DESC:Field of the Invention:
The present invention relates to non-granulated, rapid release compositions comprising varenicline. The present invention also provides a process for the preparation of such compositions.

Background of the Invention:
Varenicline or 7, 8, 9, 10-tetrahydro-6, 10-methano-6H-pyrazino[2,3-h] [3] benzazepine is a nicotinic receptor partial agonist, which is associated with reduction of cravings and effects of cigarettes and other tobacco products. Varenicline is indicated for the treatment of smoking cessation. Varenicline is present in the form of a salt with L-tartaric acid (varenicline tartrate) in products commercially marketed as CHANTIX™ in the United States, and CHAMPIX™ in Europe and Canada. The commercially available products are in the form of tablets containing varenicline in doses of 0.5 mg and 1 mg. Varenicline tablets marketed commercially use the technique of dry granulation using roller compaction to arrive at immediate release tablets of varenicline.

U.S. Patent Publication No. 2006/0057207 relates to fast disintegrating dosage forms of varenicline wherein, when the said dosage form is placed in the patient’s oral cavity it comes in contact with the saliva in the cavity, and rapidly disintegrates and/or dissolves in the oral cavity. The said dosage forms are prepared by spray drying, freeze-drying, heat molding, sublimation, and thin film manufacture.

U.S. Patent Publication No. 2020/0276113 relates to orally administered pharmaceutical preparations containing varenicline, which when administered orally effectively mask the unique bitterness of varenicline and remove irritation during swallowing. The said orally administered pharmaceutical preparations of varenicline or a pharmaceutically acceptable salt thereof as an active ingredient, contain both an anionic polymer containing carboxyl groups and a cationic polymer containing amino groups as a bitter taste masking agent.

Indian Application No. 5066/CHENP/2010 and PCT Publication No. WO2009/111623 relates to amorphous varenicline tartrate, and solid dispersions of varenicline tartrate with a pharmaceutical carrier.

Indian Application No. 3179/CHE/2008 relates to co-precipitates comprising varenicline tartrate and povidone. The co-precipitates are prepared by dissolving varenicline tartrate and povidone in a solvent, and removing the solvent from the solution.

Although the simplest way of manufacturing capsules and tablets is to blend all the ingredients as dry powders, and fill the blend into capsules or compress the blend into tablets, this has been a big challenge for low dose, high potency drugs like varenicline, due to problems such as de-mixing, segregation of the powder blend during tablet compression/capsule filling, poor flow properties, loss of blend uniformity, loss content uniformity and poor compressibility. Hence, prior art cited above use techniques and technologies such wet granulation, dry granulation, spray drying, freeze-drying, heat molding, co-precipitation, and solid dispersions to address these challenges and to improve delivery of varenicline. Such techniques and technologies help in distributing the low dose drug evenly in the blend, resulting in adequate blend uniformity, content uniformity, compressibility, and dissolution.

It has surprisingly been found that the rapid release compositions of the present invention do not use any of the prior art approaches and yet achieve desired flow properties, blend uniformity, compressibility, content uniformity, dissolution, and storage stability.

The oral, rapid release compositions of the present invention, are in the form of non-granulated compositions, comprising varenicline at low concentrations of about 5% or less (by weight of the composition), and yet achieve the desired flow properties, compressibility, blend uniformity, content uniformity, dissolution, and storage stability.

OBJECTS OF THE INVENTION
The principal object of the present invention is to provide non-granulated, rapid release compositions of varenicline for oral administration.

Another object of the present invention is to provide non-granulated, rapid release compositions of varenicline, wherein varenicline is at a concentration of not more than 5% by weight of the composition.

Yet another object of the present invention is to provide non-granulated, rapid release compositions of varenicline with the desired flow properties.

Yet another object of the present invention is to provide non-granulated, rapid release compositions of varenicline with the desired compressibility.

Yet another object of the present invention is to provide non-granulated, rapid release compositions of varenicline, with the desired blend uniformity.

Yet another object of the present invention is to provide non-granulated, rapid release compositions of varenicline, with the desired content uniformity.

Yet another object of the present invention is to provide non-granulated, rapid release compositions of varenicline with the desired dissolution, wherein the average cumulative percentage dissolution of varenicline from the said compositions is not less than 80% in 30 minutes.

Yet another object of the present invention is to provide non-granulated, rapid release compositions of varenicline with the desired storage stability.

Yet another object of the present invention is to provide non-granulated, rapid release compositions of varenicline, wherein the composition is free of surfactant(s).

Yet another object of the present invention is to provide non-granulated, rapid release compositions of varenicline, wherein the composition is free of binder(s).

Yet another object of the present invention is to provide a process for preparation of the said non-granulated, rapid release compositions of varenicline.

SUMMARY OF THE INVENTION
The present invention relates to stable, oral, non-granulated, rapid release compositions of varenicline, comprising varenicline and at least one pharmaceutically acceptable excipient. The present invention also provides a process for the preparation of such compositions.

