Compositions and methods for treating cystitis

Abstract

Described herein are aqueous pharmaceutical compositions comprising lidocaine, hyaluronic acid, and chondroitin sulfate (or pharmaceutically acceptable salts of any of these), and water, as well as methods of making such aqueous pharmaceutical compositions and methods of treatment using such aqueous pharmaceutical compositions.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Indian Patent Application No. 202311002763, filed on January 13, 2023, the entire contents of which are incorporated herein by reference.

[0002] Described herein are aqueous pharmaceutical compositions comprising, for example, lidocaine, hyaluronic acid, and chondroitin sulfate, as well as methods of making such aqueous pharmaceutical compositions and methods of treatment using such aqueous pharmaceutical compositions. [Background technology]

[0003] Cystitis is a condition of bladder inflammation. Cystitis may be caused by bladder infection, chemotherapy, or radiation treatment. Interstitial cystitis (IC) is a progressive bladder disorder with symptoms such as mild to severe bladder pain and the urgent and / or frequent need to urinate. The cause of the disease remains unknown, and it is hypothesized that there is an initial infectious insult that damages the glycosaminoglycan (GAG) layer of the bladder urothelium. When the protective GAG ​​layer is destroyed, potentially harmful substances in the urine (e.g., solutes or ions such as potassium) can reach the bladder wall, causing pain and discomfort. See C.L. Parsons, Rev. Urol. 4(Supp. 1:S49-S55 (2002)).

[0004] Current treatments for cystitis primarily target symptom control. First-line treatments may include behavioral and dietary changes, psychological stress management, urogynecological exercise, and heat or cold therapy. Second-line treatments may include oral and intravesical medications targeting pain and / or GAG supplements. Oral pentosan polysulfate is the only oral medication currently approved for the treatment of cystitis. Sodium chondroitin sulfate and sodium hyaluronate are the most widely used GAG supplements, either alone or in combination. Heparin and pentosan polysulfate may also be used to heal the bladder's GAG layer. Dimethyl sulfoxide (DMSO) is indicated for symptom relief. Lidocaine may be used intravesically off-label to relieve bladder pain. See, for example, Garzon et al., Menopause Review / Przeglad Menopauzalny 19:35-43 (2020).

[0005] Therefore, treatment with a combination of a GAG supplement (e.g., sodium chondroitin sulfate and / or sodium hyaluronate) and a local anesthetic (e.g., lidocaine) may be useful for alleviating acute pain and promoting healing of the bladder wall GAG layer in subjects suffering from cystitis, such as IC. However, such compositions have not been approved for pharmaceutical use. German Patent No. 202017104675 and European Patent No. 3415163 disclose compositions containing lidocaine and a GAG supplement, such as sodium chondroitin sulfate and sodium hyaluronate. The disclosed compositions contain a significant amount of buffering agents, which may be disadvantageous in the target patient population because the bladder wall of cystitis patients is sensitive to certain solutes and ions. Therefore, exposure to such buffering agents may cause irritation and pain in patients. Summary of the Invention [Problem to be solved by the invention]

[0006] Therefore, there remains a need for pharmaceutical compositions suitable for use in treating cystitis, such as, for example, pharmaceutical compositions comprising lidocaine, hyaluronic acid, and chondroitin sulfate. [Means for solving the problem]

[0007] Provided herein are aqueous pharmaceutical compositions comprising lidocaine, hyaluronic acid, and chondroitin sulfate (or a pharmaceutically acceptable salt of any of these), and water, as well as methods of making such aqueous pharmaceutical compositions and methods of treatment using such aqueous pharmaceutical compositions.

[0008] According to one aspect, there is provided an aqueous pharmaceutical composition comprising: (i) 0.05 w / v% to 0.6 w / v% lidocaine or a pharmaceutically acceptable salt thereof; (ii) 0.25 w / v% to 3.0 w / v% hyaluronic acid or a pharmaceutically acceptable salt thereof; (iii) 0.3 w / v% to 3.5 w / v% chondroitin sulfate or a pharmaceutically acceptable salt thereof; and (iv) a pH adjusting agent in an amount effective to adjust the pH of the composition to 6.0 to 8.5, wherein the composition does not contain a buffering agent in an amount effective to buffer the pH of the composition.

[0009] In some embodiments, the composition does not include one, more, or all of the following buffering agents: phosphate, carbonate, bicarbonate, acetic acid, acetate, silicate, citric acid, and citrate. In some embodiments, the composition does not include any of the following buffering agents: phosphate, carbonate, bicarbonate, acetic acid, acetate, silicate, citric acid, and citrate.

[0010] In some embodiments, the hyaluronic acid or pharmaceutically acceptable salt thereof has a weight average molecular weight of about 50 to about 500 kDa, hi some embodiments, the hyaluronic acid or pharmaceutically acceptable salt thereof is sodium hyaluronate.

[0011] In some embodiments, the chondroitin sulfate or pharmaceutically acceptable salt thereof has a weight-average molecular weight of about 1 to about 200 kDa. In some embodiments, the chondroitin sulfate or pharmaceutically acceptable salt thereof is sodium chondroitin sulfate.

[0012] In some embodiments, the lidocaine or pharmaceutically acceptable salt thereof is lidocaine hydrochloride.

