CONTROLLED RELEASE FORMULATIONS OF FLAVOXATE AND PROCESS FOR PREPARATION THEREOF

Abstract

The present disclosure relates to controlled or extended release formulations of Flavoxate or similar lipophilic acid soluble drugs. The disclosure also relates to methods for preparation of such formulations and uses thereof.

Claims

1. A controlled release oral formulation of Flavoxate with biphasic drug release profile comprising: about 600 to 800 mg of 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’; wherein the formulation comprises at least one immediate release drug layer and at least one extended release drug layer; wherein the at least one immediate release drug layer is about 10 to 30 wt % of the formulation; and the at least one extended release drug layer is about 70 to 90 wt % of the formulation.

2. The controlled release oral formulation as claimed in claim 1, wherein on a single dose administration about 10% w/w to 35% w/w of the Flavoxate salt is released within an initial 2 hours, and the remaining Flavoxate salt is released for up to 12 to 24 hours.

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

4. The controlled release oral formulation as claimed in claim 3, wherein the at least one polymer comprises hydroxypropylmethyl cellulose (HPMC), hydroxy propyl methyl cellulose acetyl succinate (HPMC AS), Eudragit L30D 55, Eudragit L100, or a combination thereof.

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

6. The controlled release oral formulation as claimed in claim 5 wherein the at least one surfactant comprises Polysorbate grades including Tween-20, Tween-80, or a combination thereof.

7. The controlled release oral formulation as claimed in 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. The controlled release oral formulation as claimed in claim 1, further comprising at least one binder, wherein the at least one binder comprises starch, polyvinylpyrrolidone, natural or synthetic gum, a cellulosic polymer, ethyl cellulose, hydroxypropylcellulose, gelatin, or a combination thereof.

9. The controlled release oral formulation as claimed in claim 1, further comprising at least one disintegrant, wherein the at least one disintegrant comprises starch, sodium starch glycollate, croscarmellose sodium, crospovidone, or a combination thereof.

10. The controlled release oral formulation as claimed in 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. (canceled)

12. The controlled release oral formulation as claimed in claim 1, wherein the Flavoxate salt is Flavoxate hydrochloride.

13. The controlled release oral formulation as claimed in claim 1, wherein the formulation is in a solid dosage form preferably a tablet or capsule, wherein the tablet has a hardness of about 6 kg/cm.sup.2 to about 40 kg/cm.sup.2.

14. (canceled)

15. (canceled)

16. (canceled)

17. (canceled)

18. (canceled)

19. The controlled release oral formulation as claimed in claim 1, wherein the formulation releases: between about 10% and about 35% of active ingredient during about 0 to 2 hours, between about 35% and about 75% of active ingredient during about 2 to 4 hours, between about 50% and about 90% of active ingredient during about 4 to 6 hours, and not less than about 75% during about 6 to 8 hours.

20. A method of making a tablet with biphasic drug release profile comprising Flavoxate or a salt thereof comprising: (a) blending 300 mg to 700 mg Flavoxate or salt thereof with at least one surfactant and at least one polymer in a ratio of aqueous and organic solvent media for an extended release drug layer, wherein the aqueous and organic solvent media comprises water and isopropyl alcohol in a ratio of 70:30 and comprises 30% w/w to 60% w/w of the extended release drug layer; (b) blending 100 mg to 200 mg Flavoxate or salt thereof with at least one disintegrant and at least one diluent in a suitable ratio of aqueous and organic solvent media for an immediate release drug layer, wherein the aqueous and organic solvent media comprises water and isopropyl alcohol in a ratio of 70:30 and comprises 40% w/w to 60% w/w of the immediate release drug layer; (c) separately granulating the blended material obtained in steps (a) and (b) using a wet granulator with a solution of binding polymer in non-aqueous or hydro alcoholic solvent to obtain granules, or a dry granulator; (d) separately drying the extended release granules and immediate release granules obtained in step (c) to obtain dried extended release granules and dried immediate release granules; (e) separately screening the dried extended release granules and immediate release granules obtained in step (d) through a mesh to obtain screened extended release granules and screened immediate release granules; (f) separately lubricating the screened extended release granules and screened immediate release granules obtained in step (e) with a lubricant to obtain lubricated extended release granules and lubricated immediate release granules; and (g) compressing the lubricated extended release granules and lubricated immediate release granules obtained in step (f) to form the tablet.

21. (canceled)

22. (canceled)

23. (canceled)

24. A method of making a tablet with biphasic drug release profile comprising about 600 mg to 800 mg of Flavoxate salt or similar lipophilic acid soluble drugs as an active ingredient, the method comprising: (a) blending an amount of active ingredient, fillers, binders, and controlled release polymers to individually prepare immediate release or extended release layers; (b) compressing individual layers to obtain tablets; and (c) coating the tablet with at least one coating, wherein the tablet has a hardness of 6 Kg/cm2 to 40 Kg/cm2, and wherein the tablet is bi-layered, tri-layered, multi-layered, a multicoated mini-tablet, a Multiple-Unit Pellet System tablet, a pellet, or a capsule filled with beads.

