WO2007010509A2

WO2007010509A2 - Controlled release pharmaceutical composition comprising alpha-adrenergic antagonist and muscarinic antagonist

Info

Publication number: WO2007010509A2
Application number: PCT/IB2006/052539
Authority: WO
Inventors: Rajesh Shear; Pratik Kumar; Rajeev Singh Raghuvanshi; Ashok Rampal
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2005-07-22
Filing date: 2006-07-24
Publication date: 2007-01-25
Also published as: WO2007010509A3

Abstract

The present invention pertains to orally administered controlled-release pharmaceutical compositions comprising a combination of α-adrenergic antagonists and muscarinic receptor antagonists and processes for the preparation of the composition.

Description

CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION COMPRISING α- ADRENERGIC ANTAGONIST AND MUSCARINIC ANTAGONIST

Field of the Invention

The present invention pertains to an orally administered controlled release pharmaceutical composition comprising a combination of α-adrenergic antagonists and muscarinic receptor antagonists and processes for the preparation of the composition.

Background

Problems with the storage and voiding of urine [Lower Urinary Tract Symptoms (LUTS)] are a major burden for the ageing male population. It has been estimated that approximately 30% of men aged 50 and over have mild or severe micturition problems. LUTS are very bothering, and a major indication for surgery. The aspects of quality of life which have been reported to be affected the most are sleep, worry about the disease, mobility, leisure, daily activities and sexual activities.

LUTS are quite common in elderly men, and benign prostatic obstruction (BPO) constitutes a common cause of LUTS. Storage symptoms due to BPO include urinary frequency, urgency, nocturia, and urge incontinence. The term may be used interchangeably with overflow incontinence that also includes the same frequency in urination and urinary urge.

Overflow incontinence is the uncontrollable leakage of small amounts of urine, usually caused by some type of blockage or by weak contractions of the bladder muscles. When urine flow is blocked or the bladder muscles can no longer contract, the bladder becomes overfilled and enlarged. Pressure in the bladder increases until small amounts of urine dribble out. In children, blockage of urine flow may be caused by narrowing of the end of the urethra or the bladder neck because of a birth defect. In men, an enlarged prostate can block the opening into the urethra from the bladder. Less commonly, blockage is caused by narrowing of the bladder neck or the urethra (urethral stricture), which may occur after prostate surgery. In men and women, constipation can cause overflow incontinence if stool fills the rectum to the point of putting pressure on the bladder neck and urethra.

Alpha- adrenoceptor antagonists are known to relieve the obstruction by causing relaxation of the prostate smooth muscle, a decrease in urethral resistance and increased uroflow. Doxazosin, tamsulosin, alfuzosin, abanoquil, prazosin, terazosin etc. and the like belong to this group. Tamsulosin is the most widely used adrenergic receptor. The capsules contain 0.4 mg of the active ingredient. Tamsulosin is also marketed by Yamanouchi Pharmaceutical Co., Ltd. as Harnal D orally disintegrating tablets in Japan. The tablets contain either 0.1 or 0.2 mg of the active ingredient. Storage symptoms including urgency (with or without urge incontinence, which is usually associated with frequency and nocturia), are characterized as overactive bladder (OAB). OAB is another common cause of LUTS in men. The term may be used interchangeably with urge incontinence which also includes the same frequency in urination and urinary urge. Urge incontinence is an abrupt and intense urge to urinate that cannot be suppressed, followed by an uncontrollable loss of urine. Urge incontinence is the most common type of persistent incontinence in older people and often has no clear cause. Urge incontinence in older people may be caused by a combination of overactivity of the muscles in the bladder along with poor squeezing ability of those muscles. Part of the cause of persistent urge incontinence relates to changes in the part of the brain in the frontal lobe that inhibits urination. These changes may accompany brain disorders, especially stroke and dementia, which disrupt the nervous system's ability to inhibit the bladder. Chronic overactivity of the bladder is common in older people and causes the abrupt and intense urge to urinate as well as frequent urination during the day and night. Episodes of urge incontinence can be treated with drugs that relax the bladder.

