NOVEL MULTIPARTICULATE PHARMACEUTICAL COMPOSITION OF TAMSULOSIN AND SOLIFENACIN

Abstract

The present invention relates to a novel multiparticulate pharmaceutical composition for oral administration with a controlled dissolution rate. The composition comprises Tamsulosin hydrochloride in modified release form and Solifenacin succinate in mmediate release form, wherein the core comprises Tamsulosin hydrochloride and an outer immediate layer comprises Solifenacin succinate. According to the present invention, the instant formulation release the drug at predetermined rate and prevent dose dumping as well as improving the patient compliance.

Claims

1. A multiparticulate, multilayer composition comprising of a) Tamsulosin or a pharmaceutically acceptable salt thereof in Modified or controlled release form as an inner layer b) Solifenacin or a pharmaceutically acceptable salt thereof in immediate release form as outer layer c) Optionally one or more protective layer d) One or more pharmaceutically acceptable excipient e) multiparticulate multilayer composition has an average diameter of particle ranging from 20 to 1200 um f) multiparticulate multilayer composition are either i) filled in hard or soft gelatin capsule or ii) compressed to form a tablet or iii) deliver as oral powder or iv) converted in suspension dosage form

2. The multiparticulate, multilayer composition according to claim 1, when subjected to in vivo studies in human produces a plasma profile characterized by a C.sub.max for Tamsulosin between 3.5 ng/ml to 12 ng/ml and C.sub.max for Solifenacin between 12 ng/ml to 35 ng/ml

3. A multiparticulate composition according to claim 1, wherein composition is in the form of pellet, granule, bead, spheres or extrudate.

4. A multiparticulate composition according to claim 3, wherein composition is in the form of pellet.

5. A multiparticulate composition according to claim 1, wherein one or more pharmaceutically acceptable excipient is selected from the group consisting of modified release polymers, diluents, seal coating polymers, antioxidants, plasticizers, anti-tacking agents, binders, solubilizer, coloring agent, processing solvents , opacifiers or combination thereof.

6. A multiparticulate composition according to claim 5, wherein modified release polymers are selected from the group consisting of methacrylic acid copolymer, methacrylic acid ethyl acrylate polymer, Methacrylic acid Copolymer Dispersion, Ammonio Methacrylate Copolymer (Type A), Ammonio Methacrylate Copolymer (Type B), hypromellose and ethyl cellulose or combination thereof.

7. A multiparticulate composition according to claim 6, wherein ratio of Ammonio Methacrylate Copolymer (Type A): Ammonio Methacrylate Copolymer (Type B) is ranging from 1: 1 to 1:9.

8. A multiparticulate composition according to claim 5, wherein antioxidant is selected form the group consisting of butylated Hydroxytoluene, butylated Hydroxyanisole, ascorbic acid, tocopherol, sodium ascorbate, propyl gallate or combination thereof.

9. A multiparticulate composition according to claim 1, wherein drug dissolution rate of Tamsulosin from composition is not more than of 40% after 4 hours and not more than of 80% in 12 hours; when measured in vitro in USP Apparatus Type 2 (Paddle) using pH 6.8 phosphate buffer of 900 mL, at 100 rpm.

10. The process of manufacturing multiparticulate composition comprising the step of i) Mixing Tamsulosin along with one or more pharmaceutically acceptable excipient to form granules. Spheronize the said granule in spheronizer to form the pellet ii) Seal coating the pellet prepared in step i) by using seal coating polymer iii) Coating the seal coated pellet prepared in step ii) by modified release coating iv) Drug Loading or coating the solifenacin over the modified release coated pellet prepared in step iii) along with one more pharmaceutically acceptable solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION:

[0028] The present invention relates to a multiparticulate composition comprising combination of Tamsulosin or a pharmaceutically acceptable salt thereof and Solifenacin or a pharmaceutically acceptable salt thereof.

[0029] The active ingredient Tamsulosin according to present invention may be present in its base form or their hydrochloric acid salt form or may be in the form of their other acid addition salt. Preferably, Tamsulosin is in the form of Tamsulosin hydrochloride salt form.

[0030] The active ingredient Solifenacin according to present invention may be present in its base form or their succinic acid salt form or may be in the form of their other acid addition salt. Preferably, Solifenacin is in the form of Solifenacin succinate salt form.