25. (canceled)

26. (canceled)

27. (canceled)

28. A method of treating at least one symptom of pollakiuria, nocturia, dysuria, urgency, frequency, urinary incontinence originating from various pathological situations such as prostatitis, urethritis, cystitis, urethero-cystitis, uretherotrigonitis, vesico-urethral spasms due to catheterisation, cystoscopy or pre-cytosopy, indwelling catheters or pre-insertion of indwelling catheters, sequelae of surgical intervention of the lower urinary tract, irritative symptoms of benign prostatic hyperplasia (BPH) and overactive bladder, or the side effects of radiotherapy or surgical therapy of the urinary tract in a subject in need thereof comprising administering to the subject the formulation of claim 1.

29. (canceled)

30. A controlled release oral formulation of Flavoxate exhibiting a biphasic release profile comprising one immediate release drug layer and one extended release drug layer, wherein the immediate release drug layer comprises lactose, sodium starch glycollate, hydroxypropyl cellulose, Povidone k-30, Crospovidone, microcrystalline cellulose, talc, and magnesium stearate, and wherein the extended release drug layer comprises hydroxypropyl methylcellulose (HPMC) K4M, HPMC acetyl succinate, HPMC K15M, Crospovidone, microcrystalline cellulose, ethyl cellulose, croscarmellose sodium, colloidal silicon dioxide, polysorbate-80, methacrylate L-30D, talc, and magnesium stearate.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0072] The terms “composition” and “formulation” are used interchangeably herein to refer to a Flavoxate hydrochloride containing drug product in a solid oral dosage form.

[0073] The terms “Flavoxate” and “Flavoxate hydrochloride” are used interchangeably to refer to the active ingredient in the compositions of the disclosure, 2-piperidinoethyl-3-methylflavone 8-carboxylate hydrochloride.

[0074] The term “controlled release” or “extended release” used throughout the specification shall apply to dosage forms, matrices, particles, coatings, portions thereof, or compositions that alter the release of an active ingredient in any manner. Types of controlled release include modified, prolonged, sustained, extended, delayed, and the like.

Preparing Flavoxate ER Formulations

[0075] As part of initial development plan, trials for selection of suitable sustained release polymers, binders, diluents, surfactants, disintegrants, lubricants and glidants were undertaken. The initial batches were prepared from group of suitable drug release polymers including but not limited to hydrophilic polymers and hydrophobic polymers or combination thereof.

[0076] The CR formulations of present disclosure employ CR polymers viz. non-ionic soluble cellulose, such as hypromellose, hydroxypropylmethyl cellulose (HPMC), hydroxypropylcellulose (HPC), carboxymethyl cellulose or salts of any of these polymers, hydroxylethylcellulose (HEC e.g., Natrosol™); non-ionic homopolymers of ethylene oxide, such as poly(ethylene oxide) with a molecular weight range of about 100,000 to 8000,000 Da; methyl cellulose; ethyl cellulose; water soluble natural gums of polysaccharides of natural origin or salts of any of these polymers, such as xanthum gum, karaya gum, sodium alginate, acrylic polymers, alginate, and locust bean gum; water-swellable but insoluble, high molecular weight homo-polymers and copolymers of acrylic acid chemically cross-linked with polyalkenyl alcohols with varying degree of cross-linking or particle size (for e.g. Carbopol® 71G NF, 971P, 934P); polyvinyl acetate and povidone mixture (for e.g. Kollidone® SR), cross-linked high amylose starch or ionic methacrylate copolymers (for e.g. Eudragit® L30D, Eudragit® L100 and Eudragit® L100 55); hyrdoxy propyl methyl cellulose phthalate (HPMCP); cellulose acetate phthalate (CAP) and hyrdoxy propyl methyl cellulose acetyl succinate (HPMCAS), alone or in combination. The CR formulation preferably employs different grades of HPMC and HPMC-AS alone or in combination as polymers. Among other things, formulations employing hydrophilic cellulosic polymers or salts thereof, hydrophobic cellulosic polymers or salts thereof, and/or ionic methacrylate copolymers or salts thereof, exhibit improved stability, dissolution profile, and bioavailability.

[0077] Flavoxate hydrochloride, being poorly water soluble, is employed with high load drug content. Based on initial studies, addition of pharmaceutically acceptable surfactants having a hydrophilic-lipophilic balance value (“HLB” i.e. the balance of the size and strength of the hydrophilic and lipophilic moieties of a surfactant molecule) of at least ‘8’ surprisingly leads to significant improvement in rate of dissolution in different physiological medias for Flavoxate. The suitable surfactants may, for example, be selected from long alkyl chain sulfonates or long alkyl chain sulfates such as sodium dodecylbenzene sulfonate, sodium lauryl sulfate, and dialkyl sodium sulfosuccinate, quaternary ammonium salts, fatty alcohols such as lauryl, cetyl, and steryl, glycerylesters, fatty acid esters, and polyoxyethylene derivatives of fatty acid esters, such as Polysorbates grades including polysorbate 20, polysorbate 60, and polysorbate 80 etc. or combination thereof. Different grades of polysorbates alone or in combination are the preferred surfactants. Among other things, formulations employing polysorbates exhibit improved stability, dissolution profile, and bioavailability.

