Stable pharmaceutical lozenge compositions of varenicline tartrate

Abstract

The present invention relates to the pharmaceutical lozenge compositions of varenicline or its pharmaceutically acceptable salts thereof, wherein the size of the lozenge dosage form is small and disintegrates slowly in the buccal cavity. It provides the use of the lozenge formulations of varenicline or its pharmaceutically acceptable salts thereof, for the treatment of smoking cessation. The present invention also results in the pharmaceutical composition of Varenicline Tartrate comprising the nitrosamine impurities within the daily acceptable limit of 200 ppm, preferably in the range below 30ppm.

Description

[0001] STABLE PHARMACEUTICAL LOZENGE COMPOSITIONS OF VARENICLINE TARTRATE

[0002] FIELD OF THE IN VENTION

[0003] The present invention relates to the stable pharmaceutical lozenge compositions of varenicline or its pharmaceutically acceptable salts thereof and provides the use of the lozenge formulations of varenicline or its pharmaceutically acceptable salts thereof, for the treatment of smoking cessation.

[0004] BACKGROUND OF THE INVENTION;

[0005] Varenicline is a selective alpha4-beta2 nicotinic receptor partial agonist. It works by competitively inhibiting the ability of nicotine to bind to and activate the alpha-4 beta-2 receptor. The drug exerts mild agonistic activity at this site, though at a level much lower than nicotine; it is presumed that this activation eases withdrawal symptoms.

[0006] Varenicline tartrate is chemically known as 7,8,9, 10-tetrahydro-6, 10-methano-6H-pyrazino[2,3-h][3] benzazepine, (2R,3R)-2,3 dihydroxy butane dioate (1:1) is indicated for the treatment of smoking cessation. The structural formula is depicted as follows:

[0007]

[0008] Varenicline compound is generically disclosed in U. S. Patent No. 6410550 and U. S. Patent No. 6890927 specifically disclose tartrate salt. U. S. Patent Nos. 7265119, 6787549, and 6794388 disclose various crystalline polymorphic forms of varenicline tartrate, citrate, and succinate salts.

[0009] At present, the U. S. Food and Drug Administration (FDA) has recognized seven nitrosamine impurities that could potentially be found in pharmaceutical products as a result of manufacturing iprocesses and materials that may facilitate nitrosamine formation: N,N-dimethylnitrosamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitroso-N-methyl-4-aminobutyric acid (NMBA), N-nitrosoisopropylethylamine (NIPEA), N-nitrosodiisopropylamine (NDIPA), N-nitrosodibutylamine (NDBA), and N-nitrosomethylaniline (NMPA). Among these, five impurities (NDMA, NDEA, NMBA, NIPEA, and NMPA) have been confirmed to exist in active pharmaceutical ingredients (APIs) or finished products.

[0010] Varenicline tartrate which is marketed under the brand name Chantix® film-coated tablets of 0.5 mg and 1 mg, has been approved for the treatment of smoking cessation. Chantix® film-coated tablets contain varenicline tartrate along with the following inactive ingredients included in the tablets: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate. However, Chantix® was withdrawn from the market due to undesirable impurity levels exceeding the FDA-acceptable limit. Recently, the USFDA has revised the acceptable nitrosamine impurity level, especially for varenicline tartrate to 200ppm. However, it is always desirable to minimise the impurity levels to the possible extent.

[0011] Therefore, there is an unmet essential need for high-purity and stable compositions of varenicline tartrate with desirable potency with acceptable impurity levels. In our approach, the present invention provided a stable pharmaceutical lozenge composition of varenicline or pharmaceutically acceptable salts thereof, where the lozenges dosage form offers various advantages over the conventional tablet dosage form, having more stability’ and acceptable impurity levels.

[0012] A few references W02006100595 A2, W02006072832, and W02006040680 attempted various dosage forms of varenicline and its pharmaceutically acceptable salts, however, they haven’t disclosed any specific lozenge formulation of varenicline tartrate with acceptable impurity levels.

