Controlled release formulation of flavoxate and method for preparing same

Abstract

The present disclosure relates to controlled or sustained release formulations of flavoxate or similar lipophilic acid soluble drugs as bilayer tablets, multi-layer tablets, multi-coated mini-tablets, MUPS (Multiple Unit Pellet System) tablets, pellets or beads loaded in capsules with a biphasic drug release profile. The present disclosure also relates to methods for the preparation of such formulations and their uses.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present disclosure relates to controlled or sustained release formulations of flavoxate or similar lipophilic acid soluble drugs as bilayer tablets, multi-layer tablets, multi-coated mini-tablets, MUPS (Multiple Unit Pellet System) tablets, pellets or beads loaded in capsules with a biphasic drug release profile. The present disclosure also relates to methods for the preparation of such formulations and their uses. [Background technology]

[0002] 2. Background of the Invention Oral ingestion is a convenient and commonly used drug delivery route due to ease of administration, high patient compliance, cost-effectiveness, reduced sterility constraints, and versatility in dosage form design. However, a major challenge with oral dosage forms is their poor bioavailability.

[0003] 2-Piperidinoethyl 3-methylflavone-8-carboxylate hydrochloride (hereafter referred to as flavoxate or flavoxate hydrochloride) is a flavonic acid derivative synthesized by Recordati Laboratories in 1960. Flavoxate is an antispasmodic drug with strong smooth muscle relaxant properties. It relaxes smooth muscle by inhibiting phosphodiesterase enzymes and calcium antagonistic action. The drug acts preferentially on the urogenital tract and not on the intestine. It has both central and direct smooth muscle relaxant properties. It has a local anesthetic effect as strong as lidocaine, but has no anticholinergic effect [M Zor, E Aydur, RR Dmochowski. Flavoxate in urogynecology: an old drug revisited. International Urogynecology Journal, 06 Dec 2014, 26(7):959-966]. Using rat brain tissue, it has been shown to have only weak binding activity to receptors directly or indirectly involved in the neural control of the lower urinary tract (α- and β-noradrenergic, muscarinic, serotonergic and opiate receptors and calcium binding sites).

[0004] Flavoxate hydrochloride exhibits little affinity for muscarinic receptors and has a median inhibitory concentration (IC 50 ) is 12.2 μm. This finding supports the idea that anticholinergic drugs, e.g., oxybutynin (IC 50This is in clear contrast to the strong binding to muscarinic receptors typical of urinary incontinence drugs such as 5.4 μm. It also helps explain the low incidence and severity of typical anticholinergic clinical effects (dry mouth, tremor, blurred vision, and tachycardia) exhibited by flavoxate hydrochloride in the treatment of lower urinary tract diseases. Furthermore, the smooth muscle relaxant effect of flavoxate hydrochloride reduces obstructive symptoms (urinary hesitancy, intermittency, dribbling, and retention) [R. Ruffmann. A Review of Flavoxate hydrochloride in the Treatment of Urge Incontinence, The Journal of International Medical Research 1988; 16: 317-330]. And, flavoxate does not cause the undesirable increase in residual urine volume that is usually seen when anticholinergic drugs are administered.

[0005] Flavoxate hydrochloride is used therapeutically to relieve symptoms of urinary frequency, especially nocturia, dysuria, urgency, suprapubic vesicular pain, urinary frequency and urinary incontinence due to various pathological conditions such as prostatitis, urethritis, cystitis, urethrocystitis, urethral trigonitis, and side effects of radiotherapy or surgical therapy of the urinary tract.Flavoxate is also indicated for the relief of vesicourethral spasm due to catheterization, cystoscopy or indwelling catheter, before cystoscopy or catheterization, or sequelae of surgical intervention of the lower urinary tract.Flavoxate is also used to relieve irritative symptoms of benign prostatic hyperplasia (BPH) and overactive bladder.However, the use of flavoxate hydrochloride is not limited to the treatment of bladder dysfunction only.Flavoxate hydrochloride as a drug is also used to treat premature labor and abdominal dysmenorrhea pain. Renal colic has also been effectively treated with flavoxate hydrochloride, and the compound has also been administered as an adjunctive antispasmodic during extracorporeal (shock wave) lithotripsy.

[0006] Flavoxate as a drug is commercially available in strengths of 100 mg and 200 mg sugar-coated immediate release (IR) tablets. Therapeutic doses are usually 600-800 mg per day, 3-4 times per day. In some cases, doses up to 1200 mg per day have been used and found to be more effective. Flavoxate needs to be administered 3-4 times per day, sometimes 2 tablets per day. This dosing regimen affects patient compliance and increases the tablet burden, resulting in missed doses that may affect the efficacy of the treatment. For indications requiring chronic dosing, such as urge incontinence and overactive bladder, 3-4 times per day treatment is highly unacceptable and inconvenient. With the traditional IR dosage form, there is a risk of reduced patient compliance, for example, the elderly may forget to take the tablets regularly, or there may be a more serious risk of overdosing by unknowingly taking more than the prescribed amount. Sleep deprivation in the elderly is also caused by nocturia, which is often overlooked. Taking flavoxate IR tablets in the evening does not cover the entire nighttime sleep period. Moreover, the short half-life of flavoxate makes it impossible to take a single dose of a dosage form that contains a sufficient amount of active substance to provide a therapeutic effect while the patient is asleep overnight. Thus, one of the main disadvantages of conventional flavoxate IR tablets is their administration schedule.

[0007] The advantages of controlled or extended release (CR or ER) products are well known and documented in the pharmaceutical field. The advantages include, but are not limited to, the ability to maintain desirable blood concentrations of the drug over an extended period of time by minimizing peak-to-trough fluctuations in plasma concentrations. The drug plasma levels of ER products are maintained within a narrow window with no sharp peaks and with an AUC (area under the curve) of the plasma concentration vs. time curve equivalent to the total AUC obtained from multiple administrations of an IR dosage form. This further avoids the side effects associated with high concentrations of drug released immediately into the blood. Additionally, ER products also have the advantage of avoiding repeated overnight dosing. This improves patient compliance and improves the patient's quality of life.

[0008] Flavoxate hydrochloride is a poorly soluble and poorly compressible drug. Therefore, another challenge for this drug is to form a compact, orally administrable tablet. To accommodate the large doses required in an ingestible tablet form, the amount of controlled release polymers, binders and excipients must be kept low so that the final total weight of the tablet does not exceed practical limits. Tablets that are too large and cannot be chewed are not easily ingested by the elderly, much less by those in a state of physical impairment. Delivery of ER formulations has always been a challenge, as the low solubility of flavoxate generally requires a relatively large amount of excipients to provide a particular delivery profile.

[0009] As mentioned above, the main challenge in designing oral dosage forms is their low bioavailability. Oral bioavailability depends on several factors, including aqueous solubility, drug permeability, dissolution rate, first-pass metabolism, presystemic metabolism, and susceptibility to excretion mechanisms. The most common causes of low oral bioavailability are due to poor solubility and poor permeability.