[0078] Formulations employing both hydrophilic cellulosic polymers or salts thereof, hydrophobic cellulosic polymers or salts thereof, and/or ionic methacrylate copolymers or salts thereof, and polysorbates exhibit improved stability, dissolution profile, and bioavailability.

[0079] Additionally, the ER formulation may also contain “pharmaceutically acceptable excipients” selected from, for example, one or more of diluents, binders, disintegrants, lubricants and glidants.

[0080] The diluent may, for example, may be selected from, for example, one or more of mannitol, sorbitol, microcrystalline cellulose, lactose, dicalcium phosphate and starch etc.

[0081] The binder may be selected from, for example, one or more of starch, polyvinylpyrrolidone (PVP), natural or synthetic gum and cellulosic polymers e.g. ethyl cellulose, hydroxypropylcellulose (HPC), gelatin etc.

[0082] The disintegrants may be selected from, for example, one or more of starch, sodium starch glycollate, croscarmellose sodium or crospovidone etc.

[0083] The lubricants and glidants may be selected from, for example, one or more of talc, colloidal silicon dioxide, magnesium stearate or sodium stearyl fumarate etc.

[0084] The polymers and excipients used were selected on the basis of materials and their known properties and combined into a composition so as to incorporate 600 and 800 mg of drug for formulating different layers of proposed formulations in order to achieve appropriate hardness and thickness parameters during compression stage for respective strengths.

[0085] Various batches were investigated to arrive at a final formulation that is stable and exhibits a control or extended drug release profile. Even though some of the constituents of the formulation are already known in the art, yet no one to the knowledge of the inventors could develop a commercially acceptable form of CR formulation in multi-layered dosage forms that sustains therapeutic levels of the Flavoxate drug in plasma for up to 24 hours.

[0086] The ER formulations of Flavoxate can be obtained in form of tablets, beads, pellets or capsules. The tablets can be uncoated tablets, coated tablets, MUDS tablets or mini-tablets. For instance, the ER formulations can be a bi-layer, tri-layer or multi-layered tablets with or without one or more functional or non-functional coatings. A functional film coating is a coating that has a direct influence on the drug release of API (active pharmaceutical ingredient) of the solid oral dosage form (e.g. tablet, capsule, granule or pellet). The examples include, but not limited to, ethyl cellulose dispersion with soluble polymer or enteric polymer-based dispersion with water soluble ingredients. While a non-functional film coating does not directly influence the drug release of the API. The examples include, but not limited to, HPMC based film coating dispersion with or without flavour to enhance the product acceptability of bitter tasting drugs. The tablet can be prepared by direct compression, wet granulation, dry granulation or slugging or direct compression processes. The compressed tablets can be coated with suitable film forming compositions.

[0087] The disclosure is being illustrated herein below with examples of CR Flavoxate formulations in an easily-ingestible single tablet and process for preparation thereof is also provided herein below.

Manufacturing Procedure for Wet Granulation Method

[0088] The active ingredient, fillers, binders, surfactants and controlled release polymers were blended together for IR or ER layers, and then the blend milled through a screen with appropriate size mesh. The blended material was then granulated using suitable dry granulator or with a solution of binding polymer in non-aqueous or hydro alcoholic solvent using suitable granulation equipment. The granules were then dried at a suitable temperature and screened through a mesh of appropriate size. The blend was lubricated with a soluble or insoluble lubricant. The tablets were then formed by compression. The hardness of the tablet may vary from about 6 Kg/cm.sup.2 to 40 Kg/cm.sup.2 for tablets of different strengths.

[0089] From product design perspective, the ER Flavoxate hydrochloride formulation for oral administration comprises: [0090] 1) An IR layer comprising: [0091] (a) Flavoxate or pharmaceutically acceptable salts thereof; [0092] (b) suitable binder, polymer, surfactant, dissolved or dispersed in suitable ratio of aqueous and organic solvent media; [0093] (c) filler in appropriate concentrations intragranularly; [0094] (d) suitable disintegrant, flow aids or lubricants etc. extragranularly. [0095] 2) An ER layer comprising: [0096] (a) Flavoxate or pharmaceutically acceptable salts thereof; [0097] (b) suitable binder, surfactant, dissolved or dispersed in suitable ratio of aqueous and organic solvent media; [0098] (c) suitable ratios of polymers of different viscosity grades; [0099] (d) suitable flow aids, lubricants etc. extragranularly. [0100] 3) Compressed tablets are optionally coated with a suitable film coating material.