DETAILED DESCRIPTION OF THE INVENTION
The compositions of the present invention, for oral administration, are in the form of non-granulated, rapid release compositions of varenicline.

The term ‘oral’ or ‘oral administration’, as used herein, refers to the peroral route of administration, wherein the compositions are administered through the mouth and need to be swallowed. The swallowable compositions do not remain in the oral cavity for disintegration, dissolution, or drug delivery, but are designed for passage through the gastrointestinal tract and to act by drug absorption through the various epithelia and mucosa of the gastrointestinal tract.

The term ‘non-granulated’, as used herein, refers to a powder blend of varenicline and at least one excipient(s), the said powder blend capable of being directly compressed into tablets and/or filled into capsules. In the ‘non-granulated’ compositions, varenicline and/or excipient(s) are not subjected to processes of wet granulation, dry granulation, fluidized bed granulation, rapid mixer granulation, high-shear mixer granulation, centrifugal wet granulation, steam granulation, spray drying granulation, melt granulation, melt extrusion, freeze drying granulation, heat molding, thermal adhesion granulation, foam granulation, pneumatic dry granulation, sublimation granulation, moisture-activated dry granulation, roll compaction, slug compaction, co-milling, solvent evaporation, or co-precipitation.

‘Varenicline’ as used herein includes varenicline, and its pharmaceutically acceptable salts, hydrates, esters, derivatives or solvates thereof. Varenicline can be in crystalline and/or amorphous form. Examples of varenicline salts include but are not limited to hydrochloride, phosphate, tartrate, succinate, fumarate, citrate, mesylate, tosylate, oxalate, salicylate, and benzoate. Varenicline tartrate is the preferred salt. Varenicline tartrate in crystalline form is preferred.

The present invention provides rapid release compositions of varenicline, which are non-granulated. The non-granulated compositions of the present invention may be in the form of powder blend, directly compressed tablets, or capsules.

The non-granulated, rapid release compositions comprise varenicline at a concentration of not more than 5% by weight of the composition. Despite the low concentrations, the said compositions achieve the desired characteristics of flow properties, compressibility, blend uniformity, content uniformity, rapid dissolution, and storage stability.

The non-granulated, rapid release compositions comprise varenicline in concentrations ranging from about 0.05% to about 5%, preferably from about 0.08% to about 3%, more preferably from about 0.1% to about 2%, and most preferably from about 0.2% to about 1.5% by weight of the composition.

Varenicline used in the rapid release compositions has a particle size distribution wherein 90% by volume [d (0.9)] of varenicline particles have a particle size of about 1 micron to about 250 microns, preferably about 1 micron to about 200 microns, more preferably about 1 micron to about 175 microns, and most preferably about 1 micron to about 150 microns, as determined by the laser diffraction method (Malvern Master Sizer) using the water dispersion method.

Varenicline used in the rapid release compositions has a particle size distribution wherein 90% by volume [d (0.9)] of varenicline particles have a particle size of about 1 micron to about 100 microns, preferably about 1 micron to about 70 microns, more preferably about 1 micron to about 50 microns, and most preferably about 1 micron to about 40 microns, as determined by the laser diffraction method (Malvern Master Sizer) using the water dispersion method.

Varenicline used in the rapid release compositions has a particle size distribution wherein 50% by volume [d (0.5)] of varenicline particles have a particle size of about 1 micron to about 50 microns, preferably about 1 micron to about 40 microns, more preferably about 1 micron to about 30 microns, and most preferably about 1 micron to about 20 microns, as determined by the laser diffraction method (Malvern Master Sizer) using the water dispersion method.

In an embodiment, the varenicline used in the rapid release compositions has a particle size distribution wherein 50% by volume [d (0.5)] of varenicline particles have a particle size of about 1 micron to about 10 microns, and preferably about 1 micron to about 8 microns, as determined by the laser diffraction method (Malvern Master Sizer) using the water dispersion method.

Varenicline, used in the non-granulated, rapid release compositions, has a particle size distribution wherein 10% by volume [d (0.1)] of varenicline particles have a particle size of about 1 micron to about 15 microns, preferably about 1 micron to about 10 microns, more preferably about 1 micron to about 5 microns, and most preferably about 1 micron to about 2 microns, as determined by the laser diffraction method (Malvern Master Sizer) using the water dispersion method.

In an embodiment, the varenicline used in the rapid release compositions has a particle size distribution wherein 90% by volume [d (0.9)] of varenicline particles have a particle size of about 1 micron to about 100 microns, 50% by volume [d (0.5)] of varenicline particles have a particle size of about 1 micron to about 50 microns, and 10% by volume [d (0.1)] of varenicline particles have a particle size about 1 micron to about 15 microns, as determined by the laser diffraction method (Malvern Master Sizer) using the water dispersion method.