[0013] SUMMARY OF THE INVENTION

[0014] In one aspect of the present invention provi des a lozenge dosage compositi on of varenicline including an effective amount of varenicline or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. More preferably, the size of the lozenge dosage form is small and disintegrates slowly in the buccal cavity.Another aspect of the present invention provides a lozenge dosage composition of varenicline including an effective amount of varenicline or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. More preferably, the composition of the lozenge dosage form is more stable and includes the polyols as excipients, wherein the polyols are non-sugar and act as low-level antioxidants.

[0015] In yet another aspect of the present invention provides a method for reducing nicotine addiction, aiding in the cessation of, or lessening of, tobacco use in a subject by administering to the subject an effective amount of the lozenge dosage form of varenicline or pharmaceutically acceptable salts thereof. Additionally, the present invention provides a method of treating a disorder or condition by administering an effective amount of the lozenge dosage form of varenicline.

[0016] In yet another aspect of the present invention provides various methods of manufacturing or formulating a stable lozenge dosage form of varenicline or a pharmaceutically acceptable salt thereof.

[0017] DETAIL DESCRIPTION OF THE INVENTION

[0018] The present invention has numerous embodiments. In any of the embodiments, varenicline or any of its pharmaceutically acceptable salts, solvates and / or hydrates can be used.

[0019] According to one embodiment of the present invention, a stable pharmaceutical lozenge dosage composition of varenicline or its pharmaceutically acceptable salts thereof is provided, wherein the size of the lozenge dosage form is small and disintegrates slowly in the buccal cavity.

[0020] According to another embodiment of the present invention, a pharmaceutical lozenge dosage composition of varenicline or its pharmaceutically acceptable salts thereof is provided, wherein the composition of the lozenge dosage form is more stable and includes the polyols as excipients, wherein the polyols are non-sugar and act as low-level antioxidants.

[0021] According to another embodiment of the present invention, the unit dose of varenicline in the stable pharmaceutical lozenge dosage composition of varenicline tartrate is 0.1 mg to 10 mg, preferably 0.5 mg to 5 mg, most preferably 0.5 mg or 1 mg (wherein mg refers to mg of active drug based on the free base form of the drug).According to any of the embodiments of the present invention, the drug percentage concentration of the lozenge dosage composition of varenicline tartrate is about 0.1% to 10% of varenicline base as tartrate, preferably about 0.1% to 5%, more preferably about 0.1% to 1%, and most preferred is about 0.1% to 6% w / w.

[0022] According to any of the embodiments of the present invention, the stable pharmaceutical composition of varenicline tartrate is a compressed lozenge dosage form, preferably, the size of the stable pharmaceutical lozenge dosage composition of varenicline tartrate is small.

[0023] According to any of the embodiments of the present invention, the weight of the stable pharmaceutical lozenge dosage composition of varenicline tartrate is small, preferably 50 mg to 500 mg, preferably 50 mg to 400 mg, preferably 100 mg to 400 mg, or more preferably 100 mg.

[0024] According to any of the embodiments of the present invention, the weight of the stable pharmaceutical lozenge dosage composition of varenicline tartrate for compressing a Img strength unit dose of varenicline tartrate (equivalent to base) is about 200 to 500 mg, preferably at about 200 to 400 mg, preferred at about 300 mg.

[0025] According to any of the embodiments of the present invention, the weight of the stable pharmaceutical lozenge dosage composition of varenicline tartrate for compressing a 0.5mg strength unit dose of varenicline tartrate (equivalent to base) is about 50 to 400 mg, preferably at about 100 to 250 mg, preferred at about 150 mg.

[0026] According to any of the embodiments of the present invention, the unit total weight of the stable pharmaceutical lozenge dosage composition of varenicline tartrate is about one-quarter that of a conventional lozenge, such as a COMMIT®, the nicotine lozenge having a total weight of about 1.2 gram.

[0027] According to any of the embodiments of the present invention, the active amalgam of the stable lozenge dosage composition generally includes one or more pharmaceutically acceptable excipients, preferably the excipients include but are not limited to diluents, fillers, solubilizers, stabilizers, binders, disintegrants, surfactants, lubricants, colorants, flavors, sweeteners, solvents, glidants, or mixtures thereof.