[0010] JPS63154619A attempts to address the problem of administering flavoxate hydrochloride using a delayed release formulation. This Japanese patent application describes an ER formulation by preparing a fast-dissolving flavoxate formulation and a slow-dissolving flavoxate formulation and mixing them in a ratio of 1:0.5 to achieve a release duration more than twice that obtained by 100 mg of flavoxate produced by conventional IR method. However, the pharmaceutical formulation of this patent application cannot provide 24-hour efficacy.

[0011] US Pat. No. 9,750,701 provides for achieving a delayed release profile of a drug such as flavoxate by providing the tablet with anisotropic physical properties by providing it with depressions.

[0012] Satyavathi et al. [K. Satyavathi, M. Venu, P. Gayathri, P. Bhojaraju and LK Kanthal. Formulation and development of Flavoxate hydrochloride ER capsules. IJPSR, 2014; Vol. 5(5): 1949-1956] described making ER capsules of Flavoxate using ethyl cellulose and hydroxypropyl methylcellulose, extruding them as pellets, loading the pellets with the drug, and applying an ER coating to the drug-loaded pellets. The dissolution profile indicates that this formulation cannot provide 24-hour therapeutic coverage.

[0013] EP0393572A2, EP0250374B1 and US Patent Nos. 9,642,809 and 5,165,937 attempt to provide controlled release of flavoxate, all of which are incorporated herein by reference. US Patent No. 9,642,809 describes controlled release of a drug by incorporating the drug in a water-soluble microcrystalline matrix. EP0250374B1 teaches a drug-excipient ratio of 60:40, which is inappropriate for single dose delivery of 600 mg or 800 mg of flavoxate.

[0014] EP0393572A2 and US5165937 suggest the mandatory incorporation of acidifiers (such as tartaric acid or citric acid) among other additives and excipients in oral dosage forms for the external diffusion of flavoxate. Flavoxate is not very soluble in the unsalified state and it is advantageous to maintain the salted state while present in the intestinal environment where the basic pH of the intestinal environment tends to cause gradual desalting. The challenge of formulating flavoxate without an acidifier is that flavoxate is not very soluble in the unsalified form and an acidifier is required to achieve an adequate amount of flavoxate and to facilitate the controlled release of flavoxate. A crossover study was conducted in six healthy adult volunteers who received 400 mg of flavoxate hydrochloride CR tablets. The observed duration of therapeutically effective levels of flavoxate was 11.35 hours at plasma concentrations of 1 mcg / ml or higher, which is the minimum effective value. Therefore, this test is not suitable for once-daily preparations.

[0015] RASHID et al., 2021 [Development and evaluation of Flavoxate HCl double core compressed tablet formulations by swellable granulation technique. Acta Poloniae Pharmaceutica- Drug Research, Vol. 78 No. 5 667-677] describes the development of a double core differential release tablet of flavoxate HCl. The paper discloses the incorporation of a large amount of Avicel PH10l in the outer core granules of flavoxate hydrochloride tablets. The paper also discloses the incorporation of citric acid as an essential ingredient in the extended release inner core when it contains HPMC K15. The paper also discloses an extended release inner core containing Kollidon SR and no HPMC K15. The paper teaches either the incorporation of acid or the incorporation of a large amount of excipients that limits the amount of flavoxate HCl incorporated to obtain a tablet that has both a size that ensures patient compliance and an amount of flavoxate HCl that ensures sustained release over an extended period of time.

[0016] WO202021422A1 is another patent application of the applicant relating to a CR oral formulation containing about 400-800 mg of flavoxate salt as an active ingredient, the oral formulation does not contain an acidifier as a monolayer tablet. This application discloses the preparation of a reduced size monolayer tablet with an ER drug profile.

[0017] Oral studies in humans have shown that flavoxate is readily absorbed from the intestine and is converted almost immediately to MFCA (3-methylflavone carboxylic acid). Both MFCA and flavoxate inhibit cAMP-dependent phosphodiesterase, which is important in smooth muscle relaxation. Following IV administration (equimolar to 100 mg), the following parameters were calculated for flavoxate: T1 / 2 83.3 minutes, apparent volume of distribution 2.89 liters / kg. The apparent distribution of MFCA was 0.20 liters / kg. No free flavoxate was detected in the urine (24 hours). However, 47% of the dose was excreted as MFCA.

[0018] After single oral doses of 200 mg and 400 mg flavoxate to volunteers, little free flavoxate was detected in plasma. Peak levels of MFCAs were achieved 30-60 minutes after the 200 mg dose and approximately 2 hours after the 400 mg dose. The AUC of the 400 mg dose was approximately twice that of the 200 mg dose. Approximately 50% of the administered dose was excreted as MFCAs within 12 hours, most of which was excreted within the first 6 hours. After repeated oral doses (200 mg, TDS, 7 days), the cumulative excretion of metabolites stabilized at 60% of the dose by day 3 and remained almost unchanged after 1 week (Flavoxate hydrochloride 200 mg film-coated tablets, Summary of Product Characteristics available at https: / / www.medicines.org.uk / emc / product / 322 / smpc).

[0019] The short half-life of flavoxate makes it difficult to maintain effective therapeutic levels in the circulation throughout the 24 hour period, and existing regimens administering 100 or 200 mg of flavoxate require the ingestion of many tablets per day, resulting in poor patient compliance.

[0020] Flavoxate has very low aqueous solubility and a slow dissolution rate, which creates formulation problems. Its effectiveness can be significantly limited, and absorption can vary greatly among individuals. Many techniques have been used to provide CR pharmaceutical dosage forms to maintain therapeutic serum levels of the drug. However, for relatively poorly water-soluble drugs such as flavoxate, the development of CR formulations generally requires considerable experimentation. This is because it is often not easy to predict whether a particular CR formulation will result in the desired modified release profile while maintaining suitable handling characteristics such as sufficient tablet hardness and adequate friability. The task of preparing a CR formulation of flavoxate has proven difficult due to the fact that water-insoluble drugs tend to produce inconsistent drug release profiles. The pharmacokinetic challenges are so great that, despite the passage of 50 years, the therapeutic dose regime has not changed significantly.

[0021] The low solubility of flavoxate hydrochloride in aqueous media tends to result in reduced dissolution or drug release in the lower intestinal tract after oral administration, i.e., in the pH range of 5 to 7.4, especially when it is formulated as an ER solid dosage form.

[0022] A biphasic drug delivery system is known in the art as a drug delivery system for oral administration that is composed of one immediate release, i.e. IR, layer and one sustained release, i.e. CR, layer. The concept of layered tablets is used to develop CR and sustained release formulations. This system is typically used when maximum relief needs to be achieved quickly, followed by a sustained release phase to avoid repeated administration.

[0023] There are no known "layered tablet" forms of flavoxate or its salts in the art. Moreover, known methods for preparing layered tablets of other drugs employ diverse approaches and incorporate entirely different ingredients in the formulation.