In an embodiment, the varenicline used in the rapid release compositions has a particle size distribution wherein 90% by volume [d (0.9)] of varenicline particles have a particle size of about 20 micron to about 50 microns, 50% by volume [d (0.5)] of varenicline particles have a particle size of about 2 micron to about 12 microns, and 10% by volume [d (0.1)] of varenicline particles have a particle size about 1 micron to about 4 microns, as determined by the laser diffraction method (Malvern Master Sizer) using the water dispersion method.

Varenicline, used in the non-granulated, rapid release compositions, when dried at 1000C for 3 hours, has a loss on drying (LOD) (by weight) of not more than 1.0%, preferably not more than 0.5%, and more preferably not more than 0.3%.

In one aspect, the rapid release, non-granulated compositions of the present invention comprise a powder blend of varenicline and at least one diluent.

In an aspect, the powder blends are further compressed into tablets and/or filled into capsules.

Diluent in the non-granulated, rapid release compositions is selected from water-soluble diluents, water-insoluble diluents or mixtures thereof. Water-soluble diluents are selected from mannitol, sorbitol, lactose, glucose, sucrose, maltodextrin, and mixtures thereof. Water-insoluble diluents are selected from microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, carboxymethylcellulose calcium, microfine cellulose, starch, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, and mixtures thereof.

In an embodiment, the non-granulated, rapid release compositions of varenicline comprise at least one water-insoluble diluent.

In one aspect of the invention, the diluent used in the non-granulated, rapid release compositions has a particle size such that more than 99% of the said diluent is smaller than 75 microns (more than 99% of the said diluent passes through a 200 mesh ASTM sieve [75 microns]), preferably smaller than 45 microns (more than 99% of the said diluent passes through a 325 mesh ASTM sieve [45 microns]), as determined by air jet sieve method). In an embodiment the said diluent is a water-insoluble diluent.

In another embodiment, the water-insoluble diluent used in the non-granulated, rapid release composition is dibasic calcium phosphate, and has a particle size such that more than 99.9% of the particles are smaller than 75 microns, and more than 99% of the particles are smaller than 45 microns.

In another aspect of the invention, the diluent used in the non-granulated, rapid release compositions has a particle size such that more than 90% of the said diluent is smaller than 250 microns (more than 90% of the said diluent passes through a 60 mesh ASTM sieve [250 microns]), as determined by air jet sieve method). In an embodiment the said diluent is a water-insoluble diluent.

In another aspect of the invention, the diluent used in the rapid release compositions has a particle size such that more than 45% of the said water-insoluble diluent is greater than 75 microns (more than 45% of the said diluent is retained on a 200 mesh ASTM sieve [75 microns]), as determined by air jet sieve method). In an embodiment the said diluent is a water-insoluble diluent.

In an embodiment, the water-insoluble diluent used in the non-granulated, rapid release composition is microcrystalline cellulose, and has a particle size such that more than 90% of the particles are smaller than 250 microns and less than 55% of the particles are smaller than 75 microns.

In an aspect the diluent used in the non-granulated, rapid release composition has a loss on drying (LOD) by weight (when dried at 1050C for 3 hours), of not more than 1.5%, preferably not more than 1.25%, and more preferably not more than 1%.

In another aspect the diluent used in the non-granulated, rapid release composition has a loss on ignition (LOI) by weight (ignition at 800°C– 825°C to constant weight), in the range of 5% to 8.5%, preferably 6% to 8%, and more preferably 6.5% to 7.5%.

In an embodiment, the non-granulated, rapid release compositions comprise at least two water-insoluble diluents.

In another embodiment, the non-granulated, rapid release compositions comprise at least two water-insoluble diluents, wherein the first diluent is microcrystalline cellulose and the second diluent is dibasic calcium phosphate.

In an aspect, the non-granulated, rapid release compositions comprise at least two diluents, wherein the first diluent has a particle size such that more than 99% of the said diluent is smaller than 75 microns, and the second diluent has a particle size such that more than 45% of the said diluent is greater than 75 microns. In an embodiment, both the diluents are water-insoluble diluents.

In another embodiment, the non-granulated, rapid release compositions comprise at least two diluents, wherein the first diluent is dibasic calcium phosphate, and the second diluent is microcrystalline cellulose.

In an embodiment, the non-granulated, rapid release compositions comprise at least two diluents, wherein the first diluent is dibasic calcium phosphate having a particle size such that more than 99.9% of the particles are smaller than 75 microns and more than 99% of the particles are smaller than 45 microns, and the second diluent is microcrystalline cellulose having a particle size such that more than 90% of the particles are smaller than 250 microns and more than 45% of the particles are greater than 75 microns.

In an embodiment, the non-granulated, rapid release compositions comprise a diluent having a particle size such that more than 99.9% of the particles are smaller than 75 microns and more than 99% of the particles are smaller than 45 microns, and a loss on ignition in the range of 5% to 8.5%. In an aspect of the embodiment the diluent is the water-insoluble diluent dibasic calcium phosphate.