[0028] According to any of the embodiments of the present invention, the active amalgam of the stable lozenge dosage composition generally includes one or more pharmaceutically acceptableexcipients, preferably the percentage concentration of excipients is about 30% to 99.9% of the lozenge composition, preferably the stabilizers or binders are about 10 to 30%, disintegrants are about 0.5 % to 10%, lubricants are about 0.05 % to 5%, flavors and sweeteners are about 0.5 % to 10 %.

[0029] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate comprises one or more stabilizers, one tastemasking polymer together with non-sugar ingredients of polyols or their co-processed excipients of the polyols.

[0030] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate comprises the excipients of non-sugar ingredients of polyols or its co-processed excipients of the polyols, preferably mannitol, xylitol, maltitol or its co-processed excipients of mannitol like mannitol with starch, mannitol with hydroxy propyl methyl cellulose, mannitol with microcrystalline cellulose, or a combination thereof.

[0031] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate comprises the percentage concentration of excipients of non-sugar ingredients of polyols or its co-processed excipients of the polyols is about 10% to 90%, preferably 40% to 80%, more preferably 50% to 75% of the total lozenge composition.

[0032] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate comprises the excipients of non-sugar ingredients of polyols or its co-processed excipients of the polyols acts as low-level antioxidants, but not as a pure antioxidant.

[0033] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate comprises the excipients of non-sugar ingredients of polyols or its co-processed excipients are used to a great extent as noncariogenic additives and carriers, inter alia for pharmaceutically active compounds, tablets to be chewed and sucked. Polyols are generally produced by hydrogenation of their underlying sugars. In solid form, they can be obtained both by crystallization and by spray-drying, the particular advantage of some polyols is that they are also suitable for direct pressing without further aids and additives.According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate comprises the excipients of non-sugar ingredients of polyols or their co-processed excipients of the polyols, wherein the co-processed excipients are generally regarded as safe “GRAS” status because of the absence of significant chemical change and there is no need to perform the toxicological assessment.

[0034] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate comprises one or more stabilizers, selected from glycine, beta-cyclodextrin, maltodextrin, benzoic acid, acacia, guar gum, xanthan gum, alginic acid, sodium alginate, dextrin, carbomer, maltodextrin, methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl betadex, hydroxypropyl cellulose (HPC) (e.g., KLUCEL®), hydroxypropyl methylcellulose (HPMC) (e.g., METHOCEL®), hydroxyethyl methyl cellulose, carboxymethyl cellulose sodium, cottonseed oil, povidone (various grades of KOLLIDON®, PLASDONE®), ceratonia, dextrose, polydextrose, starch, gelatin, pregelatinized starch, hydrogenated vegetable oil type I, maltodextrin, microcrystalline cellulose, polyethylene oxide, polymethacrylates and mixtures thereof; preferably selected from glycine, beta-cyclodextrin, or maltodextrin and mixtures thereof.

[0035] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate comprises one or more stabilizers, the percentage concentration of stabilizers is about 10% to 50% of the lozenge composition, preferably the stabilizers are about 10 to 40%, more preferably 10 to 25% of the lozenge composition.

[0036] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate comprises one or more lubricants, preferably selected from magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated vegetable oil, light mineral oil, polyethylene glycol, poloxamer, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, combinations thereof, more preferably magnesium striate.

[0037] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of vareni cline tartrate comprises one or more lubricants, the percentage concentration of lubricants is about 0.05 % to 5%, preferably 0.1% to 3%, most preferred is about 0.25% to 0.75%.According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate comprises one or more disintegrant selected from hydroxypropyl starch, alginic acid, calcium alginate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, powdered cellulose, chitosan, colloidal silicon dioxide, croscarmellose sodium, crospovidone, docusate sodium, guar gum, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, magnesium aluminium silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, povidone, sodium alginate, sodium starch glycolate, starch, and pregelatinized starch. In one embodiment, the preferred disintegrant is croscarmellose sodium.

[0038] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate comprises a disintegrant, the percentage concentration of disintegrant is about 0.5 % to 10%, preferably 1% to 5%, most preferred is about 1% to 2%.

