended to be limited, the mechanism of action of these drugs may be similar to that of full-length heparin. LMW heparin is usually isolated from bulk heparin. In one embodiment, heparin or another heparinoid is a heparin salt.As used herein, for purposes of this application, the phrases "pharmaceutically acceptable salts," "pharmaceutically acceptable salts thereof," or "pharmaceutically acceptable complexes" are synonymous and refer to derivatives prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases, and organic acids and bases.

[0040] These polysaccharides are negatively charged due to the presence of sulfate and / or carboxylic acid groups. It is administered in the form of a salt with a suitable cation to neutralize the negative charge of the acidic group. Typically, the cation is sodium. However, other physiologically acceptable counterions that do not induce urinary tract dysfunction, such as magnesium, aluminum, calcium, ammonium, or salts made from physiologically acceptable organic bases, including, 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, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acids such as lysine and arginine, may also be used. These cationic counterions can alternatively be used as counterions for anionic buffer solutions such as bicarbonate. Sodium is typically used as a positively charged counterion, as indicated above. Therefore, a 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 occurring glycosaminoglycans, biotechnologically prepared glycosaminoglycans, chemically modified glycosaminoglycans, and synthetic glycosaminoglycans, as well as linear anionic polysaccharides composed of pentoses, may also be used in the methods of the present invention. Reference to a heparinoid, e.g., heparin, that has a negative charge at physiological pH, in the absence of a specific reference to a counterion, should be understood to include all possible counterions that do not interfere with the biological activity of the heparin or other components of the composition and are not incompatible with any other components of the composition.

[0041] In some embodiments, heparinoids include heparin-like molecules (e.g., heparan sulfate). Heparin-like molecules, such as heparan sulfate, are glycosaminoglycans with a structure similar to that of heparin, except that heparan sulfate has undergone less polymerization than heparin and therefore has more glucuronic acid and N-acetylglucosamine than heparin. Heparan sulfate contains fewer sulfate groups and is therefore slightly less acidic. Heparin exists in various forms characterized by different degrees of sulfation. Typically, heparin has a molecular weight of about 2 kDa to about 40 kDa. Both heparin and heparan sulfate are characterized by a repeating disaccharide unit containing a uronic acid (glucuronic acid or iduronic acid) and either N-sulfated or N-acetylated glucosamine. The sugar residues may be further O-sulfated at the C-6 and C-3 positions of the glucosamine and the C-2 position of the uronic acid. There are at least 32 possible unique disaccharide units in this class of compounds. 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 mg. Heparin is measured in units by 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) relative to the USP standard that will prevent clotting of 1.0 ml of citrated sheep plasma for 1 hour at 20° C. after the addition of 0.2 ml of 1% CaCl. As used herein, "IU" refers to the amount of heparin (defined as units / ml) relative to the Fifth International Standard for Unfractionated Heparin. It refers to the amount of heparin (defined as International Units / ml) active in the assay established by the World Health Organization (WHO) Standard for Unfractionated Heparin (WHO-5) (Linhardt, RJ and Gunay, NS (1999) Semin Thromb Hemost 25:5-16). However, in some embodiments, it is possible and preferred 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 these 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 these methods is heparin.As mentioned above, other counterions may be used, but the preferred form of heparin is sodium heparin. The amount of heparin in the compositions prepared by the methods of the present invention can range from about 1,000 units to about 250,000 units per unit dose of the composition; any intermediate amount of heparin, such as 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. Examples of dosages include, but are not limited to, 75,000 Units, 80,000 Units, 85,000 Units, 90,000 Units, 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, or 250,000 Units. As used herein, "unit dose" refers to the dosage of heparin or other component of a composition according to the present invention typically administered in a single treatment.Expressed in milligrams, these amounts of heparin range from about 0.5 mg to about 1250 mg per unit dose, including, but 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. Suitable amounts 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 composition of the product has a heparin concentration of about 1,000 units of heparin per milliliter of composition to about 6,000 units of heparin per milliliter of composition. The composition of the product may have a heparin concentration selected from the group consisting of 1,000, 1,500, 2,000, 2,500, 3,000, 3,500, 4,000, 4,500, 5,000, 5,500, and 6,000 units per milliliter of composition.

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

[0045] According to the practice of the invention, and by way of example only, when the heparinoid is sodium pentosan polysulfate, the amount of heparinoid in the composition can be from about 1 mg to about 600 mg of sodium pentosan polysulfate per unit dose (e.g., from about 100 mg to about 600 mg of sodium pentosan polysulfate per unit dose). When the heparinoid is heparan sulfate, the amount of heparinoid in the composition can be about 0.5 mg to about 10,000 mg of heparan sulfate per unit dose (e.g., about 100 mg to about 300 mg of heparan sulfate per unit dose). According to the practice of the present invention, by way of example only, when the heparinoid is hyaluronic acid, the amount of heparinoid in the composition can be about 5 mg to about 600 mg of hyaluronic acid per unit dose (e.g., about 10 mg to about 100 mg of hyaluronic acid per unit dose). According to the practice of the present invention, by way of example only, when the heparinoid is chondroitin sulfate, the amount of heparinoid in the composition can be about 1 mg to about 10,000 mg of chondroitin sulfate per unit dose (e.g., about 100 mg to about 300 mg of chondroitin sulfate per unit dose). According to the practice of the present invention, and by way of example only, if the heparinoid is sodium heparin, the amount of heparinoid in the composition can be from about 10 mg to about 1000 mg of sodium heparin per unit dose.

[0046] Local anesthetics are typically sodium channel blockers, including, but not limited to, drugs commonly referred to as "caine" drugs, and other sodium channel blockers. The local anesthetic in the composition prepared by the method of the present invention can be, but is not limited to, benzocaine, lidocaine, tetracaine, bupivacaine, cocaine, etidocaine, mepivacaine, pramoxine, prilocaine, procaine, chloroprocaine, oxyprocaine, proparacaine, ropivacaine, dyclonine, dibucaine, propoxycaine, dexivacaine, diamocaine, hexylcaine, levobupivacaine, pyrocaine, lisocaine, rhodocaine, and 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 a combination thereof. A particularly preferred local anesthetic is lidocaine, preferably in the form of lidocaine hydrochloride, with chloride serving as the counterion. As 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, but the term "local anesthetic" is not intended to limit the salt form or counterion used beyond these criteria. Specifically, a reference to a local anesthetic that is positively charged at physiological or near-physiological pH, such as lidocaine, in the absence of a specific reference to a counterion, 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 are not incompatible with any other components of the composition.