In another embodiment, the non-granulated, rapid release compositions comprise a diluent having a particle size such that more than 90% of the particles are smaller than 250 microns and more than 45% of the particles are greater than 75 microns, and a loss on drying of not more than 1.5%. In an aspect of the embodiment the diluent is the water-insoluble diluent microcrystalline cellulose.

In another aspect of the embodiment, the non-granulated, rapid release compositions of varenicline comprise at least two diluents, wherein the weight ratio of the two diluents range from 1:0.1 to 1:2.5, preferably from 1:0.5 to 1:2.5, and more preferably from 1:0.5 to 1:2. In an embodiment, the diluent is a water-insoluble diluent selected from dibasic calcium phosphate, microcrystalline cellulose, and mixtures thereof.

In an aspect, the non-granulated, rapid release compositions are free of water-soluble diluents.

In another aspect, the non-granulated, rapid release compositions comprise a powder blend of varenicline, and at least one diluent, wherein the said compositions are free of binder(s) and/or surfactant(s).

The non-granulated, rapid release compositions comprise diluent(s) in total concentrations ranging from about 70% to about 99%, preferably from about 75% to about 98%, and more preferably from 80% to 95% by weight of the compositions.

In an embodiment the total concentration of diluent(s) is not less than 80% by weight of the composition. In another embodiment, the concentration of diluent(s) is not less than 85% by weight of the composition.

In one aspect, the rapid release, non-granulated compositions of the present invention comprise a powder blend of varenicline, at least one diluent, and at least one disintegrant. In an embodiment, the said powder blend is further compressed into tablets and/or filled into capsules.

Disintegrant(s) may be present in concentrations from about 1% to about 20% by weight of the composition and are selected from water-insoluble disintegrants such as sodium starch glycolate, croscarmellose sodium, starch, modified starch, pregelatinized starch, and crospovidone.

In one aspect, the rapid release, non-granulated compositions of the present invention comprise a powder blend of varenicline, at least one diluent, and at least one disintegrant, wherein the said composition is free of binder(s) and/or surfactant(s).

Lubricant(s) may be present in concentrations from about 0.25% to about 5% by weight of the composition and are selected from those known in the art such as magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, palmitic acid, and glyceryl behenate.

Glidant(s) may be present in concentrations from about 0.1% to about 10% by weight of the composition and are selected from those known in the art such as colloidal silicon dioxide, hydrated silicon dioxide, light anhydrous silicic acid, aluminum silicate, and talc.

The non-granulated, rapid release compositions may optionally be film coated with a film-coating layer comprising film-coating materials and optionally one or more pharmaceutically acceptable excipients selected from plasticizers, colorants, pigments, glidants, lubricants, and mixtures thereof. The film coating materials are selected from those known in the art.

The non-granulated, rapid release compositions may optionally be seal coated with a film-coating layer comprising seal-coating materials and optionally one or more pharmaceutically acceptable excipients selected from plasticizers, colorants, pigments, glidants, lubricants or mixtures thereof. The seal coating materials are selected from those known in the art.

In one embodiment, the non-granulated, rapid release compositions comprise a powder blend of varenicline, at least one diluent, at least one disintegrant, and at least one lubricant. In an aspect of the embodiment, the diluent is a water-insoluble diluent selected from dibasic calcium phosphate, microcrystalline cellulose, and mixtures thereof.

In another embodiment, the non-granulated, rapid release compositions comprise a powder blend of varenicline, at least two diluents, at least one disintegrant and at least one lubricant. In an aspect of the embodiment, the diluents are water insoluble diluents dibasic calcium phosphate and microcrystalline cellulose.

The non-granulated, rapid release compositions of the present invention comprise a powder blend that is prepared by a process comprising one or more of the following steps:
a) sifting diluent(s), and optionally other excipients such as disintegrant(s), lubricant(s), glidant(s) and/or lubricant(s);
b) co-sifting varenicline with diluent(s);
c) geometrically blending varenicline of step b) with diluent(s) and/or other excipients from step a), for upto 15 minutes;
d) re-sifting the mixture of step c);
e) re-blending the mixture of steps b), c) or d), for upto 15 minutes;
f) blending the mixture of steps c), d) or e) with lubricant(s), for upto 15 minutes, to give the powder blend;
g) optionally directly compressing the powder blend from step f) into tablets;
h) optionally filling the powder blend from step f) into capsules.

In an embodiment, the non-granulated, rapid release compositions comprise at least two water-insoluble diluents and is prepared by a process comprising one or more of the following steps:
a) co-sifting varenicline with a first water insoluble diluent(s);
b) sifting the second water insoluble diluent(s), disintegrant(s), glidant(s), and lubricant(s)
c) geometrically blending varenicline mixture of step a) with the sifted diluent(s), disintegrant(s) and/or glidant(s) of step b), for about 2-10 minutes;
d) sifting the mixture of step c) and blending it for about 2-10 minutes in a blender;
e) blending the mixture of step d) with lubricant(s) for about 2-10 minutes to give the powder blend;
f) optionally directly compressing the powder blend from step e) into tablets;
g) optionally filling the powder blend from step e) into capsules;

In one aspect, the flow properties and compressibility of the non-granulated, rapid release composition in the form of powder blend, was evaluated using the parameters of angle of repose, compressibility index and Hausner ratio, the said parameters being determined in accordance to the United States Pharmacopeia (USPNF-2021-Issue 1 <1174> Powder Flow).

The non-granulated, rapid release compositions comprise powder blends with a desired angle of repose of not more than 450, preferably not more than 400 and most preferably not more than 350.

The non-granulated, rapid release compositions comprise powder blends with a desired compressibility index of not more than 25%, preferably not more than 20% and most preferably not more than 15%.

The non-granulated, rapid release compositions comprise powder blends with a desired Hausner ratio of not more than 1.34, preferably not more than 1.25 and most preferably not more than 1.18.

The non-granulated, rapid release compositions of the present invention comprising a powder blend can further be directly compressed into tablets, or filled into capsules.

In another aspect, the compressibility of the non-granulated compositions was evaluated by determining the hardness and friability of the directly compressed tablets.

Hardness of the non-granulated, directly compressed tablets of the present invention was evaluated at periodic time intervals of the compression cycle (initial, middle and end), and at various compression speeds (low speed, optimum speed, high speed). The hardness of the said tablets was in the range of about 5 kilopond (kp) to about 25 kilopond (kp), preferably from about 7 kilopond (kp) to about 20 kilopond (kp), which was adequate for the product.

Friability testing of the non-granulated, directly compressed tablets of the present invention was evaluated in accordance to United States Pharmacopeia (USPNF-2021-Issue 1, <1216> Tablet Friability). Friability was determined using the Drum Friability Tester. Tablets equivalent to around 6.5g were carefully dusted before testing, and weighed. The tablets were placed in the drum of friability tester and rotated at the speed of 25 ± 1 rotations per minute for 4 minutes (100 rotations). After 100 rotations the tablets were de-dusted and re-weighed, and the friability percentage calculated. Acceptance criteria is that the loss in weight of the tablets, at the end of the test, should be not more that 1%.

In yet another aspect, the non-granulated, rapid release compositions were evaluated for varenicline content, blend uniformity, content uniformity, average cumulative % dissolution of varenicline, and total impurities.

Varenicline content (assay) in the non-granulated compositions, as determined by liquid chromatography, ranges from about 90% to about 110%, preferably from about 92.5% to about 107.5%, and most preferably 95% to about 105% of the label claim.

Blend Uniformity analysis was conducted on a powder blend by sampling (in triplicate) from three different locations from the top of the blender, three different locations from the middle of the blender and 4 different locations from the bottom of the blender, using a unit dose sampler. Acceptance criteria is that % varenicline content (assay) of individual sample is within 90% to 110% of the target content, the average % varenicline content of all the samples is within 95% to 105% of the target content, and the relative standard deviation of all samples is not more than 5%.

Content Uniformity analysis was conducted during tablet compression or capsule filling, by sampling (in triplicate) at 20 time-points which correspond to equally distributed time intervals during the tablet compression or capsule filling of the batch. Acceptance criteria is that the average % varenicline content in the sample, at each time-point, is within 90% to 110% of the target content, % varenicline content of individual sample at each time-point is from about 75% to about 125% of the target content, and the relative standard deviation for all samples is not more than 4%.

Disintegration of the non-granulated, rapid release compositions was evaluated using the parameter of ‘disintegration time’, which was determined in accordance to the United States Pharmacopeia (USPNF-2021-Issue 1 <701> Disintegration).

Disintegration time of the non-granulated, rapid release compositions was not more than 30 minutes, preferably not more than 15 minutes, more preferably not more than 10 minutes, and most preferably not more than 5 minutes.

Dissolution of varenicline from the non-granulated, rapid release compositions was studied in the following dissolution media and conditions:
i. Media 1: 500ml of 0.01N hydrochloric acid using USP – Type I (Basket) apparatus at 100rpm
ii. Media 2: 500ml of 0.1N hydrochloric acid using USP – Type I (Basket) apparatus at 100rpm
iii. Media 3: 500ml of acetate buffer pH 4.5 using USP – Type I (Basket) apparatus at 100rpm
iv. Media 4: 500ml of phosphate buffer pH 6.8 using USP – Type I (Basket) apparatus at 100rpm
v. Media 5: 500ml of water using USP – Type I (Basket) apparatus at 100rpm
Dissolution was calculated in terms of average cumulative percentage dissolution of varenicline at various time-points.