[0039] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate may comprise a flavor, preferably the flavors can be selected from any of the volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems, combinations thereof.

[0040] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate comprises a flavor, the percentage concentration of flavor is about 0.5 % to 10%, preferably 1% to 5%, most preferred is about 1% to 2%.

[0041] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate may comprise sweeteners selected from maltitol (e.g., hydrogenated starch hydrolysates; e.g., Lycasin® 80 / 55, Roquette), xylitol (Xylisorb 300®), sucralose, aspartame, steviol glycosides (e.g., Stevia®, Truvia®), thaumatin (e.g., Talin®), glycyrrhizic acid salts (MagnaSweet®), mannitol, or combinations thereof. In preferred embodiment, the sweetener comprises sucralose, sucrose, xylitol, or combinations thereof.

[0042] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate optionally comprises a sweetener, the percentageconcentration of sweetener is about 0.5 % to 10%, preferably 1% to 5%, most preferred is about 1% to 2%.

[0043] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate may comprise fillers such as mannitol.

[0044] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate optionally comprises a filler, wherein the percentage concentration of filler is about 10% to 60%, preferably 15% to 50%, and most preferred is about 15% to 35%.

[0045] According to any of the embodiments, the stable pharmaceutical lozenge dosage composition can be formulated without stabilizers such as glycine or P-cyclodextrin.

[0046] According to any of the embodiments, the stable pharmaceutical lozenge dosage composition can be formulated without stabilizers such as glycine or P-cyclodextrin, with the proviso that if stabilizers are not used in the composition, the quantity of fillers, such as mannitol (Pearlitol 200SD) should be adjusted to the final lozenge composition on a %w / w.

[0047] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate optionally comprises nitrosamine impurity.

[0048] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate optionally comprises nitrosamine impurity, wherein the nitrosamine impurity level is below 50ppm, which is far below the daily limit of nitrosamine level.

[0049] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate optionally comprises nitrosamine impurity, wherein the nitrosamine impurity level is below 30 ppm.

[0050] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate optionally comprises nitrosamine impurity, wherein the nitrosamine impurity level is stable and is below 30 ppm, under 6-month stability conditions.According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline or pharmaceutically acceptable salts thereof, comprising:

[0051] a) Varenicline tartrate: 0.568%

[0052] b) Stabilizers: 10-20%

[0053] c) Non-sugar polyols or their co-pressed excipients: 40 to 60%

[0054] d) Fillers: 15 to 20%

[0055] e) Diluents: 4 to 6%

[0056] Lubricants: 0.2 to 1.5%,

[0057] and other pharmaceutically acceptable excipients.

[0058] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline or pharmaceutically acceptable salts thereof, comprising:

[0059] a) Varenicline tartrate: 0.568%

[0060] b) Stabilizers: 1-5%

[0061] c) Non-sugar polyols or their co-pressed excipients: 40 to 60%

[0062] d) Fillers: 25 to 40%

[0063] e) Diluents: 4 to 6%

[0064] f) Lubricants: 0.2 to 1.5%,

[0065] and other pharmaceutically acceptable excipients.

[0066] According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate can be prepared by utilizing a common granule approach for both the strengths of 1.0 and 0.5mg. In the preferred embodiment, wet or dry or spray granulation processes were utilized, with the most preferred spray granulation processes.

[0067] According to any of the embodiments of the present invention, spray-drying is a widely used process in the pharmaceutical industry and can be used to produce highly porous compositions of varenicline. Spray-dried varenicline, as its free base or its suitable salt derivatives, is combined with excipients depicted in one or more aforesaid embodiments.According to any of the embodiments of the present invention, the stable pharmaceutical lozenge dosage composition of varenicline tartrate can be prepared by the process comprising: a) preparation of the binding solution by taking a solvent mix of isopropyl alcohol and purified water, added Varenicline tartrate, glycine, beta-cyclodextrin, maltodextrin, and benzoic acid heating the binder solution at 50-60 °C to get the almost clear thick solution. Use this binder solvent mix. For conventional wet binding or spray granulation in a suitable fluid bed processor.

[0068] b) The common granules approach used in the present formulations is prepared through wet or dry or spray granulation processes. In one embodiment, the spray granulation technique is employed, wherein all polyols along with sweetener are taken for fluid bed granulation. After spray granulation the granules dried in a fluid bed stream to moisture below 2.5% but not more than 3.0%. The dried and suitably sized granules are blended in a suitable blender with ingredients such as disintegrants, lubricants and optionally a flavor can be added. The lubricated granules are compressed on a rotary tablet compression machine to get the lozenge composition.

[0069] According to any of the embodiments of the present invention, there is provided use of stable pharmaceutical lozenge dosage compositions of varenicline tartrate in the manufacture of a medicament for the treatment of smoking cessation.

[0070] The invention is further defined by reference to the following examples describing in detail the method for the preparation of stable lozenge compositions of varenicline tartrate. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. The following examples are set out to illustrate the invention and do not limit the scope of the present invention.Example- 1: Varenicline Tartrate lozenges were prepared by using the quantitative formula as given in the below table:

[0071] 0.5 mg 1 mg

[0072] Sr. No Ingredients

[0073] mg / unit % w / w mg / unit % w / w Varenicline Tartrate Eq. to

[0074] 1 0.855 0.568 1.710 0.568 Varenicline base 0.5% w / w

[0075] 2 Maltodextrin 4.500 2.99 9.000 2.99 3 Sucralose 2.250 1.495 4.500 1.495 4 Mannitol 48.770 32.405 97.54 32.405 5 Xylitol 27.750 18.439 55.500 18.439 6 Maltitol 46.000 30.565 92.000 30.565 7 Hydroxy Propyl Betadex 3.000 1.993 6.000 1.993 8 Maltodextrin 4.500 2.990 9.000 2.990 9 Hydroxy Propyl cellulose 3.125 2.076 6.25 2.076 10 Orange Flavour 3.000 1.993 6.000 1.993 11 Croscarmellose Sodium 3.000 1.993 6.000 1.993 12 Co-processed Mannitol 3.000 1.993 6.000 1.993 13 Magnesium stearate 0.750 0.500 1.500 0.500 14 Isopropyl alcohol — 15 Purified Water — - — - “““ ""

[0076]

[0077] Procedure:

[0078] 1. Maltodextrin, Sucralose, Mannitol, Xylitol, and Maltitol were sifted through a 30# sieve and charged the sieved powder mix into the Fluid bed granulation bowl.

[0079] 2. Add Hydroxy Propyl Betadex in Isopropyl alcohol and Purified mixture under stirring and continue stirring to get a clear solution.

[0080] 3. Add Varenicline Tartrate in step 2 under stirring and continue stirring to get a clear solution.4. Add maltodextrin in step 3 under stirring and continue stirring till to get a uniform suspension.

[0081] 5. Add Hydroxy Propyl cellulose in step 4 under stirring and continue stirring to get a uniform suspension

[0082] 6. Materials of step 1 were granulated with the solution of step 5 by the top spray process.

[0083] 7. Granules of step 6 were dried LOD below 2.5% and sifted through a 30# sieve.

[0084] 8. Croscarmellose Sodium, Co-processed Mannitol and Flavor were sifted through a 30# sieve and mixed with dried granules of step 7.

[0085] 9. Magnesium stearate was sifted through a 60# sieve, and the blend of step 8 was lubricated with sifted magnesium stearate.

[0086] 10. Lubricated blend of step 9 was compressed to tablets using appropriate punch tooling.

[0087] 11. Compression carried out as per product specifications.

[0088] *** The results of the stability analysis for Varenicline Lozenges at dosages of 0.5 mg and 1.0 mg indicate that the levels of both known and unknown related impurities of individual Varenicline are well within the specified limits of 1.0% and 0.5%.

[0089] ***A significant observation in the table below demonstrates that the VC-09 impurity levels are well below the maximum permissible limit of 200 ppm set by the USFDA.

