DESC:The following specification describes nature of the invention and the manner in which it is to be performed:

EXTENDED RELEASE PHARMACEUTICAL FORMULATIONS COMPRISING ONDANSETRON HYDROCHLORIDE

BACKGROUND OF THE INVENTION
The present invention relates to an extended release pharmaceutical formulation comprising ondansetron and pharmaceutically acceptable salts thereof and at least one release rate controlling polymer and one or more other pharmaceutically acceptable excipients.

The present invention relates to extended release pharmaceutical formulations comprising ondansetron and its pharmaceutically acceptable salts and at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients for prevention of chemotherapy and radiation related nausea and emesis. Chemotherapy-induced nausea and vomiting (CINV) is a common side-effect of many cancer treatments. Nausea and vomiting are two of the most feared cancer treatment-related side effects for cancer patients and their families. Since the 1990s, several novel classes of antiemetics have been developed and commercialized, becoming a nearly universal standard in chemotherapy regimens, and helping to better manage these symptoms in a large portion of patients. Efficient management of these unpleasant and sometimes crippling symptoms results in increased quality of life and better overall health of the patient, and, due to better patient tolerance, more effective treatment cycles. Several treatment methods are available to help prevent CINV. 5-HT3 inhibitors, NK1 inhibitors and some neuroleptic drugs such as olanzapine are sometimes used as a therapy for treatment of CINV
Nausea and vomiting caused by radiation therapy (RT) are generally less severe than that caused by chemotherapy. However, these side effects are clinically important and can be distressing for patients. Furthermore, RT-induced nausea and vomiting (RINV) can cause patients to delay or refuse further treatment.
The 5-HT3 receptor antagonists are the primary drugs used to treat and prevent chemotherapy-induced nausea and vomiting (CINV) and radiotherapy-induced nausea and vomiting (RINV). Ondansetron is a selective 5-HT3 receptor antagonist. While its mechanism of action has not been fully characterized, ondansetron is not a dopamine-receptor antagonist.

Currently Ondansteron (HCl) is available in the US market as Zofran® as immediate release tablets, orally disintegrating tablets, oral solution and injection dosage forms from GlaxoSmithKline. There are also other dosage forms such as films.
Ondansetron hydrochloride (HCl) dihydrate, the racemic form of ondansetron is a selective blocking agent of the serotonin 5-HT3 receptor type. Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3[(2-methyl-1H-imidazol-1-yl) methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate. Ondansetron HCl dihydrate is a white to off-white powder that is soluble in water and normal saline. Ondansetron is well absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. Mean bioavailability in healthy subjects, following administration of a single 8-mg tablet, is approximately 56%. The administration regimen of Ondansetron IR tablets is 8mg tid. To improve patient compliance, it is preferred to design a extended release formulation which provides a constant rate of release through a 24hour period. At the same time, a reduction in the number of dosage units leads to better patient compliance. Hence design of extended release dosage forms of ondansetron hydrochloride is desired.
In the past, various successful polymeric sustained release preparations have been developed for release of drugs with different physical properties. Such preparations have been effective for sustaining the release rates for relatively hydrophobic and water-insoluble drugs. The predominant release mechanism in such dosage forms is initial drug erosion followed by slow diffusion through the polymer matrices.
US Patent Nos. 6,517,868 and 6,936,275 disclose oral extended release matrix dosage form for at least sparingly soluble active agent comprising a plurality of granules comprising a pharmaceutically active compound; at least one amino acid, an intragranular polymer and a hydrophilic extragranular polymer in which said granules are dispersed. The amino acid is a combination of at least two amino acids, one of which is moderately or strongly hydrophobic, the other of which is relatively more hydrophilic.
US Patent No. 7,229,642 also discloses oral extended release matrix dosage form for at least sparingly soluble active agent comprising a plurality of granules comprising a pharmaceutically active compound; at least one amino acid, an intragranular polymer and a hydrophilic extragranular polymer in which said granules are dispersed. The amino acid is a combination of at least two amino acids, one of which is moderately or strongly hydrophobic, the other of which is relatively more hydrophilic. This patent exemplifies several such amino acids and additionally claims that the extragranular polymer comprises said pharmaceutically active compound in an amount sufficient to deliver an initial therapeutic dose of said pharmaceutically active compound.
We have found that an extended release monolithic matrix tablet of ondansetron hydrochloride by the use of only one polymer in the intragranular portion or the same polymer in both the intra and extragranular portions of the tablet along with one or more amino acids provides an extended release of the active ingredient over a 24hour time period. This is a simple, cost effective approach to prepare extended release formulations of ondansetron hydrochloride that is capable of providing a extended drug release over a prolonged period of time. The present invention relates to providing extended release formulations of Ondansetron HCl for prolonged release of the drug over a 24hour time period.

