Specification
The present invention relates to solid oral pharmaceutical compositions of varenicline or its pharmaceutically acceptable salts thereof. In particular, but without restriction to the particular embodiments hereinafter described in accordance with the best mode of practice, the present invention provides an immediate-release solid oral pharmaceutical composition comprising varenicline or its pharmaceutically acceptable salts thereof and methods for preparing these compositions, and methods of use thereof. The prepared compositions are free from undesirable nitrosamine impurities. The present invention also relates to a method of detecting and controlling undesirable impurities in raw material like Active Pharmaceutical Ingredient (API) and excipients of the solid oral pharmaceutical composition comprising varenicline or its pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION Varenicline tartrate is a partial nicotinic agonist selective for a4(32 nicotinic acetylcholine receptor subtypes, which is for use as an aid to smoking cessation. Varenicline tartrate is chemically known as 7,8,9,10-tetrahydro-6,10-methano-6i/-pyrazino[2,3- h][3]benzazepine, (2i?,3i?)-2,3-dihydroxybutanedioate (1:1). Varenicline tartrate is highly soluble in water and is represented by the following formula as:
to
about 5%> by weight of one or more lubricants; and vii) one or more other
pharmaceutically acceptable excipients. In certain non-limiting embodiments, the
composition further comprises from 0.01%> to about 8%> by weight of one or more
coating agents.
In another embodiment of the invention, there is orovided a solid oral
95% by weight of one or more diluents; iii) from 0.1% to about 20% by weight of one or more disintegrants; iv) from 0.01% to about 4% by weight of one or more glidants; and v) from 0.01% to about 3% by weight of one or more lubricants. In another embodiment of the invention, there is provided a solid oral pharmaceutical composition comprising: i) about 0.01% to about 15% by weight of varenicline or its pharmaceutically acceptable salts thereof; ii) from about 30% to about 70% by weight of anhydrous calcium phosphate; iii) from about 0.01% to about 20% by weight of a binder or stabilizer; iv) from about 0.01% to about 30% by weight of microcrystalline cellulose; v) from about 0.01% to about 1% by weight of colloidal silicon dioxide; vi) from about 0.01% to about 10% by weight of low-substituted hydroxypropyl cellulose; vii) from about 0.01% to about 1% by weight of magnesium stearate; and viii) optionally a film-coating. In a preferred embodiment, the binder or stabilizer is povidone, hypromellose, starch, and maltodextrin. In a more preferred embodiment, the binder or stabilizer is maltodextrin.
In certain non-limiting embodiments, the ratio of the weight of the drug to binder or stabilizer is from 20:0.05 to 0.05:20. Preferably, the ratio of the weight of the drug to binder or stabilizer is about 1:10. In certain non-limiting embodiments, the ratio of the weight of the drug to glidant is from 10:0.05 to 0.05:10. Preferably, the ratio of the weight of the drug to glidant is about 1:0.7.
In certain non-limiting embodiments, there is provided a method of detecting and controlling N-nitroso-varenicline in an immediate release solid oral pharmaceutical film-coated tablet composition comprising: a) about 0.01% to 15% by weight of varenicline tartrate; b) from about 40% to about 95% by weight of diluent selected from the group consisting of microcrystalline cellulose; anhydrous calcium phosphate and combinations thereof; c) from about 0.01% to about 10% by weight of binder selected from the group consisting of povidone; hypromellose; starch; maltodextrin and combinations thereof; d) from about 0.01% to about 10% by weight of disintegrant selected from the group consisting of low-substituted hydroxypropyl cellulose; croscarmellose sodium; crospovidone; and combinations thereof; e) from about 0.01% to about 1% by weight of glidant selected from the
group consisting of talc; colloidal silicon dioxide; and combinations thereof; f) from about 0.01% to about 1% by weight of lubricant selected from the group consisting of sodium stearyl fumarate; magnesium stearate; and combinations thereof; and g) optional a film-coating; wherein the composition comprises less than 15 ppm of the N-nitroso-varenicline and is stable when stored at 40°C and 75% relative humidity for at least 6 months and the content is analyzed by the LCMS-MS method and the composition release not less than 80% of drug release within 15 minutes in 500 ml of 0.01 N Hydrochloric acid, using USP I apparatus (basket) at a temperature of 37±0.5°C and a rotation speed of 50 revolutions per minute. In another embodiment of the invention, the solid oral pharmaceutical composition comprising varenicline or its pharmaceutically acceptable salts thereof is prepared by a wet or dry process. In another embodiment of the invention, there is provided a solid oral pharmaceutical composition comprising varenicline or its pharmaceutically acceptable salts thereof prepared by wet granulation, extrusion-spheronization, dry granulation, dry blending, dry mixing, or direct compression process. Other formulation techniques are also contemplated within the scope of the present invention.
In another embodiment of the invention, there is provided a solid oral pharmaceutical composition comprising varenicline or its pharmaceutically acceptable salts thereof, the composition prepared in a process comprising the steps of: a) sifting the accurately weighed quantities of active agent and one or more pharmaceutically acceptable excipient(s) separately through a suitable sieve; b) mixing of sifted active agent and excipient(s) using a dry mixer; c) lubricating the sifted blend of step b), and d) compressing the lubricated blend into tablets. In another embodiment of the invention, there is provided a solid oral pharmaceutical composition comprising varenicline or its pharmaceutically acceptable salts thereof, the composition prepared in a process comprising the steps of: a) sifting the accurately weighed quantities of active agent and one or more pharmaceutically acceptable excipient(s) through a suitable sieve followed by mixing; b) granulating the mixture of step a) with a binder solution (granulation in an aqueous or non-aqueous solvent); c) drying the granulated mass, optionally
milling of the dried granules and mixed the sifted granules; d) lubricating the sifted blend of step c); and e) compressing the lubricated granules into tablets. In another embodiment of the invention, there is provided a solid oral pharmaceutical composition comprising varenicline or its pharmaceutically acceptable salts thereof, the composition is prepared in a process comprising the steps of: a) blending a mixture of varenicline and at least one pharmaceutically acceptable excipient including a binder and/or a disintegrant; b) compacting the blended material using roller compactor; c) optionally milling the compacted material; d) blend from step b) or milled material from step c) was lubricated with a suitable lubricant; and e) lubricating blend or granules from d) and was compressing into tablets with suitable tooling.
