CONTROLLED RELEASE PHARMACEUTICAL COMPOSITIONS OF TROSPIUM

Field of the Invention

The present invention relates to controlled release pharmaceutical compositions comprising trospium or its pharmaceutically acceptable salts thereof using one or more hydrophobic rate controlling agent(s).

Background of the Invention

Trospium is a quaternary ammonium derivative of tropine, and has anticholinergic properties. The hydrophilicity of the molecule, due to its permanent positive charge, limits its lipid solubility. Trospium chloride has been shown to antagonize acetylcholine on excised strips of human bladder muscle. Antispasmodic activity has been shown in the bladder, the small intestine, and on contractility of the gall bladder. Trospium chloride exhibits parasympatholytic action by reducing smooth muscle tone, such as is found in the urogenital and gastrointestinal tracts. This mechanism enables the detrusor to relax, thus inhibiting the evacuation of the bladder. Lowering the maximum detrusor pressure results in improved adaptation of the detrusor to the contents of the bladder, which in turn leads to enhanced bladder compliance with increased bladder capacity.

Trospium chloride is an agent that has been known for many years (cf. German patent 1 194 422) as an anticholinergic that is useful as a spasmolytic agent. The active agent has been available as an orally administrable solid form as tablets, for intravenous or intramuscular injection as a solution (Schwantes et al, U. S. 5,998, 430) and for rectal administration as suppositories.

Currently, in the European market there is an immediate release trospium chloride tablet (Spasmo-lyt(R)), which is indicated for the treatment of urge incontinence and detrusor hyperreflexia and is used as a 20 mg tablet taken twice daily or bid (a total dose of 40 mg per day). In common with other quaternary ammonium compounds, orally administered trospium chloride is slowly absorbed, with the maximum blood level achieved after 5-6 hrs. The oral bioavailability is approximately 10%, and is significantly reduced with the intake of high-fat

food. There are side effects associated with the use of the twice-daily trospium chloride regimen, such as dry mouth, headache, constipation, dyspepsia, and abdominal pain. These side effects are associated with a high blood concentration of trospium chloride. Moreover, studies in which a 40 mg immediate release dose was given once daily resulted in higher overall incidence of adverse events as compared to 20 mg given twice daily.

Trospium chloride is also available as the delayed release capsular dosage form for oral use in market, approved on august 3, 2007 by Indevus Pharmaceuticals once daily. It is mainly used for the treatment of bladder dysfunctions.

To maintain reasonably stable plasma concentrations, it is necessary to resort to frequent dosing, and the resulting inconvenience to the patient often results in lowered compliance with the prescribed dosing regimen. Moreover, widely fluctuating plasma concentrations of the drug may result in administration of less than therapeutic amounts of the drug in a conservative dosing regimen, or amounts too large for the particular patient in an aggressive dosing regimen.

This type of multiple administrations leads to substantial fluctuations in the plasma concentration of the drug, especially in chronic administration.

The convenience of once daily dosing generally improves patient compliance, especially for elderly patients and for patients taking multiple medications. Once per day dosing may also lessen or prevent potentially undesirable dose-related effects by reducing peak blood levels (C _max ) and may also increase drug efficacy by increasing minimum plasma concentrations (C _min ).

Once daily dosing of trospium chloride, however, presents numerous challenges as trospium chloride, is not absorbed uniformly in the gastrointestinal (Gl) tract. Trospium chloride is absorbed in the small intestine and in the ascending colon in humans, but is poorly absorbed beyond the hepatic flexure, thereby suggesting that the mean absorption window for trospium chloride is, on average, about six hours or less - any drug release from a conventional ER

dosage form beyond six hours would thus be wasted because the dosage form has traveled beyond the hepatic flexure.

Various approaches have been tried out for developing a once daily dosage form of trospium chloride.

US 2005/0191351 Al now granted as US 7,410,978 relates to once daily pharmaceutical compositions of trospium or its acceptable salt directed to release trospium in the lower intestine, colon or both (i.e. above pH 7.0). Trospium is indicated in the treatment of urinary frequency, urgency, nocturia, and urge-incontinence associated with detrusor instability, urge syndrome, and detrusor hyperreflexia.

US 2004/0028729 Al relates to sustained release pharmaceutical formulations with improved absorption and bioavailability of pharmaceutical active agents with limited or region specific absorption and/or pH dependent absorption profile after oral administration, and modified release of an active ingredient in the gastrointestinal tract comprising a plurality of irregularly shaped cores and wherein an active ingredient.