[0047] The amount of local anesthetic in the composition can vary depending on the subject, the severity and course of the disease, the subject's health, response to treatment, pharmacokinetic considerations such as liver and renal function, and the judgment of the treating physician. Thus, several compositions containing different amounts of local anesthetic per unit dose can be prepared by the methods according to the invention. For example, when the local anesthetic is lidocaine, such as lidocaine hydrochloride, the amount of lidocaine in the composition can range from about 10 mg to about 400 mg per unit dose, with any intermediate amount of lidocaine being usable, e.g., 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. Typically, the concentration of lidocaine in the composition in the product is from about 5 mg / mL to about 20 mg / mL. For example, the amount of lidocaine can be 10 mL of 1% lidocaine per unit dose or 16 mL of 2% lidocaine per unit dose. In one preferred embodiment, the composition contains 200 mg of lidocaine as lidocaine hydrochloride. Suitable amounts of local anesthetics other than lidocaine can be determined by one skilled in the art based on the molecular weight and anesthetic potency of the local anesthetic used. .

[0048] The buffer in the composition of the present invention may be a phosphate buffer, a bicarbonate buffer, a Tris (tris(hydroxymethyl)aminomethane) buffer, a MOPS buffer (3-(N-morpholino)propanesulfonic acid), a HEPES (N-(2-hydroxyethyl)piperazine-N-(2-ethanesulfonic acid) buffer, an ACES (2-[(2-amino-2-oxoethyl)amino]ethanesulfonic acid) buffer, an ADA (N-(2-acetamido)2-iminodiacetic acid) buffer, an AMPSO (3-[ (1,1-dimethyl-2-hydroxyethyl)amino]-2-propanesulfonic acid) buffer solution, BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid buffer solution, Bicine (N,N-bis(2-hydroxyethylglycine) buffer solution, Bis-Tris (bis-(2-hydroxyethyl)imino-tris(hydroxymethyl)methane) buffer solution, CAPS (3-(cyclohexylamino)-1-propanesulfonic acid) buffer solution, CAPSO (3-(cyclohexylamino)-1-propanesulfonic acid) buffer solution N-(2-hydroxyethyl)piperazine-N'-(3-propanesulfonic acid) buffer solution, CHES (2-(N-cyclohexylamino)ethanesulfonic acid) buffer solution, DIPSO (3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid) buffer solution, HEPPS (N-(2-hydroxyethylpiperazine)-N'-(3-propanesulfonic acid) buffer solution, HEPPSO (N-(2-hydroxyethyl)piperazine-N'-(2-hydroxypropanesulfonic acid) buffer solution 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, Tricine (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 buffer, phosphate buffer, Tris buffer, or a combination thereof. The most particularly preferred buffer is phosphate buffer, particularly sodium phosphate buffer. Specific examples in which the buffer of the composition is a phosphate buffer are described below. When the buffer is a bicarbonate buffer, the bicarbonate buffer is preferably sodium bicarbonate.

[0049] Phosphate can bond with up to three hydrogen ions, so 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 phosphoric acid (H3PO4) to form dihydrogen phosphate. a The pK for the ionization of dihydrogen phosphate to form monohydrogen phosphate is approximately 2.12. a The pK for the ionization of monohydrogen phosphate to form phosphate ion is approximately 7.21. ais approximately 12.67. The relative proportions of dihydrogen phosphate, monohydrogen phosphate, and phosphate ions present at a defined pH can be readily determined by use of the Henderson-Hasselbalch equation. Typically, when a phosphate buffer is used, it is used as the dihydrogen phosphate, taking into account the pH range involved. However, it is also possible to use the monohydrogen phosphate and add an alkaline agent, e.g., sodium hydroxide, to raise the pH to the desired value. Alternatively, a combination of monohydrogen phosphate and dihydrogen phosphate can be used. While other hydroxides, e.g., potassium hydroxide, can be used, it is generally preferred to use a phosphate buffer solution containing more than potassium hydroxide, given the potential role of potassium ions in the pathogenesis of some lower urinary tract conditions. It is preferred to use sodium hydroxide rather than phosphate buffer. Phosphate buffer is the preferred buffer in some alternative forms because it is more physiologically tolerated by the bladder and is normally present in urine.

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

[0051] Other additional ingredients may be included in the composition. Such additional ingredients include: (1) an osmotic component that provides an isotonic or near-isotonic solution that is compatible with human cells and blood; (2) a compound that allows the composition to persist on the surface of the bladder epithelium in an amount sufficient to treat, ameliorate, or prevent lower urinary tract disorders; (3) an antibacterial agent in an amount sufficient to treat, ameliorate, or prevent lower urinary tract disorders; (4) an antifungal agent in an amount sufficient to treat, ameliorate, or prevent a lower urinary tract disorder; (5) a vasoconstrictor in an amount sufficient to treat, ameliorate, or prevent lower urinary tract disorders; (6) preservatives, and (7) Anti-inflammatory agents Examples include:

[0052] When present, the optional osmolality component is a salt such as sodium chloride, or a sugar, or a combination of two or more of these components. The sugar can be a monosaccharide such as dextrose, a disaccharide such as sucrose or lactose, a polysaccharide such as dextran 40, dextran 60, or starch, or a sugar alcohol such as mannitol. It will be clear to those skilled in the art that all components of a solution contribute to the osmolality of the solution, but to achieve an isotonic or nearly isotonic solution, the contributions of these components should be taken into account and an appropriate proportion of osmolality components should be added to ensure that an excessive amount of osmolality component is not added, which could result in a hypertonic solution. In fact, if a composition such as that described above contains heparin sodium as the heparinoid, lidocaine hydrochloride as the anesthetic, and sodium bicarbonate as the buffer, the osmolality contributions of the sodium ions from heparin sodium and sodium bicarbonate, the chloride ions from lidocaine hydrochloride, and the carbonate / bicarbonate ions from sodium bicarbonate are sufficient to eliminate the need for additional osmolality components. Similarly, when a phosphate buffer is used, the osmolality contribution of the sodium and phosphate ions is typically sufficient so that no additional osmolality components are required, although in some alternatives additional osmolality components may be used.

[0053] When an antibacterial agent is present, the antibacterial agent can be selected from the group consisting of sulfonamides, penicillins, trimethoprim and sulfamethoxazole combinations, quinolones, methenamine, nitrofurantoin, cephalosporins, carbapenems, aminoglycosides, tetracyclines, macrolides, and gentamicin. Suitable sulfonamides include, but are not limited to, sulfanilamide, sulfadiazine, sulfamethoxazole, sulfisoxazole, sulfamethizole, 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, fleroxacin, pefloxacin, and amifloxacin. Suitable cephalosporins include cephalothin, cefazolin, cephalexin, cefadroxil, cefazolin, cefalexin, cefadroxil, cefazolin, cefaxin ... Suitable antihistamines include, but are not limited to, famandole, cefoxatin, cefaclor, cefuroxime, loracarbef, cefonicid, cefotetan, ceforanide, 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, netilmicin 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 present, the antifungal agent may be selected from the group consisting of amphotericin B, itraconazole, ketoconazole, fluconazole, miconazole, and flucytosine.