Manufacturing Procedure for Direct Compression Method

[0101] The present disclosure provides a process of preparing a pharmaceutical formulation of Flavoxate wherein the active ingredient, fillers, binders and controlled release polymers are blended together for individually preparing IR and ER layers. The individual layers are then compressed to form 600 or 800 mg bilayer tablets or tri-layer tablets of Flavoxate.

[0102] Examples for representative purpose without limiting scope of the disclosure are illustrated below.

EXAMPLE 1

Formulation of Biphasic Tablets Comprising 600 and 800 mg of Flavoxate Hydrochloride by Wet Granulation

[0103] The Flavoxate, fillers, binders, surfactants and controlled release polymers in concentrations recited in Table 1 below were blended together for IR or ER layers to obtain a blended material. The blended material was milled through a screen with a mesh of appropriate size. The blended material was then granulated. The granules were then dried at a suitable temperature and screened through a mesh of appropriate size. The blend was lubricated with a soluble or insoluble lubricant. The tablets were then formed by compression. The hardness of the tablet was adjusted from 6 Kg/cm.sup.2 to 40 Kg/cm.sup.2 for tablets of different strengths.

TABLE-US-00001 TABLE 1 Constituents in biphasic 600 mg and 800 mg tablets of Flavoxate as prepared by wet granulation 600 mg 800 mg Material IR layer ER layer IR layer ER layer Flavoxate hydrochloride 120.00 480.00 160.00 640.00 Lactose 14.775 2.44 19.70 3.25 HPMC K15 — 43.88 — 58.50 Colloidal silicon dioxide — 1.46 — 1.95 Sodium starch glycolate 3.75 — 5.00 — Brilliant blue 0.75 — 1.00 — Hydroxypropyl cellulose 6.00 27.375 8.00 36.50 Tween 80 — 2.925 — 3.90 Water* QS QS QS QS Isopropyl alcohol (IPA)* QS QS QS QS MCC PH 102 7.50 4.50 10.00 6.00 Colloidal silicon dioxide — 2.25 — 3.00 Brilliant blue 0.75 — 1.00 — Talc 1.50 — 2.00 — Magnesium stearate 1.50 5.475 2.00 7.30 *IPA:water (70:30) quantity for ER portion was—55% w/v of dry mix blend. IPA:water (70:30) quantity for IR portion was—58% w/v of dry mix blend.

EXAMPLE 2

Formulation of Biphasic Tablets Comprising 600 and 800 mg of Flavoxate Hydrochloride

[0104] The Flavoxate, fillers, binders, surfactants and controlled release polymers in concentrations recited in Table 2 below were blended together for IR or ER layers to obtain a blended material. The blended material was milled through a screen with mesh of appropriate size. The blended material was then granulated. The granules were then dried at a suitable temperature and screened through a mesh of appropriate size. The blend was lubricated with a soluble or insoluble lubricant. The tablets were then formed by compression. The hardness of the tablet was adjusted from 6 Kg/cm.sup.2 to 40 Kg/cm.sup.2 for tablets of different strengths.

TABLE-US-00002 TABLE 2 Constituents in biphasic 600 mg and 800 mg tablets of Flavoxate as prepared by wet granulation 600 mg 800 mg Material IR layer ER layer IR layer ER layer Flavoxate hydrochloride 140.00 460.00 186.00 614.00 Lactose 14.775 2.44 19.70 3.25 HPMCAS — 15.00 20.00 HPMC K4M — 15.00 — 20.00 Carbopol ® 971 13.88 18.50 Colloidal silicon dioxide — 1.46 — 1.95 Sodium starch glycolate 3.75 — 5.00 — Brilliant blue 0.75 — 1.00 — Ethyl cellulose 6.00 27.375 8.00 36.50 Tween 80 — 2.925 — 3.90 Water* QS QS QS QS Isopropyl alcohol (IPA)* QS QS QS QS MCC PH 102 7.50 4.50 10.00 6.00 Colloidal silicon dioxide — 2.25 — 3.00 Brilliant blue 0.75 — 1.00 — Talc 1.50 — 2.00 — Magnesium stearate 1.50 5.475 2.00 7.30 *IPA:water (70:30) quantity for ER portion was—54% w/v of dry mix blend. IPA:water (70:30) quantity for IR portion was—47% w/v of dry mix blend.

EXAMPLE 3

Formulation of Biphasic Tablets Comprising 600 and 800 mg of Flavoxate Hydrochloride

[0105] The Flavoxate, fillers, binders, surfactants and CR polymers in concentrations recited in Table 3 below were blended together for IR or ER layers to obtain a blended material. The blended material was milled through a screen with mesh of appropriate size. The blended material was then granulated. The granules were then dried at a suitable temperature and screened through a mesh of appropriate size. The blend was lubricated with a soluble or insoluble lubricant. The tablets were then formed by compression. The hardness of the tablet was adjusted from 6 Kg/cm.sup.2 to 40 Kg/cm.sup.2 for tablets of different strengths.