US 2006/0210625 Al relates to a oral pharmaceutical composition, comprising one or more positively charged, highly water-soluble pharmaceutically active agents such as trospium chloride, and one or more polymers containing polarized oxygen atoms, whereby the active agent(s) form an ion-dipole interaction with the polymer(s) that may be used for an immediate release system, an extended release system or a delayed release system.

Most of the above-mentioned patent applications disclose controlled delivery systems, which utilize hydrophilic, polymeric materials. However, for highly soluble drugs, such systems do not provide adequate control over the drug release rate, instead resulting in a release that approximates first-order kinetics.

Thus there is always need to develop a stable controlled release compositions of trospium, which provide complete drug release and afford stable plasma levels in a once-a-day dosing regimen using one or more hydrophobic release controlling agent(s).

A further aspect of the invention provides a solid dosage form, such as a tablet, capsules pellets, granules, powders and microtablets (mini tablets) that are adapted for once daily oral dosing.

Objects of the Invention

It is an object of the present invention to provide a controlled release pharmaceutical composition comprising Trospium or its pharmaceutically acceptable complexes, salts, polymorphs, hydrates, solvates, enantiomers or racemates, or mixtures thereof; one or more hydrophobic release controlling agent(s) and other pharmaceutically acceptable excipients.

Another object of the present invention is a process for preparation of a controlled release pharmaceutical composition comprising Trospium or its pharmaceutically acceptable complexes, salts, polymorphs, hydrates, solvates, enantiomers or racemates, or mixtures thereof; one or more hydrophobic release controlling agent(s) and other pharmaceutically acceptable excipients.

Yet another object of the present invention is to provide a controlled release pharmaceutical composition comprising portion A comprising a) a core comprising Trospium or its pharmaceutically acceptable complexes, salts, polymorphs, hydrates, solvates, enantiomers or racemates, or mixtures thereof and one or more hydrophobic release controlling agent(s) and b) an overcoat of one or more hydrophobic release controlling agent(s); and portion B comprising a) a core comprising Trospium or its pharmaceutically acceptable complexes, salts, polymorphs, hydrates, solvates, enantiomers or racemates, or mixtures thereof and pharmaceutically acceptable excipients, b) an overcoat of one or more hydrophobic release controlling agent(s).

Further an object of the invention is to provide a controlled release pharmaceutical composition, wherein the composition releases the active drug in the GIT at about a pH 6.0.

Detailed description of the Invention In accordance of the above-mentioned objects and others, the present invention in certain embodiments is directed to a controlled release pharmaceutical composition comprising Trospium or its pharmaceutically acceptable complexes, salts, polymorphs, hydrates, solvates, enantiomers or racemates, or mixtures thereof.

The compositions of the present invention typically contain 20 to 100 mg and more preferably 20mg to 80mg trospium as base. The term trospium encompasses trospium free- base or its pharmaceutically acceptable complexes, salts, polymorphs, hydrates, solvates, enantiomers or racemates, or mixtures thereof. The term "Drug" is synonymous to trospium or its above-mentioned forms.

"Pharmaceutical composition" refers to the combination of one or more drug substances and one or more excipients. "Drug product," "pharmaceutical dosage form," "dosage form," "final dosage form" and the like, refer to a pharmaceutical composition that is administered to a subject in need of treatment and generally may be in the form of tablets, capsules, tablets filled in capsule, mini tablets filled in capsule, sachets containing powder or granules, pellets, liquid solutions or suspensions, patches, and the like.

The term "controlled release compositions" herein refers to any composition or dosage form which comprises an active drug and which is formulated to provide a longer duration of pharmacological response after administration of the dosage form than is ordinarily experienced after administration of a corresponding immediate release composition comprising the same drug in the same amount. Controlled release compositions include, inter alia, those compositions described elsewhere as "extended release", "delayed release", "sustained release", "prolonged release", "programmed release", "time release" and/or "rate controlled" compositions or dosage forms.

The present invention relates to a controlled release pharmaceutical composition comprising Trospium or its pharmaceutically acceptable complexes, salts, polymorphs, hydrates, solvates, enantiomers or racemates, or mixtures thereof; one or more hydrophobic release controlling agent(s) and other pharmaceutically acceptable excipients.

The controlled release pharmaceutical compositions are prepared using one or more hydrophobic controlled release agent(s) being present in the core, or over coating layer or both.

Core:

The core is prepared by any conventional techniques known in the prior art. In one aspect of the invention the core may be prepared by granulating the drug and one or more pharmaceutically acceptable excipients together using any conventional techniques for example dry granulation, direct compression, wet granulation, melt granulation and extrusion-spheronization. Alternately the core may be prepared by loading inert beads of lactose, sugar, microcrystalline cellulose or the likes with the drug.

The core may further comprise one or more hydrophobic release controlling agents. The one or more hydrophobic release controlling agent(s) may be pH dependent or a pH independent.

The pH dependent hydrophobic release controlling agent is selected from the group comprising cellulose acetate phthalate, hydroxy propyl methyl cellulose phthalate, polyvinyl acetate phthalate, hydroxy propyl methyl cellulose acetate succinate, cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, copolymer of methylmethacrylic acid and methyl methacrylate (Eudragit L, Eudragit S), copolymer of methyl acrylate (Eudragit FS), methylmethacrylate and methacrylic acid, co-polymerized methacrylic acid/methacrylic acid methyl esters and mixtures thereof.

The pH independent hydrophobic release controlling agent is selected from the group comprising waxes like, glyceryl behenate, glyceryl monosterate, hydrogenated vegetable oils, stearic acid, palmitic acid, lauric acid, carnauba wax, cetyl alcohol, glyceryl stearate, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, zein, shellac, copal collophorium, carboxymethylcellulose, ethylcellulose, copolymers of polyacrylates and polymethacrylates (Eudragit RL, RS, E); and mixtures thereof.

The core may additionally comprise one or more pharmaceutically acceptable excipients. The pharmaceutical excipients include but are not limited to binders, lubricants, glidants, fillers, diluents and the like.

Diluents may be, for example, any pharmaceutically acceptable, non-toxic diluent. Particular examples include lactose, dextrose, sucrose, maltose, microcrystalline cellulose, starch, calcium hydrogen phosphate, mannitol and the like.

Binders may be, for example, starch, sugars, gums, low molecular weight hydroxypropyl methylcellulose, povidone, hydroxypropyl cellulose, hydroxyethyl cellulose or the like.

Lubricants may be, for example, talc, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, sodium benzoate or the like.

Antiadherents and Glidants may be, for example, colloidal silicon dioxide, talc or the like.

The present invention may optionally contain a surface-active agent and preferably polaxamer, dioctyl sulfosuccinate, triethonolamine, sodium lauryl sulphate, polyoxyethylene sorbitan esters of fatty acids (tweens) and Sorbitan esters of fatty acids (Spans).

Further, present invention may comprise wicking agents. The wicking agents are selected from the group comprising hydrophilic, organic, polymeric, fusible substance or a particulate soluble or insoluble inorganic material. Suitable hydrophilic, organic, fusible wicking agents

include polyethylene glycols (PEGs) of various molecular weights e.g. 1,000 to 20,000 preferably 4,000 to 10,000 and suitable particulate inorganic wicking agents include dicalcium phosphate and lactose. It is preferred to use a hydrophilic fusible, organic polymeric as wicking agent. Other examples of wicking agents include high HLB surfactants (for example Tween 20, Tween 60 or Tween 80; ethylene oxide propylene oxide block copolymers, ionic surfactants such as sodium lauryl sulfate, sodium docusate, non- swelling hydrophilic polymers such as cellulose ethers, complexing agents such as: polyvinyl pyrrolidone, cyclodextrins and non- ionic surface active agents; and micelle forming agents, which may be surface active agents such as Tweens (Poly (oxyethylene oxide) modified sorbitan esters of fatty acids), Spans (fatty acid sorbitan esters), sodium lauryl sulfate.

The cores may be further lubricated and compressed into minitablets or tablets. The minitablets or tablets so formed may be further filled into capsules of a suitable size. Alternately the cores may be filled directly into capsules.

Over-coating Layer:

The over coating layer may comprise one or more hydrophobic release controlling agent(s). The hydrophobic release-controlling agent may be a pH dependent release controlling agent or a pH independent release-controlling agent.

In an embodiment, the core may be overcoated with a sub-coat in between the core and the overcoat. The sub-coat may comprise coating agents selected from but are not limited to hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), polyethylene oxide, polyvinyl alcohol, polyvinylpyrrolidone, xanthan gum, guar gum, chitosan and its derivatives, carbomer, carrageenan, carboxymethyl cellulose, sodium alginate, polyglycolized glycerides, polyethyleneglycol, or mixture thereof.

The coating layers may further comprise of one or more excipients selected from the group comprising coating agents, opacifiers, taste-masking agents, colouring agents, antitacking agents and the like.

The term "controlled release pharmaceutical compositions" includes a pharmaceutical composition that encompasses one or more individual units. The final dosage form may be a delayed release units, or combination of immediate release and delayed release units. The units may be in form of granules, pellets, minitablets or beads. These units may further be processed to form capsules or tablets or sachets.

The controlled release pharmaceutical compositions of the present invention are directed to release the active agents in the GIT at a pH of about 6.0.

Examples: The following examples are intended to be illustrative and non-limiting: Example -I

Brief manufacturing procedure:

Hydrogenated vegetable oil was melted and Trospium chloride was uniformly dispersed under continuous and uniform stirring conditions and allowed to solidify. The material was passed through a suitable sieve to form granules. The granules were blended with lactose,

colloidal silicon dioxide. This blend was lubricated with magnesium stearate and compressed into minitablets.

Example II

Brief manufacturing procedure:

Hydrogenated vegetable oil was melted and Trospium chloride was uniformly dispersed under stirring and allowed to solidify under continuous and uniform stirring conditions. The material was passed through a suitable sieve to form granules. The granules were blended with lactose, colloidal silicon dioxide. This blend was lubricated with magnesium stearate and compressed into minitablets. The compressed tablets were film coated. The film coated tablets were further over coated with gastrorotective coating of Poly(methacrylic acid, methyl methacrylate).

Example- III

Brief manufacturing procedure:

A solution of Trospium chloride, and Hydroxypropyl methycellulose (HPMC) was prepared in water. Sugar spheres were loaded in the fluid bed processor and the above solution was sprayed onto them. A coating suspension of Ethyl acrylate methyl methacrylate copolymer aqueous dispersion, Talc, and Lactose was formed till a homogeneous suspension was formed. The coating suspension was sprayed on the drug loaded sugar spheres. The coated drug loaded sugar spheres are then overcoated with a seal coating. A gastric protective suspension of Poly(methacrylic acid, methyl methacrylate), Triethyl citrate, and colloidal silicon was prepared. This was sprayed onto the above-formed spheres.

Example -IV

Brief Manufacturing Procedure:

Hydrogenated vegetable oil was melted and Trospium chloride was uniformly dispersed under stirring and allowed to solidify under continuous and uniform stirring conditions. The material was passed through a suitable sieve to form granules. The granules were blended with lactose, colloidal silicon dioxide. This blend was lubricated with magnesium stearate and compressed into minitablets. The compressed tablets were coated with a dispersion of hydroxypropyl methylcellulose. The sub-coated tablets were over coated with gastrorotective coating of Poly(methacrylic acid, methyl methacrylate). Appropriate number of minitablets was then filled into a capsule of suitable size.

Example - V: Double component system (Delayed extended release portion A + Delayed release portion B) Portion A

Brief manufacturing procedure:

Hydrogenated vegetable oil was melted and Trospium chloride was uniformly dispersed under stirring and allowed to solidify under continuous and uniform stirring conditions. The material was passed through a suitable sieve to form granules. The granules were blended with lactose, colloidal silicon dioxide. This blend was lubricated with magnesium stearate and compressed into minitablets. . The compressed tablets were coated with a dispersion of hydroxypropyl methylcellulose. The subcoated tablets were coated with gastrorotective coating of Poly(methacrylic acid, methyl methacrylate).

Portion B: Delayed release portion

Brief manufacturing procedure:

Trospium chloride was mixed with lactose, microcrystalline cellulose, and croscamellose sodium and granulated using a solution of polyvinylpyrrolidone. The granules were dried and sifted. The granules were then blended with microcrystalline cellulose, and croscamellose sodium, lubricated with magnesium stearate and compressed into minitablets of suitable punch size.

Compressed tablets were sub-coated with dispersion of hydroxypropyl methylcellulose. The sub-coated tablets were coated with gastrorotective coating of Poly(methacrylic acid, methyl methacrylate).

The required quantity of minitablets from delayed extended release portion (eqt to 45 mg drug) and delayed release portion (eqt to 15 mg drug) were filled into capsules of appropriate size.

The present invention also relates to a controlled release pharmaceutical composition comprising a portion A comprising a core comprising Trospium and one or more hydrophobic release controlling agent(s) and an overcoating layer comprising one or more hydrophobic release controlling agent(s); and a portion B comprising a core comprising Trospium and pharmaceutically acceptable excipients, and an overcoating layer comprising one or more hydrophobic release controlling agent(s) wherein the composition releases the active drug in the GIT at about a pH 6.0.

The in vitro dissolution is carried out using USP Type II (Paddle Apparatus) at 50rpm in 0.1N HCl for 1 hr, followed by the media with pH 5.5 Phosphate buffer. The release of drug is measured using HPLC techniques. The dissolution pattern is given as mentioned in the table below: