Fixed dose combination of flavoxate and beta-3 adrenergic receptor agonists, and formulations and manufacturing processes thereof

Abstract

The present disclosure provides for fixed-dose combination formulations comprising flavoxate or a pharmaceutically acceptable salt thereof and at least one β3-adrenergic receptor agonist, along with methods of making and using the same to treat symptoms associated with prostate, bladder, urinary tract, and pelvic conditions.

Description

[0001] Fixed Dose Combination of Flavoxate and Beta-3 Adrenergic Receptor Agonists, and Formulations and Manufacturing Processes Thereof

[0002] FIELD OF THE DISCLOSURE

[0003] The present disclosure relates to pharmaceutical fixed dose combinations comprising a beta-3(P3)-adrenergic receptor agonist and flavoxate, and uses thereof. The present disclosure also provides methods for preparation of fixed-dose combinations comprising a p3-adrenergic receptor agonist and flavoxate. The FDC pharmaceutical formulations may be formulated in various dosage forms, including immediate-release (IR) (substantially complete release of the intended dose within about 1 to 60 minutes after administration), modified-release (MR) (providing sustained, extended, controlled release profiles typically over about 12 to 24 hours), or combination of IR, and / or MR release profiles to achieve the desired therapeutic outcomes.

[0004] BACKGROUND

[0005] Overactive Bladder (OAB) is a persistent medical condition characterized by urgency, with or without involuntary urine leakage, along with increased frequency and night-time urination in the absence of infection or any other pathology. Lower urinary tract symptoms (LUTS) encompass a broader range of urinary symptoms include storage, voiding, and post-micturition symptoms whereas OAB syndrome is a subgroup of storage symptoms characterized by urinary urgency, urge urinary incontinence, frequency, and nocturia. Primarily affecting older adults of both sexes, OAB significantly impairs quality of life, impacting social functions like work, travel, exercise, sleep, and sexual activity. The main OAB symptom is a disruption in the bladder's storage phase, characterized by difficult-to-defer urges.

[0006] Detrusor overactivity is a primary cause of OAB, often idiopathic but occasionally linked to neurological conditions, bladder outlet obstruction, or other factors. Bothersome symptoms are associated with higher levels of anxiety and depression.

[0007] Diagnosing OAB involves ruling out urinary tract infection, metabolic disorders affecting urination, or urinary stress incontinence. Only a third of OAB patients experience urge incontinence (wet OAB), distinct from incontinence caused by urethral and pelvic floor failure. Some patients exhibit both urge and urinary stress incontinence, leading to a mixed urinary symptom diagnosis. OAB treatment includes lifestyle modifications like weight loss, fluid management, and avoiding bladder irritants, alongside drug therapy, neuromodulation, and, in rare cases, surgery. Lifestyle adjustments and pelvic floor physical therapy are first-line approaches, employing techniques like timed voiding, urge suppression, fluid reduction, and pelvic floor muscle strengthening. Second-line therapy involves anticholinergic and / or p3-agonist drug therapy. Third-line options include intravesical botulinum toxin injection, sacral neuromodulation, and percutaneous tibial nerve stimulation. For cases unresponsive to these therapies, more invasive options like bladder augmentation or urinary diversion can be considered.

[0008] Anticholinergic / anti-muscarinic agents have long been the preferred medical treatment for OAB among clinicians. However, the effectiveness of anti-muscarinic treatments is often inadequate, with many patients either not responding satisfactorily or experiencing intolerable side effects such as dry mouth, constipation, blurred vision, and acute urine retention (AUR). Additionally, constipation may exacerbate symptoms by reducing bladder capacity due to the presence of excessive stools in the rectum. Also there has been increasing evidence associating anticholinergic use with cognitive decline, since it is a chronic disease and therapy is long term.

[0009] Oxybutynin, a non-selective muscarinic receptor antagonist, has demonstrated effectiveness in reducing OAB symptoms in multiple randomized controlled trials (RCTs). However, its use is associated with a notable burden of adverse drug reactions, including common anticholinergic side effects like constipation, dry mouth, and blurred vision.

[0010] To address these concerns, newer and more selective anticholinergics, such as tolterodine in the 1990s, and solifenacin, darifenacin, and fesoterodine in the 2000s, have been developed for clinical use. Despite these advancements, the pharmacological management of OAB faces challenges due to worries about tolerability and side effects, including constipation, dry mouth, and an increased risk of urinary retention.

[0011] As a result, there remains a pressing need for enhanced therapies that offer more efficient OAB management and fewer adverse effects.

[0012] P3-adrenergic receptor selective agonists, such as mirabegron, have gained popularity as an alternative to antimuscarinic agents for treating OAB. Mirabegron is a potent and selective p3-adrenergic receptor agonist and BCS Class III compound developed by Astellas Pharma, and has been in clinical use since 2012 for the potential treatment of overactive bladder (OAB) symptoms like urinary frequency, incontinence, and urgency. Mirabegron is sometimes prescribed in conjunction with anticholinergic or antimuscarinic drugs for OAB. However, combining mirabegron with another anticholinergic medicine (e.g., solifenacin succinate) may heighten the risk of urinary retention, urinary tract infections (UTIs), and other anticholinergic side effects.

[0013] The recommended initial dose of mirabegron is 25 mg once daily, with or without food, and can be increased to 50 mg daily if needed. However, existing treatment modalities may not provide sufficient symptom improvement, especially when incontinence persists. Increasing the dosage of antimuscarinic or P3 -adrenoceptor agonist may worsen adverse events, leading to treatment discontinuation.

[0014] In patients with poor response to the standard mirabegron dose, escalating the dosage may also amplify serious cardiovascular side effects, particularly in elderly patients with a history of cardiovascular disease, hypertension, or other heart-related issues. Such patients may be at a higher risk of experiencing such side effects, making dosage increase an unsuitable option.

[0015] US Patent No. 6,346,532 Bl discloses mirabegron and its salts, including dihydrochloride. Mirabegron is available in the US as Myrbetriq® and in the EU as Betmiga®, both as modified release tablets with 25 and 50 mg doses.

[0016] US Pat. No. 8,772,315 B2 covers combinations of mirabegron (25-50 mg) with solifenacin for OAB treatment.

[0017] Other patents (US Pat. No. 8,835,474, RE 44,872, US Pat. No. 7,342,117 B2, US 7,982,049 B2) disclose methods, crystal forms, and salt forms of Mirabegron.

[0018] Additionally, US 9,655,885 B2 discloses an amorphous solid dispersion of mirabegron, optionally with one or more pharmaceutically acceptable antioxidants.

[0019] Mirabegron appears as a white powder with high solubility and low permeability. It is practically insoluble in water. It is soluble in methanol and dimethyl sulfoxide.

[0020] Mirabegron's bioavailability is affected by food in the gastrointestinal tract, leading to modified release (MR) tablet formulations, specifically employing an orally controlled absorption system (OCAS®) to counteract this food effect. Clinical trials with conventional formulations showed significant variations in pharmacokinetics depending on food intake, with a threefold increase in Cmax in the fasted state compared to the fed state.

[0021] WO 2017186598 Al proposes a mixture of polyethylene oxides and small quantities of antioxidants to achieve controlled release and mitigate oxidation.

[0022] EP 3777853 Al suggests using hydroxypropyl methylcellulose (HPMC) and microcrystalline cellulose (MCC) to create mirabegron tablets with reduced weight for better patient acceptance and lower manufacturing costs. The disclosed extended-release tablets use OCAS® technology, and contain polyethylene oxide, polyethylene glycol, hydroxypropyl cellulose, butylated hydroxytoluene, and magnesium stearate in the core, with hypromellose, yellow ferric oxide, and red ferric oxide in the coating.

[0023] U.S. Pat. No. 10,842,780 discloses sustained-release, hydrogel -forming oral formulations of mirabegron.

[0024] Flavoxate is a synthetic urinary tract antispasmodic. It is used in 100 mg and 200 mg sugar-coated immediate-release tablets, typically administered at 300-1200 mg / day in 3-4 doses. Accepted for the symptomatic treatment of OAB, flavoxate stands out for being largely free from anticholinergic side effects.

[0025] EP patent application 0250374 Al introduces a modular delivery system utilizing polymeric coating for controlled release mechanisms involving diffusion, chemical erosion, hydration, and osmosis.

[0026] US patent (5,165,937) and EP patent (0393572 A2) disclose a solid dosage form with controlled release using hydroxypropyl methyl cellulose and polyvinyl alcohol within a matrix, including an acidifying agent for stability in the gut's basic environment.

[0027] WO202021422A1 presents a controlled-release oral formulation of flavoxate salt without an acidifying agent.

[0028] Another application (WO 2023089553 Al) introduces biphasic drug release profiles using at least one immediate release layer, one extended-release layer, and a surfactant.

[0029] Satyavathi et al., 2014 (Satyavathi K, Venu M, Gayathri P, Bhojaraju P and Kanthal LK: Formulation and development of Flavoxate hydrochloride extended release capsules. Int J Pharm Sci Res 2014; 5(5): 1949-56.doi: 10.13040 / IJPSR.0975-8232.5 (5).1949-56) explores extended-release capsules of Flavoxate using ethyl cellulose and hydroxypropyl methyl cellulose, providing dissolution profiles up to 98% release by the sixth hour.

[0030] US 20210052600 Al discloses a combination of a 5-HT2C receptor agonist, mirabegron, and flavoxate hydrochloride for treating overactive bladder, emphasizing reduced adverse effects and body weight.

[0031] US 20210205619 Al discloses a wearable device with an electrically conductive skin interface that excites the underlying nerves from a transcutaneous surface stimulator. It further discusses combinations of nerve stimulation and pharmacologic therapies for overactive bladder, including mirabegron and flavoxate hydrochloride. US 20170128379 Al outlines a modified release pharmaceutical preparation using drug-ion exchange resin complexes and non-polymeric multifunctional excipients, coated for controlled release.

[0032] Mirabegron has been studied as monotherapy and in combination with antimuscarinics for treating OAB. However, there is a lack of studies combining Flavoxate, an antispasmodic, with the p3-adrenergic receptor agonist such as mirabegron. There are various formulation challenges faced while combining Flavoxate with P3- adrenergic receptor agonist including, but not limited to, physical and chemical incompatibilities along with inability to control drug dissolution release rates. One issue with developing a MR formulation of flavoxate is its very low aqueous solubility, which may lead to slow dissolution rates. This slow dissolution can significantly limit the drug's efficacy and cause large inter-individual variations in absorption. Developing a MR formulation for relatively water-insoluble drugs like flavoxate may require extensive experimentation, because predicting the ability of a specific formulation to achieve the desired modified-release profile is often difficult to predict without experimentation. Additionally, flavoxate hydrochloride presents issues such as poor compressibility, poor flow characteristics, and high stickiness, which can adversely affect multiple stages of pharmaceutical formulation development, including weighing, blending, granulation, and compression. These challenges impact drug manufacturing operations, particularly tablet compression, leading to issues like low production speeds, weight variation, and frequent machine stoppages.

[0033] Mirabegron presents formulation challenges due to its insolubility in water and significant variations in pharmacokinetic parameters depending on food intake. A clinical trial of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic acid anilide or mirabegron in the form of conventional formulations revealed that pharmacokinetic data unexpectedly varied according to the presence or absence of the intake of food. For example, in a fed state (with Food), the Cmax (maximum plasma concentration) decreases by 67%, and the AUC (Area Under the Curve) decreases by 47% compared to a fasted state (Without Food). See, e.g., U.S. Pat. No. 11,707,451. These variations are likely due to changes in pharmacokinetics caused by food, making the development of a formulation that can avoid the effects of food intake a key focus of the inventors while developing this FDC.

[0034] Modified-release oral solid dosage forms are highly specialized formulations. These dosage forms may enable drug release over a defined period or at specific locations within the gastrointestinal (GI) tract for prolonged or targeted drug delivery. At the same time, they may allow for less frequent dosing, which can increase patient adherence and result in fewer side effects by reducing peaks and troughs in blood levels. Formulating combination therapies that maintain the efficacy of each active ingredient while ensuring stability can be challenging. Formulating combination drugs involves scientific, clinical, regulatory, and commercial challenges. Careful consideration has to be taken regarding drug compatibility, stability, and clinical effectiveness.

[0035] Manufacturing combination formulations with desired release profiles (IR, MR, or combinations thereof) is further challenging. To obtain the desired release profile or multiple desired release profiles when there are more than one active pharmaceutical ingredient (API), a holistic approach is necessary. Knowledge of the APIs, their physical and chemical compatibility, inclusion of appropriate excipients, selection of dosage form, and manufacturing techniques are some of the considerations that play a role in formulation development. These considerations, along with the desired pharmacokinetic (PK) profile, may help build a robust system that attempts to deliver the therapeutic in a fashion that best benefits the patient.

[0036] Formulating a once-daily modified-release dosage form of a fixed-dose combination (FDC) of flavoxate and mirabegron presents significant challenges due to the differing dose ranges and dosing frequencies of the two drugs. Flavoxate requires a high daily dose, ranging from 300 to 1500 mg, and has a shorter half-life, making it difficult to maintain effective therapeutic levels in the bloodstream for 12-24 hours. In contrast, Mirabegron is administered at a comparatively lower dose, typically ranging from 25 to 50 mg once or twice a day, and has a longer half-life of 26-31 hours.

[0037] Given the documented issues with anticholinergic use in older adults, the rationale behind dual therapy with flavoxate and mirabegron arises from their separate modes of action, potentially improving adherence, reducing pill burden, and ensuring better tolerance and efficacy. Flavoxate hydrochloride is available as 100 mg and 200 mg immediate-release tablets. In trials flavoxate has been safely given in doses of 600, 800, 1200 and 1500 mg / day with good tolerability. The therapeutic dose usually ranges from 300 to 1200 mg per day in 3-4 administrations. For patients prescribed multiple medications, the number of tablets could range from 4 to 7 tablets per day, significantly increasing the pill burden, which directly impacts patient compliance. By combining these medications into a single pill, the pill burden can be reduced, thereby improving adherence. The use of combination formulations is particularly beneficial in patients with multiple chronic conditions, as it simplifies medication regimens and increases adherence.

[0038] The fixed dose combinations may be IR, MR formulations or combinations thereof. While, IR dosage formulations exhibits effects of drug quickly by dissolving the drug without delaying or prolonging dissolution or absorption of the drug, (MR) formulations may be prescribed to overcome the low persistence rates and to offer convenience of once daily administration. Combining IR and MR release profiles in formulations may provide both fast relief and prolonged therapeutic effects. Flavoxate OD (once-daily) addresses non-compliance issues associated with multiple daily doses. To address these issues, the present disclosure aims to provide fixed-dose combination formulations of flavoxate and at least one p3-adrenergic receptor agonist exhibiting IR, MR formulations or combinations thereof and offering non-limiting advantages in terms of stability, efficacy and safety and improved patient compliance.

[0039] SUMMARY OF THE DISCLOSURE

[0040] According to the present disclosure there is provided a new fixed dose combination (FDC) pharmaceutical formulation which comprises (a) flavoxate (or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, esters, or prodrugs thereof) in a pharmaceutically effective amount and (b) at least one P3 adrenoceptor agonist (or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, esters, or prodrugs thereof) in a pharmaceutically effective amount as active ingredients.

[0041] The FDCs may be formulated as IR, MR, and / or combinations thereof.

[0042] Suitable P3 adrenoceptor agonists for the practice of the disclosure include, but are not limited to, mirabegron, solabegron, ritobegron and vibegron, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, esters, or prodrugs thereof.

[0043] The preferred P3 adrenoceptor agonist employed in the present disclosure is mirabegron or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, cocrystals, esters, or prodrugs thereof.

[0044] The present disclosure of pharmaceutical fixed dose combination (FDC) compositions may provide for immediate release of both actives i.e. within 1 to 60 minutes after administration, for slow or sustained release, i.e. a release within 12-24 hours, and / or combination of Immediate, modified release profiles. The desired release rate may vary dependent on the intended actual use, therapeutic purpose, and therapeutic amount or frequency of administration.

[0045] The objective of the present disclosure is to develop modified-release formulations of mirabegron with flavoxate hydrochloride, offering immediate release and / or extended drug release over 12-24 hours and stable plasma profiles. This combination aims to enhance efficacy and reduce side effects compared to mirabegron combined with anticholinergic drugs, potentially minimizing cardiovascular issues, constipation, dry mouth, blurred vision, urinary retention and the risk of cognitive decline.

[0046] Additionally, the combination may decrease administration frequency, particularly for flavoxate, thereby improving long-term quality of life for patients, especially those of advanced age. The flavoxate and mirabegron combination emerges as a novel and improved treatment option for OAB patients.

[0047] Given the long-term and prolonged nature of flavoxate and mirabegron therapy, there is a significant need for a controlled release drug delivery system ensuring extended drug release profiles over 12-24 hours in a single dosage form, stable and suitable for commercial use. The present disclosure addresses these unmet needs in the field as the present disclosure aims to provide the fixed-dose combination of flavoxate hydrochloride or pharmaceutically acceptable salt thereof and mirabegron or pharmaceutically acceptable salt or ester thereof in the dose range of 50 mg to 2000 mg of flavoxate active and in the dose range of 1 to 400 mg of mirabegron active per day, respectively.

[0048] The present disclosure provides fixed-dose combinations (FDC) of at least one P3 adrenoceptor agonist, and flavoxate or pharmaceutically acceptable salt thereof and uses of the FDC. The present disclosure also relates to methods for preparing the FDC of at least one P3 adrenoceptor agonist with flavoxate.

[0049] The formulations of the present disclosure combine flavoxate with a P3 adrenoceptor agonist such as mirabegron, solabegron, ritobegron or vibegron, in a modified-release formulation. The FDC of flavoxate and a P3 adrenoceptor agonist will help improving patient compliance.

[0050] The present disclosure also provides the FDC of at least one P3 adrenoceptor agonist and flavoxate or pharmaceutically acceptable salt or ester thereof in the dose range of 50 mg to 2000 mg of flavoxate active and in the dose range of 1 to 400 mg of P3 adrenoceptor agonist per day, respectively.

[0051] The present disclosure provides the FDC of at least one P3 adrenoceptor agonist and flavoxate or pharmaceutically acceptable salt or ester thereof in the dose range of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1500 mg or 2000 mg of flavoxate active per day, and in the dose range of 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg or 125 mg, or 150 mg or 200 mg or 250 mg, 300 mg or 350 mg or 400 mg of P3 adrenoceptor agonist per day, respectively.

[0052] Using novel manufacturing process, the disclosed formulations may be prepared in oral solid dosage form such as, but not limited to, tablets, MUPS (Multiple Unit Pellet System), pills, granules, caplets, tablets-in-capsule, capsules, granules-in-capsule, pellets, pellets-in-capsule, powders, or any suitable form for oral administration.

[0053] Embodiments of the present disclosure provide stable fixed-dose combination formulations comprising therapeutically effective amount of flavoxate or a salt thereof and at least one P3 -adrenoceptor agonist or a salt or ester thereof of the sorts described below in embodiments and detailed description.

[0054] In an embodiment the present disclosure provides a fixed-dose combination pharmaceutical formulation of at least one p3-adrenergic receptor agonist and an antispasmodic agent, wherein the antispasmodic agent is flavoxate or a pharmaceutically acceptable salt thereof.

[0055] In another embodiment, the p3-adrenergic receptor agonist is selected from mirabegron, solabegron, ritobegron, and vibegron, or a pharmaceutically acceptable salt or ester thereof.

[0056] In a yet another embodiment, the P3-adrenergic receptor agonist is mirabegron or a pharmaceutically acceptable salt or ester thereof.

[0057] In still another embodiment, the formulation comprises flavoxate or a pharmaceutically acceptable salt thereof in an amount of about 50 mg to 2000 mg. The P3- adrenergic receptor agonist component is typically present in an amount ranging from about 1 mg to 400 mg.

[0058] In a further embodiment, the formulation may optionally comprise one or more pharmaceutically acceptable excipients. Suitable excipients include fillers, disintegrants, binders, surfactants, controlled-release polymers, lubricants, glidants, diluents, antioxidants, pH modifiers, anti-sticking agents, or coating agents.

[0059] In a still further embodiment, the controlled-release polymer in the formulation comprises a combination of at least one hydrophilic polymer and at least one hydrophobic polymer. In a yet further embodiment, the weight ratio of the hydrophilic polymer to the hydrophobic polymer is in the range of about 1 : 1 to about 9: 1.

[0060] In an additional embodiment, the controlled-release polymer in the formulation is selected from hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetyl succinate, hydroxyethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyethylene oxide, povidone (for example, PVP K 30 and PVP K 90), homo-polymers and copolymers of acrylic acid chemically cross-linked with polyalkenyl alcohols, Ethyl cellulose, ammonio methacrylate copolymers, polyvinyl acetate, HPMC E15, HPMC K4M, HPMC K15M, HPMC K-100M, HPMC K15, or cross-linked high amylose starch or salts or derivatives thereof.

[0061] In another embodiment, the controlled-release polymer further comprises at least one pH-dependent polymer in an amount of about 1.0% to 15% w / w of the formulation.

[0062] In a yet another embodiment, the pH-dependent polymer is selected from ionic methacrylate copolymers, methacrylic acid-methyl methacrylate copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, sodium alginate or alginic acid derivatives, and aminoalkyl methacrylate copolymers or salts or derivatives thereof.

[0063] In still another embodiment, the disintegrant in the formulation is selected from starch, sodium starch glycollate, croscarmellose sodium, and crospovidone.

[0064] In a further embodiment, the disintegrant is present in an amount of about 0.1% to about 15% w / w of the formulation.

[0065] In a still further embodiment, the surfactant is selected from long alkyl chain sulfonates or sulfates, sodium dodecylbenzene sulfonate, sodium lauryl sulphate, dialkyl sodium sulfosuccinate, quaternary ammonium salts, fatty alcohols, lauryl, cetyl, stearyl, glyceryl esters, fatty acid esters, and polyoxyethylene derivatives thereof.

