FIELD OF THE INVENTION

The invention relates to a bilayer pharmaceutical composition of Otilonium Bromide comprising an immediate and a sustained release layer useful in the treatment of irritable bowel syndrome (IBS) and/or or spasmodic pain of the gut.
BACKGROUND OF THE INVENTION
Otilonium bromide (I) chemically known as N-diethylmethylammoniummethyl-p-(2-(N-octyloxy)benzoyl)aminobenzoate bromide and its chemical structure is as follows:
Br

Otilonium bromideis an antispasmodic category drug with exerts its action by reducing hypermotility and modulating visceral sensation, factors thought to be responsible for pain in irritable bowel syndrome. It is used for treating spastic painful conditions of the distal tract of the intestinal tract, including irritable bowel syndrome. It has a complex mechanism of action.
Otilonium bromide may alter the Ca2+ flow from the main intracellular and extracellular regions and inhibits Ca2+ from entering the smooth muscle cells by binding to the muscarinic and tachykinin receptors of Ca2+ channels. The activity of Otilonium bromide may be described as a combination of the blockage of the Ca2+ channel and the mild anti-muscarinic effect.
Otilonium Bromide 40mg tablet was approved by Central Drugs Standard Control Organisation, India on Dec 15, 2000 for the treatment of irritable bowel syndrome, painful spastic condition of distal enteric tract. It sold under the registered tradename as Spasmoctyl®.
Otilonium Bromide have been disclosed as a novel compound in US3536723 (Menarini, Mario Ghelardoni et a/JUS '723 discloses the derivatives

of quaternary ammonium salts of N-alkylamino-alkyl which indicated for the antispastic-spasmolytic activitiesand coronary-dilatory properties. Column 2 para 7 of the patent disclosed the compound related to Otilonium and its bromide salts. Other examplediscloses the process for preparation of the compound related to same or with other derivatives.
Spasmoctyl® marketed tablets of Otilonium Bromide are prepared by using of granulation technics. For preparing the Spasmoctyl® tablets, the blended product is granulated prior to pressing (M Blanco et al, Development and validation of a near infrared method for the analytical control of a pharmaceutical preparation in three steps of the manufacturing process, Fresenius J Anal Chem, 2000, 368 :534-539, page 535).
FarhadFarshi et al. in WO2011024028 relates to direct compression of Otilonium or its pharmaceutically acceptable salt having perfect powder flow ability, good tablet weight distribution and no sticking to the dies or punches of tablet press.
Philipp Daniel Haas et al in EP2481395 Al discloses a pharmaceutical formulation and a manufacturing process for the preparation of the unit dose powder dosage of Otilonium or pharmaceutically acceptable salt. Moreover, a unit dose powder is a sachet containing a single dose of a pharmaceutical formulation, sachet, as well as processes of preparation of these dosage forms.
Yon Zhao et al. discloses the unstable drug Otilonium bromide in human plasma by LC-ESI-MS and its application to a pharmacokinetic study (Journal of Chromatography. 2010, vol. B, no.878, p. 2896-2900)disc\oses that the stability tests indicate that Otilonium bromide degrades rapidly in plasma and readily undergoes hydrolysis by the plasma esterase.
Sutton, et al. covers the clinical pharmacology of single doses of Otilonium bromide in healthy volunteers {European Journal of Clinical Pharmacology 1997, no.52, p.365-369) discloses that when orally administered at doses that produce

spasmolytic effects in humans, Otilonium bromide was devoid of both central and peripheral atropine-like side effects.
ZhangMing et al. in CN101053562 relates to pharmaceutical compositions comprising 5- 100 mg of otilonium bromide, where the preferred pharmaceutical dosage form is capsule and said composition disintegrates within five minutes in water.
Philipp Daniel Haas et al. in EP0270503 discloses a new pharmaceutical form of Otilonium bromide which is suitable to effect a local application in the gastrointestinal tract, i.e. a topical direct administration, rather than an oral administration.
Concerning qualitative composition of Spasmoctyl® 40 mg Film Coated Tablets; starch is the only excipient that can be used as a binder. In tablet formulations technology, freshly prepared starch paste at 50°-70°C is used in tablet granulations as a binder {Raymond C Rowe et al ,Handbook of Pharmaceutical Excipients) thus it is understood that in Spasmoctyl® starch is used and it points out that tablet formulation is prepared through using of granulation methods.
Chmielewska-Wilkoh et al covers the efficacy and safety of Otilonium bromide in treatment-sensitive functional irritable bowel syndrome (IBS) clinical parameters (World J Gastroenterol 2014 September 14; 20(34): 12283-12291). This study also findings from this dose-ranging study demonstrate that OB at 40 and 80 mg can improve individual and global clinical symptoms of IBS compared to placebo over a 4-wk period. As a part of conclusion this study supported by Menarini Group indicates the safety and efficacy of concentration ranges between 20 to 120mg of Otilonium Bromide.
The prior art documents described above are related to a single unit compositions of Otilonium Bromide as well as different dosage forms of Otilonium Bromide indicated for the treatment of IBS. Despite the availability of different types of compositions, it is cumbersome, inconvenient and expensive to the patient intake a three times a day as per the conventional dosage form available in market.

Otilonium Bromide absorption and mode of action is also a critical parameter behind the motivation of this invention. Clinical trial shows the maximum absorption in distal part of intestine and begin the pharmacological response at the dose of 20mg with the maximum tolerable limit of 120mg.The dosing frequency three time a day is also a motivation to formulate such a composition which can reduce the dosing frequency and able to provide the optimum onset of action. Thus there is a continuous unmet need to provide a composition, which is simple, stable and easy to manufacture and at the same time provides a steady state plasma concentration of drug and the composition is scalable on industrial scale with enhance release profile.
SUMMARY OF INVENTION
The present invention in general aspect relates to a bilayer pharmaceutical composition comprising an immediate release component and a sustained release component of Otilonium Bromide.
In one aspect of present invention, it relates to bilayer pharmaceutical composition of Otilonium Bromide comprising; an immediate release layer comprising of Otilonium Bromide thereof and one or more other pharmaceutical acceptable excipients and; a sustained release layer comprising Otilonium Bromide thereof, one or more pharmaceutically acceptable release controlling polymer with one or more pharmaceutical acceptable excipients.
In another aspects of the present invention, it relates to bilayer pharmaceutical composition, wherein the Otilonium or a pharmaceutically acceptable salt thereof present in the range of 10 to 120mg.
In yet another aspects of the present invention, it relates to a process for preparing bilayer pharmaceutical composition of Otilonium wherein the process comprising the steps of:
a) sifting sustain polymer with filler, binder and Otilonium Bromide
b) blending the mixture for 25-35 min.

c) sifted glidant and lubricant and added to blend mixture
d) lubricating the mixture of step c) with suitable lubricant to obtain sustained release layer.
e) mixing disintegrant, binder and filler with Otilonium Bromide after sifting separately.
f) mixing the coloring agent
g) mixing the step f) blend material with glidant followed by lubrication to prepare
immediate release layer.
h) compressing the sustained release layer of step d) along with the immediate release layer of step g) to get the desired bilayer composition dosage form.
In yet another aspects of the present invention, it relates bilayer pharmaceutical composition prepared, wherein the said composition provides the drug release ranging between 20-50% within first 30 minutes.
In further another aspects of the present invention, it relates A bilayer tablet of Otilonium Bromide, wherein composition provides prolonged release of the drug up to 12 hours.
The bilayer pharmaceutical composition of Otilonium Bromide according to present invention may be useful as anti-spasmodic agent for the treatment of irritable bowel syndrome or spasmodic pain of the gut.
Various other specific aspects of the invention are further detailed in the description part of the specification, wherever appropriate.
DETAILED DESCRIPTION
The present invention provides bilayer pharmaceutical composition of Otilonium Bromide which is used as anti-spasmodic effect for the treatment of irritable bowel syndrome or spasmodic pain of the gut.
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The inventors of the present invention have surprisingly found that it is possible to prepare stable bilayer pharmaceutical compositions of Otilonium Bromide or a pharmaceutically acceptable salt thereof, which provides a steady drug release concentration with reduced side effects.
In one embodiment according to present invention, it provides bilayer pharmaceutical composition of Otilonium bromide comprising; an immediate release layer comprising of Otilonium Bromide thereof and one or more other pharmaceutical acceptable excipients and; a sustained release layer comprising Otilonium Bromide thereof, one or more pharmaceutically acceptable release controlling polymer with one or more pharmaceutical acceptable excipients.
Otilonium Bromide as orally administered, anti-spasmodic activity to reduce the IBS pain severity effectively. Pharmacologically, Otilonium Bromide is one of the quaternary ammonium derivatives with GI smooth muscle spasmolytic activity via inhibition of calcium ion influx through L-type voltage operated calcium channels. The prescribed dose 40mg (03 tablet a day) for 3 weeks. It is a white, essentially odourless, crystalline powder with freely soluble in water, methanol, ethanol and chloroform; insoluble in diethyl ether. Otilonium bromide exerts its action through three mechanisms: reduction of intestinal smooth muscle contraction and dysmotility by modulation of calcium entry into intestinal smooth muscle; inhibition of calcium release from sarcoplasmic reticulum. Otilonium Bromide mainly eliminated by faeces (98%) and minimally excreted in the urine (1%). The pharmacokinetic responses also result in satisfactory prescribed at 03 times a day or as per recommendation. Thus, in view of the dosage desired for the therapy and the nature of active ingredients, there is further need to design such a dosage form which is capable to deliver the onset of action on a single dose and maintain the release for full day. The frequency of dose and long treatment of Irritable Bowel Syndrome is an expensive and need to monitored for a long time therapy. So further there is a need to optimised such a convenient dosage form which capable to minimise the dose frequency with the steady release of drug.
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It is also required that the said pharmaceutical dosage forms exhibit stability upon storage, as this is essential to ensure an adequate shelf life of the final dosage form. Further there is an apparent need to develop an optimized stable pharmaceutical dosage form that contains an appropriate dosage amount of Otilonium Bromide and also exhibits stability throughout the shelf life with enhance dissolution profile. The immediate layer and sustained layer of finished dosage is having a significant impact on release profile and achieve the onset of action for full day.
The term "Otilonium Bromide" used throughout the specification refers to only Otilonium Bromide per se, not the pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.
The term "pharmaceutically acceptable salts" refer to derivatives of the disclosed compound wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Preferably the present invention may comprise otilonium bromide.
The present invention particularly provides a pharmaceutical composition of Otilonium Bromide and active pharmaceutical ingredient (API) in the composition of Otilonium Bromide according to present invention may be isomer or racemic mixture physically or crystalline powdered material.
The term "immediate release" shall mean that the release of the majority of the active material content occurs within a relatively short time, for example within 1 hour, preferably within 30 minutes, after oral ingestion. Immediate release can also be referred to as instant release.
8

The term "sustained release" refers to the release of a drug substance from a pharmaceutical formulation, at a slower rate than from an immediate release formulation. Sustained release can also be referred to as controlled release, prolonged release, extended release, or modified release.
The term "release controlling polymer" refers to a substance which can control the release of a drug from the dosage form for a prolonged period of time. The release controlling polymer may include a hydrophilic and/or a hydrophobic substance.
The term “convenient dosage form” refers to unit composition which is easy to carry, convenient to intake and minimise the multiple dose dependency for onset of action. The convenient dosage form also refers to a bilayer composition which consist an immediate release and sustained release layer.
In release controlling polymer particularly hydrophilic polymer substances are selected from, but not limited to one or more of cellulosic polymer, copolymers or its derivatives including methylcellulose, hydroxyl propyl methylcellulose, hydroxyethyl cellulose, hydroxyl propyl cellulose, hydroxyethyl methylcellulose, carboxy methylcellulose, sodium carboxy methylcellulose; poly acrylates, methyl acrylates, polyethylene oxides, polyethylene glycols, chitosan, gums, starch derivatives, polyurethanes, galactomannans, poly alcohols, pectin, zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen, chitosan, oligosaccharides and polysaccharides such ascellulose, dextrans, tamarind seed polysaccharide, gellan gum, carrageenan gum, xanthan gum, gum Arabic, hyaluronic acid, poly hyaluronic acid, alginic acid, sodium alginate acrylic acid or acrylamide derivatives and the like..
Suitable hydrophobic substances are selected from, but not limited to one or more of ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnauba wax, hydrogenated vegetable oil and its derivatives, e.g. hydrogenated castor oil, glycerol monostearate, stearylalcohol, glyceryl behenate, poly anhydrides, acrylate and phthalate polymers and copolymers such as poly(methy1 methacrylate),
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poly(ethy1 methacrylate),poly(buty1 methacrylate), poly(isobutyl methacrylate),
poly(hexy1methacrylate), poly (isodecyl methacrylate), poly(lauryl
methacrylate),poly(pheny1 methacrylate), poly(methy1 acrylate), poly(isopropyl acrylate),poly(isobutyl acrylate), poly (octadecyl acrylate) polyethylene, polypropylene, poly(ethylene glycol), poly(ethy1ene oxide), poly (ethylene terephthalate) and the like.
In specific embodiment preferred hydrophilic substance is selected from hydroxyl propyl methylcellulose or mixture of grades thereof.
The present invention also provides the bilayer pharmaceutical composition consist of sustained and immediate release layer with suitable pharmaceutical acceptable excipients.
In suitable pharmaceutical acceptable excipients, “binders” are compounds which cause agglomeration of drug and excipient particles during the manufacturing process and act to control the release of drug from the dosage form. The agglomeration can be in the form of a granulation or a powder. The present invention provides the bilayer pharmaceutical composition of otilonium bromide comprising binder selected from cellulose derivatives e.g. ethyl cellulose, methyl cellulose, guar gum, blende guargum and other cellulose e.g. cellulose gums (carboxymethyl cellulose, hydroxypropyl methylcellulose, and hydroxyl propyl cellulose), polyvinyl pyrrolidone (povidone), cross-linked polyvinyl pyrrolidone, pre-gelatinized starch, acacia, alginic acid, carbomer, dextrin, malto dextrin.
In a specific embodiment according to present invention the binder used in the pharmaceutical composition was pre-gelatinized starch.
In suitable pharmaceutical acceptable excipients, “disintegrant” wherein disintegrant is selected from mannitol, alginic acid, carboxy methylcellulose, hydroxyl propyl cellulose, microcrystalline cellulose, croscarmellose sodium, povidone, polyvinyl-n-pyrrolidone (crospovidone), magnesium aluminum silicate, methylcellulose, sodium alginate, starches or modified starches such as sodium starch glycolate, corn starch, potato starch or pre-gelatinized starch.
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In a specific embodiment according to present invention the disintegrant used in the pharmaceutical composition was sodium starch glycolate.
In one embodiment according to the present invention, it provides the bilayer pharmaceutical composition wherein the Otilonium or a pharmaceutically acceptable salt thereof present in the range of 10 to 120mg.
In one of the specific embodiment, otilonium as an active ingredient used in the range of 50 to 120mg, particularity 80mg or 120mg.
The process for preparation of bilayer pharmaceutical composition of the invention may involve wet granulation, dry granulation, direct compression, slugging, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion-spheronization, spray drying and solvent evaporation. The wet granulation process involves use of water or any other suitable solvent. The dry granulation may involve use of roller compacter or any suitable technique.
In yet another embodiment of the present invention, it provides to a process for preparing bilayer pharmaceutical composition of Otilonium wherein the process comprising the steps of:
a) sifting sustain polymer with filler, binder and Otilonium Bromide
b) blending the mixture for 25-35 min.
c) sifted glidant and lubricant and added to blend mixture

d) lubricating the mixture of step c) with suitable lubricant to obtain sustained release layer.
e) mixing disintegrant, binder and filler with Otilonium Bromide after sifting separately.
f) mixing the coloring agent
g) mixing the step f) blend material with glidant followed by lubrication to prepare
immediate release layer.
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h) compressing the sustained release layer of step d) along with the immediate release layer of step g) to get the desired bilayer composition dosage form.
The step a) of sifting the sustain polymer, filler, binder and otilonium bromide according to the present invention, carried out in a shifter by conventional method using mesh size ranges between #30 to 50#, however it was optimised by the inventors of the present invention that sifting at temperature ranges between 15-30°C give better tabletting properties.
Furthermore, the step b) of mixing the sifted material using blender. The mixing was performed at the temperature ranges 30-40°C for a time period of 30min using the rotation speed of 20-25 RPM.
The step c) of sifting the glidant and lubricant using the using the mesh size ranges between #50 to 70# give the uniform particles and an advantage of the present application found that this kind of step has satisfactory outcome and betterment of further step.
Further process carried out in step d), performed by mixing the sifted material for 5-20 min at the 30-35°C. The mixed part carried for lubricating step to obtain the sustain release layer.
In further to prepare the immediate layer as on step e) of the present invention sifted the disintegrant, binder and filler with active ingredient using the sieve size ranges between 30-50# and mixed well for 20-30 min.
Further the next process carried out as step f) of mixing the coloring agent and mixed using blender for 25-35 min to get the uniform color distribution.
The blended material as in step f) is mixed with glidant and lubricating in further step g) of present invention to prepare the immediate release layer of the bilayer pharmaceutical composition.
The prepared mixture as per above of present invention further processed for compression and/or encapsulating in capsules shell.
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In yet another embodiment of the present invention, it provides to prepare pharmaceutical compositions for oral administration comprising a step of admixing the otilonium bromide with pharmaceutically acceptable excipients, optionally, comprising a step of compressing the composition into tablets, and optionally followed by a film-coating or directly encapsulating in desired capsule size.
The bilayer pharmaceutical composition of otilonium bromide according to present invention involves necessarily use of lubricant, wherein lubricant is selected from magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, vegetable oil, mineral oil.
The critical aspect of the present invention to prepare bilayer tablet of immediate release layer which able to achieve the release profile within an hour and the sustained release layer maintain the profile for steady period of time to provide the drug release for long period of time. The pharmaceutical composition also helps to minimise the dose dependency of the patient.
It has been observed by present inventors that various composition discussed in prior art suffer a multiple dependency of dose or either not meeting the dissolution profile parameters or making coating process non-uniform and difficult which may results as blistering, chipping, picking, blushing, cracking (splitting) or the like.
The inventors of the present invention of bilayer pharmaceutical composition of otilonium bromide gives the advantages over aforementioned difficulties while preparing for pharmaceutical composition by admixing an optimized lubricant, glidant and fillers.
Present invention, provides a process for making the bilayer pharmaceutical composition for oral administration comprising a step of admixing pharmaceutically acceptable excipients and otilonium bromide, comprising a step of compressing the composition into tablets, optionally followed by a non-aqueous film-coating.
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The term "oral" administration means that the active agent is in a formulation designed to be ingested, i.e. designed to be delivered to the gastrointestinal system for absorption.
The term "bilayer pharmaceutical composition "or "oral pharmaceutical composition" comprises capsule, tablet (film coated tablet, controlled release tablet, modified release tablet, delayed release, immediate release etc.), micro tablet, powder, granule and pellets. Capsules used as oral dosage form can be soft or hard capsules, though oral dosage form of the present invention is tablet or capsule.
The term "about" is a value that can be considered ±5% of the given value. Based on context of discussion, the term "% w/w" refers to the relative valueto total weight of granules or to total weight of pharmaceutical composition and “%v/v” refer to volume by total volume percentage.
In one of embodiments, the application provides pharmaceutical dosage forms of otilonium bromide having content uniformities (CU) from about 90% to about 110% by weight, with relative standard deviations (RSD) of not more than about 5%. In embodiments, the invention relates to pharmaceutical formulations having a disintegration time of less than about 15 minutes. In embodiments, the invention relates to pharmaceutical formulations having friability not more than about 1 % w/w.
Usage of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e. meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The term wt % refers to percent by weight. All
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methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g. "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.
The terms “pharmaceutically acceptable excipients”, “pharmaceutically compatible excipients”, and “excipients” are used interchangeably in this disclosure. They refer to non-API substances such as disintegrators, binders, fillers, and lubricants used in formulating pharmaceutical composition. They are generally safe for administering to humans according to established governmental standards, including those promulgated by the United States Food and Drug Administration.
Particular embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those particular embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in best possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
While the forgoing pages provide a detailed description of the preferred embodiments of the invention, it is being understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.
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Table 01
Example 01-04 Preparation of SR tablet

S. No.
1.
2.
3.
4. 5. 6. Ingredient Quantity per tablet (mg)

Example 01 Example 02 Example 03 Example 04

Otilonium bromide * 80 80 80 80

HPMC E-15 LV 45 50 40 30

HPMC K100-M CR 35 30 22 15

Lactose BP 100 100 110 115

MCC (102) 37 37 45 57

Silicon di-oxide 1.5 1.5 1.5 1.5
Lub rication
7. Magnesium stearate 1.5 1.5 1.5 1.5

Total 300 mg
Manufacturing process for preparation of otilonium bromide sustained release tablet composition using dry granulation:
1. Otilonium bromide and HPMC E-15 LV are sifted through sieve #40.
2. HPMC K-100M CR, Lactose BP & MCC (102) are sifted through sieve #40
3. Step -1 & 2 materials are mixed together and then material is loaded in blender for proper mixing for 30 min at 22 RPM.
4. The weighed quantity of silicon di-oxide and Magnesium stearate sifted
separately through sieve #60 and added to the step-3 material and mixed for 5 min,
followed with lubrication stage.
5. The final blend of step-4 is compressed with appropriate punches.
Table 02
Example 05-08 Preparation of Bilayer tablet
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a) Preparation of sustained release component of Otilonium Bromide

S. No. Ingredients Name Quantity per tablet (mg)

Example 05 Example 06 Example 07 Example 08
1 Otilonium bromide * 60 50 50 80
2 HPMC E-15 LV 40 40 40 56
3 HPMC K100-M CR 22 22 20 28
4 Lactose Anhydrous 90 100 92 118
5 MCC (102) 45 45 45 63
6 Silicon di-oxide 1.5 1.5 1.5 2.5
7 Magnesium stearate 1.5 1.5 1.5 2.5
Total 260 260 250 350
b) Preparation of immediate release component of Otilonium Bromide

S. No. Ingredients Name Quantity per tablet (mg)

Example 05 Example 06 Example07 Example 08
1 Otilonium bromide 20 30 30 40
2 Lactose Anhydrous 68 58 68 90
3 MCC (102) 25 25 25 34
4 Pregilatinised Starch 20 20 20 27
5 Sodium starch glycolate 5 5 5 6.5
Lubrication
6 Magnesium stearate 1 1 1 1
7 Silicon di-oxide 0.5 0.5 0.5 0.7
Coloring
8 Sunset yellow lake 0.5 0.5 0.5 0.85
Total 140 140 150 200
Manufacturing process for preparation of otilonium bromide bilayer tablet composition:
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A. Preparation of sustained release layer
1. Otilonium bromide and HPMC E-15 LV are sifted through sieve #40 & mixed for 5 min.
2. HPMC K-100M CR, Lactose BP & MCC (102) are sifted through sieve #40.
3. Step -1 & 2 materials are mixed together and then material is loaded in blender for proper mixing for 30 min at 22 RPM.
4. The weighed quantity of silicon dioxide and magnesium stearate sifted separately through sieve #60 and added to the step-3 material and mixed for 5 min, followed with lubrication stage.
B. Preparation of immediate release layer
5. Otilonium bromide and Lactose was sifted through sieve #40 & mixed
cumulative mixing.
6. Sodium starch glycolate & pre-gilatinised starch are sifted through sieve # 40 & mixed in step 01.
7. MCC (102) passed through 40 # sieve and add to step 02 & mixed manually for 2 min.
8. Sift the colouring agent through 60 # sieve then a portion of blend and required quantity of colour was mixed and add in whole blend and blend was transferred to blender and mixed for 30min at 22 rpm.
9. The weighed quantity of silicon dioxide and Magnesium stearate sifted separately through sieve #60 and added to the step-4 material and mixed for 5 min, followed with lubrication stage.
C. Compression of controlled release and immediate release
Components into bilayer tablets The controlled release component and the immediate release components of naproxen sodium were compressed together using appropriate tooling to provide bilayer tablets.
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Tablets prepared of Examples is packaged in closed HOPE containers, together with desiccant canister, and stored at three different conditions: 25°C and60% relative humidity (Condition 1), 30°C and 65% RH (Condition 2) or 40°C and75% RH (Condition 3) for one month. Dissolution testing results of initial and stored samples are shown in Table 02. The dissolution study is conducted in 900 ml of pH 6.8 phosphate buffer, using type 2 (basket) apparatus, stirred for 12 hours.
Dissolution testing results of tablets of Examples 05-07 are shown in Table 02
TABLE 02

Release Time (hours) % release of drug

Example 05 Example 06 Example 07
1 19 29 30
2 24 35 37
4 33 41 47
8 49 58 73
12 71 81 97

WE CLAIM:

A bilayer pharmaceutical composition of Otilonium bromide (I) comprising:
> an immediate release layer comprising of Otilonium bromide and one or more other pharmaceutical acceptable excipients and,
> a sustained release layer comprising Otilonium bromide, one or more pharmaceutically acceptable release controlling polymer with one or more pharmaceutical acceptable excipients.

2. The bilayer pharmaceutical composition according to claim 1, wherein the Otilonium bromide is present in the range of 40 to 120mg.
3. The bilayer pharmaceutical composition according to claim 1, wherein the percentage ratio of Otilonium bromide in immediate release layer to controlled release layer is in the range of 20-50 : 30-50 .
4. A process for preparing bilayer pharmaceutical composition of Otilonium bromide, wherein the process comprising the steps of:

a) sifting sustain polymer with filler, binder and Otilonium Bromide
b) blending the mixture for 25-35 min.
c) sifted glidant and lubricant and added to blend mixture
d) lubricating the mixture of step c) with suitable lubricant to obtain sustained release layer.
e) mixing disintegrant, binder and filler with Otilonium Bromide after sifting separately.
f) mixing the coloring agent
g) mixing the step f) blend material with glidant followed by lubrication to prepare
immediate release layer.
h) compressing the sustained release layer of step d) along with the immediate release layer of step g) to get the desired bilayer composition dosage form.

5. The bilayer pharmaceutical composition prepared according to claim 4, wherein the said composition provides the drug release ranging between 20-50% within first 30 minutes.
6. A bilayer pharmaceutical composition of Otilonium Bromide as claimed in claim 4, wherein the composition provides prolonged release of the drug up to 12 hours.
7. The bilayer pharmaceutical composition according to claim 1 may be used for the treatment of irritable bowel syndrome or spasmodic pain of the gut.