[0031] The term “multiparticulate” as used herein means a plurality of discrete or aggregated particles, pellets, beads, granules or mixture thereof irrespective of their size, shape or morphology. The term “multiparticulate” wherein the particulate are pellets, granules, beads, extrudates and seeds or mixture thereof irrespective of their size, shape or morphology.

[0032] The multiparticulate multilayer composition according to present invention may be in the form of pellet, granule, bead, spheres or extrudate.

[0033] The term formulation or composition according to present invention is intended to encompass at least one active ingredient, and the other inert ingredient(s) (pharmaceutical acceptable excipients). Such compositions, depending upon the context, are also synonymous with “formulation” and “dosage form”. These formulations/composition may be prepared in any form, such as solid and liquid dosage form. The solid dosage form can include oral dosage form (powder, tablet, capsule, soft capsule, aqueous medicine, pill, powder, sachet, granule and pellet) and liquid formulation can include solution, suspension, emulsion, syrup, elixirs, etc.

[0034] In another embodiment of the present invention is to provide a multiparticulate composition comprising combination of Tamsulosin or a pharmaceutically acceptable salt thereof and Solifenacin or a pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable excipient.

[0035] The term pharmaceutically acceptable excipient means a pharmacologically inactive component. The excipient(s) that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for human as well as veterinary pharmaceutical use.

[0036] In another embodiment of the present invention is to provide a multiparticulate composition comprising combination of Tamsulosin or a pharmaceutically acceptable salt thereof and Solifenacin or a pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable excipient; wherein Tamsulosin is in the inner core and solifenacin is in the outer coating.

[0037] In another embodiment of the present invention is to provide a multiparticulate composition comprising combination of Tamsulosin or a pharmaceutically acceptable salt thereof and Solifenacin or a pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable excipient; wherein Tamsulosin is in the form of modified release and solifenacin is in the form of immediate release.

[0038] The term “modified release” as used in describing the present invention means a slower release of the active ingredient than an immediate release dosage form. The term “modified release” can be used interchangeably with “sustained release”, “slow release”, “controlled release”, “extended release” or “long term release.

[0039] The multiparticulate composition comprising combination of Tamsulosin or a pharmaceutically acceptable salt thereof and Solifenacin or a pharmaceutically acceptable salt thereof according to present invention contain one or more pharmaceutically acceptable excipient.

[0040] The one or more pharmaceutically acceptable excipient according to present invention may be selected from the group consisting of diluents, sustained release (SR) polymers, seal coating polymers, antioxidants, plasticizers, anti-tacking agents, binders, solubilizer, coloring agent, processing solvents , opacifiers or combination thereof and alike.

[0041] The diluent include but not limited to microcrystalline cellulose, lactose monohydrate, mannitol or combination thereof and alike. The most preferably diluent is microcrystalline cellulose. The formulation according to present invention contains from 40 to 95% by weight of diluents.

[0042] The sustained release (SR) polymers include but not limited to methacrylic acid copolymer, methacrylic acid ethyl acrylate polymer, Methacrylic acid Copolymer Dispersion (Eudragit L 30D55), Ammonio Methacrylate Copolymer (Type A) (Eudragit RL 100), Ammonio Methacrylate Copolymer (Type B), hypromellose and ethyl cellulose or combination thereof and alike. The most preferably sustained release (SR) polymers is methacrylic acid ethyl acrylate copolymer, Methacrylic acid Copolymer Dispersion (Eudragit L 30D55), Ammonio Methacrylate Copolymer (Type B), Ammonio Methacrylate Copolymer (Type A) (Eudragit RL 100). The formulation according to present invention contains from 5 to 40% by weight of SR polymer. The ratio of Ammonio Methacrylate Copolymer (Type A): Ammonio Methacrylate Copolymer (Type B) according to present invention in the composition is ranging from 1:1 to 1:9.

[0043] The term “Seal Coating Polymer” herein refers to as a polymer, used to prevent interaction between two layers. The seal coating polymer(s) is selected from the group consisting of hypromellose, hydroxyl propyl cellulose, methylcellulose, ethyl cellulose or combination thereof and alike. Preferably, seal coating polymer is hypromellose. The formulation according to present invention contains from 2 to 30% by weight of seal coating polymer(s).

[0044] The term “Antioxidants” herein refers to those compounds, that inhibit oxidation and added to prevent deterioration due to oxidation process. The antioxidant(s) is selected form the group consisting of butylated Hydroxytoluene, butylated Hydroxyanisole, ascorbic acid, tocopherol, sodium ascorbate, propyl gallate or combination thereof and alike. Preferably, antioxidants are butylated Hydroxytoluene, butylated Hydroxyanisole and propyl gallate. The formulation according to present invention contains from 0.02 to 0.3% by weight of antioxidant(s).

[0045] The binder include but not limited to hypromellose, povidone, cellulose or combination thereof and alike. Preferably, binder is povidone. The formulation according to present invention contains from 1 to 20% by weight of binder.

[0046] The term “Plasticizer(s)” are used mainly for oral solid dosage forms. Plasticizers are added to the polymers used as film forming agents in order to make the polymer pliable and soft, enhancing the flexibility and plasticity of the films. They are added to these products to reduce the glass transition temperature facilitating the thermal stability of the drug and other ingredients. The plasticizer(s) is selected form the group consisting of Triethyl citrate, triacetin, Polyethylene glycol, Propylene glycol or combination thereof and alike. Preferably, plasticizer is Triethyl citrate. The formulation according to present invention contains from 1-5% by weight of plasticizer(s).

[0047] The term “Anti-tacking Agent” is a necessary component in a coating system to prevent tackiness of the dosage forms during the manufacturing process. The anti-tacking agent(s) is selected form the group consisting of talc, silicon dioxide, simethicone, glycerol monosterate or combination thereof and alike. Preferably, anti-tacking agents are talc and silicon dioxide. The pharmaceutical composition contains from 1-10% by weight of anti-tacking agent(s).

[0048] The term “Opacifier(s)” used to give more pastel color and increase film coverage. They can provide white coat or mask the color of the tablet/pellet/granule core. These are mostly inorganic material. Opacifier is titanium dioxide, yellow iron oxide. Preferably, opacifier is titanium dioxide. The formulation according to present invention contains from 0.2 to 5% by weight of opacifier.

[0049] The term “Processing Solvent(s)” or “Solvent(s)’ can serve one or more functions in pharmaceutical manufacture or formulation. Solvents are chemical substances that can dissolve, suspend or extract other materials usually without chemically changing either the solvents or the other materials. Solvents can be organic or inorganic. They used to enhance solubility, taste, anti-microbial effectiveness or stability, to reduce dose volume or to optimize insolubility. Solvents also used to help the final product in achieving proper consistency. The processing solvent(s) is selected form the group consisting of isopropyl alcohol, dichloromethane, Acetone and Purified water or combination thereof and alike.

[0050] In another embodiment of the present invention is to provide a multiparticulate, multilayer composition comprising of [0051] a) Tamsulosin or a pharmaceutically acceptable salt thereof in Modified or controlled release form as an inner layer [0052] b) Solifenacin or a pharmaceutically acceptable salt thereof in immediate release form as outer layer [0053] c) Optionally one or more protective layer [0054] d) One or more pharmaceutically acceptable excipient [0055] e) multiparticulate multilayer composition has an average diameter of particle ranging from 20 to 1200 um [0056] f) multiparticulate multilayer composition are either [0057] i) filled in hard or soft gelatin capsule or [0058] ii) compressed to form a tablet or [0059] iii) deliver as oral powder or [0060] iv) converted in suspension dosage form

[0061] The multiparticulate, multilayer composition according to present invention wherein average diameter of particle in the composition ranging from 20 to 1200 micrometer (μm). The particle size in the composition is measured by Malvern particle size analyzer.

[0062] The multiparticulate, multilayer composition according to present invention optionally comprises protective layers. The said protective layers or seal coating layers may be present in the or outside the composition. The multilayer composition According to present invention comprises two or more than two layers in the composition.

[0063] The multiparticulate, multilayer composition according to present invention can be filled in to the capsule, or compressed in to tablet or deliver as an oral powder or converted in to the suspension dosage form suitable for human administration.

