The present invention relates to a method for preparing a stable extended release suspension composition comprising multiple coated cores of an active ingredient by using a suspension base, wherein the suspension base ensures substantially similar in-vitro dissolution release profile of the active ingredient upon storage of the suspension compositions for at least seven days.

Background of the Invention

Extended release solid compositions are preferred dosage forms over immediate release solid compositions, especially for active ingredients showing fluctuations in the plasma concentration and for active ingredients having short half-lives. Extended release solid compositions can be in the form of tablets or capsules, wherein the release of the active ingredient is controlled by using a reservoir or a matrix system. However, extended release solid oral compositions suffer from certain drawbacks such as difficulty in swallowing, particularly for certain groups of patients, e.g., pediatrics and geriatrics, resulting in poor patient compliance. Further, high doses of active ingredient lead to large-sized compositions which aggravates this problem. Also, there remains a tendency to divide extended release solid compositions such as tablets into small pieces in order to facilitate administration, which may ultimately lead to inaccurate dosing and/or dose dumping. In view of all this, extended release liquid compositions provide the best alternative over extended release solid compositions. Extended release liquid

compositions are easy to administer, thereby leading to enhanced patient compliance. Additionally, extended release liquid compositions provide a unique advantage of having a flexible dosing regimen.

Although extended release liquid compositions are advantageous, there remain some complexities involved in formulating such compositions. The important prerequisite of these compositions is to provide the desired extended release of the active ingredient throughout its shelf life, as irregular release may lead to sub-therapeutic or toxic effects. The key hurdle remains to overcome the leaching of the active ingredient from the coated cores into a suspension base during storage. The objective for a scientist remains to develop a formulation such that the release of the active ingredient into the suspension base during storage is avoided, and only when the suspension enters the gastrointestinal tract the release is allowed.

The prior art discloses various approaches to overcome the leaching problem for the preparation of extended release liquid compositions.

PCT Publication No. WO 2012/063257 and U.S. Publication No. 2008/0118570 disclose extended release suspensions employing ion-exchange resins. Although ion-exchange resin systems provide the desired extended release of the active ingredient without significant leaching during storage, these systems require chemical binding of the active ingredient to the resin, which is complicated and not suitable for many active ingredients.

PCT Publication No. WO 2011/107855 discloses a ready to use sustained release oral suspension comprising inert pellets surrounded by a seal coating, an active ingredient layer surrounding the seal coated inert pellets, and a coating layer comprising a rate-controlling polymer surrounding the active ingredient layer. Said sustained release pellets are further coated with a protective coating layer which prevents the leaching of the active ingredient.

PCT Publication No. WO 2008/122993 discloses a suspension of an active ingredient containing microparticles with at least one coat of a pH-independent polymer. Further, there is an additional coat of pH-dependent polymer which provides stability to the formulation by avoiding leaching of active ingredient in the liquid phase after reconstitution during storage.

In the formulations disclosed in these prior art, the leaching of the active ingredients from the coated units into the media during storage is primarily prevented by the use of a multiple coating systems. However, the process of applying multiple coating systems remains time-consuming, complicated, and difficult to be functionally reproducible.

U.S. Patent No. 7,906, 145 discloses a sustained release suspension comprising microcapsules suspended in an aqueous liquid phase saturated with an active ingredient, wherein each microcapsule comprises a core of the active ingredient and a coating layer applied to the core which controls the modified release of the active ingredient in gastrointestinal fluids. Said coating layer comprises a film-forming polymer, a nitrogen-containing polymer, a plasticizer, and a surfactant/lubricant. The coating layer is designed in a way such that the release profile is not perturbed in the liquid phase and the active ingredient contained in the microcapsules is prevented from escaping into the liquid phase throughout the storage of the suspension. However, this system also requires mandatory use of an aqueous phase saturated with the active ingredient which may not be suitable for active ingredients having low aqueous solubility and/or low dose. Further, this system is limited to class of active ingredients which require an immediate dose or an initial spike in the release profile and therefore is not suitable for active ingredients which do not require any immediate dose of the active ingredient. Also, the aqueous phase saturated with the active ingredient remains physically unstable as a small variation in temperature, pH, and/or ionic concentration may lead to salting out or precipitation of the active ingredient.

In view of all these, there remains a need in the art to formulate extended release suspension compositions of the active ingredients which are based on a simplified and robust technology and which provide significant advancement over the existing prior art. The extended release suspension compositions of the present invention are suitable for variety of active ingredients including active ingredients having low aqueous solubility or active ingredients which do not require any immediate dose of the active ingredient. The extended release suspension compositions of the present invention remain physically stable to any variation in temperature, pH, and/or ionic concentration. Furthermore, the extended release suspension compositions of the present invention provide the desired extended release throughout the shelf life of the compositions.

The present invention provides extended release suspension compositions based on a simplified technology, prepared by a process which is relatively simple, easy to commercially manufacture, and functionally reproducible. The present invention uses a unique suspension base which prevents the leaching of the active ingredient from the coated cores during storage. The suspension base thus ensures substantially similar in-vitro dissolution release profile of the active ingredient upon storage throughout the shelf life of the compositions. This consistent in-vitro release then ensures a steady plasma concentration with no fluctuations throughout the shelf life of the compositions.

Additionally, the extended release suspension compositions of the present invention are able to incorporate two or more active ingredients with different release profiles or two or more incompatible active ingredients in a single composition.

Summary of the Invention

The present invention relates to a method for preparing a stable extended release suspension composition comprising multiple coated cores of an active ingredient by using a suspension base, wherein the suspension base ensures substantially similar in-vitro dissolution release profile of the active ingredient upon storage of the suspension composition for at least seven days.

The extended release suspension composition of the present invention is easy to administer, thereby leading to enhanced patient compliance. Further, said extended release suspension composition provides better dose flexibility depending on the age and body weight of the patient. Also, said extended release suspension composition is stable, easy to commercially manufacture, and provide reproducible bioavailability.

Additionally, said extended release suspension composition provides a pleasant mouth feel and taste masking for bitter drugs, thereby further enhancing patient compliance. The present invention provides such composition and improves patient compliance by reducing dosing frequency for pediatric as well as geriatric patients.

Brief Description of the Drawings

Figure 1 shows the in-vitro dissolution release on day 0, day 30, and day 66 of the extended release suspension composition prepared according to Example 4 upon storage at room temperature. This figure also shows the in-vitro dissolution release on day 0, day 36, and day 66 of the extended release suspension composition (at room temperature) formed after reconstituting the powder stored for one month at accelerated conditions.

Figure 2 shows the in-vitro dissolution release on day 0 and day 30 of the extended release suspension composition prepared according to Example 5 upon storage at room temperature. This figure also shows the in-vitro dissolution release on day 0 and day 32 of the extended release suspension composition (at room temperature) formed after reconstituting the powder stored for three months and six months at accelerated conditions.

Figure 3 shows the in-vitro dissolution release on day 0 and day 30 of the extended release suspension composition prepared according to Example 6 upon storage at room temperature. This figure also shows the in-vitro dissolution release on day 0 and day 30 of the extended release suspension composition (at room temperature) formed after reconstituting the powder stored for one month at accelerated conditions.

Detailed Description of the Invention

A first aspect of the present invention provides a method for preparing a stable extended release suspension composition comprising multiple coated cores of an active ingredient by using a suspension base, wherein the suspension base ensures substantially similar in-vitro dissolution release profile of the active ingredient upon storage of the suspension composition for at least seven days.

According to one embodiment of the above aspect, the suspension base is characterized by having the features of:

(i) a viscosity in a range of about 500 cps to about 15,000 cps; and

(ii) an osmolality of at least about 1 osmol/kg of the suspension base.

According to another embodiment of the above aspect, the suspension base comprises:

(i) a suspending agent;

(ii) an osmogent; and

(iii) an aqueous vehicle.

According to another embodiment of the above aspect, the suspension base does not include a saturated solution of the active ingredient.

According to another embodiment of the above aspect, the suspension base generates a hypertonic condition such that there is no substantial change in the in-vitro dissolution release profile of the active ingredient upon storage of the extended release suspension composition for at least seven days.

According to another embodiment of the above aspect, the stable extended release suspension composition is characterized by having an osmolality ratio of at least about 1.

According to another embodiment of the above aspect, the coated core comprises a core of the active ingredient and a coating layer over said core comprising one or more release-controlling agents.

According to another embodiment of the above aspect, the core of the active ingredient is in the form of a bead, a pellet, a granule, a spheroid, or the like.

According to another embodiment of the above aspect, the active ingredient is layered onto an inert particle to form the core.

According to another embodiment of the above aspect, the inert particle is selected from the group comprising a non-pareil seed, a microcrystalline cellulose sphere, a dibasic calcium phosphate bead, a mannitol bead, a silica bead, a tartaric acid pellet, a sugar bead, or a wax based pellet.

According to another embodiment of the above aspect, the average diameter of the coated cores ranges from about 10 μιη to about 2000 μιη. In a preferred embodiment, the average diameter of the coated cores ranges from about 50 μιη to about 1000 μιη. In a more preferred embodiment, the average diameter of the coated cores ranges from about 150 μιη to about 500 μιη.

According to another embodiment of the above aspect, the stable extended release suspension composition is a taste-masked composition.

According to another embodiment of the above aspect, the stable extended release suspension composition is in the form of a suspension or a reconstituted powder for suspension.

According to another embodiment of the above aspect, the release-controlling agent is selected from the group comprising a pH-dependent release-controlling agent, a pH-independent release-controlling agent, or mixtures thereof.

A second aspect of the present invention provides a process for the preparation of a stable extended release suspension composition, wherein the process comprises the steps of:

(i) preparing cores comprising an active ingredient and one or more pharmaceutically acceptable excipients;

(ii) dissolving/dispersing a release-controlling agent and one or more pharmaceutically acceptable coating additives in a suitable solvent;

(iii) applying the coating composition of step (ii) over the cores of step (i);

(iv) dissolving/dispersing one or more suspending agents, one or more osmogents, and optionally one or more pharmaceutically acceptable excipients into an aqueous vehicle to form a suspension base; and

(v) dispersing the coated cores of step (iii) in the suspension base of step (iv) to obtain the stable extended release suspension composition.

A third aspect of the present invention provides a process for the preparation of a stable extended release suspension composition, wherein the process comprises the steps of:

(A) preparing a powder for suspension comprising the steps of:

(i) preparing cores comprising an active ingredient and one or more pharmaceutically acceptable excipients;

(ii) dissolving/dispersing a release-controlling agent and one or more pharmaceutically acceptable coating additives in a suitable solvent;

(iii) applying the coating composition of step (ii) over the cores of step

(i);

(iv) mixing one or more pharmaceutically acceptable excipients with the coated cores of step (iii) to obtain the powder for suspension;

(B) preparing a suspension base by dissolving/dispersing one or more

suspending agents, one or more osmogents, and optionally one or more pharmaceutically acceptable excipients into an aqueous vehicle; and

(C) reconstituting the powder for suspension of step (A) with a suspension base of step (B) to obtain the extended release suspension composition.

A fourth aspect of the present invention provides a process for the preparation of a stable extended release suspension composition, wherein the process comprises the steps of:

(A) preparing a powder for suspension comprising the steps of:

(i) preparing cores comprising an active ingredient and one or more pharmaceutically acceptable excipients;

(ii) dissolving/dispersing a release-controlling agent and one or more pharmaceutically acceptable coating additives in a suitable solvent;

(iii) applying the coating composition of step (ii) over the cores of step

(i);

(iv) mixing one or more suspending agents, one or more osmogents and optionally one or more pharmaceutically acceptable excipients with the coated cores of step (iii) to obtain the powder for suspension; and

(B) reconstituting the powder for suspension of step (A) with an aqueous vehicle to obtain the extended release suspension composition.

The term "extended release," as used herein, refers to the release profile of the active ingredient over an extended period of time, e.g. , over a period of 4, 6, 8, 12, 24 hours, or more.

The term "osmolality ratio," as used herein, means the ratio of the osmolality of the external phase to the osmolality of the internal phase. The external phase herein, means the suspension base without multiple coated cores of the active ingredient. The internal phase herein means the coated cores of the active ingredient. As the direct measurement of the osmolality of the internal phase i.e., coated cores is difficult, the osmolality of the internal phase herein, is represented as the osmolality of a solution which prevents significant leaching of the active ingredient from the coated cores into the solution. The leaching of the active ingredient from the coated cores is determined by the difference in the osmolalities across the coating layer and the absence of any significant leaching from the coated cores directs that the osmolality of the solution has become equal to the osmolality of the coated cores. The osmolality ratio of the extended release suspension compositions of present invention is at least about 1.

The term "hypertonic condition," as used herein, means the suspension base has higher solute concentration which helps to generate high osmotic pressure such that there is no leaching of the active ingredient from the coated cores into the suspension base. In the present invention, the solutes are osmogents i.e., pharmaceutically acceptable inert water-soluble compounds that contribute towards generating hypertonic conditions in the suspension base.

The term "osmolality," as used herein, is expressed as number of moles of any water-soluble compound per kg of a liquid phase. The liquid phase can be a suspension base or a solution. In the present invention, the osmolality may be measured according to known methods, such as using a vapor pressure osmometer, a colloid osmometer, or a freezing point depression osmometer such as Osmomat® 030-D or Osmomat® 3000, in

particular by a freezing point depression osmometer. The suspension base of the present invention has an osmolality of at least about 1 osmol/kg of the suspension base. In particular, the suspension base of the present invention has an osmolality of at least about 2 osmol/kg of the suspension base. The suspension base of the present invention has an osmolality ranging from about 1 osmol/kg to about 20 osmol/kg of the suspension base.

The osmolality of the suspension base of the extended release suspension compositions of the present invention remains equivalent upon storage for at least seven days. Particularly, the osmolality of the suspension base measured after one month remains equivalent to the osmolality of the suspension base measured as soon as practicable after preparation of the extended release suspension compositions. More particularly, the osmolality of the suspension base measured after three months or six months remains equivalent to the osmolality of the suspension base measured as soon as practicable after preparation of the extended release suspension compositions. The equivalent osmolality of the suspension base ensures that there is no leaching of the active ingredient from the coated cores into the suspension base.

The viscosity of the suspension base of the present invention ranges from about 500 cps to about 15,000 cps. Preferably, the viscosity of the suspension base ranges from about 1,000 cps to about 10,000 cps. More preferably, the viscosity of the suspension base ranges from about 2,000 cps to about 7,000 cps. The viscosity of the suspension base of the present invention is measured by using a Brookfield Viscometer having a # 2 spindle rotating at 5 rpm at 25°C.

The term "stable," as used herein, refers to chemical stability, wherein not more than 5% w/w of total related substances are formed on storage at 40°C and 75% relative humidity (R.H.) or at 25°C and 60% R.H. for a period of at least three months to the extent necessary for the sale and use of the composition.

The term "inert particle," as used herein, refers to a particle made from a sugar sphere also known as a non-pareil seed, a microcrystalline cellulose sphere, a dibasic calcium phosphate bead, a mannitol bead, a silica bead, a tartaric acid pellet, a wax based pellet, and the like.

The term "about," as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.

The term "equivalent" as used herein, refers to any value which lies within the range defined by a variation of up to ±30% of the value.

The term "significant leaching," as used herein means more than 20% of the active ingredient is leached out from the coated cores into the solution.

The in-vitro dissolution release profile of the extended release suspension composition of the present invention upon storage for at least seven days remains substantially similar to the initial in-vitro dissolution release profile obtained as soon as practicable after preparation of the extended release suspension composition. Particularly, the in-vitro dissolution release profile of the extended release suspension composition of the present invention upon storage for at least one month remains substantially similar to initial in-vitro dissolution release profile obtained as soon as practicable after preparation of the extended release suspension composition. More particularly, the in-vitro dissolution release profile of the extended release suspension composition of the present invention upon storage for at least three months remains substantially similar to initial in-vitro dissolution release profile obtained as soon as practicable after preparation of the extended release suspension compositions. More particularly, the in-vitro dissolution release profile of the extended release suspension composition of the present invention upon storage for at least six months remains substantially similar to initial in-vitro dissolution release profile obtained as soon as practicable after preparation of the extended release suspension composition. In the present invention, wide ranges of dissolution methodologies can be utilized for different active ingredients. These methodologies can be adopted to vary in hydrodynamic mechanism to simulate in-vivo conditions by using different dissolution apparatuses, volume of media, pH of media ranging from 1.0 to 7.5, any standard USP buffers with standard molarity, addition of surfactants, and or enzymes.

The extended release suspension composition of the present invention provides the consistent in-vivo release which ensures steady and predictable active ingredient release with minimal inter and intra subject variation throughout the shelf life of the composition.

The term "substantial," as used herein refers to any value which lies within the range as defined by a variation of up to ±15 from the average value.

The term "suspension base," as used herein, refers to a medium which is used to suspend the coated cores of the active ingredient. The suspension base of the present

invention is characterized by having a viscosity in a range of about 500 cps to about 15,000 cps; and an osmolality of at least about 1 osmol/kg of the suspension base.

The suspension base generates a hypertonic condition such that there is no substantial change in the in-vitro dissolution release profile of the active ingredient upon storage of the suspension composition for at least seven days. Alternatively, the suspension base may have a pH such that there is no substantial change in the in-vitro dissolution release profile of the active ingredient upon storage of the suspension composition for at least seven days. In this case, the active ingredient may have a pH-dependent solubility and the pH of the suspension base is adjusted to a pre-determined pH at which the active ingredient remains substantially insoluble.

The extended release suspension composition of the present invention may be in the form of a suspension or a reconstituted powder for suspension.

The suspension base of the present invention comprises one or more suspending agents, one or more osmogents, and an aqueous vehicle. It may further comprise one or more pharmaceutically acceptable excipients. The powder for suspension having coated cores of active ingredient of the present invention may be reconstituted with the suspension base having suspending agents, osmogents, pharmaceutically acceptable excipients, and an aqueous vehicle. Alternatively, suspending agents, osmogents, or other pharmaceutically acceptable excipients may be premixed with the coated cores which may be reconstituted with an aqueous vehicle. In case of powder for suspension, the suspension base may be pre-formed or formed at the time of reconstitution.

The aqueous vehicle may comprise of purified water or a mixture of purified water with one or more suitable organic solvents.

The average diameter of the coated cores of the present invention ranges from about 10 μπι to about 2000 μπι, particularly from about 50 μπι to about 1000 μπι, and more particularly from about 150 μπι to about 500 μπι. The finer sizes of the coated cores help in avoiding grittiness in the mouth and are therefore more acceptable. The cores of the present invention may comprise one or more pharmaceutically acceptable excipients such as a binder, a release-controlling agent, an osmogent, a stabilizer, a solubilizer, or a pH modifying agent. The stabilizer may include but not limited to a pH modifying agent, a chelating agent, or an anti-oxidant. The solubilizer may include but not limited to a solubility enhancing agent, a pH modifying agent, an adsorbent, or a complexing agent.

The active ingredient of the present invention includes any active ingredient belonging to a therapeutic category, including but not limited to antidiabetic, antibiotic, antimicrobial, analgesic, antiallergic, antianxiety, antiasthmatic, anticancer, antidepressant, antiemetic, antiinflammatory, anti-Parkinson's, antiepileptic, antitussive, antiviral, immunosuppressant, diuretic, antimigraine, antihypertensive, hypolipidemics, antiarrhythmics, vasodilators, anti-anginals, sympathomimetic, cholinomemetic, adrenergic, antimuscarinic, neuroleptics, antispasmodic, skeletal muscle relaxants, expectorants, and drugs for treating attention deficit hyperactive disorder. The active ingredient of the present invention can be present in the form of a free base or in the form of

pharmaceutically acceptable salts. Specific examples of active ingredients include but are not limited to the group comprising metformin, acarbose, miglitol, voglibose, repaglinide, nateglinide, glibenclamide, glimepride, glipizide, gliclazide, chloropropamide, tolbutamide, phenformin, aloglitin, sitagliptin, linagliptin, saxagliptin, rosiglitazone, pioglitazone, troglitazone, faraglitazar, englitazone, darglitazone, isaglitazone, zorglitazone, liraglutide, muraglitazar, peliglitazar, tesaglitazar, canagliflozin,

dapagliflozin, remogliflozin, sergliflozin, verapamil, albuterol, salmeterol, acebutolol, sotalol, penicillamine, norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, trovafloxacin, gatifloxacin, cefixime, cefdinir, cefprozil, cefadroxil, cefuroxime, cefpodoxime, tetracycline, demeclocycline hydrochloride, amoxicillin, clavulanate potassium, azithromycin, losartan, irbesartan, eprosartan, valsartan, diltiazem, isosorbide mononitrate, ranolazine, propafenone, hydroxyurea, hydrocodone, delavirdine, pentosan polysulfate, abacavir, amantadine, acyclovir, ganciclovir, valacyclovir, valganciclovir, saquinavir, indinavir, nelfinavir, lamivudine, didanosine, zidovudine, nabumetone, celecoxib, mefenamic acid, naproxen, propoxyphene, cimetidine, ranitidine, albendazole, mebendazole, thiobendazole, pyrazinamide, praziquantel, chlorpromazine, sumatriptan, bupropion, aminobenzoate, pyridostigmine bromide, potassium chloride, niacin, tocainide, quetiapine, fexofenadine, sertraline, chlorpheniramine, rifampin, methenamine, nefazodone, modafinil, metaxalone, morphine, sevelamer, lithium carbonate, flecainide acetate, simethicone, methyldopa, chlorthiazide, metyrosine, procainamide, entacapone, metoprolol, propanolol hydrochloride, chlorzoxazone, tolmetin, tramadol, bepridil, phenytoin, gabapentin, fluconazole, terbinafine, atorvastatin, doxepine, rifabutin,

mesalamine, etidronate, nitrofurantoin, choline magnesium trisalicylate, theophylline, nizatidine, methocarbamol, mycophenolate mofetil, tolcapone, ticlopidine, capecitabine, orlistat, colsevelam, meperidine, hydroxychloroquine, guaifenesin, guanfacine, amiodarone, quinidine, atomoxetine, felbamate, pseudoephedrine, carisoprodol, venlafaxine, etodolac, chondrotin, lansoprazole, pantoprazole, esomeprazole, dexlansoprazole, dexmethylphenidate, methylphenidate, sodium oxybate, valproic acid or its salts, divalproex, topiramate, carbamazepine, oxcarbazepine, and isotretinoin. The dose of any active ingredient depends upon the individual active ingredient used in the extended release suspension compositions of the present invention. Further, the extended release suspension compositions of the present invention permit ready dose titration, /'. e. , adjusting the dose of the active ingredient based on recommended dose range and frequency until the desired therapeutic effect is achieved. In particular, the active ingredients used in the present invention are active ingredients with a high dose.

The suspension base may additionally include an immediate release component of the active ingredient. However, the suspension base of the present invention does not include any saturated solution of the active ingredient. The suspension base may include an immediate release component of the active ingredient, wherein the active ingredient is present in an amount that does not exceed the amount required to form the saturated solution either initially or during storage. The active ingredient may be present in the form of a powder, a pellet, a bead, a spheroid, or a granule, or in the form of immediate release coating over the extended release coated cores. Alternatively, the amount of active ingredient may exceed the amount required to form the saturated solution. However, the saturated solution of active ingredient is not formed, as the release of active ingredient into the suspension base is prevented during storage. This is achieved by using a coating layer over the cores of the active ingredient, wherein the coating layer comprises a polymer that remain insoluble in the suspension base during storage and which releases the active ingredient in the immediate release form once ingested. Alternatively, this can also be done by using a complexation approach such as an ion-exchange resin complex, wherein the complex prevents any release of the active ingredient into the suspension base during storage, and releases the active ingredient only when exposed to the physiological conditions upon ingestion. The polymer can be a water-soluble polymer in which the release of active ingredient is prevented by using a high molar concentration of the solutes in the suspension base, wherein the solutes have a higher affinity towards water in

comparison to the polymer. Further, the polymer can be having a pH-dependent solubility in which the release of active ingredient is prevented by using a pre-adjusted pH of the suspension base such that the polymer does not get dissolved in the suspension base but get dissolved when exposed to the physiological conditions. For instance, acrylic polymers available under the trade mark Eudragit® E and Eudragit® EPO are soluble at an acidic pH. The pH of the suspension base can be pre-adjusted to a basic pH such that the coating does not get dissolved during storage but get dissolved in the stomach when ingested.

The immediate release component may help in providing an immediate therapeutic effect which could be subsequently followed by an extended therapeutic effect over a longer duration of time once ingested. Depending upon the type of polymer and percentage weight gain of the coating, the lag between the two phases can be adjusted to get the desired release profile.

Further, the extended release suspension composition of the present invention may comprise two or more similar or different active ingredients with different type of release profiles.

The extended release suspension composition of the present invention may also comprise two or more incompatible active ingredients present in a single composition. One of the active ingredients would be present in the form of coated cores providing the extended release and another incompatible active ingredient may be present in the form of a powder, a pellet, a bead, a spheroid, or a granule providing the immediate release or the extended release.

The extended release suspension compositions of the present invention are homogeneous which means the compositions provide the content uniformity and deliver the desired dose of the active ingredient in every use without any risk of overdosing or underdosing.

The release-controlling agents used to form the extended release coating are selected from a group comprising a pH-dependent release-controlling agent, a pH-independent release-controlling agent, or mixtures thereof. For an extended release coating comprising a pH-dependent release-controlling agent, the pH of the suspension base is pre-adjusted such that the coating remains insoluble in the suspension base during the storage. The extended release coating comprising a pH-dependent release-controlling agent may alternatively be coated with a coating layer comprising a polymer such that said coating layer remain insoluble in the suspension base during storage. The core may comprise release -controlling agents in the form of a matrix with the active ingredient, which can be coated with a coating layer that remain insoluble in the suspension base during storage.

Suitable examples of pH-dependent release-controlling agent are selected from the group comprising acrylic copolymers such as methacrylic acid and methyl methacrylate copolymers, e.g., Eudragit® L 100 and Eudragit® S 100, methacrylic acid and ethyl acrylate copolymers, e.g., Eudragit® L 100-55 and Eudragit® L 30 D-55,

dimethylaminoethyl methacrylate and butyl methacrylate and methyl methacrylate copolymers e.g., Eudragit® E 100, Eudragit® E PO, methyl acrylate and methacrylic acid and octyl acrylate copolymers, styrene and acrylic acid copolymers, butyl acrylate and styrene and acrylic acid copolymers, and ethylacrylate-methacrylic acid copolymer; cellulose acetate phthalate; cellulose acetate succinates; hydroxyalkyl cellulose phthalates such as hydroxypropylmethyl cellulose phthalate; hydroxyalkyl cellulose acetate succinates such as hydroxypropylmethyl cellulose acetate succinate; vinyl acetate phthalates; vinyl acetate succinate; cellulose acetate trimelliate; polyvinyl derivatives such as polyvinyl acetate phthalate, polyvinyl alcohol phthalate, polyvinyl butylate phthalate, and polyvinyl acetoacetal phthalate; zein; shellac; and mixtures thereof.

Suitable examples of pH-independent release-controlling agent are selected from the group comprising cellulosic polymers such as ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose, and carboxy methylcellulose; acrylic copolymers such as methacrylic acid copolymers, e.g., Eudragit® RS, Eudragit® RL, Eudragit® NE 30 D; cellulose acetate; polyethylene derivatives e.g., polyethylene glycol and polyethylene oxide; polyvinyl alcohol; polyvinyl acetate; gums e.g., guar gum, locust bean gum, tragacanth, carrageenan, alginic acid, gum acacia, gum arabic, gellan gum, and xanthan gum; triglycerides; waxes, e.g., Compritol®, Lubritab®, and Gelucires®; lipids; fatty acids or their salts/derivatives; a mixture of polyvinyl acetate and polyvinyl pyrrolidone, e.g., Kollidon® SR; and mixtures thereof.

The term "osmogent," as used herein, refers to all pharmaceutically acceptable inert water-soluble compounds that can imbibe water and/or aqueous biological fluids. Suitable examples of osmogents or pharmaceutically acceptable inert water-soluble compounds are selected from the group comprising carbohydrates such as xylitol,

mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, dextrose and raffinose; water-soluble salts of inorganic acids such as magnesium chloride, magnesium sulfate, potassium sulfate, lithium chloride, sodium chloride, potassium chloride, lithium hydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and sodium phosphate tribasic; water-soluble salts of organic acids such as sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, and sodium ascorbate; water-soluble amino acids such as glycine, leucine, alanine, methionine; urea or its derivatives; propylene glycol; glycerin; polyethylene oxide; xanthan gum; hydroxypropylmethyl cellulose; and mixtures thereof. Particularly, the osmogents used in the present invention are xylitol, mannitol, glucose, lactose, sucrose, and sodium chloride.

Suitable suspending agents are selected from the group comprising cellulose derivatives such as co-processed spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, carboxymethyl cellulose and its salts/derivatives, and microcrystalline cellulose; carbomers; gums such as locust bean gum, xanthan gum, tragacanth gum, arabinogalactan gum, agar gum, gellan gum, guar gum, apricot gum, karaya gum, sterculia gum, acacia gum, gum arabic, and carrageenan; pectin; dextran; gelatin; polyethylene glycols; polyvinyl compounds such as polyvinyl acetate, polyvinyl alcohol, and polyvinyl pyrrolidone; sugar alcohols such as xylitol and mannitol; colloidal silica; and mixtures thereof. Co-processed spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium have been marketed under the trade names Avicel® RC-501, Avicel® RC-581, Avicel® RC-591, and Avicel® CL-611. The suspending agent is present in an amount of not more than about 20% w/w, based on the total weight of the suspension base.

The term "pharmaceutically acceptable excipients," as used herein, refers to excipients that are routinely used in pharmaceutical compositions. The pharmaceutically acceptable excipients may comprise glidants, sweeteners, anti-caking agents, wetting agents, preservatives, buffering agents, flavoring agents, anti-oxidants, chelating agents, solubility enhancing agents, pH modifying agents, adsorbents, complexing agents, and combinations thereof.

Suitable glidants are selected from the group comprising silica, calcium silicate, magnesium silicate, colloidal silicon dioxide, cornstarch, talc, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, hydrogenated vegetable oil, and mixtures thereof.

Suitable sweeteners are selected from the group comprising saccharine or its salts such as sodium, potassium, or calcium, cyclamate or its salt, aspartame, alitame, acesulfame or its salt, stevioside, glycyrrhizin or its derivatives, sucralose, and mixtures thereof.

Suitable anti-caking agents are selected from the group comprising colloidal silicon dioxide, tribasic calcium phosphate, powdered cellulose, magnesium trisilicate, starch, and mixtures thereof.

Suitable wetting agents are selected from the group comprising anionic, cationic, nonionic, or zwitterionic surfactants, or combinations thereof. Suitable examples of wetting agents are sodium lauryl sulphate; cetrimide; polyethylene glycols;

polyoxyethylene-polyoxypropylene block copolymers such as poloxamers; polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate; sorbitan fatty acid esters such as sorbitan monostearate; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate; polyethylene glycol fatty acid esters such as polyoxyethylene monostearate; polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether; polyoxyethylene castor oil; and mixtures thereof.

We claim:

1. A method for preparing a stable extended release suspension composition comprising multiple coated cores of an active ingredient by using a suspension base, wherein the suspension base ensures substantially similar in-vitro dissolution release profile of the active ingredient upon storage of the suspension composition for at least seven days.

2. The method of preparation of claim 1, wherein the suspension base is characterized by having the features of:

(i) a viscosity in a range of about 500 cps to about 15,000 cps and

(ii) an osmolality of at least about 1 osmol/kg of the suspension base.

3. The method of preparation of claim 1, wherein the suspension base comprises:

(i) a suspending agent;

(ii) an osmogent; and

(iii) an aqueous vehicle.

4. The method of preparation of claim 1, wherein the stable extended release suspension composition is a suspension or a reconstituted powder for suspension.

5. The method of preparation of claim 1, wherein the coated core comprises a core of an active ingredient and a coating layer over said core comprising one or more release-controlling agents.

6. The method of preparation of claim 5, wherein the active ingredient is layered onto an inert particle to form the core.

7. The method of preparation of claim 6, wherein the inert particle is selected from the group comprising a non-pareil seed, a microcrystalline cellulose sphere, a dibasic calcium phosphate bead, a mannitol bead, a silica bead, a tartaric acid pellet, or a wax based pellet.

8. The method of preparation of claim 3, wherein the osmogent is selected from the group comprising carbohydrates such as xylitol, mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, dextrose and raffinose; water-soluble salts of inorganic acids such as magnesium chloride, magnesium sulfate, potassium sulfate, lithium chloride, sodium chloride, potassium chloride, lithium hydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and sodium phosphate tribasic; water-soluble salts of organic acids such as sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, and sodium ascorbate; water-soluble amino acids such as glycine, leucine, alanine, methionine; urea or its derivatives; propylene glycol; glycerin; polyethylene oxide; xanthan gum;

hydroxypropylmethyl cellulose; and mixtures thereof.

9. The method of preparation of claim 3, wherein the suspending agent is selected from group consisting of cellulose derivatives such as co-processed spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, carboxymethyl cellulose and its salts/derivatives, and microcrystalline cellulose; carbomers; gums such as locust bean gum, xanthan gum, tragacanth gum, arabinogalactan gum, agar gum, gellan gum, guar gum, apricot gum, karaya gum, sterculia gum, acacia gum, gum arabic, and carrageenan; pectin; dextran; gelatin; polyethylene glycols; polyvinyl compounds such as polyvinyl acetate, polyvinyl alcohol, and polyvinyl pyrrolidone; sugar alcohols such as xylitol and mannitol; colloidal silica; and mixtures thereof.

10. The method of preparation of claim 5, wherein the release-controlling agent is selected from the group comprising a pH-dependent release-controlling agent, a pH-independent release-controlling agent, or mixtures thereof.

11. The method of preparation of claim 10, wherein the pH-dependent release-controlling agent is selected from the group comprising acrylic copolymers such as methacrylic acid and methyl methacrylate copolymers, e.g., Eudragit® L 100 and

Eudragit® S 100, methacrylic acid and ethyl acrylate copolymers, e.g., Eudragit® L 100-55 and Eudragit® L 30 D-55, dimethylaminoethyl methacrylate and butyl methacrylate and methyl methacrylate copolymer e.g., Eudragit® E 100, Eudragit® E PO, methyl acrylate and methacrylic acid and octyl acrylate copolymers, styrene and acrylic acid copolymers, butyl acrylate and styrene and acrylic acid copolymers, and ethylacrylate -methacrylic acid copolymer; cellulose acetate phthalate; cellulose acetate succinates; hydroxyalkyl cellulose phthalates such as hydroxypropylmethyl cellulose phthalate; hydroxyalkyl cellulose acetate succinates such as hydroxypropylmethyl cellulose acetate succinate; vinyl acetate phthalates; vinyl acetate succinate; cellulose acetate trimelliate; polyvinyl derivatives such as polyvinyl acetate phthalate, polyvinyl alcohol phthalate, polyvinyl butylate phthalate, and polyvinyl acetoacetal phthalate; zein; shellac; and mixtures thereof.

12. The method of preparation of claim 10, wherein the pH-independent release-controlling agent is selected from the group comprising cellulosic polymers such as ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,

hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose, and carboxy

methylcellulose; acrylic copolymers such as methacrylic acid copolymers, e.g., Eudragit® RS, Eudragit® RL, Eudragit® NE 30 D; cellulose acetate; polyethylene derivatives e.g., polyethylene glycol and polyethylene oxide; polyvinyl alcohol; polyvinyl acetate; gums e.g., guar gum, locust bean gum, tragacanth, carrageenan, alginic acid, gum acacia, gum arabic, gellan gum, and xanthan gum; triglycerides; waxes, e.g., Compritol®, Lubritab®, and Gelucires®; lipids; fatty acids or their salts/derivatives; a mixture of polyvinyl acetate and polyvinyl pyrrolidone, e.g., Kollidon® SR; and mixtures thereof.

13. The method of preparation of claim 1, wherein the active ingredient is selected from the group comprising metformin, acarbose, miglitol, voglibose, repaglinide, nateglinide, glibenclamide, glimepride, glipizide, gliclazide, chloropropamide, tolbutamide, phenformin, aloglitin, sitagliptin, linagliptin, saxagliptin, rosiglitazone, pioglitazone, troglitazone, faraglitazar, englitazone, darglitazone, isaglitazone, zorglitazone, liraglutide, muraglitazar, peliglitazar, tesaglitazar, canagliflozin, dapagliflozin, remogliflozin, sergliflozin, verapamil, albuterol, salmeterol, acebutolol, sotalol, penicillamine, norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, trovafloxacin, gatifloxacin, cefixime, cefdinir, cefprozil, cefadroxil, cefuroxime, cefpodoxime, tetracycline, demeclocycline hydrochloride, amoxicillin, clavulanate potassium, azithromycin, losartan, irbesartan, eprosartan, valsartan, diltiazem, isosorbide mononitrate, ranolazine, propafenone, hydroxyurea, hydrocodone, delavirdine, pentosan polysulfate, abacavir, amantadine, acyclovir, ganciclovir, valacyclovir, valganciclovir, saquinavir, indinavir, nelfinavir, lamivudine, didanosine, zidovudine, nabumetone, celecoxib, mefenamic acid, naproxen, propoxyphene, cimetidine, ranitidine, albendazole, mebendazole, thiobendazole, pyrazinamide, praziquantel, chlorpromazine, sumatriptan, bupropion, aminobenzoate, pyridostigmine bromide, potassium chloride, niacin, tocainide, quetiapine, fexofenadine, sertraline, chlorpheniramine, rifampin, methenamine, nefazodone, modafinil, metaxalone, morphine, sevelamer, lithium carbonate, flecainide acetate, simethicone, methyldopa, chlorthiazide, metyrosine, procainamide, entacapone, metoprolol, propanolol hydrochloride, chlorzoxazone, tolmetin, tramadol, bepridil, phenytoin, gabapentin, fluconazole, terbinafine, atorvastatin, doxepine, rifabutin, mesalamine, etidronate, nitrofurantoin, choline magnesium trisalicylate, theophylline,

nizatidine, methocarbamol, mycophenolate mofetil, tolcapone, ticlopidine, capecitabine, orlistat, colsevelam, meperidine, hydroxychloroquine, guaifenesin, guanfacine, amiodarone, quinidine, atomoxetine, felbamate, pseudoephedrine, carisoprodol, venlafaxine, etodolac, chondrotin, lansoprazole, pantoprazole, esomeprazole, dexlansoprazole, dexmethylphenidate, methylphenidate, sodium oxybate, valproic acid or its salts, divalproex, topiramate, carbamazepine, oxcarbazepine, and isotretinoin.

14. The method of preparation of claim 3, wherein the suspension base further comprises one or more pharmaceutically acceptable excipients selected from the group comprising anti-caking agents, wetting agents, preservatives, buffering agents, flavoring agents, anti-oxidants, chelating agents, solubility enhancing agents, pH modifying agents, adsorbents, complexing agents, and combinations thereof.