WO2020097328A1 - Fixed dose pharmaceutical compositions for treating overactive bladder and related conditions - Google Patents

Abstract

The present invention relates to fixed dose pharmaceutical compositions for oral administration comprising a core of a therapeutically effective amount of mirabegron, or a pharmaceutically acceptable salt thereof, coated with a layer of a therapeutically effective amount of solifenacin, or a pharmaceutically acceptable salt thereof, and methods of use for treating overactive bladder and related conditions. The formulations described herein have desirable stability and pharmacokinetic characteristics.

Description

FIXED DOSE PHARMACEUTICAL COMPOSITIONS FOR TREATING OVERACTIVE BLADDER AND RELATED CONDITIONS

PRIORITY

[0001] This PCT Application claims priority to US Provisional Application No. 62/756,836 filed on November 7, 2018 titled“Fixed Dose Pharmaceutical Compositions for Treating Overactive Bladder and Related Conditions,” and is incorporated herein by reference.

SUMMARY

[0002] Embodiments of the present invention relate to fixed dose pharmaceutical compositions for oral administration comprising a therapeutically effective amount of mirabegron, or a pharmaceutically acceptable salt thereof, coated with a layer of a therapeutically effective amount of solifenacin, or a pharmaceutically acceptable salt thereof, in a single composition, and methods of use for treating overactive bladder and related conditions.

[0003] Mirabegron is b3 -adrenergic receptor agonist compound having the following structural formula.

[0004] Its chemical name is (R)-2-(2-aminothiazol-4-yl)-4'-{2-[(2-hydroxy-2- phenylethyl)amino]ethyl}acetanilide (also known as 2-(2-amino-l,3-thiazol-4-yl)-N-[4-(2- {[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide). Mirabegron and its pharmaceutically acceptable salts exhibit b3 -adrenergic receptor agonist activity, and are useful as a therapeutic agent for overactive bladder. Mirabegron is marketed in the U.S. as Myrbetriq. Formulations and uses of Mirabegron have been described and include the following patents: RE44872; U.S. Patent No. 8,835,474; U.S. Patent No. 8,772,315; U.S. Patent No. 6,346,532; U.S. Patent No. 6,562,375; U.S. Patent No. 7,982,049; U.S. Patent No. 7,342,117. Another compound with therapeutic effects for treating overactive bladder is solifenacin. VESIcare (solifenacin succinate) is the commercial name for this muscarinic receptor antagonist. Chemically, solifenacin succinate is butanedioic acid, compounded with (l S)-(3R)-l-azabicyclo[2.2.2]oct-3-yl 3,4-dihydro-l-phenyl-2(lH)- iso-quinolinecarboxylate (1 : 1) having an empirical formula of C₂₃H₂₆N₂0_2*C₄H₆0₄, and a molecular weight of 480.55. The structural formula of solifenacin succinate is:

[0005] The chemical name is: [(3R)-l-azabicyclo[2.2.2]octan-3-yl](l S)-l-phenyl- 3,4-dihydro-lH-isoquinoline-2-carboxylate;butanedioic acid. Like other anticholinergics, solifenacin is an ester of a carboxylic acid containing (at least) an aromatic ring with an alcohol containing a nitrogen atom. While in the prototype anticholinergic atropine the bicyclic ring is tropane, solifenacin replaces it with quinuclidine. Formulations and uses of solifenacin succinate, known commercially as VESIcare in the U.S. have been described and include the following patent: U.S. Patent No. 6,017,927.

[0006] While a number of combinations and mixtures for treating overactive bladder has been described, none have exhibited desirable stability, efficacy, and/or maintained desired release profiles. W02004/047838 broadly describes compositions containing multiple active ingredients, but does not describe the combination of mirabegron and solifenacin. W02004/041276 describes compositions containing a single active agent with b₃ adrenergic receptor agonist activities that is useful for treating overactive bladder. WO1996/20194 describes compositions containing a single active agent having muscarinic M₃ receptor antagonistic activities useful for treating overactive bladder.

[0007] There is a need for new fixed dose combination pharmaceutical compositions that effectively combine two active ingredients for treating overactive bladder into a single composition, while maintaining the desired properties and features (e.g. pharmacokinetics) of the single ingredient formulations. DESCRIPTION OF DRAWINGS

[0008] For a fuller understanding of the nature and advantages of the present invention, reference should be had to the following detailed description taken in connection with the accompanying drawings, in which:

[0009] Figure 1 shows the mean concentration-time profiles of mirabegron on Day 10 by gender at 50 mg and 200 mg once daily.

[0010] Figure 2 shows plasma PK parameters of mirabegron on Day 10 by gender at 50 mg, 100 mg, and 200 mg once daily.

[0011] Figure 3 shows the mean plasma concentration versus time profiles for oral administration of single doses of 5-100 mg of solifenacin.

DETAILED DESCRIPTION

[0012] Before the present compositions and methods are described, it is to be understood that this invention is not limited to the particular processes, compositions, or methodologies described, as these may vary. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the preferred methods, devices, and materials are now described. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0013] It must also be noted that as used herein and in the appended claims, the singular forms“a”,“an”, and“the” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to a“fibroblast” is a reference to one or more fibroblasts and equivalents thereof known to those skilled in the art, and so forth.

[0014] As used herein, the term“about” means plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 45%-55%.

[0015]“Administering” when used in conjunction with a therapeutic means to administer a therapeutic directly into or onto a target tissue or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted. [0016] The term "animal" as used herein includes, but is not limited to, humans and non-human vertebrates such as wild, domestic and farm animals.

[0017] The term“improves” is used to convey that the present invention changes either the appearance, form, characteristics and/or the physical attributes of the tissue to which it is being provided, applied or administered.

[0018] The term "inhibiting" includes the administration of a compound of the present invention to prevent the onset of the symptoms, alleviating the symptoms, or eliminating the disease, condition or disorder.

[0019] "Patient" or "subject" refers to mammals and includes human and veterinary subjects.

[0020] By "pharmaceutically acceptable", it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In embodiments, it refers to molecular entities and compositions that are "generally regarded as safe", e.g., that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human. Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeias for use in animals, and more particularly in humans.

[0021] “Pharmaceutically acceptable salt”, as used herein, represents salts or zwitterionic forms of the compounds disclosed herein which are water or oil-soluble or dispersible and therapeutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (i sethi onate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L- tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para- toluenesulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds disclosed herein can be quatemized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

[0022] As used herein, the term“therapeutic” means an agent utilized to treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient. In part, embodiments of the present invention are directed to the treatment of overactive bladder, and any combination of related conditions such as: urinary urgency, pollakiuria and/or urinary incontinence.

[0023] A“therapeutically effective amount” or“effective amount” of a composition is a predetermined amount calculated to achieve the desired effect, i.e., to inhibit, block, or reverse the activation, migration, or proliferation of cells. The activity contemplated by the present methods includes both medical therapeutic and/or prophylactic treatment, as appropriate. The specific dose of a compound administered according to this invention to obtain therapeutic and/or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, and the condition being treated. The compounds are effective over a wide dosage range and, for example, dosages per day will normally fall within the range of from 0.001 to 10 mg/kg, more usually in the range of from 0.01 to 1 mg/kg. However, it will be understood that the effective amount administered will be determined by the physician in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. A therapeutically effective amount of compound of this invention is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in the tissue.

[0024] The terms "treat," "treated," or "treating" as used herein refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (z.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

[0025] Embodiments of the present invention relate to fixed dose pharmaceutical compositions of a core comprising a therapeutically effective amount of mirabegron (a b-3 adrenergic agonist), or a pharmaceutically acceptable salt thereof, coated with a layer of a therapeutically effective amount of a solifenacin (a muscarinic antagonist), or a pharmaceutically acceptable salt thereof, and methods of use for treating overactive bladder and related conditions.

Fixed Dose Pharmaceutical Compositions

[0026] In embodiments, the therapeutically effective amount of mirabegron is from about 25 milligrams to about 100 milligrams. In embodiments, the therapeutically effective amount of mirabegron is about 25 milligrams or about 50 milligrams or about 100 milligrams.

[0027] In embodiments, the mirabegron is the free base. In embodiments, the mirabegron is a pharmaceutically acceptable salt thereof.