[0064] In another embodiment of the present invention is to provide a multiparticulate composition comprising combination of Tamsulosin or a pharmaceutically acceptable salt thereof and Solifenacin or a pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable excipient in the form of single pellet formulation.

[0065] In another embodiment of the present invention is to provide single pellet formulation comprising combination of Tamsulosin or a pharmaceutically acceptable salt thereof and Solifenacin or a pharmaceutically acceptable salt thereof.

[0066] In another embodiment of the present invention is to provide single pellet formulation comprising combination of Tamsulosin or a pharmaceutically acceptable salt thereof and Solifenacin or a pharmaceutically acceptable salt thereof; wherein tamsulosin is in the core and solifenacin is in the outer coating

[0067] In another embodiment of the present invention is to provide single pellet formulation comprising combination of Tamsulosin or a pharmaceutically acceptable salt thereof and Solifenacin or a pharmaceutically acceptable salt thereof; wherein tamsulosin is in the modified release form and solifenacin is in the immediate release form.

[0068] In another embodiment of the present invention is to provide single pellet formulation comprising combination of Tamsulosin or a pharmaceutically acceptable salt thereof and Solifenacin or a pharmaceutically acceptable salt thereof; wherein tamsulosin is in the modified release form, which is in the core of pellet, and solifenacin is in the immediate release form; which is in the outer coating.

[0069] In another embodiment of the present invention is to provide a process of manufacturing multiparticulate composition comprising combination of Tamsulosin or a pharmaceutically acceptable salt thereof and Solifenacin or a pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable excipient.

[0070] In another embodiment of the present invention is to provide a process of manufacturing single pellet formulation comprising combination of Tamsulosin or a pharmaceutically acceptable salt thereof and Solifenacin or a pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable excipient.

[0071] In another embodiment of the present invention is to provide a process of manufacturing single pellet formulation comprising the step of [0072] i) Preparing the core of Tamsulosin along with one or more pharmaceutically acceptable excipient. [0073] ii) Drug Loading or coating the solifenacin over the tamsulosin core prepared in step [0074] i) along with one more pharmaceutically acceptable solvent.

[0075] In another embodiment of the present invention is to provide a process of manufacturing single pellet formulation comprising the step of [0076] i) Mixing Tamsulosin along with one or more pharmaceutically acceptable excipient to form granules. [0077] ii) Spheronize the said granule in spheronizer to form the pellet. [0078] iii) Drug Loading or coating the solifenacin over the tamsulosin pellet prepared in step ii) along with one more pharmaceutically acceptable solvent.

[0079] In another embodiment of the present invention is to provide a process of manufacturing single pellet formulation comprising the step of [0080] i) Mixing Tamsulosin along with one or more pharmaceutically acceptable excipient to form granules. Spheronize the said granule in spheronizer to form the pellet. [0081] ii) Coating the pellet prepared in step i) by sustained release coating. [0082] iii) Drug Loading or coating the solifenacin over the sustained release coated pellet prepared in step ii) along with one more pharmaceutically acceptable solvent.

[0083] In another embodiment of the present invention is to provide a process of manufacturing single pellet formulation comprising the step of [0084] i) Mixing Tamsulosin along with one or more pharmaceutically acceptable excipient to form granules. Spheronize the said granule in spheronizer to form the pellet. [0085] ii) Seal coating the pellet prepared in step i) by using seal coating agent. [0086] iii) Coating the seal coated pellet prepared in step ii) by sustained release coating. [0087] iv) Drug Loading or coating the solifenacin over the sustained release coated pellet prepared in step iii) along with one more pharmaceutically acceptable solvent.

[0088] In another embodiment of the present invention is to provide a process of manufacturing single pellet formulation comprising the step of [0089] i) Mixing Tamsulosin along with one or more pharmaceutically acceptable excipient to form granules. Spheronize the said granule in spheronizer to form the pellet. [0090] ii) Seal coating the pellet prepared in step i) by using seal coating agent. [0091] iii) Coating the seal coated pellet prepared in step ii) by sustained release coating. [0092] iv) Seal coating the sustained release coated pellet prepared in step iii) by using seal coating agent. [0093] v) Drug Loading or coating the solifenacin over the seal coated pellet prepared in step iv) along with one more pharmaceutically acceptable solvent.

[0094] In another embodiment of the present invention is to provide a process of manufacturing multiparticulate composition comprising combination of Tamsulosin or a pharmaceutically acceptable salt thereof and Solifenacin or a pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable excipient; wherein core of the formulation may be in the form of pellet, granule, bead, sphere, extrudate. The said core contain Tamsulosin or a pharmaceutically acceptable salt in the form of modified release and immediate release solifenacin over the said core.

[0095] In another embodiment of the present invention is to provide multiparticulate composition comprising combination of Tamsulosin or a pharmaceutically acceptable salt thereof and Solifenacin or a pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable excipient may be in the form of pellet, granule, bead, sphere, extrudate. The said pellet, granule, bead, sphere, or extrudate may be filled in to the capsule, or converted in to the pharmaceutical dosage form for administration to the patient.

[0096] In another embodiment of the present invention is to provide multiparticulate composition, wherein concentration of Tamsulosin or a pharmaceutically acceptable salt thereof and Solifenacin or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable excipient is optimized in such way that, formulation provides desired release in the treatment of benign prostatic hyperplasia (BPH) and associated symptoms.

[0097] The multiparticulate composition comprising combination of Tamsulosin or a pharmaceutically acceptable salt thereof and Solifenacin or a pharmaceutically acceptable salt thereof according to present invention provides similar in-vitro drug release profile as the of commercially available Vesomni® modified release tablet; therefore multiparticulate formulation according to present invention found to be in the compliance.

[0098] In another embodiment of the present invention is to provide multiparticulate composition comprising Tamsulosin and Solifenacin wherein, dissolution rate of Tamsulosin from composition is not more than of 40% after 4 hours and not more than of 80% in 12 hours. The dissolution measured in vitro in USP Apparatus Type 2 (Paddle) using pH 6.8-phosphate buffer of 900 mL, at 100 rpm.

[0099] In another embodiment of the present invention is to provide, multiparticulate, multilayer composition were subjected to in vivo studies in human produces a plasma profile characterized by a C.sub.max for Tamsulosin between 3.5 ng/ml to 12 ng/ml and C.sub.max for Solifenacin between 12 ng/ml to 35 ng/ml.

[0100] C.sub.max is a maximum concentration that a drug achieves in tested area after the drug has been administrated and prior to the administration of a second dose. C.sub.max is the opposite of C.sub.min, which is the minimum concentration that a drug achieves after dosing. T.sub.max is the term used in pharmacokinetics to describe the time at which the C.sub.max is observed.

Bioequivalence Summary for Multiparticulate Composition of Comprising Tamsulosin and Solifenacin:

[0101] The ratio of geometric LS means with corresponding 90% confidence interval calculated from the exponential of the difference between the Test and Reference product for the ln-transformed parameters C.sub.max and AUCO-t (tamsulosin) or AUC 0-24 (solifenacin) were all within 80.00 to 125.00% bioequivalence range for fasted BE study.

[0102] The 90% confidence intervals of the T/R ratios shown in the following table:

TABLE-US-00001 TABLE 1 Bioequivalence Criteria Solifenacin TEST/ 90% CONFIDENCE INTER PHARMACOKINETIC REFERENCE INTERVAL FOR SUBJECT PARAMETERS RATIO TEST Vs REFERENCE CV LN_Cmax 100.92% (89.3% TO 111.8%) 18.4% LN_AUC0-24 98.15% (92.3% TO 112.2%) 13.7%

TABLE-US-00002 TABLE 2 Bioequivalence Criteria Tamsulosin TEST/ 90% CONFIDENCE INTER PHARMACOKINETIC REFERENCE INTERVAL FOR SUBJECT PARAMETERS RATIO TEST Vs REFERENCE CV LN_Cmax 104.15% (90.5% TO 108.7%) 20.1% LN_AUC0-t 100.42% (88.10% TO 118.1%) 24.3%
The multiparticulate composition comprising combination of Tamsulosin or a pharmaceutically 20 acceptable salt thereof and Solifenacin or a pharmaceutically acceptable salt thereof according to present invention were loaded for stability study at condition of 40° C./75% RH, 30° C./75% RH, 25° C./60% RH as per ICH guideline. After stability study, in-vitro drug release profile, assay, related substances and other parameters found to be in the compliance.

[0103] Accordingly, multiparticulate composition of the present invention found to be stable, which is simple, economical, less cumbersome to manufacture and easy to swallow. In addition, which avoids issue like dose dumping, segregation issue, content uniformity and provides efficacy, patient compliance and less adverse clinical effect in the treatment of benign prostatic hyperplasia (BPH) and associated symptoms.

[0104] The multiparticulate composition of the present invention packaged in suitable airtight containers and moisture proof packs. The pharmaceutical composition of the present invention preferably packaged in to the strip, blister, bottle or sachet.

EXAMPLE

[0105] The following Examples are provided solely for illustrative purposes and are not meant to limit the invention in any way.

TABLE-US-00003 TABLE 3 Composition of Tamsulosin and Solifenacin pellet: Sr. No. Ingredients % (Range) 1. Tamsulosin HCl 0.1-0.5 2. Microcrystalline Cellulose PH 101 40-95 3. Methacrylic acid Copolymer Dispersion (Eudragit L 30D55)  5-15 4. Ammonio Methacrylate Copolymer, Type A  5-20 5. Ammonio Methacrylate Copolymer, Type B  5-20 6. Hypromellose 5 cps  5-20 7. Purified Talc  2-10 8. Ammonio Methacrylate Copolymer (Type A) (Eudragit RL 100) 2-8 9. Ethyl cellulose 2-8 10. Triethyl Citrate 1-5 11. Butylated Hydroxytoluene 0.02-0.2  12. Solifenacin Succinate 1-5 13. Isopropyl alcohol:DCM q.s. 14. Purified Water q.s. q.s.—Quantity Sufficient

Brief Manufacturing Process:

[0106] Stage I: Dry mix/Granulation

[0107] Dry mix drug Tamsulosin, Diluent (i.e. Microcrystalline Cellulose PH101), blend for suitable time, and granulate with purified water and optional Release Modifying Agent (i.e. Methacrylic acid copolymer dispersion Eudragit L-30 D55).

Stage II: Extrusion/ Spheronization

[0108] Mass obtained was Extruded using suitable screen (1.2 mm) and spheronized further into pellets. Spheronized pellets dried in FLP/FBD and sifted through suitable screen.

Stage III: Seal Coating 1

[0109] Obtained Tamsulosin pellets subjected to Seal coating in FBC using solution of Hypromellose 5 cps, Purified Talc in Purified Water.

Stage IV: Sustained Release Coating

[0110] Tamsulosin seal coated pellets were enrobed in sustain release coat in FBC using one or more sustain release polymers like Methacrylic acid copolymer dispersion Eudragit L-30 D55, Ammonio Methacrylate copolymer Type A, Ammonio Methacrylate copolymer Type B and Ethyl cellulose.

Stage V: Seal Coating 2

[0111] Tamsulosin SR pellets were sprayed with solution containing Hypromellose 5 cps, Antioxidant (Butylated Hydroxy Toluene or Butylated Hydroxy anisole), Purified Talc and Triethyl citrate in solvent(Mixture of Isopropyl Alcohol and Methylene Chloride) to obtain a sub coat over Tamsulosin SR pellets.
Stage VI: Drug layering/loading:
Drug solution of Solifenacin Succinate was prepared by dispersing Solifenacin Succinate, Hypromellose 50 cps and Antioxidant (Butylated Hydroxyl Toluene or Butylated Hydroxy anisole) in Isopropyl Alcohol and this solution was applied uniformly over Sub coated Tamsulosin SR pellets to form Solifenacin layer.
Stage VII: Final seal coating:
In order to Protect Solifenacin layer, A protective layer of Hypromellose 5 cps, Antioxidant (Butylated Hydroxyl Toluene or Butylated Hydroxy anisole), Purified Talc and Triethyl citrate in solvent(Mixture of Isopropyl Alcohol and Methylene Chloride) was applied. Obtained pellets were dried using FBC.