Muscarinic antagonists block contraction of the detrusor muscle and are used as first line therapy for patients with overactive bladder. Darifenacin, tolterodine, oxybutynin etc. belong to this group. Tolterodine the most widely used muscarinic receptor is currently marketed as a film coated tablet containing 1 mg or 2 mg of tolterodine L-tartrate for immediate release in the gastrointestinal tract, the recommended dosage usually being 2 mg twice a day. Tolterodine tartrate is also marketed as extended release capsules. The capsules contain either 2 or 4 mg of the active ingredient to be administered once daily. The clinical presentation of OAB is often similar to BPO, involving nocturia, frequent micturition, incontinence and dribbling. The prevalence of OAB increases significantly with age, which is similar to the natural history associated with BPO. Therefore, a substantial proportion of men with LUTS exhibit a combination of both storage and voiding symptoms, which suggests the possibility of coexistence of BPO and detrusor overactivity. OAB occurs in 50% to 75% of men with BPO.

There is a requirement for a treatment modality for patients in whom OAB coexists with BPO. BPO treatment is hardly controversial and alpha adrenoceptor antagonists remain the most widely used pharmaceutical agents. The drug of choice in patients who have OAB as mentioned earlier are antimuscarinic agents. Treatment with antimuscarinic agents may relieve storage symptoms and the administration of alpha blockers may improve obstructive symptoms and to a lesser extent storage symptoms.

International Application No. WO 01/21167, filed by Merck discloses pharmaceutical compositions comprising a muscarinic receptor antagonist and at least one other active ingredient selected from a 5α-reductase inhibitor and an α-adrenergic receptor blocker for the treatment of LUTS. The muscarinic receptor antagonists can include, for example, tolterodine, oxybutynin, darifenacin, and the like etc. The α-adrenergic receptor blockers according to the invention can include, for example terazosin, doxazosin, prazosin, bunazosin, alfuzosin, tamsulosin, phentolamine and yohimbine. The application further describes the pharmaceutical compositions containing the active ingredients which may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs.

U.S. Patent Application Publication No., U.S. 20010044438, discloses pharmaceutical combinations suitable for treating the lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) in men, which combinations contain an alpha- adrenoceptor antagonist and a muscarinic antagonist. The application further discloses that the product is a combined preparation for simultaneous, separate or sequential use of an alpha- adrenoceptor antagonist and a muscarinic antagonist. The compositions of the invention may be suitable for topical, oral, parenteral or rectal administration. The compositions may be formulated to provide immediate or sustained release of the therapeutic agents. The examples provided in this application disclose a combination of immediate release α-adrenergic receptor antagonists and controlled-release muscarinic antagonists.

However, none of these applications disclose a combination of α-adrenergic receptor antagonists and muscarinic antagonists wherein both the actives are present in controlled release form.

PCT application WO 00/27364 relates to a tolterodine formulation containing controlled-release beads, and to a method of preparing the beads. These beads include: (i) a core unit of water-soluble or water- swellab Ie polymer; (ii) a first layer on the core unit of a substantially water-insoluble polymer; (iii) a second layer covering the first layer and containing the active ingredient and (iii) a third layer on the second layer of polymer effective for controlled-release of active ingredient. The first layer is adapted to control water penetration into the core.

U.S. Patent No. 4,772,475 discloses an oral pharmaceutical controlled-release multiple unit formulation of tamsulosin in which the individual units comprise a granulation product of a release-controlling agent, physiologically active substance and units-forming substance (s).

In light of the above background, it will be appreciated by those versed in the pharmaceutical dispensing art that a need exists for a controlled-release pharmaceutical composition that can deliver a combination of α-adrenergic antagonists and muscarinic receptor antagonists in a controlled, extended form. At the same time, the composition must be capable of being formulated by employing a simple process that involves fewer steps.

Summary

In one general aspect there is provided a solid dosage form comprising α-adrenergic antagonists and muscarinic receptor antagonists, wherein the dosage form provides controlled-release of the α-adrenergic antagonists and the muscarinic receptor antagonists.

It is yet another aspect to provide a solid dosage form comprising α-adrenergic antagonists and muscarinic receptor antagonists, which, when administered once daily, provides equivalent efficacy when compared to controlled-release α-adrenergic antagonists and controlled-release muscarinic receptor antagonists in separate dosage forms administered together.

The solid dosage forms may take form of several different embodiments. The α- adrenergic antagonists and muscarinic receptor antagonists may be present in a single unit dosage form, such as monolithic matrix dosage forms and the matrix may include a uniform mixture of the two actives and one or more rate-controlling polymers. In one embodiment these dosage forms may take the shape of tablets or pellets. In another embodiment, the two actives may be present as multiparticulates, such as particles, beads or granules.

In yet another embodiment, a solid dosage form is provided, wherein the two actives are formulated as bilayered or multilayered tablets, with the two actives present in separate layers.

In yet another embodiment, the dosage form may comprise an inner and an outer portion. The inner portion may be surrounded by the outer portion in such a manner that only one surface of the inner portion is exposed, i.e., a tablet within a tablet or in-lay tablet.

In yet another embodiment, the dosage forms may be prepared as reservoir-type formulations in which the two actives are admixed with pharmaceutically acceptable excipients to form a core. This core is then surrounded by polymeric coatings. Alternatively, the dosage forms may be prepared as a combination of reservoir-type and matrix-type formulations which include controlled- or sustained-release coatings on controlled release matrices in which the two actives are uniformly dispersed.

The compositions may be formulated using any pharmaceutically acceptable technique that achieves uniform blending, e.g., dry blending, extrusion, extrusion-spheronization, direct compression, wet granulation, compaction and fluid bed granulation.

In addition to the two actives and rate-controlling polymers the dosage form comprises pharmaceutically acceptable excipients which may act in one or more capacities as diluents, binders, lubricants, glidants, colorants or flavoring agents. The dosage forms may further contain functional or non-functional coating layer applied onto the tablets, pellets or beads. This coating layer may be applied by conventional coating techniques such as pan coating or fluid bed coating using solutions or suspensions of polymers in suitable solvents.

In another embodiment, the dosage form is provided in which the two actives are present in form of multiparticulates comprising first particulate phase of one active and second particulate phase of the other active. The multiparticulates are in the form selected from one or more of pellets, beads, granules, slugs, powders and particles. These multiparticulates are filled into capsules or compressed into tablets.

In another embodiment an osmotic controlled- delivery system is provided, comprising a core of the two active agents, a semipermeable membrane enclosing the core and at least one passageway in the semipermeable membrane, for delivering the contents of the core into the surrounding media.

The core may further include an osmotic agent. The osmotic agent may be one or more of water soluble salts of inorganic acids, water soluble salts of organic acids, non ionic organic compounds having high water solubility, water-soluble amino acids, urea and urea derivatives. The semipermeable membrane may be made of semipermeable membrane-forming polymers and coating additives.

The semipermeable membrane-forming polymers may be one or more of, for example, cellulose derivatives, acrylic acid derivatives, carbohydrate based polymers, polyglycols, polylactic acid derivatives, alginates, gums and starch.

The coating additives may be one or more of flux enhancers and pharmaceutically acceptable inert excipients. The flux enhancer may be one or more of hydroxymethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, hydroxypropylcellulose, propylene glycol and polyvinylpyrrolidone. It is one of the aspects to provide a process for preparing a dosage form, the process comprising: a. blending alpha- adrenergic antagonist, muscarinic receptor antagonist and rate- controlling polymers and optionally other excipients, b. granulating the blend of step (a), c. lubricating and compressing the granules of step (b) into pellets or tablets.

Alternatively, the blend or granules may be filled into capsules.

In one of the embodiments, separate pellets or granules may be prepared for the two actives and then filled into capsules in an appropriate ratio.