[0024] The therapeutic dose of flavoxate is generally 600-800 mg / day, and in some cases may require multiple doses up to 1200 mg / day. The half-life of flavoxate hydrochloride is very short, with a duration of therapeutic activity of approximately 5-6 hours. Therefore, there is a need to develop a formulation that maintains the therapeutic effect of the drug for a longer period and reduces the frequency of administration, thereby significantly improving patient compliance and quality of life.

[0025] Clearly, there is an unmet need for a CR drug delivery system that ensures an immediate and sustained drug release profile of flavoxate to achieve desired therapeutic plasma concentrations over a 12-24 hour period in a single dose dosage form. Summary of the Invention

[0026] The present disclosure provides CR or ER release formulations or drug delivery systems comprising flavoxate or its salts that provide once or twice daily treatment and effective plasma concentrations for up to 12-24 hours. The present disclosure provides CR or ER formulations of flavoxate or its salts as bilayer, multi-layer tablets, multi-coated mini-tablets, MUPS (multiple unit pellet system) tablets, pellets or beads filled in capsules with a biphasic drug release profile. The present disclosure also provides methods for preparing such formulations and uses thereof.

[0027] In some embodiments, the ER formulations of flavoxate or its salts provided are designed so that a sufficient amount of drug is released immediately to achieve plasma levels similar to those of the IR dosage form, and the remaining drug is released gradually over an extended period of time to maintain drug concentrations within the therapeutic window. Thus, the formulations provided herein provide rapid and extended release of flavoxate. In some embodiments, the ER formulations of flavoxate provided herein provide reduced side effects and avoided plasma level fluctuations due to a simplified administration schedule compared to the IR dosage form, thereby improving patient compliance.

[0028] Thus, in one aspect, the present disclosure provides a flavoxate formulation with improved patient compliance.The present disclosure in some embodiments provides a drug delivery system for flavoxate that offers the advantages of both IR and ER profiles, and a simple and low-cost method for manufacturing the drug delivery system or formulation.In some embodiments, the CR or ER formulation of the present disclosure can be administered as a single ingestible dosage form and has improved bioavailability.

[0029] In another aspect, the present disclosure provides a simple and economical manufacturing method to provide a biphasic drug delivery system of flavoxate and also develops a bioavailable ER dosage form of flavoxate that upon oral administration provides adequate plasma levels and therapeutic effect for about 12 to about 24 hours.

[0030] The ER formulations or drug delivery systems of the present disclosure provide an extended sustained release profile of about 12 to about 24 hours and are suitable for administration as a single ingestible dosage form. In some embodiments, the formulations exhibit a biphasic drug release profile, whereby a sufficient amount of drug is released in the first few hours to achieve plasma levels similar to conventional IR dosage forms, and the remaining drug is released gradually to maintain drug concentrations within the therapeutic window.

[0031] In some embodiments, the formulations of the present disclosure exhibit a biphasic drug release profile in which a sufficient amount of drug is initially released within 2 hours to achieve plasma levels similar to conventional IR dosage forms, and the remaining drug is gradually released over about 12 to about 24 hours to maintain drug concentrations within the therapeutic window. In some embodiments, the formulations developed include an IR drug layer of about 10-30 wt% and an ER drug layer of about 70-90 wt%. In some embodiments, the ER formulations of the present disclosure are developed by using a careful selection of controlled release polymers, resulting in a formulation that can be manufactured into a commercially acceptable form, e.g., a tablet that exhibits unexpectedly superior bioavailability of flavoxate and extended duration of action. This allows a single dose to deliver therapeutic levels of drug to the recipient for up to about 12 to about 24 hours.

[0032] The present disclosure provides ER formulations as bilayer tablets, multi-layer tablets, multi-coated mini-tablets, MUPS tablets, pellets or beads filled into capsules. In some embodiments, the ER formulations can be easily manufactured by direct compression, dry granulation, wet granulation, fluid bed processing or hot melt granulation techniques.

[0033] Other aspects of the present disclosure include methods for treating diseases or disorders responsive to flavoxate, such as disorders of the urogenital tract, including, but not limited to, urinary frequency, nocturia, dysuria, urgency, vesicle suprapubic pain, frequency, urinary incontinence, and side effects of radiation or surgical therapy of the urinary tract, vesicourethral spasm due to catheterization, cystoscopy or indwelling catheters, irritative symptoms of benign prostatic hyperplasia (BPH) and overactive bladder, due to various pathological conditions such as, but not limited to, prostatitis, urethritis, cystitis, urethro-cystitis, uretherotrigonitis, or methods for treating as prophylaxis prior to cystoscopy, catheter therapy, or methods for treating sequelae of surgical intervention of the lower urinary tract.

[0034] In some embodiments, the present disclosure provides a controlled release oral formulation of flavoxate having a biphasic drug release profile comprising about 600-800 mg of a flavoxate salt as an active ingredient, at least one surfactant, and at least one polymer, wherein the surfactant has a hydrophilic-lipophilic balance value of at least "8", the formulation comprising at least one immediate release drug layer and at least one sustained release drug layer, wherein the at least one immediate release drug layer is about 10-30 wt% of the formulation, and the at least one sustained release drug layer is about 70-90 wt% of the formulation.

[0035] In some embodiments, the present disclosure provides a controlled release oral formulation of flavoxate having a biphasic drug release profile, where upon single administration, about 10% w / w to 35% w / w of the flavoxate salt is released within the first 2 hours, and the remaining flavoxate salt is released over a period of up to 12 to 24 hours.

[0036] In some embodiments, the present disclosure provides that at least one polymer in the controlled release oral formulation comprises a hydrophilic cellulosic polymer or a salt thereof, a hydrophobic cellulosic polymer or a salt thereof, an ionic methacrylate copolymer or a salt thereof, or a combination thereof.

[0037] In some embodiments, the present disclosure provides that at least one polymer in the controlled release oral formulation comprises hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetylsuccinate (HPMC AS), Eudragit L30D55, Eudragit L100, or a combination thereof.

[0038] In some embodiments, the disclosure provides that at least one surfactant in the controlled release oral formulation comprises a long chain alkyl sulfonate or long chain alkyl sulfate, sodium dodecylbenzenesulfonate, sodium lauryl sulfate, a dialkyl sodium sulfosuccinate, a quaternary ammonium salt, a fatty alcohol, e.g., lauryl, cetyl, steryl, etc., a glyceryl ester, a fatty acid ester, a polyoxyethylene derivative of a fatty acid ester, or a combination thereof.

[0039] In some embodiments, the present disclosure provides that at least one surfactant in the controlled release oral formulation comprises a polysorbate grade that includes Tween-20, Tween-80, or a combination thereof.

[0040] In some embodiments, the disclosure provides that the controlled release oral formulation comprises at least one diluent, wherein the at least one diluent comprises mannitol, sorbitol, microcrystalline cellulose, lactose, dicalcium phosphate, starch, or a combination thereof.