[0090] Varenicline Lozenges 1.0 mg

[0091] 1M- 2M- 3M- 6M- 3M- 6M- 3M- 6M- Condition /

[0092] Initial 40°C / 7 40°C / 75 40°C / 7 40°C / 7 30°C / 6 30°C / 6 25°C / 60 25°C / 60 Strength

[0093] 5%RH %RH 5%RH 5%RH 5%RH 5%RH %RH %RH VC-09 4.29 5.74 6.76 7.98 7.90 7.19 6.40 6.91 6.19

[0094] Varenicline Lozenges 0.5 mg

[0095] VC-09 4.09 6.24 6.59 7.55 7.56 6.01 6.37 6.41 6.38

[0096]

[0097] Example -2: Varenicline Tartrate lozenges were prepared by using the quantitative formula as given in the table below:

[0098] 0.5 mg 1 mg Sr. No Ingredients

[0099] mg / unit % w / w mg / unit % w / w Varenicline Tartrate Eq. to

[0100] 1 0.855 0.568 1.710 0.568 Varenicline base 0.5%w / w.

[0101] 2 Maltodextrin 9.000 5.980 18.000 5.980 3 Sucralose 2.250 1.495 4.500 1.495 4 Mannitol 27.770 18.452 55.540 18.452 5 Xylitol 27.750 18.439 55.500 18.439 6 Beta cyclodextrin 15.000 9.967 30.000 9.967 7 Co-processed Mannitol 3.000 1.993 6.000 1.993 8 Maltitol 46.000 30.565 92.000 30.565 9 Hydroxy Propyl Betadex 3.000 1.993 6.000 1.993 10 Hydroxy Propyl cellulose 3.125 2.08 6.25 2.076 11 Orange Flavour 3.000 1.993 6.000 1.993 12 Croscarmellose Sodium 3.000 1.993 6.000 1.993 13 Glycine 6.000 3.986 12.00 3.986 14 Magnesium stearate 0.750 0.500 1.500 0.500 15 Isopropyl alcohol — - — — 16 Purified Water — — —

[0102]

[0103] Procedure:

[0104] 1. Maltodextrin, Sucralose, Mannitol, Xylitol, Beta cyclodextrin, co-processed Mannitol, and Maltitol were sifted through a 30# sieve and charged into the Fluid Bed Granulation processor bowl.

[0105] 2. Add Hydroxy Propyl Betadex in Purified water under stirring and continue stirring to get a clear solution.3. Add Hydroxy Propyl cellulose in step 2 under stirring, continue stirring to get a clear solution.

[0106] 4. Add Varenicline Tartrate in step 3 under stirring and continue stirring to get a clear solution.

[0107] 5. Add isopropyl alcohol in step 4 under stirring and continue stirring to get a clear solution.

[0108] 6. Materials of step 1 were granulated with the solution of step 5 by the top spray process.

[0109] 7. Granules of step 6 were dried to LOD of below 2.5% and sifted through a 30# sieve.

[0110] 8. Croscarmellose Sodium, Glycine and Flavour were sifted through a 20# sieve and mixed with dried granules of step 7.

[0111] 9. Magnesium stearate was sifted through a 60# sieve, and the blend of step 8 was lubricated with sifted magnesium stearate.

[0112] 10. The lubricated blend of step 9 was compressed into tablets using appropriate punch tooling.

[0113] 11. Compression carried out as per product specifications.

[0114] ***The results of the stability analysis for Varenicline Lozenges at dosages of 0.5 mg and 1.0 mg indicate that the levels of both known and unknown related impurities of individual Varenicline are well within the specified limits of 1.0% and 0.5%.

[0115] ***A significant observation in the table below demonstrates that the VC-09 impurity7levels are well below the maximum permissible limit of 200 ppm set by the USFDA.

