MXPA06004017A - Once daily dosage forms of trospium - Google Patents

Abstract

A pharmaceutical composition of a pharmaceutically acceptable trospium salt, with upon administration to a human patient generates an average steady state blood levels of trospium with a minimum (Cmin) and maximum (Cmax) blood levels of about 0.5-2.5 ng/ml and about 2.0-6.0 ng/ml, respectively.

Description

For two-letter codes and olher abbrevialions. Referto I have "Guidance Npte on Codes and Abbreviations" appearing at the begin-ning ofeach regular issue of the PCT Gazette.

DOSAGE FORMS ONCE THROUGH DAY Field of the Invention The present invention is directed to pharmaceutical compositions that allow once-daily dosage forms of trospium. Trospium is indicated in the treatment of urinary frequency, urgency, nocturnal enuresis, and urge incontinence associated with detrusor instability, emergency need syndrome, and detrusor hyperreflexia. These compositions are useful for treating the conditions mentioned above with once-a-day administration.

Background of the Invention Trospium is a quaternary ammonium derivative of tropine, and has anticholinergic properties. The hydrophilic property of the molecule, due to its permanent positive charge, limits its lipid solubility. It has been shown that trospium chloride antagonizes acetylcholine in strips excised from the human bladder muscle. Antispasmodic activity has been demonstrated in the bladder, the small intestine and in the contractility of the gallbladder. Trospium chloride exhibits parasympathetic action by reducing smooth muscle tone, as found in the urogenital and gastrointestinal tracts. This mechanism allows the detrusor to relax, thus inhibiting the evacuation of the bladder. Decreasing the maximum detrusor pressure results in improved adaptation of the detrusor to the contents of the bladder, which in turn leads to improved bladder behavior with increased bladder capacity. Trospium chloride was introduced into the market as a spasmolytic agent in 1967 (German Patent 1 194 422). Trospium chloride has been available in an orally administrable solid form of administration (tablets and lozenges), for intravenous or intramuscular injection as a solution, and for rectal administration as suppositories, and is used primarily for the treatment of bladder dysfunction ( imperious incontinence, detrusor hyperreflexia). The product has been on the market in Germany and several other European countries for several years for specific therapeutic indications including urinary frequency, urgency, nocturnal enuresis and urge incontinence associated with detrusor instability, urge need syndrome and detrusor hyperreflexia. Currently, in the European market there is an immediate-release trospium chloride tablet (Spasmo-lyt®), which is indicated for the treatment of urge incontinence e-detrusor hyperreflexia and is used as a 20 mg tablet taken twice daily or dosed (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 hours. The oral bioavailability is approximately 10%, and is significantly reduced with the consumption of high-fat food. There are side effects associated with the use of the trospium chloride regimen twice a day, such as dry mouth, headache, constipation, dyspepsia and abdominal pain. These side effects are associated with a high blood concentration of trospium chloride. In addition, studies in which an immediate-release dose of 40 mg occurred as a result once a day in the highest total incidence of adverse events as compared to 20 mg given twice daily. A once-a-day administration of trospium is advantageous over administration twice a day in terms of compliance of the patient and reduced adverse events, thus providing a better treatment of the conditions for which trospium chloride is indicated. In order to provide an effective once-a-day form of trospium, there is a need for unique formulation methods that provide the desired therapeutic effects while minimizing, if not eliminating, the undesired side effects mentioned above.This means that the minimum trospium blood concentration (Cmin) in a stable state must be above the minimum therapeutically effective blood concentration and the maximum blood trospium concentration (Cmax) also in steady state must be below the maximum toxic blood concentration during the period of treatment. Trospium chloride and other quaternary ammonium compounds exhibit a limited window of absorption in the human gastrointestinal tract, presenting a significant challenge in formulating a composition once a day.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a pharmaceutical composition and any pharmaceutically acceptable trospium salt, typically trospium chloride, which can be given once a day while still meeting the steady-state blood levels required for treatment or prevention of diseases or conditions that would be beneficial from their spasmolytic activity. Such a disease or condition includes, and the present invention is directed primarily to, bladder dysfunctions such as urge incontinence or detrusor hyperreflexia, nocturnal enuresis and urinary frequency. Such once-daily compositions of a trospium salt are oriented to result in blood levels in the average steady state of trospium with blood levels of minimum (Cmin) and maximum (Cma?) Of approximately 0.5-2.5 ng / ml and approximately 2.0. -6.0 ng / ml, respectively, whose blood levels have been shown to be safe and effective. Steady-state blood levels preferably average between a Cmin of about 0.75 ng / ml and a Craax of about 5.0 ng / ml for dose forms of the present invention corresponding to 20 mg of dose regimen. In one aspect of the invention, there is provided an extended release pharmaceutical composition (XR), which contains between about 25 mg and about 60 mg of trospium chloride for once-a-day or cd (each day) administration, and which is characterized by having the following in vitro release profile in a phosphate buffer dissolution medium (pH 7.5): about 0-40% released in about 1 hour, about 20-85% released in about 4 hours and over 70% released in approximately 12 hours. In yet another aspect of this invention, a pharmaceutical delayed release (DR) composition is provided, which contains between about 25 mg and about 80 mg of trospium chloride for administration once a day or each day, depending on the length of the delay phase. The in vivo delay in release can be designed to a particular application, but is generally from about 0.5 hours to about 6 hours, more preferably from about 2.5 hours to about 5 hours, during which time there would be minimal detectable blood in the blood, if I would have The release profile in vi tro of such formulation is generally characterized as having less than about 10% released in an acidic medium within 2 hours and more than about 80% released in a buffer medium of pH 6.8 and higher inside. of the lapse of 1 hour. In yet another aspect of the present invention, an immediate release (IR) composition is provided, which contains no more than about 20 mg of the active drug, combined with a delayed release composition which is designed to dissolve at a pH of about 7.0 (ie, in the lower part of the Gl tract), such as the DR2 composition of the examples, which form a once daily simple trospium chloride formulation, containing in total about 80 mg of the drug. Another aspect of the present invention is to provide a method for treating urinary frequency, urgency, nocturnal enuresis and urge incontinence associated with detrusor instability, urge need syndrome, and detrusor hyperreflexia with once-a-day administration of trospium chloride .

Yet another aspect of the invention provides a simple dose form that allows for an additional release, or pulse, of a drug with a short half-life at approximately its half-life (T? / 2). Such dosage forms are a significant challenge to develop when the drug is one, such as trospium, which has a defined absorption region in the upper Gl tract, and is absorbed more poorly in the lower Gl tract (i.e., the area of the ileus and the colon). The invention is also directed to a method for enteral administration of a pharmaceutical composition comprising an effective amount of a trospium salt (e.g., trospium chloride), wherein an improvement comprises including a delayed release formulation of such a trospium salt. , which releases trospium at a pH of approximately 7.0. In another embodiment of the invention, there is provided a method for enteral administration in a pharmaceutical composition comprising an effective amount of a trospium salt (e.g., trospium chloride), wherein an improvement comprises including a delayed-release formulation of such a trospium salt, which releases trospium in the lower intestine, preferably in the colon. Accordingly, the invention is further directed to a pharmaceutical composition comprising a trospium salt (preferably, trospium chloride), as at least one active pharmaceutical ingredient wherein at least a portion of such a trospium salt is contained in a formulation of delayed release, which releases trospium at a pH of approximately 7.0. In an alternative embodiment, the invention is still further directed to a pharmaceutical composition comprising a trospium salt (preferably, trospium chloride), as at least one active pharmaceutical ingredient wherein at least a portion of said trospium salt is contained in a delayed-release formulation, which releases trospium in the lower intestine, colon or both. Finally, another aspect of the invention is to provide processes for preparing the once-a-day compositions of the present invention, and methods of treatment utilizing them.

Brief Description of the Drawings Figure 1 shows the dissolution profiles for the immediate release trospium chloride granules in 0.1N HCl, pH 1.1. The profiles show a release that reaches completion in approximately 15 minutes. Figure 2 shows the dissolution profiles for trospium granules coated with ethylcellulose (extended release or "XR"). Figure 3 shows the dissolution profiles for delayed release granules ("DR") of trospium chloride. Figure 4 shows the average dissolution profile for 50 mg of trospium chloride granules XR1-2. Figure 5 shows the average dissolution profile for 40 mg of trospium chloride granules XR1-1. Figure 6 shows the average dissolution profile for 35 mg of DR1 trospium chloride granules. Figure 7 shows the average dissolution profile for 40 mg of trospium chloride DR2 granules. Figure 8 shows the average dissolution profile for 60 mg granules of trospium chloride XR1 / DR2. Figure 9 shows the pharmacokinetic profiles of four exemplary controlled release release compositions against two immediate release products. Figure 10 shows the same data illustrated in Figure 4 with Formulation D removed for ease of comparison. Figure 11 shows the stable-state pharmacokinetic profiles of four controlled-release formulations of trospium chloride.

Detailed Description of the Invention The present invention is directed primarily to orally administrable once-daily forms of trospium, which due to its charged nature is usually found in the form of a salt, usually trospium chloride. Such formulations have not been previously known, most likely due to the present challenges of trospium chloride due to its high solubility and its limited absorption window. In addition, previous investigators have observed that due to the limited region of absorption, conventional modified release dosage forms were not thought practical. See, for example, Schroder, S. et al.

(Institute for Pharmacology, Clinical Pharmacology, University of K In and Madaus AG, in, Ger any). However, the present inventors have discovered oral dosage forms, which can be given once a day while still meeting the steady state blood levels required for the treatment or prevention of diseases or conditions that would benefit from their spasmolytic activity. The present invention is achieved by providing an orally administered trospium composition designed to provide certain steady-state blood levels of the drug comparable to a twice-daily regimen, preferably with some refinements, even in a formulation that requires the mammal, preference the human being, take only one dose a day. The preferred blood level of trospium is between about 0.5 and about 6.0 ng / ml in steady state. Preferably, blood levels remain within the preferred blood level, with dosing once a day, for the course of treatment. More preferably, blood levels are between about 0.5 ng / ml and 5.0 ng / ml in the steady state. In addition, more preferably, a suitable once a day formulation exhibits a Cmax within 80 to 120% of the average Cmax of a corresponding formulation twice a day (typically an IR of 20 mg twice a day, but could be titrated above). or below) and a Cmin between 80 and 120% of the average Cmin of such regimen twice a day. The concepts of the present invention can likewise be used to formulate controlled release compositions containing therapeutically active agents exhibiting similar solubility, window of limited absorption and bioavailability characteristics such as trospium. Examples of such compounds include, for example, propantheline, emepronium, clidinium and glycopyrrolate, which are quaternary ammonium compounds. As used herein, "approximately" means within the pharmaceutically acceptable limits found in the United States Pharmacopeia (USP-NF 21), 2003 Annual Edition, or available at www.usp.org, for amounts of pharmaceutical ingredients assets. With respect to blood levels, "approximately" means within the acceptable guidelines of the FDA. The compositions of the present invention may be in the form of, inter alia, a granule, a tablet (including matrix or osmotic), a pill, a powder, a pill, a capsule, a gel, a dispersion, a solution or a suspension. The only requirement is that the dosage forms are composed in such a way as to achieve the profiles established herein. The in vivo profiles for trospium chloride which provide the appropriate blood concentration levels or, more particularly, plasma) over time in order to meet the therapeutic requirements for once-a-day administration were determined in the present invention. . The method used in the present for the determination of the plasma concentration was the liquid chromatography / mass spectrometry / mass spectrometry or LC / MS / MS method. With this technique, the trospium is extracted from an aliquot of plasma using a solid phase extraction procedure. This extract is then analyzed using HPLC equipped with a mass spectrometer as a detector. These profiles are such that average blood levels of trospium chloride provide an effective amount of the drug for the treatment of such conditions as urinary frequency, urgency, nocturnal enuresis and urge incontinence due to detrusor instability, the need syndrome urgently, and detrusor hyperreflexia, even within such upper limits as to minimize the occurrence of adverse side effects normally associated with sudden increases in plasma concentration following multiple administration of immediate release formulations. The concentrations of blood trospium chloride against the time profiles are characterized by a steady state Cmin from about 0.5 to about 1.5 ng / ml, and a stable Cmax from about 2.0 to about 6.0 ng / ml. With the present invention, it was surprisingly found that the once-a-day dosing of trospium chloride in a delayed-release formulation provides the required blood profile. Furthermore, it was surprisingly found that dosing once a day with a dose unit containing a combination of immediate and delayed release components provides a desired therapeutic blood profile. Still further, it was discovered that the once-daily dosing of trospium chloride in an extended-release preparation also provides a desired therapeutically effective blood profile. Thus, with the present invention, it was found that a concentration of effective blood trospium chloride in steady state could be achieved by formulating the trospium chloride in several. inventive ways. These dosage units are in the form of an extended release, a delayed release or various combinations of forms of immediate, extended or delayed release.

Immediate Release Composition By "immediate release composition" is meant a dosage form that is formulated to release substantially all of the active ingredient in the administration without enhanced, delayed or extended release effect. Such a composition for purposes of the present invention is, at least initially, in the form of a granule (a term used interchangeably with "beads" or "pellets" herein). The immediate release granule can be a component of a plurality of components of a dosage form. The immediate release granule can also serve as a precursor to an extended or delayed release granule.

Non-active ingredients and processes for preparing such immediate release granules are well known in the art, and the present invention is not limited in these aspects. See, for example, Remington's Pharmaceutical Sciences, 18th Edition, A. Gennaro, Ed., Mack Pub. Co. (Easton, PA 1990), Chapters 88-91; the totalities of which are incorporated herein for reference. For example, an immediate release granule can be prepared by mixing the trospium salt (eg, trospium chloride) with a bulking agent. Additionally, disintegrating, non-sticking and sliding agents can be added to the formulation. The fillers employable in these compositions can be chosen from among others: microcrystalline cellulose, for example, (AVICEL® (FMC Corp.), or EMCOCEL® (Mendell Inc.) which also has binding properties: dicalcium phosphate, example, EMCOMPRESS® (Mendell Inc.), calcium sulfate, for example, COMPACTROL® (Mendell Inc.), and starches, eg, Starch 1500, and polyethylene glycols (CARBOWAX®). range from about 5% to about 75% (w / w) with a preferred range from about 25% to about 50% (w / w) Suitable disintegrants include, but are not limited to: cross-linked sodium carboxymethylcellulose (AC-) DI-SOL®), sodium starch glycolate (EXPLO ®, PRIMOJEL®) and cross-linked polyvinylpolypyrrolidone (Plasone-XL®). Disintegrants are used to facilitate granule disintegration during administration and are normally present in an amount of approximately 3% to about 15% (w / w) with a preferred range of about 5% to about 10% (w / w). The anti-adherents and glidants employable in such formulations may include talc, corn starch, silicon dioxide, sodium lauryl sulfate, colloidal silica dioxide and metal stearates, among others. In addition, the immediate release composition may contain one or more binders to give the cohesion of granules. Such binders are well known in the art, and include such substances as microcrystalline cellulose, polyvinylpyrrolidone, starch, maltrine, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sucrose solution, dextrose solution, acacia gum, tragacanth and locust bean which can be applied wet. The binding agent may be present in the composition in an amount from about 0.2 wt% to about 20 wt%, preferably from about 5 wt% to about 15 wt%. The granules can be made, for example, by simple granulation such as wet granulation or dry granulation, followed by sieving; extrusion and marumerization (spheronization); broken-granulation; or any agglomeration process that results in a granule of reasonable size and robustness. For extrusion and marumerization, the drug and other additives are granulated by the addition of a binder solution. The wet mass is passed through an extruder equipped with a certain size classification, and the extrudates are spheronized in a marumerizer. The resulting granules are dried and sieved for additional applications. High-shear granulation can also be used, wherein the drug and other additives are mixed dry and then the mixture is wetted by the addition of a binder solution in a high shear granulator / mixer. The granules are kneaded after wetting by the combined actions of mixing and grinding. The resulting granules or agglomerates are dried and sieved for additional applications. Alternatively, and preferably, immediate release pellets or pellets are prepared by solution or suspension coating, whereby a solution or dispersion of drugs, with or without a binder and optionally an anti-packing agent such as talc, is sprayed on a seed core or seed (either prepared or a commercially available product) in a fluid bed processor or other suitable equipment. The starting nuclei or seeds can be for example sugar spheres or spheres made of microcrystalline cellulose. The binder in the formula can be present in amounts ranging from about 0% to about 5% by weight, and preferably about 0.5% to about 2% by weight. The amount of anti-tack agent used can be from about 0% to about 5%, preferably about 0.5% to about 2% by weight. The drug is thus coated on the surface of the starting seeds. The drug can also be coated on the granules containing drugs described above, if desired. Following the drug coating, the granules loaded with resulting drugs are dried for further applications. A protective layer, or a finish, may be desired to ensure that granules loaded with drugs do not aggregate during processing or storage. The protective coating layer can be applied immediately outside the core, either a drug-containing core or a drug-coated core, by conventional coating techniques such as tray coating or fluid bed coating using polymer solutions in water or organic solvents. suitable or using aqueous polymer dispersions. OPADRY®, OPADRY II®) (Colorcon) and the corresponding color and colorless grades from Colorcon can be used to protect the granules from being sticky and provide colors to the product. Suggested levels of protective coating or color are from about 1% to about 6%, preferably about 2% to about 3% (w / w). Many ingredients can be incorporated into the finishing formulation, for example to provide quicker immediate release, such as plasticizers: acetyltriethyl citrate, triethyl citrate, acetyl tributyl citrate; dibutylcebacate, triacetin, polyethylene glycols, propylene glycol and others; lubricants: talc, colloidal silica dioxide, magnesium stearate, calcium stearate, titanium dioxide, magnesium silicate, and the like. The immediate release granules are contemplated as being used in combination with the extended release granules and / or the delayed release granules in a single dose form.

Extended Release Composition (XR) Granules of extended release of rrospium chloride can be prepared, for example by coating inert stratified granules with drugs with release control polymers. First, the inert granule is coated with the drug layer or a drug loaded granule is prepared, as described above. Then the active granule is coated (loaded with drug) with a polymeric release control membrane. The release control coating layer can be applied immediately outside the core (such as a core containing a drug or a stratified core with drug), by conventional coating techniques, such as tray coating or a fluid bed coating, using solutions of polymers in water or suitable organic solvents or using aqueous polymer dispersions. As an alternative embodiment, the release control membrane can separate additional drug layers in the core; for example, after coating with the substance controlling the release, another layer of drugs can be applied, which is followed by another layer of release control, etc. Suitable materials for the release control layer include EUDRAGIT® RL, EUDRAGIT® RS, cellulose derivatives such as aqueous dispersions of ethylcellulose (AQUACOAT®, SURELEASE®, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone / vinyl acetate copolymer, OPADRY® and the like.

The thickness of the coating affects the release profile, and then this parameter can be used to customize the profile. Suggested coating levels are from about 1% to about 40%, preferably about 5% to about 30% (w / w), and about 20% or about 25% as the most preferred embodiments. A coating of 20% w / w should release approximately 80% of the trospium chloride in 3.5 hours after ingestion, and a coating of 25% w / w should result in the release of approximately 80% in the trospium chloride in 4.5 hours after ingestion. The extended release granules contain between about 25 and about 60 mg of trospium chloride, and may be used alone, or in combination with delayed release or immediate release granules which constitute a simple daily dosage form.

Delayed Release Composition (DR) The delayed release component has a coating applied to the surface of the active granule that delays the release of the drug from the granule after administration for a certain period of time. This delayed release is achieved by applying a coating of enteric materials. "Enteric materials" are polymers that are substantially insoluble in the acidic environment of the stomach, but are predominantly soluble in intestinal fluids at various specific pH. The enteric materials are pharmaceutically acceptable, non-toxic polymers and include, for example, cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMSP), polyvinyl acetate-phthalate (PVAP), hydroxypropylmethylcellulose acetate-succinate (HPMSAS), cellulose acetate-rimelitate, hydroxypropylmethylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, copolymer of methylmethacrylic acid and methyl methacrylate, methyl acrylate copolymer, methyl methacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-ethyl chlorotrimethylammonium acrylate copolymer, natural residues such as zein, shellac and copal rosin, carboxymethylethylcellulose, methylesters of methacrylic acid / copolymerized methacrylic acid such as for example , materials known under the brand EUDRAGIT® L12.5, L100 or EUDRAGIT® S12.5, S100, and several commercially available enteric dispersion systems (eg, EUDRAGIT® L30D55, EUDRAGIT® FS30D, EUDRAGIT® L100-55, EUDRAGIT® S100 (Rohm Pharma), KOLLICOAT® MAE30D and 30DP (BASF), ESTACRYL® 30D (Eastman Chemical), AQUATERIC® and AQUACOAT® CPD30 (FMC)). The above is a list of possible materials, but one skilled in the art will appreciate that there are other such materials that would meet the objectives of the present invention by providing a delayed release profile including the design of the release based on the pH environment environment, temporary considerations and other factors. These coating materials can be employed by coating the surfaces in a range from about 1.0% (w / w) to about 50% (w / w) of the granule composition. Preferably, these coating materials are in the range of from about 20 percent to about 40 percent (w / w). The granules can be coated in a fluidized bed apparatus or a tray coating for example, in a conventional manner. . With the enteric coated granules, there is no substantial release of trospium in the acidic environment of the stomach below about pH 4.5. The trospium becomes available when the enteric layer sensitive to pH dissolves at a higher pH in the Gl tract, after a certain type of delay, or after the unit passes through the stomach. The preferred type of delay is in the range of about 0.5 to about 6 hours, but more preferable is about 0.5 to about 4 hours.

More particularly, the preferred DR granules are those that are coated with Eudragit® L30D-55 (which dissolve at about a pH of 5.5-6.0, ie in the upper intestines), and others that are coated with Eudragit FS30D ( which dissolve in approximately a pH of 7.0, ie in the lower intestine and colon). As a variation of this embodiment, the DR granule contains layers of the trospium, separated by protective (XR) or release control (DR) layers, optionally surrounded by an IR layer, which will result in a pulsed dose delivery; in other words, a combination of an IR or XR with a DR in the same granule. Such dosage form is made as an alternative way to meet the blood level requirements of the release profile of the present invention, which can be comparable to separate IR / XR and IR / DR granules in the same capsule. Preferably, the DR granules are used in combination with XR granules, but can also be used with IR granules or a combination of the three.

Immediate Release Dose Units (IR / Delayed Release (DR) Pulsatile drug release can be achieved through a combination of immediate release and delayed release components in a single dose form, eg, a combination of granules of immediate release (IR) and delayed-release granules (DR) described herein may be employed. With this method, granules coated with enteric polymer (DR granules) are combined with drug-coated granules (IR granules) that provide immediate release followed by a pulsed release of trospium.

While the IR portion provides a rapid rinse in the plasma-time profile, the DR portion helps to ensure that an effective plasma level is maintained for a longer period of time, preferably a 24 hour period. The relationship between the immediate release component and the delayed release component can be used to adjust the in vitro drug release profile and the blood concentration profile in vivo. In addition, the profile can be manipulated by the properties of the delayed release coating. By providing the desired drug release profiles according to the present invention, the compositions eliminate the need for a second dose per day. Additionally, the total dose of trospium is preferably at or below 80 mg to avoid undesirable side effects, but more than 30 mg to achieve the desired antispasmodic effect.

Immediate Release Dose Units (IR / Extended Release (XR)) As an alternative modality, the once daily dose unit may contain a combination of IR and XR granules, in ratios designed to be substantially equivalent to a regimen twice per day, or otherwise provide a dose form once a day that is safe and effective with minimal side effects.The immediate release portion is designed to provide an effective plasma level at early time points. Extended release dosage form is designed to maintain effective blood level throughout a 24-hour period, thus providing coverage for 24 hours.The IR portion provides approximately 20 mg or less of trospium which provides effective blood levels and avoids a side effect associated with increases in the plasma profile.The extended release portion provides approx 20 mg to about 60 mg of the trospium chloride, more preferably from about 20 to about 40 mg in the extended release form.

Immediate Release (IR) / Delayed Release (DR) / Extended Release (XR) Units Yet another embodiment of the present invention is a multi-particulate dosage form, which combines all three types of granules. This type of dose unit will provide multiple pulses of drug release, with the effect being a more or less sustained blood level of trospium within the acceptable range. With this combination, the IR portion is designed to provide an effective blood level immediately after ingestion, which is maintained by the combinations of DR and XR. The DR portion provides an immediate release after a delay. The XR portion provides an extended release profile that maintains the effective blood level of trospium during the course of the day. The total dose of the trospium in this composition is no greater than 80 mg, preferably 60 mg with the IR portion which determines a maximum of approximately 20 mg of the total. The DR and XR portions determine 10 mg to 60 mg combined with ratios of XR to DR ranging from about 1:10 to about 10: 1.

Delayed Release (DR) / Extended Release (XR) Dosage Units Yet another embodiment of the present invention is a multiparticulate dosage form, which combines the extended release granules with delayed release granules. Although the XR portion provides a sustained blood profile, the DR portion prevents the blood level form from falling below the effective level at the later time points. The XR is designed to provide between 10 mg to 40 mg, preferably between 20 mg to 40 mg, more preferably 30 mg of trospium chloride. The DR portion is preferably a longer delayed release with a delay of about 2-4 hours and provides between 10 mg and 40 mg, preferably between 20 mg and 40 mg, and more preferably 30 mg of trospium chloride.

Dose Forms As noted hereinabove, the compositions of the present invention may be in several different forms, such as tablets, powders, suspensions, solutions, etc. The composition is preferably in pellet / pellet form, which can be incorporated into a hard gelatin or other kind of capsules, either with additional excipients, or alone. Typical excipients that are added to a capsule formulation include, but are not limited to: fillers such as microcrystalline cellulose, soy polysaccharides, calcium phosphate-dihydrate, calcium sulfate, lactose, sucrose, sorbitol or any other inert filler. In addition, there may be flow aids such as smoked silicon dioxide, silicon gel, magnesium stearate, calcium stearate or any other materials that impart good flow properties. A lubricant can also be added if desired, such as polyethylene glycol, leucine, glyceryl behenate, magnesium stearate or calcium stearate. The multi-particulate capsules are preferred because they provide an increased surface area as opposed to a tablet, which allows for better release profiles and thus bioavailability. However, the granules described above can be incorporated into a tablet, in particular by incorporation into a tablet matrix, which rapidly disperses the particles after ingestion. In order to incorporate these particles into such a tablet, a filler / binder must be used in the tapping process which will not allow the destruction of the granules during the tapping process. Materials that are suitable for this purpose include, but are not limited to, microcrystalline cellulose (AVICEL®), soy polysaccharide (EMCOSOY®), pre-gelatinized starches (STARCH® 1500, NATIONAL® 1551), and polyethylene glycols (CARBO AX ®). These materials should be presented in the range of about 5% -75% (w / w), and preferably between about 25% -50% (P / p) • In addition, disintegrants are added to the tablets in order to disperse the beads once the tablet is swallowed. Suitable disintegrants include, but are not limited to: cross-linked sodium carboxymethylcellulose (AC-DI-SOL®), sodium starch glycolate (EXPLO ®, PRIMOJEL®), and cross-linked polyvinylpolypyrrolidone (Plasone-XL). These materials should be presented in the range of about 3% -15% (w / w), with a preferred range of about 5% -10% (w / w). Lubricants are also added to ensure proper rattling, and these may include, but are not limited to: magnesium stearate, calcium stearate, stearic acid, polyethylene glycol, leucine, glyceryl behenate and hydrogenated vegetable oil. These lubricants should be presented in amounts of about 0.1% and -10% (w / w), with a preferred range of about 0.3% -3.0% (w / w). The tablets are formed, for example as follows. The granules are introduced in a mixer together with AVICEL®, disintegrants and a lubricant, mixed for a set number of minutes to provide a homogeneous mixture which is then placed in the hopper of a tablet press with which the tablets are compressed. The compression force used is adequate to form a tablet; however, this is not enough to fracture the pellets or coatings. A pharmaceutical formulation for the supply of trospium chloride for the effective treatment of urinary frequency, urgency, nocturnal enuresis and urge incontinence associated with detrusor instability, urgently needed syndrome and / or detrusor hyperreflexia in a human patient comprising a composition of extended release that provides extended release in oral administration to the patient; and an acceptable pharmaceutical carrier; wherein the pharmaceutical formulation is sufficient to maintain an effective level of trospium chloride in the patient during the course of at least 12 hours without additional administration of trospium chloride. The total dose of trospium chloride can be about 30 mg to 70 mg producing in a human patient a plasma concentration against the time curve having an area under the curve of about 30,000 pg-Hr / ml to about 80,000 pg-Hr / ml. The plasma concentration can have a maximum concentration of about 1.5 ng / ml to about 6.0 ng / ml. The plasma concentration can have a minimum concentration of about 0.5 ng / ml to about 1.5 ng / ml. The maximum concentration of the plasma concentration curve value can be reached in about 3 to about 24 hours after oral administration. A pharmaceutical formulation for the supply of trospium chloride for the effective treatment of urinary frequency, urgency, nocturnal enuresis and urge incontinence associated with detrusor instability, urgently needed syndrome and / or detrusor hyperreflexia in a human patient comprising a composition of extended release that provides a delayed release in oral administration to the patient; and an acceptable pharmaceutical carrier; wherein the pharmaceutical formulation is sufficient to maintain an effective level of trospium chloride in the patient during the course of at least 12 hours without additional administration of trospium chloride. The total dose of trospium chloride may be about 30 to 70 mg producing in a human patient a plasma concentration against the time curve having an area under the curve of about 30,000 pg / ml * hr to about 80,000 pg / ml * hr. The plasma concentration can have a maximum concentration of about 1.5 ng / ml to about 60 ng / ml. The plasma concentration can have a minimum concentration of about 0.5 ng / ml to about 1.5 ng / ml. The maximum concentration of the plasma concentration curve value can be reached in about 3 to about 24 hours after oral administration. A pharmaceutical formulation for the supply of trospium chloride for the effective treatment of urinary frequency, urgency, nocturnal enuresis and urge incontinence associated with detrusor instability, urge need syndrome and / or detrusor hyperreflexia in a human patient comprising an immediate release and / or an extended release composition that provides immediate release and / or a extended release in oral administration to the patient; a delayed release composition that provides delayed release in oral administration to the patient; and an acceptable pharmaceutical carrier; wherein the pharmaceutical formulation is sufficient to maintain an effective level of trospium chloride in the patient during the course of at least 12 hours without additional administration of trospium chloride, and a peak plasma concentration of trospium chloride reached after the release of the delayed release composition exceeds the peak plasma concentration previously reached after the release of the immediate release composition or the extended release composition. The total dose of trospium chloride may be about 30 to 70 mg producing in a human patient a plasma concentration against the time curve having an area under the curve from about 30,000 pg / ml * hr to about 80,000 pg / ml * hr. The plasma concentration can have a maximum concentration of about 1.5 ng / ml to about 6.0 ng / ml. The plasma concentration can have a minimum concentration of about 0.5 ng / ml to about 1.5 ng / ml. The maximum concentration of the plasma concentration curve value can be reached in about 3 to about 24 hours after oral administration. A once-a-day pharmaceutical formulation of trospium chloride comprising an immediate release or an extended release composition combined with a delayed release composition wherein the formulation composition contains sufficient trospium chloride to obtain a concentration of trospium in blood plasma average in a human patient is approximately 500 pg / mL to approximately 800 pg / mL within approximately 1-3 hours of oral administration; a concentration of plasma against the time of the formulation once a day has an area under the curve from about 30,000 pg / ml * hr to about 80,000 pg / ml * hr. The maximum concentration pf of the plasma concentration curve is about 1.5 ng / ml to about 6.0 ng / ml. The Tmax is approximately 5 and approximately 6 hours. The total trospium chloride dose is approximately 30 mg to 80 mg per dose. The immediate release or extended release composition has a release of trospium chloride equal to about 5% to about 20% of the total dose content within 2 hours as measured in an in vitro dissolution test using an Apparatus USP II at 50 RPM in 950 ML of 50 mM phosphate buffer at a pH between 6.8 and 7.5 at 37 ° C. Such immediate release or an extended composition release combined with a delayed release composition can be in a single unit or in separate units. Such a unit or units may be erodible matrix systems, coated systems, osmotic systems or combinations thereof. The invention contemplates a pharmaceutical composition suitable for once-a-day administration of trospium chloride comprising an amount of solid, particulates containing trospium chloride, each particulate including one or more control substances releasing trospium chloride, so that the once-daily administration of such a pharmaceutical composition provides a stable state (ie, no single dose, but then at least a few daily doses, or starting approximately between about 72 hours to about 120 hours of dosing once a day continuous) blood levels of trospium, which are substantially equivalent to the steady state blood levels of trospium achieved with twice-daily administration of 20 mg immediate-release trospium chloride tablets, provided the solid, the particulates that contain trospium chloride can not contain substances trospium chloride release control controls selected exclusively from the immediate release substances. In a preferred embodiment of the invention, the once-a-day administration of the controlled release pharmaceutical composition provides steady state blood levels of the trospium which fall in the range of about 0.5 ng / ml to about 6.0 ng / ml and preferably, for the corresponding dose level. at the dosage regimen of 20 mg of trospium chloride, which falls in the range of about 0.75 ng / ml to about 3.0 ng / ml. It will be understood by clinical specialists and other experts in the art that patients may be titrated above or below from a conventional dosed dose of 20 mg trospium chloride, in which case the dose units of the present invention would be adjusted correspondingly The concentration range of the drug in the formulations of the present invention determines such adjustments, it being understood that the preferred drug ranges correspond approximately to the typical 20 mg dose regimen. The invention is also contemplated to provide a pharmaceutical composition wherein administration once a day provides Cmax blood levels of steady state of the trospium falling in the range of about 2.5 ng / ml to about 4.5 ng / ml and Cm levels: trospium that fall in the range of about 0.5 ng / ml to about 1.5 ng / ml. In addition, the invention provides pharmaceutical compositions wherein administration once a day provides areas in steady state under the curve falling in the range of about 30 to about 60 ng / ml * hr, preferably falling in the range of about 35. at about 45 ng / ml * hr. In a particular embodiment of the invention, pharmaceutical compositions are provided wherein once-a-day administration provides steady-state% F (ie, relative bioavailability) values that fall in the range of about 80 to about 120, preferably, which falls in the range of about 90 to about 110. Therefore, the invention contemplates that a broad selection of one or more control substances releasing trospium chloride is selected for inclusion in the solid, the particulates comprising trospium, including, for example, one or more control substances releasing trospium chloride selected from substances that provide immediate release, delayed release, extended release or pH-sensitive release of trospium chloride, provided that a substance of Immediate release is selected, the weight and the pharmaceutical composition also include one or more substances of delayed release, extended release, pH sensitive release or combinations thereof. The specific embodiments described in further detail in the examples include, but are not limited to, formulations which are designated DR1, DR2, XR, XR1-1, XR1-2, XR1 + DR2 and IR / DR2, to name a few. The invention also contemplates a method for treating a mammal suffering from a condition that would benefit from once-daily administration of an effective amount of trospium chloride, which comprises administering to a mammal in need thereof a formulation once a day comprising an effective amount of trospium chloride which provides steady-state blood levels of trospium, which are substantially equivalent to the steady state blood levels of trospium achieved with the twice-daily administration of 20 mg of Immediate-release trospium chloride tablets (or a corresponding titrated dose) and which will reduce such effects. The invention will now be described in particular with the. following illustrative examples; however, the scope of the present invention is not intended to be, and will not be limited to the embodiments exemplified below. This invention provides profiles that would perform a once daily regimen acceptable for trospium chloride. Trospium chloride is a highly water soluble compound with a saturation solubility of 500 mg / ml. This invention overcomes the challenge imposed by highly water soluble drugs as the active pharmaceutical ingredient in extended release preparations. The dosage once a day obtains a decided advantage over the multiple dosage, increasing for example, the compliance rates of the patient. Also, dosing once a day with controlled release formulations reduces the side effects associated with increases in plasma concentration, which follow the administration of multiple doses of immediate release formulations. Thus, the present invention is also directed to methods of treating a mammal, preferably a human being by administering once a day a composition according to the present invention, which will give blood levels in steady state average of trospium of a minimum of about 0.5 ng / ml and a maximum of about 6.0 ng / ml, and preferably between about 0.75 and about 5.0 ng / ml. Any of the various compositions described in this application can achieve those blood levels, an achievement not previously thought possible. Schroder, S. et al., Vide supra. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, this specification, including definitions, will be controlled. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting.

EXAMPLES Example 1: immediate release granules of trospium chloride Immediate (IR) granules of trospium chloride were made by spheres of 30/35 mesh sugar coated with trospium chloride from a coating dispersion consisting of trospium chloride, hydroxypropylmethylcellulose (HPMC E5, a binder), talc (an anti-tack agent), and water in a Glatt 's® GPCG-1 fluid bed coater. Table 1 provides the composition of the IR capsule formula of trospium chloride, as well as modified release compositions, and Table 2 sets forth the composition of the granules. The stratification dispersion of the drug is prepared by dissolving the HPMC E5 in water, dissolving the trospium chloride in the present, then dispersing the talc, and stirring for 20 minutes. The resulting dispersion was stirred throughout the coating process to avoid hardening of the coating components. The coating parameters for Glatt 's® GPCG-1 are given in Table 3. The granules generated contain approximately 20% w / w of the trospium chloride. The procedure followed to determine the dissolution profiles was: Figure 1 Apparatus USP II, 50 RPM: Medium: 950 ml, 0.1 N HCl, pH 1.1 Figure 2: USP II apparatus, 50RPM: Medium: 950 ml 50 mM phosphate buffer, pH 7.5 Figure 3: USP II device, 50RPM: Medium: 750 ml 0.1N HCl pH 1.1 for the first 2 hours and then the medium was adjusted to pH 6.8 to 2 hours using a phosphate buffer (volume of total medium = 950 ml) Figure 4: USP II Apparatus, 50RPM. Medium: 950 ml 50 mM phosphate buffer, pH 7.5 Figure 5: USP II apparatus, 50RPM. Medium: 950 ml 50 mM phosphate buffer, pH 7.5 Figure 6: USP II device, 50RPM. Medium: 750 ml 0.1N HCl pH 1.1 for the first 2 hours and then the medium was adjusted to pH 6.8 to 2 hours using phosphate buffer (volume of total medium = 950 ml) Figure 7 Apparatus USP II, 50RPM, Medium: 750 ml 0.1N HCl pH 1.1 for the first 2 hours and then the medium adjusted to pH 7.5 in 2 hours using phosphate buffer (volume of total medium = 950 ml) Figure 8: Apparatus USP II, 50RPM, Medium: 750 ml 0.1N HCl pH 1.1 during the first 2 hours and then the medium adjusted to pH 7.5 in 2 hours using phosphate buffer (total medium volume = 950 ml). Figure 1 shows the dissolution profiles for the trospium chloride granules of immediate release in 0.1N HCl, pH 1.1. The profiles show a greater release of about 90% in about 15 minutes. Figure 2 shows the dissolution profiles for extended release trospium chloride granules in a phosphate buffer, pH 6.8. The profiles show a release between about 25% and about 80% in about 4 hours, between about 50% and about 95% in about 8 hours, between about 70% and about 98% in about 12 hours and between about 90% and about 100% in 24 hours. Figure 3 shows the dissolution profiles for the delayed release trospium chloride granules in 0.1N HCl and phosphate buffer, pH 6.8. The profiles show a release below 1% in an acidic medium and a release greater than about 90% in about 15 minutes after the pH changes. Figure 4 shows the average dissolution profiles for the 50 mg extended-release trospium chloride granules in phosphate buffer, pH 6.8. The profiles show a release of less than 10% in about 2 hours, between about 20% and about 30% in about 4 hours, between about 50% and about 60% in about 8 hours, between about 70% and about 80% in approximately 12 hours and between approximately 90% and approximately 100% in 24 hours. Figure 5 shows the average dissolution profiles for 40 mg extended-release trospium chloride granules in phosphate buffer, pH 6.8. The profiles show a release of less than about 10% in about 2 hours, between about 20% and about 30% in about 2 hours, between about 40% and about 60% in about 4 hours, between about 80% and about 90% in about 8 hours and between about 90% and about 100% in 12 hours. Figure 6 shows the average dissolution profile for delayed release trospium chloride granules of 35 mg in 0.1N HCl and a phosphate buffer, pH 6.8. The profiles show a release below 1% in an acidic medium and a release greater than about 40% in about 15 minutes after the pH changes, greater than 80% in 30 minutes after the pH changes and greater than 90% within one hour after the pH changes. Figure 7 shows the average solution profile for delayed release trospium chloride granules of 35 mg in 0.1N HCl and a phosphate buffer, pH 6.8. The profiles show a release below 1% in an acidic medium and a release greater than about 30% in about 30 minutes after the pH changes, greater than 60% release in about 60 minutes after the pH changes and greater 80% release within one hour after the pH changes and greater than 90% release within approximately 4 hours after the pH changes. Figure 8 shows the average solution profile for trospium chloride granules of 60 mg of extended release / delayed release in 0.1 N HCl and a phosphate buffer, pH 6.8. The profiles show a release between about 10% and about 20% during the first two hours in an acidic medium, and a release between 30% and 40% in about 30 minutes after the pH changes, between 60% and 70% release about 1 hour after the pH changes, between 60% and 80% release in about 2 hours after the pH changes, between 70% and 80% release in about 4 hours after the pH changes, between 80% and 90% release in about 6 hours after the pH changes and greater than 90% release after a period of about 8 hours after which the pH changes. All dissolution profiles are generated at 37 ° C.

Table la. Composition of percent by weight of dosage forms of trospium chloride Table Ib. Composition of percent by weight of dosage forms of trospium chloride Table 2. Composition of percent by weight of granules of trospium chloride Table 3. Parameters of the coating process Parameter GPCG-1 Temperature air inlet (° C) 50-55 Product temperature (° C) 40-42 Atomization air (bar) 1.5 Dew point (g / minutes) 8 -12 Example 2. Granules of extended release of trospium chloride The composition of capsules filled with XR granules of trospium chloride is given in Table 1. XR granules of trospium chloride were made by coating granules of immediate release of trospium chloride with a Surelease® Clear coating dispersion using a Glatt® fluid bed coater. Surelease® Clear is a 24% w / w aqueous dispersion supplied by Colorcon (West Point, PA). The Surelease® Clear coating dispersion was prepared by adding water to Surelease® Clear and mixing for 20 minutes to achieve a dispersion of 20% w / w Surelease® Clear. This Surelease® Clear dispersion of 20% w / w was used for the coating. The resulting dispersion was stirred throughout the coating process to prevent settlement of coating components. Several levels of the Surelease® Clear coating were examined in order to achieve extended release granules with different degrees of retardation in the coating solution, which are shown in Table 4. Figure 2 shows the dissolution profiles of the granules of trospium coated with ethylcellulose.

Table 4. Composition of extended release granules of trospium chloride Example 3: Delayed release granules of trospium chloride The composition of the capsules filled with DR granules of trospium chloride is given in Table 1. Table 2 provides the composition of delayed release granules. Trospium chloride immediate release granules were coated with Eudragit® L30D55 from a coating dispersion, consisting of Eudragit® L30D55, triethyl citrate (a plasticizer), talcum (an anti-tack agent) and water using a coater Glatt® fluid bed, Eudragit® L30D55 is a 30% w / w aqueous dispersion supplied by Rohm America (Piscataway, NJ). The Eudragit® L30D55 coating dispersion was prepared by dispersing talc in water and mixing for at least 20 minutes. The Eudragit® L30D55 dispersion was sieved through an 80 mesh screen. Triethyl citrate was added to the Eudragit® L30D55 dispersion and mixed for at least 30 minutes. The talc dispersion was then poured slowly into the dispersion of Eudragit® L30D55 / TEC and mixed for at least 30 minutes. The resulting dispersion (an 11.7% w / w aqueous dispersion of Eudragit® L30D55) was filtered through an 80 mesh screen and stirred throughout the process to avoid settling of coating components. Several levels of the coating of Eudragit® L30D55 were examined in order to achieve an acid-resistant coating. Figure 3 shows the dissolution profiles for delayed release granules of trospium chloride.

Example 4 - Combination of XR / DR Extended release granules were prepared as in Example 2 with 15% w / w SURELEASE® coating. Delayed release granules were made by coating immediate release granules with Eudragit FS30D, in a manner similar to Example 3. Eudragit® FS30D is a 30% aqueous dispersion supplied by Rohm America (Piscataway, NJ). Eudragit® coating dispersion FS30D is 18% w / w of Eudragit® FS30D. Enteric coated granules are combined with extended release granules in the ratio of XR granules to DR granules of 1: 1, to achieve a total trospium chloride dose of 60 mg.

Example 5. Delayed Release of Trospium Chloride in 35 mg of Strength The delayed-release granules, manufactured by coating immediate release granules with Eudragit® L30D55 as described in Example 3, were filled into capsules in a fill weight that provides mg of trospium chloride in the dose unit of the capsule.

Example 6 - Single Dose Human Pharmacokinetic Studies A human trial of four controlled release formulations was conducted. The study compared four controlled release dose units described in the previous examples (DRl 40 mg, DR2 40 mg, XR 40 mg and a mixture of IR 20 mg: 120 mg DR2) with an IR capsule of 40 mg given as a single dose once a day and the 20 mg IR tablet (Spasmo-Lyt®, Madaus), which was given twice a day at 12-hour intervals. Figure 4 shows the pharmacokinetic profiles of the controlled release compositions once a day against the two immediate release products. Figure 5 shows the same data with Formulation D removed for ease of comparison. These data demonstrate that DRl, XR1 and the IR / DR2 combination produced pharmacokinetic profiles and parameters that are similar to the commercial IR product twice a day (Figures 4 and 5). Table 5 presents single dose data in areas under the curve (AUC) over given time periods (0.24 hours and 0-72 hours) for immediate release product (20 mg) and controlled release products (40 mg of DRI, 40 mg of XR1 and combination of 20 mg / 120 mg of IR / DR2), including% F, which is a measure of bioequivalence. It can be appreciated that at least the DRl and XR controlled release products provide AUC data, which are comparable to those obtained with 20 mg immediate release trospium chloride administered twice daily.

Table 5. Single Dose Data for Various Formulations of Trospium Chloride Single Dose Example 7 - Human Pharmacokinetic Studies in steady state A second human test was conducted comparing four controlled release formulations described in Table Ib with an IR 20 mg tablet (Spasmo-Lyt®, Madaus), which was given twice daily at 12-hour intervals. Table 6 presents stable state data in AUC (for a period of 72 hours), Cmax, Crain and% F obtained during the administration of various trospium chloride formulations discussed in the preceding paragraph.

Table 6. Stable-state data for Various Trospium Chloride Formulations Example 8 - Enteric Administration of a Trospium Chloride Pharmaceutical Composition A delayed-release formulation is prepared, according to the method of the invention, using a trospium salt, such as fluorine, chlorine, bromine or iodine, using a delayed release coating, which releases trospium at a pH of about 7.0. For example, an EUDRAGIT release control layer is selected so that the active ingredient is released at about a neutral pH, which substantially matches the pH of the lower Gl tract (eg, lower intestine, colon, or both). Other release control layers can also be selected for the purpose of providing a pharmaceutical composition comprising trospium as at least one active ingredient, which releases trospium in sections of the Gl tract previously not thought to play a role in the supply / absorption of amounts significant of trospio. See for example, Schroder, S. et al., In International Journal of Clinical Pharmacology and Therapeutics, Vol. 42 -No. 10/2004 (543-549).

Claims (77)

1. CLAIMS 1. An oral pharmaceutical composition, containing trospium, which at a dose of once a day will give steady-state blood levels of trospium of a minimum of about 0.5 ng / ml and a maximum of about 6.0 ng / ml. The composition of claim 1, which in a once-a-day dose will give minimum steady state blood levels (Cmin) of trospium of between about 0.5 and about 1.5 ng / ml, and maximum blood levels (Cmax) of between about 2.0 and approximately 6.0 ng / ml. 3. The composition of claim 2, wherein the blood levels at steady state are between about 1.0 ng / ml and about 5.0 ng / ml. 4. The composition of claim 1, wherein between 25 mg and 80 mg of trospium chloride is present. The composition of claim 1, which comprises an immediate release component that contains no more than about 20 mg of trospium chloride. The composition of claim 2, which comprises an extended release component containing between about 25 and about 60 mg of trospium chloride. The composition of claim 1, which comprises a delayed release component containing between about 25 to about 80 mg of trospium chloride. 8. The composition of claim 1, which is a combination of a trospium chloride IR component and a DR trospium chloride component. The composition of claim 8, wherein the IR component contains no more than about 20 mg of trospium chloride and wherein the total dose of the trospium chloride is less than about 80 mg. 10. The composition of claim 1, which is a combination of a trospium chloride XR component and a DR trospium chloride component. The composition of claim 10, wherein the XR component contains between about 10 to about 40 mg of trospium chloride and the DR component contains between about 10 mg and about 40 mg of trospium chloride. The composition of claim 11, wherein the XR component contains about 30 mg of trospium chloride and the DR component contains about 30 mg of trospium chloride. The composition of claim 1, which is a combination of a trospium chloride IR component and a trospium chloride XR component. 14. The composition of claim 13, wherein the IR component contains no more than about 20 mg and the XR component contains about 20 mg to about 60 mg of trospium chloride. 15. The composition of claim 14, wherein the XR component contains about 20 mg to about 40 mg of trospium chloride. 16. The composition of claim 1, which is a combination of an IR trospium chloride component, a trospium chloride XR component and a DR trospium component. The composition of claim 16, wherein the IR component contains no more than about 20 mg of trospium chloride, and the combined XR and DR components contain between about 10 mg and 60 mg of trospium chloride and are in a ratio of XR: DR from 1:10 to 10: 1. 18. The composition of claim 1, which is in the form of a granule, tablet, granule, powder, sachet, capsule, gel, dispersion, solution or suspension. 19. The composition of claim 1, which is in the form of granules contained within a capsule. 20. The composition of claim 1, which is in the form of granules that are compressed into a tablet. The composition of claim 8-17, which is a stratified tablet, wherein each layer contains one of the components. 22. The composition of claim 8-17, which is a stratified granule, wherein the portion of DR and / or XR comprises the core of the granule., and the IR portion surrounds the nucleus. 23. A method for treating a disease or condition of urinary incontinence in a mammal, comprising administering a daily dose of a trospium composition according to claim 1 to the mammal, for at least a sufficient time to ameliorate the disease or condition . 24. The method of claim 23, wherein the mammal is a human being. 25. The method of claim 23, wherein between 25 and 80 mg of trospium chloride is present in the composition. 26. The method of claim 23, wherein about 60 mg of trospium chloride is present in the composition. 27. The method of claim 23, which composition comprises an immediate release component contains no more than about 20 mg of trospium chloride. The method of claim 23, which composition comprises an extended release component containing between about 25 and about 60 mg of trospium chloride. 29. The method of claim 23, which composition comprises a sustained release component containing between about 24 and about 80 mg of trospium chloride. 30. The method of claim 23, which composition is a combination of a trospium chloride IR component and a trospium chloride DR component. 31. The method of claim 30, wherein the IR component contains no more than about 20 mg of trospium chloride and wherein the total dose of trospium chloride is less than about 80 mg. 32. The method of claim 23, which composition is a combination of a trospium chloride component XR and a trospium chloride component DR. The method of claim 32, wherein the XR component contains between about 10 to about 40 mg of trospium chloride and the DR component contains between about 10 mg and about 40 mg of trospium chloride. 34. The method of claim 33, wherein the XR component contains about 30 mg of trospium chloride and the DR component contains about 30 mg of trospium chloride. 35. The method of claim 23, which composition is a combination of a trospium chloride IR component and a trospium chloride XR component. 36. The method of claim 35, wherein the IR component contains no more than about 20 mg and the XR component contains about 20 mg to about 60 mg of trospium chloride. 37. The method of claim 36, wherein the XR component contains about 20 'mg to about 40 mg of trospium chloride. 38. The method of claim 23, which composition is a combination of a trospium chloride IR component, a trospium chloride XR component and a DR trospium component. 39. The method of claim 38, wherein the IR component contains no more than about 20 mg of trospium chloride, and the combined XR and DR components contain between about 10 mg and 60 mg of trospium chloride and are in a ratio of XR: DR from 1:10 to 10: 1. 40. A process for preparing an immediate release pharmaceutical composition containing trospium, comprising spraying an drug solution containing trospium chloride onto an inert core whereby it forms a drug layer in the core. 41. The process of claim 40, wherein a binder and the anti-tack agents are also in the drug solution. 42. The process of claim 40, further comprising applying a protective coating of a polymeric composition to the stratified core with drug. 43. A process for preparing an extended release composition of trospium chloride, comprising obtaining a stratified core with drug or a granule comprised of drug, and applying a cover on the core or granule of a release control polymer. 44. A process for the preparation of a delayed-release trospium chloride composition, which comprises obtaining a stratified core of drug or a granule comprised of drug, and applying a cover on the core or granule of an enteric material. 45. A process for preparing a daily dose unit of trospium chloride, which will give steady-state blood levels of trospium of a minimum of about 0.5 ng / ml and a maximum of about 60 ng / ml, comprising combining granules of immediate release containing no more than about 20 mg of trospium chloride with XR granules containing about 20 mg to about 60 mg of trospium chloride within a capsule. 46. The process of claim 45, wherein the XR granules contain between about 20 mg and about 40 mg of trospium chloride. 47. A process for preparing a daily dose unit of trospium chloride, which will give steady-state blood levels of trospium from a minimum of about 0.5 ng / ml to a maximum of about 6.0 ng / ml, comprising combining granules of immediate release containing no more than about 20 mg of trospium chloride with DR granules, so that the total dose of the combination is less than about 80 mg, within one capsule. 48. A process for preparing a once-daily dose unit of trospium chloride, which will give steady-state blood levels of trospium from a minimum of about 0.5 ng / ml to a maximum of about 6.0 ng / ml, comprising combining the extended release granules containing between about 10 and 40 mg of trospium chloride with DR granules containing between about 10 and 40 mg within a capsule. 49. The process of claim 48, wherein each of the XR and DR granules contains about 30 mg of trospium chloride. 50. The process of claim 40-49, wherein the steady state blood level is between about 1.0 ng / ml and about 5.0 ng / ml. 51. The composition of claim 7, wherein about 35 mg of trospium are present, and the DR component is coated with a polymeric substance that will dissolve at pH 5.5 -6.0. 52. The composition of claim 15, wherein the release control coating gives an in vivo release profile of 3.5 hours. 53. The composition of claim 14, wherein the XR component contains approximately 50 mg of trospium chloride, and the release control coating gives an in vivo release profile of 4.5 hours. 54. A pharmaceutical composition suitable for once-a-day administration of trospium chloride comprising a plurality of particulates comprising trospium chloride, solid, the plurality being of an extended release, a delayed release, or a combination thereof or a combination of either with immediate release particulates, so that a once a day administration of the pharmaceutical composition provides steady state blood levels of trospium that are substantially equivalent to steady state blood levels of trospium achieved with twice-daily administration 20 mg day of immediate release trospium chloride tablets. 55. The composition of claim 54, wherein a once-a-day administration of the controlled release pharmaceutical composition provides steady-state blood levels of trospium that fall in the range of about 0.5 ng / ml to about 6.0 ng / ml. 56. The composition of claim 55, wherein a once a day administration of the controlled release pharmaceutical composition provides steady state blood levels of trospium falling in the range of about 1.0 ng / ml to about 5.0 ng / ml. 57. The composition of claim 55, wherein a once a day administration of the controlled release pharmaceutical composition provides Cmax levels of steady state blood of trospium falling in the range of about 2.5 ng / ml to about 4.5 ng / ml and Cm? n levels of trospium falling in the range of about 0.5 ng / ml to about 1.5 ng / ml 58. The composition of claim 55, wherein a once-a-day administration of the pharmaceutical release composition. controlled provides areas of steady state under the curve (AUC) that falls in the range of about 30 to about 60 ng / ml * hr 59. The composition of claim 58, wherein a once a day administration of the composition Pharmaceutical controlled release provides areas in stable state under the curve that falls in the range of about 35 to about 45 ng / ml * hr 60. The composition of the claim 54, wherein a once-a-day administration of the controlled release pharmaceutical composition provides single dose% F values that fall in the range of about 80 to about 120. The composition of claim 60, wherein one administration once a day of the controlled release pharmaceutical composition provides single dose% F values that fall in the range of about 90 to about 110. 62. The composition of claim 54, wherein the plurality of the particulates is selected from delayed release or extended release, each alone or in combination, or each alone or in combination with an immediate release particulate. 63. The. The composition of claim 62, wherein the particulates are all of a delayed release formulation. 64. The composition of claim 62, wherein the particulates are all of an extended release formulation that allows the release of approximately 80% trospium chloride at 3.5 hours after ingestion. 65. The composition of claim 62, wherein the particulates are all of a liberated formulation that allows the release of approximately 80% trospium chloride at 4.5 hours after ingestion. 66. The composition of claim 62, comprising particulates of an extended release formulation that allows the release of approximately 80% trospium chloride at 3.5 hours after ingestion, and delayed release particulates. 67. The composition of claim 66, wherein the delayed release particulates are those that release the trospium chloride when they reach the area of the Gl tract where the pH is about 7. 68. A method for treating a mammal suffering from a condition that would benefit from an once-a-day administration of an effective amount of trospium chloride, which comprises administering to a mammal in need thereof a once a day formulation comprising an effective amount of trospium chloride which provides steady-state blood levels of trospium substantially equivalent to the steady-state trospium blood levels achieved with twice-daily administration of 20 mg of immediate-release trospium chloride tablets and with a reduction in side effects. 69 A once-a-day dosage form of trospium chloride, which results in a single dose profile that is equivalent to the corresponding twice-daily regimen. 70. The dosage form of claim 69, wherein the corresponding twice daily regimen is equivalent to 40 mg per day. 71. The dosage form of claim 70, wherein the corresponding twice daily regimen equals 20 mg per day. 72. The dosage form of claim 71, wherein the regimen-twice daily corresponding to 80 mg per day. 73. A method of enteral administration of a pharmaceutical composition comprising an effective amount of trospium chloride, the improvement comprises including a delayed release formulation of trospium chloride, which releases trospium chloride at a pH of about 7.0. 74. A method of enteral administration of a pharmaceutical composition comprising an effective amount of trospium chloride, the improvement comprises including a delayed release formulation of trospium chloride, which releases trospium chloride in the lower intestine. 75. An enteral administration method of a pharmaceutical composition comprising an effective amount of trospium chloride, the improvement comprises including a delayed release formulation of trospium chloride, which releases trospium chloride into the colon. 76. A pharmaceutical composition comprising trospium chloride as at least one active pharmaceutical ingredient wherein at least a portion of the trospium chloride is contained in a delayed release formulation, which releases trospium chloride at a pH of about 7.0. 77. A pharmaceutical composition comprising trospium chloride as at least one active pharmaceutical ingredient wherein at least a portion of the trospium chloride is contained in a delayed release formulation, which releases trospium chloride in the lower intestine, the colon or both of them .