[0041] In some embodiments, the present disclosure provides that the controlled release oral formulation comprises at least one binder, wherein the at least one binder comprises starch, polyvinylpyrrolidone, a natural or synthetic gum, a cellulosic polymer, ethyl cellulose, hydroxypropyl cellulose, gelatin, or a combination thereof.

[0042] In some embodiments, the present disclosure provides that the controlled release oral formulation comprises at least one disintegrant, wherein the at least one disintegrant comprises starch, sodium starch glycolate, croscarmellose sodium, crospovidone, or a combination thereof.

[0043] In some embodiments, the disclosure provides that the controlled release oral formulation comprises at least one lubricant or glidant, wherein said at least one lubricant or glidant comprises talc, colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, or a combination thereof.

[0044] In some embodiments, the disclosure provides that the controlled release oral formulation releases the flavoxate salt over a period of 12 to 24 hours.

[0045] In some embodiments, the disclosure provides that the flavoxate salt in the controlled release oral formulation is flavoxate hydrochloride.

[0046] In some embodiments, the present disclosure provides that the controlled release oral formulation is a solid dosage form, preferably a tablet or capsule.

[0047] In some embodiments, the disclosure provides that the tablet is a bilayer tablet, a trilayer tablet or a multi-layer tablet, a multi-coated mini tablet, a multiple unit pellet system tablet, a pellet or a bead filled capsule.

[0048] In some embodiments, the present disclosure provides a tablet having a packing capacity of about 6 kg / cm 2 ~ approx. 40kg / cm 2 It is stipulated that the hardness of the material is 100%.

[0049] In some embodiments, the disclosure provides that the tablet comprises one or more functional or non-functional coatings.

[0050] In some embodiments, the present disclosure provides that the functional film coating of the tablet is an ethylcellulose dispersion with a soluble polymer or an enteric polymer based dispersion with a water soluble component.

[0051] In some embodiments, the present disclosure provides that the non-functional film coating of the tablet is a hydroxypropyl methylcellulose-based film coating dispersion with or without flavorings to enhance product acceptability of bitter tasting drugs.

[0052] In some embodiments, the disclosure provides that the controlled release oral formulation releases about 10% to about 35% of the active ingredient between about 0-2 hours, about 35% to about 75% of the active ingredient between about 2-4 hours, about 50% to about 90% of the active ingredient between about 4-6 hours, and about 75% or more of the active ingredient between about 6-8 hours.

[0053] In some embodiments, the present disclosure provides a method for producing a tablet having a biphasic drug release profile comprising a flavoxate salt as an active ingredient, the method comprising: (a) mixing an amount of flavoxate salt with an amount of suitable filler, binder, surfactant and controlled release polymer in an appropriate ratio of aqueous and organic solvent media to obtain a blend material for immediate release layer or sustained release layer, respectively; (b) granulating the blended material obtained in step (a) using a suitable dry granulator or using a suitable granulating apparatus with a solution of binding polymer in a non-aqueous or hydroalcoholic solvent to obtain granules; (c) drying the granules obtained in step (b) at a suitable temperature to obtain dried granules; (d) sieving the dried granules obtained in step (c) through a suitable size mesh to obtain granules of desired size; (e) lubricating the granules obtained in step (d) with a soluble or insoluble lubricant to obtain a formulation; and (f) compressing the formulation obtained in step (e) to form tablets; Includes.

[0054] In some embodiments, the disclosure provides that the amount of the flavoxate salt in the method is about 100 mg to 200 mg for the immediate release layer and about 300 mg to 700 mg for the sustained release layer.

[0055] In some embodiments, the disclosure provides in the method, the aqueous and organic solvent medium in step (a) is water and isopropyl alcohol.

[0056] In some embodiments, the present disclosure provides that the suitable ratio of water to isopropyl alcohol in the method is 70:30, about 30% w / v to 60% w / v of the dry mix blend for the immediate release layer, and about 40% w / v to 60% w / v of the dry mix blend for the immediate release layer.

[0057] In some embodiments, the present disclosure provides a method for producing a tablet having a biphasic drug release profile containing about 600 mg to 800 mg of a flavoxate salt or a similar lipophilic acid-soluble drug as an active ingredient, the method comprising: (a) preparing an immediate release layer or a sustained release layer separately by mixing an amount of an active ingredient, a filler, a binder, and a controlled release polymer; and (b) compressing the individual layers to obtain a tablet; Includes.

[0058] In some embodiments, the disclosure provides that the method further comprises coating the tablet with or without one or more functional or non-functional coatings.

[0059] In some embodiments, the present disclosure provides a tablet obtained by this method having a mass of 6 Kg / cm 2 ~40kg / cm 2 It is stipulated that the hardness of the material is 100%.

[0060] In some embodiments, the disclosure provides that the tablet prepared by the method is a bilayer tablet, a trilayer tablet or a multi-layer tablet, a multi-coated mini-tablet, a multiple unit pellet system tablet, a pellet, or a bead filled capsule.

[0061] In some embodiments, the present disclosure provides a method of treating or ameliorating at least one symptom of urinary frequency, nocturia, dysuria, urgency, vesicle suprapubic pain, frequency, urinary incontinence resulting from various pathological conditions such as prostatitis, urethritis, cystitis, urethro-cystitis, uretherotrigonitis, catheterization, cystoscopy or indwelling catheter; relief of vesicourethral spasm prior to cystoscopy or catheterization; sequelae of surgical intervention of the lower urinary tract and / or side effects of radiation or surgical therapy of the urinary tract comprising administration of a formulation of the present disclosure.

[0062] In some embodiments, the disclosure provides for use of the formulations for the treatment or relief of symptoms of urinary frequency, nocturia, dysuria, urgency, suprapubic vesicle pain, urinary frequency, urinary incontinence, and side effects of radiotherapy or surgical therapy of the urinary tract due to various pathological conditions such as prostatitis, urethritis, cystitis, urethrocystitis, bladder trigonitis, etc.; vesicourethral spasm due to catheterization, cystoscopy, or indwelling catheters; irritative symptoms of benign prostatic hyperplasia (BPH) and overactive bladder, or as prophylaxis prior to cystoscopy, catheterization, or for the treatment or relief of symptoms of sequelae of surgical intervention of the lower urinary tract. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0063] Detailed Description of the Invention The terms "composition" and "formulation" are used interchangeably herein to refer to a flavoxate hydrochloride-containing pharmaceutical product in solid oral dosage form.

[0064] The terms "flavoxate" and "flavoxate hydrochloride" are used interchangeably to refer to 2-piperidinoethyl-3-methylflavone 8-carboxylate hydrochloride, the active ingredient in the compositions of the present disclosure.

[0065] As used throughout this specification, the term "controlled release" or "sustained release" is intended to apply to a dosage form, matrix, particle, coating, portion thereof, or composition that alters in some way the release of an active ingredient. Types of controlled release include modified, prolonged, sustained, extended, delayed, etc.