TABLE-US-00003 TABLE 3 Constituents in biphasic 600 mg and 800 mg tablets of Flavoxate as prepared by wet granulation 600 mg 800 mg Material IR layer ER layer IR layer ER layer Flavoxate hydrochloride 135.975 468.45 181.30 624.60 Lactose 14.775 12.44 19.70 3.25 Hydroxypropyl cellulose — 10.00 — 40.00 Xanthan gum 10.88 18.50 Colloidal silicon dioxide — 1.46 — 1.95 Sodium starch glycolate 3.75 — 5.00 — Brilliant blue 0.75 — 1.00 — PVP K 30 6.00 27.375 8.00 36.50 Sodium lauryl sulphate — 2.925 — 3.90 Water* QS QS QS QS Isopropyl alcohol (IPA)* QS QS QS QS MCC PH 102 7.50 4.50 10.00 6.00 Colloidal silicon dioxide — 2.25 — 3.00 Brilliant blue 0.75 — 1.00 — Talc 1.50 — 2.00 — Magnesium stearate 1.50 5.475 2.00 7.30 *IPA:water (70:30) quantity for ER portion was—45% w/v of dry mix blend. IPA:water (70:30) quantity for IR portion was—35% w/v of dry mix blend.

EXAMPLE 4

Formulation of Biphasic Tablets Comprising 600 and 800 mg of Flavoxate Hydrochloride

[0106] The Flavoxate, fillers, binders, surfactants and controlled release polymers in concentrations recited in Table 4 below were blended together for IR or ER layers to obtain a blended material. The blended material was milled through a screen with mesh of appropriate size. The blended material was then granulated. The granules were then dried at a suitable temperature and screened through a mesh of appropriate size. The blend was lubricated with a soluble or insoluble lubricant. The tablets were then formed by compression. The hardness of the tablet was adjusted from 6 Kg/cm.sup.2 to 40 Kg/cm.sup.2 for tablets of different strengths.

TABLE-US-00004 TABLE 4 Constituents in biphasic 600 mg and 800 mg tablets of Flavoxate as prepared by wet granulation 600 mg 800 mg Material IR layer ER layer IR layer ER layer Flavoxate hydrochloride 120.00 480.00 160.00 640.00 Lactose 14.775 5.44 19.70 6.25 Eudragit L30D 55 — 20.00 30.00 Ethyl cellulose — 20.88 — 25.50 Colloidal silicon dioxide — 1.46 — 1.95 Crospovidone 3.75 — 5.00 — Brilliant blue 0.75 — 1.00 — Hydroxypropyl cellulose 6.00 27.375 8.00 36.50 Tween 80 — 2.925 — 3.90 Water* QS QS QS QS Isopropyl alcohol (IPA)* QS QS QS QS MCC PH 102 7.50 4.50 10.00 6.00 Colloidal silicon dioxide — 2.25 — 3.00 Brilliant blue 0.75 — 1.00 — Talc 1.50 — 2.00 — Magnesium stearate 1.50 5.475 2.00 7.30 *IPA:water (70:30) quantity for ER portion was—55% w/v of dry mix blend. IPA:water (70:30) quantity for IR portion was—58% w/v of dry mix blend.

EXAMPLE 5

Formulation of Biphasic Tablets Comprising 600 and 800 mg of Flavoxate Hydrochloride

[0107] The Flavoxate, fillers, binders, surfactants and controlled release polymers in concentrations recited in Table 5 below were blended together for IR or ER layers to obtain a blended material. The blended material was milled through a screen with mesh of appropriate size. The blended material was then granulated. The granules were then dried at a suitable temperature and screened through a mesh of appropriate size. The blend was lubricated with a soluble or insoluble lubricant. The tablets were then formed by compression. The hardness of the tablet was adjusted from 6 Kg/cm.sup.2 to 40 Kg/cm.sup.2 for tablets of different strengths.

TABLE-US-00005 TABLE 5 Constituents in biphasic 600 mg and 800 mg tablets of Flavoxate as prepared by wet granulation 600 mg 800 mg Material IR layer ER layer IR layer ER layer Flavoxate hydrochloride 140.00 460.00 186.00 614.00 Lactose 14.775 12.44 19.70 13.25 HPMC K15M — 20.00 — 30.00 Carbopol ® 971 13.88 18.50 Colloidal silicon dioxide — 1.46 — 1.95 Sodium starch glycolate 3.75 — 5.00 — Brilliant blue 0.75 — 1.00 — Ethyl cellulose 6.00 27.375 8.00 36.50 Tween 80 — 2.925 — 3.90 Water* QS QS QS QS Isopropyl alcohol (IPA)* QS QS QS QS MCC PH 102 7.50 4.50 10.00 6.00 Colloidal silicon dioxide — 2.25 — 3.00 Brilliant blue 0.75 — 1.00 — Talc 1.50 — 2.00 — Magnesium stearate 1.50 5.475 2.00 7.30

EXAMPLE 6

Formulation of Biphasic Tablets Comprising 600 and 800 mg of Flavoxate Hydrochloride

[0108] The Flavoxate, fillers, binders, surfactants and controlled release polymers in concentrations recited in Table 6 below were blended together for IR or ER layers to obtain a blended material. The blended material was milled through a screen with mesh of appropriate size. The blended material was then granulated. The granules were then dried at a suitable temperature and screened through a mesh of appropriate size. The blend was lubricated with a soluble or insoluble lubricant. The tablets were then formed by compression. The hardness of the tablet was adjusted from 6 Kg/cm.sup.2 to 40 Kg/cm.sup.2 for tablets of different strengths.