It is another aspect to provide a process for preparing a bilayered tablet for the combination of alpha- adrenergic antagonist and muscarinic receptor antagonist, the process comprising: a. dispersing alpha-antagonist in a solid matrix to form granules/blend which provides extended release of the alpha-antagonist, b. dispersing muscarinic antagonist in another solid matrix to form granules/blend which provides extended release of the muscarinic antagonist; c. compressing the two granules/blend to form a bilayered tablet. Alternatively, an inert layer or seal-coat layer may be incorporated between the two granules/blend to form multilayered tablets.

It is yet another aspect to provide a process for preparing a tablet within a tablet for the combination of alpha-antagonist and muscarinic-antagonist, the process comprising: a. dispersing alpha-antagonist in a solid matrix to form granules/blend which provides extended release of alpha-antagonist, b. dispersing muscarinic-antagonist homogeneously in a solid matrix to form granules/blend which provides extended release of muscarinic-antagonist; c. compressing the granules/blend of muscarinic-antagonist to form the inner portion, d. embedding the inner portion into the alpha-antagonist granules/blend and compressing such that the upper surface of the inner portion remains uncovered.

In another aspect there is provided a method of treating overactive bladder which coexists with benign prostatic hyperplasia, comprising administering a solid dosage form comprising α-adrenergic antagonist and a muscarinic receptor antagonist, wherein the dosage form provides controlledO-release of the α-adrenergic antagonist and the muscarinic receptor antagonist.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and claims. Detailed Description

The inventors have now developed an oral solid dosage form which includes a combination of α-adrenergic receptor antagonists and muscarinic receptor antagonists wherein the dosage form releases both the actives on a prolonged basis.

The pharmaceutical compositions of the present invention can be administered orally in the form of tablets, such as monolithic tablets, tablet in a tablet, bilayered or multilayered tablets. The composition may also be in the form of capsules containing pellets, beads, granules, multiparticulates, tablets, powder or osmotic dosage forms comprising a core covered with a semipermeable membrane containing one or more additional immediate release layers, and various other controlled release compositions known to a person skilled in the art.

The α-adrenergic receptor antagonists useful in the pharmaceutical compositions of this invention include, but are not limited to, terazosin, doxazosin, prazosin, bunazosin, indoramin, alfuzosin, abanoquil, naftopidil, phentolamine, tamsulosin, trazodone, dapiprazole, phenoxybenzamine, idazoxan, efaroxan and yohimbine; and pharmaceutically acceptable salts thereof. Particularly, the α- adrenergic receptor antagonists can include, for example, doxazosin, tamuslosin, terazosin, and prazosin; and more particularly tamsulosin and pharmaceutically acceptable salts thereof.

Tamsulosin may comprise free base, pharmaceutically acceptable salts or isomers of tamsulosin thereof. The pharmaceutically acceptable salts may include, for example, hydrochloride, hydroiodide, hydrobromide and hydrogen fumarate.

The α-adrenergic antagonist may be present in an amount of about 0.05% to about 5% by weight of the dosage form.

The muscarinic receptor antagonists useful in the compositions of this invention include but are not limited to tolterodine, oxybutinin, darifenacin and pharmaceutically acceptable salts thereof. Particularly the muscarinic receptor antagonist may be, for example, tolterodine or pharmaceutically acceptable salts thereof. Tolterodine for the purpose of the present invention may be selected from tolterodine base, i.e., (R)-N, N-diisopropyl-3-(2-hydroxy-5- methylphenyl)- 3 phenylpropanamine, as well as the corresponding (S)- enantiomer, the racemate and the active 5 -hydroxy methyl metabolites, prodrug forms and pharmaceutically acceptable salts thereof such as tartarate.

The muscarinic receptor antagonist may be present in an amount of about 0.05% to about 10% by weight of the dosage form. The term "actives" used herein includes α-adrenergic receptor antagonists and muscarinic receptor antagonists.

The term "controlled-release" as used herein includes any type of controlled-release such as prolonged-release, sustained-release, modified-release and extended-release. The term "matrix", as used herein, refers to a uniform mixture of the actives, rate- controlling polymers, and one or more pharmaceutically acceptable excipients.

The controlled release dosage forms may be present in a tablet form in which the two actives are formulated together as a bilayered or multilayered tablet. The term "bilayered or multilayered" may encompass dosage forms where there are two separate drug layers, one on top of the other with only one surface in mutual contact or with an inert layer in between. These may also be prepared by compression granulation of one drug on a previously compressed granulation of another drug, or alternatively by feeding previously compressed tablets of one drug into a machine and compressing granulation layer of another drug on the preformed tablets. The dosage forms may be multiple-compression tablets comprising an inner core and an outer coat of the actives, and may be prepared such that one surface of the inner core is exposed. These types of tablets are also referred to as inlay or bull's-eye tablets and these are similar to compression-coated tablets except that one surface of the coating is eliminated.

The rate-controlling agent may include one or more of enteric polymers, water insoluble polymers, water-soluble polymers, alkaline metal salts of a higher fatty acid, waxes, and mixtures thereof.

Suitable enteric polymers include those known in the art, such as hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, polymethylacrylates and copolymers of acrylic and methacrylic acid (commercially available under the trade name of Eudragit), for example, Eudragit L30D- 55 (anionic aqueous polymer dispersion of methacrylic acid ethyl acrylate copolymer), Eudragit L100-55 (Spray-dried Eudragit L30D-55 which can be reconstituted as aqueous dispersion), Eudragit LlOO (anionic polymer powder solubilizing above pH 6.0) and Eudragit SlOO (anionic polymer powder solubilizing above pH 7.0).

Suitable waxes include one or more of hydrogenated vegetable oils, esters of long chain fatty acids, long chain fatty acids such as stearic acid and oleic acid, and mixtures thereof.

Suitable water-insoluble polymers include one or more of ethyl cellulose, cellulose acetate, copolymers of polyethylene and vinyl acetate, methacrylic acid methyl methacrylate copolymers with quaternary ammonium groups such as those sold under the trade name Eudragit(D RL, Eudragit RS and Eudragit(E NE, and the like. Suitable examples of the alkaline metal salts of a higher fatty acid include one or more of magnesium stearate, zinc stearate, calcium stearate, and the like.

Suitable water-soluble polymers may include one or more of, for example, polyvinylpyrrolidone; polyalkylene glycol such as polyethylene glycol, gelatin, polyvinyl alcohol, starch and derivatives thereof; cellulose derivatives, such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxyethylcellulose, carboxy-methyl-hydroxy- ethyl cellulose, acrylic acid polymers, polymethacrylates, or any other pharmaceutically acceptable polymer.

The rate controlling polymers may comprise about 20 to about 90% by weight of the formulation. The rate controlling polymers in accordance with this invention may also act as binder and may be added as such or dissolved or dispersed in an appropriate solvent system and the resulting solution or dispersion is then used to granulate the active agent.

The multiparticulates may be one or more of pellets, beads, granules, tablets or compacts prepared by roller-compaction, slugging or extrusion-spheronization. The multiparticulates may be of any geometric shape, though spheres are preferred.

In addition to the active ingredient and rate controlling polymers, the multiparticulates may also contain other pharmaceutically acceptable excipients. The dosage form according to the present invention may further include an enteric coating over the multiparticulates. This coating will substantially eliminate dissolution in the acidic environment of the stomach but will dissolve sufficiently to permit release in a controlled manner over an extended period in the intestine. Examples of enteric coatings include one or more of neutralized hydroxypropyl methylcellulose phthalate (HPMCP) coating, beeswax, glyceryl monostearate, shellac and cellulose, shellac and stearic acid; neutral copolymer of methacrylic acid and methacrylic acid methyl ester (Eudragit) or a neutral copolymer of polymethacrylic acid esters; containing metallic stearates. The other enteric coating polymers known in the art may also be employed, including one or more of polyvinyl acetate phthalate, cellulose acetate phthalate and cellulose acetate succinate.

Some of the enteric coating materials are acidic in nature and hence may cause chemical instability when in contact with active ingredient. However, this can be avoided by using suitable alkalizing agents like sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carboxymethylcellulose, magnesium oxide and magnesium hydroxide.

The enteric coating may also include anti-adherent or tack- modifiers as an inert aid in the stability of coating process. Suitable tack-modifier may include one or more of talc, kaolin or colloidal anhydrous silica. The coating may also include an opacifier such as titanium dioxide.

The enteric coating layer can be formed on the surface of the multiparticulates using conventional coating methods, such as fluidized or pan coating.

Alternatively the multiparticulates may comprise active ingredients along with the rate-controlling polymers and other pharmaceutically acceptable excipients coated over inert cores.

The inert core may be selected from one or more of pharmaceutically inert insoluble or soluble or swellable materials. Alternatively, the inert core may also be a commercially available product. The insoluble inert cores can be composed of, for example, dicalcium phosphate, microcrystalline cellulose and the like, either alone or in combination. The soluble inert cores are composed of sugar selected from glucose, mannitol, lactose, xylitol, dextrose, sucrose and the like. Commercially available inert cores are selected from sugar sphere, nonpareil seed and celphere. The dosage form may be an osmotic-controlled dosage form prepared by blending the actives, at least one swelling agent, optionally an osmotic agent and one or more pharmaceutically acceptable inert excipient; and compressing the blend into a compact core; enclosing the core with a solution/dispersion of an enclosing composition comprising one or more semipermeable membrane-forming polymers and other coating additives. The immediate release layer containing the active may be layered to cover at least a portion of the core, using a conventional coating pan, a spray coater, a rotating perforated pan, or an automated system, such as a centrifugal fluidizing (CF) granulator, a fluidized bed process, or any other suitably automated coating equipment.

The swelling agents may be selected from any such pharmaceutically acceptable polymers, which swells in presence of aqueous media, i.e. cellulose derivatives, starch, gums, alginates, acrylic acid derivatives, polyethylene oxides and carbohydrate based polymers.

The osmotic agents may be one or more of water soluble salts of inorganic acids, water soluble salts of organic acids, non ionic organic compounds having high water solubility, water-soluble amino acids, urea and urea derivatives. Semi-permeable membranes of the osmotic dosage form are permeable to the passage of an external fluid, such as water and biological fluids, but is substantially impermeable to the passage of components in the internal compartment. Materials useful for forming the wall are essentially nonerodible and are substantially insoluble in biological fluids during the life of the dosage form. Flux-regulating agents can be admixed with the wall-forming material to modulate the fluid permeability of the wall. For example, agents that produce a marked increase in permeability to fluid such as water are often essentially hydrophilic, while those that produce a marked permeability decrease to water are essentially hydrophobic. Examples of flux regulating agents include, but are not limited to, polyhydric alcohols, polyalkylene glycols, polyalkylenediols, polyesters of alkylene glycols, and the like.

The semipermeable membrane may be one or more of semipermeable membrane- forming polymers and coating additives. The semipermeable membrane-forming polymers may be one or more of cellulose derivatives, starch, gums, alginates, acrylic acid derivatives and carbohydrate based polymers.

The immediate -release outer layer may further include film-forming polymers and optionally other pharmaceutically acceptable excipients.

The dosage form also includes excipients that may act in one or more capacities as diluents, binders, lubricants, glidants, colorants or flavoring agents.

Suitable diluents include, but are not limited to, corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, starch and pregelatinized starch.

Suitable binders include, but are limited to methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone (povidone), copolymer of polyvinylpyrrolidone and vinyl acetate (copovidone), gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, and propylene glycol.

Suitable lubricants and glidants include, but are not limited to, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax and white beeswax.

The coating layer may additionally comprise plasticizers, coloring agents, lubricants, antiadherents, and the like. Suitable plasticizers include, but are not limited to, propylene glycol, Methylene glycol, oleic acid, triethylcitrate, tributylcitrate, triacetin, diethyl phthalate, dibutyl phthalate, dibutylsebacate, glyceryl monostearate, castor oil, ethylene glycol monooleate.

The coloring agents and flavoring agents of the present invention may be selected from any FDA-approved colors and flavors for oral use.

A method of treating overactive bladder which coexists with benign prostatic hyperplasia is provided, comprising administering a solid dosage form of a combination of α- adrenergic antagonist and a muscarinic receptor antagonist, wherein the dosage form provides controlled-release of both actives.

While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention. For example, controlled-release tamsulosin and tolterodine multiparticulates can be prepared as given below.

EXAMPLE 1

Preparation of tamsulosin multiparticulates - A

Process:

1. Tamsulosin hydrochloride was dissolved in water and the solution obtained was used to granulate microcrystalline cellulose.

2. Granulate of step 1 was dried in fluidized bed dryer at 60⁰C and sieved to a particle size of less than 600 μm.

3. Magnesium stearate and starch were sieved to a particle size of less than 600 μm and mixed with granulate of step 2 in a mixer.

4. The blend of step 3 was granulated with the dispersion of methacrylic acid-ethyl acrylate copolymer (Eudragit L30D 55), sodium hydroxide, triacetin, talc and titanium dioxide in water, in a rotary mixer grinder.

5. Granulate of Step 4 was extruded through a bore of inner diameter of lmm.

6. The extrudates of step 5 were spheronized-using a spheronizer.

7. Spherical cores obtained in step 6 were dried in fluidized bed dryer at 60⁰C for one hour. 8. Enteric coating dispersion of Eudragit LlOO: 55 was prepared by dispersing enteric coating materials in water.

9. The spherical cores of step 7 were coated with the dispersion of step 8, to a weight gain of 3.33% w/w.

Preparation of tolterodine beads - B

Process:

Hydroxypropyl methylcellulose and tolterodine tartrate were dissolved in water and the solution obtained was sprayed onto non-pareil beads and the coating was dried. Drug coated beads were further coated with a solution of ethyl cellulose and hydroxypropyl methylcellulose in a mixture of Isopropyl alcohol and water (83:17). The coated beads were dried and filled into capsules.

The multiparticulates of A (tamsulosin) and B (tolterodine) were mixed in appropriate ratios and filled into a capsule.

EXAMPLE 2 Preparation of tamsulosin multiparticulates - A

Process: Same as example 1.

Preparation of tolterodine beads - B: Same as example 1.

Claims

We Claim 1. A solid dosage form comprising α-adrenergic antagonist and a muscarinic receptor antagonist, wherein the dosage form provides controlled release of the α-adrenergic antagonist and the muscarinic receptor antagonist.

2. The dosage form according to claim 1, wherein the α-adrenergic antagonist comprises doxazosin, tamsulosin, alfuzosin, abanoquil, prazosin, terazosin and pharmaceutically acceptable salts thereof.

3. The dosage form according to claim 1, wherein the α-adrenergic antagonist comprises about 0.05% to about 5% by weight of the dosage form.

4. The dosage form according to claim 1, wherein the muscarinic receptor antagonist is selected from tolterodine, oxybutinin, darifenacin and pharmaceutically acceptable salts thereof.

5. The dosage form according to claim 1, wherein the muscarinic receptor antagonist omprises about 0.05% to about 10% by weight of the dosage form.

6. The dosage form according to claim 1, wherein the dosage form comprises from about 20% to about 90% by weight of rate controlling polymers selected from one or more of enteric polymers, water insoluble polymers, water soluble polymers, alkaline metal salts of a higher fatty acid, waxes, and mixtures thereof.

7. The dosage form according to claim 1, wherein the dosage form further comprises pharmaceutically acceptable excipients selected from one or more of diluents, binders, lubricants and glidants.

8. The dosage form according to claim 1 wherein the solid dosage form is tablet or capsule.

9. The dosage form according to claim 8 wherein the tablet is a single matrix, bilayered or multilayered and the capsules contain pellets, beads, granules, multiparticulates, tablets or powder.

10. A method of treating overactive bladder which coexists with benign prostatic hyperplasia, comprising administering a solid dosage form comprising α-adrenergic antagonist and a muscarinic receptor antagonist, wherein the dosage form provides controlled- release of the α-adrenergic antagonist and the muscarinic receptor antagonist.