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

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

[0057] When preservative is present, it can be selected from the group consisting of paraben, chlorobutanol, phenol, sorbic acid and thimerosal.However, typically, the composition that forms part of the product according to the present invention does not need preservative ingredients and meets stability requirements without them.However, in some alternative forms, it may be desirable to include preservative ingredients.

[0058] When anti-inflammatory agent is present, it can be steroid or non-steroid anti-inflammatory agent.Suitable steroid and non-steroid anti-inflammatory agent are known in the art.Suitable steroid includes but is not limited to hydrocortisone, cortisone, beclomethasone dipropionate, betamethasone, dexamethasone, prednisone, methylprednisolone, triamcinolone, fluocinolone acetonide and fludrocortisone.Suitable steroid anti-inflammatory agent includes but is 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, choline magnesium 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, nimesulide, aceclofenac, alclofenac, alminoprofen, amfenac, ampiroxicam, apazone, alaprofen, azapropazone, bendazac, benox, Saprofen, benzydamine, bermoprofen, benzpiperylone, bromfenac, bucloxic acid, bumadizone, butibufen, carprofen, cimicoxib, cinmetacin, cinnoxicam, clidanac, clofesone, clonixin, clopirac, darbuferon, deracoxib, droxicam, eltenac, enfenamic acid, epirizole, esflurbiprofen, ethenzamide, etofenamate, etoricoxib, felbinac, fenbufen, fenclofenac, feni anclozic acid, fenclozine, fendosal, fentiazac, feprazone, firenadol, flobufen, florifenin, flosulide, fluvitin methanesulfonate, flufenamic acid, flufenisal, flunixin, flunoxaprofen, fluprofen, fluproquazone, furofenac, ibufenac, imrecoxib, indoprofen, isofezolac, isoxepac, isoxicam, licofelone, lobuprofen, lomoxicam, lonazolac, loxoprofen ( loxaprofen), lumaricoxib, mabuprofen, miroprofen, mofebutazone, mofezolac, morazone, nepafanac, niflumic acid, nitrofenac, nitroflurbiprofen, nitronaproxen, orpanoxin, oxaceprol, oxidanac, oxypinac, oxyphenbutazone, pamicogrel, parcetasar, parecoxib, parsalmide, perbiprofen, pemedrac, phenylbutazone, pyrazolac, pirprofen, pranoprofen, salicin , salicylamide, salicylsalicylic acid, satigrel, sudoxicam, suprofen, talmetacin, talniflumate, tazoferone, tebuferone, tenidap, tenoxicam, tepoxalin, tiaprofenic acid, tiaramide, tilmacoxib, tinoridine, tiopinac, tioxaprofen, tolfenamic acid, triflusal, tropesin, ursolic acid, valdecoxib, ximofen, zaltoprofen, zidometacin, and zomepirac.

[0059] If any of these optional components, i.e., osmotic component, compound that allows the composition to persist on the surface of the bladder epithelium, antibacterial component, antifungal compound, vasoconstrictor, preservative, or anti-inflammatory agent, are present, they are typically added after the stable solution containing heparinoid, fast-acting anesthetic, and buffer solution is prepared.The amount of these additional optional components, if used, is selected so that the solution of heparinoid, fast-acting anesthetic, and buffer solution remains stable, the precipitation of fast-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. Methods for preparing compositions to be incorporated into products

[0061] Several methods are described for preparing compositions to be incorporated into products according to the present invention. These methods result in compositions that, if packaged in syringes or vials, are then used to fill the syringes or vials, which is the final step in preparing the products of the present invention. Alternatives to the methods described below may also be used to prepare the compositions.

[0062] The first method is (1) providing a heparinoid, either as a solid or an aqueous liquid, in an amount of about 100 units to about 250,000 units per unit dose, or alternatively, about 0.5 mg to about 1250 mg per unit dose; (2) providing a local anesthetic, either as a solid or an aqueous liquid, in an amount of about 5 mg to about 1000 mg per unit dose; (3) combining a heparinoid with a local anesthetic; and (4) The heparinoid and local anesthetic combination of step (3) is prepared from a buffer compatible with both the heparinoid and the fast-acting anesthetic and sodium hydroxide and potassium hydroxide. buffering to a pH value of greater than about 6.8 to about 8.3, possibly by addition of a base selected from the group consisting of: Includes.

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

[0064] The second method is (1) providing a heparinoid, either as a solid or an aqueous liquid, in an amount of about 100 units to about 250,000 units per unit dose, or alternatively, about 0.5 mg to about 1250 mg per unit dose; (2) buffering the heparinoid to a pH value of greater than about 6.8 to about 8.3 with a buffer compatible with both the heparinoid and the subsequently added local anesthetic; (3) adding a local anesthetic, either as a solid or an 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 comprising the heparinoid, the local anesthetic, and the buffer; and (4) If necessary, rebuffering the solution of step (3) to a pH value of greater than about 6.8 to about 8.3 to form a stable solution. Includes.

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

[0066] In one particularly preferred method of preparing a composition according to the invention, the composition is prepared by the following steps: (1) mixing a heparinoid and a fast-acting anesthetic to produce a liquid form in which the heparinoid and fast-acting anesthetic are slightly more concentrated than in the final product; (2) adding a buffer to obtain a pH of about 7.0 to 7.3 in the solution of (1); and (3) raising the pH to a value in the range of about 7.1 to about 8.3 with sodium hydroxide, and optionally by adding water, to achieve the desired final concentration of heparinoid and fast-acting anesthetic. It is prepared by

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

[0068] The above-described compositions contained in the products according to the present invention are useful for the treatment of bacterial cystitis, fungal / yeast cystitis, vestibulitis, vulvodynia, dyspareunia, urethral syndrome, and endometriosis in women; The compositions of the present invention may be formulated or suitable for treating, ameliorating, or preventing lower urinary tract disorders selected from the group consisting of prostatitis and chronic pelvic pain syndrome in men and women; and radiation-induced cystitis, chemotherapy-induced cystitis, interstitial cystitis (also known as bladder pain syndrome (BPS) or overactive 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 " treating, ameliorating or preventing " refers to any detectable improvement, whether subjective or objective, in the lower urinary tract disorder of the subject to which the composition is administered.For example, the term " treating, ameliorating or preventing " can refer to the improvement as determined by the PORIS scale, PUF scale, or any suitable evaluation of these scales; reduction in pain; reduction in urinary frequency; reduction in urgency; reduction in the need for narcotic medication; reduction in incontinence; reduction in the abnormal potassium permeability of urothelium; or the improvement of two or more of these parameters.The term " treating, ameliorating or preventing " does not state or imply the cure of the underlying lower urinary tract disorder.

[0070] III. Glass and high-density polyethylene, high-density non-nucleated polypropylene, COP, or COC plastic for syringes and vials

[0071] Articles according to the invention include syringes or vials constructed from either (i) glass or (ii) plastics selected from the group consisting of COP (cyclic olefin polymer) plastic, COC (cyclic olefin copolymer) plastic, high density polyethylene plastic, and high density non-nuclear polypropylene plastic.

[0072] Cyclic olefin polymer plastics are disclosed in U.S. Patent No. 5,008,356 to Ishimaru et al.; U.S. Patent No. 5,087,677 to Brekner et al.; U.S. Patent No. 5,304,596 to Moriya et al.; U.S. Patent No. 5,324,801 to Brekner et al.; U.S. Patent No. 5,331,057 to Brekner et al.; U.S. Patent No. 5,422,409 to Brekner et al.; U.S. Patent No. 5,795,945 to Natori; U.S. Patent No. 6,090,888 to Khananian et al.; U.S. Patent No. 6,197,804 to Sunaga et al.; U.S. Patent No. 6,388,032 to Yamaura et al.; U.S. Patent No. 6,980,970 to Tsunogae et al.; U.S. Patent No. 7,202,312 to Choi et al.; U.S. Patent No. 7,648,937 to Yoon et al.; U.S. Patent No. 5,422,409 to Brekner et al.; U.S. Patent No. 5,795,945 to Natori; U.S. Patent No. 6,090,888 to Khananian et al.; U.S. Patent No. 6,197,804 to Sunaga et al.; U.S. Patent No. 6,388,032 to Yamaura et al.; U.S. Patent No. 6,980,970 to Tsunogae et al.; U.S. Patent No. 7,202,312 to Choi et al.; U.S. Patent No. 7,648,93 No. 7,814,713 to Suzuki et al.; U.S. Pat. No. 7,838,088 to Suzuki et al.; U.S. Pat. No. 7,964,680 to Choi et al.; U.S. Pat. No. 7,989,570 to Chun et al.; U.S. Pat. No. 8,148,472 to Baugh et al.; U.S. Pat. No. 8,158,732 to Wakatsuki et al.; U.S. Pat. No. 8,293,674 to Chung et al.; U.S. Pat. No. 8,344,070 to Squire et al.; U.S. Pat. No. 8,883,925 to Kizu et al.; U.S. Pat. No. 8,946,366 to Yoo et al.; U.S. Pat. No. 9,056,938 to Sunaga et al.; U.S. Pat. No. 9,151,988 to Yoo et al.; U.S. Pat. No. 9,163,113 to Choi et al.; U.S. Pat. No. 9,206,278 to Yoshida et al.; and U.S. Pat. No. 9,359,588 to Smith.

[0073] Monomers that can be used to form cyclic olefin polymer plastics include norbornene; tetracyclododecene; bicyclo[2,2,1]hept-2-ene; 1-methylbicyclo[2,2,1]hept-2-ene; hexacyclo[6,6,1,1 3,6 ,1 10,13 ,0 2,7 ,0 9,14]-4-Heptadecene;1,4,5,8-dimethano-1,2,3,4,4a,5,8a-octahydronaphthalene;2-Methyl-1,4,5,8-dimethano-1,2,3,4,4a,5,8,8a-octahydronaphthalene;2-Ethyl-1,4,5,8-dimethano-1,2,3,4,4a,5,8,8a-octahydronaphthalene 2-Propyl-1,4,5,8-dimethano-1,2,3,4,4a,5,8,8a-octahydronaphthalene;2-Hexyl-1,4,5,8-dimethano-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;Bicyclo[2,2,1]hept-2-ene;6-Methylbicyclo[2,2,1]hept-2-ene Cyclo[2,2,1]hept-2-ene;5,6-Dimethylbicyclo[2,2,1]hept-2-ene;1-Methylbicyclo[2,2,1]hept-2-ene;6-Ethylbicyclo[2,2,1]hept-2-ene;6-n-Butylbicyclo[2,2,1]hept-2-ene;6-i-Butylbicyclo[2,2,1]hept-2-ene;7-Methylbicyclo[2,2,1]hept-2-ene;5,10-Dimethyltetracyclo[4,4,0,1 2,5 ,1 7,10]3-dodecene;2,10-dimethyltetracyclo[4,4,0,1 2,5 ,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-dimethyl-tetracyclo[4,4,0,1 2,5 ,1 7,10 ]3-dodecene;9-isobutyl-2,7-dimethyl-tetracyclo[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-dimethyl-tetracyclo[4,4,0,1 2,5 ,1 7,10 ]3-dodecene;9-isobutyl-11,12-dimethyl-tetracyclo[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 ,02,7 ,0 9,14 ]4-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 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 ,09,13 ]-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 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 ethylene bis(indenyl)zirconium dichloride; ethylene bis(indenyl)zirconium monochloride monohydride; ethylene bis(indenyl)ethoxyzirconium chloride; ethylene bis(4,5,6,7-tetrahydro-1-indenyl)ethoxyzirconium chloride; ethylene bis(indenyl)dimethylzirconium; ethylene bis(indenyl)diethylzirconium; ethylene bis(indenyl)diphenylzirconium; ethylene bis(indenyl)dibenzylzirconium; ethylene bis(indenyl)methylzirconium monobromide; ethylene bis(indenyl)ethylzirconium monochloride; ethylene bis(indenyl)benzylzirconium monochloride; ethylene bis(indenyl)methylzirconium monochloride; ethylene bis(indenyl)zirconium dichloride; ethylene bis Bis(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 dichlorideEthylenebis(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; ethylene bis(4,5,6,7-tetrahydro-1-indenyl)methylenebis(indenyl)methylzirconium ethoxide, methylene bis(indenyl)zirconium dichloride; methylene bis(indenyl)dimethyl zirconium; methylene bis(4,5,6,7-tetrahydro-1-indenyl)zirconium dichloride; propylene bis(indenyl)zirconium dichloride; propylene bis(indenyl)dimethyl zirconium, and propylene bis(4,5,6,7-tetrahydro-1-indenyl)zirconium dichloride.