[0066] Preparation of flavoxate ER formulation As part of the initial development plan, tests were conducted to select suitable sustained release polymers, binders, diluents, surfactants, disintegrants, lubricants and glidants. Initial batches were prepared from a group of suitable drug release polymers including, but not limited to, hydrophilic and hydrophobic polymers or combinations thereof.

[0067] The CR formulations of the present disclosure may be prepared using a CR polymer, i.e., a non-ionic soluble cellulose, such as hypromellose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose, or salts of any of these polymers, such as hydroxyethyl cellulose (HEC, e.g., Natrosol™); a non-ionic homopolymer of ethylene oxide, such as poly(ethylene oxide) having a molecular weight range of about 100,000 to 8000,000 Da; methylcellulose; ethylcellulose; water-soluble natural gums of naturally occurring polysaccharides or salts of these polymers, such as xanthan gum, karaya gum, sodium alginate, acrylic polymers, alginates, and locust bean gum; water-swellable but insoluble high molecular weight homopolymers and copolymers of acrylic acid chemically crosslinked with polyalkenyl alcohols of various crosslinking degrees or particle sizes (e.g., Carbopol® 71G, NF, 971P, 934P); mixtures of polyvinyl acetate and povidone (e.g., Kollidone® SR), cross-linked high amylose starch or ionic methacrylate copolymers (e.g., Eudragit® L30D, Eudragit® L100 and Eudragit® L100 55); hydroxypropyl methylcellulose phthalate (HPMCP); cellulose acetate phthalate (CAP) and hydroxypropyl methylcellulose acetylsuccinate (HPMCAS), used alone or in combination. CR formulations preferably use different grades of HPMC and HPMC-AS, alone or in combination as polymers. In particular, formulations using hydrophilic cellulosic polymers or salts thereof, hydrophobic cellulosic polymers or salts thereof, and / or ionic methacrylate copolymers or salts thereof show improved stability, dissolution profiles, and bioavailability.

[0068] Flavoxate hydrochloride is used at high load drug content due to its low water solubility. Based on early studies, the addition of a pharma- ceutically acceptable surfactant with a hydrophilic-lipophilic balance value (HLB, i.e., the balance between the size and strength of the hydrophilic and lipophilic portions of the surfactant molecule) of at least "8" surprisingly leads to a significant improvement in increasing the dissolution rate of flavoxate in various physiological media. Suitable surfactants can be selected from, for example, long-chain alkyl sulfonates or long-chain alkyl sulfates, such as sodium dodecylbenzene sulfonate, sodium lauryl sulfate, and dialkyl sodium sulfosuccinate, quaternary ammonium salts, fatty alcohols, such as lauryl, cetyl, and steryl, glyceryl esters, fatty acid esters, and polyoxyethylene derivatives of fatty acid esters, such as polysorbate grades including polysorbate 20, polysorbate 60, and polysorbate 80, or combinations thereof. Different grades of polysorbates, alone or in combination, are preferred surfactants. In particular, formulations using polysorbates exhibit improved stability, dissolution profiles, and bioavailability.

[0069] Formulations using both a hydrophilic cellulosic polymer or its salt, a hydrophobic cellulosic polymer or its salt, and / or an ionic methacrylate copolymer or its salt and a polysorbate exhibit improved stability, dissolution profiles, and bioavailability.

[0070] Additionally, the ER formulation may also include "pharmaceutical acceptable excipients" selected from, for example, one or more of a diluent, a binder, a disintegrant, a lubricant, and a glidant.

[0071] The diluents may be selected from, for example, one or more of mannitol, sorbitol, microcrystalline cellulose, lactose, dicalcium phosphate, starch, and the like.

[0072] The binder may be selected from, for example, one or more of starch, polyvinylpyrrolidone (PVP), natural or synthetic gums, and cellulosic polymers such as ethyl cellulose, hydroxypropyl cellulose (HPC), gelatin, and the like.

[0073] The disintegrant may be selected from, for example, one or more of starch, sodium starch glycolate, croscarmellose sodium, or crospovidone, and the like.

[0074] Lubricants and glidants may be selected, for example, from one or more of talc, colloidal silicon dioxide, magnesium stearate, or sodium stearyl fumarate, and the like.

[0075] The polymers and excipients used were selected based on the material and its known properties and mixed into the composition to incorporate 600 and 800 mg of drug for formulating the various layers of the proposed formulation to achieve appropriate hardness and thickness parameters at the compression stage of each strength.

[0076] Various batches were investigated to arrive at a final formulation that is stable and exhibits a controlled or sustained drug release profile. Although some of the formulation components are already known in the art, to the best of the inventors' knowledge, no one has been able to develop a commercially acceptable form of CR formulation in a multi-layered dosage form that maintains therapeutic levels of flavoxate drug in plasma for up to 24 hours.

[0077] The ER formulation of flavoxate is available in the form of tablets, beads, pellets or capsules. The tablets can be uncoated tablets, coated tablets, MUPS tablets or mini-tablets. For example, the ER formulation can be a bi-layer, tri-layer or multi-layer tablet with or without one or more functional or non-functional coatings. A functional film coating is a coating that directly affects the drug release of the API (active pharmaceutical ingredient) of a solid oral dosage form (e.g., tablet, capsule, granule or pellet). Examples include, but are not limited to, ethylcellulose dispersions with soluble polymers or enteric polymer-based dispersions with water-soluble components. A non-functional film coating does not directly affect the drug release of the API. Examples include, but are not limited to, HPMC-based film coating dispersions with or without flavorings to enhance product acceptance of bitter tasting drugs. Tablets can be prepared by direct compression, wet granulation, dry granulation or slugging or direct compression processes. Compressed tablets can be coated with a suitable film-forming composition.

[0078] The present disclosure is illustrated herein below with the example of an easily ingestible single tablet CR flavoxate formulation, the preparation method of which is also provided herein below.

[0079] Manufacturing steps of wet granulation: The active ingredient, filler, binder, surfactant and controlled release polymer were mixed together for IR or ER layer, and then the blend was milled through a screen of suitable mesh size. The blended material was then granulated using a suitable dry granulator or with a solution of the binding polymer in a non-aqueous or hydroalcoholic solvent using a suitable granulator. The granules were then dried at a suitable temperature and sieved through a suitable mesh size. The blend was lubricated with a soluble or insoluble lubricant. The tablets were then formed by compression. The hardness of the tablets was about 6Kg / cm for different strength tablets. 2 ~40kg / cm 2can be changed.

[0080] From a product design perspective, the oral ER flavoxate hydrochloride formulation: 1) IR layer, which includes: a. flavoxate or a pharma- ceutically acceptable salt thereof; b. Suitable binders, polymers, surfactants dissolved or dispersed in aqueous and organic solvent media in appropriate ratios; c. An appropriate concentration of filler intragranularly; d. Extragranularly suitable disintegrants, flow aids or lubricants, etc. 2) The ER layer, which includes: a) flavoxate or a pharma- ceutically acceptable salt thereof; b) suitable binders, surfactants, dissolved or dispersed in aqueous and organic solvent media in appropriate proportions; c) Proper ratio of polymers of different viscosity grades; d) Extragranularly suitable flow aids, lubricants, etc. 3) The compressed tablets are optionally coated with a suitable film coating material; Includes.