SUMMARY OF THE INVENTION
In embodiments, the present invention relates to an extended release pharmaceutical formulation comprising ondansetron hydrochloride, at least one release rate controlling polymer and one or more other pharmaceutically acceptable excipients.
In embodiments, the present invention relates to an extended release monolithic matrix tablet comprising ondansetron hydrochloride which comprises intragranular and extragranular portions.
In embodiments, the present invention relates to an extended release monolithic matrix tablet comprising ondansetron hydrochloride, at least one release rate controlling polymer and one or more pharmaceutically acceptable excipients which include atleast one amino acid.
In embodiments, the present invention relates to an extended release monolithic matrix tablet comprising ondansetron hydrochloride, at least one release rate controlling polymer and atleast one amino acid in the intragranular portion.
In embodiments, the present invention relates to an extended release monolithic matrix tablet comprising ondansetron hydrochloride, at least one release rate controlling polymer in both the intragranular and extragranular portions and one or more other pharmaceutically acceptable excipients wherein the monolithic tablet does not include an amino acid in either the intragranular or the extragranular portions of the tablet.
In embodiments, the present invention relates to an extended release monolithic matrix tablet comprising ondansetron hydrochloride, at least one release rate controlling polymer and one or more other pharmaceutically acceptable excipients which includes atleast one amino acid wherein the same grade of the rate controlling polymer is present in the intragranular and extragranular portions of the tablet.
In embodiments, the present invention relates to an extended release monolithic matrix tablet comprising ondansetron hydrochloride, at least one release rate controlling polymer and one or more other pharmaceutically acceptable excipients which includes atleast one amino acid and an organic acid in the intragranular portion.

In embodiments, the present invention relates to an extended release monolithic matrix tablet comprising ondansetron hydrochloride, at least one release rate controlling polymer and one or more other pharmaceutically acceptable excipients wherein at least one release rate controlling polymer is selected from a group consisting of cellulose ethers, gums natural fats and their modified forms such as totally or partially hydrogenated castor oil and hydrogenated vegetable oil.
In embodiments, the present invention relates to an extended release monolithic matrix tablet comprising ondansetron hydrochloride, at least one release rate controlling polymer and one or more other pharmaceutically acceptable excipients which includes atleast one amino acid which include either a or ß amino acids or both.
In embodiments, the present invention relates to an extended release monolithic matrix tablet comprising ondansetron hydrochloride, atleast one release rate controlling polymer and one or more pharmaceutically acceptable excipients which includes atleast one amino acid and an organic acid.
In embodiments, the present invention relates to a process of preparation of an extended release monolithic matrix tablet comprising ondansetron hydrochloride, at least one release rate controlling polymer and one or more other pharmaceutically acceptable excipients, wherein the process is wet granulation.
In embodiments, the present invention relates to a wet granulation process of preparation of an extended release monolithic matrix tablet of ondansetron hydrochloride, wherein the process comprises the steps of:
a) Blending ondansetron hydrochloride, at least one release rate controlling polymer and one or more intra-granular pharmaceutically acceptable excipients;
b) Granulating the blend of step a) using a granulating solvent;
c) Drying and sifting the granules of step b);
d) Blending the granules of step c) with extra-granular excipients; and;
e) Compressing the blend of step d) into tablets or filling the blend of step e) into capsules.
In embodiments, the present invention relates to an extended release monolithic matrix tablets comprising ondansetron hydrochloride, at least one release rate controlling polymer and one or more other pharmaceutically acceptable excipients which includes atleast one amino acid for prevention of chemotherapy and radiation related nausea and emesis.

DETAILED DESCRIPTION

The present invention relates to an extended release pharmaceutical formulation comprising ondansetron hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients.
The term "extended release" refers to release of a drug from a formulation for an extended period of time, such as more than about 4 hours as determined using an in vitro dissolution method.
The extended release pharmaceutical formulations of the present invention may provide in-vivo drug release such that blood levels of the drug are maintained within the therapeutic range, i.e., at or above a minimum effective concentration (MEC) but below toxic concentrations over a extended period of time such as more than about 4 hours.
Ondansetron may be present in the form of any of its pharmaceutically acceptable salts, solvates, esters and derivatives thereof. Ondansetron is present as amorphous form, crystalline form, or mixtures thereof. In a preferred embodiment ondansetron is present as ondansetron hydrochloride. The dose of ondansetron hydrochloride may include from about 2 mg to about 50 mg.
The term “release rate controlling polymer” as used herein refers to any polymer which can alter or modify the drug release time, rate, and extent from a formulation in any manner, such as the drug release is obtained over an extended period of time such as more than about 4 hours.
The term ‘final blend’ refers to a blend of ingredients that provides the formulations of the present invention after a single processing step.
The term “monolithic matrix” refers to a tablet dosage form in which the active ingredient and the pharmaceutical excipients are intimately mixed and compressed into a single unit dosage form and does not contain any distinguishable portions.

Final blend of the present invention can be characterized for specific flow properties and compression characteristics.
In embodiments, the present invention relates to a extended release monolithic matrix tablet comprising ondansetron hydrochloride, at least one release rate controlling polymer and one or more other pharmaceutically acceptable excipients wherein the final blend has Hausner’s ratio of less than 1.
In embodiments, the present invention relates to an extended release monolithic matrix tablet comprising ondansetron hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein the final blend has compressibility index between15 to 20.
In embodiments, the present invention relates to an extended release monolithic matrix tablet comprising ondansetron hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients wherein the formulation is a compressed tablet comprising 2 mg to 50mg of ondansetron hydrochloride.
In embodiments, the release rate controlling polymer that is useful in preparing extended release formulations of the present invention is selected from a group consisting of cellulose ethers such as hydroxypropylmethyl cellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, carboxymethyl cellulose, polyvinylpyrrolidones such as cross-linked and non-crosslinked polyvinylpyrrolidone, polyethylene oxide, gums such as xanthan gum, guar gum and tragacanth, natural fats such as coconut, soya, cocoa and their modified forms such as totally or partially hydrogenated castor oil, hydrogenated vegetable oil, and any mixtures thereof.
In embodiments, the release rate controlling polymer that is useful in preparing extended release formulations of the present invention includes but not limited to, hydrophilic substances, hydrophobic substances, lipophilic substances, water soluble excipients, water insoluble excipients, pH dependent polymers, pH independent polymers, swelling polymers, non-swelling polymers, gelling polymers, non-gelling polymers, gums, waxes, oily substances, polyethylene glycol glycerides such as Gelucire® products, hydrogenated vegetable oils, alginic acid and alginates, acrylic and/or methacrylic acid polymers or copolymers, and the like, and any mixtures thereof.
Examples of release rate controlling polymer include without limitation thereto, polymers such as cellulose ethers like hydroxypropyl methylcellulose (hypromellose or HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose, ethylcellulose, carboxymethyl celluloses, polyvinylpyrrolidone like cross-linked and non-crosslinked polyvinylpyrrolidone, polyethylene glycol glycerides, polyethylene oxide, polyvinyl alcohol, polysaccharides such as glucan, carrageenan, scleroglucan, mannan, galactomannan, gellan, alginic acid and its derivatives such as sodium alginate, calcium alginate, propylene glycol alginate, polyaminoacids such as gelatin, polymethyl vinyl ether maleic anhydride, polymethacrylates such as copolymers of acrylic and methacrylic acid esters containing quaternary ammonium groups, acrylic acid polymers such as carbomer, cellulose acetate, and mixtures thereof.
Examples of lipophilic and hydrophobic substances that can be used in the present disclosure include, without limitation thereto, waxes such as carnauba wax, microcrystalline wax, beeswax, and polyethoxylated beeswax, gums such as xanthan gum, guar gum and tragacanth, natural fats such as coconut, soya, cocoa and their modified forms such as totally or partially hydrogenated castor oil, hydrogenated vegetable oil, fatty acid derivatives such as mono-, bi- and tri-substituted glycerides, phospholipids, glycerophospholipids, glyceryl palmitostearate, glyceryl behenate, glyceryl monostearate, diethyleneglycol palmitostearate, polyethyleneglycol stearate, polyethyleneglycol palmitostearate, polyoxyethylene-glycol palmitostearate, glyceryl monopalmitostearate, cetyl palmitate, fatty alcohols associated with polyethoxylate fatty alcohols, cetyl alcohol, stearic acid, saturated or unsaturated fatty acids and their hydrogenated derivatives, lecithin, cephalins, chitosan and derivatives thereof, sphingolipids, sterols such as cholesterol and its substituted derivatives, and mixtures thereof.
In embodiments, the extended release monolithic matrix tablet also includes other pharmaceutically excipients which include atleast one amino acid.
Useful amino acids are selected from the group consisting of a amino acids such as glycine, alanine, valine, leucine, iso-leucine, phenylalanine, proline, aspartic acid, glutamic acid, lysine, arginine, histidine, serine, threonine, cysteine, asparagine and glutamine. Exemplary ß-amino acids include ß-alanine.
In embodiments, the present invention relates to an extended release monolithic matrix tablet comprising ondansetron hydrochloride, atleast one release rate controlling polymer and one or more pharmaceutically acceptable excipients which includes atleast one amino acid and an organic acid.
Organic acids are used in pharmaceutical formulation as solubility enhancers and stabilizers. The commonly available pharmaceutically acceptable organic acids are fumaric acid, tartaric acid, citric acid, succinic acid, adipic acid, malic acid, maleic acid, lactic acid, or a mixture of one or more thereof.
Organic acids when triturated with Ondansetron hydrochloride enhance the solubility of the weakly basic drug. Amino acids in the composition exhibit a potential synergistic effect with the organic acid, in the situ solubilization of Ondansetron hydrochloride.
The organic and amino acids together possibly lower the pH of the microenvironment and may lower the surface tension within the swollen matrices thus enhancing the solubility of weakly basic drug Ondansetron within the gel domain. Furthermore, low ionic strength may impact additional solubilization via ‘salting-in’ phenomenon.
Auxiliary pharmaceutically acceptable excipients according to the present invention include, for example, any one or more of diluents, binders, stabilizers, lubricants and glidants that are useful in preparation of pharmaceutical formulations.
Various useful fillers or diluents include, but are not limited to, sugars such as lactose monohydrate, lactose anhydrous, mannitol, starches maize starch, corn starch, pregelatinized starches such as PCS PC10 from Signet Chemical Corporation and starch 1500 and cellulose derivatives such as crystalline cellulose and powdered cellulose. Examples of crystalline cellulose products include but are not limited to Ceolus™ KG801, Avicel™ PH101, PH102, PH301, PH302 and PH-F20, PH-112, microcrystalline cellulose 114, and microcrystalline cellulose 112. Other useful diluents include, but are not limited to, sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.

Various useful binders include, but are not limited to, hydroxypropylcellulose, also called HPC (e.g., Klucel™ LF and Klucel™ EXF), various grades of hydroxypropyl methylcellulose, also called hypromellose or HPMC (e.g., Methocel™ products), various grades, polyvinylpyrrolidone or povidone (such as grades K25, K29, K30, and K90), copovidone (e.g., Plasdone™ S 630), powdered acacia, gelatin, guar gum, carbomers (e.g., Carbopol® products), methylcellulose, polymethacrylates, and starches.
Useful lubricants include magnesium stearate, glyceryl monostearate, palmitic acid, talc, carnauba wax, calcium stearate, sodium stearate, sodium lauryl sulfate, magnesium lauryl sulfate, zinc stearate, polyoxyethylene monostearate, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid, and mixtures thereof.
One or more glidant materials, which improve the flow of powder blends, pellets, or mini-tablets, and minimize dosage form weight variations, can be used. Useful glidants include, but are not limited to, silicon dioxide, talc, and mixtures thereof.
In embodiments, the present invention relates to a process of preparation of extended release monolithic matrix tablet comprising ondansetron hydrochloride, at least one release rate controlling polymer and one or more other pharmaceutically acceptable excipients, wherein the process is wet granulation.
In embodiments, the present invention relates to a wet granulation process for preparation of a extended release monolithic matrix tablet comprising ondansetron hydrochloride, wherein the process comprises the steps of:
a) Blending ondansetron hydrochloride, at least one release rate controlling substance and one or more intra-granular pharmaceutically acceptable excipient;
b) Granulating the blend of step a) using granulating solvent;
c) Drying and sifting the granules of step b);
d) Blending the granules of step c) with extra-granular excipients; and;
e) Compressing the blend of step d) into tablets or filling the blend of step e) into capsules.

In embodiments of the current invention, extended release matrix tablets are prepared by sifting the active ingredient along with intragranular excipients such as a release rate controlling polymer, atleast one amino acid and an organic acid.
These ingredients are mixed and then granulated using a suitable granulating fluid. The granulation fluid may be water so that the process is aqueous granulation or it may be isopropyl alcohol and therefore non- aqueous granulation.
Following the granulation, the wet mass is milled using a suitable milling equipment and then dried.
The dried mass is then milled again to desired particle size of the granules to achieve proper flow.
The extragranular excipients which include diluents are then sifted and added to the blend from the above step and blended to form a pre-lubricated blend.
In some embodiments a part of the release rate controlling polymer is also added in the extragranular portion. Preferably the same grade of polymer that has been used in the intragranular portion is used.
The pre-lubricated blend is then finally blended with lubricants and glidants to achieve desirable flow and proper content uniformity.
This blend is then compressed on high speed tabletting machines to obtain compressed tablets of desired weight, size and hardness by the use of appropriate tooling and machine parameters.
The pharmaceutical formulation of the present invention may be further coated using a functional coating or a non-functional coating. The coating can be carried out using conventional techniques known to the art such as spray coating, compression coating, powder coating.

The pharmaceutical formulations of the present invention were subjected to in-vitro dissolution testing in a dissolution media. Rate and content of active ondansetron that is released from the formulations were determined using techniques such as high performance liquid chromatography (HPLC).

The extended release monolithic matrix tablets comprising ondansetron hydrochloride as per the present invention are cost-effective and also are easy to make on a commercial scale.

Various solvents can be used in the processes for preparation of pharmaceutical formulations of the present invention, include but are not limited to, water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, N,N-dimethylformamide, tetrahydrofuran, and mixtures thereof. These solvents can be used as granulating solvent and coating solvent.

In embodiments, the extended release monolithic matrix tablets comprising ondansetron hydrochloride, at least one release rate controlling substance and one or more other pharmaceutically acceptable excipients as per the present invention are intended for oral administration to a subject in need thereof.

In embodiments, the present invention relates to an extended release monolithic matrix tablet comprising ondansetron hydrochloride, at least one release rate controlling polymer and one or more other pharmaceutically acceptable excipients which includes atleast one amino acid for prevention of chemotherapy and radiation related nausea and emesis.
While this invention has been described with reference to specific embodiments, the scope of the invention is not limited to these embodiments alone. Further some of the embodiments are illustrated as working examples below and are meant to be representative only. The invention may be construed in any other forms and embodiments which may be understood and applied by a person skilled in the art within the scope of the present invention.

EXAMPLES
Example 1: Ondansetron Hydrochloride tablets containing amino acid(s) and rate controlling polymer in intragranular portion only
Ingredients mg/tab
1A 1B 1C
Core Tablets
Intragranular Portion
Ondansetron HCl dihydrate 30.00* 30.00* 30.00*
Microcrystalline cellulose PH 101
(AVICEL PH 101) 69.00 94.00 q.s.
Glycine 25.00 - 25.00
HPMC K100 M CR prem./HPMC K 15 M CR premium 150.00 150.00 -
HPMC/ Polyethylene oxide/Guar gum/ combination of either - - 90.00/150.00/168.00
Fumaric acid 120.00 120.00 -
Citric acid anhydrous - - 75.00
Granulation
Hot Water q.s. q.s. q.s.
Extragranular portion
Lactose 3.00 3.00 q.s.
Microcrystalline cellulose PH 102 (AVICEL PH 102) 30.00 30.00 -
Colloidal silicon dioxide 3.00 3.00
Magnesium stearate 4.50
Core Tablet Weight 430.00 430.00 430.00
Film Coating
Opadry 15.00 15.00 20.00
Purified water** q.s. q.s. q.s.
Total tablet weight 445.00 445.00 450.00
*30 mg of Ondansetron hydrochloride dihydrate is equiv. to 24 mg of Ondansetron (base)
**Does not appear in the final product

Example 2:
Ondansetron Hydrochloride tablets without amino acids

Ingredients mg/tab
2A 2B 2C
Core Tablet
Intragranular Portion
Ondansetron hydrochloride 30.00* 30.00* 30.00*
Citric acid anhydrous 75.00 75.00 75.00
Lactose monohydrate/ Microcrystalline cellulose/Maltodextrin /Combination q.s. q.s. q.s.
HPMC 30.00 - -
Extragranular portion
Polyethylene oxide 150.00 180.00 -
Guar gum - - 168.00
Purified water/Isopropyl alcohol** q.s. q.s. q.s.
Magnesium stearate 4.50 4.50 4.50
Core Tablet Weight 430.00 430.00 430.00
Film Coating
Opadry 20.00 20.00 20.00
Purified water** q.s q.s q.s
Total tablet weight 450.00 450.00 450.00
*30 mg of Ondansetron hydrochloride dihydrate is equiv. to 24 mg of Ondansetron (base)
**Does not appear in the final product

Example 3: Ondansetron Hydrochloride tablets containing amino acid and use of same grade of only one polymer in intragranular and extragranular portions

Ingredients mg/tab
Core Tablet
Intragranular components
Ondansetron hydrochloride 30.00*
Glycine/aspartic acid/iso leucine/combination 25.00
Citric acid anhydrous 75.00
HPMC/ Polyethylene oxide/Guargum# 90.00/150.00/168.00
Purified water/Isopropyl alcohol* q.s.
Extragranular portion
HPMC/ Polyethylene oxide/Guargum# q.s.
Magnesium stearate 4.50
Core Tablet weight 430.00 mg
Film coating
Opadry 20.00
Purified water** q.s.
Total tablet weight 450.00mg
*30 mg of Ondansetron hydrochloride dihydrate is equiv. to 24 mg of Ondansetron (base)
**Does not appear in the final product
,CLAIMS:WE CLAIM:
1. An extended release pharmaceutical formulation of ondansetron comprising ondansetron hydrochloride, at least one release rate controlling polymer and one or more other pharmaceutically acceptable excipients.
2. The extended release pharmaceutical formulation of ondansetron of claim 1 comprising at least one release rate controlling polymer is selected from a group consisting of cellulose ethers, gums natural fats and their modified forms such as totally or partially hydrogenated castor oil and hydrogenated vegetable oil.
3. The extended release pharmaceutical formulation of ondansetron of claim 1 comprising at least one organic acid and optionally amino acid(s).
4. The extended release pharmaceutical formulation of ondansetron of claim 1, wherein the pharmaceutical formulation is a monolithic tablet comprising intragranular and extragranular portions.
5. The extended release pharmaceutical formulation of ondansetron of claim 4, wherein the pharmaceutical formulation is prepared by wet granulation process.
6. The wet granulation process of claim 5 comprises the steps of:
f) Blending ondansetron hydrochloride, at least one release rate controlling polymer and one or more intra-granular pharmaceutically acceptable excipients;
g) Granulating the blend of step a) using a granulating solvent;
h) Drying and sifting the granules of step b);
i) Blending the granules of step c) with extra-granular excipients; and;
j) Compressing the blend of step d) into tablets or filling the blend of step e) into capsules
7. An extended release pharmaceutical formulation of ondansetron comprising ondansetron hydrochloride, wherein the formulation is as described and illustrated in the examples herein.