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

[0076] Other catalysts and catalyst 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 to Felts et al.; U.S. Patent No. 9,220,631 to Sigg et al.; U.S. Patent No. 8,939,940 to Haury et al.; U.S. Patent No. 8,747,726 to Haury et al.; U.S. Patent No. 8,721,603 to Lundquist; U.S. Patent No. 8,679,068 to Young; U.S. Patent No. 8,398,600 to Hirookane et al.; U.S. Patent No. 8,303,540 to Shue et al.; U.S. Patent No. 7,766,882 to Sudo et al.; and U.S. Patent No. 7,740,792 to Haury et al. Syringe barrels may be formed by injection molding or other techniques known in the art.

[0078] Cyclic olefin polymer plastics are disclosed in U.S. Patent No. 5,559,199 to Abe et al.; U.S. Patent No. 6,627,714 to Yamamoto et al.; U.S. Patent No. 6,639,021 to Oshima et al.; U.S. Patent No. 6,844,403 to Oshima et al.; U.S. Patent No. 6,992,154 to Oshima et al.; U.S. Patent No. 7,122,239 to Bennett et al.; U.S. Patent No. 7,258,930 to Rivett et al.; U.S. Patent No. 7,258,930 to Jang et al. No. 7,662,445 to Nagaura et al.; U.S. Pat. No. 7,854,873 to Heidari et al.; U.S. Pat. No. 8,084,563 to Sakagami et al.; U.S. Pat. No. 8,541,621 to Shin et al.; U.S. Pat. No. 8,637,128 to Jemelin; U.S. Pat. No. 9,206,278 to Yoshida et al.; and U.S. Pat. No. 9,359,558 to Smith.

[0079] Cyclic olefins suitable as comonomers in cyclic olefin copolymers, including those described above, are known in the art. Other olefins useful as comonomers are known in the art and include ethylene and 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 producing these copolymers are described above in relation to the production of cyclic olefin polymers.Other catalysts are known in the art and include zirconium compounds, nickel compounds, cobalt compounds, palladium compounds, platinum compounds, rhenium compounds, and ruthenium compounds, as well as tungsten salts and organoaluminum halide complexes.Additional catalysts are described in U.S. Patent No. 5,559,199 to Abe et al.; U.S. Patent No. 6,639,021 to Oshima et al.; U.S. Patent No. 6,844,403 to Oshima et al.; U.S. Patent No. 7,468,417 to Jang et al.; and U.S. Patent No. 8,084,563 to Sakagami et al.

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

[0082] High density polyethylene is typically 0.93 g / cm 3 to 0.97 g / cm 3High-density polyethylene has a density of 1000 MPa. High-density polyethylene has little branching, which is ensured by the proper selection of catalysts, such as Ziegler-Natta catalysts, and reaction conditions. Syringes constructed from high-density polyethylene are disclosed in U.S. Patent Nos. 9,533,103 to Okihara, 9,381,687 to Felts et al., and 9,302,050 to Creaturo et al.

[0083] High density polypropylene is typically 0.895 g / cm 3 to 0.92 g / cm 3 Such polypropylene may be produced using a metallocene catalyst. A particularly useful form of polypropylene is non-nuclear polypropylene, such as Eltex® MED 100-MG03 (INEOS Olefins and Polymers). Syringes constructed from high-density polypropylene are disclosed in U.S. Patent No. 5,820,605 to Zdeb et al.

[0084] When composition needs to be sterilized before being filled into syringe, sterilization is typically carried out by heat sterilization or steam sterilization, which is generally recommended by FDA and EMA.A suitable method for terminal sterilization is sterilization by autoclave, which is known in the art.Other sterilization methods, including filtration sterilization, are known in the art and can be used alternatively.In another alternative, syringe can be sterilized separately, and then solution can be aseptically filled.Final product can be produced by terminal sterilization or aseptically.Terminal sterilization is generally preferred.

[0085] Particularly preferred syringes are 20 mL capacity syringes constructed from glass or plastic polymers as described above.

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

[0087] One alternative for the preferred composition is prepared in purified water as follows: (1) 16.67 g / L heparin sodium; (2) 13.33 g / L lidocaine hydrochloride; (3) 10.03 g / L of Na2HPO4·12H2 to obtain a concentration of 0.028 M O, and (4) 0.02N NaOH to adjust pH as needed.

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

[0089] The composition can then be loaded into syringes or vials constructed from glass or plastic as described above.

[0090] The present invention is illustrated by the following examples, which are included for illustrative purposes only and are not intended to limit the invention. [Example]

[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 with a stopper and 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 in an upright 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 in an upright 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 in an upright 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 solutions were stable, heparin and lidocaine assays showed no substantial change from initial values, no impurities were detected, and when biological growth testing was performed, no biological growth was detected. Example 2 Stability of compositions containing heparin, lidocaine, and phosphate buffer in cyclic olefin polymer and polypropylene syringes and glass

[0096] This test 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 2 N NaOH, and (5) Purified water to bring the total volume to 100 mL A composition containing the compound was used. (1) 16 g / L heparin sodium; (2) 14.2 g / L lidocaine hydrochloride; (3) 10.03 g / L Na2HPO4·12H2O to obtain a concentration of 0.028 M, and (4) 0.02N NaOH to adjust the pH, if necessary. Includes.

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

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

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

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

[0101] Table 5 shows the sterility, appearance, pH value, lidocaine assay, DMA (2,6-dimethyl-2,6-dimethyl-1,2,3,4,5-trimethyl ... aniline), and more detailed results for total impurities. [Table 5-1] [Table 5-2]

[0102] Table 6 shows more detailed results for sterility, appearance, pH value, lidocaine assay, DMA (2,6-dimethylaniline) assay, and total impurities for compositions stored in COP syringes at the start (before and after 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 sterility, appearance, pH value, lidocaine assay, DMA assay, and total impurities of the compositions stored in PP syringes at the start (before and after 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; the polypropylene was not nucleated. [Table 7-1] [Table 7-2]

[0104] Table 8 shows more detailed results regarding sterility, appearance, pH value, lidocaine assay, DMA assay, and total impurities of the compositions stored in PP syringes at the start (before and after 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; the polypropylene was not nucleated. [Table 8-1] [Table 8-2]

[0105] Figure 1 shows the results for the stability of pH values ​​in COP syringes (left panel) and PP syringes (right panel) at 25°C / 60%RH and 40°C / 75%RH up to 6 months. The polypropylene was not unpenetrated.

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

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

[0108] In storage stability studies, the lidocaine assay was stable in COP syringes, meeting the specification of 1.26-1.40 g / 100 g at all test points. However, in PP syringes, the lidocaine assay decreased after sterilization but remained stable during further storage. The lidocaine assay continued to decrease under accelerated conditions, such as elevated temperatures. In PP syringes (where the polypropylene was not coreless), all time points after sterilization were out of specification.

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

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

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

[0112] Figure 5 shows the results of a storage stability test in a PP syringe at 25°C / 60% RH. The polypropylene syringe was not coreless.

[0113] Figure 6 shows the results of a storage stability test in a PP syringe at 40°C / 75% RH. The polypropylene syringe was not coreless.

[0114] FIG. 7 shows the results of pH measurements in COP syringes at either 25° C. / 60% RH or 40° C. / 75% RH for 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 for up to 12 months. The polypropylene syringes were not coreless.

[0116] In conclusion, storage in COP syringes results in the stability of compositions containing heparin, lidocaine, and phosphate buffer throughout the storage period, including the stability of pH, heparin concentration, lidocaine concentration, and the presence of impurities, both at 25°C / 60% RH and at 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 compositions stored in COP syringes for the treatment of urinary tract diseases and conditions, such as interstitial cystitis. However, storage in non-coreless PP syringes resulted in a significant loss of lidocaine. Lidocaine loss occurred at both 25°C / 60% RH and 40°C / 75% RH, although it was much greater at 40°C / 75% RH.

[0117] This difference in stability between storage in COP syringes and storage in non-cored 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, especially for the treatment of urinary tract diseases and conditions, such as interstitial cystitis.The increased stability of the composition allows for more accurate dosing and administration of the composition to patients with such urinary tract diseases or conditions, without the risk of administering a dose that is less than the effective dose.

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

[0119] Figure 9 shows the loss of lidocaine hydrochloride after sterilization in glass vials and plastic syringes at different molarity of phosphate buffer. There is no loss in glass vials except for a small loss in 80 mM phosphate buffer, but there is significant loss in plastic syringes, which increases with the molarity of the phosphate buffer.

[0120] Additionally, syringe parts (plunger and syringe body) were analyzed for leachables. Rubber and plastic parts (sizes corresponding to actual contact surfaces) in glass containers containing 11 mL of solution (no loss observed) were tested with 18 mL of Tris and phosphate buffer formulations. The results are presented in Table 10. Table 10 shows that there is loss of lidocaine hydrochloride in both rubber plunger and plastic syringe body materials. There is greater loss of lidocaine hydrochloride and greater pH loss in the syringe body than in the plunger. There is also greater loss of lidocaine in the phosphate buffer formulation than in the Tris buffer formulation. [Table 10]

[0121] Additionally, different extraction procedures were attempted to separate lidocaine from the plastic or rubber components of the syringes. These procedures used 10 sterilized samples of phosphate buffer formulations with 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). Less than 0.02 mg of lidocaine hydrochloride could be isolated using this procedure. Other extractants (tetrahydrofuran, ethanol, and water at pH 3) were used to separate the lidocaine hydrochloride from the syringes. The syringe bodies were tested using Soxhlet extraction. 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] FIG. 10 shows the loss of lidocaine hydrochloride in the plunger and syringe body with a Tris buffer formulation (left bar) and a phosphate buffer formulation (right bar).

[0123] FIG. 11 shows the amount of lidocaine hydrochloride extracted from a 10× syringe body using tetrahydrofuran (THF) (left bar), ethanol (middle bar), and pH 3 water (right-most bar) using a Soxhlet extractor.

[0124]

[0125]

[0126] Table 12 shows the pH dependence of lidocaine loss without (A) and with (B) buffer; multiple cycles of sterilization cause additive effects (C). Shows. [Table 12-1] [Table 12-2] [Table 12-3]

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

[0128] FIG. 13 shows the loss of lidocaine from the samples in Table 14(C) as a function of repeated sterilizations.

[0129] Table 13 shows the stability (without prior sterilization) 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 for up to 24 months. [Table 13]

[0130] Table 14 shows the stability (without prior sterilization) 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 25° C.±2° C. and 60%±5% relative humidity for up to 21 months. [Table 14]

[0131] Table 15 shows the stability (without prior sterilization) 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 40° C.±2° C. and 75%±5% relative humidity for up to 21 months. [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 Invention

[0133] The present invention provides improved products containing compositions comprising a glycosaminoglycan, a local anesthetic, and a buffer solution packaged in a syringe, which can be constructed of glass, cyclic olefin polymer (COP), or cyclic olefin copolymer (COC), or alternatively, high-density non-nuclear polypropylene. These improved products unexpectedly have improved stability after terminal heat sterilization and long-term storage, which 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 allows for more accurate dosing and administration of the compositions to patients with such urinary tract diseases or conditions, without the risk of administering a dose that may be less than the effective dose.

[0134] The product according to the present invention has industrial applicability as a packaged composition for the treatment of urinary tract diseases, such as, but not limited to, interstitial cystitis.

[0135] The inventions illustratively described herein may suitably be practiced in the absence of any element or elements, limitation, not specifically disclosed herein. Thus, for example, the terms "comprising," "including," "containing," etc., should be interpreted broadly and without limitation. Furthermore, the transitional phrase "comprising" is intended to encompass the transitional phrases "consisting essentially of" and "consisting of," unless the terms "consisting essentially of" and "consisting" are clearly excluded expressly or by context. Furthermore, the terms and expressions used herein are used as terms of description and not as terms of limitation, and the use of such terms and expressions does not imply any right to any equivalents or any portion thereof shown and described hereafter. No exclusion is intended, and it is recognized that various modifications are possible within the scope of the invention as claimed. Thus, while the present invention has been specifically disclosed by preferred embodiments and optional features, it should be understood that those skilled in the art may reclassify modifications and variations of the invention disclosed herein, and that such modifications and variations are considered to be within the scope of the invention disclosed herein. The inventions are broadly and generically described herein. Each of the more limited species and generic groupings falling within the generic disclosure also form part of these inventions. This includes the generic description of each invention with a condition or negative limitation that removes any subject matter from the genus, regardless of whether the deleted matter is specifically present in the genus.

[0136] Additionally, where features or aspects of the invention are described in terms of a Markush group, those skilled in the art will recognize that the invention is also thereby described in terms of any individual element or subgroup of elements of the Markush group. It should also be understood that the above description is intended to be illustrative and not limiting. Many embodiments will be apparent to those skilled in the art upon review of the above description. Accordingly, the scope of the invention should be determined not by the above description, but rather by the appended claims, along with the full scope of equivalents to which such claims are entitled. The disclosures of all articles and references, including patent publications, are incorporated herein by reference.

[0137] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) An article of manufacture comprising a composition comprising a glycosaminoglycan, a local anesthetic, and a buffer solution 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 non-nuclear polypropylene, cyclic olefin polymer, and cyclic olefin copolymer. (Section 2) Item 1. The product according to item 1, wherein the glycosaminoglycan is a heparinoid. (Section 3) Item 3. The product according to item 2, wherein the heparinoid is selected from the group consisting of heparin, chondroitin sulfate, heparan sulfate, hyaluronic acid, keratan sulfate, dermatan sulfate, hyaluronan, sodium pentosan polysulfate, dalteparin, and enoxaparin. (Section 4) Item 4. The product according to item 3, wherein the heparinoid is heparin. (Section 5) Item 5. The product according to item 4, wherein the heparin is heparin sodium. (Section 6) Item 5. The product according to item 4, wherein the heparin has a molecular weight of about 2,000 daltons to about 8,000 daltons. (Section 7) Item 5. The product according to item 4, wherein the heparin has a molecular weight of about 8,000 daltons to about 40,000 daltons. (Section 8) Item 5. The product of item 4, wherein the heparin contains at least 130 USP units per milligram of heparin. (Section 9) 5. The product of claim 4, wherein the unit dose of the composition contained in the product comprises from about 1,000 units of heparin to about 250,000 units of heparin per unit dose of the composition. (Section 10) Item 5. The product according to item 4, wherein the concentration of the 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 product contains a unit dose of the composition of 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, 10. The product of claim 9, 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) Item 11. 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 composition. (Section 13) 10. The product of claim 9, wherein the unit dose of the composition contained in the product contains about 40,000 units of heparin. (Section 14) 10. The product of claim 9, wherein the unit dose of the composition contained in the product contains about 50,000 units of heparin. (Section 15) 10. The product of claim 9, wherein the unit dose of the composition contained in the product contains about 60,000 units of heparin. (Section 16) Item 5. 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) 17. The product of claim 16, wherein the unit dose of the composition contained in the product comprises 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) Item 4. The product of item 3, wherein the heparinoid is sodium pentosan polysulfate and the composition comprises about 1 mg to about 600 mg of sodium pentosan polysulfate per unit dose of the composition. (Section 19) Item 4. The product of 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) Item 4. The product of item 3, wherein the heparinoid is hyaluronic acid and the composition comprises about 5 mg to about 600 mg of hyaluronic acid per unit dose of the composition. (Section 21) 4. The product of claim 3, wherein the heparinoid is chondroitin sulfate and the composition comprises about 1 mg to about 10,000 mg of chondroitin sulfate per unit dose of the composition. (Section 22) Item 1. The product according to item 1, wherein the local anesthetic is selected from the group consisting of benzocaine, lidocaine, tetracaine, bupivacaine, cocaine, etidocaine, mepivacaine, pramoxine, prilocaine, procaine, chloroprocaine, oxyprocaine, proparacaine, ropivacaine, dyclonine, dibucaine, propoxycaine, dexivacaine, diamocaine, hexylcaine, levobupivacaine, pyrrocaine, lisocaine, rhodocaine, and pharmaceutically acceptable derivatives and bioequivalents thereof, and combinations thereof. (Section 23) 23. The product of paragraph 22, 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) 24. The product according to item 23, wherein the local anesthetic is lidocaine. (Section 25) 25. The product according to item 24, wherein the lidocaine is lidocaine hydrochloride. (Section 26) 25. The product of claim 24, wherein the unit dose of the composition contained in the product comprises lidocaine in an amount of about 10 mg to about 400 mg per unit dose of the composition. (Section 27) 27. The product according to claim 26, wherein the unit dose of the composition contained in the product contains lidocaine in an amount 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) Item 25. The product according to item 24, wherein the concentration of the lidocaine in the composition contained in the product is from about 5 mg / mL to about 20 mg / mL. (Section 29) 25. The product of claim 24, wherein the unit dose of the composition contained in the product comprises 10 mL of 1% lidocaine. (Section 30) 25. The product of claim 24, wherein the unit dose of the composition contained in the product contains 16 mL of 2% lidocaine. (Section 31) The buffer solution may be a phosphate buffer solution, a bicarbonate buffer solution, a Tris (tris(hydroxymethyl)aminomethane) buffer solution, a MOPS buffer solution (3-(N-morpholino)propanesulfonic acid), a HEPES (N-(2-hydroxyethyl)piperazine-N-(2-ethanesulfonic acid) buffer solution, an ACES (2-[(2-amino-2-oxoethyl)amino]ethanesulfonic acid) buffer solution, an ADA (N-(2-acetamido)2-iminodiacetic acid) buffer solution, an AMPSO (3-[(1,1- dimethyl-2-hydroxyethyl)amino]-2-propanesulfonic acid) buffer solution, BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid buffer solution, bicine (N,N-bis(2-hydroxyethylglycine) buffer solution, bis-tris (bis-(2-hydroxyethyl)imino-tris(hydroxymethyl)methane) buffer solution, CAPS (3-(cyclohexylamino)-1-propanesulfonic acid) buffer solution, CAPSO (3-(cyclohexylamino) )-2-hydroxy-1-propanesulfonic acid) buffer solution, CHES (2-(N-cyclohexylamino)ethanesulfonic acid) buffer solution, DIPSO (3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid) buffer solution, HEPPS (N-(2-hydroxyethylpiperazine)-N'-(3-propanesulfonic acid) buffer solution, HEPPSO (N-(2-hydroxyethyl)piperazine-N'-(2-hydroxypropanesulfonic acid) Buffer solution, MES (2-(N-morpholino)ethanesulfonic acid) buffer solution, triethanolamine buffer solution, imidazole buffer solution, glycine buffer solution, ethanolamine buffer solution, MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid) buffer solution, PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid) buffer solution, POPSO (piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) buffer solution, TAPS (N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid) buffer solution;The product according to item 1, which 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, Tricine (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) 32. The product of claim 31, wherein the buffer is selected from the group consisting of phosphate buffer, bicarbonate buffer, Tris buffer, and combinations thereof. (Section 33) 33. The product according to item 32, wherein the buffer is a phosphate buffer. (Section 34) 34. The product according to claim 33, wherein the phosphate buffer is a sodium phosphate buffer. (Section 35) 33. The product of claim 32, wherein the buffer is a bicarbonate