[0116] Varenicline Lozenges 1.0 mg

[0117] 1M- 2M- 3M- 6M- 3M- 6M- Impurity7Initial 40°C / 75%R 40°C / 75 40°C / 75 40°C / 75 25°C / 60 25°C / 60

[0118] H %RH %RH %RH %RH %RH VC-09 5.10 19.72 21.75 22.65 22.79 17.13 18.85 Varenicline Lozenges 0.5 mg

[0119] VC-09 4.77 19.99 20.79 22.19 22.99 15.83 19.48

[0120]

[0121] Example -3: Varenicline Tartrate lozenges were prepared by using the quantitative formula as given in the table below:

[0122] 0.5 mg 1 mg

[0123] Sr. No Ingredients

[0124] mg / unit % w / w mg / unit % w / w 1 Varenicline Tartrate 0.855 0.568 1.710 0.568 2 Maltodextrin 9.000 5.980 18.000 5.980 3 Sucralose 2.250 1.495 4.500 1.495 4 Mannitol 48.77 32.405 97.54 32.405 5 Xylitol 27.750 18.439 55.500 18.439 6 Maltitol 46.000 30.564 92.000 30.564 7 Hydroxy Propyl Betadex 3.000 1.993 6.000 1.993 8 Hydroxy Propyl cellulose 3.125 2.076 6.250 2.076 9 Isopropyl alcohol ““

[0125] 10 Purified Water - — — 11 Orange Flavour 3.000 1.993 6.000 1.993 12 Croscarmellose Sodium 3.000 1.993 6.000 1.993 13 Co-processed Mannitol 3.000 1.993 6.000 1.993 14 Magnesium stearate 0.750 0.500 1.500 0.500

[0126]

[0127] Procedure:

[0128] 1. Maltodextrin, Sucralose, Mannitol, Xylitol, co-processed Mannitol, and Maltitol were sifted through 30# sieve and charged this powder mix in to fluid bed granulation processor Bowl.

[0129] 2. Add Hydroxy Propyl Betadex in Purified water under stirring and continue stirring to get a clear solution.

[0130] 3. Add Hydroxy Propyl cellulose in step 2 under stirring, continue stirring to get a clear solution.4. Add Varenicline Tartrate in step 3 under stirring and continue stirring to get a clear solution.

[0131] 5. Add isopropyl alcohol in step 4 under stirring and continue stirring to get a clear solution.

[0132] 6. Materials of step 1 were granulated with the solution of step 5 by the top spray process.

[0133] 7. Granules of step 6 were dried to LOD of below 2.5% and sifted through a 30# sieve. 8. Croscarmellose Sodium and Flavour were sifted through a 30# sieve and mixed with dried granules of step 7.

[0134] 9. Magnesium stearate was sifted through 60# sieve, and blend of step 8 was lubricated with sifted magnesium stearate.

[0135] 10. Lubricated blend of step 9 was compressed into tablets using appropriate punch tooling.

[0136] 11. Compression carried out as per product specifications.

[0137] ***The results of the stability analysis for Varenicline Lozenges at dosages of 0.5 mg and 1.0 mg indicate that the levels of both known and unknown related impurities of individual Varenicline are well within the specified limits of 1.0% and 0.5%.

[0138] ***A significant observation in the table below’ demonstrates that the VC-09 impurity levels are well below’ the maximum permissible limit of 200 ppm set by the USFDA.

[0139] Varenicline Lozenges 1.0 mg

[0140] 1M- 2M- 3M- 6M- Impurity Initial

[0141] 40°C / 75%RH 40°C / 75%RH 40°C / 75%RH 40°C / 75%RH VC-09 4.49 10.23 10.28 11.43 12.55

[0142]

Claims

CLAIMS:

1. A pharmaceutical lozenge dosage composition of varenicline or pharmaceutically acceptable salts thereof, comprising one or more pharmaceutically acceptable excipients selected from a) non-sugar ingredients of polyols or its co-processed excipients of the polyols, b) one or more stabilizers, c) one or more diluents, and d) a sweetener; wherein the composition contains nitrosamine impurities within the daily acceptable limit.

2. The pharmaceutical lozenge dosage composition according to claim 1, further comprises one or more other pharmaceutically acceptable excipients.

3. The pharmaceutical lozenge dosage composition according to claim 1, wherein the non¬ sugar ingredients of polyols or their co-processed excipients of the polyols include but are not limited to mannitol, xylitol, maltitol or its co-processed excipients of mannitol, such as mannitol with starch, mannitol with hydroxy propyl methyl cellulose, mannitol with microcrystalline cellulose, or a combination thereof.