[0081] Direct compression manufacturing steps: The present disclosure provides a method for preparing a pharmaceutical formulation of flavoxate, in which an active ingredient, a filler, a binder and a controlled release polymer are mixed together to prepare an IR layer and an ER layer separately, and then the individual layers are compressed to form a 600 or 800 mg bilayer or trilayer tablet of flavoxate.

[0082] Without intending to limit the scope of the present disclosure, examples are provided below for representative purposes. EXAMPLES

[0083] Example 1: Formulation of biphasic tablets containing 600 mg and 800 mg of flavoxate hydrochloride by wet granulation Flavoxate, filler, binder, surfactant and controlled release polymer in the concentrations listed in Table 1 below were mixed together for IR or ER layer to obtain blended material. The blended material was milled through a screen with a suitable size mesh. The blended material was then granulated. The granules were then dried at a suitable temperature and sieved through a suitable size mesh. The blend was lubricated with a soluble or insoluble lubricant. Tablets were then formed by compression. The hardness of the tablets was 6Kg / cm for different strength tablets. 2 ~40kg / cm 2 was adjusted.

[0084] [Table 1] *The amount of IPA:water (70:30) in the ER part was 55% w / v of the dry mix blend. The amount of IPA:water (70:30) in the IR portion was 58% w / v of the dry mix blend.

[0085] Example 2: Formulation of biphasic tablets containing 600 mg and 800 mg of flavoxate hydrochloride Flavoxate, filler, binder, surfactant and controlled release polymer in the concentrations listed in Table 2 below were mixed together for IR or ER layer to obtain blended material. The blended material was milled through a screen with a suitable size mesh. The blended material was then granulated. The granules were then dried at a suitable temperature and sieved through a suitable size mesh. The blend was lubricated with a soluble or insoluble lubricant. Tablets were then formed by compression. The hardness of the tablets was 6Kg / cm for different strength tablets. 2 ~40kg / cm 2 was adjusted.

[0086] [Table 2] *The amount of IPA:water (70:30) in the ER part was 54% w / v of the dry mix blend. The amount of IPA:water (70:30) in the IR portion was 47% w / v of the dry mix blend.

[0087] Example 3: Formulation of biphasic tablets containing 600 and 800 mg of flavoxate hydrochloride Flavoxate, filler, binder, surfactant and CR polymer in the concentrations as listed in Table 3 below were mixed together for IR or ER layer to obtain blended material. The blended material was milled through a screen with a suitable size mesh. The blended material was then granulated. The granules were then dried at a suitable temperature and sieved through a suitable size mesh. The blend was lubricated with a soluble or insoluble lubricant. Tablets were then formed by compression. The hardness of the tablets was 6Kg / cm for different strength tablets. 2 ~40kg / cm 2 was adjusted.

[0088] [Table 3] *The amount of IPA:water (70:30) in the ER part was 45% w / v of the dry mix blend. The amount of IPA:water (70:30) in the IR part was 35% w / v of the dry mix blend.

[0089] Example 4: Formulation of biphasic tablets containing 600 and 800 mg of flavoxate hydrochloride Flavoxate, filler, binder, surfactant and controlled release polymer in the concentrations listed in Table 4 below were mixed together for IR or ER layer to obtain blended material. The blended material was milled through a screen with a suitable size mesh. The blended material was then granulated. The granules were then dried at a suitable temperature and sieved through a suitable size mesh. The blend was lubricated with a soluble or insoluble lubricant. Tablets were then formed by compression. The hardness of the tablets was 6Kg / cm for different strength tablets. 2 ~40kg / cm 2 was adjusted.

[0090] [Table 4] *The amount of IPA:water (70:30) in the ER part was 55% w / v of the dry mix blend. The amount of IPA:water (70:30) in the IR portion was 58% w / v of the dry mix blend.

[0091] Example 5: Formulation of biphasic tablets containing 600 and 800 mg of flavoxate hydrochloride Flavoxate, filler, binder, surfactant and controlled release polymer in the concentrations listed in Table 5 below were mixed together for IR or ER layer to obtain blended material. The blended material was milled through a screen with a suitable size mesh. The blended material was then granulated. The granules were then dried at a suitable temperature and sieved through a suitable size mesh. The blend was lubricated with a soluble or insoluble lubricant. Tablets were then formed by compression. The hardness of the tablets was 6Kg / cm for different strength tablets. 2 ~40kg / cm 2 was adjusted.

[0092] [Table 5]

[0093] Example 6: Formulation of biphasic tablets containing 600 and 800 mg of flavoxate hydrochloride Flavoxate, filler, binder, surfactant and controlled release polymer in the concentrations listed in Table 6 below were mixed together for IR or ER layer to obtain blended material. The blended material was milled through a screen with a suitable size mesh. The blended material was then granulated. The granules were then dried at a suitable temperature and sieved through a suitable size mesh. The blend was lubricated with a soluble or insoluble lubricant. Tablets were then formed by compression. The hardness of the tablets was 6Kg / cm for different strength tablets. 2 ~40kg / cm 2 was adjusted.

[0094] [Table 6] *The amount of IPA:water (70:30) in the ER part was 55% w / v of the dry mix blend. The amount of IPA:water (70:30) in the IR portion was 58% w / v of the dry mix blend.

[0095] Example 7: Formulation of biphasic tablets containing 600 and 800 mg of flavoxate hydrochloride Flavoxate, filler, binder, surfactant and controlled release polymer in the concentrations listed in Table 7 below were mixed together for IR or ER layer to obtain blended material. The blended material was milled through a screen with a suitable size mesh. The blended material was then granulated. The granules were then dried at a suitable temperature and sieved through a suitable size mesh. The blend was lubricated with a soluble or insoluble lubricant. Tablets were then formed by compression. The tablet hardness was 6Kg / cm for different strength tablets. 2 ~40kg / cm 2 was adjusted.

[0096] [Table 7] *The amount of IPA:water (70:30) in the ER part was 55% w / v of the dry mix blend. The amount of IPA:water (70:30) in the IR portion was 58% w / v of the dry mix blend.

[0097] Example 8: Formulation of biphasic tablets containing 600 and 800 mg of flavoxate hydrochloride Flavoxate, filler, binder, surfactant and controlled release polymer in the concentrations listed in Table 8 below were mixed together for IR or ER layer to obtain blended material. The blended material was milled through a screen with a suitable size mesh. The blended material was then granulated. The granules were then dried at a suitable temperature and sieved through a suitable size mesh. The blend was lubricated with a soluble or insoluble lubricant. Tablets were then formed by compression. The tablet hardness was 6Kg / cm for different strength tablets. 2 ~40kg / cm 2 was adjusted.

[0098] [Table 8] *The amount of IPA:water (70:30) in the ER part was 55% w / v of the dry mix blend. The amount of IPA:water (70:30) in the IR portion was 58% w / v of the dry mix blend.

[0099] Example 9: Formulation of ER capsules containing 600 mg of flavoxate hydrochloride Drug-loaded drug pellets were prepared by coating flavoxate onto MCC spheres along with ethyl cellulose, HPMC K4M, talc and polysorbate 80 using a fluidized bed process that produces flavoxate CR pellets. The coated pellets were then appropriately lubricated with extragranular contents as listed in Table 9. The coated drug pellets were filled into gelatin (hard or soft) capsules and non-gelatin capsule shells (e.g., HPMC or sodium alginate vegetarian capsules).

[0100] [Table 9]

[0101] Example 10: Formulation of ER MUPS tablets containing 600 mg of flavoxate hydrochloride MUPS tablets were prepared by compressing a mixture of flavoxate-containing pellets and powdered excipients at the concentrations shown below in Table 10. The pellets have a spherical core containing or optionally coated with flavoxate, and one or more protective layers to control drug release.

[0102] [Table 10]

[0103] Example 11: In vitro dissolution drug release profile In a pH gradient dissolution study simulating the physiological pH media in which the product would be administered orally (at pH 1.2, pH 4.5, pH 6.8 and pH 7.4, respectively, every 2 hours for a total of 8 hours), a representative in vitro drug dissolution release rate profile of the formulation of Example 1 is shown below (Table 11).

[0104] [Table 11]

[0105] The in vitro dissolution release profiles of the ER formulation were found to be about 10% to about 35% released in about 0 to 2 hours, about 35% to about 75% released in about 2 to 4 hours, about 50% to about 90% released in about 4 to 6 hours, and greater than about 75% (NIL) released in about 6 to 8 hours.

[0106] Example 12: Comparative evaluation of the in vitro dissolution drug release profiles of the formulations of WO202021422A1 to the formulation of Example 1 The formulation of Example 1 was evaluated using in vitro drug dissolution methodology as part of a simulation study in the human GIT using pH gradient dissolution media (pH 1.2, pH 4.5, pH 6.8 and pH 7.4, respectively, every 2 hours for a total of 8 hours) simulating physiological pH media when the product is administered orally, compared to the formulations disclosed in WO202021422A1, along with the 24 hour dissolution study profiles (Tables 12 and 13) shown below.

[0107] [Table 12]

[0108] [Table 13]

[0109] From Table 13 above, it is evident that the formulation of Example 1 has improved drug dissolution release at each pH evaluation step, demonstrating improved drug release profile in both the 8 hour pH gradient and 24 hour dissolution profile studies.

[0110] Example 13: Comparative study of in vivo bioavailability (%) of an exemplary formulation of the present disclosure versus immediate release tablets Either the formulation of Example 1 or the reference IR formulation (Urispas® (Flavoxate HCl, 200 mg)) was administered to 18 male participants aged 18-45 years (inclusive). All participants fasted for at least 10 hours prior to dosing and then administered the test formulation with water. Participants received either one extended release tablet of 600 mg strength prepared in Example 1 or three IR tablets of 200 mg strength. One IR tablet was administered every 8 hours (i.e., at 0, 8, and 16 hours). Blood samples were taken from participants at several time points up to 24 hours and a comparison of the plasma concentrations at the given time points is shown in Table 14.

[0111] [Table 14]

[0112] Additionally, the percentage (%) of bioavailability of the formulation of Example 1 was evaluated in terms of AUC (area under the curve) in comparison to an immediate release formulation (Urispas® (Flavoxate HCl, 200 mg)) (Table 15).

[0113] [Table 15] CI=confidence interval ISCV=Intrasubject Variation

[0114] Example 14: In vitro dissolution profile of exemplary formulations of Example 1 versus immediate release tablets Based on the results of the comparative study in Example 13, the formulation in Example 1 was fine-tuned to obtain the formulation in Example 8. The in vitro dissolution profile of each formulation was studied. The comparative in vitro dissolution profile in biorelevant dissolution test method of the tablets prepared by the formulation in Example 8 was studied at pH 1.2 for the first 2 hours, and then at pH 7.4 buffer for up to 24 hours (Table 16).

[0115] [Table 16]

[0116] As can be seen from the results in Table 16 above, the tablets prepared according to the formulation of Example 8 exhibit an improved release profile compared to the formulation of Example 1.

[0117] Example 15: Stability Data The ER pharmaceutical formulations of flavoxate or its salts developed in Example 1 and Example 8 have shown good chemical stability based on accelerated stability data. The developed formulations have improved chemical stability with individual unknown impurity levels below 0.2% w / w (as per globally accepted standards for currently available pharmaceutical products).

[0118] The stable ER or CR formulations and methods for their preparation described in this application accurately describe the efficacy and usefulness of these formulations and methods for their preparation for restoring healthy function in humans and treating the human conditions and disorders identified and described in this application.

[0119] Although the subject matter has been described herein with reference to certain preferred embodiments thereof, other embodiments are possible.For illustrative purposes, the formulation contains flavoxate hydrochloride as active ingredient.However, those skilled in the art will understand that the scope of the present disclosure extends to other similar lipophilic acid-soluble drugs known in the art.

[0120] Other embodiments will be apparent to those skilled in the art from consideration of the specification and practice of the embodiments disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the present disclosure being indicated by the following claims. Further, where this application recites method or procedure steps in a particular order, it is intended that the order in which some steps are performed may be varied or may even be advantageous in certain circumstances, and that the method or procedure steps described herein below are not to be construed as being order specific, unless such order specificity is expressly recited in the claims. Thus, the scope of the present disclosure is indicated by the appended claims, rather than the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. 1. A controlled release oral formulation of flavoxate having a biphasic drug release profile, comprising: Approximately 600 to 800 mg of flavoxate salt as the active ingredient; at least one surfactant and at least one polymer; Including, the surfactant has a hydrophilic-lipophilic balance value of at least "8"; the formulation comprises at least one immediate release drug layer and at least one sustained release drug layer; the at least one immediate release drug layer is about 10-30 wt% of the formulation; and A controlled release oral dosage form, wherein said at least one sustained release drug layer is about 70-90 wt% of said dosage form.

2. 10. The controlled release oral formulation of claim 1, wherein upon single administration, about 10% w / w to 35% w / w of the flavoxate salt is released within the first 2 hours, and the remaining flavoxate salt is released for up to 12 to 24 hours.

3. 10. The controlled release oral formulation of claim 1, wherein the at least one polymer comprises a hydrophilic cellulosic polymer or a salt thereof, a hydrophobic cellulosic polymer or a salt thereof, an ionic methacrylate copolymer or a salt thereof, or a combination thereof.

4. 4. The controlled release oral formulation of claim 3, wherein the at least one polymer comprises hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetylsuccinate (HPMC AS), Eudragit L30D55, Eudragit L100, or a combination thereof.

5. 10. The controlled release oral formulation of claim 1, wherein the at least one surfactant comprises a long-chain alkyl sulfonate or long-chain alkyl sulfate, sodium dodecylbenzenesulfonate, sodium lauryl sulfate, sodium dialkyl sulfosuccinate, a quaternary ammonium salt, a fatty alcohol such as lauryl, cetyl, and steryl, a glyceryl ester, a fatty acid ester, a polyoxyethylene derivative of a fatty acid ester, or a combination thereof.

6. 6. The controlled release oral formulation of claim 5, wherein the at least one surfactant comprises a polysorbate grade comprising Tween-20, Tween-80, or a combination thereof.

7. 10. The controlled release oral formulation of claim 1, further comprising at least one diluent, wherein the at least one diluent comprises mannitol, sorbitol, microcrystalline cellulose, lactose, dicalcium phosphate, starch, or a combination thereof.

8. 10. The controlled release oral formulation of claim 1, further comprising at least one binder, wherein the at least one binder comprises starch, polyvinylpyrrolidone, a natural or synthetic gum, a cellulosic polymer, ethyl cellulose, hydroxypropyl cellulose, gelatin, or a combination thereof.

9. 10. The controlled release oral formulation of claim 1, further comprising at least one disintegrant, wherein the at least one disintegrant comprises starch, sodium starch glycolate, croscarmellose sodium, crospovidone, or a combination thereof.

10. 10. The controlled release oral formulation of claim 1, further comprising at least one lubricant or glidant, wherein the at least one lubricant or glidant comprises talc, colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, or a combination thereof.

11. 10. The controlled release oral formulation of claim 1, wherein the formulation releases the flavoxate salt over a period of 12 to 24 hours.

12. 2. The controlled release oral formulation of claim 1, wherein the flavoxate salt is flavoxate hydrochloride.

13. 2. The controlled release oral formulation of claim 1, wherein the formulation is a solid dosage form, preferably a tablet or capsule.

14. 14. The controlled release oral formulation of claim 13, wherein the tablet is a bilayer tablet, a trilayer tablet or a multilayer tablet, a multicoated mini-tablet, a multiple unit pellet system tablet, a pellet, or a bead filled into a capsule.

15. The tablet has a hardness of about 6 kg / cm ２ ~ approx. 40 kg / cm ２ 14. The controlled release oral formulation of claim 13, wherein:

16. 14. The controlled release oral formulation of claim 13, wherein the tablet comprises one or more functional or non-functional coatings.

17. 17. The controlled release oral formulation of claim 16, wherein the functional film coating is an ethyl cellulose dispersion containing a soluble polymer or an enteric polymer-based dispersion containing a water-soluble component.

18. 17. The controlled release oral formulation of claim 16, wherein the non-functional film coating is a hydroxypropyl methylcellulose-based film coating dispersion with or without flavoring to enhance product acceptability of bitter tasting drugs.

19. The formulation comprises: about 10% to about 35% of the active ingredient between about 0 and 2 hours; About 35% to about 75% of the active ingredient in about 2 to 4 hours, Approximately 50% to approximately 90% of the active ingredient is released within approximately 4 to 6 hours. Approximately 75% or more of the active ingredient is released within approximately 6 to 8 hours.

2. The controlled release oral formulation of claim 1, wherein the formulation releases

20. 1. A method for producing a tablet having a biphasic drug release profile containing a flavoxate salt as an active ingredient, comprising: (a) mixing an amount of flavoxate salt with an amount of suitable filler, binder, surfactant, and controlled-release polymer in an aqueous and organic solvent medium in appropriate ratios to obtain a blend material for an immediate-release layer or a sustained-release layer, respectively; (b) granulating the blended material obtained in step (a) using a suitable dry granulator or with a solution of a binding polymer in a non-aqueous or hydroalcoholic solvent using a suitable granulation equipment to obtain granules; (c) drying the granules obtained in step (b) at a suitable temperature to obtain dried granules; (d) sieving the dried granules obtained in step (c) through a suitable size mesh to obtain granules of the desired size; (e) lubricating the granules obtained in step (d) with a soluble or insoluble lubricant to obtain a formulation; and (f) compressing the formulation obtained in step (e) to form tablets; A method comprising:

21. 21. The method of claim 20, wherein the amount of the flavoxate salt is about 100 mg to 200 mg for the immediate release layer and about 300 mg to 700 mg for the sustained release layer.

22. 21. The method of claim 20, wherein the aqueous and organic solvent medium in step (a) is water and isopropyl alcohol.

23. 23. The method of claim 22, wherein the suitable ratio of water to isopropyl alcohol is 70:30, about 30% w / v to 60% w / v of the dry mix blend for the immediate release layer, and about 40% w / v to about 60% w / v of the dry mix blend for the immediate release layer.

24. 1. A method for producing a tablet having a biphasic drug release profile containing about 600 mg to 800 mg of a flavoxate salt or similar lipophilic acid-soluble drug as an active ingredient, comprising: (a) separately preparing an immediate release layer or a sustained release layer by mixing a certain amount of an active ingredient, a filler, a binder, and a controlled release polymer; and (b) compressing the individual layers to obtain a tablet; A method comprising:

25. 21. The method of claim 20, further comprising coating the tablet with or without one or more functional or non-functional coatings.

26. The tablet has a hardness of 6 kg / cm ２ ~40 kg / cm ２ 21. The method of claim 20, wherein:

27. 21. The method of claim 20, wherein the tablet is a bilayer tablet, a trilayer tablet, or a multilayer tablet, a multicoated mini-tablet, a multiple unit pellet system tablet, a pellet, or a bead filled into a capsule.

28. 20. A method for treating or ameliorating at least one of the symptoms of frequency, nocturia, dysuria, urgency, vesicle suprapublic pain, urinary frequency, urinary incontinence resulting from various pathological conditions such as prostatitis, urethritis, cystitis, urethrocystitis, urethrotrigonitis, catheterization, cystoscopy or indwelling catheter; relief of vesicourethral spasm prior to cystoscopy or catheterization; sequelae of surgical intervention of the lower urinary tract and / or side effects of radiotherapy or surgical therapy of the urinary tract, comprising administering a formulation according to any one of claims 1 to 19.

29. 20. Use of a formulation according to any one of claims 1 to 19 for the treatment or symptomatic relief of irritative symptoms of urination, nocturia, dysuria, urgency, suprapubic vesicular pain, urinary frequency, urinary incontinence due to various pathological conditions such as prostatitis, urethritis, cystitis, urethrocystitis, trigonitis, and side effects of radiotherapy or surgical therapy of the urinary tract; vesicourethral spasm due to catheterization, cystoscopy or indwelling catheters; benign prostatic hyperplasia (BPH) and overactive bladder, or as prophylaxis before cystoscopy or catheterization, or for the treatment or symptomatic relief of sequelae of surgical intervention of the lower urinary tract.