buffer. (Section 36) 36. The product of claim 35, wherein the bicarbonate buffer is sodium bicarbonate. (Section 37) 33. The product according to claim 32, wherein the buffer is a Tris buffer. (Section 38) The composition contained in the product comprises: (a) an osmotic component that provides an isotonic or near-isotonic solution that is 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, ameliorate, or prevent a lower urinary tract disorder; (c) an antimicrobial agent in an amount sufficient to treat, ameliorate, or prevent a lower urinary tract disorder; (d) an antifungal agent in an amount sufficient to treat, ameliorate, or prevent a lower urinary tract disorder; (e) a vasoconstrictor in an amount sufficient to treat, ameliorate, or prevent a lower urinary tract disorder; (f) preservatives, and (g) anti-inflammatory agents Item 1. The product according to item 1, further comprising an additional ingredient selected from the group consisting of: (Section 39) 39. The product of claim 38, wherein the additional ingredient is an osmotic ingredient selected from the group consisting of sodium chloride, dextrose, sucrose, lactose, dextran 40, dextran 60, starch, and mannitol. (Section 40) 39. The product of claim 38, wherein the additional ingredient is an antibacterial agent selected from the group consisting of sulfonamides, penicillins, trimethoprim and sulfamethoxazole combinations, quinolones, methenamine, nitrofurantoin, cephalosporins, carbapenems, aminoglycosides, tetracyclines, macrolides, and gentamicin. (Section 41) 39. The product of claim 38, wherein the additional ingredient is an antifungal agent selected from the group consisting of amphotericin B, itraconazole, ketoconazole, fluconazole, miconazole, and flucytosine. (Section 42) 39. The product of claim 38, wherein the additional ingredient is a vasoconstrictor, and the vasoconstrictor is epinephrine. (Section 43) 39. The product of claim 38, wherein the additional component is a compound that enables the composition to persist on the surface of the bladder epithelium, and the compound that enables the composition to persist 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-acryloxysuccinimide, 1-2% xyloglucansol, a graft copolymer of Pluronic and poly(acrylic acid), Pluronic-chitosan hydrogel, and a [poly(ethylene glycol)-poly[lactic acid-co-glycolic acid]-poly(ethylene glycol)] (PEG-PLGA-PEG) copolymer. (Section 44) The additional ingredients may include parabens, chlorobutanol, phenol, sorbic acid, and thiamine. 39. The product according to claim 38, wherein the preservative is selected from the group consisting of merosal. (Section 45) 39. The product of claim 38, wherein the additional ingredient is an anti-inflammatory agent. (Section 46) 46. ​​The product of claim 45, 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 anti-inflammatory agent is acetylsalicylic acid (aspirin), sodium salicylate, choline magnesium 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, nimeth Lidl, aceclofenac, alclofenac, alminoprofen, amfenac, ampiroxicam, apazone, alaprofen, azapropazone, bendazac, benoxaprofen, benzydamine, bermoprofen, benzpiperylone, bromfenac, bucloxic acid, bumadizone, butibufen, carprofen, cimicoxib, cinmetacin, cinnoxicam, clidanac, clofezone, clonixin, clopirac, darbuferon, deracoxib, droxicam, eltenac, enfenamic acid, epirizole, esflurbiprofen, Ethenzamide, etofenamate, etoricoxib, felbinac, fenbufen, fenclofenac, fenclozic acid, fenclozine, fendosal, fentiazac, feprazone, firenadol, flobufen, florifenin, flosulide, fluvitin methanesulfonate, flufenamic acid, flufenisal, flunixin, flunoxaprofen, fluprofen, fluproquazone, furofenac, ibufenac, imrecoxib, indoprofen, isofezolac, isoxepac, isoxicam, licofelone, lobuprofen fluphen, romoxicam, lonazolac, loxaprofen, lumaricoxib, mabuprofen, miroprofen, mofebutazone, mofezolac, morazone, nepafanac, niflumic acid, nitrofenac, nitroflurbiprofen, nitronaproxen, orpanoxin, oxaceprol, oxidanac, oxypinac, oxyphenbutazone, pamicogrel, parcetasar, parecoxib, parsalmide, perbiprofen, pemedrac, phenylbutazone, pyrazolac, pirprofen, pranoprofen, salicin,Item 46. The product according to item 45, which is a nonsteroidal anti-inflammatory agent selected from the group consisting of salicylamide, salicylsalicylic acid, satigrel, sudoxicam, suprofen, talmetacin, talniflumate, tazoferon, tebuferon, tenidap, tenoxicam, tepoxalin, tiaprofenic acid, tiaramide, tilmacoxib, tinoridine, tiopinac, tioxaprofen, tolfenamic acid, triflusal, tropesin, ursolic acid, valdecoxib, ximofen, zaltoprofen, zidometacin, and zomepirac. (Section 48) Item 1. The product according to item 1, wherein the pH of the composition contained in the product is from about 6.8 to about 8.3. (Section 49) Item 49. The product according to item 48, wherein the pH of the composition contained in the product is from about 7.2 to about 7.6. (Section 50) Item 50. The product according to item 49, wherein the pH of the composition contained in the product is about 7.5. (Section 51) The composition contained in the product is effective in treating bacterial cystitis, fungal / yeast cystitis in women, The product according to item 1 above, which is formulated to treat a lower urinary tract disorder selected from the group consisting of vaginal vestibulitis, vulvodynia, dyspareunia, urethral syndrome, and endometriosis; prostatitis and chronic pelvic pain syndrome in men; and radiation-induced cystitis, chemotherapy-induced cystitis, interstitial cystitis (painful bladder syndrome or irritable bladder syndrome), and overactive bladder in men or women. (Section 52) 52. The product according to item 51, wherein the composition contained in the product is formulated for treating interstitial cystitis (painful bladder syndrome or irritable bladder syndrome). (Section 53) Item 1, wherein the syringe or vial is constructed from glass. (Section 54) Item 1, wherein the syringe or vial is constructed from a cyclic olefin polymer plastic. (Section 55) Item 1, wherein the syringe or vial is constructed from a cyclic olefin copolymer plastic. (Section 56) Item 1, wherein the syringe or vial is constructed from high-density polyethylene. (Section 57) Item 1, wherein the syringe or vial is constructed from high-density non-nucleated polypropylene. (Section 58) Item 1. The product according to item 1, wherein the syringe or vial is a syringe. (Section 59) 59. The product of claim 58, wherein the syringe has a capacity of 20 mL. (Section 60) Item 59. The product of item 58, wherein the inside of the syringe barrel is coated to reduce adhesion of the local anesthetic to the syringe. (Section 61) 61. The article of claim 60, wherein the coating is a siloxane coating applied by plasma deposition. (Section 62) The product described in item 1 above, which has been terminally sterilized. (Section 63) Item 63. The product according to item 62, wherein the terminal sterilization is by heat sterilization. (Section 64) Item 64. The product according to item 63, wherein the sterilization by heating is carried out by autoclaving.

Claims

[Claim 1] The invention described in the specification.

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