[0013] In some embodiments, the pH adjuster is selected from meglumine and NaOH.

[0014] In some embodiments, the composition comprises (i) 0.4% w / v lidocaine hydrochloride, (ii) 1.6% w / v sodium hyaluronate, (iii) 2% w / v sodium chondroitin sulfate, and (iv) a pH adjuster selected from meglumine and NaOH.

[0015] The composition can include about 4 mg / mL lidocaine hydrochloride, about 16 mg / mL sodium hyaluronate, and about 20 mg / mL sodium chondroitin sulfate (CS).

[0016] The composition may be packaged in a unit dosage form containing 200 mg of lidocaine hydrochloride in 50 mL.

[0017] In some embodiments, the composition comprises (i) 0.2 w / v% lidocaine hydrochloride, (ii) 0.8 w / v% sodium hyaluronate, (iii) 1 w / v% sodium chondroitin sulfate, and (iv) a pH adjuster selected from meglumine and NaOH.

[0018] The composition can include about 2 mg / mL lidocaine hydrochloride, about 8 mg / mL sodium hyaluronate, and about 10 mg / mL sodium chondroitin sulfate (CS).

[0019] The composition may be packaged in a unit dosage form containing 100 mg of lidocaine hydrochloride in 50 mL.

[0020] In any embodiment, the composition may have a pH of 7.3 to 7.5, such as about 7.4.

[0021] In any embodiment, the composition may include a pH adjusting agent in an amount effective to adjust the pH to about 7.4.

[0022] In any embodiment, the composition may be a sterile solution formulated for instillation in the genitourinary tract or bladder.

[0023] In any embodiment, the composition may be stable for at least 3 months when stored at 25°C and 60% relative humidity. After 3 months of storage at 25°C and 60°C relative humidity, the amount of lidocaine degradation products in the composition may be less than 0.4 wt%. The composition may be stable for at least 3 months when stored at 30°C and 75% relative humidity. After 3 months of storage at 30°C and 75°C relative humidity, the amount of lidocaine degradation products in the composition may be less than 0.4 wt%. The composition may be stable for at least 3 months when stored at 40°C and 75% relative humidity. After 3 months of storage at 40°C and 75°C relative humidity, the amount of lidocaine degradation products in the composition may be less than 0.5 wt%. After 3 months of storage at 25°C and 60% relative humidity, the pH of the composition may differ from the original pH by no more than about 0.3.

[0024] Also provided is a method for treating cystitis, comprising administering to a subject in need thereof a pharmaceutical composition described herein. The pharmaceutical composition may be administered by instillation into the genitourinary tract or bladder. The subject may experience a decrease in nociceptive pain score after administration of the pharmaceutical composition. The subject may experience a decrease in bladder pressure after administration of the pharmaceutical composition. The cystitis being treated may be interstitial cystitis.

[0025] Also provided is an aqueous pharmaceutical composition according to any embodiment described herein for use in treating cystitis, which can be interstitial cystitis.

[0026] Also provided is the use of an aqueous pharmaceutical composition according to any embodiment described herein for the manufacture of a medicament for treating cystitis, which can be interstitial cystitis. [Brief explanation of the drawings]

[0027] [Figure 1] 1 shows the stability (with respect to lidocaine degradation products) of the aqueous pharmaceutical compositions described in Table 1 under various conditions (25°C and 60% relative humidity, 30°C and 75% relative humidity, and 40°C and 75% relative humidity, respectively). [Figure 2] The stability (with respect to pH) of the aqueous pharmaceutical compositions described in Table 1 under various conditions (25°C and 60% relative humidity, 30°C and 75% relative humidity, and 40°C and 75% relative humidity, respectively) is shown. [Figure 3] 1 shows the stability (with respect to lidocaine degradation products) of the aqueous pharmaceutical compositions described in Table 2 under various conditions (25°C and 60% relative humidity, 30°C and 75% relative humidity, and 40°C and 75% relative humidity, respectively). [Figure 4] The stability (with respect to pH) of the aqueous pharmaceutical compositions described in Table 2 under various conditions (25°C and 60% relative humidity, 30°C and 75% relative humidity, and 40°C and 75% relative humidity, respectively) is shown. DETAILED DESCRIPTION OF THE INVENTION

[0028] As described above, provided herein are aqueous pharmaceutical compositions comprising lidocaine, hyaluronic acid, and chondroitin sulfate (or a pharmaceutically acceptable salt of any of these), and water, as well as methods for producing such aqueous pharmaceutical compositions and therapeutic methods using such aqueous pharmaceutical compositions, for example, to treat cystitis (including IC). The compositions of the present disclosure do not rely on buffering agents to maintain pH, thereby avoiding the risks that buffering agents may pose to patients with cystitis.

[0029] Lidocaine is a local anesthetic with anti-inflammatory effects. When used to treat cystitis, lidocaine is most potent when administered in its alkalized form, which allows for better penetration across the bladder epithelium. Therefore, the compositions of the present disclosure can be formulated at a pH that supports the formation of alkalized lidocaine (e.g., a pH of 7.4 to 8.0). Without being bound by theory, formulating lidocaine at such a pH may confer advantages such as better penetration capacity and longer analgesic effects compared to neutral lidocaine formulations. See, e.g., Henry et al., Urology 85:1025-1033 (2015); Henry et al., J Urol. 165:1900-1903 (2001).