In an embodiment, the dissolution of varenicline, from the non-granulated, rapid release compositions, in 5 minutes, is from 70% to 110%, preferably from 75% to 110%, more preferably from 80% to 110%, and most preferably from 85% to 110%.

In an embodiment, the dissolution of varenicline, from the non-granulated, rapid release compositions, in 10 minutes, is from 75% to 110%, preferably from 80% to 110%, more preferably from 85% to 110%, and most preferably from 90% to 110%.

In another embodiment, the dissolution of varenicline, from the non-granulated, rapid release compositions, in 15 minutes, is from 80% to 110%, preferably from 85% to 110%, more preferably from 90% to 110%, and most preferably from 95% to 110%.

In another embodiment, the dissolution of varenicline, the non-granulated, rapid release compositions, in 30 minutes, is from 80% to 110%, preferably from 85% to 110%, more preferably from 90% to 110%, and most preferably from 95% to 110%.

Total impurities content in the non-granulated, rapid release compositions, as determined by liquid chromatography, is not more than 3%, preferably not more than 2.5%, more preferably not more than 2%, and most preferably not more than 1.5%.

In an embodiment, the content of total impurities in the non-granulated, rapid release compositions is not more than 1%, preferably not more than 0.75%

Storage stability of the non-granulated, rapid release compositions of the present invention was studied in one or more of the following conditions:
i) 400C ± 20C and 75% ± 5 % relative humidity (400C/75%RH)
ii) 300C ± 20C and 75% ± 5 % relative humidity (300C/75%RH)
iii) 250C ± 20C and 60% ± 5 % relative humidity (250C/60%RH)

After specific time-periods of storage, the compositions were analyzed for % varenicline content, % total impurities, and average cumulative % dissolution of varenicline.

The invention is now illustrated with non – limiting examples.

Example 1: Non-granulated powder blend of Varenicline Tartrate Varenicline tartrate (0.86%w/w) (LOD of 0.15%) and anhydrous dibasic calcium phosphate (100% of particles smaller than 75 microns; LOI of 7.18%) (33.5%w/w) were co-sifted through 40 mesh ASTM sieve to give a first blend. Microcrystalline cellulose (84.6% of particles greater than 75 microns, LOD of 1.1%) (60.64%w/w), croscarmellose sodium (3.0%w/w) and colloidal silicon dioxide (1.0%w/w) were sifted through 40 mesh ASTM sieve, and geometrically mixed with the first blend to give a second blend. The second blend was mixed for 5 minutes and sifted through 40 mesh ASTM sieve and blended again for about 20 minutes. Magnesium stearate (1.0%w/w) was sifted through 60 mesh ASTM sieve, and mixed with the second blend for about 5 minutes, to give the lubricated powder blend.

Flow Properties of the lubricated powder blend was evaluated, and was found to have a compressibility index of 23.8%, a Hausner ratio of 1.3, and an angle of repose of 400.

Blend uniformity analysis of 3 batches manufactured according to Example 1 was conducted on the lubricated powder blend. Percent varenicline content (assay) of individual sample met the acceptance criteria, and was within 90% to 110% of the target content. The location ‘average % varenicline content’ met the acceptance criteria, and was within 95% to 105% of the target content. The relative standard deviation calculated for the batches met the acceptance criteria, and was in the range of 0.8% to 2.13%.

The powder blend prepared in accordance with Example 1 was filled in HDPE bottles, and packed in triple laminate bags and LDPE transparent bags. The packs were subjected to storage stability studies at 400C/75%RH and 300C/75%RH. The results of the stability storage studies is provided in Table 1.

Table 1: Storage stability of Example 1 at 6 months at various conditions
Time Point [Months(M)] / Condition % Varenicline content % Total impurities
Initial 96.3 BQL
6M at 400C/75%RH 97.2 BQL
6M at 300C/75%RH 96.2 BQL
BQL = Below Quantification Limit

Example 2: Non-granulated tablets of Varenicline 0.5mg
Lubricated powder blend from example 1 was directly compressed into tablets, such that each tablet had a dose of 0.5mg of varenicline. The direct compression was done using capsular shaped, 8 mm by 4 mm, concave punch tooling. The compressed tablets were film-coated using Opadry® aqueous dispersions (containing hypromellose 6mPas, titanium dioxide, and macrogol) to a weight gain of about 5%w/w based on the weight of the core tablets. The film-coated tablets were further seal-coated using Opadry® aqueous dispersions (containing hypromellose 15mPas and triacetin) to a weight gain of about 3%w/w based on the weight of the film-coated tablets.

Content uniformity was evaluated for 3 batches of non-granulated, directly compressed, uncoated tablets, manufactured in accordance to Example 2. Average % varenicline content and individual tablet % varenicline content, at each time-point, met the acceptance criteria. The relative standard deviation calculated for the batches met the acceptance criteria, and was determined to be in the range of 1.7% to 2.7%.

Friability of the non-granulated, directly compressed tablets of Example 2, when evaluated at periodic time intervals of the compression cycle, was found to be not more than 0.5%.

Hardness of the non-granulated, directly compressed tablets of Example 2, when evaluated at periodic time intervals of the compression cycle, and at different compression speeds (low speed of 15 rpm; optimum speed of 25 rpm; high speed of 35 rpm), was found to be in the range of about 12 kp to about 17 kp.

Dissolution of varenicline from the seal coated tablets of Example 2 was studied in accordance with the media and conditions mentioned under Media 1 - 5. The average cumulative percentage dissolution of varenicline, in Media 1 - 5, was found to be
• not less than 85% in 5 minutes
• not less than 90% in 10 minutes
• not less than 94% in 15 minutes

Storage Stability study was conducted on the non-granulated, directly compressed tablet compositions prepared in accordance with Example 2 and packed in two packs:
i) PVC-PVDC blister
ii) HDPE Bottles (with a CR cap and induction seal)

The packs were stored at the following conditions:
i. 400C ± 20C and 75% ± 5 % relative humidity (400C/75%RH)
ii. 300C ± 20C and 75% ± 5 % relative humidity (300C/75%RH)
iii. 250C ± 20C and 60% ± 5 % relative humidity (250C/60%RH)

After storage for specific time intervals, the tablets were analyzed for % varenicline content, % total impurities, and average cumulative % dissolution of varenicline from the tablets, the results of which are given in Table 2.

Table 2: Storage stability of Example 2 at 6 and 24 months at various conditions
Time Point [Months(M)]
/ Condition % Varenicline content % Total impurities Average cumulative % dissolution
(30 minutes)
Initial 100.3 0 101
Blister Pack
6M at 400C/75%RH 97.5 1.12 98
6M at 300C/75%RH 99.7 0.44 99
24M at 300C/75%RH 96.0 1.41 99
6M at 250C/60%RH 101.4 0.30 99
24M at 250C/60%RH 99.5 0.62 102
Bottle Pack
6M at 400C/75%RH 97.4 0.83 101
6M at 300C/75%RH 98.0 0.33 103
24M at 300C/75%RH 97.9 0.85 100
6M at 250C/60%RH 97.9 0.28 101
24M at 250C/60%RH 99.5 0.52 102

Example 3: Non-granulated tablets of Varenicline Tartrate 1mg
Varenicline tartrate (0.855%w/w) (LOD not more than 0.5%) and anhydrous dibasic calcium phosphate (100% of particles smaller than 75 microns; LOI of 7.18%) (66.145%w/w) were co-sifted through 40 mesh ASTM sieve to give a first blend. Microcrystalline cellulose (84% of particles greater than 75 microns; LOD of 1.1%) (28.0%w/w), croscarmellose sodium (3.0%w/w) and colloidal silicon dioxide (1.0%w/w) were sifted through 40 mesh ASTM sieve, and geometrically mixed with the first blend to give a second blend. The second blend was mixed for 5 minutes and sifted through 40 mesh ASTM and blended again for about 20 minutes. Magnesium stearate (1.0%w/w) was sifted through 60 mesh ASTM sieve, and mixed with the second blend for about 5 minutes. The lubricated blend was directly compressed using capsular shaped, 10 mm by 5 mm, concave punch tooling. The compressed tablets were film-coated using Opadry® aqueous dispersions (containing hypromellose 6mPas, titanium dioxide, macrogol, and FD&C blue #2) to a weight gain of about 5%w/w based on the weight of the core tablets. The film-coated tablets were further seal-coated using Opadry® aqueous dispersions (containing hypromellose 15mPas and triacetin) to a weight gain of about 3%w/w based on the weight of the film-coated tablets.

Dissolution of varenicline from the seal coated tablets of Example 3 was studied in accordance with the conditions mentioned under Media 1. The average cumulative % dissolution of varenicline was determined to be not less than 95% in 5 minutes.

Example 4: Non-granulated tablets of Varenicline 1 mg
Lubricated powder blend from example 1 was directly compressed tablets, such that each tablet had a dose of 1.0 mg of varenicline. The direct compression was done using capsular shaped, 10 mm by 5 mm, concave punch tooling. The compressed tablets were film-coated using Opadry® aqueous dispersions (containing hypromellose 6mPas, titanium dioxide, macrogol, and FD&C blue #2) to a weight gain of about 5%w/w based on the weight of the core tablets. The film-coated tablets were further seal-coated using Opadry® aqueous dispersions (containing hypromellose 15mPas and triacetin) to a weight gain of about 3%w/w based on the weight of the film-coated tablets.

Content uniformity was evaluated for 3 batches of non-granulated, directly compressed, uncoated tablets, manufactured in accordance to Example 4. Average % varenicline content, and individual tablet % varenicline content, at each time-point, met the acceptance criteria. The relative standard deviation calculated for the batches met the acceptance criteria and was in the range of 1.6% to 1.8%.

Friability of the non-granulated, directly compressed tablets of Example 4, when evaluated at periodic time intervals of the compression cycle, was found to be not more than 0.03%.

Hardness of the non-granulated, directly compressed tablets of Example 4, when evaluated at periodic time intervals of the compression cycle, and at different compression speeds (low speed of 15 rpm; optimum speed of 25 rpm; high speed of 35 rpm), was found to be in the range of about 12 kp to about 20 kp.

Dissolution of varenicline from the seal coated tablets of Example 4 was studied in accordance with the conditions mentioned under Media 1 - 5. The average cumulative percentage dissolution of varenicline, in Media 1 - 5, was found to be not less than 85% in 5 minutes of dissolution.

Storage Stability of the non-granulated, directly compressed, tablet compositions, prepared in accordance with Example 4, was studied in the following packs:
i) PVC-PVDC blister
ii) HDPE Bottles (with a CR cap and induction seal)

The packs were stored at the following conditions:
i) 400C ± 20C and 75% ± 5 % relative humidity (400C/75%RH)
ii) 300C ± 20C and 75% ± 5 % relative humidity (300C/75%RH)
iii) 250C ± 20C and 60% ± 5 % relative humidity (250C/60%RH)

After storage for specified time intervals, the tablets were analyzed for % varenicline content, % total impurities and average cumulative % dissolution of varenicline from the tablets, the results of which are given in Table 3.

Table 3: Storage stability of Example 4 at 6 and 24 months at various conditions
Time Point [Months(M)]
/ Condition % Varenicline content % Total impurities Average cumulative % dissolution
(30 minutes)
Initial 98.0 0 100
Blister Pack
6M at 400C/75%RH 94.5 0.84 97
6M at 300C/75%RH 97.4 0.21 98
24M at 300C/75%RH 94.9 0.99 96
6M at 250C/60%RH 97.2 0.13 98
24M at 250C/60%RH 97.2 0.32 100
Bottle Pack
6M at 400C/75%RH 96.1 0.56 97
6M at 300C/75%RH 96.4 0.20 98
24M at 300C/75%RH 97.0 0.22 99
6M at 250C/60%RH 96.5 0.11 97
24M at 250C/60%RH 96.7 0.54 99

Thus, the non-granulated, rapid release, tablet compositions of the present invention, comprising varenicline at concentrations of not more than 5%, was found to provide the desired flow properties, compressibility, blend uniformity, content uniformity, hardness, and friability. The non-granulated compositions provide rapid release (dissolution), and were found to be storage stable for a period of at least 24 months. ,CLAIMS:WE CLAIM

1. A stable, oral, non-granulated, rapid release composition comprising varenicline and at least one excipient.

2. The non-granulated composition as claimed in claim 1, wherein varenicline used in the composition is in the form of varenicline tartrate having a particle size such that 90% by volume [d (0.9)] of particles have a size of 1 micron to 250 microns.

3. The non-granulated composition as claimed in claim 1, wherein the excipient is selected from diluents, disintegrants, lubricants, glidants, and mixtures thereof.

4. The non-granulated composition as claimed in claim 3, wherein the diluent(s) is a water-insoluble diluent selected from dibasic calcium phosphate, microcrystalline cellulose, and mixtures thereof.

5. The non-granulated composition as claimed in claims 4, wherein the composition comprises two water-insoluble diluents in a weight ratio of ranging from 1:0.1 to 1:2.5.

6. The non-granulated composition as claimed in claims 3, wherein the diluent(s) is present in a total concentration of 70% to 99% by weight of the composition.

7. The non-granulated composition as claimed in claim 3, wherein the disintegrant(s) is a water-insoluble disintegrant selected from sodium starch glycolate, croscarmellose sodium, starch, modified starch, pregelatinized starch, crospovidone, and mixtures thereof.

8. The non-granulated composition as claimed in claim 1, wherein the composition is free of binder(s) and surfactant(s).
9. The non-granulated composition as claimed in claim 1 wherein the composition is in the form of powder blend, directly compressed tablets, or capsules.

10. The non-granulated composition of claim 1, wherein the composition comprises at least two water-insoluble diluents, and is prepared using the following process steps:
a) co-sifting varenicline with a first water insoluble diluent;
b) sifting a second water insoluble diluent, disintegrant(s), glidant(s), and lubricant(s)
c) geometrically blending varenicline mixture of step a) with the sifted diluent, disintegrant(s) and/or glidant(s) of step b);
d) sifting the mixture of step c) and blending it for 2-10 minutes in a blender;
e) blending the mixture of step d) with lubricant(s) from step b), to give a powder blend;
f) optionally directly compressing the powder blend from step e) into tablets;
g) optionally filling the powder blend from step e) into capsules;
wherein the concentration of varenicline is 0.05% to 55 by weight of the composition and
wherein the total concentration of water-insoluble diluent(s) is 75% to 98% by weight of the composition.