[0028] In embodiments, the core of the fixed dose pharmaceutical composition comprises a therapeutically effective amount of mirabegron and a pharmaceutically acceptable excipient. In embodiments, the pharmaceutically acceptable excipient of the core is selected from the group consisting of polyethylene oxide, polyethylene glycol, hydroxypropyl cellulose, butylated hydroxytoluene, magnesium stearate, hypromellose, yellow ferric oxide, red ferric oxide and combinations thereof. The pharmaceutically acceptable excipient of the core is present in [an amount / ratio to mirabegron]. In embodiments, core of the fixed dose pharmaceutical composition is in extended release form (e.g. Myrbetriq). [0029] In embodiments, the therapeutically effective amount of solifenacin is from about 5 milligrams to about 10 milligrams. In embodiments, the therapeutically effective amount of solifenacin is about 5 milligrams or about 10 milligrams.

[0030] In embodiments, the solifenacin is the free base. In embodiments, the solifenacin is a pharmaceutically acceptable salt thereof. In embodiments, solifenacin is solifenacin succinate.

[0031] In embodiments, the layer coating the core of the fixed dose pharmaceutical composition comprises a therapeutically effective amount of solifenacin and a pharmaceutically acceptable excipient. In embodiments, the pharmaceutically acceptable excipient of the coating layer is selected from the group consisting of [opadry], lactose monohydrate, com starch, hypromellose 2910, magnesium stearate, talc, polyethylene glycol 8000 and titanium dioxide with yellow ferric oxide (5 mg VESIcare tablet) or red ferric oxide (10 mg VESIcare tablet) or combinations thereof. The pharmaceutically acceptable excipient of the coating layer is present in an about 1 : 1 ratio of solifenacin and pharmaceutically acceptable excipient.

[0032] In embodiments, the fixed dose pharmaceutical composition is suitable for oral administration.

[0033] In embodiments, the fixed dose pharmaceutical composition is a solid oral dosage form.

[0034] In embodiments, the fixed dose pharmaceutical composition is selected from a tablet, a capsule, a cachet, a pellet, a pill, a powder, a dragee, and a granule. In embodiments, the fixed dose pharmaceutical composition is a tablet.

[0035] In certain embodiments, the pharmaceutical composition for oral use provides a stable pharmaceutical composition by the addition of a coating or by physical mixture of yellow ferric oxide and/or red ferric oxide, which provides a composition that exhibits little or no changes in drug release.

[0036] In addition, aspects of the present invention include providing a combination composition that prevents changes in drug release in a matrix type sustained-release preparation containing a drug, a hydrophilic base, and a polyethylene oxide.

[0037] The fixed dose pharmaceutical compositions can be solid dosage forms which include, but are not limited to, tablets, capsules, cachets, pellets, pills, powders, dragees, granules and the like, for oral ingestion by a patient to be treated. It is also known in the art that the active ingredients can be contained in such compositions with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like. The means and methods for administration are known in the art and an artisan can refer to various pharmacologic references for guidance. For example, Modem Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman & Gilman's The Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co., New York (1980) and Remington: The Science and Practice of Pharmacy. Lippincott Williams & Wilkins (A. R. Gennaro edit. 2005) can be consulted. The choice of pharmaceutical excipient, diluent, and carrier can be selected with regard to the intended route of administration and standard pharmaceutical practice. Suitable excipients include, but are not limited to, fillers such as sugars, including, but not limited to, lactose, sucrose, mannitol, and sorbitol; cellulose preparations such as, but not limited to, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, such as, but not limited to, the cross- linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0038] Dragee cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0039] Pharmaceutical compositions which can be used orally include, but are not limited to, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as, e.g ., lactose, binders such as, e.g, starches, and/or lubricants such as, e.g. , talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration.

[0040] Pharmaceutical compositions of the compounds also can comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as, e.g. , polyethylene glycols. [0041] The compounds of the present invention can also be administered in combination with other active ingredients, such as, for example, adjuvants, protease inhibitors, or other compatible drugs or compounds where such combination is seen to be desirable or advantageous in achieving the desired effects of the methods described herein.

[0042] In some embodiments, the disintegrant component comprises one or more of croscarmellose sodium, carmellose calcium, crospovidone, alginic acid, sodium alginate, potassium alginate, calcium alginate, an ion exchange resin, an effervescent system based on food acids and an alkaline carbonate component, clay, talc, starch, pregelatinized starch, sodium starch glycolate, cellulose floe, carboxymethylcellulose, hydroxypropylcellulose, calcium silicate, a metal carbonate, sodium bicarbonate, calcium citrate, or calcium phosphate.

[0043] In some embodiments, the diluent component comprises one or more of mannitol, lactose, sucrose, maltodextrin, sorbitol, xylitol, powdered cellulose, microcrystalline cellulose, carboxymethylcellulose, carboxyethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, starch, sodium starch glycolate, pregelatinized starch, a calcium phosphate, a metal carbonate, a metal oxide, or a metal aluminosilicate.

[0044] In some embodiments, the optional lubricant component, when present, comprises one or more of stearic acid, metallic stearate, sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, silica, silicic acid, talc, propylene glycol fatty acid ester, polyethoxylated castor oil, polyethylene glycol, polypropylene glycol, polyalkylene glycol, polyoxyethylene-glycerol fatty ester, polyoxyethylene fatty alcohol ether, polyethoxylated sterol, polyethoxylated castor oil, polyethoxylated vegetable oil, or sodium chloride.

[0045] As used herein, the term“calcium silicate” refers to a silicate salt of calcium.

[0046] As used herein, the term“calcium phosphate” refers to monobasic calcium phosophate, dibasic calcium phosphate or tribasic calcium phosphate.

[0047] Cellulose, cellulose floe, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, carboxyethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, ethylcellulose, methylcellulose, carboxymethylcellulose sodium, and carboxym ethyl cellulose calcium include, but are not limited to, those described in R. C. Rowe and P. J. Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed., which is incorporated herein by reference in its entirety. As used herein, cellulose refers to natural cellulose. The term“cellulose” also refers to celluloses that have been modified with regard to molecular weight and/or branching, particularly to lower molecular weight. The term “cellulose” further refers to celluloses that have been chemically modified to attach chemical functionality such as carboxy, hydroxyl, hydroxyalkylene, or carboxyalkylene groups. As used herein, the term“carboxyalkylene” refers to a group of formula -alkylene-C(0)OH, or salt thereof. As used herein, the term“hydroxyalkylene” refers to a group of formula - alkylene-OH.

[0048] Suitable powdered celluloses for use in the invention include, but are not limited to Arbocel (available from JRS Pharma), Sanacel (available from CFF GmbH), and Solka-Floc (available from International Fiber Corp.).

[0049] Suitable microcrystalline celluloses include, but are not limited to, the Avicel pH series (available from FMC Biopolymer), Celex (available from ISP), Celphere (available from Asahi Kasei), Ceolus KG (available from Asahi Kasei), and Vivapur (available from JRS Pharma).

[0050] As used herein, the term“silicified microcrystalline cellulose” refers to a synergistic intimate physical mixture of silicon dioxide and microcrystalline cellulose. Suitable silicified microcrystalline celluloses include, but are not limited to, ProSolv (available from JRS Pharma).

[0051] As used herein, the term “carboxymethylcellulose sodium” refers to a cellulose ether with pendant groups of formula Na⁺ O-C(0)-CH₂-, attached to the cellulose via an ether linkage. Suitable carboxymethylcellulose sodium polymers include, but are not limited to, Akucell (available from Akzo Nobel), Aquasorb (available from Hercules), Blanose (available from Hercules), Finnfix (available from Noviant), Nymel (available from Noviant), and Tylose CB (available from Clariant).

[0052] As used herein, the term “carboxymethylcellulose calcium” refers to a cellulose ether with a pendant groups of formula -CH₂-0-C(0)-0 ½ Ca²⁺, attached to the cellulose via an ether linkage.

[0053] As used herein, the term“carboxymethylcellulose” refers to a cellulose ether with pendant carboxymethyl groups of formula HO-C(0)-CH₂-, attached to the cellulose via an ether linkage. Suitable carboxymethylcellulose calcium polymers include, but are not limited to, Nymel ZSC (available from Noviant). [0054] As used herein, the term“carboxyethylcellulose” refers to a cellulose ether with pendant carboxymethyl groups of formula H0-C(0)-CH₂-CH₂-, attached to the cellulose via an ether linkage.

[0055] As used herein, the term“hydroxyethylcellulose” refers to a cellulose ether with pendant hydroxyethyl groups of formula HO-CH2-CH2-, attached to the cellulose via an ether linkage. Suitable hydroxyethylcelluloses include, but are not limited to, Cellosize HEC (available from DOW), Natrosol (available from Hercules), and Tylose PHA (available from Clariant).

[0056] As used herein, the term“methylhydroxyethylcellulose” refers to a cellulose ether with pendant methyloxyethyl groups of formula CH3-O-CH2-CH2-, attached to the cellulose via an ether linkage. Suitable methylhydroxyethylcelluloses include, but are not limited to, the Culminal MHEC series (available from Hercules), and the Tylose series (available from Shin Etsu).

[0057] As used herein, the term“hydroxypropylcellulose”, or“hypomellose”, refers a cellulose that has pendant hydroxypropoxy groups, and includes both high- and low- substituted hydroxypropylcellulose. In some embodiments, the hydroxypropylcellulose has about 5% to about 25% hydroxypropyl groups. Suitable hydroxypropylcelluloses include, but are not limited to, the Klucel series (available from Hercules), the Methocel series (available from Dow), the Nisso HPC series (available from Nisso), the Metolose series (available from Shin Etsu), and the LH series, including LHR-l l, LH-21, LH-31, LH-20, LH-30, LH-22, and LH-32 (available from Shin Etsu).

[0058] As used herein, the term“methyl cellulose” refers to a cellulose that has pendant methoxy groups. Suitable methyl celluloses include, but are not limited to Culminal MC (available from Hercules).

[0059] As used herein, the term“ethyl cellulose” refers to a cellulose that has pendant ethoxy groups. Suitable ethyl celluloses include, but are not limited to Aqualon (available from Hercules).

[0060] As used herein, the term“carmellose calcium” refers to a crosslinked polymer of carboxymethylcellulose calcium.

[0061] As used herein, the term“croscarmellose sodium” refers to a crosslinked polymer of carboxymethylcellulose sodium.

[0062] As used herein, the term“crospovidone” refers to a crosslinked polymer of polyvinylpyrrolidone. Suitable crospovidone polymers include, but are not limited to Polyplasdone XL- 10 (available from ISP) and Kollidon CL and CL-M (available from BASF).

[0063] As used herein, the term“crosslinked poly(acrylic acid)” refers to a polymer of acrylic acid which has been crosslinked. The crosslinked polymer may contain other monomers in addition to acrylic acid. Additionally, the pendant carboxy groups on the crosslinked polymer may be partially or completely neutralized to form a pharmaceutically acceptable salt of the polymer. In some embodiments, the crosslinked poly(acrylic acid) is neutralized by ammonia or sodium hydroxide. Suitable crosslinked poly(acrylic acid) polymers include, but are not limited to, the Carbopol series (available from Noveon).

[0064] As used herein, the term“fatty acid”, employed alone or in combination with other terms, refers to an aliphatic acid that is saturated or unsaturated. In some embodiments, the fatty acid in a mixture of different fatty acids. In some embodiments, the fatty acid has between about eight to about thirty carbons on average. In some embodiments, the fatty acid has about eight to about twenty-four carbons on average. In some embodiments, the fatty acid has about twelve to about eighteen carbons on average. Suitable fatty acids include, but are not limited to, stearic acid, lauric acid, myristic acid, erucic acid, palmitic acid, palmitoleic acid, capric acid, caprylic acid, oleic acid, linoleic acid, linolenic acid, hydroxystearic acid, l2-hydroxystearic acid, cetostearic acid, isostearic acid, sesquioleic acid, sesqui-9-octadecanoic acid, sesquiisooctadecanoic acid, benhenic acid, isobehenic acid, and arachidonic acid, or mixtures thereof.

[0065] As used herein, the term“fatty acid ester” refers to a compound formed between a fatty acid and a hydroxyl containing compound. In some embodiments, the fatty acid ester is a sugar ester of fatty acid. In some embodiments, the fatty acid ester is a glyceride of fatty acid. In some embodiments, the fatty acid ester is an ethoxylated fatty acid ester.

[0066] As used herein, the term“fatty alcohol”, employed alone or in combination with other terms, refers to an aliphatic alcohol that is saturated or unsaturated. In some embodiments, the fatty alcohol in a mixture of different fatty alcohols. In some embodiments, the fatty alcohol has between about eight to about thirty carbons on average. In some embodiments, the fatty alcohol has about eight to about twenty-four carbons on average. In some embodiments, the fatty alcohol has about twelve to about eighteen carbons on average. Suitable fatty alcohols include, but are not limited to, stearyl alcohol, lauryl alcohol, palmityl alcohol, palmitolyl acid, cetyl alcohol, capryl alcohol, caprylyl alcohol, oleyl alcohol, linolenyl alcohol, arachidonic alcohol, behenyl alcohol, isobehenyl alcohol, selachyl alcohol, chimyl alcohol, and linoleyl alcohol, or mixtures thereof.

[0067] As used herein, the term“ion-exchange resin” refers to an ion-exchange resin that is pharmaceutically acceptable and that can be weakly acidic, weakly basic, strongly acidic or strongly basic. Suitable ion-exchange resins include, but are not limited to Amberlite™ IRP64, IRP88 and IRP69 (available from Rohm and Haas) and Duolite™ AP143 (available from Rohm and Haas). In some embodiments, the ion-exchange resin is a crosslinked polymer resin comprising acrylic acid, methacrylic acid, or polystyrene sulfonate, or salts thereof. In some embodiments, the ion-exchange resin is polacrilex resin, polacrilin potassium resin, or cholestyramine resin.

[0068] Suitable mannitols include, but are not limited to, PharmMannidex (available from Cargill), Pearlitol (available from Roquette), and Mannogem (available from SPI Polyols).

[0069] As used herein, the term“metal aluminosilicate” refers to any metal salt of an aluminosilicate, including, but not limited to, magnesium aluminometasilicate. Suitable magnesium aluminosilicates include, but are not limited to Neusilin (available from Fuji Chemical), Pharmsorb (available from Engelhard), and Veegum (available from R.T. Vanderbilt Co., Inc.). In some embodiments, the metal aluminosilicate is bentonite.

[0070] As used herein, the term“metal carbonate” refers to any metallic carbonate, including, but not limited to sodium carbonate, calcium carbonate, and magnesium carbonate, and zinc carbonate.

[0071] As used herein, the term “metal oxide” refers to any metallic oxide, including, but not limited to, calcium oxide or magnesium oxide.

[0072] As used herein, the term“metallic stearate” refers to a metal salt of stearic acid. In some embodiments, the metallic stearate is calcium stearate, zinc stearate, or magnesium stearate. In some embodiments, the metallic stearate is magnesium stearate.

[0073] As used herein, the term“mineral oil” refers to both unrefined and refined (light) mineral oil. Suitable mineral oils include, but are not limited to, the Avatech™ grades (available from Avatar Corp.), Drakeol™ grades (available from Penreco), Sirius™ grades (available from Shell), and the Citation™ grades (available from Avater Corp.).

[0074] As used herein, the term“polyethoxylated castor oil”, refers to a compound formed from the ethoxylation of castor oil, wherein at least one chain of polyethylene glycol is covalently bound to the castor oil. The castor oil may be hydrogenated or unhydrogenated. Synonyms for polyethoxylated castor oil include, but are not limited to polyoxyl castor oil, hydrogenated polyoxyl castor oil, mcrogolglyceroli ricinoleas, macrogolglyceroli hydroxystearas, polyoxyl 35 castor oil, and polyoxyl 40 hydrogenated castor oil. Suitable polyethoxylated castor oils include, but are not limited to, the Nikkol™ HCO series (available from Nikko Chemicals Co. Ltd.), such as Nikkol HCO-30, HC-40, HC-50, and HC-60 (polyethylene glycol-30 hydrogenated castor oil, polyethylene glycol-40 hydrogenated castor oil, polyethylene glycol-50 hydrogenated castor oil, and polyethylene glycol-60 hydrogenated castor oil, Emulphor™ EL-719 (castor oil 40 mole-ethoxylate, available from Stepan Products), the Cremophore™ series (available from BASF), which includes Cremophore REMO, RH60, and EL35 (polyethylene glycol -40 hydrogenated castor oil, polyethylene glycol-60 hydrogenated castor oil, and polyethylene glycol-35 hydrogenated castor oil, respectively), and the Emulgin® RO and HRE series (available from Cognis PharmaLine). Other suitable polyoxyethylene castor oil derivatives include those listed in R. C. Rowe and P. J. Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed., which is incorporated herein by reference in its entirety.

[0075] As used herein, the term“polyethoxylated sterol” refers to a compound, or mixture of compounds, derived from the ethoxylation of sterol molecule. Suitable polyethoyxlated sterols include, but are not limited to, PEG-24 cholesterol ether, Solulan™ C-24 (available from Amerchol); PEG-30 cholestanol, Nikkol™ DHC (available from Nikko); Phytosterol, GENEROL™ series (available from Henkel); PEG-25 phyto sterol, Nikkol™ BPSH-25 (available from Nikko); PEG-5 soya sterol, Nikkol™ BPS-5 (available from Nikko); PEG-10 soya sterol, Nikkol™ BPS-10 (available from Nikko); PEG-20 soya sterol, Nikkol™ BPS-20 (available from Nikko); and PEG-30 soya sterol, Nikkol™ BPS-30 (available from Nikko). As used herein, the term“PEG” refers to polyethylene glycol.

[0076] As used herein, the term “polyethoxylated vegetable oil” refers to a compound, or mixture of compounds, formed from ethoxylation of vegetable oil, wherein at least one chain of polyethylene glycol is covalently bound to the the vegetable oil. In some embodiments, the fatty acids has between about twelve carbons to about eighteen carbons. In some embodiments, the amount of ethoxylation can vary from about 2 to about 200, about 5 to 100, about 10 to about 80, about 20 to about 60, or about 12 to about 18 of ethylene glycol repeat units. The vegetable oil may be hydrogenated or unhydrogenated. Suitable polyethoxylated vegetable oils, include but are not limited to, Cremaphor™ EL or RH series (available from BASF), Emulphor™ EL-719 (available from Stepan products), and Emulphor™ EL-620P (available from GAF). [0077] As used herein, the term“polyethylene glycol” refers to a polymer containing ethylene glycol monomer units of formula -O-CH2-CH2-. Suitable polyethylene glycols may have a free hydroxyl group at each end of the polymer molecule, or may have one or more hydroxyl groups etherified with a lower alkyl, e.g., a methyl group. Also suitable are derivatives of polyethylene glycols having esterifiable carboxy groups. Polyethylene glycols useful in the present invention can be polymers of any chain length or molecular weight, and can include branching. In some embodiments, the average molecular weight of the polyethylene glycol is from about 200 to about 9000. In some embodiments, the average molecular weight of the polyethylene glycol is from about 200 to about 5000. In some embodiments, the average molecular weight of the polyethylene glycol is from about 200 to about 900. In some embodiments, the average molecular weight of the polyethylene glycol is about 400. Suitable polyethylene glycols include, but are not limited to polyethylene glycol-200, polyethylene glycol-300, polyethylene glycol-400, polyethylene glycol-600, and polyethylene glycol-900. The number following the dash in the name refers to the average molecular weight of the polymer. In some embodiments, the polyethylene glycol is polyethylene glycol-400. Suitable polyethylene glycols include, but are not limited to the Carbowax™ and Carbowax™ Sentry series (available from Dow), the Lipoxol™ series (available from Brenntag), the Lutrol™ series (available from BASF), and the Pluriol™ series (available from BASF).

[0078] As used herein, the term“polyoxyethylene-alkyl ether” refers to a monoalkyl or dialkylether of polyoxyethylene, or mixtures thereof. In some embodiments, the polyoxyethylene-alkyl ether is a polyoxyethylene fatty alcohol ether.

[0079] As used herein, the term’’polyoxyethylene fatty alcohol ether” refers to an monoether or diether, or mixtures thereof, formed between polyethylene glycol and a fatty alcohol. Fatty alcohols that are useful for deriving polyoxyethylene fatty alcohol ethers include, but are not limited to, those defined herein. In some embodiments, the polyoxyethylene portion of the molecule has about 2 to about 200 oxyethylene units. In some embodiments, the polyoxyethylene portion of the molecule has about 2 to about 100 oxyethylene units. In some embodiments, the polyoxyethylene portion of the molecule has about 4 to about 50 oxyethylene units. In some embodiments, the polyoxyethylene portion of the molecule has about 4 to about 30 oxyethylene units. In some embodiments, the polyoxyethylene fatty alcohol ether comprises ethoxylated stearyl alcohols, cetyl alcohols, and cetylstearyl alcohols (cetearyl alcohols). Suitable polyoxyethylene fatty alcohol ethers include, but are not limited to, the Brij™ series of surfactants (available from Uniqema), which includes Brij 30, 35, 52, 56, 58, 72, 76, 78, 93Veg, 97, 98, and 721, the Cremophor™ A series (available from BASF), which includes Cremophor A6, A20, and A25, the Emulgen™ series (available from Kao Corp.), which includes Emulgen 104P, 123P, 210P, 220, 320P, and 409P, the Ethosperse™ (available from Lonza), which includes Ethosperse 1A4, 1A12, TDAa6, S120, and G26, the Ethylan™ series (available from Brenntag), which includes Ethylan D252, 253, 254, 256, 257, 2512, and 2560, the Plurafac™ series (available from BASF), which includes Plurafac RA20, RA30, RA40, RA43, and RA340, the Ritoleth™ and Ritox™ series (available from Rita Corp.), the Volpo™ series (available from Croda), which includes Volpo N 10, N 20, S2, S10, C2, C20, CS10, CS20, L4, and L23, and the Texafor™ series, which includes Texafor A1P, AP, A6, A10, A14, A30, A45, and A60. Other suitable polyoxyethylene fatty alcohol ethers include, but are not limited to, polyethylene glycol (l3)stearyl ether (steareth-l3), polyethylene glycol (l4)stearyl ether (steareth-l4), polyethylene glycol (l5)stearyl ether (steareth-l5), polyethylene glycol (l6)stearyl ether (steareth-l6), polyethylene glycol (l7)stearyl ether (steareth-l7), polyethylene glycol (l8)stearyl ether (steareth-l8), polyethylene glycol (l9)stearyl ether (steareth-l9), polyethylene glycol (20)stearyl ether (steareth-20), polyethylene glycol

(12)isostearyl ether (isosteareth-l2), polyethylene glycol (l3)isostearyl ether (isosteareth-l3), polyethylene glycol (l4)isostearyl ether (isosteareth-l4), polyethylene glycol (l5)isostearyl ether (isosteareth-l5), polyethylene glycol (l6)isostearyl ether (isosteareth-l6), polyethylene glycol (l7)isostearyl ether (isosteareth-l7), polyethylene glycol (l8)isostearyl ether (isosteareth-l8), polyethylene glycol (l9)isostearyl ether (isosteareth-l9), polyethylene glycol (20)isostearyl ether (isosteareth-20), polyethylene glycol (l3)cetyl ether (ceteth-l3), polyethylene glycol (l4)cetyl ether (ceteth-l4), polyethylene glycol (l5)cetyl ether (ceteth- 15), polyethylene glycol (l6)cetyl ether (ceteth-l6), polyethylene glycol (l7)cetyl ether (ceteth-l7), polyethylene glycol (l8)cetyl ether (ceteth-l8), polyethylene glycol (l9)cetyl ether (ceteth-l9), polyethylene glycol (20)cetyl ether (ceteth-20), polyethylene glycol

(13)isocetyl ether (isoceteth-l3), polyethylene glycol (l4)isocetyl ether (isoceteth-l4), polyethylene glycol (l5)isocetyl ether (isoceteth-l5), polyethylene glycol (l6)isocetyl ether (isoceteth-l6), polyethylene glycol (l7)isocetyl ether (isoceteth-l7), polyethylene glycol (l8)isocetyl ether (isoceteth-l8), polyethylene glycol (l9)isocetyl ether (isoceteth-l9), polyethylene glycol (20)isocetyl ether (isoceteth-20), polyethylene glycol (l2)oleyl ether (oleth-l2), polyethylene glycol (l3)oleyl ether (oleth-l3), polyethylene glycol (l4)oleyl ether (oleth-l4), polyethylene glycol (l5)oleyl ether (oleth-l5), polyethylene glycol (l2)lauryl ether (laureth-l2), polyethylene glycol (l2)isolauryl ether (isolaureth-l2), polyethylene glycol (l3)cetylstearyl ether (ceteareth-l3), polyethylene glycol (l4)cetylstearyl ether (ceteareth-l4), polyethylene glycol (l5)cetylstearyl ether (ceteareth-l5), polyethylene glycol (l6)cetylstearyl ether (ceteareth-l6), polyethylene glycol (l7)cetylstearyl ether (ceteareth- 17), polyethylene glycol (l8)cetylstearyl ether (ceteareth-l8), polyethylene glycol (l9)cetylstearyl ether (ceteareth-l9), and polyethylene glycol (20)cetylstearyl ether (ceteareth-20). The numbers following the“polyethylene glycol” term refer to the number of oxyethylene repeat units in the compound. Blends of polyoxyethylene fatty alcohol ethers with other materials are also useful in the invention. A non-limiting example of a suitable blend is Arlacel™ 165 or 165 VEG (available from Uniqema), a blend of glycerol monostearate with polyethylene glycol- 100 stearate. Other suitable polyoxyethylene fatty alcohol ethers include those listed in R. C. Rowe and P. J. Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed., which is incorporated herein by reference in its entirety.