[0030] Compositions of the present disclosure can exhibit good stability under ambient conditions (eg, 25° C. and 60% relative humidity) and are suitable for long-term storage (eg, at least 3 months).

[0031] definition Unless otherwise defined, technical and scientific terms used herein have the meanings commonly understood by those skilled in the art of pharmaceutical formulation to which this disclosure pertains. Various methodologies known to those skilled in the art are referenced herein. In carrying out this disclosure, suitable materials and / or methods known to those skilled in the art may be utilized. However, specific materials and methods are described. Materials, reagents, etc. referred to in the following description and examples are available from commercial sources unless otherwise noted.

[0032] As used herein, the singular forms "a," "an," and "the" refer to both the singular and the plural unless expressly stated to refer to the singular only.

[0033] As used herein, the phrases "A / B" or "A and / or B" mean (A), (B), or (A and B), and the phrase "at least one of A, B, and C" means (A), (B), (C), (A and B), (A and C), (B and C), or (A, B, and C).

[0034] As used herein, the terms "comprising," "including," and "containing" are used expansively to mean that the composition, method, or kit being described includes at least the elements specified, and may include other elements not specified.

[0035] As used herein, the term "about" means that the number or range so modified is not limited to the exact number or range stated, but rather encompasses values ​​before and after the stated number or range, as would be understood by one of ordinary skill in the art depending on the context in which the number or range is used. Unless otherwise clear from the context or customary practice in the art, "about" means up to plus or minus 10% of the particular term.

[0036] As used herein, "subject" refers to any mammal, including a human. For example, the subject may be suffering from or at risk of developing a condition that can be diagnosed, treated, or prevented using the pharmaceutical compositions described herein, or may be taking the pharmaceutical compositions described herein for other purposes.

[0037] The terms "administer," "administration," or "administering," as used herein, refer to (1) providing, giving, dispensing, and / or prescribing, e.g., by or under the supervision of a healthcare professional or their authorized agent, or by a subject, and (2) injecting, ingesting, or consuming, e.g., by a healthcare professional or a subject.

[0038] The terms "treat," "treating," or "treatment," as used herein, include alleviating, relieving, or ameliorating a disease or condition, regardless of whether the disease or condition is considered "treated" or "cured," and regardless of whether all symptoms are resolved. These terms also include reducing, slowing, or preventing the progression of the disease or condition, interfering with or preventing the underlying mechanism of the disease or condition, and achieving a therapeutic and / or prophylactic benefit for the disease or condition.

[0039] As used herein, the phrase "therapeutically effective amount" refers to a dose that produces a specific pharmacological effect for which a drug is administered to a subject in need of such treatment. It is emphasized that a therapeutically effective amount is not necessarily effective in treating the conditions described herein, even if one of ordinary skill in the art would consider such a dose to be therapeutically effective. For convenience only, exemplary doses and therapeutically effective amounts relevant to adult human subjects are set forth below. One of ordinary skill in the art can adjust such amounts according to standard techniques as needed to treat a particular subject and / or condition / disease.

[0040] The term "pharmaceutically acceptable salt," as used herein, refers to a pharmaceutically acceptable organic or inorganic salt of a reference compound. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, "mesylate," ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)) salts, alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts.

[0041] Exemplary pharmaceutical compositions, methods of making and using the pharmaceutical compositions, as well as certain exemplary embodiments, are discussed in more detail below.

[0042] composition As described above, provided herein is an aqueous pharmaceutical composition comprising lidocaine, hyaluronic acid, and chondroitin sulfate, or a pharmaceutically acceptable salt of any one or more of these, and water (e.g., purified water).

[0043] For example, the compositions described herein can include lidocaine or a pharmaceutically acceptable salt thereof. In some embodiments, the lidocaine or a pharmaceutically acceptable salt thereof is lidocaine hydrochloride. The lidocaine (or a pharmaceutically acceptable salt thereof, e.g., lidocaine hydrochloride) can be present in any suitable amount, for example, any therapeutically effective amount for treating a condition described herein (e.g., cystitis).

[0044] In some embodiments, the compositions described herein contain about 0.05% to about 0.6% w / v lidocaine (or a pharmaceutically acceptable salt thereof, e.g., lidocaine hydrochloride), e.g., 0.05% to 0.6% w / v, e.g., about 0.05%, about 0.075%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, or about 0.6% w / v, or any value therebetween. In some embodiments, the compositions described herein comprise about 0.4% w / v lidocaine (or a pharmaceutically acceptable salt thereof, e.g., lidocaine hydrochloride), e.g., 0.4% w / v lidocaine hydrochloride. In some embodiments, the compositions described herein comprise about 0.2% w / v lidocaine (or a pharmaceutically acceptable salt thereof, e.g., lidocaine hydrochloride), e.g., 0.2% w / v lidocaine hydrochloride.

[0045] The pharmaceutical compositions described herein also include hyaluronic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the hyaluronic acid or a pharmaceutically acceptable salt thereof is sodium hyaluronate. In some embodiments, the hyaluronic acid or a pharmaceutically acceptable salt thereof has a weight-average molecular weight of about 50 to about 500 kDa, such as about 50 kDa, about 100 kDa, about 200 kDa, about 300 kDa, about 400 kDa, or about 500 kDa, or any value therebetween.

[0046] Hyaluronic acid (or a pharmaceutically acceptable salt thereof, e.g., sodium hyaluronate) can be present in any suitable amount, for example, any therapeutically effective amount for the treatment of a condition described herein (e.g., cystitis). In some embodiments, the compositions described herein contain about 0.25% to about 3.0% w / v hyaluronic acid (or a pharmaceutically acceptable salt thereof, e.g., sodium hyaluronate), for example, 0.25% to 3.0% w / v, for example, about 0.25%, about 0.5%, about 0.75%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, or about 3.0% w / v, or any value therebetween. In some embodiments, the compositions described herein comprise about 1.5 w / v% hyaluronic acid or a pharmaceutically acceptable salt thereof (e.g., sodium hyaluronate), e.g., 1.5 w / v%. In some embodiments, the compositions described herein comprise 1.6 w / v% hyaluronic acid or a pharmaceutically acceptable salt thereof (e.g., sodium hyaluronate). In some embodiments, the compositions described herein comprise about 0.75 w / v% hyaluronic acid or a pharmaceutically acceptable salt thereof (e.g., sodium hyaluronate), e.g., 0.75 w / v%. In some embodiments, the compositions described herein comprise 0.8 w / v% hyaluronic acid or a pharmaceutically acceptable salt thereof (e.g., sodium hyaluronate).

[0047] The pharmaceutical compositions described herein also include chondroitin sulfate or a pharmaceutically acceptable salt thereof. In some embodiments, the chondroitin sulfate or a pharmaceutically acceptable salt thereof is sodium chondroitin sulfate. In some embodiments, the chondroitin sulfate or a pharmaceutically acceptable salt thereof (e.g., sodium chondroitin sulfate) has a weight-average molecular weight of about 1 to about 200 kDa, for example, about 1, about 50 kDa, about 100 kDa, about 150 kDa, or about 200 kDa, or any value therebetween.

[0048] Chondroitin sulfate (or a pharmaceutically acceptable salt thereof, e.g., sodium chondroitin sulfate) can be present in any suitable amount, for example, any therapeutically effective amount for the treatment of a disease described herein (e.g., cystitis). In some embodiments, the compositions described herein contain about 0.3% to about 3.5% w / v of chondroitin sulfate (or a pharmaceutically acceptable salt thereof, e.g., sodium chondroitin sulfate), for example, 0.3% to 3.5% w / v, for example, about 0.3%, about 0.5%, about 0.75%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, or about 3.5% w / v, or any value therebetween. In some embodiments, the compositions described herein comprise about 2.0 w / v% chondroitin sulfate (or a pharmaceutically acceptable salt thereof, e.g., sodium chondroitin sulfate), e.g., 2.0 w / v%. In some embodiments, the compositions described herein comprise about 1.0 w / v% chondroitin sulfate (or a pharmaceutically acceptable salt thereof, e.g., sodium chondroitin sulfate), e.g., 1.0 w / v%. In some embodiments, the compositions described herein comprise 2.0 w / v% sodium chondroitin sulfate. In some embodiments, the compositions described herein comprise 1.0 w / v% sodium chondroitin sulfate.

[0049] As discussed above, formulating a composition to promote the formation of alkalized lidocaine (the ionized form of lidocaine) can be advantageous in connection with providing analgesia to a subject in need thereof (e.g., a subject suffering from cystitis). In this regard, aqueous pharmaceutical compositions having a pH of 6.0 or less typically do not provide a sufficient amount of ionized lidocaine to achieve this beneficial effect. Accordingly, the aqueous pharmaceutical compositions described herein are typically prepared to have a pH of about 6.0 to about 8.5 (e.g., 6.0 to 8.5), such as about 7.3 to about 7.5 (e.g., about 7.3 to about 7.5), e.g., about 7.4 or 7.4. In some embodiments, the compositions described herein have a pH of about 7.4. In some embodiments, the compositions described herein have a pH of 7.4.

[0050] In some embodiments, the compositions described herein further comprise a pH adjuster. Examples of suitable pH adjusters include meglumine, sodium hydroxide (NaOH), and sodium bicarbonate. In some embodiments, the pH adjuster is meglumine. In some embodiments, the pH adjuster is NaOH. NaOH may be used at a concentration of 0.1-0.2 M so that the amount of sodium ions it contributes to the composition is negligible and does not cause irritation or exacerbate pain or other symptoms. In some embodiments, the pH adjuster is sodium bicarbonate. However, as discussed below, in some embodiments, the compositions described herein do not contain bicarbonate. Therefore, in some embodiments, the pH adjuster is not sodium bicarbonate.

[0051] When present, the pH adjusting agent may be present in any suitable amount, such as any amount effective to achieve a target pH of the composition. Thus, for example, the pH adjusting agent may be present in an amount effective to bring the pH of the composition to about 6.0 to about 8.5, e.g., 6.0 to 8.5, e.g., about 7.3 to about 7.5, e.g., 7.3 to 7.5, e.g., about 7.4 or 7.4.

[0052] The compositions described herein do not rely on or require a buffer to maintain pH at a target value or within a target range. Thus, in some embodiments, the compositions described herein do not include a buffer, e.g., the compositions are prepared without the addition of a buffer, and thus the compositions are buffer-free. In some embodiments, the compositions described herein do not include a buffer in an amount effective to buffer the pH of the composition. In such embodiments, small amounts of species that could theoretically act as buffers may be accidentally or intentionally present in the composition. In some embodiments, species that could theoretically act as buffers are present in amounts less than 0.1 mg / mL. In some embodiments, species that could theoretically act as buffers are present in amounts less than 0.05 mg / mL. In some embodiments, species that could theoretically act as buffers are present in amounts less than 0.01 mg / mL.

[0053] Examples of buffering agents (e.g., species that could theoretically act as buffering agents) that may be excluded from the compositions described herein include one, more, or all of the following: phosphate, carbonate, bicarbonate, acetic acid, acetate, silicate, citric acid, and citrate. In some embodiments, the compositions described herein do not include any of the following buffering agents: phosphate, carbonate, bicarbonate, acetic acid, acetate, silicate, citric acid, and citrate. Thus, in some embodiments, none of these are present in the composition. In some embodiments, the total amount present is less than 0.1 mg / mL, e.g., less than 0.05 mg / mL, or less than 0.01 mg / mL. In specific embodiments, the compositions described herein do not include a phosphate buffering agent. In other specific embodiments, the compositions described herein do not include more than 0.1 mg / mL of a phosphate buffering agent, or do not include more than 0.05 mg / mL of a phosphate buffering agent, or do not include more than 0.01 mg / mL of a phosphate buffering agent. In this context, the term "phosphate buffer" includes any phosphate salt that can act as a buffer in an aqueous composition.

[0054] The following are disclosed as specific exemplary embodiments of the aqueous pharmaceutical compositions described herein:

[0055] In some embodiments, the aqueous pharmaceutical compositions described herein comprise: (i) 0.05 w / v% to 0.6 w / v% lidocaine or a pharmaceutically acceptable salt thereof; (ii) 0.25 w / v% to 3.0 w / v% hyaluronic acid or a pharmaceutically acceptable salt thereof; (iii) 0.3 w / v% to 3.5 w / v% chondroitin sulfate or a pharmaceutically acceptable salt thereof; and (iv) a pH adjuster in an amount effective to adjust the pH of the composition to 6.0 to 8.5; Includes:

[0056] In some embodiments, the composition does not contain a buffering agent. In some embodiments, the composition does not contain a buffering agent in an amount effective to buffer the pH of the composition.

[0057] In some embodiments, provided herein is an aqueous pharmaceutical composition comprising: (i) 0.05 w / v% to 0.6 w / v% lidocaine or a pharmaceutically acceptable salt thereof; (ii) 0.25 w / v% to 3.0 w / v% hyaluronic acid or a pharmaceutically acceptable salt thereof; (iii) 0.3 w / v% to 3.5 w / v% chondroitin sulfate or a pharmaceutically acceptable salt thereof; and (iv) a pH adjuster in an amount effective to adjust the pH of the composition to 6.0 to 8.5; Including, The composition does not include a buffering agent in an amount effective to buffer the pH of the composition.

[0058] In some embodiments, the aqueous pharmaceutical compositions described herein comprise: (i) 0.4 w / v% lidocaine hydrochloride, (ii) 1.6 w / v% sodium hyaluronate; (iii) 2% sodium chondroitin sulfate, and (iv) a pH adjuster selected from meglumine and NaOH Including, The composition does not include a buffering agent in an amount effective to buffer the pH of the composition.

[0059] In some embodiments, the aqueous pharmaceutical compositions described herein comprise: (i) 0.2 w / v% lidocaine hydrochloride, (ii) 0.8 w / v% sodium hyaluronate; (iii) 1% sodium chondroitin sulfate, and (iv) a pH adjuster selected from meglumine and NaOH Including, The composition does not include a buffering agent in an amount effective to buffer the pH of the composition.

[0060] According to specific embodiments of any of the foregoing embodiments, the composition does not include one, more, or all of the following buffering agents: phosphate, carbonate, bicarbonate, acetic acid, acetate, silicate, citric acid, and citrate. According to specific embodiments of any of the foregoing embodiments, the composition does not include any of the following buffering agents: phosphate, carbonate, bicarbonate, acetic acid, acetate, silicate, citric acid, and citrate.

[0061] According to specific embodiments of any of the foregoing embodiments, the composition may comprise about 4 mg / mL of lidocaine hydrochloride, e.g., about 4 mg / mL of lidocaine hydrochloride, or about 2 mg / mL of lidocaine hydrochloride, e.g., about 2 mg / mL of lidocaine hydrochloride.

[0062] According to a specific embodiment of any of the foregoing embodiments, the composition comprises about 16 mg / mL of sodium hyaluronate, e.g., 16 mg / mL of sodium hyaluronate. Alternatively, the composition may comprise about 8 mg / mL of sodium hyaluronate, e.g., 8 mg / mL of sodium hyaluronate.

[0063] According to a specific embodiment of any of the foregoing embodiments, the composition comprises about 20 mg / mL sodium chondroitin sulfate, e.g., 20 mg / mL sodium chondroitin sulfate. Alternatively, the composition may comprise about 10 mg / mL sodium chondroitin sulfate, e.g., 10 mg / mL sodium chondroitin sulfate.

[0064] According to a specific embodiment of any of the foregoing embodiments, the composition comprises about 4 mg / mL lidocaine hydrochloride, about 16 mg / mL sodium hyaluronate, and about 20 mg / mL sodium chondroitin sulfate. According to a more specific embodiment of any of the foregoing embodiments, the composition comprises 4 mg / mL lidocaine hydrochloride, 16 mg / mL sodium hyaluronate, and 20 mg / mL sodium chondroitin sulfate.

[0065] Alternatively, according to a specific embodiment of any of the foregoing embodiments, the composition comprises about 2 mg / mL lidocaine hydrochloride, about 8 mg / mL sodium hyaluronate, and about 10 mg / mL sodium chondroitin sulfate. According to a more specific embodiment of any of the foregoing embodiments, the composition comprises 2 mg / mL lidocaine hydrochloride, 8 mg / mL sodium hyaluronate, and 10 mg / mL sodium chondroitin sulfate.

[0066] According to any of the foregoing embodiments, the aqueous pharmaceutical compositions described herein may be prepared as sterile solutions formulated for instillation into the genitourinary tract or bladder.

[0067] According to any of the foregoing embodiments, the aqueous pharmaceutical compositions described herein may be packaged in a unit dosage form (unit dose) containing a pharmaceutically effective dose of lidocaine hydrochloride. In some embodiments, the aqueous pharmaceutical composition is packaged in a unit dosage form containing 200 mg of lidocaine hydrochloride in 50 mL. In some embodiments, the aqueous pharmaceutical composition is packaged in a unit dosage form containing 100 mg of lidocaine hydrochloride in 50 mL.

[0068] stability The aqueous pharmaceutical compositions described herein exhibit good stability against the formation of impurities, such as degradation products. For example, the compositions described herein may be stable for at least one month when stored at about 25°C and 60% relative humidity, about 30°C and 75% relative humidity, or about 40°C and 75% relative humidity, e.g., stable for at least two months or at least three months when stored under one of these conditions. In some embodiments, the aqueous pharmaceutical compositions described herein are stable for at least one month when stored at 25°C and 60% relative humidity. In some embodiments, the aqueous pharmaceutical compositions described herein are stable for at least two months when stored at 25°C and 60% relative humidity. In some embodiments, the aqueous pharmaceutical compositions described herein are stable for at least three months when stored at 25°C and 60% relative humidity.

[0069] In some embodiments, the stability of the aqueous compositions described herein can be assessed by the amount of lidocaine degradation products present in the composition. For example, in some embodiments, a composition containing less than about 0.5 wt% (e.g., less than 0.5 wt%) of degradation products can be considered stable. In some embodiments, the amount of lidocaine degradation products present in the composition is less than about 0.4 wt%, e.g., less than 0.4 wt%, e.g., less than about 0.3 wt%, e.g., less than 0.3 wt%, e.g., less than about 0.2 wt%, e.g., less than 0.2 wt%, less than about 0.1 wt%, or less than 0.1 wt% after storage at 25°C and 60% relative humidity for 3 months. In some embodiments, the amount of lidocaine degradation products in the pharmaceutical composition is less than about 0.4 wt%, such as less than 0.4 wt%, for example less than about 0.3 wt%, for example less than 0.3 wt%, for example less than about 0.2 wt%, for example less than 0.2 wt%, for example less than about 0.1 wt%, or less than 0.1 wt% after storage for 3 months at 30° C. and 75% relative humidity. In some embodiments, the amount of lidocaine degradation products in the pharmaceutical composition is less than about 0.5 wt%, for example less than 0.5 wt%, after storage for 3 months at 40° C. and 75% relative humidity.

[0070] Additionally or alternatively, in some embodiments, the stability of the aqueous compositions described herein may be assessed by a change in pH. For example, a composition with a pH change of 0.3 or less may be considered stable. In some embodiments, the pH change of the compositions described herein is about 0.3 or less after storage at 25°C and 60% relative humidity for 3 months, e.g., 0.3 or less, about 0.2 or less, 0.2 or less, or about 0.1 or less, or 0.1 or less. In some embodiments, the pH change of the compositions described herein is about 0.3 or less after storage at 30°C and 75% relative humidity for 3 months, e.g., 0.3 or less, about 0.2 or less, 0.2 or less, about 0.1 or less, or 0.1 or less. In some embodiments, the pH change of the compositions described herein is about 0.3 or less after storage at 40°C and 75% relative humidity for 3 months, e.g., 0.3 or less, about 0.2 or less, 0.2 or less, about 0.1 or less, or 0.1 or less.

[0071] Treatment methods / therapeutic uses As mentioned above, the aqueous pharmaceutical compositions described herein may be used in methods of treatment, such as methods for treating cystitis. Such methods include administering a therapeutically effective dose of a composition described herein to a subject in need thereof. For example, the subject may be a human subject suffering from cystitis (e.g., infection-associated cystitis, chemotherapy-induced cystitis, radiation-induced cystitis, or interstitial cystitis). The composition may be administered by any suitable route of administration. In some embodiments, the composition is administered by instillation into the genitourinary tract or bladder.

[0072] By administering the compositions described herein to a subject in need thereof, a therapeutic effect can be achieved, for example, one or more of a decrease in nociceptive pain score and a decrease in bladder pressure after administration. As mentioned above, administration of the compositions described herein can be associated with fewer side effects than compositions containing buffering agents, due to the avoidance of the risk of irritation and pain that may be associated with ions present in the buffer. [Example]

[0073] The following examples are included as illustrative of the compositions described herein. These examples are not intended to limit the scope of the disclosure in any way. Other aspects of the disclosure will be apparent to those skilled in the art to which this disclosure pertains.

[0074] Example 1: Preparation of aqueous pharmaceutical composition Aqueous pharmaceutical compositions having the components shown in Table 1 below were prepared as outlined below. Under a nitrogen purge, buffering agents (e.g., NaHPO·2H O and NaHPO·H O) (if used) were added to purified water, followed by lidocaine hydrochloride and sodium chondroitin sulfate. The nitrogen purge was stopped, and sodium hyaluronate was added. The pH of the resulting solution was adjusted to a target pH (e.g., 7.4) using a pH adjuster (e.g., meglumine or NaOH), and additional purified water was added to make up the final volume.

[0075] [Table 1]

[0076] Example 2: Stability of aqueous pharmaceutical compositions Comparative Formulations 1 and 2 and Formulations 3 and 4, prepared as described above, were stored under various conditions (25°C and 60% relative humidity, 30°C and 75% relative humidity, and 40°C and 75% relative humidity, respectively) for up to 3 months. Stability was assessed visually for the formation of lidocaine degradation products and pH change. All formulations remained clear and colorless after 3 months of storage under all conditions. As reported in Figures 1 and 2, both Formulations 3 and 4 showed less than 0.3 wt.% lidocaine degradation product formation after up to 3 months of storage at 25°C and 60% relative humidity or 30°C and 75% relative humidity, and less than 0.4 wt.% lidocaine degradation product formation after 3 months of storage at 40°C and 75% relative humidity, and showed a pH change of less than 0.3 after 3 months of storage under all conditions.

[0077] These results surprisingly demonstrate that the pH of the compositions described herein is stable over time, even in the absence of a buffer. These results also surprisingly demonstrate that the stability of the compositions described herein against the formation of degradation products is at least comparable to compositions formulated with a buffer (e.g., Formulations 1 and 2) (e.g., the compositions are stable without the need for a buffer).

[0078] Example 3: Additional aqueous pharmaceutical compositions An aqueous pharmaceutical composition having the components shown in Table 2 below was prepared as outlined above.

[0079] [Table 2]

[0080] Formulations 5-8 were prepared as described above and stored for one month under various conditions (25°C and 60% relative humidity, 30°C and 75% relative humidity, and 40°C and 75% relative humidity, respectively). Stability was assessed visually for the formation of lidocaine degradation products and pH change. All formulations remained clear and colorless after one month of storage under all conditions. As reported in Figures 3 and 4, Formulations 5, 7, and 8 showed less than 0.3 wt.% lidocaine degradation product formation after one month of storage at 25°C and 60% relative humidity or 30°C and 75% relative humidity, and less than 0.4 wt.% lidocaine degradation product formation after one month of storage at 40°C and 75% relative humidity, and showed a pH change of less than 0.3 after one month of storage under all conditions.

[0081] The results for Formulation 6 formulated at pH 8.3 are shown in Figures 3 and 4. As can be seen in these figures, Formulation 6 exhibited a pH change of less than 0.3 after one month of storage under all conditions. Formulation 6 exhibited less than 0.3 wt.% lidocaine degradation product formation after one month of storage at 25°C and 60% relative humidity or 30°C and 75% relative humidity, and less than 0.5 wt.% lidocaine degradation product formation after one month of storage at 40°C and 75% relative humidity. These results indicate that formulations prepared at a pH greater than 8.5 may not be as stable to the formation of lidocaine degradation products as formulations prepared at a pH less than 8.5 (e.g., a pH of 6.0 to 8.5).

Claims

1. 1. An aqueous pharmaceutical composition comprising: (i) 0.05% w / v to 0.6% w / v of lidocaine or a pharmaceutically acceptable salt thereof; (ii) 0.25% w / v to 3.0% w / v of hyaluronic acid or a pharmaceutically acceptable salt thereof; (iii) 0.3 w / v% to 3.5 w / v% chondroitin sulfate or a pharmaceutically acceptable salt thereof; and (iv) a pH adjuster in an amount effective to adjust the pH of the composition to 6.0 to 8.5; Including, The composition does not include a buffering agent in an amount effective to buffer the pH of the composition.

2. 10. The composition of claim 1, wherein the composition does not include one, more, or all of the following buffering agents: phosphate, carbonate, bicarbonate, acetic acid, acetate, silicate, citric acid, and citrate.

3. 10. The composition of claim 1, wherein the composition does not contain any of the following buffering agents: phosphate, carbonate, bicarbonate, acetic acid, acetate, silicate, citric acid, and citrate.