TABLE-US-00006 TABLE 6 Constituents in biphasic 600 mg and 800 mg tablets of Flavoxate as prepared by wet granulation 600 mg 800 mg Material IR layer ER layer IR layer ER layer Flavoxate hydrochloride 120.00 480.00 160.00 640.00 Microcrystalline cellulose 13.00 2.44 17.70 3.25 HPMC K15 — 43.88 — 58.50 Colloidal silicon dioxide — 1.46 — 1.95 Croscarmellose sodium 5.53 — 7.00 — Brilliant blue 0.75 — 1.00 — Hydroxypropyl cellulose 6.00 27.375 8.00 36.50 Tween 80 — 2.925 — 3.90 Water* QS QS QS QS Isopropyl alcohol (IPA)* QS QS QS QS MCC PH 102 7.50 4.50 10.00 6.00 Colloidal silicon dioxide — 2.25 — 3.00 Brilliant blue 0.75 — 1.00 — Talc 1.50 — 2.00 — Sodium stearyl fumarate 1.50 5.475 2.00 7.30 *IPA:water (70:30) quantity for ER portion was—55% w/v of dry mix blend. IPA:water (70:30) quantity for IR portion was—58% w/v of dry mix blend.

EXAMPLE 7

Formulation of Biphasic Tablets Comprising 600 and 800 mg of Flavoxate Hydrochloride

[0109] The Flavoxate, fillers, binders, surfactants and controlled release polymers in concentrations recited in Table 7 below were blended together for IR or ER layers to obtain a blended material. The blended material was milled through a screen with mesh of appropriate size. The blended material was then granulated. The granules were then dried at a suitable temperature and screened through a mesh of appropriate size. The blend was lubricated with a soluble or insoluble lubricant. The tablets were then formed by compression. The hardness of the tablet was adjusted from 6 Kg/cm.sup.2 to 40 Kg/cm.sup.2 for tablets of different strengths.

TABLE-US-00007 TABLE 7 Constituents in biphasic 600 mg and 800 mg tablets of Flavoxate as prepared by wet granulation 600 mg 800 mg Material IR layer ER layer IR layer ER layer Flavoxate hydrochloride 120.00 480.00 160.00 640.00 Microcrystalline cellulose 13.00 2.44 17.70 3.25 Eudragit L100 — 20.00 30.00 HPMC K15 — 23.88 — 28.50 Colloidal silicon dioxide — 1.46 — 1.95 Crospovidone 5.53 — 7.00 — Brilliant blue 0.75 — 1.00 — Hydroxypropyl cellulose 6.00 27.375 8.00 36.50 Tween 80 — 2.925 — 3.90 Water* QS QS QS QS Isopropyl alcohol (IPA)* QS QS QS QS MCC PH 102 7.50 4.50 10.00 6.00 Colloidal silicon dioxide — 2.25 — 3.00 Brilliant blue 0.75 — 1.00 — Talc 1.50 — 2.00 — Sodium stearyl fumarate 1.50 5.475 2.00 7.30 *IPA:water (70:30) quantity for ER portion was—55% w/v of dry mix blend. IPA:water (70:30) quantity for IR portion was—58% w/v of dry mix blend.

EXAMPLE 8

Formulation of Biphasic Tablets Comprising 600 and 800 mg of Flavoxate Hydrochloride

[0110] The Flavoxate, fillers, binders, surfactants and controlled release polymers in concentrations recited in Table 8 below were blended together for IR or ER layers to obtain a blended material. The blended material was milled through a screen with mesh of appropriate size. The blended material was then granulated. The granules were then dried at a suitable temperature and screened through a mesh of appropriate size. The blend was lubricated with a soluble or insoluble lubricant. The tablets were then formed by compression. The hardness of the tablet was adjusted from 6 Kg/cm.sup.2 to 40 Kg/cm.sup.2 for tablets of different strengths.

TABLE-US-00008 TABLE 8 Constituents in biphasic 600 mg and 800 mg tablets of Flavoxate as prepared by wet granulation 600 mg 800 mg Material IR layer ER layer IR layer ER layer Flavoxate hydrochloride 120.00 480.00 160.00 640.00 HPMCAS — 30.00 40.00 Starch 14.00 2.44 18.70 3.25 HPMC K15 — 13.88 — 18.50 Colloidal silicon dioxide — 1.46 — 1.95 Croscarmellose sodium 4.53 — 6.00 — Brilliant blue 0.75 — 1.00 — Hydroxypropyl cellulose 6.00 27.375 8.00 36.50 Tween 80 — 2.925 — 3.90 Water* QS QS QS QS Isopropyl alcohol (IPA)* QS QS QS QS MCC PH 102 7.50 4.50 10.00 6.00 Colloidal silicon dioxide — 2.25 — 3.00 Brilliant blue 0.75 — 1.00 — Talc 1.50 — 2.00 — Magnesium stearate 1.50 5.475 2.00 7.30 *IPA:water (70:30) quantity for ER portion was—55% w/v of dry mix blend. IPA:water (70:30) quantity for IR portion was—58% w/v of dry mix blend.

EXAMPLE 9

Formulation of ER Capsule Comprising 600 mg of Flavoxate Hydrochloride

[0111] The drug loaded drug pellets were produced by coating of Flavoxate along with ethyl cellulose, HPMC K4M, Talc and polysorbate 80 on MCC spheres using fluidized bed process to product CR pellets of Flavoxate. The coated pellets were then appropriately lubricated with extragranular contents as recited in Table 9. The coated drug pellets were filled in capsules of gelatin (hard or soft) and non-gelatin capsule shells (e.g., HPMC or sodium alginate vegetarian capsules).

TABLE-US-00009 TABLE 9 Constituents in 600 mg capsule of Flavoxate as prepared by wet granulation MUPS Capsules Qty Per unit Ingredient (in mg) Flavoxate hydrochloride 600.00 HPMC K4M 12.00 Cellulose acetate phthalate 10.00 Polysorbate 80 12.00 Talc 5.00 Microcrystalline cellulose spheres 40.00 355-425 μm Ethyl cellulose coating dispersion 20.00 Microcrystalline cellulose 93.00 Magnesium stearate 4.00 Colloidal silicon dioxide 4.00

EXAMPLE 10

Formulation of ER MUPS Tablets Comprising 600 mg of Flavoxate Hydrochloride

[0112] MUPS tablets were produced by compressing a mixture of Flavoxate containing pellets and powder excipients in concentration as provided in Table 10 below. The pellets have a spherical core that contains or is optionally coated with the Flavoxate and one or more protective layers to control drug release.

TABLE-US-00010 TABLE 10 Constituents in 600 mg MUPS tablets of Flavoxate as prepared by wet granulation method MUPS Tablets Ingredient Qty Per unit (in mg) Flavoxate hydrochloride 600.00 HPMC phthalate 6.00 HPMC K15M 6.00 Polysorbate-80 12.00 Talc 5.00 Sugar spheres 355-425 μm 50.00 Ethyl cellulose coating dispersion 20.00 Microcrystalline cellulose 93.00 Magnesium stearate 4.00 Colloidal silicon dioxide 4.00

EXAMPLE 11

In-vitro Dissolution Drug Release Profile

[0113] A representative in-vitro drug dissolution release rate profile for the formulation of Example 1 in pH gradient dissolution studies (every 2 hours in pH 1.2, pH 4.5, pH 6.8 and pH 7.4 respectively for total period of 8 hours) in simulating physiological pH media when product is dosed orally is presented herein below (Table 11).

TABLE-US-00011 TABLE 11 In-vitro dissolution drug release profile in simulated physiological pH conditions for the formulation of Example 1 Time % Cumulative pH dissolution media duration drug release range pH 1.2, 0.1N Hydrochloric acid 0-2 hours 10-35 pH 4.5, Acetate buffer 2-4 hours 35-75 pH 6.8, Phosphate buffer 4-6 hours 50-90 pH 7.4, Phosphate buffer 6-8 hours NLT 75%

[0114] The in-vitro dissolution release profile of ER formulations is found to be between about 10% and about 35% released during about 0 to 2 hours, between about 35% and about 75% released during about 2 to 4 hours, between about 50% and about 90% released during about 4-6 hours, and not less than (NLT) about 75% during about 6 to 8 hours.

EXAMPLE 12

Comparative Evaluation of In Vitro Dissolution Drug Release Profile of the Formulation of WO202021422A1 Versus Formulation of Example 1

[0115] The formulation of Example 1 was evaluated vis-à-vis the formulations disclosed in WO202021422A1 using in-vitro drug dissolution methodology as part of simulation study with human GIT using pH gradient dissolution medias (every 2 hours in pH 1.2, pH 4.5, pH 6.8 and pH 7.4 respectively for total period of 8 hours) in simulating physiological pH media when product is dosed orally is presented herein below along with 24 hours dissolution study profile (Tables 12 and 13).

TABLE-US-00012 TABLE 12 In-vitro dissolution drug release profile in simulated physiological pH conditions Example 1 Formulation WO202021422A1 Dissolution media (pH) % Cumulative drug release 0.1N Hydrochloric acid 30 16 (0-2 hours) 4.5 pH Acetate buffer 67 37 (2-4 hours) 6.8 pH Phosphate buffer 84 53 (4-6 hours) 7.4 pH Phosphate buffer 93 68 (6-8 hours)

TABLE-US-00013 TABLE 13 Comparative 24 hours dissolution profile study of Example 1 and formulations of WO202021422A1 24 hours dissolution Example 1 profile study Formulation WO202021422A1 Time in hours % Drug released % Drug released 2 28 11 4 44 25 6 57 41 8 69 56 10 80 66 12 89 77 14 96 89 16 100 99 24 100 100

[0116] It is evident from above Table 13 that the formulation of Example 1 has improved drug dissolution release at each pH evaluation stages indicating improved drug release profiles in both 8 hours pH gradient and 24 hours dissolution profile studies.