[0080] As used herein, the term“polyoxyethylene-glycerol fatty ester” refers to ethoxylated fatty acid ester of glycerine, or mixture thereof. In some embodiments, the polyoxyethylene portion of the molecule has about 2 to about 200 oxyethylene units. In some embodiments, the polyoxyethylene portion of the molecule has about 2 to about 100 oxyethylene units. In some embodiments, the polyoxyethylene portion of the molecule has about 4 to about 50 oxyethylene units. In some embodiments, the polyoxyethylene portion of the molecule has about 4 to about 30 oxyethylene units. Suitable polyoxyethylene-glycerol fatty esters include, but are not limited to, PEG-20 glyceryl laurate, Tagat™ L (Goldschmidt); PEG-30 glyceryl laurate, Tagat™ L2 (Goldschmidt); PEG- 15 glyceryl laurate, Glycerox™ L series (Croda); PEG-40 glyceryl laurate, Glycerox™ L series (Croda); PEG-20 glyceryl stearate, Capmul™ EMG (ABITEC), Aldo MS-20 KFG (Lonza); PEG-20 glyceryl oleate, Tagat™ 0 (Goldschmidt); PEG-30 glyceryl oleate, Tagat™ 02 (Goldschmidt).

[0081] As used herein, the term’’propylene glycol fatty acid ester” refers to an monoether or diester, or mixtures thereof, formed between propylene glycol or polypropylene glycol and a fatty acid. Fatty acids that are useful for deriving propylene glycol fatty alcohol ethers include, but are not limited to, those defined herein. In some embodiments, the monoester or diester is derived from propylene glycol. In some embodiments, the monoester or diester has about 1 to about 200 oxypropylene units. In some embodiments, the polypropylene glycol portion of the molecule has about 2 to about 100 oxypropylene units. In some embodiments, the monoester or diester has about 4 to about 50 oxypropylene units. In some embodiments, the monoester or diester has about 4 to about 30 oxypropylene units. Suitable propylene glycol fatty acid esters include, but are not limited to, propylene glycol laurates: Lauroglycol™ FCC and 90 (available from Gattefosse); propylene glycol caprylates: Capryol™ PGMC and 90 (available from Gatefosse); and propylene glycol dicaprylocaprates: Labrafac™ PG (available from Gatefosse).

[0082] Suitable sorbitols include, but are not limited to, PharmSorbidex E420 (available from Cargill), Liponic 70-NC and 76-NC (available from Lipo Chemical), Neosorb (available from Roquette), Partech SI (available from Merck), and Sorbogem (available from SPI Polyols).

[0083] Starch, sodium starch glycolate, and pregelatinized starch include, but are not limited to, those described in R. C. Rowe and P. J. Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed., which is incorporated herein by reference in its entirety.

[0084] As used herein, the term“starch” refers to any type of natural or modified starch including, but not limited to, maize starch (also known as com starch or maydis amylum), potato starch (also known as solani amylum), rice starch (also known as oryzae amylum), wheat starch (also known as tritici amylum), and tapioca starch. The term“starch” also refers to starches that have been modified with regard to molecular weight and branching. The term“starch” further refers to starches that have been chemically modified to attach chemical functionality such as carboxy, hydroxyl, hydroxyalkylene, or carboxyalkylene groups. As used herein, the term“carboxyalkylene” refers to a group of formula -alkylene-C(0)OH, or salt thereof. As used herein, the term“hydroxyalkylene” refers to a group of formula -alkylene-OH. Suitable sodium starch glycolates include, but are not limited to, Explotab (available from JRS Pharma), Glycolys (available from Roquette), Primojel (available from DMV International), and Vivastar (available from JRS Pharma).

[0085] Suitable pregelatinized starches include, but are not limited to, Lycatab C and PGS (available from Roquette), Merigel (available from Brenntag), National 78-1551 (available from National Starch), Spress B820 (available from GPC), and Starch 1500 (available from Colorcon).

[0086] As used herein, the term “stearoyl macrogol glyceride” refers to a polyglycolized glyceride synthesized predominately from stearic acid or from compounds derived predominately from stearic acid, although other fatty acids or compounds derived from other fatty acids may used in the synthesis as well. Suitable stearoyl macrogol glycerides include, but are not limited to, Gelucire® 50/13 (available from Gattefosse). [0087] As used herein, the term“vegetable oil” refers to naturally occurring or synthetic oils, which may be refined, fractionated or hydrogenated, including triglycerides. Suitable vegetable oils include, but are not limited to castor oil, hydrogenated castor oil, sesame oil, corn oil, peanut oil, olive oil, sunflower oil, safflower oil, soybean oil, benzyl benzoate, sesame oil, cottonseed oil, and palm oil. Other suitable vegetable oils include commercially available synthetic oils such as, but not limited to, Miglyol™ 810 and 812 (available from Dynamit Nobel Chicals, Sweden) Neobee™ M5 (available from Drew Chemical Corp.), Alofine™ (available from Jarchem Industries), the Lubritab™ series (available from JRS Pharma), the Sterotex™ (available from Abitec Corp.), Softisan™ 154 (available from Sasol), Croduret™ (available from Croda), Fancol™ (available from the Fanning Corp.), Cutina™ HR (available from Cognis), Simulsol™ (available from CJ Petrow), EmCon™ CO (available from Amisol Co.), Lipvol™ CO, SES, and HS-K (available from Lipo), and Sterotex™ HM (available from Abitec Corp.). Other suitable vegetable oils, including sesame, castor, corn, and cottonseed oils, include those listed in R. C. Rowe and P. J. Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed., which is incorporated herein by reference in its entirety.

[0088] It will be clear to a person skilled in the art that, where appropriate, the other therapeutic ingredient(s) may be used in the form of salts, for example as alkali metal or amine salts or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for example hydrates, to optimize the activity and/or stability and/or physical characteristics, such as solubility, of the therapeutic ingredient. It will be clear also that, where appropriate, the therapeutic ingredients may be used in optically pure form.

Methods of Use

[0089] Embodiments of the present invention related to methods of treating overactive bladder in a subject in need thereof comprising orally administering to the subject a fixed dose pharmaceutical composition as described herein, wherein overactive bladder is treated.

[0090] In embodiments, the fixed dose pharmaceutical composition is administered once or twice a day.

[0091] In embodiments, treating overactive bladder is to diminish or alleviate one or more of the following typical symptoms of overactive bladder: urinary frequency, urinary urgency, and urinary incontinence.

[0092] In embodiments, the fixed dose pharmaceutical composition may be orally administered to the subject with or without food. [0093] In embodiments, the fixed dose pharmaceutical compositions exhibit the same pharmacokinetic (PK) and pharmacodynamics (PD) profiles as the reference single active agents mirabegron (as Myrbetriq) and solifenacin (as VESIcare).

[0094] In embodiments, the fixed dose pharmaceutical compositions exhibit the plasma-concentration curves of either 5mg or 10 mg of solifenacin as shown in Figure 3 and the 25 mg, 50 mg or 100 mg of mirabegron as shown in Figure 1.

[0095] Pharmacokinetics of Mirabegron

[0096] Absorption

[0097] After oral administration of mirabegron in healthy volunteers, mirabegron is absorbed to reach maximum plasma concentrations (Cmax) at approximately 3.5 hours. The absolute bioavailability increases from 29% at a dose of 25 mg to 35% at a dose of 50 mg. Mean Cmax and AUC increase more than dose proportionally. This relationship is more apparent at doses above 50 mg. In the overall population of males and females, a 2-fold increase in dose from 50 mg to 100 mg mirabegron increased Cmax and AUCtau by approximately 2.9- and 2.6-fold, respectively, whereas a 4-fold increase in dose from 50 to 200 mg mirabegron increased Cmax and AUCtau by approximately 8.4- and 6.5-fold. Steady state concentrations are achieved within 7 days of once-daily dosing with mirabegron. After once-daily administration, plasma exposure of mirabegron at steady state is approximately double that seen after a single dose.

[0098] Distribution

[0099] Mirabegron is extensively distributed in the body. The volume of distribution at steady state (Vss) is approximately 1670 L following intravenous administration. Mirabegron is bound (approximately 71%) to human plasma proteins, and shows moderate affinity for albumin and alpha- 1 acid glycoprotein. Mirabegron distributes to erythrocytes. Based on an in vitro study, erythrocyte concentrations of l4C-mirabegron were about 2-fold higher than in plasma.

[00100] Metabolism

[00101] Mirabegron is metabolized via multiple pathways involving dealkylation, oxidation, (direct) glucuronidation, and amide hydrolysis. Mirabegron is the major circulating component following a single dose of l4C-mirabegron. Two major metabolites were observed in human plasma and are phase 2 glucuronides representing 16% and 11% of total exposure, respectively. These metabolites are not pharmacologically active toward beta-3 adrenergic receptor. Although in vitro studies suggest a role for CYP2D6 and CYP3A4 in the oxidative metabolism of mirabegron, in vivo results indicate that these isozymes play a limited role in the overall elimination. In healthy subjects who are genotypically poor metabolizers of CYP2D6, mean Cmax and AUCtau were approximately 16% and 17% higher than in extensive metabolizers of CYP2D6, respectively. In vitro and ex vivo studies have shown the involvement of butylcholinesterase, uridine diphospho-glucuronosyltransferases (UGT) and possibly alcohol dehydrogenase in the metabolism of mirabegron, in addition to CYP3A4 and CYP2D6.

[00102] Excretion

[00103] Total body clearance (CLtot) from plasma is approximately 57 L/h following intravenous administration. The terminal elimination half-life (tl/2) is approximately 50 hours. Renal clearance (CLR) is approximately 13 L/h, which corresponds to nearly 25% of CLtot. Renal elimination of mirabegron is primarily through active tubular secretion along with glomerular filtration. The urinary elimination of unchanged mirabegron is dose- dependent and ranges from approximately 6.0% after a daily dose of 25 mg to 12.2% after a daily dose of 100 mg. Following the administration of 160 mg l4C-mirabegron solution to healthy volunteers, approximately 55% of the radioactivity dose was recovered in the urine and 34% in the feces. Approximately 25% of unchanged mirabegron was recovered in urine and 0% in feces.

[00104] It is expected that the elimination half-life of mirabegron in the fixed-dose combination pharmaceutical formulations described herein would be the same, or very similar to that described for the single mirebegron formulation compound, e.g. Myrbetriq.

[00105] Pharmacokinetics of Solifenacin

[00106] Absorption

[00107] After oral administration of VESIcare to healthy volunteers, peak plasma levels (Cmax) of solifenacin are reached within 3 to 8 hours after administration, and at steady state ranged from 32.3 to 62.9 ng/mL for the 5 and 10 mg VESIcare tablets, respectively. The absolute bioavailability of solifenacin is approximately 90%, and plasma concentrations of solifenacin are proportional to the dose administered.

[00108] Distribution

[00109] Solifenacin is approximately 98% (in vivo ) bound to human plasma proteins, principally to ocl-acid glycoprotein. Solifenacin is highly distributed to non-CNS tissues, having a mean steady-state volume of distribution of 600L.

[00110] Metabolism

[00111] Solifenacin is extensively metabolized in the liver. The primary pathway for elimination is by way of CYP3 A4; however, alternate metabolic pathways exist. The primary metabolic routes of solifenacin are through N-oxidation of the quinuclidin ring and 4R- hydroxylation of tetrahydroisoquinoline ring. One pharmacologically active metabolite (4R- hydroxy solifenacin), occurring at low concentrations and unlikely to contribute significantly to clinical activity, and three pharmacologically inactive metabolites (N-glucuronide and the N-oxide and 4R-hydroxy-N-oxide of solifenacin) have been found in human plasma after oral dosing.

[00112] Excretion

[00113] Following the administration of 10 mg of l4C-solifenacin succinate to healthy volunteers, 69.2% of the radioactivity was recovered in the urine and 22.5% in the feces over 26 days. Less than 15% (as mean value) of the dose was recovered in the urine as intact solifenacin. The major metabolites identified in urine were N-oxide of solifenacin, 4R- hydroxy solifenacin and 4R-hydroxy-N-oxide of solifenacin and in feces 4R-hydroxy solifenacin. The elimination half-life of solifenacin following chronic dosing is approximately 45-68 hours.

[00114] It is expected that the elimination half-life of solifenacin in the fixed-dose combination pharmaceutical compositions described herein would be the same, or very similar to that described for the single solifenacin formulation compound, e.g. VESIcare.

[00115] Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents may be added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[00116] Conventional pharmacological techniques include, e.g., one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachman et ah, The Theory and Practice of Industrial Pharmacy (1986). Other methods include, e.g., spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extruding and the like. [00117] The pharmaceutical solid dosage forms described herein can include any of the active agents and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof. In still other aspects, using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000), a film coating is provided around the formulation of any of the active agents . In one embodiment, some or all of the particles of the any of the active agents are coated. In another embodiment, some or all of the particles of the active agents are microencapsulated. In still another embodiment, the particles of the any of the active agents are not microencapsulated and are uncoated.

[00118] In order to release any of the active agents from a solid dosage form matrix as efficiently as possible, disintegrants may be utilized in the formulation, especially when the dosage forms are compressed with binder. Disintegrants help rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as com starch or potato starch, a pregelatinized starch such as National 1551 or Amijel.RTM., or sodium starch glycolate such as Promogel.RTM. or Explotab.RTM., a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel.RTM., Avicel.RTM. PH101, Avicel.RTM. PH102, Avicel.RTM. PH105, Elcema.RTM. P100, Emcocel.RTM., Vivacel.RTM., Ming Tia.RTM., and Solka-Floc.RTM., methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol.RTM.), cross-linked carboxymethylcellulose, or cross- linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum.RTM. HV (magnesium aluminum silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and the like. In some embodiments provided herein, the disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross- linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, or a gum. In some embodiments provided herein, the disintegrating agent is croscarmellose sodium.

[00119] Binders impart cohesiveness to solid oral dosage form formulations: for powder filled capsule formulation, they aid in plug formation that can be filled into soft or hard shell capsules and for tablet formulation, they ensure the tablet remaining intact after compression and help assure blend uniformity prior to a compression or fill step. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel.RTM.), hydroxypropylmethylcellulose (e.g. Hypromellose USP Pharmacoat-603, hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel.RTM.), ethylcellulose (e.g., Ethocel.RTM.), and microcrystalline cellulose (e.g., Avicel.RTM.), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac.RTM.), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab.RTM.), lactose, a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone (e.g., Povidone.RTM. CL, Kollidon.RTM. CL, Polyplasdone.RTM. XL- 10, and Povidone.RTM. K-12), larch arabogalactan, Veegum.RTM., polyethylene glycol, waxes, sodium alginate, and the like.

[00120] Binder usage level in tablet formulations varies whether direct compression, wet granulation, roller compaction, or usage of other excipients such as fillers which itself can act as moderate binder. Formulators skilled in art can determine the binder level for the formulations, but binder usage level of up to 70% in tablet formulations is common.

[00121] Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, com starch, sodium stearyl fumerate, alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet.RTM., boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as Carbowax.TM., PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like. In some embodiments provided herein, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, com starch, sodium stearyl fumerate, stearic acid, sodium stearates, magnesium stearate, zinc stearate, and waxes. In some embodiments provided herein, the lubricant is magnesium stearate.

[00122] Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins and the like. In some embodiments provided herein, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc. In some embodiments provided herein, the diluent is microcrystalline cellulose.

[00123] The term "non water-soluble diluent" represents compounds typically used in the formulation of pharmaceuticals, such as calcium phosphate, calcium sulfate, starches, modified starches and microcrystalline cellulose, and microcellulose (e.g., having a density of about 0.45 g/cm³, e.g. Avicel, powdered cellulose), and talc.

[00124] Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10.RTM.), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS and the like.

[00125] Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic.RTM. (BASF), and the like. In some embodiments provided herein, the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide. In some embodiments provided herein, the surfactant is sodium lauryl sulfate.

[00126] Suitable suspending agents for use in the solid dosage forms described here include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, vinyl pyrrolidone/vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like.

[00127] Suitable antioxidants for use in the solid dosage forms described herein include, for example, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[00128] It should be appreciated that there is considerable overlap between additives used in the solid dosage forms described herein. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in solid dosage forms described herein. The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired.

[00129] In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Illustratively, a plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.

[00130] Compressed tablets are solid dosage forms prepared by compacting the bulk blend of the formulations described above. In various embodiments, compressed tablets which are designed to dissolve in the mouth will include one or more flavoring agents. In other embodiments, the compressed tablets will include a film surrounding the final compressed tablet. In some embodiments, the film coating can provide a delayed release of any of the active agents from the formulation. In other embodiments, the film coating aids in patient compliance (e.g., Opadry™ coatings or sugar coating). Film coatings including Opadry™ typically range from about 1% to about 3% of the tablet weight. In a preferred embodiment, the Opadry™ is mixed at a 1 : 1 ratio (w/w) with solifenacin.

[00131] In other embodiments, the compressed tablets include one or more excipients. [00132] In various embodiments, the particles of any of the active agents and one or more excipients are dry blended and compressed into a mass, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, after oral administration, thereby releasing the formulation into the gastrointestinal fluid.

[00133] In another aspect, dosage forms may include microencapsulated formulations. In some embodiments, one or more other compatible materials are present in the microencapsulation material. Exemplary materials include, but are not limited to, pH modifiers, erosion facilitators, anti-foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[00134] Materials useful for the microencapsulation described herein include materials compatible with any of the active agents , which sufficiently isolate the actives (mirabegron and solifenacin) from other non-compatible excipients. Materials compatible with the compounds are those that delay the release of the actives of any of the the active agents in vivo.

[00135] Exemplary microencapsulation materials useful for delaying the release of the formulations including compounds described herein, include, but are not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel.RTM. or Nisso HPC, low- substituted hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat.RTM., Metolose SR, Methocel.RTM.-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymers such as Methocel.RTM.-A, hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS) and Metolose. RTM., Ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel.RTM., Aqualon.RTM.-EC, Surelease.RTM., Polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethylcelluloses such as Natrosol.RTM., carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aqualon.RTM.-CMC, polyvinyl alcohol and polyethylene glycol co-polymers such as Kollicoat IR.RTM., monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit.RTM. EPO, Eudragit.RTM. L30D-55, Eudragit.RTM. FS 30D Eudragit.RTM. L100-55, Eudragit.RTM. L100, Eudragit.RTM. S100, Eudragit.RTM. RD100, Eudragit.RTM. E100, Eudragit.RTM. L12.5, Eudragit.RTM. S12.5, Eudragit.RTM. NE30D, and Eudragit.RTM. NE 40D, cellulose acetate phthalate, sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures of these materials.

[00136] In still other embodiments, plasticizers such as polyethylene glycols, e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material. In other embodiments, the microencapsulating material useful for delaying the release of the pharmaceutical compositions is from the ETSP or the National Formulary (NF). In yet other embodiments, the microencapsulation material is Klucel. In still other embodiments, the microencapsulation material is methocel.

[00137] Microencapsulated active agents may be formulated by methods known by one of ordinary skill in the art. Such known methods include, e.g., spray drying processes, spinning disk-solvent processes, hot melt processes, spray chilling methods, fluidized bed, electrostatic deposition, centrifugal extrusion, rotational suspension separation, polymerization at liquid-gas or solid-gas interface, pressure extrusion, or spraying solvent extraction bath. In addition to these, several chemical techniques, e.g., complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid media, in situ polymerization, in-liquid drying, and desolvation in liquid media could also be used. Furthermore, other methods such as roller compaction, extrusion/spheronization, coacervation, or nanoparticle coating may also be used.

[00138] In one embodiment, the particles of any of the active agents are microencapsulated prior to being formulated into one of the above forms. In still another embodiment, some or most of the particles are coated prior to being further formulated by using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000).

[00139] In other embodiments, the solid dosage formulations of any of the active agents are plasticized (coated) with one or more layers. Illustratively, a plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.

[00140] In other embodiments, a powder including the formulations with any of the active agents may be formulated to include one or more pharmaceutical excipients and flavors. Such a powder may be prepared, for example, by mixing the formulation and optional pharmaceutical excipients to form a bulk blend composition. Additional embodiments also include a suspending agent and/or a wetting agent. This bulk blend is uniformly subdivided into unit dosage packaging or multi-dosage packaging units.

[00141] In certain embodiments, the non-pH dependent water soluble coating film which is impermeable barrier to both moisture and light in the above embodiments comprises one or more of the following film substances selected from the group consisting of Kollicoat® IR, hydroxypropyl methylcellulose (HPMC), a combination of titanium dioxide and talc powder, and Opadry II® containing the combination of hydroxypropyl methylcellulose (HPMC), titanium dioxide and talc powder. In certain embodiments, Opadry II® consists of polyvinyl alcohol, iron oxide or titanium dioxide, Macrogol and talc. Oral solid formulation compositions are described, for example in U.S. Patent No. 9,555,003.

[00142] The methods and formulations of U.S. Patent 6,562,375 are incorporated herein by reference. In particular, U.S. Patent 6,562,375 describes stable pharmaceutical compositions comprising yellow ferric oxide and/or red ferric oxide in a matrix-type of sustained-release preparations containing the active drug ingredient, a hydrophilic base, and a polyethylene oxide. Such stable compositions are also encompassed by the present combination formulations, as described herein.

[00143] Exemplary Mirabegron Formulations

50 mg Mirabegron Composition A

Tablet

Active ingredient: 50.0 mg

Lactose: 199.5 mg

Corn starch: 40.0 mg

Hydroxypropyl cellulose: 9.0 mg

Magnesium stearate: 1.5 mg

Subtotal: 300 mg

Coat

Hydroxypropyl methyl cellulose 2910: 8.7 mg

Polyethylene glycol 6000: 1.2 mg

Titanium oxide: 4.8 mg

Talc: 0.3 mg

Subtotal: 15 mg

Grand total: 315 mg 50 mg Mirabegron Composition B

Tablet

Active ingredient: 50.0 mg

Lactose: 99.75 mg

Corn starch: 20.0 mg

Hydroxypropyl cellulose: 4.5 mg

Magnesium stearate: 0.75 mg

Subtotal: 175 mg

Coat

Hydroxypropyl methyl cellulose 2910: 8.7 mg

Polyethylene glycol 6000: 1.2 mg

Titanium oxide: 4.8 mg

Talc: 0.3 mg

Subtotal: 15 mg

Grand total: 190 mg

100 mg Mirabegron Composition C

Tablet

Active ingredient: 100.0 mg

Lactose: 199.5 mg

Corn starch: 40.0 mg

Hydroxypropyl cellulose: 9.0 mg

Magnesium stearate: 1.5 mg

Subtotal: 350 mg

Coat

Hydroxypropyl methyl cellulose 2910: 8.7 mg

Polyethylene glycol 6000: 1.2 mg

Titanium oxide: 4.8 mg

Talc: 0.3 mg

Subtotal: 15 mg

Grand total: 365 mg

[00144] Exemplary 100 mg Mirabegron Tablet

The active ingredient (200.0 g) and 399.0 g of lactose were mixed in a polyethylene bag. The mixture was mixed and disintegrated in a sample mill (manufactured by Hosokawa Micron). The disintegrated mixture (450.0 g) and 60.1 g of com starch were uniformly mixed in a fluidized granulation coating apparatus (manufactured by Ogawara Seisakusho). A 10% hydroxypropyl cellulose solution (192 g) was sprayed thereon to granulate. After being dried, the above was passed through a sieve of 20 meshes, 2.3 g of magnesium stearate was added thereto and the mixture was made into tablets each comprising 350 mg by a rotary tabletting machine (manufactured by Hata Tekkosho) using a pounder of c/9.0 mm.times.l0.8 R. The tablets were sprayed with 150 g of a coating solution containing 8.7 g of hydroxypropyl methyl cellulose, 1.2 g of polyethylene glycol 6000, 4.8 g of titanium oxide and 0.3 g of talc in a coating apparatus (manufactured by Freund Sangyo) to give film-coated tablets each being coated with 15 mg.

Core tablet Excipients:

Macrogol 8,000 and 2,000,000

Hydroxypropylcellulose

Butylhydroxytoluene

Magnesium stearate

Film coating:

Option 1

Betmiga 25 mg prolonged-release tablets*

Hypromellose 2910, 6 mPa.s

Macrogol 8,000

Iron oxide yellow (El 72)

Iron oxide red (El 72)

Option 2

Betmiga 50 mg prolonged-release tablets

Hypromellose 2910, 6 mPa.s

Macrogol 8,000

Iron oxide yellow (El 72)

*Betmiga is another name for Mirabegron. [00145] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

[00146] EXAMPLE 1

(i) a core of mirabegron (as Myrbetriq) (25 mg)

(ii) coated with layer of 5mg solifenacin + Opadry at a 1 : 1 ratio.

[00147] EXAMPLE 2

(i) a core of mirabegron (as Myrbetriq) (50 mg)

(ii) coated with layer of 5mg solifenacin + Opadry at a 1 : 1 ratio

[00148] EXAMPLE 3

(i) a core of mirabegron (as Myrbetriq) (25 mg)

(ii) coated with layer of lOmg solifenacin + Opadry at a 1: 1 ratio

[00149] EXAMPLE 4

(i) a core of mirabegron (as Myrbetriq) (50 mg)

(ii) coated with layer of lOmg solifenacin +Opadry at a 1 : 1 ratio

[00150] Patents, patent applications, and publications are cited throughout this application, the disclosures of which, particularly, including all disclosed chemical structures, are incorporated herein by reference. Citation of the above publications or documents is not intended as an admission that any of the foregoing is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents. All references cited herein are incorporated by reference to the same extent as if each individual publication, patent application, or patent, was specifically and individually indicated to be incorporated by reference.

Claims

WHAT IS CLAIMED IS:

1. A fixed dose pharmaceutical composition comprising

a core comprising about 50 milligrams or about 100 milligrams of mirabegron, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients; and

a coating layer comprising about 5 milligrams or about 10 milligrams of solifenacin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient wherein the pharmaceutically acceptable excipient of the coating layer is selected from the group consisting of Opadry, lactose monohydrate, com starch, hypromellose 2910, magnesium stearate, talc, polyethylene glycol 8000, and titanium dioxide with yellow ferric oxide or red ferric oxide, or combinations thereof;

and optionally further comprising an outer layer of the composition comprising a non- pH dependent water soluble coating film which serves as a barrier to both moisture and light.

2. The pharmaceutical composition according to claim 1, wherein said non-pH dependent water soluble coating film which serves as a barrier to both moisture and light is formed by one of the coating films selected from the group consisting of polyvinyl alcohol- polyethylene glycol graft copolymer, hydroxypropyl methyl cellulose (HPMC), a

combination of titanium dioxide and talc powder, Opadry and Opadry II.

3. The pharmaceutical composition according to claim 2, wherein said non-pH dependent water soluble coating film is Opadry II which comprises a combination of hydroxypropyl methylcellulose (HPMC), titanium dioxide and talc powder.

4. The pharmaceutical composition according to claim 1, further comprising a pharmaceutical carrier selected from the group consisting of: a filler, a binder, a lubricating agent, a glidant, and a disintegrant.

5. The pharmaceutical composition according to claim 1, wherein the weight ratio (w/w) of the active drug ingredients to the outer layer coating film is 1 : 1.

6. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipient of the coating layer is Opadry II .

7. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipient of the coating layer is present in an about 1 : 1 ratio (w/w) with solifenacin.

8. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipient of the core is selected from the group consisting of polyethylene oxide, polyethylene glycol, hydroxypropyl cellulose, butylated hydroxytoluene, magnesium stearate, hypromellose 2910, yellow ferric oxide, red ferric oxide, and combinations thereof.

9. The pharmaceutical composition according to claim 1, which is suitable for oral administration.

10. The pharmaceutical composition according to claim 1, which is a solid oral dosage form.

11. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is selected from the group consisting of a tablet, a capsule, a cachet, a pellet, a pill, a powder, a dragee, and a granule.

12. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a tablet.

13. The pharmaceutical composition according to claim 1, comprising about 5 mg of solifenacin and wherein the pharmaceutically acceptable excipient of the coating layer comprises titanium dioxide with yellow ferric oxide.

14. The pharmaceutical composition according to claim 1, comprising about 10 mg of solifenacin and wherein the pharmaceutically acceptable excipient of the coating layer comprises titanium dioxide with red ferric oxide.

15. The pharmaceutical composition of any of claims 1-10, wherein the core further comprises: a yellow ferric oxide and/or a red ferric oxide in an amount effective to stabilize a matrix sustained-release preparation containing:

(a) 5 to 80 wt % of hydrophilic base having a solubility that the amount of water needed to dissolve 1 g of said hydrophilic base is 5 ml or less at 20. +-.5° C., and

(b) 10 to 95 wt % of polyethylene oxide

(i) having a viscosity of 2,000 cP or higher as an aqueous 2% solution at 25°C or

(ii) having a viscosity-average molecular weight of 2,000,000 or higher, wherein said matrix preparation contains polyethylene oxide as a base of a sustained-release preparation,

wherein said active drug ingredient and said hydrophilic base are dispersed in a polyethylene oxide, and wherein said amount of yellow ferric oxide is 1 to 20 wt % or red ferric oxide is 3 to 20 wt %, with physical mixing in the matrix per preparation weight, or said amount of yellow ferric oxide and/or red ferric oxide is 0.3 to 2 wt %, in film coating per tablet weight.

16. The pharmaceutical composition of claim 15, wherein said amount of yellow ferric oxide is 3 to 10, or red ferric oxide is 5 to 20 wt %, with physical mixing in the matrix per preparation weight.

17. The pharmaceutical composition of claim 16, wherein said amount of red ferric oxide is 10 to 15 wt % per preparation weight.

18. The pharmaceutical composition of claim 15, wherein said amount of yellow ferric oxide and/or red ferric oxide is 0.3 to 2 wt %, in film coating per tablet weight.

19. The pharmaceutical composition of claim 18, wherein said amount of yellow ferric oxide and/or red ferric oxide is 0.5 to 1.5 wt %, in film coating per tablet weight.

20. The pharmaceutical composition of claim 15, wherein the concentration in film material of a yellow ferric oxide and/or a red ferric oxide is 5 to 50%.

21. The pharmaceutical composition according to any of claims 1-20, wherein after about 15 minutes of administration, 85% or more of solifenacin is released and further wherein after about 4 hours of administration, 85% of mirabegron is released.

22. A method for treating overactive bladder comprising administering an effective amount of any of the pharmaceutical compositions of claims 1-21 to a subject in need thereof.

23. The method according to claim 22, wherein said overactive bladder is a result of benign prostatic hyperplasia.

24. The method according to claim 22, wherein said subject has urinary urgency.

25. The method according to claim 22, wherein said subject has urinary incontinence.

26. The method according to claim 22, wherein said subject has pollakiuria.

27. A method for treating overactive bladder comprising administering an effective amount of any of the pharmaceutical compositions of claims 1-21 to a subject in need thereof, wherein when the subject is not an adult, and the subject is not suffering from diabetes.

28. The method according to claim 27, wherein said overactive bladder is a result of benign prostatic hyperplasia.

29. The method according to claim 27, wherein said subject has urinary urgency.

30. The method according to claim 27, wherein said subject has urinary incontinence.

31. The method according to claim 27, wherein said subject has pollakiuria.

32. A method for treating urinary urgency, pollakiuria and/or urinary incontinence accompanying overactive bladder, comprising administering an effective amount of any of the pharmaceutical compositions of claims 1-21 to a subject in need thereof.