[0112] Different trials were taken using optimized concentration of polymers and coating layer optimization were done to match in-vitro dissolution profile for Tamsulosin SR layer and Solifenacin Succinate IR layer with reference product Vesomm , from trials most promising batch with different strategy close to reference product were selected for further study. List of examples with composition has been enlisted below:

Examples 1 to 5

[0113]

TABLE-US-00004 TABLE 4 Examples of Pellet Ingredient Example1 Example-2 Example3 Example4 Example 5 Tamsulosin HCl 0.1-0.5 0.1-0.5 0.1-0.5 0.1-0.5 0.1-0.5 Solifenacin Succinate 6 6 6 6 6 Microcrysatlline 242.1 229.6 250.1 250.1 250.1 Cellulose PH101 Methacrylic acid 25 . . . . . . . . . . . . copolymer dispersion Eudragit L-30 D55 Ammonio . . . 25 20 15 5 Methacrylate copolymer Type A Ammonio . . . 25 30 35 45 Methacrylate copolymer Type B Hypromellose 5 cps 28.3 28.8 28.8 28.8 28.8 Ammonio 22 10 . . . . . . . . . Methacrylate copolymer (Type A) Eudragit RL 100 Ethylcellulose 11 10 . . . . . . . . . Triethyl citrtae 5 5.5 5.5 5.5 5.5 Butylated Hydroxy . . . . . . 0.5 0.5 0.5 anisol Butylated 0.7 0.7 0.7 0.7 0.7 Hydroxytoulene Purified Talc 8.5 8 8 8 8 purified water Qs Qs Qs Qs Qs IPA:DCM Qs Qs Qs Qs Qs Total 350 350 350 350 350

Dissolution Profile for Examples 1 to 5:

Tamsulosin:

[0114] Dissolution media for Tamsulosin HCl: pH 6.8 Phosphate buffer, 900 ml, 100 RPM, USP 2 apparatus (paddle) with sinker, Temperature 37±0.5° C.

TABLE-US-00005 TABLE 5 Dissolution results for Tamsulosin HCl SR: Time Exam- Exam- Exam- Exam- Exam- (Hr) Vesomni ple-1 ple-2 ple-3 ple-4 ple-5 2 16 6 16 23 21 18 4 26 16 34 32 30 28 6 39 26 47 48 48 45 8 48 37 56 59 58 55 10 53 49 63 67 64 58 12 68 63 70 77 75 74 18 85 90 79 93 91 90 20 90 92 82 96 95 93 24 93 95 85 97 96 96

Solifenacin:

[0115] Dissolution media for Solifenacin succinate: Water, 900 ml, 100 RPM, USP 2apparatus (paddle) with sinker, Temperature 37±0.5° C.

TABLE-US-00006 TABLE 6 Dissolution result of Solifenacin Succinate: Time Exam- Exam- Exam- Exam- Exam- (Mi) Vesomni ple-1 ple-2 ple-3 ple-4 ple-5 15 86 65 96 88 90 89 30 87 72 98 89 91 92 45 90 74 100 91 95 93 60 91 76 100 95 96 95
Conclusion: As per above result, the dissolution of the test product, example 1 to 5 were found to be similar to reference product Vesomni.

STABILITY DATA (For Example 5):

[0116]

TABLE-US-00007 TABLE 7 Stability condition: 40° C./75% RH (1, 3, 6 Month): Dissolution (%) of Related Substances Dissolution Solifenacin Tamsulosin HCl Solifenacin Succinate (%) of Succinate Highest Highest Tamsulosin HCl 900 ml, 0.1N Unknown Unknown Assay 900 ml, Phosphate HCl, pH 1.2, Impurity Individual Total Impurity Individual Total Tests Tamsulosin Solifenacin buffer pH 6.8, paddle, H Impurity impurity I Impurity impurity Condition/ HCL Succinate Paddle, 100 RPM 100 RPM NMT NMT NMT NMT NMT NMT Interval Limit: 95.0-105.0% 2 hr 12 hr 24 hr 45 mins 1.0% 1.0% 2.0 0.8% 0.33% 2.0 Initial 97.6 99.5 5 62 95 93 ND ND ND 0.29 0.12 0.41 40° C./75% 99.6 100.3 6 65 97 92 ND ND ND 0.38 0.25 0.63 RH_1 M 40° C./75% 96.1 97.0 3 55 90 90 ND ND ND 0.55 0.31 0.86 RH_3 M 40° C./75% 96.4 95.0 4 55 87 90 ND ND ND 0.49 0.28 0.77 RH_6 M

TABLE-US-00008 TABLE 8 Stability condition: 30° C./75% RH (1, 3, 6 Month): Dissolution (%) of Related Substances Dissolution Solifenacin Tamsulosin HCl Solifenacin Succinate (%) of Succinate Highest Highest Tamsulosin HCl 900 ml, 0.1N Unknown Unknown Assay 900 ml, Phosphate HCl, pH 1.2, Impurity Individual Total Impurity Individual Total Tests Tamsulosin Solifenacin buffer pH 6.8, paddle, H Impurity impurity I Impurity impurity Condition/ HCL Succinate Paddle, 100 RPM 100 RPM NMT NMT NMT NMT NMT NMT Interval Limit: 95.0-105.0% 2 hr 12 hr 24 hr 45 mins 1.0% 1.0% 2.0 0.8% 0.33% 2.0 30° C./75% 100.3 98.9 6 61 93 99 ND ND ND 0.34 0.19 0.53 RH_1 M 30° C./75% 96.6 96.8 4 58 95 99 ND ND ND 0.45 0.32 0.77 RH_3 M 30° C./75% 96.9 97.0 4 54 91 100 ND ND ND 0.41 0.34 0.75 RH_6 M

TABLE-US-00009 TABLE 9 Stability condition: 25° C./60% RH (1, 3, 6 Month): Dissolution (%) of Related Substances Dissolution Solifenacin Tamsulosin HCl Solifenacin Succinate (%) of Succinate Highest Highest Tamsulosin HCl 900 ml, 0.1N Unknown Unknown Assay 900 ml, Phosphate HCl, pH 1.2, Impurity Individual Total Impurity Individual Total Tests Tamsulosin Solifenacin buffer pH 6.8, paddle, H Impurity impurity I Impurity impurity Condition/ HCL Succinate Paddle, 100 RPM 100 RPM NMT NMT NMT NMT NMT NMT Interval Limit: 95.0-105.0% 2 hr 12 hr 24 hr 45 mins 1.0% 1.0% 2.0 0.8% 0.33% 2.0 25° C./60% 102.1 99.1 5 62 95 96 ND ND ND 0.33 0.16 0.49 RH_1 M 25° C./60% 97.3 97.2 4 58 93 97 ND ND ND 0.42 0.26 0.68 RH_3 M 25° C./60% 96.5 98.8 6 62 92 95 ND ND ND 0.37 0.12 0.49 RH_6 M

Examples 6 to 8

[0117]

TABLE-US-00010 TABLE 10 Examples of Soft gelatin capsule Ingredients Example-6 Example-7 Example-8 Tamsulosin & 350 350 350 Solifinacin Pellets Mono-di-glycerides of 80 100 120 caprylic/capric acid Butylhydroxytoluene 0.8 0.8 0.8 Soft Capsules . . . . . . . . . Gelatin 185.2 195.2 196.2 Glycerol 46 46 46 Titanium dioxide (E171) 22 22 22 Iron Oxide Yellow (El72) 11 11 11 Triglycerides, medium chain 5 5 5 Lecithin (may contain soya oil) 10 10 10 Total 710 740 761

Examples 9 to 13

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TABLE-US-00011 TABLE 11 Examples of MUPS Ingredients Example-9 Example-10 Example-11 Example-12 Example-13 Tamsulosin & 350 350 350 350 350 Solifinacin Pellets Cushioning agent Microcrysatlline 100 100 100 100 100 Cellulose (Ceolus-KG 1000) Colloidal 15 15 15 15 15 Anhydrous Silica (Aerosil 200) Polyethylene 20 30 40 50 60 Glycol 6000 Total 485 495 505 515 525

Examples 14 to 18

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TABLE-US-00012 TABLE 12 Examples of Oral Suspension Ingredients Example-14 Example-15 Example-16 Example-17 Example-18 Pellets Tamsulosin & 350 350 350 350 350 Solifinacin Pellets Oral Suspension Xanthan gum 10 15 20 10 10 (Xantural-75) Guar Gum 30 40 45 45 50 Sucrose 145 130 120 130 125 Colloidal 5 5 5 5 5 anhydrous Silica Banana Flavour 10 10 10 10 10 Total 550 550 550 550 550