4. The pharmaceutical lozenge dosage composition according to claim 1, wherein percentage concentration of the non-sugar ingredients of polyols or their co-processed excipients of the polyols is about 40% to 80% of the total lozenge composition.

5. The pharmaceutical lozenge dosage composition according to claim 1, wherein the percentage concentration of the non-sugar ingredients of polyols or their co-processed excipients of the polyols is about 50% to 75% of the total lozenge composition.

6. The pharmaceutical lozenge dosage composition according to claim 1, wherein the non-sugar ingredients of polyols or their co-processed excipients of the polyols is combined with a further non-polyol sweetener.

7. The pharmaceutical lozenge dosage composition according to claim 1, wherein it comprises one or more stabilizers, selected from glycine, beta-cyclodextrin, maltodextrin, methylcellulose,ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl betadex (HPB), hydroxypropyl cellulose (HPC), or hydroxypropyl methylcellulose (HPMC), or a mixture thereof.

8. The pharmaceutical lozenge dosage composition according to claim 1, wherein the percentage concentration of the stabilizers is about 10% to 45% of the total lozenge composition.

9. The pharmaceutical lozenge dosage composition according to claim 1, wherein it comprises filler, eg, mannitol, the percentage concentration of mannitol is about 15% to 35% of the total lozenge composition.

10. The pharmaceutical lozenge dosage composition according to claim 1, wherein the lozenge dosage composition is formulated without stabilizers such as glycine or P-cyclodextrin.

11. The pharmaceutical lozenge dosage composition according to claim 1, wherein the lozenge dosage composition is formulated without stabilizers such as glycine or P-cyclodextrin, with the proviso that if stabilizers are not used in the composition, the quantity of fillers, such as mannitol (Pearlitol 200SD) should be adjusted to the final lozenge composition on a %w / w.

12. The pharmaceutical lozenge dosage composition according to claim 1, wherein it comprises one or more lubricants, selected from magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl behenate, and glyceryl palmitostearate.

13. The pharmaceutical lozenge dosage composition according to claim 1, wherein the percentage concentration of the lubricant is about 0.15% to 1% of the total lozenge composition.

14. The pharmaceutical lozenge dosage composition according to claim 1, wherein it comprises a disintegrant and a flavouring agent in the percentage concentration of 1 to 5% of each in the total lozenge composition.

15. The pharmaceutical lozenge dosage composition according to claim 1, wherein the weight of the pharmaceutical lozenge composition of varenicline tartrate for compressing a 0.5mg strength unit dose of varenicline tartrate (equivalent to base) is about 50 to 400 mg.

16. The pharmaceutical lozenge dosage composition according to claim 1, wherein the weight of the pharmaceutical lozenge composition of varenicline tartrate required to compress a 0.5 mg unit dose of varenicline tartrate (equivalent to base) is about 150 mg.

17. The pharmaceutical lozenge dosage composition according to claim 1, wherein the lozenge composition contains nitrosamine impurities under a 50ppm level.

18. The pharmaceutical lozenge dosage composition according to claim 1, wherein the lozenge composition contains nitrosamine impurities under a 30ppm level.

19. A pharmaceutical lozenge dosage composition of varenicline or pharmaceutically acceptable salts thereof, comprising:a) Varenicline tartrate: 0.568%b) Stabilizers: 10-20%c) Non-sugar polyols or their co-pressed excipients: 40 to 60%d) Fillers: 15 to 20%e) Diluents: 4 to 6%f) Lubricants: 0.2 to 1.5%,and other pharmaceutically acceptable excipients.

20. A pharmaceutical lozenge dosage composition of varenicline or pharmaceutically acceptable salts thereof, comprising:a) Varenicline tartrate: 0.568%b) Stabilizers: 1-5%c) Non-sugar polyols or their co-pressed excipients: 40 to 60%d) Fillers: 25 to 40%e) Diluents: 4 to 6%f) Lubricants: 0.2 to 1.5%,and other pharmaceutically acceptable excipients.

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