EXAMPLE 13

Comparative Study for In Vivo % Bioavailability of Exemplary Formulations of the Present Disclosure Versus Immediate Release Tablets

[0117] 18 male participants between the age of 18-45 years (both inclusive) were administered either the Example 1 formulation or the reference IR formulation [Urispas® (Flavoxate HCl, 200 mg)]. All participants fasted for at least 10 hours before administration and then the test formulation was administered with water. Participants received either one extended release tablet of 600 mg strength as prepared in Example 1, or three IR tablets of 200 mg strength. One IR tablet was administered every 8 hours (i.e., at 0 hours, 8 hours, and 16 hours). Blood samples were collected from the participants at the several time points up to 24 hours, and the comparative plasma concentration at given times is shown in Table 14.

TABLE-US-00014 TABLE 14 Comparative blood concentration for formulation of Example 1 and immediate release formulation 200 mg × 3 600 mg Time (in hrs) tablets (μg/ml) (μg/ml) 0 0 0 0.333 2.1 3.2 0.667 3.6 6.9 1 3.1 6.1 1.333 2.7 5.6 1.667 2.2 5.4 2 1.9 5.3 2.333 4.6 2.5 1.5 2.667 4.7 3 1.2 4.2 3.5 3.3 4 0.9 2.5 5 1.6 6 0.5 1.4 8 0.2 0.8 10 4.3 0.9 12 2.1 0.9 16 0.4 0.4 24 0.6 0.10

[0118] Further, the percentage (%) bioavailability of the formulation in Example 1 was evaluated vis-à-vis an immediate release formulation [Urispas® (Flavoxate HCl, 200 mg)] (Table 15) in terms of AUC (Area Under the curve).

TABLE-US-00015 TABLE 15 Comparative % bioavailability [as AUC (Area under curve) parameter] for formulation of Example 1 and immediate release formulation BA of Example 1/BA Acceptance Parameter of Ref. IR (in %) criteria (in %) AUC.sub.24[90% CI] 78.03 80-125 [67.71-89.93] AUC.sub.inf [90% CI] 69.52 80-125 [55.48-87.11] Intra-subject % 25.536/41.597 — CV[ISCV] CI = confidence intervals ISCV = intra-subject variability

EXAMPLE 14

In-vitro Dissolution Profile of Exemplary Formulations of Example 1 Versus Immediate Release Tablets

[0119] Based on results of comparative studies of Example 13 the formulation of Example 1 was fine-tuned to arrive at the formulation of Example 8. The in-vitro dissolution profile of each formulation was studied. Comparative in-vitro dissolution profile in biorelevant dissolution test method for the tablets prepared by formulation of Example 8 was studied at pH 1.2 for first 2 hours followed by pH 7.4 buffer until 24 hours (Table 16).

TABLE-US-00016 TABLE 16 Comparative in-vitro dissolution profile for formulations of Example 1 and Example 8 Dissolution study [pH 1.2 for 1.sup.st 2 hours followed by pH 7.4 buffer until 24 hours] (in hrs.) Batch/time 0.5 1 2 3 4 6 8 10 12 16 20 24 Example 1 9 22 35 30 31 32 34 35 36 39 40 41 (tested in BA study) Example 8 31 37 49 54 61 61 62 66 66 66 68 68 (for further BA study)

[0120] As is evident from the results of Table 16 above, tablet prepared by the formulation of Example 8 exhibits improved release profile relative to the formulation of Example 1.

EXAMPLE 15

Stability Data

[0121] The developed ER pharmaceutical formulations of Flavoxate or salt thereof in Example 1 and Example 8 demonstrate good chemical stability as per accelerated stability data. The developed formulations have improved chemical stability wherein individual unknown impurity levels are less than 0.2% w/w (as per currently available globally acceptable standards for drug products).

[0122] The stable ER or CR formulations and methods for preparation thereof as set forth in the present application accurately describe the efficacy and utility of these formulations and methods for preparation thereof to restore healthy functioning in humans and treat the conditions and disorders in humans as identified and described in this patent application.

[0123] Although the subject matter has been described herein with reference to certain preferred embodiments thereof, other embodiments are possible. For illustrative purpose, the formulations comprise Flavoxate hydrochloride as the active ingredient. However, those skilled in the art would appreciate that scope of the disclosure would extend to other similar lipophilic acid soluble drugs known in the field of art.

[0124] 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 a true scope and spirit of the disclosure being indicated by the following claims. 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.

[0125] Scope of the disclosure is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein