Field of the Invention
The present invention relates to controlled release pharmaceutical compositions
comprising trospium or salts thereof using one or more hydrophobic rate controlling
components.
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 (Cmax) and may also increase drug efficacy by increasing minimum plasma
concentrations (Cmin).
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 relates to a directed to pharmaceutical compositions that allow for
once daily dosage forms of trospium. Trospium is indicated in the treatment of urinary

frequency, urgency, nocturia, and urge-incontinence associated with detrusor instability,
urge syndrome, and detrusor hyperreflexia. These compositions are useful in treating the
afore-mentioned conditions with once-a-day administration.
US 2004/0028729 Al relates to sustained release pharmaceutical formulations with
improved absorption and bioavailability of pharmaceutical active agents w,ith 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 matrices. However, for highly soluble drugs, such
matrices 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 ideal 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.
Summary of the invention
In one aspect of the invention, a delayed released pharmaceutical composition is
provided, in which contains between about 25 mg and about 80 mg trospium chloride for
once a day administration, depending on the length of the lag phase. The in-vitro release
profile of such a formulation is generally characterized by having release profile of about
24hrs in acid media followed by buffer media of pH 6.8 and higher

In second aspect of invention an immediate release composition is provided, which
contains no mere than about 20mg active drug, combined with a delayed release
composition that is designed to dissolve in lower GIT.
In third aspect of invention is to provide processes for preparing the once daily
compositions of the present invention, and methods of treatment using them.
Detailed description of the Invention
The dosage forms of the present invention typically contain 20 to 100 mg trospium as
base. The dosage forms of the invention optionally may comprise pharmaceutically
acceptable complexes, salts, polymorphs, hydrates, solvates, enantiomers or racemates of
trospium.
"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 term "wicking agent" is defined as any material with the ability to draw water into
the network of a delivery dosage form. By so doing, a wicking agent provides enhanced
flow channels for the pharmaceutical agent, which has been made predominantly into its
solubilized form.

The hydrophobic release controlling agents are selected from but are not limited to
polyvinyl acetate dispersion, ethyl cellulose, cellulose acetate, cellulose propionate
(lower, medium or higher molecular weight), cellulose acetate propionate, cellulose
acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly (methyl
methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl
methacrylate), and poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl
methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl
acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), waxes such as beeswax,
carnauba wax, paraffin wax, microcrystalline wax, and. ozokerite; fatty alcohols such as
cetostearyl alcohol, stearyl alcohol, cetyl alcohol and myristyl alcohol, and fatty acid
esters such as glyceryl monostearate; glycerol monooleate, acetylated monoglycerides,
tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, zein
and hydrogenated vegetable oils or their mixtures thereof.
The enteric materials are selected from but not limited to Eudragit of all types which
release the drug in medium pH>5, zein, cellulose phthalates, hydroxy propyl cellulose
phthalates or their mixtures thereof.
The hydrophilic release controlling agents are 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 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).
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 term "controlled release pharmaceutical compositions" includes a pharmaceutical
composition that encompasses one or more individual units. The units may be a capsule
or tablet or may be in form of granules, pellets, minitablets or beads.
The compositions of the present invention can also include other materials such as
binders, diluents, anti-adherents, glidants and lubricants.
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.
Solid oral dosage forms of the present invention may be prepared by any conventional
techniques for example dry granulation, direct compression, wet granulation, melt
granulation and extrusion-spheronization.
Examples:
The following examples are intended to be illustrative and non-limiting:


Brief manufacturing procedure:
Step-I: Granulation & Compression:
1) Melt the hydrogenated vegetable oil and uniformly disperse the trospium chloride
under stirring and allow solidifying under continuous and uniform stirring.
2) Pass the solidified material through #25 mesh, granules are blended with lactose,
colloidal silicon dioxide for 10 min and finally lubricated with magnesium
stearate.
3) Lubricated granules are compressed into mini tablets using 3 mm punch.
Step II: Sub coating:
4) Compressed tablets are coated with Opadry white to give a wt build up of 3 %
w/w
Step III: Gastric protective coating:
5) Sub coated tablets are coated with Eudragit L100 suspension to give a wt builds up
of3-6%


Brief manufacturing procedure:
Step-I: Granulation & Compression:
1) Melt the hydrogenated vegetable oil and uniformly disperse the trospium chloride
under stirring and allow solidifying under continuous and uniform stirring.
2) Pass the solidified material through #25 mesh, granules are blended with lactose,
colloidal silicon dioxide for 10 min and finally lubricated with magnesium stearate.
Lubricated granules are compressed into mini tablets using 3 mm punch.


Brief manufacturing procedure:
1. Prepare a Soln of Trospium chloride, Hydroxypropyl methycellulose in water under
constant stirring.
2. Load sugar sphere in the fluid bed processor and spray the solution of step 01.
3. Prepare a coating suspension of Eudragit NE 30 D, Talc, and Lactose under constant
stirring till a homogenous suspension is formed.
4. Spray the coating suspension of step 03 on the drug loaded sugar sphere.
5. Prepare a seal coating suspension with Opadry and purified water and spay the
suspension on spheres of step 04.
6. Prepare a gastric coating suspension with Eudragit L 100, Triethyl citrate, Aerosil -
200 in purified water under constant stirring.
7. Spray the suspension of step 06 on the sugar sphere of step 05.


Brief manufacturing procedure:
Step-I: Granulation & Compression:
1. Melt the hydrogenated vegetable oil and uniformly disperse the trospium chloride
under stirring and allow solidifying under continuous and uniform stirring.
2. Pass the solidified material through #25 mesh, granules are blended with lactose,
colloidal silicon dioxide for 10 min and finally lubricated with magnesium
stearate.
3. Lubricated granules are compressed into mini tablets using 3 mm punch.
Step II: Sub coating:
4. Compressed tablets are coated with HPMC dispersion a wt build up of 3 % to
5%w/w
Step III: Enteric coating
5) Sub coated tablets are coated with Eudragit L100 suspension to give a wt builds up
of 10-15 %w/w
Step IV: Capsule filling
Fill the required quantity of mini tablets into appropriate size capsule.

Brief manufacturing procedure:
A) (For Delayed extended release tablets)
Step-I: Granulation & Compression:
1) Melt the hydrogenated vegetable oil and uniformly disperse the trospium chloride
under stirring and allow solidifying under continuous and uniform stirring.
2) Pass the solidified material through #25 mesh, granules are blended with lactose,
colloidal silicon dioxide for 10 min and finally lubricated with magnesium stearate.
3) Lubricated granules are compressed into mini tablets using 3 mm punch.
Step II: Sub coating:
4) Compressed tablets are coated with HPMC dispersion a wt build up of 3 % to
5%w/w
Step III: Enteric coating
5) Sub coated tablets are coated with Eudragit L100 suspension to give a wt builds up
of 10-15 %w/w
B) (For Delayed extended release tablets)
Step-I: Granulation & Compression:
1) Mix Intragranular material and granulate using PVP K-30 solution to desired
consistency.
2) Dry the granules to desired LOD.

3) Pass the dried material through #25 mesh, granules are blended with extra granular
materials for 10 min and finally lubricated with magnesium stearate.
4) Lubricated granules are compressed into mini tablets using 3 mm punch.
Step II: Sub coating:
Compressed tablets are coated with HPMC dispersion to a wt build up of 3 % to
5%w/w
Step III: Enteric coating
5. Sub coated tablets are coated with Eudragit L100 suspension to give a wt build up
of 10-15%w/w
C) Capsule filling
Fill the required quantity of mini tablets from delayed extended release portion (eqt to
45 mg drug) and delayed release portion (eqt to 15 mg drug) into appropriate size
capsule.

We claim:
1. An oral pharmaceutical composition, comprising one or more positively charged,
highly water soluble pharmaceutically active agents, and one or more material
substance containing non-polarized oxygen atoms, whereby the active agents will
not form any sort of interaction with the polymer(s).
2. The composition of claim 1, wherein the one or more positively charged, and
highly water-soluble active agents are quaternary ammonium compounds.
3. The composition of claim 1, wherein the one or more positively charged, and
highly water-soluble active agents are selected from clidinium, glycopyrrolate,
propantheline, or trospium chloride.
4. The composition of claim 3, wherein the active agent is trospium chloride.
5. The composition of claim 1, wherein the one or more material substances
containing non-polarized oxygen atoms are selected from waxes like, glyceryl
behenate, glyceryl monosterate, hydrogenated vegetable oils, stearic acid, palmitic
acid, lauric acid, carnauba wax, cetyl alcohol, glyceryl stearate, 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, copolymer of methyl acrylate,
methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and
maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate-
chlorotrimethylammonium ethyl acrylate copolymer, zein, shellac, copal
collophorium, carboxymethyl ethylcellulose, or co-polymerized methacrylic
acid/methacrylic acid methyl esters and Eudragit series E, L, S, RL, RS and NE
(Rohm Pharma).

6. A pharmaceutical composition suitable for once a day administration of trospium
chloride comprising controlled release solid, trospium chloride bearing tablets,
said tablets comprising at one or more polymer selected from enteric polymers,
release controlling polymers, or combinations thereof.
7. The composition of claim 6, in which tablets are selected from the group
consisting of a) an extended release, b) a delayed release, c) a combination of
extended release and delayed release, d) a combination of either an extended
release or a delayed release and a delayed release with an immediate release
formulation.
8. The once a day dosage forms of claim 6, which comprises between about 25 mg
and about 80 mg of trospium chloride.
9. The composition of claim 6, in which said release controlling polymers are
selected from a group consisting of co-polymer of acrylic and methacrylic acid
esters, ethylcellulose aqueous dispersions, hydroxy ethylcellulose, hydroxy propyl
cellulose, hydroxy propyl methyl cellulose, poly vinyl pyrrolidone, vinyl acetate
co-polymer, polyethylene glycols and combinations thereof.
10. The composition of claim 6, in which said enteric polymers are selected from a
group consisting of cellulose acetate phthalate, hydroxy propyl methyl cellulose
phthalate, hydroxy propyl methyl cellulose acetate succinate, cellulose acetate
succinate, cellulose acetate hydro phthalate, cellulose propionate phthalate,
copolymer of methylmethacrylic acid and methylmethacrylate, copolymer of
methyl acrylate, methyl methyl acrylate and methacrylic acid, copolymer of
methylvinyl ether and maleic anhydride, ethyl methyarylate-methmethacrylate-
chloro-trimethyl ammonium ethyl acrylate copolymer, zein, shellac, copal
collophorium, carboxymethyl ethyl cellulose, co-polymerized methacrylic acid
methyl esters and combinations thereof.

11. The composition of claim 6, in which at least some of said tablets are comprised
of a trospium-containing core, which is coated with at least one polymer selected
from enteric polymers, release controlling polymers, or combinations thereof.
12. A pharmaceutical composition comprising trospium chloride as at least one active
pharmaceutical ingredient in which atleast a portion of said trospium chloride is
contained in a delayed release formulation, which releases trospium chloride in
the GI tract, said delayed release formulation comprising atleast, one nonpolarized
polymer.
13. The composition of claim 12, in which the trospium chloride is formulated in the
form of delayed release tablets, capsules, micro-tablets, tablets filled in a capsule,
delayed release pellets, pellets filled in the capsule, tablets made of matrix
material made of fatty acid derivatives, pellets made of matrix material made of
fatty acid material filled in a capsule.

An oral pharmaceutical composition, which comprises one or more positively charged,
highly water soluble pharmaceutically active agents, and one or more material substance
containing non-polarized oxygen atoms, in a manner such that the active agents will not
form any sort of interaction with the polymer(s).