[0066] In a yet further embodiment, the diluent is selected from mannitol, sorbitol, microcrystalline cellulose, lactose, dicalcium phosphate, and starch such as maize starch, and corn starch. These listed diluents used in the current disclosure can be powder grade or directly compressible (DC) grades. The examples of DC grades diluents include MCC PH 102, MCC PH 112, Pregelatinized starch, spray dried lactose etc.

[0067] In an embodiment, the binder is selected from starch, polyvinylpyrrolidone, natural or synthetic gum, cellulosic polymers, ethyl cellulose, hydroxypropyl cellulose, and gelatin. In another embodiment, the lubricant and glidant are selected from talc, colloidal silicon dioxide, stearic acid, magnesium stearate, and sodium stearyl fumarate.

[0068] In a still another embodiment, the coating agent is selected from one or more of polyvinylpyrrolidone, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, dextrin, maltodextrin, lactose, D-mannitol, polyvinyl alcohol polymer, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, ethyl acrylate methyl methacrylate copolymer, plasticizer, antitacking agent, opacifier, and coloring agent.

[0069] In a yet another embodiment, the formulation is in a dosage form suitable for oral administration, preferably an oral solid dosage form.

[0070] In an additional embodiment, the oral solid dosage form of the pharmaceutical formulation is selected from tablets, MUPS (Multiple Unit Pellet System), pills, granules, caplets, tablets-in-capsule, capsules, granules-in-capsule, pellets, pellets-in-capsule, powders, or any suitable form for oral administration.

[0071] In another embodiment, the solid dosage form the pharmaceutical formulation is a tablet, capsule, or MUPS.

[0072] In a yet another embodiment, the tablet has a hardness of about 5 kg / cm2to about 50 kg / cm2.

[0073] In an embodiment, the present disclosure provides a fixed-dose combination pharmaceutical formulation comprising flavoxate or a pharmaceutically acceptable salt thereof, and at least one p3-adrenergic receptor agonist, and one or more pharmaceutically acceptable excipients,

[0074] - wherein the formulation exhibits the dissolution profile for flavoxate or a pharmaceutically acceptable salt thereof as:

[0075] (a) from about 5% to about 45% of the total flavoxate is released at about 1 hour;

[0076] (b) from about 35% to about 70% of the total flavoxate is released at about 2 hours; and

[0077] (c) not less than 80% of the total flavoxate is released at about 12 hours;

[0078] - wherein the formulation exhibits the dissolution profile for the P3-adrenergic receptor agonist as:

[0079] (a) from about 5% to about 35% of the total p3-adrenergic receptor agonist is released at about 1 hour;

[0080] (b) from about 35% to about 70% of the total p3-adrenergic receptor agonist is released at about 2 hours; and (c) not less than 80% of the total p3-adrenergic receptor agonist is released at about 12 hours.

[0081] In an embodiment, the present disclosure provides that the dissolution profile for flavoxate or a pharmaceutically acceptable salt thereof and for P3 -adrenergic receptor agonist is assessed using dissolution media having pH of about 5 to 8 for suitable duration at about 20 to 200 rpm.

[0082] In another embodiment, the present disclosure provides that the dissolution profile for flavoxate or a pharmaceutically acceptable salt thereof is assessed using dissolution media having pH of about 1 to 2 followed by pH of about 6 to 8 for suitable duration at about 50 to 150 rpm; and the dissolution profile for the P3 -adrenergic receptor agonist or a pharmaceutically acceptable salt thereof is assessed using dissolution media comprising required quantity of at least one surfactant having pH of about 1 to 2 followed by pH of about 7 to 8 for suitable duration at about 50 to 150 rpm.

[0083] In an embodiment, the present disclosure provides a fixed-dose combination pharmaceutical formulation comprising flavoxate or a pharmaceutically acceptable salt thereof, and at least one P3 -adrenergic receptor agonist, and one or more pharmaceutically acceptable excipients,

[0084] - wherein the formulation exhibits the dissolution profile for flavoxate as not less than 85% of the total flavoxate is released by about 60 minutes;

[0085] - wherein the formulation exhibits the dissolution profile for the P3-adrenergic receptor agonist as not less than 60% of the total p3-adrenergic receptor agonist is released by about 60 minutes.

[0086] In another embodiment, the present disclosure provides that the dissolution profile for the flavoxate and / or the p3-adrenergic receptor agonist is assessed using dissolution media having pH of about 1 to 2 for suitable duration at about 50 to 150 rpm.

[0087] In another embodiment, the present disclosure provides a fixed-dose combination pharmaceutical formulation comprising: a) a therapeutically effective amount of flavoxate or a pharmaceutically acceptable salt thereof, and b) a therapeutically effective amount of at least one p3-adrenergic receptor agonist, wherein the formulation is a modified-release oral solid dosage form capable of releasing both active agents over a period of about 12 to 24 hours, and wherein the P3-adrenergic receptor agonist is present in an amount from about 0.04% to about 25% w / w, and flavoxate is present in an amount ranging from about 4% to 85% w / w of the total formulation weight.

[0088] In a yet another embodiment, the dosage form is a mono-layered, bi-layered tablet, or multi-layered tablet, capsule, or MUPS.

[0089] In still another embodiment, the modified-release profile is achieved using a combination of at least one hydrophilic polymer and at least one hydrophobic polymer, in a weight ratio of about 1 : 1 to about 9: 1.

[0090] In another embodiment, the modified-release dosage form further comprises at least one pH-dependent polymer in an amount of about 1.0% to 15% w / w of the formulation.

[0091] In yet another embodiment, the P3-adrenergic receptor agonist per unit dosage form is from about 1 mg to about 400 mg, and flavoxate per unit dosage form is from about 50 mg to 2000 mg.

[0092] In an embodiment, the present disclosure provides that the p3-adrenergic receptor agonist per unit dosage form is from about 5 mg to about 350 mg, preferably from about 20 mg to about 250 mg, more preferably from about 50 mg to 200 mg; and flavoxate per unit dosage form is from about 100 mg to 1800 mg, preferably from about 300 mg to about 1500 mg, more preferably from about 600 mg to 1500 mg.

[0093] In a further embodiment, the present disclosure provides that the P3 -adrenergic receptor agonist per unit dosage form is from about 10 mg to about 250 mg, preferably from about 25 mg to about 200 mg, more preferably from about 50 mg to 150 mg; and flavoxate per unit dosage form is from about 300 mg to 1800 mg, preferably from about 400 mg to about 1500 mg, more preferably from about 600 mg to 1500 mg.

[0094] In a still further embodiment, the present disclosure provides that the P3- adrenergic receptor agonist per unit dosage form is from about 20 mg to about 250 mg, preferably from about 50 mg to about 75 mg, more preferably from about 25 mg to 50 mg; and flavoxate per unit dosage form is from about 300 mg to 1200 mg, preferably from about 400 mg to about 1200 mg, more preferably from about 800 mg to 1200 mg.

[0095] In a still another embodiment, the dosage form has a total weight ranging from about 100 mg to about 3000 mg.

[0096] In an embodiment, the present disclosure provides a solid oral fixed-dose combination pharmaceutical formulation in the form of a bi-layered tablet or multi-layered tablet comprising: (a) at least one immediate-release (IR) layer comprising flavoxate or a pharmaceutically acceptable salt thereof and optionally, at least one P3 -adrenergic receptor agonist;

[0097] (b) at least one modified-release (MR) layer comprising flavoxate or a pharmaceutically acceptable salt thereof and optionally, at least one P3 -adrenergic receptor agonist;

[0098] (c) optionally, at least one intermediate layer disposed between the IR and MR layers, comprising an inert excipient and configured to prevent interaction between the layers and preserve the independent dissolution profiles of each active agent; wherein the formulation delivers flavoxate and the p3-adrenergic receptor agonist in one or both of IR and MR forms.

[0099] In a yet another embodiment, the formulation comprises flavoxate or a pharmaceutically acceptable salt thereof in a total amount of about 50 mg to about 2000 mg; and P3-adrenergic receptor agonist in an amount of about 1 mg to about 400 mg; and wherein the tablet comprises one or more controlled-release polymers and other pharmaceutically acceptable excipients.

[0100] In a still another embodiment, the formulation comprises drug-related impurities of each active agent present at less than about 5% by weight relative to the labeled amount of each active agent; and wherein the total drug-related impurities present in the formulation are less than about 6% by weight relative to the combined labeled amounts of the active agents.

[0101] In a further embodiment, the formulation comprises flavoxate or a pharmaceutically acceptable salt thereof in an amount of about 0.4% to about 90% by weight of the formulation; p3-adrenergic receptor agonist in an amount of about 0.04% to about 30% by weight of the formulation; and one or more pharmaceutically acceptable excipients in an amount of about 5% to about 95% by weight of the formulation, or about 35% to about 85% by weight of the formulationin a still further embodiment, the P3- adrenergic receptor agonist and / or flavoxate or a pharmaceutically acceptable salt thereof in the pharmaceutical formulation of the present disclosure exhibit a modified-release, immediate-release, or a combination thereof drug release profile.

[0102] In an embodiment, the p3-adrenergic receptor agonist and / or flavoxate or a pharmaceutically acceptable salt thereof in the pharmaceutical formulation of the present disclosure exhibits a modified-release profile or an immediate-release profile. In another embodiment, the p3-adrenergic receptor agonist and / or flavoxate or a pharmaceutically acceptable salt thereof in the pharmaceutical formulation of the present disclosure exhibits an immediate-release profile, said formulation is substantially free of controlled-release polymer.

[0103] In a still another embodiment, the p3-adrenergic receptor agonist and / or flavoxate or a pharmaceutically acceptable salt thereof in the pharmaceutical formulation of the present disclosure exhibits an immediate-release and a modified-release profile.

[0104] In a yet another embodiment, the flavoxate or a pharmaceutically acceptable salt thereof is present in the immediate-release portion of the pharmaceutical formulation of the present disclosure, and optionally in the modified-release portion of the oral dosage form.

[0105] In a further embodiment, the flavoxate or pharmaceutically acceptable salt thereof is present in the immediate-release and modified-release portions of the pharmaceutical formulation of the present disclosure in a ratio of about 1 : 1 to about 1 :8.

[0106] In a yet further embodiment, the P3-adrenergic receptor agonist is present in the modified-release portion and optionally in the immediate-release portion of the oral dosage form.

[0107] In a still further embodiment, the P3-adrenergic receptor agonist is present in the immediate-release and modified-release portions of the oral dosage form in a ratio of about 1 : 1 to about 1 :8.

[0108] In an additional embodiment, the flavoxate or pharmaceutically acceptable salt thereof is present in an immediate-release portion at about 2.5% w / w to about 100% w / w and in a modified-release portion at about 0% w / w to about 97.5% w / w of the total weight of the flavoxate or pharmaceutically acceptable salt thereof in the oral dosage form.

[0109] In another embodiment, the P3-adrenergic receptor agonist is present in an immediate-release portion at about 0% w / w to about 100% w / w and / or in modified-release portion at about 0.25% w / w to about 100% w / w of the total weight of the p3-adrenergic receptor agonist in the oral dosage form.

[0110] In a still embodiment, the p3-adrenergic receptor agonist and / or flavoxate or a pharmaceutically acceptable salt thereof in the pharmaceutical formulation of the present disclosure exhibits a modified-release profile or a combination of modified-release and immediate-release profile, the disintegrant is present in an amount of about 0.1% to about 1.5% w / w of the formulation. In a yet another embodiment, the p3-adrenergic receptor agonist and / or flavoxate or a pharmaceutically acceptable salt thereof in the pharmaceutical formulation of the present disclosure exhibits an immediate-release profile, the disintegrant is present in an amount of about 0.1% to about 15 % w / w of the formulation.

[0111] In a further embodiment, the present disclosure provides a method for the preparation of a mono-layered, bi-layered tablet, multi-layered tablet, MUPS (Multiple Unit Pellet System), or capsule comprising at least one p3-adrenergic receptor agonist and flavoxate or a pharmaceutically acceptable salt thereof, the method comprising: a) blending required quantities of at least one p3-adrenergic receptor agonist and flavoxate or a pharmaceutically acceptable salt thereof, along with one or more pharmaceutically acceptable excipients, to obtain a dry blend mixture separately for one or more of immediate-release (IR) and / or modified-release (MR) layers; b) optionally passing the blend mixture of IR and / or MR layers of step a) through a screen having a mesh of appropriate size to obtain a uniformly sized particulate mixture for each layer; c) granulating the uniformly sized particulate mixture of IR and / or MR layers as per step b), or the blend mixture of step a), by suitable means to obtain wet granules; d) drying the wet granules of step c) for a suitable time and at a suitable temperature to obtain dried granules of IR and / or MR layers; e) lubricating the dried granules of step d), with at least one extra-granular excipient and at least one lubricant to obtain lubricated granules; f) compressing the granules of step e) by suitable means to obtain the tablet, or filling the granules into capsules.

[0112] In an embodiment, the present disclosure provides that the method further comprises screening the dried granules of step d) through a mesh of appropriate size to obtain uniformly sized granules prior to step e).

[0113] In an additional embodiment the present invention provided a method of preparing a mono-layered pharmaceutical tablet comprising flavoxate or pharmaceutically acceptable salt thereof and at least one p3-adrenergic receptor agonist comprising: a) blending required quantities of at least one P3 -adrenergic receptor agonist and flavoxate or pharmaceutically acceptable salt thereof with pharmaceutically acceptable excipients to obtain a dry blended mixture; b) optionally screening the blended mixture of step a) through a mesh of appropriate size to obtain screened mixture; c) granulating the blended mixture of step a), or screened mixture of step b) by suitable means to obtain wet granules; d) drying the wet granules of step c) by suitable means at a suitable temperature to obtain dried granules; e) optionally screening the dried granules of step d) through a mesh of appropriate size to obtain screened dried granules; f) lubricating the dried granules of steps d) or e), with at least one extra-granular excipient and at least one lubricant to obtain lubricated granules; g) compressing the granules of step f) by suitable means to obtain the tablet.

[0114] In an embodiment the method comprises coating the granules of any one of steps c) to f) with a polymer dispersion to obtain polymer-coated modified-release granules.

[0115] In a yet another embodiment, the present disclosure provides that the pharmaceutically acceptable excipient of step a) or the extra-granular excipient of step e) in the method is selected from one or more of filler, disintegrant, binder, surfactant, controlled-release polymer, lubricant, glidant, diluent, antioxidant, pH modifier, antisticking agent, or coating agent.

[0116] In a still another embodiment, the method further comprising coating the tablets with film to obtain weight build-up of around 1 to 4% w / w.

[0117] In a further embodiment, the tablet obtained by the method has a hardness of about 5 kg / cm2to about 50 kg / cm2.

[0118] In another embodiment, the present disclosure provides a method for the preparation of a capsule comprising at least one p3-adrenergic receptor agonist and flavoxate or a salt thereof, the method comprising: a) preparing at least one tablet comprising at least one p3-adrenergic receptor agonist; b) preparing at least one tablet comprising flavoxate; c) preparing the capsule comprising the tablets of step a) and step b); d) optionally adding one or more pharmaceutically acceptable excipients in steps a) and b); e) optionally preparing the capsule in the step c) by adding one or more pharmaceutically acceptable excipients.

[0119] In a still another embodiment, the present disclosure provides a method of treating and / or ameliorating at least one symptom of benign prostatic hyperplasia, benign prostatic enlargement, detrusor overactivity, overactive bladder, bladder outlet obstruction, lower urinary tract symptoms due to bladder dysfunction or neurogenic bladder, chronic prostatitis / chronic pelvic pain syndrome, or post-operative irritative voiding symptoms, comprising administering a formulation of the present disclosure.

[0120] In a yet another embodiment, the present disclosure provides use of the formulation of the present disclosure for the treatment, alleviation, amelioration and / or prevention of at least one of benign prostatic hyperplasia, benign prostatic enlargement, detrusor overactivity, overactive bladder, bladder outlet obstruction, lower urinary tract symptoms due to bladder dysfunction or neurogenic bladder, chronic prostatitis / chronic pelvic pain syndrome, or post-operative irritative voiding symptoms, and / or one or more symptoms associated therewith.

[0121] In an additional embodiment, the present disclosure provides use of the formulations of the present disclosure in the preparation of a medicament for the treatment, alleviation, amelioration and / or prevention of at least one of benign prostatic hyperplasia, benign prostatic enlargement, detrusor overactivity, overactive bladder, bladder outlet obstruction, lower urinary tract symptoms due to bladder dysfunction or neurogenic bladder, chronic prostatitis / chronic pelvic pain syndrome, or post-operative irritative voiding symptoms, and / or one or more symptoms associated therewith.

[0122] DETAILED DESCRIPTION OF DISCLOSURE

[0123] The present disclosure provides FDC oral pharmaceutical formulations comprising flavoxate (and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, esters, prodrugs or derivatives thereof) and at least one P3 -adrenergic receptor agonist (as pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs or derivatives thereof), and methods for preparing and using such combinations. The disclosed FDC pharmaceutical formulations may provide for IR, MR, and / or combinations thereof for one or both actives. The desired release rate or drug release profile may vary dependent on the intended use, therapeutic purpose, and therapeutic amount or frequency of administration.

[0124] Definitions:

[0125] Unless otherwise indicated, the following definitions apply throughout the specification:

[0126] Fixed-dose combination” (FDC) means a single unit oral dosage form containing defined amounts of flavoxate and at least one p3-adrenergic receptor agonist. “Flavoxate” includes flavoxate and pharmaceutically acceptable salts, acid addition salts (for example flavoxate hydrochloride), solvates, hydrates, polymorphs, cocrystals, esters, prodrugs, stereoisomers and derivatives thereof. Flavoxate hydrochloride is a preferred salt.

[0127] “P3 -adrenergic receptor agonist” (also known as beta-3 adrenergic agonists or beta-3 adrenergic receptor stimulants) includes mirabegron, solabegron, ritobegron, and vibegron and other P3 -adrenergic receptor agonists, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof. P3- adrenergic receptor agonist (for example mirabegron) are preferred in certain embodiments.

[0128] The term "modified release" applies to dosage forms, matrices, particles, coatings, portions, or compositions that alter the release of an active ingredient in any manner, including prolonged, sustained, extended, or delayed release, and other similar methods. As used herein, the terms "modified-release," "controlled-release," "sustained-release," “extended-release” and "delayed-release" are used interchangeably to describe a pharmaceutical formulation or dosage form that is designed to release the active ingredient(s) at a controlled rate over an extended period, rather than immediately upon administration. These formulations are intended to maintain therapeutic plasma concentrations within a desired range for a prolonged duration, reducing the frequency of dosing and improving patient compliance. The terms refer to various strategies for achieving controlled or delayed release profiles, which may include but are not limited to, the use of polymers, matrix systems, or coatings that regulate the rate of drug release.

[0129] “Pharmaceutically acceptable” salt, solvate, hydrate, polymorph, co-crystal, ester, prodrug, or derivative refers to any non-toxic chemical form of the stated compound that retains pharmacological activity and is suitable for pharmaceutical use in humans and animals.

[0130] A pharmaceutically acceptable salt refers to a salt form of a compound that retains the desired biological activity and is non-toxic when administered to a subject. Such salts are commonly used to improve properties like solubility, stability, bioavailability, and ease of formulation. For flavoxate hydrochloride, the hydrochloride salt is itself a pharmaceutically acceptable salt. Other acid addition salts may include salts with sulfuric acid, citric acid, maleic acid, fumaric acid, and the like. A “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. The pharmaceutically acceptable salt of flavoxate include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and the like; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, and the like. It is understood that the pharmaceutically acceptable salts are nontoxic.

[0131] A preferable pharmaceutically acceptable salt of flavoxate is flavoxate hydrochloride. For p 3 -adrenoceptor agonists, acceptable salts include but are not limited to salts formed with mineral acids (e.g., hydrochloric, hydrobromic, sulfuric, phosphoric) or organic acids (e.g., acetic, citric, tartaric, methanesulfonic, benzenesulfonic).

[0132] A hydrate refers to a form of the active pharmaceutical ingredient (API) or its salt that incorporates water molecules into its crystalline structure. Hydrated forms may affect the solubility, stability, and bioavailability of the compound, one example may be flavoxate hydrochloride monohydrate.

[0133] A solvate refers to a crystalline form of a compound or its salt that includes solvent molecules other than water. If the solvent is water, the solvate is specifically termed a hydrate. Solvents may include ethanol, methanol, isopropanol, acetone, ethyl acetate, and the like, provided the resulting solvate is pharmaceutically acceptable. The non-limiting examples may be ethanol solvate of a P3 -adrenoceptor agonist.

[0134] Polymorphs refer to different crystalline forms of the same chemical compound. These forms may differ in physical properties such as melting point, solubility, and bioavailability. The present disclosure includes all pharmaceutically acceptable polymorphic forms of flavoxate hydrochloride and the P3 -adrenoceptor agonist(s), whether metastable or stable under physiological conditions.

[0135] Co-crystals are crystalline structures composed of the active compound and one or more neutral co-formers (e.g., pharmaceutically acceptable excipients) bound in a definite stoichiometric ratio through non-covalent interactions (e.g., hydrogen bonding). The nonlimiting examples of co-crystals of flavoxate may be with benzoic acid or nicotinamide. Co-crystals may be used to improve physicochemical or pharmacokinetic properties such as dissolution rate or chemical stability.

[0136] Esters of the active compound refer to derivatives formed by the reaction of the parent compound with an acid or alcohol. Esters must be pharmaceutically acceptable, non-toxic, and hydrolyzable to the active compound in the body. Esters may act as prodrugs that are hydrolyzed in vivo to release the active parent compound. The nonlimiting examples of ester derivatives of flavoxate may be used to modify absorption profiles or improve lipophilicity.

[0137] A prodrug is a compound that is converted in vivo, by enzymatic or chemical processes, into the active drug. Prodrugs are often used to overcome limitations such as poor solubility, stability, or bioavailability of the parent compound. Prodrugs of flavoxate or p 3 -adrenoceptor agonists may be ester-based, amide-based, or other masked forms of functional groups that regenerate the active moiety after administration.

[0138] “Immediate release (IR)” denotes a dosage form that releases a substantial portion of an API within about 1-60 minutes after administration.

[0139] “Modified release (MR)” denotes sustained, extended, prolonged, controlled or delayed release (for example release over about 12-24 hours), and includes any non- immediate release kinetic profile specifically described herein.

[0140] “Pharmaceutically acceptable excipient” or “carrier” means diluents, binders, disintegrants, lubricants, glidants, surfactants, coating agents and polymers, including pharmaceutically acceptable grades, salts, hydrates, solvates and derivatives of the excipients recited herein.

[0141] “Total unit weight” means the combined mass of a coated or uncoated dosage unit and is the reference base for % w / w values unless otherwise specified.

[0142] “Therapeutically effective amount” or “effective amount” means an amount sufficient to achieve the intended therapeutic effect. The term “effective amount” means the amount of a drug or pharmaceutical agent, or that amount of a combination of drugs or pharmaceutical agents that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term “therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder, as was known in the art as of the date of the present disclosure. The term also includes within its scope amounts effective to enhance normal physiological function, as was known in the art as of the date of the present disclosure.

[0143] The term "excipient" or "pharmaceutically acceptable excipients" refers to pharmacologically inactive components useful in preparing dosage forms, generally safe and non-toxic for both veterinary and human pharmaceutical use. “A pharmaceutically acceptable carrier / excipient” as used in the specification and claims includes both one and more than one such carrier or excipient.

[0144] The term ‘pharmaceutically acceptable excipient’ includes excipients, their pharmaceutically acceptable salts, hydrates, solvates and derivatives.”

[0145] As used herein, the terms “P3-adrenergic receptor agonist,” “beta-3 adrenergic agonists,” and “beta-3 adrenergic receptor stimulants,” are used interchangeably and are intended to refer to agents that activate P3 -adrenergic receptors, which are part of the adrenergic receptor family. As used herein, unless specifically stated otherwise, these terms may be used interchangeably to refer to any p3-adrenergic receptor agonists having promising therapeutic roles in treating overactive bladder, obesity, and potentially metabolic diseases. Their effects are primarily due to their ability to activate P3 receptors and trigger relaxation of smooth muscles or influence metabolic processes. In certain embodiments, pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, esters, prodrugs and derivativesof these agents may also be employed.

[0146] The term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass ± 20%, preferably ± 10%, more preferably ± 5%, most preferably ± 1%, the recited value and the range is included.

[0147] “Treating” or “treatment” of a disease or condition includes:

[0148] (1) preventing the disease or condition, i.e. causing the clinical symptoms of the disease or condition not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease or condition;

[0149] (2) inhibiting the disease or condition, i.e., arresting or reducing the development of the disease or condition or clinical symptoms thereof; or

[0150] (3) relieving the disease or condition, i.e., causing regression of the disease or condition or clinical symptoms thereof.

[0151] "Stable" means that tablets comply with dissolution specifications in a 6-month stability study at accelerated conditions of about 40°C and about 75% RH or long-term conditions of about 25 to 30°C and about 60 to 75% RH.

[0152] The term "total weight" refers to the combined weight of the coated and / or uncoated tablet. In certain embodiments of the present disclosure, the pharmaceutical compositions comprise a fixed dose combination (FDC) of P3-adrenergic receptor agonist and antispasmodics (particularly flavoxate), processes for their preparation, and their use to treat certain diseases.

[0153] As used in the present disclosure, the term "pH-dependent polymer" refers to pharmaceutically acceptable polymeric materials that exhibit solubility or permeability characteristics that vary depending on the pH of the surrounding environment. These polymers may be used in oral pharmaceutical formulations to control the site and rate of drug release in the gastrointestinal (GI) tract by responding to changes in pH from the stomach to the intestines.

[0154] As used in the present disclosure, the term "independent dissolution profile" refers to a characteristic of an oral pharmaceutical formulation comprising combination of two active APIs, such as flavoxate or a pharmaceutically acceptable salt and P3 -adrenergic receptor agonist or a pharmaceutically acceptable salt, in which each API and / or each functional layer (e.g., immediate-release and modified-release) may exhibit a distinct and non-overlapping release behaviour in vitro, such that the release kinetics of one layer or active agent is not substantially influenced or altered by the presence of the other layer(s) or active agent(s).

[0155] In the context of a bi-layered or multi-layered fixed-dose combination (FDC) formulation comprising flavoxate and at least one P3-adrenergic agonist, having immediate-release (IR) and / or modified-release (MR) layers, the phrase “independent dissolution profile” is intended to mean that the release of the API(s) from the IR layer occurs rapidly upon contact with dissolution media, without being retarded or modulated by the adjacent MR layer or by excipients in other layers; or the release of the API(s) from the MR layer follows a predetermined, extended, or controlled-release pattern over a longer time interval, and is not significantly accelerated or interfered with by proximity to the IR layer; and / or where an intermediate layer is present between the IR and MR layers, it acts as a barrier layer or separation layer comprising inert excipients (e.g., polymers, waxes, or buffering agents) to minimize interaction (physical, chemical, or diffusional) between the IR and MR layers, thus preserving the designed dissolution behaviour of each functional layer.

[0156] The independence of the dissolution profiles may be verified using standard dissolution testing procedures (e.g., USP Apparatus I or II) in appropriate dissolution media, by comparing the dissolution curves of individual actives in combination versus in monotherapy or simulated layer-separated forms. Substantial overlap or unintended modification of one layer’s release profile by another would be inconsistent with the concept of independent dissolution.

[0157] As used in the present disclosure, the term “suitable” refers to the selection, application, or performance of a process parameter, material, method, or condition that is capable of achieving the intended result within the context of pharmaceutical formulation and manufacturing, as would be understood by a person skilled in the art.

[0158] In the context of the methods described in the present disclosure for the preparation of a tablet, MUPS, or capsule comprising at least one p3-adrenergic agonist and flavoxate or a pharmaceutically acceptable salt thereof, the term “suitable” is intended to encompass:

[0159] “Suitable means” for granulation or compression refers to any standard or conventional granulation or compression techniques (e.g., high-shear granulation, fluidbed granulation, dry granulation, rotary tablet compression) that effectively process the blend into granules or tablets without adversely affecting the integrity, stability, or performance of the active pharmaceutical ingredients (APIs).

[0160] “Suitable time” and “suitable temperature” for drying refer to time and temperature ranges that are sufficient to remove excess moisture from the wet granules without causing degradation, polymorphic transformation, or undesirable agglomeration of the active ingredients or excipients.

[0161] “Suitable” mesh sizes, excipients, lubricants, or process aids refer to those known in the field to be compatible with the APIs and capable of facilitating flow, compression, blend uniformity, disintegration, or dissolution as intended by the specific formulation design (e.g., for immediate-release and / or modified-release performance).

[0162] The determination of "suitability" may be guided by established pharmacopeial standards (e.g., USP, Ph. Eur.), regulatory guidelines (e.g., ICH), or empirical data derived from stability studies, dissolution profiling, pharmacokinetic evaluations, or other studies. A person skilled in the art will appreciate that such suitability may vary depending on formulation composition, equipment scale, and desired dosage form characteristics.

[0163] The term "substantial" in the context of the release profile of the dosage forms of the pharmaceutical formulations refers to the majority of the intended dose being released, typically defined as the release of at least 85% of the active ingredients within the specified time frame. For immediate-release (IR) dosage forms, this means a release of the intended dose occurring within about 1 to 60 minutes after administration. For modified- release (MR) dosage forms, "substantial release" refers to the controlled release profile that allows for the release of the active ingredients over a prolonged period, typically in the range of about 12 to 24 hours, ensuring that a significant portion of the dose is released within that time frame. This term is intended to encompass formulations where the release rate of the active ingredients is considered therapeutically effective, providing the intended pharmacological effect within the described release windows."

[0164] The terms "composition," "pharmaceutical composition," "dosage form," "solid oral composition," and "formulation" are used interchangeably to describe a combination of flavoxate and p3-adrenergic agonists in a solid oral dosage form.

[0165] The present disclosure provides a fixed dose combination of flavoxate or pharmaceutically acceptable salt thereof in an amount of about 50 mg to about 2,000 mg per unit dosage form (or total daily dose as appropriate) and at least one P3 -adrenergic agonist in an amount of about 1 mg to about 400 mg per unit dosage form (or total daily dose as appropriate). Representative flavoxate strengths include, by way of example and not limitation: 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 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, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg per unit. Representative P3-adrenergic agonist strengths include, by way of example and not limitation: 1 mg, 2 mg, 4 mg, 8 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg,

[0166] 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg,

[0167] 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg,

[0168] 235 mg, 240 mg, 245 mg, 250 mg, 300 mg, 325 mg, 350 mg, 375 mg and 400 mg per unit.

[0169] It will be noted that the actual therapeutic strengths of flavoxate and P3 -adrenergic agonist such as mirabegron, solabegron, ritobegron, and vibegron, are well known in the art and routinely prescribed at clinically established dosages. Accordingly, the present disclosure encompasses all pharmaceutically relevant dosage strengths of such P3- adrenergic agonists, whether within or outside the specific representative values recited herein.

[0170] The present disclosure pertains to a FDC formulation comprising flavoxate or a pharmaceutically acceptable salt thereof, combined with a p3-adrenergic agonist. Exemplary p3-adrenergic agonists include mirabegron, solabegron, ritobegron, and vibegron. The concentration of flavoxate in the FDC formulation ranges from 50 mg to 2000 mg per dose, while the amount of the P3 -adrenergic agonist ranges from 1 mg to 400 mg per dose.

[0171] The FDC formulation of the present disclosure exhibiting immediate-release profile comprises flavoxate (from about 100 mg to about 400 mg) and mirabegron (from about 1 mg to about 50 mg).

[0172] The FDC formulation of the present disclosure exhibiting modified-release or combination release profile comprises flavoxate (from about 300 mg to about 2000 mg) and mirabegron (from about 1 mg to about 100 mg).

[0173] A FDC formulation of the present disclosure exhibiting immediate-release profile comprises flavoxate (from about 100 mg to about 400 mg) and solabegron (from about 1 mg to about 150 mg).

[0174] A FDC formulation of the present disclosure exhibiting modified-release or combination release profile comprises flavoxate (from about 300 mg to about 2000 mg) and solabegron (from about 1 mg to about 300 mg).

[0175] A FDC formulation exhibiting immediate-release profile comprises flavoxate (from about 100 to about 400 mg) and ritobegron (from about 1 mg to about 200 mg).

[0176] A FDC formulation exhibiting modified-release or combination release profile comprises flavoxate (from about 300 to about 2000 mg) and ritobegron (from about 1 mg to about 400 mg).

[0177] A FDC formulation exhibiting immediate-release profile comprises flavoxate (from about 100 mg to about 600 mg) and vibegron (from about 1 mg to about 75 mg).

[0178] A FDC formulation exhibiting modified-release or combination release profile comprises flavoxate (from about 300 mg to about 2000 mg) and vibegron (from about 1 mg to about 150 mg).

[0179] In certain embodiments of the present disclosure, the fixed-dose combinations comprise prophylactic or therapeutic amounts of at least one P3-adrenergic agonist and at least one antispasmodic agent in a single dosage form.

[0180] In certain embodiments of the present disclosure, the fixed-dose combinations comprise at least one p3-adrenergic agonist and at least one urinary antispasmodic agent in a single dosage form, together with one or more pharmaceutically acceptable excipients.

[0181] In certain embodiments of the present disclosure, pharmaceutical dosage forms comprise prophylactic or therapeutic amounts of at least one P3-adrenergic agonist and at least one antispasmodic agent, wherein dosage forms is in the form of a Multiple-Unit Pellet System (MUPS), tablet or capsule. In certain embodiments of the present disclosure, capsule dosage forms comprise one or more active agents formulated as pellets, granules, mini-tablets, powders, or any mixtures thereof.

[0182] In certain embodiments of the present disclosure, at least two active agents may be delivered as a single co-formulation and provide particularly beneficial therapeutic results. Co-formulations comprise two or more active pharmaceutical ingredients (APIs) combined within a single dosage form. Co-formulations have the patient-compliance advantages of reducing the number of distinct doses and fixing the ratio of the two active agents being administered.

[0183] In certain embodiments of the present disclosure, a pharmaceutical composition, particularly a solid preparation (e.g., an oral solid dosage form, such as a tablet, particularly for modified-release such as sustained drug release), comprises a first composition comprising flavoxate and one or more excipients and a second composition comprising a selected p3-adrenergic agonist and one or more excipients.

[0184] In certain embodiments of the present disclosure, said one or more pharmaceutically acceptable excipients in the FDC pharmaceutical formulation are selected from one or more of filler, disintegrants, binder, surfactant, controlled-release polymer, lubricant, glidant, diluent, antioxidant, pH modifier, anti-sticking agent, or coating agent.

[0185] The pharmaceutical composition may include one or more antioxidants to enhance the stability and shelf-life of the active pharmaceutical ingredient(s) by preventing oxidative degradation. Suitable antioxidants include but are not limited to synthetic and natural agents such as butylated hydroxy toluene (BHT), butylated hydroxy anisole (BHA), alpha-tocopherol (Vitamin E), ascorbic acid (Vitamin C), sodium metabisulphite, propyl gallate, sodium bisulphite, and glutathione. These antioxidants may be employed individually or in combination, depending on the formulation requirements and compatibility with other excipients. The concentration of the anti oxi dant(s) is optimized to achieve effective protection against oxidation without compromising the safety, efficacy, or organoleptic properties of the final pharmaceutical product.

[0186] The pharmaceutical composition may include one or more solvents to facilitate the dissolution, dispersion, or processing of the active pharmaceutical ingredient(s) and excipients. Suitable solvents include, but are not limited to, water, purified water, ethanol, isopropyl alcohol, propylene glycol, polyethylene glycol (various grades), glycerin, dimethyl sulfoxide (DMSO), and other pharmaceutically acceptable organic and inorganic solvents or co-solvents. These solvents may be employed individually or in combination, depending on the solubility profile of the active ingredient, formulation type, and desired processing characteristics. The concentration of the solvent(s) is optimized to ensure appropriate solubilization, stability, and manufacturability of the final dosage form without compromising safety or efficacy.

[0187] The pharmaceutical composition may optionally include one or more colorants to enhance the appearance, identification, or branding of the dosage form. Suitable colorants include, but are not limited to, synthetic dyes such as FD&C and D&C colors, natural colorants like iron oxides, titanium dioxide, brilliant blue, sunset yellow, tartrazine, erythrosine, annatto, and beetroot red, as well as lake pigments and organic dyes approved for pharmaceutical use. These colorants can be incorporated in various forms, including powders, dispersions, or solutions. To facilitate their uniform dispersion and application, solvents such as isopropyl alcohol, ethanol, purified water, or other pharmaceutically acceptable solvents may be employed. The choice and concentration of colorants and solvents are optimized to achieve the desired aesthetic effect without adversely affecting the stability, safety, or efficacy of the final pharmaceutical product.

[0188] The FDC formulations of the present disclosure comprise one or more of sustained release polymer, binder, diluent, surfactant, disintegrant, lubricant, glidant, or combination thereof.

[0189] The controlled-release polymer in the FDC formulations may comprises a combination of at least one hydrophilic polymer and at least one hydrophobic polymer. The weight ratio of the hydrophilic polymer to the hydrophobic polymer is in the range of about 1 : 1 to about 9: 1.

[0190] In certain embodiments, initial batches of fixed dose combination formulations were prepared from suitable grades of controlled release polymers including non-ionic soluble cellulose either, such as hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetyl succinate, hydroxypropyl cellulose, hydroxyethyl cellulose (HEC e.g., Natrosol); insoluble cellulose polymers such as Ethyl cellulose etc., non-ionic homopolymers of ethylene oxide, such as poly(ethylene oxide) with a molecular weight range of 100,000 to 8000,000; Water soluble natural gums of polysaccharides of natural origin, such as xanthan gum, alginate, and locust bean gum; Water swellable, but insoluble, high molecular weight homopolymers and copolymers of acrylic acid chemically cross-linked with poly-alkenyl alcohols with varying degree of cross-linking or particle size (Carbopol 71G NF, 97 IP, 934P); Polyvinyl acetate and povidone mixture (e.g. Kollidon SR); Cross-linked high amylose starch or Ionic methacrylate copolymers (Eudragit L30D) alone or in combination were selected.

[0191] Polyethylene glycol (PEG) is available in a wide range of molecular weights, each suited for different pharmaceutical applications. Low molecular weight PEGs, such as PEG 200 to PEG 600, are used as solvents, plasticizers, and solubilizers in oral liquids, topical creams, and injectable. Medium molecular weight PEGs, like PEG 1000 to PEG 1500, are waxy solids often employed as ointment bases, tablet binders, and suppository bases due to their semi-solid consistency. High molecular weight PEGs, such as PEG 3350 PEG 4000 and above, are solid powders used in controlled-release matrices, osmotic laxatives, and as excipients in sustained-release formulations. The choice of PEG grade depends on the desired physical properties, drug compatibility, and release profile required for the dosage form.

[0192] The controlled-release polymer in the FDC formulations of the present disclosure is selected from hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetyl succinate, hydroxyethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyethylene oxide, povidone, homo-polymers and copolymers of acrylic acid chemically cross-linked with poly-alkenyl alcohols, Ethyl cellulose, ammonio methacrylate copolymers, polyvinyl acetate, HPMC El 5, HPMC K4M, HPMC K15M, HPMC K-100M, HPMC K15, and cross-linked high amylose starch or ionic methacrylate copolymers.

[0193] The controlled-release polymer in the FDC formulations of the present disclosure further comprises at least one pH-dependent polymer in an amount of about 1.0% to 15% w / w of the formulation.

[0194] The FDCs of the present disclosure comprises at least one surfactant. As flavoxate hydrochloride is poorly soluble in water, and with high amounts of drug necessary for therapeutic effectiveness, appropriate levels of surfactants alone or in combination are used. The surfactants may, for example, comprise long alkyl chain sulfonates / sulfates such as sodium dodecylbenzene sulfonate, sodium lauryl sulphate, and dialkyl sodium sulfosuccinate, quaternary ammonium salts, fatty alcohols such as lauryl, cetyl, and stearyl, glyceryl esters, fatty acid esters, and polyoxyethylene derivatives thereof.

[0195] The diluent in FDCs of the present disclosure may, for example, comprise one or more of mannitol, sorbitol, microcrystalline cellulose, lactose, dicalcium phosphate, or starch such as maize starch, and com starch. The binder in FDCs of the present disclosure may, for example, comprise one or more of starch, polyvinylpyrrolidone, natural or synthetic gum and cellulosic polymers e.g., Ethyl cellulose, HPC, or Gelatin.

[0196] The disintegrants in FDCs of the present disclosure may, for example, comprise one or more of Starch, Sodium Starch Glycollate, Croscarmellose Sodium, or Crospovidone.

[0197] While disintegrants are usually included in the immediate -release compositions, in certain embodiments of the present disclosure, at least one disintegrant is included in the modified-release layer (MR Layer), which has surprisingly and unexpectedly helped in ensuring controlled and complete release of high dose flavoxate active from the disclosed FDC compositions. The non-limiting examples of these disintegrant may include sodium starch glycollate, croscarmellose sodium and crospovidone alone or in combination.

[0198] The amount of disintegrants in the FDC formulations of the present disclosure is present in the range of about 0.1 to 1.5 % w / w of the modified-release formulation layer.

[0199] The lubricant and / or glidant may, for example, comprise one or more of talc, colloidal silicon dioxide, stearic acid, magnesium stearate, or sodium stearyl fumarate.

[0200] The flavoxate is in the form of flavoxate hydrochloride and the pharmaceutically acceptable additives are selected from the diluents, disintegrants, glidants, lubricants, colorants, and combinations thereof.

[0201] The pH-dependent polymer in the FDC formulations of the present disclosure is selected from methacrylic acid-methyl methacrylate copolymers

[0202] The pH-dependent polymers in FDCs of the present disclosure may be employed in enteric coatings or functional membrane coatings of tablets, pellets, or granules to achieve delayed-release or site-specific release of active pharmaceutical ingredients (APIs). These polymers remain substantially insoluble in the acidic pH of the stomach (typically pH 1 to 3), but dissolve or become permeable in the neutral to alkaline pH conditions of the small intestine (typically pH 5.5 to 7.5), thereby initiating or accelerating drug release at desired intestinal sites. Examples of suitable pH-dependent polymers include, but are not limited to Methacrylic acid-methyl methacrylate copolymers, such as those commercially available under the trade name Eudragit® L100, L100-55, and S100, which dissolve at pH values above 5.5, 5.5, and 7.0, respectively; Cellulose acetate phthalate (CAP); Hydroxypropyl methylcellulose phthalate (HPMCP); Hydroxypropyl methylcellulose acetate succinate (HPMCAS); Polyvinyl acetate phthalate (PVAP); Shellac; Sodium alginate or alginic acid derivatives, which can exhibit pH-responsive gelling or solubilization behavior; Aminoalkyl methacrylate copolymers, such as Eudragit® E, which are soluble at low pH and may also be employed in reverse-release strategies.

[0203] The pH-dependent polymers in FDCs of the present disclosure may be applied to drug-containing cores (e.g., pellets, tablets, granules, or beads) using conventional coating techniques such as fluidized bed coating, pan coating, or spray-drying, optionally with plasticizers, opacifiers, anti-tacking agents, and / or pore-formers to modify mechanical and dissolution properties.

[0204] The pH-dependent polymer in FDCs of the present disclosure may be used alone or in combination with other polymers, such as hydrophilic or hydrophobic controlled- release polymers, to achieve modified-release profiles of two actives flavoxate and a P3- adrenergic receptor agonist or a pharmaceutically acceptable salt thereof, wherein an immediate-release drug profile is followed by a sustained-release, or a delayed-release followed by a controlled-release.

[0205] The coating agent in FDCs of the present disclosure is selected from one or more of polyvinylpyrrolidone, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, dextrin, maltodextrin, lactose, D-mannitol, polyvinyl alcohol polymer, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, ethyl acrylate methyl methacrylate copolymer, plasticizer, antitacking agent, opacifier, and coloring agent.

[0206] Methods for the preparation of FDCs of the present disclosure:

[0207] In certain embodiments, the pharmaceutical compositions described above herein can be made using conventional equipment well-known in the art.

[0208] A method for the preparation of a bi-layered or multi-layered tablet, MUPS, or capsule of flavoxate or pharmaceutically acceptable salt thereof and at least one P3- adrenergic receptor agonist comprising: a) blending required quantities of at least one 3-adrenergic receptor agonist and flavoxate or a pharmaceutically acceptable salt thereof, along with one or more pharmaceutically acceptable excipients, to obtain a dry blend mixture separately for one or more of immediate-release (IR) and / or modified-release (MR) layers; b) optionally passing the blend mixture of IR and / or MR layers of step a) through a screen having a mesh of appropriate size to obtain a uniformly sized particulate mixture for each layer; c) granulating the uniformly sized particulate mixture of IR and / or MR layers of step b), or the blend mixture of step a), by suitable means to obtain wet granules; d) drying the wet granules of step c) for a suitable time and at a suitable temperature to obtain dried granules of IR and / or MR layers; e) optionally screening the dried granules of step d) through a mesh of appropriate size to obtain uniformly sized granules; f) lubricating the dried granules of step d) or e), with at least one extra-granular excipient and at least one lubricant to obtain lubricated granules; g) compressing the granules of step e) by suitable means to obtain the tablet, or filling the granules into capsules.

[0209] The pharmaceutically acceptable excipients in step a) may include one or more of filler, disintegrant, binder, surfactant, controlled-release polymer, lubricant, glidant, diluent, antioxidant, anti-sticking agent, or coating agent in appropriate concentrations.

[0210] The wet granulation in the method may be performed by using high shear granulator of required capacity. The granules may be dried using fluidized bed dryer at a suitable temperature and screened through a mesh of appropriate size.

[0211] The tablets may be obtained by compressing granules using rotary tablet compression machine.

[0212] The method further comprises coating the granules of any one of steps c) to f) with a polymer dispersion to obtain polymer-coated modified-release granules.

[0213] A method of preparing a mono-layered pharmaceutical tablet comprising flavoxate or pharmaceutically acceptable salt thereof and at least one P3 -adrenergic receptor agonist comprising: a) blending required quantities of flavoxate or pharmaceutically acceptable salt thereof and at least one p3-adrenergic receptor agonist with pharmaceutically acceptable excipients to obtain a dry blended mixture; b) optionally screening the blended mixture of step a) through a mesh of appropriate size to obtain screened mixture; c) granulating the blended mixture of step a) or screened mixture of step b) by suitable means to obtain wet granules; d) drying the wet granules of step c) by suitable means at a suitable temperature to obtain dried granules; e) lubricating the dried granules of step d), with at least one extra-granular excipient and at least one lubricant to obtain lubricated granules; f) compressing the granules of step e) by suitable means to obtain the tablet.

[0214] The method may further comprise screening the dried granules of step d) through a mesh of appropriate size to step e). The method may further comprise coating the granules of any one of steps c) to e) with a polymer dispersion to obtain polymer-coated modified- release granules.

[0215] The pharmaceutically acceptable excipient or the extra-granular excipient in the methods above are selected from one or more of filler, disintegrant, binder, surfactant, controlled-release polymer, lubricant, glidant, diluent, antioxidant, pH modifier, antisticking agent, or coating agent.

[0216] The methods may further comprise coating the tablets with film to obtain weight build-up of around 1 to 4% w / w.

[0217] The methods may further comprise adjusting hardness of the compressed tablets in the range of 5 kg / cm2to 50 kg / cm2, depending on the strength of the tablets.

[0218] The methods of the present disclosure employs mesh size of sieve of about 1-80 mesh (ASTM / BSS).

[0219] The methods of the present disclosure comprise granulating at about 50 to 400 rpm with chopper at about 50 to 2500 rpm.

[0220] The methods of the present disclosure comprise isopropyl alcohol, water or mixture thereof in ratio of IPA: water from about 05:95 to 95:05, preferably 20:80 to 70:30.

[0221] The methods of the present disclosure comprise drying at a temperature of about 20 to 80 °C.

[0222] A method for the preparation of a capsule comprising at least one P3 -adrenergic receptor agonist and flavoxate or a salt thereof, the method comprising: a) preparing at least one tablet or granules comprising at least one p3-adrenergic receptor agonist; b) preparing at least one tablet or granules comprising flavoxate; c) preparing the capsule comprising the tablets or granules of step a) and step b); d) optionally adding one or more pharmaceutically acceptable excipients in steps a) and b); e) optionally preparing the capsule in the step c) by adding one or more pharmaceutically acceptable excipients.

[0223] The present disclosure provides FDC formulations exhibiting IR, MR, or combinations thereof of at least one P3 -adrenoceptor agonist (also known as beta-3 adrenergic agonists, p3-agonists, P3 receptor agonists, P3 -adrenomimetics) with flavoxate or pharmaceutically acceptable salts, acid addition salts (for example flavoxate hydrochloride), solvates, hydrates, polymorphs, co-crystals, esters, prodrugs, stereoisomers and derivatives thereof.

[0224] In certain embodiments, the present disclosure relates to pharmaceutical combinations comprising a p3-adrenergic receptor agonist and flavoxate, and uses thereof. In certain embodiments, suitable p3-adrenoceptor agonists include, but are not limited to, mirabegron, solabegron, ritobegron and vibegron. In certain embodiments, the P3 adrenoceptor agonists may be present as pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof.

[0225] In one embodiment, the pharmaceutical composition comprises a fixed-dose combination of:

[0226] (a) flavoxate hydrochloride or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, ester, or prodrug thereof, and

[0227] (b) at least one P3 -adrenoceptor agonist or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, ester, or prodrug thereof.

[0228] In various embodiments, the flavoxate hydrochloride may be present as flavoxate hydrochloride monohydrate, an ester prodrug of flavoxate, a co-crystal of flavoxate with a pharmaceutically acceptable co-former, a polymorphic form of flavoxate hydrochloride with improved solubility.

[0229] In various embodiments, the P3 -adrenoceptor agonist may be selected from mirabegron, solabegron, ritobegron, vibegron, or other pharmaceutically acceptable P3- agonists, in the form of their hydrochloride or fumarate salts, their hydrate or solvate forms, ester-based prodrugs of such agonists. All such forms are included within the scope of the present disclosure unless otherwise specified or excluded.

[0230] In one embodiment, the P3 -adrenoceptor agonist is mirabegron hydrochloride, a pharmaceutically acceptable salt form which improves solubility and stability. Other salts include fumarate, maleate, citrate, or phosphate salts. In another embodiment, the P3- adrenoceptor agonist is mirabegron monohydrate or dihydrate, which may alter pharmacokinetic properties or improve manufacturing characteristics. In certain embodiments, mirabegron is present as a pharmaceutically acceptable solvate, such as an ethanol solvate or isopropanol solvate. In one embodiment, the mirabegron is present in a specific crystalline polymorphic form, such as Form A, Form B, or Form C, as disclosed in known literature or proprietary data, each having distinct melting point, stability, or solubility profiles. In some embodiments, mirabegron is administered as a co-crystal with pharmaceutically acceptable co-formers such as benzoic acid, nicotinamide, or succinic acid, which may enhance dissolution or shelf-life. In one embodiment, mirabegron is provided as an ester derivative, such as an acetate or carbonate ester, which acts as a prodrug and undergoes in vivo hydrolysis to release active mirabegron. In another embodiment, a prodrug of mirabegron is used, where the molecule is chemically modified to improve oral bioavailability or tissue targeting, and is subsequently converted to active mirabegron after administration.

[0231] In one embodiment, solabegron is present as solabegron hydrochloride, or other pharmaceutically acceptable acid addition salts such as mesylate or besylate. In a further embodiment, solabegron may exist as a hydrate, for example, the monohydrate or hemihydrate form, which may be advantageous in terms of stability or processing. In another embodiment, solabegron is provided as a solvate, such as a methanol or ethanol solvate. In certain embodiments, solabegron is provided in a polymorphic form having improved or altered physicochemical characteristics. Such forms may be characterized by unique XRPD or DSC profiles. In one embodiment, solabegron is administered in a cocrystal form with a suitable co-former such as saccharin, tartaric acid, or malic acid to improve solubility or taste-masking. In some embodiments, solabegron is provided as a short-chain ester, such as an ethyl ester, serving as a prodrug that releases solabegron upon enzymatic cleavage. In further embodiments, solabegron prodrugs are used, for example, by conjugating a promoiety to the phenol or hydroxyl group to enhance absorption or tissue selectivity.

[0232] In one embodiment, ritobegron is present as ritobegron hydrochloride, sulfate, or maleate, offering improved aqueous solubility. In another embodiment, ritobegron is present as a monohydrate or dihydrate, which may affect dissolution behavior. In some embodiments, ritobegron is used in solvated form, such as ethanol, acetone, or DMF solvates, subject to pharmaceutically acceptable toxicity limits. Ritobegron may exist in multiple crystalline polymorphs, each offering different dissolution and processing characteristics. These polymorphs may be produced via controlled crystallization methods. In one embodiment, ritobegron forms a co-crystal with pharmaceutically acceptable co- formers like oxalic acid or glutaric acid, enhancing shelf life or bioavailability. In a further embodiment, ritobegron is derivatized into esters, such as acetate or propionate esters, acting as prodrugs that convert in vivo to the active parent compound. Prodrugs of ritobegron include derivatives where hydroxyl groups are masked with cleavable groups that enable improved intestinal absorption and controlled release.

[0233] In one embodiment, vibegron is present as vibegron hydrochloride, mesylate, or fumarate, enhancing solubility and bioavailability. In another embodiment, the P3- adrenoceptor agonist is vibegron monohydrate, or other hydrated forms, suitable for tablet or capsule formulations. In certain embodiments, vibegron is present as a solvate, such as an ethanol or isopropanol solvate, obtained during crystallization. In one embodiment, vibegron is present in a specific polymorphic form, which may be optimized for pharmaceutical processing, storage, or dissolution. These forms may be characterized via PXRD and thermal analysis. In some embodiments, vibegron is administered as a cocrystal with suitable co-formers like caffeic acid, nicotinamide, or vanillic acid, improving taste masking or bioavailability. Vibegron may be formulated as an ester prodrug, such as an acetate, butyrate, or other ester that is hydrolyzed in vivo to release the active parent drug. In another embodiment, vibegron is administered as a prodrug, including modifications at the phenolic hydroxyl group or secondary amine, designed to enhance tissue penetration or metabolic stability.

[0234] Unless otherwise specified, the term “P3 -adrenoceptor agonist” as used herein encompasses mirabegron, solabegron, ritobegron, and vibegron, and includes all pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, esters, and prodrugs thereof.

[0235] In various embodiments, the pharmaceutical FDC composition comprises:

[0236] (a) Flavoxate, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, ester, or prodrug thereof, in an amount ranging from 50 mg to 2000 mg, and

[0237] (b) A P3 -adrenoceptor agonist selected from mirabegron, solabegron, ritobegron, vibegron, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, ester, or prodrug thereof, in a pharmaceutically effective amount, as further defined below.

[0238] In certain embodiments, flavoxate (or a pharmaceutically acceptable derivative thereof) is present in an amount selected from 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, 1800 mg, or 2000 mg. Preferably, the flavoxate component is present in a daily dosage of 100 to 1200 mg, administered once or multiple times per day.

[0239] In embodiments where the P3-adrenergic receptor agonist is mirabegron, the FDC composition may comprise mirabegron in an amount selected from 1 mg, 2 mg, 3 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg. Preferably, the amount of mirabegron is in the range of 25 mg to 75 mg, either in a single daily dose or in divided doses.

[0240] In embodiments where the P3-agonist is solabegron, the FDC composition may comprise solabegron in an amount selected from 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, or 400 mg. Preferred amounts include 100 mg to 300 mg, once or twice daily depending on formulation design.

[0241] In embodiments where the P3 -agonist is ritobegron, the FDC composition may comprise ritobegron in an amount selected from 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg. Preferably, ritobegron is present in an amount of 40 to 80 mg, per unit dose or per daily regimen.

[0242] In some embodiments where the P3 -agonist is vibegron, the FDC composition may comprise vibegron in an amount selected from 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, or 75 mg. A preferred amount of vibegron is 50 to 75 mg, administered once daily.

[0243] In various embodiments, the FDC composition is formulated to provide immediate release (IR), modified release (MR), or combination release profiles for one or both of the active agents.

[0244] In some embodiments, the FDC composition is an IR oral dosage form (e.g., tablet, capsule, granule, suspension) wherein both flavoxate and the P3 -adrenoceptor agonist are released rapidly upon administration to enable prompt onset of action. Such FDC formulations are suitable for patients requiring quick relief from urinary urgency, frequency, or incontinence.

[0245] In some embodiments, the exemplary FDC formulations may comprise 50 to 800 mg of flavoxate and 25 to 50 mg of mirabegron 25 mg as IR tablet or capsule.

[0246] In some embodiments, the exemplary FDC formulations may comprise 50 to 800 mg of flavoxate and 25 to 75 mg of vibegron as IR tablet or capsule. In some embodiments, the exemplary FDC formulations may comprise 50 to 800 mg of flavoxate and 75 to 250 mg of solabegron as IR tablet or capsule.

[0247] In some embodiments, the exemplary FDC formulations may comprise 50 to 800 mg of flavoxate and 10 to 200 mg of ritobegron as IR tablet or capsule.

[0248] In some embodiments, the FDC composition is formulated for modified release, which includes MR (sustained drug release over 12-24 hours), delayed release (release begins after a predetermined time), or controlled release (steady plasma concentrations over a defined period).

[0249] In some embodiments, the exemplary FDC formulations may comprise 400 to 2000 mg of flavoxate and 25 to 100 mg of mirabegron 25 mg as MR tablet or capsule.

[0250] In some embodiments, the exemplary FDC formulations may comprise 400 to 2000 mg of flavoxate and 25 to 150 mg of vibegron as MR tablet or capsule.

[0251] In some embodiments, the exemplary FDC formulations may comprise 400 to 2000 mg of flavoxate and 75 to 400 mg of solabegron as MR tablet or capsule.

[0252] In some embodiments, the exemplary FDC formulations may comprise 400 to 2000 mg of flavoxate and 10 to 400 mg of ritobegron as MR tablet or capsule.

[0253] In some embodiments, the FDC composition is formulated for combination (dual or biphasic) release profiles. In some embodiments, the composition is a biphasic or combination release formulation, wherein one of the actives is released immediately, and the other is released in a controlled or delayed manner; or both actives are formulated with dual-release layers (e.g., bilayer tablets or multi -particulate capsules).

[0254] In some embodiments, the FDC composition is formulated as bi-layered tablet, granules for capsule, mini -tablets for capsules wherein IR portion has flavoxate 100 mg to 400 mg and optionally the 1 mg to 100 mg of P3-adrenergic receptor agonist; and the MR portion optionally has flavoxate 300 mg to 1500 mg and 5 mg to 400 mg of P3-adrenergic receptor agonist.

[0255] In some embodiments, the FDC of the present disclosure provides IR profile wherein substantial amount of drug is released in about 1 to 60 minutes.

[0256] In certain embodiments, the FDC of the present disclosure provides MR or combination of IR and MR profile such as extended drug release over 12-24 hours and stable plasma profiles.

[0257] In one embodiment, the formulation comprises flavoxate and mirabegron in an oral solid dosage form that exhibits either an IR profile or a MR profile. In another embodiment, the formulation comprises flavoxate and solabegron in an oral solid dosage form that exhibits either an IR or MR profile.

[0258] In yet another embodiment, the formulation comprises flavoxate and ritobegron in an oral solid dosage form that exhibits either an IR or MR profile.

[0259] In a further embodiment, the formulation comprises flavoxate and vibegron in an oral solid dosage form that exhibits either an IR or MR profile.

[0260] Each of the above may include the p3-adrenergic receptor agonist as a pharmaceutically acceptable salt or ester, such as mirabegron hydrochloride, solabegron mesylate, ritobegron fumarate, or vibegron acetate.

[0261] In one embodiment, the formulation comprises flavoxate and mirabegron hydrochloride, wherein the oral solid dosage form exhibits both an IR portion and / or a MR portion.

[0262] In another embodiment, the formulation comprises flavoxate and solabegron mesylate in a biphasic oral solid dosage form exhibiting both IR and MR.

[0263] Similarly, the formulation may include ritobegron fumarate or vibegron acetate, combined with flavoxate, in a dosage form with dual-release characteristics.

[0264] In certain embodiments, the flavoxate is incorporated into the IR portion of the oral dosage form, while mirabegron (or other p3-adrenergic receptor agonist) may be present in either or both the IR and MR portions.

[0265] Optionally, a portion of the flavoxate is also included in the modified-release portion, for example, to sustain antispasmodic activity over an extended period.

[0266] In one embodiment, flavoxate is present in the IR and MR portions in a ratio of about 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1:8.

[0267] In one embodiment, flavoxate is present in the IR and MR portions in a ratio of about 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1:8 and all possible ratio in between, with each ratio optionally varying by about ±0.1. Accordingly, the possible values of the ratio include about 1:0.9, about 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.0, 1:3.1, 1:3.2, 1:3.3,

[0268] 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4.0, 1:4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6, 1:4.7,

[0269] 1:4.8, 1:4.9, 1:5.0, 1:5.1, 1:5.2, 1:5.3, 1:5.4, 1:5.5, 1:5.6, 1:5.7, 1:5.8, 1:5.9, 1:6.0, 1:6.1,

[0270] 1:6.2, 1:6.3, 1:6.4, 1:6.5, 1:6.6, 1:6.7, 1:6.8, 1:6.9, 1:7.0, 1:7.1, 1:7.2, 1:7.3, 1:7.4, 1:7.5,

[0271] 1:7.6, 1:7.7, 1:7.8, 1:7.9, or 1:8.0. This embodiment applies whether the p3-adrenergic receptor agonist is mirabegron, solabegron, ritobegron, or vibegron, and regardless of whether the P3-adrenergic receptor agonist itself is IR or MR. In another embodiment, the oral dosage form further comprises a P3-adrenergic receptor agonist. The P3-adrenergic receptor agonist is present in the MR portion, optionally with a portion in the IR portion. This embodiment applies to formulations containing flavoxate and any of mirabegron hydrochloride, solabegron mesylate, ritobegron fumarate, or vibegron acetate.

[0272] In some embodiments, the P3-adrenergic receptor agonist is present in the IR and MR portions in a ratio selected from 1:1, 1:2, 1:3, 1:4, 1:5, 1 :6, 1 :7, or 1 :8 and all possible ratio in between, with each ratio optionally varying by about ±0.1. Accordingly, the possible values of the ratio include about 1:0.9, about 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.0, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4.0, 1:4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6, 1:4.7, 1:4.8, 1:4.9, 1:5.0, 1:5.1, 1:5.2, 1:5.3, 1:5.4, 1:5.5, 1:5.6, 1:5.7, 1:5.8, 1:5.9, 1:6.0, 1:6.1, 1:6.2, 1:6.3, 1:6.4, 1:6.5, 1:6.6, 1:6.7, 1:6.8, 1:6.9, 1:7.0,

[0273] 1:7.1, 1:7.2, 1:7.3, 1:7.4, 1:7.5, 1:7.6, 1:7.7, 1:7.8, 1:7.9, or 1:8.0. This embodiment allows tailored P3 -adrenergic receptor agonist plasma profiles to match flavoxate pharmacodynamics.

[0274] In certain embodiments, flavoxate or a pharmaceutically acceptable salt is present in the IR portion at about 2.5% to 100% w / w of the total flavoxate content, and MR portion at about 0% to 97.5% w / w. Applies to all p3-adrenergic receptor agonist combinations and release profiles.

[0275] In certain embodiments, the P3-adrenergic receptor agonist is present in the IR portion at about 0% to 100% w / w, and MR portion at about 0% to 100% w / w, provided the total equals 100% of the administered dose.

[0276] This embodiment provides flexibility in optimizing the pharmacokinetic profile of P3-adrenergic receptor agonists to align with the action of p3-agonists and flavoxate.

[0277] The present disclosure of FDC pharmaceutical formulations may provide for IR of both actives i.e. within 1 to 60 minutes after administration, for slow or sustained release, i.e. a release within 12-24 hours, and / or combination of IR and MR profiles. The desired release rate may vary dependent on the intended use, therapeutic purpose, and therapeutic amount or frequency of administration .

[0278] In certain embodiments, the disclosed combinations include modified-release fixed dose combinations of at least one P 3 -adrenoceptor agonist with flavoxate or a salt thereof, immediate and / or extended drug release over 12-24 hours and stable blood plasma profiles. This combination enhances efficacy and reduces side effects compared to at least one P 3 -adrenoceptor agonist combined with anticholinergic drugs, potentially minimizing cardiovascular issues, constipation, dry mouth, blurred vision, and urinary retention.

[0279] The present disclosure provides the FDC of at least one P3 -adrenoceptor agonist and flavoxate or pharmaceutically acceptable salt or ester thereof. The FDC comprises in the dose range of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1500 mg or 2000 mg of flavoxate active per day, and in the dose range of 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg or 250 mg, 300 mg or 350 mg or 400 mg of P3 adrenoceptor agonist per day, respectively.

[0280] In an embodiment, the FDC comprises flavoxate pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof in an amount of about 50 mg to about 2000 mg, and at least one P3 -adrenergic receptor agonist selected from mirabegron, solabegron, ritobegron, or vibegron or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof in an amount of about 1 mg to about 400 mg, wherein the dosage form is selected from immediate-release, sustained-release, controlled-release, modified-release, extended-release, or a combination thereof, and formulated as a mono-layered, bi-layered, or multi-layered tablet, capsule, or MUPS.

[0281] In another embodiment, the FDC comprises flavoxate as pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof in 300 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, or 1500 mg in modified-release portion together with mirabegron 12.5 mg, 25 mg, 50 mg or 75 mg modified-release portion, administered once daily.

[0282] In another embodiment, the FDC comprises flavoxate as pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof in an amount of 300 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, or 1500 mg in modified-release portion and vibegron 25 mg, 50 mg or 75 mg immediate-release portion, administered once daily.

[0283] In a further embodiment, the FDC comprises flavoxate as pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof in an amount of about 50 to 2000 mg; and solabegron from about 1 mg to about 300 mg per day, wherein the dosage form is selected from immediate-release, modified-release, or a combination thereof. In another embodiment, the FDC comprises flavoxate as pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof in an amount of about 50 to about 2000 mg; and ritobegron from about 1 mg to about 400 mg per day, wherein the dosage form is selected from immediate- release, modified-release, or a combination thereof.

[0284] The FDC formulation of the present disclosure exhibiting immediate-release profile comprises flavoxate or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof from about 100 mg to about 400 mg; and mirabegron or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof from about 1 mg to about 50 mg.

[0285] The FDC formulation of the present disclosure exhibiting modified-release or combination release profile comprises flavoxate or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof from about 300 mg to about 2000 mg; and mirabegron or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof from about 1 mg to about 100 mg.

[0286] The FDC formulation of the present disclosure exhibiting immediate-release profile comprises flavoxate or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof from about 100 mg to about 400 mg; and solabegron or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof from about 1 mg to about 150 mg.

[0287] The FDC formulation of the present disclosure exhibiting modified-release or combination release profile comprises flavoxate or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof from about 300 mg to about 2000 mg; and solabegron or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof from about 1 mg to about 300 mg.

[0288] The FDC formulation exhibiting immediate-release profile comprises flavoxate or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof from about 50 to about 400 mg; and ritobegron or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof from about 1 mg to about 200 mg. The FDC formulation exhibiting modified-release or combination release profile comprises flavoxate or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof from about 300 to about 2000 mg; and ritobegron or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, esters, prodrugs and derivatives thereof from about 1 mg to about 400 mg.

[0289] The FDC formulation exhibiting immediate-release profile comprises flavoxate or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof from about 100 mg to about 600 mg; and vibegron or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof from about 1 mg to about 75 mg.

[0290] The FDC formulation exhibiting modified-release or combination release profile comprises flavoxate or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, esters, prodrugs and derivatives thereof from about 300 mg to about 2000 mg; and vibegron or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, esters, prodrugs and derivatives thereof from about 1 mg to about 150 mg.

[0291] In certain embodiments, the present disclosure also provides an improved method of treating overactive bladder, wherein the method comprises administering to a patient in need thereof a beta-3 adrenergic receptor agonist, and flavoxate or a salt thereof, in a fixed-dose combination. In certain embodiments, P3 adrenoceptor agonists employed in the present disclosure include, but are not limited to, mirabegron, solabegron, ritobegron and vibegron. In certain embodiments, the present disclosure provides fixed-dose combinations of flavoxate or a salt thereof and at least one P3 adrenoceptor agonist as a single ingestible dosage form by successfully overcoming the sticking property and poor compressibility characteristics of flavoxate API.

[0292] In the initial development studies, Mirabegron inclusion in a fixed-dose combination with flavoxate or salt thereof significantly reduced drug dissolution release rates of flavoxate. The Table 1 below shows the significant fall in dissolution rates when flavoxate and mirabegron actives are combined together compared to a formulation containing only flavoxate. Table 1

[0293] Another challenge encountered during the initial development studies was the physical and chemical incompatibility of mirabegron when mixed with flavoxate along with other excipients used in the pre-formulation development studies. The details of one of the trial batches are given in Table 2 below.

[0294] Table 2

[0295] After accelerated stability conditions (at about 40°C and about 75% RH), there were yellow-colored stains observed on the surface of the MR layer of the tablets. In addition to the physical discoloration, a significant increase in impurity levels was also observed for both flavoxate and mirabegron. The accelerated stability data is given in below Table 3.

[0296] Table 3: Accelerated stability data for formulation as per Table 2

[0297] As shown in the above Table 3, there was significant increase of impurities (both for individual actives and total) and discoloration in tested tablets at the end of studies conducted for testing stability at accelerated storage conditions.

[0298] In certain embodiments, the fixed-dose combination of the present disclosure successfully overcomes the above noted physical and chemical instabilities resulted by combining flavoxate and mirabegron.

[0299] In certain embodiments, the developed modified-release preparation of flavoxate or salt thereof and mirabegron will exhibit stable plasma profiles for the duration of 12-24 hours and thus reduces any adverse effects.

[0300] In certain embodiments, the present disclosure provides a manufacturing process that provides a biphasic drug delivery system i.e., immediate release of drug levels of both flavoxate or salt thereof and mirabegron followed by extended drug release levels of both actives over 12-24 hours duration.

[0301] In certain embodiments, the present disclosure provides a novel modified-release fixed dose combination of flavoxate or salt thereof and at least one beta 3 -adrenoceptor agonist, for instance mirabegron, solabegron, ritobegron, and vibegron designed for extended or controlled drug release profiles.

[0302] Modified-Release Formulation: In certain embodiments, the disclosed modified- release pharmaceutical compositions provide an extended-release mechanism, wherein flavoxate or salt thereof and Mirabegronare released initially within 1-2 hours, and achieve plasma levels similar to individual marketed immediate-release formulations of each individual active ingredient. In certain embodiments, the remaining amount of flavoxate or salt thereof and Mirabegron is gradually released over 12-24 hours, maintaining therapeutic concentrations for effective therapeutic action. Controlled Release Polymers: In certain embodiments, the modified-release (MR) formulation is prepared by employing one or more controlled-release polymers. One or more controlled-release polymers enable the preparation of commercially acceptable forms, such as monolayer, bi-layered, or multi-layered tablets, as well as multicoated minitablets, pellets, or beads filled in capsules, or MUPS for tablets or capsule.

[0303] Manufacturing Techniques: In certain embodiments, the MR formulation is manufactured using various techniques, including dry granulation, wet granulation, fluidized bed processing, or hot melt granulation.

[0304] In certain embodiments, the present disclosure presents an innovative modified- release fixed dose combination, offering targeted drug release and optimized bioavailability levels for both flavoxate or salt thereof and mirabegron over a prolonged duration of action. The formulation provides flexibility in its presentation as tablets, minitablets, or capsules, utilizing diverse manufacturing techniques.

[0305] In certain embodiments, the present disclosure involves fixed-dose pharmaceutical compositions containing a therapeutically effective amount of Mirabegron or its pharmaceutically acceptable salt, and Flavoxate or its pharmaceutically acceptable salt, along with a process for their preparation.

[0306] The terms "composition," "pharmaceutical composition," "dosage form," "solid oral composition," and "formulation" are used interchangeably to describe a combination of Flavoxate or its pharmaceutically acceptable salt and at least one P3 adrenoceptor agonist in a solid oral dosage form. This includes tablets, modified release tablets, pills, granules, caplets, tablet-in-capsule, capsules, granules in a capsule, pellets, pellets in a capsule, powder, suspension, MUPS for tablet or capsule, or any suitable form for oral administration.

[0307] In some embodiments, the pharmaceutical compositions disclosed herein encompass various forms such as mono-layered tablets, bi-layered tablets, tri-layered tablet, multi-layered tablet, drug-layered tablet, caplets, minitablets, tablet-in-tablet, tablets in a capsule, capsules, granules in a capsule, pellets, pellets in a capsule, beads, powder, granules, sachets, MUPS for tablet or capsule, or any other suitable dosage form for oral administration. Preferably, the pharmaceutical composition is a bilayer tablet or monolay er / single layer tablet.

[0308] The present disclosure, in some embodiments, relates to pharmaceutical compositions featuring fixed dose combinations of two or more active agents. In certain embodiments, it relates to managing subjects with Overactive Bladder (OAB) syndrome, impacting the quality of life in both men and women. OAB affects daily activities and social functions such as work, travel, exercise, sleep, and sexual function.

[0309] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising mirabegron in amorphous, crystalline and / or co-amorphous form along with one or more pharmaceutically acceptable carriers, excipients, or diluents.

[0310] In certain embodiments of the present disclosure, the pharmaceutical composition comprises solid dispersions of amorphous mirabegron together with one or more pharmaceutically acceptable excipients.

[0311] In certain embodiments of the present disclosure, the pharmaceutical composition comprises the crystalline form of mirabegron obtained according to any of the processes described in this application.

[0312] In certain embodiments of the present disclosure, the pharmaceutical compositions comprise a fixed dose combination (FDC) of a P3-adrenergic agonist (particularly mirabegron) and antispasmodics (particularly flavoxate), processes for their preparation, and their use to treat certain diseases.

[0313] In certain embodiments of the present disclosure, the fixed-dose combinations comprise prophylactic or therapeutic amounts of at least one P3 -adrenergic receptor agonist and at least one antispasmodic agent in a single dosage form.

[0314] In certain embodiments of the present disclosure, the compositions comprise fixed- dose combinations containing at least one p3-adrenergic receptor agonist and at least one antispasmodic agent in a single dosage form, together with one or more pharmaceutically acceptable excipients.

[0315] In certain embodiments of the present disclosure, the pharmaceutical dosage forms comprise prophylactic or therapeutic amounts of one P3-adrenergic receptor agonist and at least one antispasmodic agent, wherein the dosage forms are in the form of a capsule.

[0316] In certain embodiments of the present disclosure, the capsule dosage forms comprise compositions of one or more active agents formulated as pellets, granules, minitablets, powders, MUPS, or any mixtures thereof.

[0317] In certain embodiments of the present disclosure, two active agents may be delivered as a single co-formulation and provide particularly beneficial therapeutic results. Co-formulations comprise two or more active pharmaceutical ingredients (APIs) combined within a single dosage form. Co-formulations have the patient-compliance advantages by reducing the number of distinct doses and fixing the ratio of the two active agents being administered. In certain embodiments of the present disclosure, a pharmaceutical composition, particularly a solid preparation (e.g., an oral solid dosage form, such as a tablet, particularly for sustained drug release), comprises a first composition comprising Flavoxate and one or more excipients and a second composition comprising a selected P3- adrenergic agonist (particularly mirabegron) and one or more excipients.

[0318] In certain embodiments of the present disclosure, a fixed dose combination comprises a sustained or extended-release pharmaceutical formulation comprising flavoxate hydrochloride and mirabegron. The modified-release formulation (MR) may comprise a combination of at least one hydrophilic polymer and at least one hydrophobic polymer. The weight ratio of the hydrophilic polymer to the hydrophobic polymer may be in a range of about one-to-one (1 : 1) to about nine-to-one (9: 1).

[0319] In certain embodiments of the present disclosure the controlled-release polymer is selected from the non-limiting examples of one or more of Hydroxypropyl methylcellulose (HPMC), Hydroxypropyl cellulose (HPC), Sodium carboxymethyl cellulose (NaCMC), Polyethylene oxide (PEO), Ethyl cellulose (EC), Ammonio Methacrylate Copolymers, and Polyvinyl acetate (PVAc) or their salts or derivatives.

[0320] In certain embodiments of the present disclosure the controlled-release polymer is selected from HPMC E15, HPMC K4M, HPMC K15M, HPMC K-100M, and HPMC K15.

[0321] In certain embodiments of the present disclosure the pH-dependent polymers such as Hydroxypropyl methylcellulose acetyl succinate (HPMCAS) and HPMC Phthalate along with hydrophilic and hydrophobic polymers are employed to control the dissolution release profile of flavoxate and p3-adrenergic agonist so that the formulation releases the flavoxate or both actives slowly, stably and continuously as the formulation passed through the gastrointestinal tract.

[0322] In certain preferred embodiments of the present disclosure, the amount of pH- dependent polymers is present in the range of about 1.0 to 15 % w / w of the modified- release formulation layer.

[0323] The present disclosure provides a pharmaceutical composition of mirabegron and flavoxate comprising a first and second component, wherein the first component is physically separated from the second component.

[0324] The present disclosure provides a pharmaceutical composition of mirabegron and flavoxate comprising a first and second component, wherein the first component is separated from the second component by an intermediate, inactive layer. The inactive layer comprises one or more of the excipients viz. mannitol, sorbitol, microcrystalline cellulose, lactose, dicalcium phosphate, or starch such as maize starch, and corn starch etc. The inactive layer further comprises binders, polymers, glidants, disintegrants, stabilizers, surfactants lubricants etc.

[0325] The present disclosure provides a pharmaceutical composition of mirabegron and flavoxate comprising a first and second component, wherein the first and second components are administered in one unit dosage form.

[0326] In certain embodiments of the present disclosure, the developed modified-release tablet is capable of releasing therapeutically effective amounts of flavoxate and mirabegron over an extended period, e.g., 12-24 hours.

[0327] In certain embodiments of the present disclosure, a bioavailable modified-release dosage form of flavoxate and mirabegron formulated as a fixed dose combination product will provide a 24-hour therapeutic effect with adequate plasma levels when administered orally. In addition, the current disclosure also relates to modified release pharmaceutical compositions comprising other beta3 -adrenoceptor agonists, such as solabegron, ritobegron and vibegron.

[0328] In certain embodiments, the present disclosure encompasses a modified-release composition that comprises at least two portions (e.g., a bi-layer tablet, or capsule, etc.), an immediate release formulation (IR) portion, and a modified release formulation (MR) portion. In some embodiments, the formulation comprises a specific quantity of flavoxate and mirabegron.

[0329] The present disclosure is of FDC of flavoxate or salt thereof and mirabegron or salt thereof formulated as dry powder or granules or mini-tablets filled in capsules or as tablet formulations.

[0330] The tablet formulations as per current disclosure can be as single layered or multilayered tablets.

[0331] In certain embodiments, the disclosed tablets are film coated using suitable combinations of physically and chemically compatible excipients of suitable ratios along with polymer coating compositions imparting the required barrier for moisture and hence ensuring physical and chemical stability.

[0332] In certain embodiments, the prepared tablets are in form of mono-layered, bilayered, multi-layered tablets, multicoated mini-tablets, MUPS (Multiple Unit Pellet System) tablets dosage forms. In certain embodiments, the prepared capsules are in form of pellets, granules, mini-tablets, powders, or any mixtures thereof. In certain embodiments, the prepared formulations are in form of lozenges, drops, syrups, suspensions, or solutions.

[0333] In certain embodiments, the prepared oral dosage forms exhibit modified-release profile.

[0334] In certain embodiments, the FDC product of the disclosure comprising flavoxate and mirabegron performs similar or better to standalone flavoxate and mirabegron containing products.

[0335] In certain embodiments, the disclosure provides that the dosage forms of the formulations may be in form of monolayer tablets comprising flavoxate granules intra- granularly and mirabegron granules extra-granularly or vice-versa. In certain embodiments, the tablets comprise flavoxate and mirabegron granules intra-granularly and one or more pharmaceutically acceptable excipients extra-granularly. Such tablets are mono-layered tablets.

[0336] In certain embodiments, the dosage forms of the formulations may be in form of tablets comprising flavoxate granules in one layer and mirabegron granules in another layer. The tablets comprising flavoxate and mirabegron granules in separate layers are bilayered tablets.

[0337] In certain embodiments, the dosage forms of the formulations may be in form of multilayer tablets comprising flavoxate granules in one layer, placebo granules as a sandwich second layer and mirabegron granules in third layer. The tablets comprising flavoxate granules in one layer, placebo granules as a sandwich second layer and mirabegron granules in third layer are tri-layered tablets. The placebo granules in trilayered tablets are present as sandwich second layer between the first and third layers of actives.

[0338] In certain embodiments, the formulations may be in form of a capsule comprising at least one tablet comprising flavoxate and at least one another tablet comprising mirabegron, wherein one or both of these tablets are optionally coated.

[0339] In certain embodiments, the formulations may be in form of a capsule comprising at least one tablet comprising flavoxate and granules or pellets or powder blends comprising mirabegron, wherein flavoxate tablets are optionally coated.

[0340] In certain embodiments, the formulations may be in the form of a capsule comprising mini-tablets comprising flavoxate and mirabegron, wherein mini-tablets of one or both of flavoxate and mirabegron are optionally coated. In certain embodiments, the tablets are coated by one or more functional or nonfunctional coatings. In certain embodiments, the functional film coating of the tablet is ethyl cellulose dispersion with soluble polymer or enteric polymer-based dispersion with water soluble ingredients. In certain embodiments, the non-functional film coating of the tablet is hydroxypropyl methyl cellulose based film coating dispersion with or without flavour.

[0341] In certain embodiments, the pharmaceutical formulations may be in the form of a tablet or capsule, comprising flavoxate, prepared from flavoxate granules having a bulk density between about 0.10 g / ml to about 1 g / ml or about 0.20 g / ml to about 0.95 g / ml, and comprising mirabegron, prepared from mirabegron granules having bulk density between about 0.10 g / ml to about 1 g / ml or about 0.20 g / ml to about 0.90 g / ml, or a mixture of flavoxate and mirabegron granules having a bulk density between about 0.10 g / ml to about 1 g / ml or about 0.20 g / ml to about 0.95 g / ml.

[0342] In certain embodiments, the capsule dosage forms of the disclosure comprise at least two active agents, wherein the active agents, prepared in the forms of pellets, granules, mini-tablets, powders, microcapsules, or any mixtures thereof, are filled into capsules, and wherein the capsule sizes range from size 2 to 00, including capsule size of Oel (el means elongated).

[0343] In certain embodiments, the tablet dosage forms comprising the active agents may be prepared in the forms of mono-layered, bi-layered or multi-layered tablets, are compressed into tablets and optionally coated, and wherein said tablets have core weights of at least about 50 mg, at least about 100 mg, at least about 200 mg, of at least about 350 mg, at least about 900 mg, at least about 1200 mg, or at least about 2500 mg.

[0344] In a preferred embodiment, the disclosure provides tablet dosage forms, wherein the active agents, prepared in the forms of monolayer, bilayer or multilayer tablets, are compressed into tablets and optionally coated. In a further preferred embodiment, the disclosure provides tablet dosage forms, wherein the said tablets have core weights of at least about 250 mg to 2000 mg.

[0345] As per current disclosure the dosage form unit weight can range from 300 mg to 1950 mg to accommodate the per day dose of the both actives.

[0346] The amount of flavoxate hydrochloride or the pharmaceutically acceptable salt thereof is present in the range from 500 mg to 2000 mg and of P3-adrenergic agonist or the pharmaceutically acceptable salt thereof is present in the range of 1 mg to 2400 mg per dosage unit. In preferred embodiments of the present disclosure, the amount of flavoxate hydrochloride is present in the range of about 4% to 85%w / w and P3-adrenergic agonist is present in the range of about 0.04% to about 25% w / w of the formulation.

[0347] In certain embodiments, the capsule dosage forms comprising the active agents may be prepared in the forms of pellets, granules, mini-tablets, powders, microcapsules, or any mixtures thereof, are filled into capsules, and wherein the said capsule has fill weights of at least about 50 mg, at least about 330 mg, at least about 750 mg, or at least about 1000 mg.

[0348] In a preferred embodiment, the disclosure provides capsule dosage forms, wherein the active agents, prepared in the forms of pellets, granules, mini-tablets, powders, microcapsules, or any mixtures thereof, are filled into capsules, and wherein the said capsule have fill weights of at least about 330 mg, or at least about 750 mg.

[0349] In certain embodiments, the pharmaceutical formulations of the disclosure release not more than (NMT) 45% in 60-120 minutes and NLT 80% of the actives in 12-24 hours when tested in in-vitro dissolution studies for both actives, in multi-media dissolution profile studies of pH ranging from 1.2 to 7.2, apparatus USP Type 2 (Paddle), with 900 ml of dissolution medium and 20-200 rpm speed.

[0350] In certain embodiments, the pharmaceutical formulations have less than about 5% by weight or less than about 2% by weight of the label content of the active agents of any drug-related impurity, and may have total drug-related impurities less than about 6% by weight or less than about 4% by weight of the label content of the active agents.

[0351] In certain embodiments, the pharmaceutical compositions contain related impurities of the actives less than or equal to about 5% or about 1% of the content of both actives.

[0352] In certain embodiments, the FDC formulations are in pharmaceutical dosage form suitable for oral administration, comprising at least two active agents flavoxate or salt thereof in an amount of about 1.0 % to about 90% or about 5.0 % to about 65% by weight of the formulation; and mirabegron or salt thereof, in an amount of about 0.10 % to about 30% or 0.20 % to about 25% by weight of the formulation; together with one or more pharmaceutically acceptable excipients in an amount of about 5% to 95% or about 35% to 85% by weight of the formulation.

[0353] In certain embodiments, the FDC formulations are in pharmaceutical dosage form suitable for oral administration, comprising at least two active agents flavoxate or a pharmaceutically acceptable salt thereof in an amount of about 0.4% to about 90% by weight of the formulation; and P3-adrenergic receptor agonist in an amount of about 0.04% to about 30% by weight of the formulation. The formulation further comprises one or more pharmaceutically acceptable excipients in an amount of about 10% to 95% or about 35% to 85% by weight of the formulation.

[0354] In certain embodiments, the present disclosure also relates to methods of manufacturing modified-release formulations of the fixed dose combination of Flavoxate and Mirabegron.

[0355] In certain embodiments, the present disclosure also relates to sustained-release preparations of the type described above in the form of capsules having beads or granules of both immediate release formulation and beads or granules of sustained release formulation. The beads may comprise a mixture of discrete beads. In some embodiments, the beads are a mixture of either SR formulation beads or IR formulation beads. In some embodiments, the beads have both SR and IR formulations within in a single bead, or combinations of the foregoing. Alternatively, the sustained-release formulation may comprise a core that is coated by a layer of the immediate release formulation to form a single tablet wherein both actives are part of the core and coated layer in suitable proportions.

[0356] In certain embodiments, the present disclosure provides multilayer dosage forms that are suitable for the consecutive release of two or more actives in combination and for modified-release dosage forms wherein one layer is for the loading dose, such as the immediate release portion, and another layer is for the maintenance dose, i.e., the sustained release portion of the same or different drug. This type of dosage form can be used for chronic conditions that require combination drug therapy and to avoid chemical incompatibility between two active agents. Multilayer dosage forms allow designing and developing different or dual release profiles in a single formulation.

[0357] In certain embodiments, the present disclosure also relates to methods of manufacturing modified-release formulations of the fixed dose combination of flavoxate and P3-adrenergic receptor agonist. Formulation development is initiated with the characterization of both active drugs, viz., flavoxate hydrochloride and mirabegron hydrochloride, along with an evaluation of individual reference products. The drug dissolution profile and drug-drug and drug-excipient compatibility are characterized. Additionally, the process operations were defined, and a process control strategy was examined. The manufacturing process development study undertaken, and the manufacturing process as wet granulation finalized, which comprises the manufacturing stages of geometric mixing of drug actives, especially Mirabegron, which is having very low drug content per dosage unit in the 1st step of blending, followed by compression, and coating stages.

[0358] Dissolution parameters (e.g., media, volume, apparatus, and agitation speed) are chosen based on finalized analytical methods for both active ingredients. The particle size of Flavoxate is crucial for dissolution, leading to the use of micronized API. Limits for known and unspecified impurities, in line with ICH Q3B (R2), were established to ensure impurity control in finished drug products.

[0359] Physical properties of modified-release core tablets, including hardness (in kg / cm), friability (in %), weight variation, drug content, and thickness, must be measured and documented for tablet stability.

[0360] Formulation development scientists commonly face challenges formulating compounds from the Biopharmaceutical Classification System (BCS) class IV, as these compounds are poorly water-soluble, resulting in poor dissolution and subsequent absorption in the gastrointestinal tract. In this disclosure, pharmaceutical compositions include Flavoxate hydrochloride, categorized as a BCS Class IV drug.

[0361] In certain embodiments, the present disclosure provides fixed dose combination formulations that comprise a sustained release polymer, binder, diluent, surfactant, disintegrant, lubricant, glidant, or combination thereof. In certain embodiments, initial batches of fixed dose combination formulations were prepared from suitable grades of controlled release polymers including non-ionic soluble cellulose either, such as hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetyl succinate, hydroxypropyl cellulose, hydroxyethyl cellulose (HEC e.g., Natrosol); insoluble cellulose polymers such as Ethyl cellulose etc., non-ionic homopolymers of ethylene oxide, such as poly(ethylene oxide) with a molecular weight range of 100,000 to 8000,000; Water soluble natural gums of polysaccharides of natural origin, such as xanthan gum, alginate, and locust bean gum; Water swellable, but insoluble, high molecular weight homopolymers and copolymers of acrylic acid chemically cross-linked with poly-alkenyl alcohols with varying degree of cross-linking or particle size (Carbopol 71G NF, 97 IP, 934P); Polyvinyl acetate and povidone mixture (e.g. Kollidon SR); Cross-linked high amylose starch or Ionic methacrylate copolymers (Eudragit L30D) alone or in combination were selected.

[0362] The surfactants suitable for use in FDC formulations of the present disclosure include, but are not limited to, polyoxyethylenealkylaryl ethers such as polyoxyethylene lauryl ether, polyoxyethylenecetyl ether, polyoxyethylenestearyl ether; polyethylene glycol fatty acid esters such as PEG monolaurate, PEG dilaurate, PEG distearate, PEG dioleate; sorbitan fatty acid monoesters; polyoxyethylene castor oil derivates such as polyoxyl hydrogenated castor oil; sodium monooleate, sodium monolaurate, sodium monopalmitate, sodium monostearate, stearylic alcohol, cetostearylic alcohol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, glycerol fatty acid esters, polyethylene glycol fatty acids esters, polyethylene glycol glycerol fatty acid esters, polyoxyethylene glycerides, lauryl macrogolglycerides, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene vegetable oils, polyoxyethylene hydrogenated vegetable oils; fatty acids, glycerides, tocopherol polyethylene glycol succinates, a triglyceride selected from the group consisting of vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, synthetic triglycerides, modified triglycerides, and fractionated triglycerides.

[0363] Some exemplary anionic surfactants suitable for use in FDC formulations of the present disclosure include, without limitation to sodium deoxycholate, dicetyl phosphate, sodium lauryl sulfate (sodium dodecyl sulfate), sodium cetylstearyl sulfate, sodium dioctylsulfosuccinate (docusate sodium), and the corresponding potassium or calcium salts thereof.

[0364] Some exemplary non-ionic surfactants suitable for use in FDC formulations of the present disclosure include, without limitation to polyoxyl 20 stearate, polyoxyl 40 stearate, polyoxyl 60 stearate, polyoxyl 35 castor oil (Cremophor EL), polyoxyethylenesorbitanmonoisostearate (Tween 20, Tween 80), polyethylene glycol 40 sorbitandiisostearate, polyoxyethyleneoctyl phenyl ether (Triton XI 00), polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40), polysorbates (polysorbate 20, polysorbate 40, polysorbate 80, polysorbate 85, polysorbate 60), polyoxyethylene fatty acid esters, polyoxyl 40 castor oil, tri block polyoxypropylene (polypropylene oxide)) polymers (pol oxamer 188, pol oxamer 407) poly oxy ethylenepoly oxypropylene 1800, oleic acid, sorbitan fatty acid monoesters such as sorbitanmonolaurate (Span 20), sorbitanmonooleate (Span 80), sorbitanmonopalmitate (Span 40), sorbitantrioleate (Span 85), sorbitansesqui oleate; N- Carbamoylmethoxypolyethylene glycol 2000-1,2-distearol, myristic acid, polyoxyethylene stearates (MYRJ), steareth, sucrose stearate, polyoxyl castor oil, stearic acid, triglyceride synthetic, trimyristin, tristearin, Vitamin E, d-alpha- tocopheryl polyethylene glycol 1000 succinate (TPGS), egg yolk phosphatides, dimyristoylphosphatidylglycerol, dimyristoyl lecithin, propylene glycol monocaprylate (Capryol 90), propylene glycol monocaprylate (Capryol PGMC), deoxycholate, cholesterol, propylene glycol alginate, PEG 60 almond glycerides (Crovol™ A- 10), oleoyl macrogol-6 glycerides (Labrafil 1944), linoleoyl macrogol-6 glycerides (Labrafil 2125), caprylocaproyl macrogol-8 glycerides (Labrasol), propylene glycol monolaurate (Lauroglycol 90), propylene glycol laurate (Lauroglycol FCC), calcium stearate, lecithin, Lecithin Centromix E, Lecithin Centrophase 152, Lecithin Central 3F21B, POE (26) glycerine, Olepalisosteariques (PEG-6 isostearate), Pluroldiisostearique (polyglycerol-3 - diisostearate), PlurolOleique CC, POE 20 Sorbitantrioleate, polyoxyethylene glycerol trioleate, or macrogol-15 hydroxy stearate (Solutol) and a mixture of one or more thereof. Examples of cationic surfactants suitable for use in the present invention include, but are not limited to quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetyltrimethyl ammonium bromide, cetyltrimethyl ammonium chloride, 5-bromo-5-nitro-l, 3 -dioxane, dimethyldioctadecylammonium chloride, dimethyldioctadecylammonium bromide; and hydrohalide salts of amines, such as octenidinedihydrochloride.

[0365] Preferably, the surfactants suitable for use in the present invention include polysorbates, tocopherols (tocopheryl polyethylene glycol 1000 succinate), propylene glycol monocaprylate, caprylocaproyl macrogol-8 glycerides, glycerylcaprylate, poloxamers, PEG-40 hydrogenated castor oil, lecithin, propylene glycol stearates, and polyethylene glycol glycerides.

[0366] The FDC formulations of the present disclosure may include one or more binder, or solublilizer such as, but not limited to, polyethylene glycol 300 (PEG 300) polyethylene glycol 400 (PEG 400), polyethylene glycol 600 (PEG 600), polyethylene glycol 1000 (PEG 1000), polyethylene glycol 2000 (PEG 2000), polyethylene glycol 3000 (PEG 3000), polyethylene glycol 4000 (PEG 4000), polyethylene glycol 6000 (PEG 6000), polyethylene glycol 8000 (PEG 8000), polyethylene glycol 10000 to polyethylene glycol 20000, propylene glycol, glycerol, glycerin triacetate, sorbitol, and a mixture of one or more thereof.

[0367] The FDC formulations of the present disclosure may include one or more antioxidants, or preservatives such as, but not limited to, butylatedhydroxyanisole (BHA), butylatedhydroxytoluene (BHT), ethylenediaminetetraacetic acid (EDTA), methylparaben, propylparaben, sodium benzoate, propyl gallate, and a mixture of one or more thereof. Preferably, the preservatives include butylatedhydroxyanisole, butylatedhydroxytoluene, and propyl gallate. The FDC formulations of the present disclosure may include at least one carbomer as a binder, a synthetic high molecular weight polymer of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol, which functions primarily as a gelling agent and viscosity -increasing excipient. Suitable carbomers for use in the FDC formulations of the present disclosure include, but are not limited to, Carbomer 940, Carbomer 980, and Carbomer 974P, each differing in molecular weight and viscosity profiles, thus offering flexibility in formulation design. These carbomers may be present in concentrations ranging from 0.1% to 2.0% w / w, depending on the desired consistency, drug release characteristics, or application route. The selected carbomer may further enhance bioadhesive properties or stabilize emulsions where applicable.

[0368] The formulation optionally includes one or more antioxidants to enhance the stability of oxidation-sensitive active ingredients. In a preferred embodiment, the antioxidant is selected from sulphite-based reducing agents, such as sodium metabisulphite, which functions by scavenging molecular oxygen and preventing oxidative degradation. Sodium metabisulphite is a pharmaceutically acceptable antioxidant commonly used in both liquid and solid dosage forms to stabilize active pharmaceutical compounds, particularly those susceptible to hydrolysis or oxidative stress. Other suitable antioxidants that may be employed include sodium bisulphite, ascorbic acid, and tocopherols. The concentration of the antioxidant may range from 0.01% to 0.5% w / w, depending on the sensitivity of the active ingredient and the dosage form.

[0369] In certain embodiments, the present disclosure provides fixed dose combinations comprising a surfactant. As flavoxate hydrochloride is poorly soluble in water, and with high amounts of drug necessary for therapeutic effectiveness, appropriate levels of surfactants alone or in combination are used.

[0370] In certain embodiments, the surfactants may, for example, comprise long alkyl chain sulfonates / sulfates such as sodium dodecylbenzene sulfonate, sodium lauryl sulphate, and dialkyl sodium sulfosuccinate, quaternary ammonium salts, fatty alcohols such as lauryl, cetyl, and stearyl, glyceryl esters, fatty acid esters, and polyoxyethylene derivatives thereof.

[0371] In certain embodiments, the diluent may, for example, comprise one or more of mannitol, sorbitol, microcrystalline cellulose, lactose, dicalcium phosphate, or starch such as maize starch, and com starch.

[0372] In certain embodiments, the binder may, for example, comprise one or more of starch, polyvinylpyrrolidone, natural or synthetic gum and cellulosic polymers e.g., Ethyl cellulose, HPC, Gelatin, or polyethylene glycol or suitable grades of polyethylene glycol. In certain embodiments, the disintegrants may, for example, comprise one or more of Starch, Sodium Starch Glycollate, Croscarmellose Sodium, or Crospovidone.

[0373] While disintegrants are usually included in the immediate -release compositions, in certain embodiments of the present disclosure, at least one disintegrant is included in the modified-release layer (MR Layer), which has surprisingly and unexpectedly helped in ensuring controlled and complete release of high dose flavoxate active from the disclosed FDC compositions. The non-limiting examples of these disintegrant may include sodium starch glycollate, croscarmellose sodium and crospovidone alone or in combination.

[0374] In preferred embodiments of the present disclosure, the amount of disintegrant is present in the range of about 0.1 to 1.5 % w / w of the modified-release formulation layer.

[0375] In certain embodiments, the lubricant and / or glidant may, for example, comprise one or more of talc, colloidal silicon dioxide, stearic acid, magnesium stearate, or sodium stearyl fumarate.

[0376] In certain embodiments, the Flavoxate is in the form of Flavoxate hydrochloride and the pharmaceutically acceptable additives are selected from the diluents, disintegrants, glidants, lubricants, colorants, and combinations thereof.

[0377] The present invention addresses these challenges by overcoming the difficulties associated with the release of two different release timings of two different drugs and also the physical and chemical incompatibilities of the flavoxate and mirabegron binary mixtures. Additionally, it resolves the incompatibilities between these drugs and certain excipients used in the formulation, as identified in development studies conducted by the inventors.

[0378] In certain embodiments of this disclosure, the pharmaceutically acceptable additives are selected from the diluents, disintegrants, glidants, lubricants, colorants, and combinations thereof. The present disclosure overcomes the significant formulation challenge of timings viz., two different release timings of two different drugs. The granulation of mirabegron is also undertaken separately.

[0379] In some embodiments, the formulation comprises at least one colouring agent or colourants to provide an appealing colour to the pharmaceutical formulation. Suitable colouring agents are well known to those skilled in the art and are those that are deemed safe for human consumption by relevant governmental regulatory bodies and which avoid chemical incompatibilities with other ingredients. Suitable colouring agents may include, but not limited to, soluble supra colours, example tartrazine, quinoline yellow, erythrosine, sunset yellow colour, ponceau 4R, and the likes or mixtures thereof. The quantities of colorant used may be in the range of about 0% w / v to about 2.0% w / v of the formulation. The preferred quantities of the colorant used may be in the range of about 0%w / v to 1.0% w / v of the formulation.

[0380] In certain embodiments, the resultant granules of standalone granulations of both actives can be mixed together and compressed as a single layer tablet or filled in capsules. In few embodiments, these individual active granules are compressed as bilayer tablets or trilayer tablets with sandwich layer of placebo granules.

[0381] In certain embodiments, the disclosure provides processes for making the disclosed FDC compositions. The processes for manufacturing a formulation of the present disclosure are not limited to the processes described herein. The description in this application should be interpreted as preferential embodiments of the present invention.

[0382] In certain embodiments, one or more than one active ingredient can be used, together with or without directly compressible grade excipients, by granulation together or separately, using wet granulation or dry granulation, with or without other excipients. Further, one or more than one active agent can be granulated while the others may be used without granulation. Spray drying and spray granulation techniques may also be used to prepare compositions of the present disclosure. Hot melt granulation may also be employed to prepare the compositions of the present disclosure.

[0383] In certain embodiments, pharmaceutical compositions of the disclosure are prepared as follows: active agents are prepared by sifting at least one active agent and one or more excipients through a desired mesh size sieve and then mixing, using a rapid mixer granulator, planetary mixer, mass mixer, ribbon mixer, fluid bed processor, or any other suitable device. The blend can be granulated, such as by adding a solution or suspension with or without a binder, whether alcoholic or hydro-alcoholic or aqueous, in a low or high shear mixer, fluidized bed granulator and the like, or by dry granulation. The granules can be dried using a tray dryer, fluid bed dryer, rotary cone vacuum dryer, and the like. The granules can be sized using an oscillating granulator or comminuting mill or any other conventional equipment equipped with a suitable screen. Alternatively, granules can be prepared by extrusion and spheronization, or roller compaction. Also, the manufacture of granules containing active agents can include mixing with directly compressible excipients or roller compaction. The present disclosure provides a pharmaceutical formulation comprising flavoxate or a pharmaceutically acceptable salt thereof, in combination with at least one P3-adrenergic receptor agonist, and one or more pharmaceutically acceptable excipients, wherein the formulation is designed to deliver one or more active pharmaceutical ingredients (APIs) in combination release profile of immediate-release and modified- release over an extended period of about 12 to 24 hours.

[0384] In particular, the formulation is characterized by a defined in vitro dissolution profile for each of the active agents, as measured under standard pharmacopeial conditions (e.g., USP Apparatus Paddle II, 200- 1000 mL dissolution media, pH-adjusted buffer, about 20-200 rpm, 37±2°C), using a suitable validated analytical method (e.g., HPLC).

[0385] The dissolution profile of flavoxate or a pharmaceutically acceptable salt thereof from the formulation is controlled such that from about 5% to about 45% of the total flavoxate content is released at approximately 1 hour; from about 35% to about 70% of the total flavoxate content is released at approximately 2 hours; and not less than 80% of the total flavoxate content is released at approximately 12 hours as per specific in-vitro dissolution test method conditions used.

[0386] The release profile of flavoxate or a pharmaceutically acceptable salt thereof indicates a sustained or controlled-release behaviour, designed to provide prolonged therapeutic coverage, reduced peak plasma fluctuations, and improved patient compliance by minimizing the need for multiple daily doses.

[0387] The dissolution profile of the P3-adrenergic receptor agonist, which may be selected from mirabegron, solabegron, ritobegron and vibegron, or a pharmaceutically acceptable salt or ester thereof, is similarly designed to ensure extended and synchronized delivery. The P- adrenergic receptor agonist or its salt or ester exhibits the in vitro release characteristics such that from about 5% to about 35% of the total p3-adrenergic receptor agonist content is released at approximately 1 hour; from about 25% to about 70% of the total p3-adrenergic receptor agonist content is released at approximately 2 hours; and not less than 80% of the total p3-adrenergic receptor agonist content is released at approximately 12 hours as per specific in-vitro dissolution test method conditions used.

[0388] The release profile of the p3-adrenergic receptor agonist allows for a controlled onset and sustained action of the p3-adrenergic receptor agonist, facilitating continuous adrenergic receptor blockade, particularly beneficial in treating conditions such as lower urinary tract symptoms (LUTS), detrusor over activity, overactive bladder, bladder dysfunction, neurogenic bladder, chronic prostatitis / chronic pelvic pain syndrome, or postoperative irritative voiding symptoms.

[0389] The dissolution profiles of two actives flavoxate or a pharmaceutically acceptable salt thereof and p3-adrenergic receptor agonist in the formulations of the present disclosure as described above offers several non-limiting clinical and pharmacokinetic advantages as there is complementary release kinetics of both actives. Some of the advantages may be for instance, improved pharmacodynamics, reduced adverse effects, improved adherence and therapeutic versatility. The coordinated but sustained release ensures effective therapeutic levels of both agents during the dosing interval, promoting synergistic relief of lower urinary tract symptoms (LUTS), including both irritative (e.g., urgency, frequency) and sensory components. The modified-release of both actives minimizes abrupt plasma peaks of either agent, potentially reducing side effects such as dry mouth, dizziness, or blood pressure fluctuations associated with their respective pharmacologic classes.

[0390] Additionally, a once-daily dosing schedule enabled by the modified-release formulation of flavoxate and a p3-adrenergic receptor agonist reduces pill burden and improves patient compliance, especially in elderly populations commonly affected by urological disorders. Further, the formulations of the present disclosure are suitable for chronic administration and can be tailored for urological co-morbidities where both smooth muscle relaxation and P3 -adrenergic receptor activation are therapeutically beneficial.

[0391] The modified-release behaviour of two actives in the prepared formulations may beachieved through incorporation of controlled-release polymers in the formulation matrix and / or coating layers applied to pellets, granules, or tablets. These may include but are not limited to Hydrophilic polymers such as hydroxypropyl methylcellulose (HPMC), polyethylene oxide (PEO), and xanthan gum; Hydrophobic polymers such as ethyl cellulose, polyvinyl acetate, or polymethacrylate copolymers; pH-dependent enteric polymers such as Eudragit® for targeting specific segments of the gastrointestinal tract.

[0392] The formulations may be prepared in various oral solid dosage forms, including but not limited to matrix tablets; bi-layered or multi-layered tablets; capsules filled with controlled-release pellets; MUPS; tablets-in-capsule or pellets-in-capsule formats. The drug layering for pellet-based dosage forms may involve powder layering, solution / suspension -based coating, or a combination thereof, typically over sugar spheres or inert microcrystalline cores, followed by successive functional membrane coatings to modulate release rates.

[0393] The present disclosure also provides methods for preparation of illustrative formulations, MUPS, tablets, capsules and / or granules to be filled in capsules.

[0394] In certain embodiments, the method for preparing tablets comprising stable pharmaceutical formulations of the disclosure comprises: a) preparing a mono-layered, bi-layered or multi-layered tablet comprising a layer of at least one p3-adrenergic receptor agonist; b) preparing another layer comprising flavoxate.

[0395] The steps a) and b) of the above method may optionally comprise adding one or more pharmaceutical acceptable excipients.

[0396] The above method may optionally comprise an additional step c) of preparing another layer sandwiched between the two active drug layers prepared in steps a) and b). Another layer prepared in step c) can optionally comprise one or more pharmaceutical acceptable coating polymers along with other suitable adjuvants for ensuring the smooth film coating on core tablets.

[0397] In certain embodiments, the tablets obtained by the methods have hardness of from 05 Kg / cm2to 50 Kg / cm2depending on the dosage strengths of the disclosed FDC formulations.

[0398] In certain embodiments, the method for preparing capsules comprising stable pharmaceutical formulations of the disclosure comprises: a) preparing a tablet comprising at least one p3-adrenergic receptor agonists; b) preparing a tablet comprising Flavoxate; and c) preparing a capsule comprising the tablets prepared in steps a) and b).

[0399] The above method may optionally comprise adding one or more pharmaceutical acceptable excipients in the steps a) and b).

[0400] The above method may optionally comprise preparing capsule in the step c) together with one or more pharmaceutical acceptable excipients.

[0401] In certain embodiments, the pharmaceutical formulations of the disclosure may also be manufactured by the process which comprises: a) sifting at least one active agent and one or more excipients through a desired mesh size sieve and then mixing by suitable means to prepare a blend; b) granulating the blend obtained in step a) by suitable agents using suitable means to obtain granules; c) drying the granules obtained in step b) using suitable means to obtain dried granules; d) sizing the dried granules obtained in step c) by suitable means.

[0402] In certain embodiments, the suitable means in step a) of the above method include, but not limited to, rapid mixer granulator, planetary mixer, mass mixer, ribbon mixer, fluid bed processor, or any other suitable device.

[0403] In certain embodiments, the suitable agents in step b) of the above method include, but not limited to, binder, alcoholic or hydro-alcoholic or aqueous agents. In certain embodiments, the suitable means in step b) of the above method include, but not limited to, low or high shear mixer, fluidized bed granulator, dry granulator and the like.

[0404] In certain embodiments, the granules can be prepared by extrusion and spheronization, or roller compaction. Also, the manufacturing of granules containing active agents can include mixing with directly compressible excipients or roller compaction.

[0405] In certain embodiments, the granules obtained by a dry or wet technique can be blended with one or more lubricants and / or one or more anti-adherents. The lubricated blend can be compressed using a suitable device, such as a rotary machine to form slugs, which are passed through a mill or fluid energy mill or ball mill or roller mill or hammer mill and the like, equipped with a suitable screen to obtain the milled slugs of actives.

[0406] In certain embodiments, the granules obtained by a dry or wet technique can be blended with one or more lubricants and / or one or more anti -adherents and then compressed as tablets or filled into single capsule or into different capsules of different sizes, such that a smaller capsule can be filled into another larger capsule.

[0407] In certain embodiments, the tablets (including mini-tablets) of the disclosure can be made by compressing granules, using dies and punches of various sizes and shapes, as desired. Optionally, a coating can be applied to the tablets, if desired, by techniques known to a person skilled in the art such as spray coating, dip coating, fluidized bed coating and the like. The compressed tablets may be film coated with weight build-up of around 1 to 4%w / w.

[0408] The major problems in formulating once a day modified-release dosage form of fixed dose combination of flavoxate and mirabegron is different dose ranges and also difference in dosing frequencies. Additionally, flavoxate is having high dose per day which ranges from 300-1200mg having shorter half-life, hence maintaining effective therapeutic levels of the drug for 12-24 hours duration in blood circulation remains a major challenge. In contrast, mirabegron dose is having comparatively lower dose which can range from 25 to 50 mg once or twice a day. Additionally, the Mirabegron is having longer half-life which ranges between 26-31 hours.

[0409] Due to very low aqueous solubility of flavoxate, as this being a poorly soluble drug, presents formulation challenges, leading to slow dissolution rates. This slow dissolution can severely limit its drug efficacy and result in large inter-individual variations in absorption. Various techniques have been employed to create controlled- release pharmaceutical dosage forms, aiming to sustain therapeutic serum levels of medicaments. However, in the case of relatively water-insoluble drugs like Flavoxate, developing a controlled-release formulation typically involves substantial experimentation, as predicting a specific formulation's ability to achieve the desired modified release profile is often challenging.

[0410] Moreover, flavoxate hydrochloride API faces issues such as poor compressibility, poor flow characteristics, and high stickiness. This stickiness adversely affects multiple stages in the development of pharmaceutical formulations, including weighing, blending, granulation, and compression. These challenges impact drug manufacturing operations, particularly tablet compression (resulting in low rpm operation, weight variation, and frequent machine stoppages). The inventors of the current disclosure have conducted extensive studies to maintain suitable handling properties, ensuring adequate tablet hardness and appropriate friability.

[0411] Mirabegron API is insoluble in water and its pharmacokinetic parameters vary significantly in the presence or absence of the intake of food. A clinical trial of (R)-2-(2- aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic acid anilide or Mirabegron in the form of conventional formulations revealed that pharmacokinetic data unexpectedly varied according to the presence or absence of the intake of food. For example, the rate of decrease of Cmax in a fed state (With Food) was 67%, and the rate of decrease of AUC (Area Under the Curve) in the fed state was 47%, in comparison with those in a fasted state (Without Food). See, e.g., U.S. Pat. No. 11,707,451. These problems are considered to be raised by, for example, the changes in pharmacokinetics caused by food, and therefore, the development of a formulation capable of avoiding the effects by food intake has also been a focus of the current inventors while developing the FDC. In order to ensure target drug release in-vivo and dissolution rates of both actives, several trials and evaluation studies are undertaken and the developed pharmaceutical compositions are disclosed in this application.

[0412] In certain embodiments, the FDC formulations disclosed herein comprise active agents, wherein the active agents remain stable during manufacturing and storage for commercially relevant times (e.g., at least about 6 months, 1 year, 2 years, 3 years and more, including any intermediate times), and wherein the active agents provide the desired bioavailability for providing the desired pharmacological action. In certain embodiments, the FDC formulations may comprise lower doses of one or more active agent than generally used in the art to achieve the desired pharmacological response.

[0413] The present disclosure further relates to the therapeutic application of the pharmaceutical formulations as described herein for the treatment and / or amelioration of urological and associated disorders, particularly those characterized by abnormal bladder or prostate function.

[0414] In particular, the present disclosure provides a method of treating and / or ameliorating at least one symptom or condition selected from detrusor overactivity, overactive bladder (OAB), lower urinary tract symptoms (LUTS) due to bladder dysfunction or neurogenic bladder, chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS), or post-operative irritative voiding symptoms. The method comprises administering to a subject in need thereof an effective amount of pharmaceutical formulations of the present disclosure, which comprises a P3-adrenergic receptor agonist and flavoxate, or pharmaceutically acceptable salts or ester thereof, optionally in a modified-release dosage form.

[0415] The combination of antispasmodic agent such as flavoxate and a P3 -adrenergic receptor agonist is particularly advantageous in addressing both irritative and storage- related components of urinary tract dysfunction. The P3-adrenergic receptor agonist component improves urine flow and reduces bladder outlet resistance, while flavoxate acts as a smooth muscle relaxant, reducing bladder spasms and urinary urgency. This dualaction approach provides synergistic benefits for patients with complex urological conditions, especially those with overlapping symptoms such as OAB with neurogenic bladder or LUTS.

[0416] Furthermore, the present disclosure includes the use of the formulations for the treatment, alleviation, amelioration, and / or prevention of one or more of the aforementioned urological disorders. The formulations may be administered as a fixed- dose combination (FDC) or as a multiple unit dosage form such as a MUPS tablet or capsule, allowing for tailored drug release profiles (e.g., immediate-release and / or controlled-release) to enhance therapeutic efficacy and improve patient compliance.

[0417] Additionally, the present disclosure provides for the use of the formulations in the manufacture of a medicament for the treatment, alleviation, amelioration, and / or prevention of any of the above conditions or symptoms associated therewith. The medicament may be presented in a form suitable for oral administration and may include additional excipients and release-modifying polymers to modulate pharmacokinetics according to clinical requirements.

[0418] In embodiments, the formulation may be particularly useful for patients exhibiting symptoms of OAB, detrusor overactivity, or irritative voiding symptoms, including those occurring post-surgically or in the context of neurogenic bladder. The use of a modified- release matrix ensures sustained therapeutic levels of both active agents over an extended period, reducing dosing frequency and improving adherence.

[0419] Thus, the pharmaceutical formulations disclosed herein provide a novel and effective means for addressing a broad spectrum of urological disorders through the combined therapeutic actions of flavoxate and a p3-adrenergic receptor agonist in a single dosage form.

[0420] The present disclosure is further illustrated by the following examples, which are provided to be exemplary of the disclosure and do not limit the scope of the disclosure. While the present disclosure has been described in terms of its specific embodiments, certain modifications and equivalents are intended to be included within the scope of the present disclosure.

[0421] As representative suitable formulations consistent with the objects, features, and advantages of the present disclosure, the following non-limiting examples are provided;

[0422] Example 1: Method for preparation of a mono-layered., bi-layered or multi-layered tablet or capsule

[0423] A method for preparation of a bi-layered or multi-layered tablet or capsule of flavoxate or pharmaceutically acceptable salt thereof and p3-adrenergic receptor agonist comprising: a) blending about 50 mg to about 2000 mg of flavoxate hydrochloride and about 1 to about 25 mg of P3-adrenergic receptor agonist with one or more of pharmaceutically acceptable excipients separately for immediate-release (IR) and modified-release (MR) layers to obtain dry blended material mixtures; b) optionally passing the blended IR and MR material mixtures through #8 to 60 mesh (ASTM / BSS);; c) granulating the blended mixture of step a) or screened blended mixture of step b) by using high shear granulator of required capacity to obtain wet granules; d) drying the wet granules of step c) by suitable means at a about 35 to 75°C temperature and 15 to 120 minutes depending on the batch size to obtain dried granules; e) optionally screening the dried granules of step d) through a mesh of #10 to 30 mesh (ASTM / BSS)to obtain uniform granules; f) optionally lubricating the granules of step d) or step e) with at least one extra- granular excipient and at least one lubricant to obtain lubricated granules; g) compressing the lubricated granules of step f) to obtain bi-layered or multilayered tablets by suitable means or filling granules of step f) in capsules.

[0424] A method of preparing a mono-layered pharmaceutical tablet comprising flavoxate or pharmaceutically acceptable salt thereof and at least one P3 -adrenergic receptor agonist comprising: a) blending required quantities of flavoxate or pharmaceutically acceptable salt thereof and at least one p3-adrenergic receptor agonist with pharmaceutically acceptable excipients to obtain a dry blended mixture; b) optionally screening the blended mixture of step a) through a mesh of about #8 to 60 mesh (ASTM / BSS)to obtain screened mixture; c) granulating the blended mixture of step a) or screened mixture of step b) by suitable means to obtain wet granules; d) optionally drying the wet granules of step c) by suitable means at about 35 to 75°C temperature and about 15 to 120 minutes depending on the batch size to obtain dried granules; e) optionally screening the dried granules of step d) through a mesh of #10 to 30 mesh (ASTM / BSS) to obtain uniform granules; f) optionally lubricating the sized granules of step e), with at least one extra- granular excipient and at least one lubricant to obtain lubricated granules; g) compressing the granules of any one of steps c) to e) by suitable means to obtain the tablet. The method may further comprise screening the dried granules of step d) through a mesh of appropriate size to step e). The method may further comprise coating the granules of any one of steps c) to e) with a polymer dispersion to obtain polymer-coated modified- release granules.

[0425] A method for the preparation of a capsule comprising at least one p3-adrenergic receptor agonist and flavoxate or a salt thereof, the method comprising: a) preparing at least one tablet comprising at least one P3 -adrenergic receptor agonist; b) preparing at least one tablet comprising flavoxate; c) preparing the capsule comprising the tablets of step a) and step b); d) optionally adding one or more pharmaceutically acceptable excipients in steps a) and b); e) optionally preparing the capsule in the step c) by adding one or more pharmaceutically acceptable excipients.

[0426] The methods above may further comprise adjusting the hardness of the compressed tablets within a range of 5 kg / cm2to 50 kg / cm2based on the respective tablet strengths.

[0427] The pharmaceutically acceptable excipients in the methods above may include one or more of filler, disintegrant, binder, surfactant, controlled-release polymer, lubricant, glidant, diluent, antioxidant, anti-sticking agent, or coating agent in appropriate concentrations.

[0428] The wet granulation in the method may be performed by using high shear granulator of required capacity. The granules may be dried using fluidized bed dryer at a suitable temperature and screened through a mesh of appropriate size.

[0429] The tablets may be obtained by compressing granules using rotary tablet compression machine.

[0430] The dried granules are screened or sieved to ensure uniformity of particle size. This ensures consistent filling of the capsules and improves the uniformity of the drug release. The capsule filling may be achieved by a capsule filling machine (e.g., manual or automatic) to fill the granules or pellets into the capsules. Hard gelatin capsules may be prepared by filling granules into hard gelatin capsules (or other suitable capsule materials like HPMC for vegetarian formulations). The filling process may ensure that correct dose of each drug is delivered, and capsules must be uniform in weight. If the capsule is a dualchambered capsule, one chamber may contain the immediate-release granules and the other chamber may contain the modified-release granules. Alternatively, for multiparticulate formulations the capsule may contain beads, pellets, or granules with different release profiles. The IR beads will dissolve quickly, while the MR beads will dissolve more slowly over time.

[0431] If using hard capsules, the two halves of the capsule are sealed together. Some formulations might use a heat-sealing method for soft gel capsules. Capsules may be visually inspected for defects such as broken or improperly sealed capsules. Any defective capsules are removed from the batch.

[0432] Each of the mini-tablets, pellets, granules, or beads in the prepared capsule exhibit immediate or modified release dissolution profile.

[0433] Example 2: Exemplary bi-layered tablets

[0434] Various bi-layered FDC tablets of flavoxate and mirabegron were prepared as part of the present disclosure. The exemplary tablets of FDC of flavoxate and mirabegron have strengths of flavoxate from about 100 to 1200 mg and mirabegron from about 05 to 250 mg, respectively.

[0435] Table 4 below illustrates two such bi-layered tablets having flavoxate at 600 and 800 mg strength along with 50 mg of mirabegron. As shown in the Table 4 below, flavoxate and mirabegron are present in both IR and MR layers.

[0436] Table 4: Details of constituents in bi-layered tablets

[0437] * IPA: water (70: 30) quantity for ER portion was - 55.27% w / v of dry mix blend.

[0438] IPA: water (70: 30) quantity for IR portion was - 56.60% w / v of dry mix blend. The compressed tablets may be further film coated with weight buildup of 1 to 4%w / w.

[0439] Example 3: Exemplary bi-layered tablets

[0440] Various bi-layered FDC tablets of flavoxate and mirabegron were prepared as part of the present disclosure. Table 5 below illustrates two such bi-layered tablets having flavoxate at 600 and 800 mg strength along with 50 mg of mirabegron. As shown in the Table 5 below, flavoxate is present in both IR and MR layers and mirabegron is present in only MR layer.

[0441] Table 5: Details of constituents in bi-layered tablets

[0442] * IPA: water (70: 30) quantity for ER portion was - 55.27% w / v of dry mix blend.

[0443] IPA: water (70: 30) quantity for IR portion was - 56.60% w / v of dry mix blend. The compressed tablets may be further film coated with weight buildup of 1 to 4%w / w.

[0444] Example 4: Exemplary bi-layered tablets

[0445] Various bi-layered FDC tablets of flavoxate and mirabegron were prepared as part of the present disclosure. Table 6 below illustrates two such bi-layered tablets having flavoxate at 600 and 800 mg strength along with 50 mg of mirabegron. As shown in the Table 6 below, flavoxate and mirabegron are present in both IR and MR layers.

[0446] Table 6: Details of constituents in bi-layered tablets

[0447] * IPA: water (70: 30) quantity for ER portion was - 55.27% w / v of dry mix blend.

[0448] IPA: water (70: 30) quantity for IR portion was - 56.60% w / v of dry mix blend. The compressed tablets may be further film coated with weight buildup of 1 to 4%w / w.

[0449] Example 5: Exemplary bi-layered tablets

[0450] Various bi-layered FDC tablets of flavoxate and mirabegron were prepared as part of the present disclosure. Table 7 below illustrates two such bi-layered tablets having flavoxate at 600 and 800 mg strength along with 25 mg of mirabegron. As shown in the Table 7 below, flavoxate and mirabegron are present in both IR and MR layers. Table 7: Details of constituents in bi-layered tablet

[0451] The compressed tablets may be further film coated with weight buildup of 1 to 4%w / w.

[0452] Example 6: Exemplary mono-layered tablets

[0453] Various mono-layered FDC tablets of flavoxate and mirabegron were prepared as part of the present disclosure. Table 8 below illustrates one such mono-layered tablet having flavoxate at 600 mg strength along with 50 mg of mirabegron. Table 8: Details of constituents in mono-layered tablet

[0454] The compressed tablets may be further film coated with weight buildup of 1 to 4%w / w.

[0455] Example 7: Exemplary bi-layered tablet

[0456] A bi-layered FDC tablet of flavoxate and mirabegron were prepared as part of the present disclosure. Table 9 below illustrates bi-layered tablet having flavoxate at 600 mg strength along with 50 mg of mirabegron. As shown in the Table 9 below, flavoxate is present as a single layer with IR and MR portions granulated separately while mirabegron as MR layer only. Table 9: Details of constituents in bi-layered tablet

[0457] *-These constituents are present in extra granular portion of flavoxate layer only. The compressed tablets may be further film coated with weight buildup of 1 to 4%w / w. Example 8: Exemplary bi-layered tablet

[0458] A bi-layered FDC tablet of flavoxate and mirabegron were prepared as part of the present disclosure. Table 10 below illustrates bi-layered tablet having flavoxate at 800 mg strength along with 25 mg of mirabegron. As shown in the Table 10 below, flavoxate is present as a single layer with IR and MR portions granulated separately while mirabegron as MR layer only.

[0459] Table 10: Details of constituents in bi-layered tablet

[0460] *-These constituents are present in extra granular portion of flavoxate layer only.

[0461] The compressed tablets may be further film coated with weight buildup of 1 to 4%w / w.

[0462] Example 9: Exemplary bi-layered tablet

[0463] A bi-layered FDC tablet of flavoxate and mirabegron was prepared as part of the present disclosure. Table 11 below illustrates bi-layered tablet having flavoxate at 600 mg strength along with 25 mg of mirabegron. As shown in the Table 11 below, flavoxate is present as a single layer with IR and MR portions granulated separately while mirabegron as MR layer only.

[0464] Table 11 : Details of constituents in bi-layered tablet

[0465] *-These constituents are present in extra granular portion of flavoxate layer only.

[0466] The compressed tablets may be further film coated with weight buildup of 1 to 4%w / w.

[0467] Example 10: Exemplary bi-layered tablet

[0468] A bi-layered FDC of flavoxate and mirabegron was prepared as part of the present disclosure. Table 12 below illustrates bi-layered tablet having flavoxate at 1200 mg strength along with 100 mg of mirabegron. As shown in the Table 12 below, flavoxate is present as a single layer with IR and MR portions granulated separately while mirabegron as ER layer only.

[0469] Table 12: Details of constituents in bi-layered tablet

[0470] *-These constituents are present in extra granular portion of flavoxate layer only.

[0471] The compressed tablets may be further film coated with weight buildup of 1 to 4%w / w.

[0472] Example 11: Exemplary bi-layered tablet

[0473] A bi-layered FDC tablet of flavoxate and mirabegron was prepared as part of the present disclosure. Table 13 below illustrates bi-layered tablet having flavoxate at 400 mg strength along with 10 mg of mirabegron. As shown in the Table 13 below, flavoxate is present as a single layer with IR and MR portions granulated separately while mirabegron as MR layer only.

[0474] Table 13: Details of constituents in bi-layered tablet

[0475] *-These constituents are present in extra granular portion of flavoxate layer only.

[0476] The compressed tablets may be further film coated with weight buildup of 1 to 4%w / w.

[0477] Example 12: Exemplary bi-layered tablet A bi-layered FDC tablet of flavoxate and mirabegron was prepared as part of the present disclosure. Table 14 below illustrates bi-layered tablet having flavoxate at 600 mg strength along with 50 mg of mirabegron. As shown in the Table 14 below, flavoxate is present in both IR and MR portions while mirabegron is present in MR layer only. The flavoxate IR and MR portions are manufactured separately by wet granulation process while the dry granulation process by roller compaction or slugging technique is used for the manufacturing of the mirabegron layer.

[0478] Table 14: Details of constituents in bi-layered tablet

[0479] *-These constituents are present in extra granular portion of flavoxate layer only.

[0480] The compressed tablets may be further film coated with weight buildup of 1 to 4%w / w.

[0481] Example 13: Exemplary mono-layered tablet

[0482] The monolayer FDC tablet of flavoxate and mirabegron were prepared as part of the present disclosure. Table- 15 below illustrates one such tablet formulation having flavoxate at 300 mg strength along with 25 mg strength of mirabegron, respectively exhibiting immediate release drug release profiles.

[0483] Table 15: Details of components in mono-layered tablet

[0484] Manufacturing Procedure:

[0485] The mono-layered tablet was prepared by using method described in Example 1 above by using concentrations recited in Table- 15 for actives and excipients. The compressed tablets may be further film coated with weight buildup of 1 to 4%w / w.

[0486] Example 14: Exemplary bi-layered tablet

[0487] A bi-layered FDC tablet of flavoxate and mirabegron prepared as part of the present disclosure. Table 16 below illustrates such bi-layered tablet embodiment having flavoxate at 300 mg strength along with 12.5 mg strength of mirabegron, respectively. As shown in the Table 16 below, flavoxate is present as IR and mirabegron as MR layer.

[0488] Table 16: Details of components in bi-layered tablet

[0489] Manufacturing Procedure:

[0490] The bi-layered tablet was prepared by using method described in Example 1 above by using concentrations recited in Table 16 for actives and excipients. The compressed tablets may be further film coated with weight buildup of 1 to 5%w / w.

[0491] Example 15: In-vitro dissolution drug release profiles of IR and MR formulations

[0492] The in-vitro drug dissolution release rate profiles of the disclosed compositions as per present disclosure are evaluated using one of the following dissolution test method conditions.

[0493] A. For IR formulations: The following test method conditions are used for assessing dissolution profile of IR formulations as per the present disclosure.

[0494] For flavoxate hydrochloride and mirabegron

[0495] Dissolution Media: pH 1.2 HC1 (1000 ml)

[0496] Apparatus: Basket (I)

[0497] RPM: 100

[0498] Time points: 1 hr

[0499] The dissolution release data for flavoxate and mirabegron actives in IR formulations will range as per Table 17 for respective actives. Table 17

[0500] B. For MR formulations: The following test method conditions are used for assessing dissolution profile of MR formulations as per the present disclosure.

[0501] Dissolution Media: Phosphate Buffer pH-6.8

[0502] Volume - 900ml

[0503] RPM- 200

[0504] Apparatus: USP-II (Paddle)

[0505] Time points: 1 hr, 2 hrs and 12 hrs

[0506] The dissolution release data of a representative FDC formulation disclosed in the present application for both flavoxate and mirabegron will range as per Table 18 for respective actives.

[0507] Table 18: Dissolution release data for FDC formulation as per current disclosure

[0508] Example 16: Stability data

[0509] The developed MR FDC pharmaceutical formulations of Flavoxate or salt thereof and at least one P3 adrenoceptor agonist demonstrate good chemical stability. The stability data of one of the representative formulations of Example 6 is provided in in Table 18 below.

[0510] Table 19: Stability data for FDC formulations under normal and accelerated storage conditions PM005-TX0600-0050 (Example 6)

[0511] The developed formulations have exhibited good chemical stability wherein individual unknown impurity levels are meeting the globally acceptable standards for drug products. Example 16: Efficacy studies

[0512] Assessment of pain relief by the FDC formulations of the present disclosure will be done in various animal models. The obtained data will be correlated with in vivo human studies for prediction of human pain relief.

[0513] The developed formulations are stable, exhibit desired release profile for both APIs, good chemical stability and are efficacious.

[0514] Specific embodiments of the present disclosure are described above by way of representative examples only but not limited to these specific details.

[0515] Although the subject matter has been described herein with reference to certain preferred embodiments thereof, other embodiments are possible. However, those skilled in the art would appreciate that scope of the disclosure would extend to combinations and formulations comprising other flavonoids and actives known in the field of art. For illustrative purpose, the formulations, combinations and compositions of disclosure preferably comprise flavoxate hydrochloride and mirabegron. However, those skilled in the art would appreciate that scope of the disclosure would extend to combinations and formulations comprising other salts of flavoxate in combination with other P3 adrenoceptor agonist or salt or ester thereof known in the field of art. In addition, where this application has listed the steps of a method or procedure in a specific order, it may be possible, or even expedient in certain circumstances, to change the order in which some steps are performed, and it is intended that the particular steps of the method or procedure claims set forth herein below not be construed as being order-specific unless such order specificity is expressly stated in the claim. It will be obvious to those skilled in the art to make various changes, modifications and alterations to the invention described herein. To the extent that these various changes, modifications, and alteration do not depart from scope of the present invention, they are intended to be encompassed therein.

Claims

CLAIMS1. A fixed-dose combination pharmaceutical formulation of at least one beta-3 (P3)- adrenergic receptor agonist and an antispasmodic agent, wherein the antispasmodic agent is flavoxate or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical formulation as claimed in claim 1, wherein the p3-adrenergic receptor agonist is selected from mirabegron, solabegron, ritobegron, and vibegron, or a pharmaceutically acceptable salt or ester thereof.

3. The pharmaceutical formulation as claimed in claim 2, wherein the p3-adrenergic receptor agonist is mirabegron or a pharmaceutically acceptable salt or ester thereof.

4. The pharmaceutical formulation as claimed in any one of claims 1 to 3, comprising flavoxate or a pharmaceutically acceptable salt thereof in an amount of about 50 mg to 2000 mg.

5. The pharmaceutical formulation as claimed in any one of claims 1 to 4, comprising the P3-adrenergic receptor agonist in an amount of about 1 mg to 400 mg.

6. The pharmaceutical formulation as claimed in any one of claims 1 to 5, further comprising one or more pharmaceutically acceptable excipients selected from filler, disintegrant, binder, surfactant, controlled-release polymer, lubricant, glidant, diluent, antioxidant, pH modifier, anti-sticking agent, or coating agent.

7. The pharmaceutical formulation as claimed in claim 6, wherein the controlled-release polymer comprises a combination of at least one hydrophilic polymer and at least one hydrophobic polymer.

8. The pharmaceutical formulation as claimed in claim 7, wherein the weight ratio of the hydrophilic polymer to the hydrophobic polymer is in the range of about 1 : 1 to about 9: 1.

9. The pharmaceutical formulation as claimed in claim 7, wherein the controlled-release polymer is selected from hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetyl succinate, hydroxyethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyethylene oxide, povidone, homo-polymers and copolymers of acrylic acid chemically cross-linked with poly-alkenyl alcohols, Ethyl cellulose, ammonio methacrylate copolymers, polyvinyl acetate, HPMC E15, HPMC K4M, HPMC K15M, HPMC K-100M, HPMC KI 5, and cross-linked high amylose starch, or salts or derivatives thereof.

10. The pharmaceutical formulation as claimed in any one of claims 6 to 9, wherein the controlled-release polymer further comprises at least one pH-dependent polymer in an amount of about 1.0% to 15% w / w of the formulation.

11. The pharmaceutical formulation as claimed in claim 10, wherein the pH-dependent polymer is selected from ionic methacrylate copolymers, methacrylic acid-methyl methacrylate copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, sodium alginate or alginic acid derivatives, and aminoalkyl methacrylate copolymers, or salts or derivatives thereof.

12. The pharmaceutical formulation as claimed in any one of claims 6 to 11, wherein the disintegrant is selected from starch, sodium starch glycollate, croscarmellose sodium, and crospovidone.

13. The pharmaceutical formulation as claimed in any one of claims 6 to 12, wherein the disintegrant is present in an amount of about 0.1% to about 15% w / w of the formulation.

14. The pharmaceutical formulation as claimed in any one of claims 6 to 13, wherein the surfactant is selected from long alkyl chain sulfonates or sulfates, sodium dodecylbenzene sulfonate, sodium lauryl sulphate, dialkyl sodium sulfosuccinate, quaternary ammonium salts, fatty alcohols, lauryl, cetyl, stearyl, glyceryl esters, fatty acid esters, and polyoxyethylene derivatives thereof.

15. The pharmaceutical formulation as claimed in any one of claims 6 to 14, wherein the diluent is selected from mannitol, sorbitol, microcrystalline cellulose, lactose, dicalcium phosphate, and starch.

16. The pharmaceutical formulation as claimed in any one of claims 6 to 15, wherein the binder is selected from starch, polyvinylpyrrolidone, natural or synthetic gum, cellulosic polymers, ethyl cellulose, hydroxypropyl cellulose, and gelatin.

17. The pharmaceutical formulation as claimed in any one of claims 6 to 16, wherein the lubricant and glidant are selected from talc, colloidal silicon dioxide, stearic acid, magnesium stearate, and sodium stearyl fumarate.

18. The pharmaceutical formulation as claimed in any one of claims 6 to 17, wherein the coating agent is selected from one or more polyvinylpyrrolidone, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, dextrin, maltodextrin, lactose, D-mannitol, polyvinyl alcohol polymer, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, ethyl acrylate methyl methacrylate copolymer, one plasticizer, anti-tacking agent, opacifier, and coloring agent.

19. The pharmaceutical formulation as claimed in any one of the preceding claims, wherein the formulation is in a dosage form suitable for oral administration, preferably an oral solid dosage form.

20. The pharmaceutical formulation as claimed in claim 19, wherein the oral solid dosage form is selected from tablets, MUPS (Multiple Unit Pellet System), pills, granules, caplets, tablets-in-capsule, capsules, granules-in-capsule, pellets, pellets-in-capsule, powders, or any suitable form for oral administration.

21. The pharmaceutical formulation as claimed in claim 19 or 20, wherein the solid dosage form is a tablet, capsule, or MUPS.

22. The pharmaceutical formulation as claimed in claim 21, wherein the tablet has a hardness of about 5 kg / cm2to about 50 kg / cm2.

23. A fixed-dose combination pharmaceutical formulation comprising flavoxate or a pharmaceutically acceptable salt thereof, and at least one p3-adrenergic receptor agonist, and one or more pharmaceutically acceptable excipients,- wherein the formulation exhibits the dissolution profile for flavoxate or a pharmaceutically acceptable salt thereof as:(a) from about 5% to about 45% of the total flavoxate is released at about 1 hour;(b) from about 35% to about 70% of the total flavoxate is released at about 2 hours; and(c) not less than 80% of the total flavoxate is released at about 12 hours;- wherein the formulation exhibits the dissolution profile for the P3-adrenergic receptor agonist as:(a) from about 5% to about 35% of the total P3 -adrenergic receptor agonist is released at about 1 hour;(b) from about 35% to about 70% of the total P3 -adrenergic receptor agonist is released at about 2 hours; and(c) not less than 80% of the total P3 -adrenergic receptor agonist is released at about 12 hours.

24. The pharmaceutical formulation as claimed in claim 23, wherein the dissolution profile for flavoxate or a pharmaceutically acceptable salt thereof and for P3- adrenergic receptor agonist is assessed using dissolution media having pH of about 5 to 8 for suitable duration at about 20 to 200 rpm.

25. The fixed-dose combination pharmaceutical formulation as claimed in claim 23, wherein the dissolution profile for flavoxate or a pharmaceutically acceptable salt thereof is assessed using dissolution media having pH of about 1 to 2 followed by pH of about 6 to 8 for suitable duration at about 50 to 150 rpm; and the dissolution profile for the p3-adrenergic receptor agonist or a pharmaceutically acceptable salt thereof is assessed using dissolution media comprising required quantity of at least one surfactant having pH of about 1 to 2 followed by pH of about 7 to 8 for suitable duration at about 50 to 150 rpm.

26. A fixed-dose combination pharmaceutical formulation comprising flavoxate or a pharmaceutically acceptable salt thereof, and at least one P3 -adrenergic receptor agonist, and one or more pharmaceutically acceptable excipients,- wherein the formulation exhibits the dissolution profile for flavoxate as not less than 85% of the total flavoxate is released by about 60 minutes;- wherein the formulation exhibits the dissolution profile for the P3-adrenergic receptor agonist as not less than 60% of the total p3-adrenergic receptor agonist is released by about 60 minutes.

27. The fixed-dose combination pharmaceutical formulation as claimed in claim 26, wherein the dissolution profile for the flavoxate and / or the P3 -adrenergic receptor agonist is assessed using dissolution media having pH of about 1 to 2 for suitable duration at about 50 to 150 rpm.

28. A fixed-dose combination pharmaceutical formulation comprising: c) a therapeutically effective amount of flavoxate or a pharmaceutically acceptable salt thereof, and d) a therapeutically effective amount of at least one p3-adrenergic receptor agonist, wherein the formulation is a modified-release oral solid dosage form capable of releasing both active agents over a period of about 12 to 24 hours, and wherein the 3-adrenergic receptor agonist is present in an amount from about 0.04% to about 25% w / w, and flavoxate is present in an amount ranging from about 4% to 85% w / w of the total formulation weight.

29. The formulation as claimed in claim 28, wherein the dosage form is a mono-layered, bi-layered tablet, or multi-layered tablet, capsule, or MUPS.

30. The formulation as claimed in claim 28 or 29, wherein the modified-release profile is achieved using a combination of at least one hydrophilic polymer and at least one hydrophobic polymer, in a weight ratio of about 1 : 1 to about 9: 1.

31. The formulation as claimed in any one of claims 28 to 30, wherein the modified- release dosage form further comprises at least one pH-dependent polymer in an amount of about 1.0% to 15% w / w of the formulation.

32. The formulation as claimed in any one of claims 28 to 31, wherein the p3-adrenergic receptor agonist per unit dosage form is from about 1 mg to about 400 mg, and flavoxate per unit dosage form is from about 50 mg to 2000 mg.

33. The formulation as claimed in any one of claims 1 to 32, wherein the P3-adrenergic receptor agonist per unit dosage form is from about 5 mg to about 350 mg, preferably from about 20 mg to about 250 mg, more preferably from about 50 mg to 200 mg; and flavoxate per unit dosage form is from about 100 mg to 1800 mg, preferably from about 300 mg to about 1500 mg, more preferably from about 600 mg to 1500 mg.

34. The formulation as claimed in any one of claims 1 to 33, wherein the P3-adrenergic receptor agonist per unit dosage form is from about 10 mg to about 250 mg, preferably from about 25 mg to about 200 mg, more preferably from about 50 mg to 150 mg; and flavoxate per unit dosage form is from about 300 mg to 1800 mg, preferably from about 400 mg to about 1500 mg, more preferably from about 600 mg to 1500 mg.

35. The formulation as claimed in any one of claims 1 to 34, wherein the P3 -adrenergic receptor agonist per unit dosage form is from about 20 mg to about 250 mg, preferably from about 50 mg to about 75 mg, more preferably from about 25 mg to 50 mg; and flavoxate per unit dosage form is from about 300 mg to 1200 mg, preferably from about 400 mg to about 1200 mg, more preferably from about 800 mg to 1200 mg.

36. The formulation as claimed in any one of claims 1 to 35, wherein the dosage form has a total weight ranging from about 100 mg to about 3000 mg.

37. A solid oral fixed-dose combination pharmaceutical formulation in the form of a bilayered tablet or multi-layered tablet comprising:(a) at least one immediate-release (IR) layer comprising flavoxate or a pharmaceutically acceptable salt thereof and optionally, at least one P3 -adrenergic receptor agonist;(b) at least one modified-release (MR) layer comprising flavoxate or a pharmaceutically acceptable salt thereof and optionally, at least one P3 -adrenergic receptor agonist;(c) optionally, at least one intermediate layer disposed between the IR and MR layers, comprising an inert excipient and configured to prevent interaction between the layers and preserve the independent dissolution profiles of each active agent; wherein the formulation delivers flavoxate and the P3 adrenergic receptor agonist in one or both of IR and MR forms.

38. The formulation as claimed in claim 37, wherein the formulation comprises flavoxate or a pharmaceutically acceptable salt thereof in a total amount of about 50 mg to about 2000 mg; and 3-adrenergic receptor agonist in an amount of about 1 mg to about 400 mg; and wherein the tablet comprises one or more controlled-release polymers and other pharmaceutically acceptable excipients.

39. The formulation as claimed in any one of the preceding claims, wherein the formulation comprises drug-related impurities of each active agent present at less than about 5% by weight relative to the labeled amount of each active agent; and wherein the total drug-related impurities present in the formulation are less than about 6% by weight relative to the combined labeled amounts of the active agents.

40. The formulation as claimed in any one of the preceding claims, wherein the formulation comprises flavoxate or a pharmaceutically acceptable salt thereof in an amount of about 4% to about 90% by weight of the formulation;P3-adrenergic receptor agonist in an amount of about 0.04% to about 30% by weight of the formulation; and one or more pharmaceutically acceptable excipients in an amount of about 5% to about 95% by weight of the formulation, or about 35% to about 85% by weight of the formulation.

41. The formulation as claimed in any one of the preceding claims, wherein the P3- adrenergic receptor agonist and / or flavoxate or a pharmaceutically acceptable salt thereof exhibits a modified-release, immediate-release, or a combination thereof drug release profile.

42. The formulation as claimed in claim 41, wherein the P3 -adrenergic receptor agonist and / or flavoxate or a pharmaceutically acceptable salt thereof exhibits a modified- release profile or an immediate-release profile.

43. The fixed-dose combination pharmaceutical formulation as claimed in claim 42, wherein when the P3 -adrenergic receptor agonist and / or flavoxate or a pharmaceutically acceptable salt thereof exhibits an immediate-release profile, said formulation is substantially free of controlled-release polymer.

44. The formulation as claimed in claim 41, wherein the P3 -adrenergic receptor agonist and / or flavoxate or a pharmaceutically acceptable salt thereof exhibits an immediate- release and a modified-release profile.

45. The formulation as claimed in claim 44, wherein the flavoxate or a pharmaceutically acceptable salt thereof is present in the immediate-release portion, and optionally in the modified-release portion of the oral dosage form.

46. The formulation as claimed in claim 44, wherein the flavoxate or pharmaceutically acceptable salt thereof is present in the immediate-release and modified-release portions in a ratio of about 1 : 1 to about 1 :8.

47. The formulation as claimed in any one of claims 44 to 46, wherein the P3-adrenergic receptor agonist is present in the modified-release portion and optionally in the immediate-release portion of the oral dosage form.

48. The formulation as claimed in claim 44, wherein the P3-adrenergic receptor agonist is present in the immediate-release and modified-release portions of the oral dosage form in a ratio of about 1 : 1 to about 1 :8.

49. The formulation as claimed in claim 44 or 45, wherein the flavoxate or pharmaceutically acceptable salt thereof is present in an immediate-release portion at about 2.5% w / w to about 100% w / w and in a modified-release portion at about 0% w / w to about 97.5% w / w of the total weight of the flavoxate or pharmaceutically acceptable salt thereof in the oral dosage form.

50. The formulation as claimed in claim 49, wherein the P3 -adrenergic receptor agonist is present in an immediate-release portion at about 0% w / w to about 100% w / w and / or in modified-release portion at about 0.25%w / w to about 100% w / w of the total weight of the p3-adrenergic receptor agonist in the oral dosage form.

51. The fixed-dose combination pharmaceutical formulation as claimed in claim 41 or 44, wherein the p3-adrenergic receptor and / or flavoxate or a pharmaceutically acceptable salt thereof exhibits a modified-release profile or a combination of modified-release and immediate-release profile, and wherein the disintegrant is present in an amount of about 0.1% to about 1.5% w / w of the formulation.

52. The fixed-dose combination pharmaceutical formulation as claimed in claim 43 or 44, wherein the p3-adrenergic receptor and / or flavoxate or a pharmaceutically acceptable salt thereof exhibits an immediate-release profile, and wherein the disintegrant is present in an amount of about 0.1 % to about 15 % w / w of the formulation.

53. A method for the preparation of a bi-layered tablet, multi-layered tablet, Multiple Unit Pellet System (MUPS), or capsule comprising at least one 3-adrenergic receptor agonist and flavoxate or a pharmaceutically acceptable salt thereof, the method comprising: g) blending required quantities of at least one 3-adrenergic receptor agonist and flavoxate or a pharmaceutically acceptable salt thereof, along with one or more pharmaceutically acceptable excipients, to obtain a dry blend mixture separately for one or more of immediate-release (IR) and / or modified-release (MR) layers; h) optionally passing the blend mixture of IR and / or MR layers of step a) through a screen having a mesh of appropriate size to obtain a uniformly sized particulate mixture for each layer; i) granulating the uniformly sized particulate mixture of IR and / or MR layers of step b), or the blend mixture of step a), by suitable means to obtain wet granules;j) drying the wet granules of step c) for a suitable time and at a suitable temperature to obtain dried granules of IR and / or MR layers; k) optionally screening the dried granules of step d) through a mesh of appropriate size to obtain uniformly sized granules; l) lubricating the dried granules of step d) or e), with at least one extra-granular excipient and at least one lubricant to obtain lubricated granules; m) compressing the granules of step e) by suitable means to obtain the tablet, or filling the granules into capsules.

54. A method of preparing a mono-layered pharmaceutical tablet comprising flavoxate or pharmaceutically acceptable salt thereof and at least one P3 -adrenergic receptor agonist comprising: h) blending required quantities of at least one P3 -adrenergic receptor agonist and flavoxate or pharmaceutically acceptable salt thereof with pharmaceutically acceptable excipients to obtain a dry blended mixture; i) optionally screening the blended mixture of step a) through a mesh of appropriate size to obtain screened mixture; j) granulating the blended mixture of step a), or screened mixture of step b) by suitable means to obtain wet granules; k) drying the wet granules of step c) by suitable means at a suitable temperature to obtain dried granules; l) optionally screening the dried granules of step d) through a mesh of appropriate size to obtain screened dried granules; m) lubricating the dried granules of steps d) or e), with at least one extra-granular excipient and at least one lubricant to obtain lubricated granules; n) compressing the granules of step f) by suitable means to obtain the tablet.

55. The method as claimed in claim 53 or 54, comprising coating the granules of any one of steps c) to f) with a polymer dispersion to obtain polymer-coated modified-release granules.

56. The method as claimed in any one of claims 53 to 55, wherein the pharmaceutically acceptable excipient of step a) or the extra-granular excipient of step f) is selected from one or more of filler, disintegrant, binder, surfactant, controlled-release polymer, lubricant, glidant, diluent, antioxidant, pH modifier, anti-sticking agent, coating agent.

57. The method as claimed in any one of claims 53 to 56, comprising coating the tablets with film to obtain weight build-up of around 1 to 4% w / w.

58. The method as claimed in any one of claims 53 to 57, wherein the tablet has a hardness of about 5 kg / cm2to about 50 kg / cm2.

59. A method for the preparation of a capsule comprising at least one P3 -adrenergic receptor agonist and flavoxate or a salt thereof, the method comprising: a) preparing at least one tablet or granules comprising at least one P3 -adrenergic receptor agonist; b) preparing at least one tablet or granules comprising flavoxate; c) preparing the capsule comprising the tablets or granules of step a) and step b); d) optionally adding one or more pharmaceutically acceptable excipients in steps a) and b); e) optionally preparing the capsule in the step c) by adding one or more pharmaceutically acceptable excipients.

60. A method of treating and / or ameliorating at least one symptom of benign prostatic hyperplasia, benign prostatic enlargement, detrusor overactivity, overactive bladder, bladder outlet obstruction, lower urinary tract symptoms due to bladder dysfunction or neurogenic bladder, chronic prostatitis / chronic pelvic pain syndrome, or post-operative irritative voiding symptoms, comprising administering a formulation as claimed in any one of claims 1 to 52.

61. Use of the formulation as claimed in any one of claims 1 to 52 for the treatment, alleviation, amelioration and / or prevention of at least one of benign prostatic hyperplasia, benign prostatic enlargement, detrusor overactivity, overactive bladder, bladder outlet obstruction, lower urinary tract symptoms due to bladder dysfunction orneurogenic bladder, chronic prostatitis / chronic pelvic pain syndrome, or post-operative irritative voiding symptoms, and / or one or more symptoms associated therewith.

62. The formulation as claimed in any one of claims 1 to 52 for use in the preparation of a medicament for the treatment, alleviation, amelioration and / or prevention of at least one of benign prostatic hyperplasia, benign prostatic enlargement, detrusor overactivity, overactive bladder, bladder outlet obstruction, lower urinary tract symptoms due to bladder dysfunction or neurogenic bladder, chronic prostatitis / chronic pelvic pain syndrome, or post-operative irritative voiding symptoms, and / or one or more symptoms associated therewith.

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