4. The composition according to any one of claims 1 to 3, wherein the hyaluronic acid or a pharmaceutically acceptable salt thereof has a weight-average molecular weight of about 50 to about 500 kDa.

5. The composition according to any one of claims 1 to 4, wherein the chondroitin sulfate or a pharmaceutically acceptable salt thereof has a weight-average molecular weight of about 1 to about 200 kDa.

6. The composition according to any one of claims 1 to 5, wherein the lidocaine or a pharmaceutically acceptable salt thereof is lidocaine hydrochloride.

7. The composition according to any one of claims 1 to 6, wherein the hyaluronic acid or a pharmaceutically acceptable salt thereof is sodium hyaluronate.

8. The composition according to any one of claims 1 to 7, wherein the chondroitin sulfate or pharmaceutically acceptable salt thereof is sodium chondroitin sulfate.

9. The composition according to any one of claims 1 to 8, wherein the pH adjuster is selected from meglumine and NaOH.

10. (i) 0.4% w / v lidocaine hydrochloride; (ii) 1.6% w / v sodium hyaluronate; (iii) 2% w / v sodium chondroitin sulfate, and (iv) a pH adjuster selected from meglumine and NaOH The composition of any one of claims 1 to 9, comprising:

11. The composition of any one of claims 1 to 10, wherein the pharmaceutical composition comprises about 4 mg / mL lidocaine hydrochloride, about 16 mg / mL sodium hyaluronate, and about 20 mg / mL sodium chondroitin sulfate (CS).

12. The composition of any one of claims 1 to 11, wherein the composition is packaged in a unit dosage form containing 200 mg of lidocaine hydrochloride in 50 mL.

13. (i) 0.2% w / v lidocaine hydrochloride; (ii) 0.8% w / v sodium hyaluronate; (iii) 1% w / v sodium chondroitin sulfate, and (iv) a pH adjuster selected from meglumine and NaOH The composition of any one of claims 1 to 9, comprising:

14. 14. The composition of any one of claims 1 to 9 or 13, wherein the pharmaceutical composition comprises about 2 mg / mL lidocaine hydrochloride, about 8 mg / mL sodium hyaluronate, and about 10 mg / mL sodium chondroitin sulfate (CS).

15. 15. The composition of any one of claims 1 to 9, 13 or 14, wherein the composition is packaged in a unit dosage form containing 100 mg of lidocaine hydrochloride in 50 mL.

16. The composition according to any one of claims 1 to 15, having a pH of 7.3 to 7.

5.

17. The composition of any one of claims 1 to 16, wherein the pH is about 7.

4.

18. The composition of any one of claims 1 to 17, comprising a pH adjusting agent in an amount effective to adjust the pH to about 7.

4.

19. The composition of any one of claims 1 to 18, wherein the composition is a sterile solution formulated for instillation in the urogenital tract or bladder.

20. 20. The composition of any one of claims 1 to 19, wherein the composition is stable for at least 3 months when stored at 25°C and 60% relative humidity.

21. 21. The composition of any one of claims 1 to 20, wherein the amount of lidocaine degradation products in the pharmaceutical composition is less than 0.4 wt% after storage at 25°C and 60°C relative humidity for 3 months.

22. 22. The composition of any one of claims 1 to 21, wherein the composition is stable for at least 3 months when stored at 30°C and 75% relative humidity.

23. 23. The composition of any one of claims 1 to 22, wherein the amount of lidocaine degradation products in the pharmaceutical composition is less than 0.4 wt% after storage at 30°C and 75°C relative humidity for 3 months.

24. 24. The composition of any one of claims 1 to 23, wherein the composition is stable for at least 3 months when stored at 40°C and 75% relative humidity.

25. 25. The composition of any one of claims 1 to 24, wherein the amount of lidocaine degradation products in the pharmaceutical composition is less than 0.5 wt% after storage at 40°C and 75°C relative humidity for 3 months.

26. 26. The composition of any one of claims 1 to 25, wherein after storage at 25°C and 60% relative humidity for 3 months, the pH of the pharmaceutical composition differs from the original pH by no more than about 0.

3.

27. A method for treating cystitis, comprising administering to a subject in need thereof a pharmaceutical composition according to any one of claims 1 to 26.

28. 28. The method of claim 27, wherein the pharmaceutical composition is administered by instillation into the genitourinary tract or bladder.

29. 29. The method of claim 27 or 28, wherein the subject has a reduced nociceptive pain score after administration of the pharmaceutical composition.

30. 30. The method of any one of claims 27 to 29, wherein the subject has reduced bladder pressure after administration of the pharmaceutical composition.

31. The method according to any one of claims 27 to 30, wherein the cystitis is interstitial cystitis.

32. 27. The aqueous pharmaceutical composition according to any one of claims 1 to 26, for use in the treatment of cystitis.

33. 33. The pharmaceutical composition for use according to claim 32, wherein the cystitis is interstitial cystitis.

34. Use of the aqueous pharmaceutical composition according to any one of claims 1 to 26 for the manufacture of a medicament for treating cystitis.

35. 35. The use of claim 34, wherein the cystitis is interstitial cystitis.

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