In yet an additional aspect, provided herein is a method of detecting levels of N-nitroso-varenicline impurity of compounds of formula II in a composition comprising varenicline or its salts thereof. The method comprises the steps of: a) providing tablet compositions comprising varenicline or its salts thereof and at least one or more pharmaceutically acceptable excipients in a suitable quantity (such as 10-20); b) calculating the average weight of the tablet compositions; c) crushing the tablet compositions to obtain fine powder and optionally homogenizing the sample; d) weighing and transferring powder sample equivalent to 2 mg varenicline into a clean, dry 15 ml of the centrifuge tube; e) adding 2 ml of diluent (mixing of water and methanol in the ratio of 80:20(v/v)), mixing well and centrifuging the solution for a suitable time (10-15 minutes); and f) filtering the solution with 0.22 um nylon filter, discarding the 4 drops and collecting the solution into sampler vial and then injecting.
In yet an additional aspect, provided herein is a process for preparing a pharmaceutical composition, the process comprises: a) analyzing the content of N-nitroso-varenicline by the LCMS-MS method in each drug substance; excipients; and final composition; and b) if the drug substance; excipients; and final composition meets pre-set specifications for the amount of the N-nitroso-varenicline, then continuing to process the final composition; or c) if the composition does not meet said pre-set specifications for the amount of the N-
nitroso-varenicline then further purifying or discarding the compositions; wherein the pre-set specification includes less than 20 ppm of the N-nitroso-varenicline. In a preferred embodiment, the pre-set specification includes less than 15 ppm of the N-nitroso-varenicline.
In yet an additional aspect, provided herein is a process for preparing a pharmaceutical composition, the process comprises: a) analyzing the content of nitrates and/or nitrites in each excipient; and b) if excipients meet pre-set specifications for the amount of the nitrates and/or nitrites, then continuing to process the final composition; or c) if the composition does not meet said pre-set specifications for the amount then further purifying or using other excipients free of nitrates and/or nitrites or having content within pre-set specifications; wherein the pre-set specification includes less than 15 ppm of the nitrates and/or nitrites in each excipient.
In another embodiment of the invention, there is provided a solid oral pharmaceutical composition of the present invention in the manufacture of a medicament for treating as an aid to smoking cessation treatment, reducing nicotine addiction, or aiding in the cessation or lessening of tobacco use and other diseases as described herein such as inflammatory bowel disease, irritable bowel syndrome, anxiety, depression, bipolar disorder, sleep disorders, epilepsy, schizophrenia, Parkinson's disease (PD), and ADHD.
In another embodiment, the solid oral pharmaceutical composition of the present invention particularly tablet dosage form may be packaged in HDPE bottles or blister packs. HDPE bottles may optionally contain desiccants. Preferably, granulating solvents include, but are not limited to, water, esters such as ethyl acetate, ketones such as acetone, alcohols such as methanol, ethanol, isopropanol, butanol, dichloromethane, chloroform, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), ether, diethyl ether and combinations thereof. Preferably, the granulating solvent used during wet granulation is water. Various useful fillers or diluents include, but are not limited to microcrystalline cellulose ("MCC"), sodium alginate, silicified MCC (e.g., PROSOLV™), microfine cellulose, lactitol, cellulose acetate, kaolin, glucose, lactose, maltose,
fructose, sucrose, trehalose, starch, pregelatinized starch, mannitol, xylitol, maltitol, sorbitol, dextrates, dextrin, maltodextrin, compressible sugar, confectioner's sugar, dextrose, polydextrose, simethicone, calcium carbonate, calcium sulfate, calcium phosphate, dicalcium phosphate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, isomalt, and mixtures thereof. The amount of diluent according to the present invention ranges from 0 to about 98% by weight of the composition. Preferably, the amount of diluent according to the present invention ranges from 0 to about 95% by weight of the composition. In an embodiment, the diluent according to the present invention is present in an amount of about 95% or less, 90% or less, 80% or less, e.g. 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less.
Various useful binders include, but are not limited to acacia, guar gum, xanthan gum, alginic acid, sodium alginate, dextrin, carbomer, maltodextrin, methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC) (e.g., KLUCEL®), hydroxypropyl methylcellulose (HPMC) (e.g., METHOCEL®), hydroxyethylmethyl cellulose, carboxymethyl cellulose sodium, cottonseed oil, povidone (various grades of KOLLIDON®, PLASDONE®), ceratonia, dextrose, polydextrose, starch, gelatin, pregelatinized starch, hydrogenated vegetable oil type I, microcrystalline cellulose, polyethylene oxide, polymethacrylates and mixtures thereof. Binder can be present in powder form or as a dispersion or mixture of both in intra and/or extra granular part of the composition. The amount of binder according to the present invention ranges from 0 to about 50% by weight of the composition. Preferably, the amount of binder according to the present invention ranges from 0 to about 30% by weight of the composition. In an embodiment, the binder according to the present invention is present in an amount of about 50% or less, 40% or less, e.g. 30% or less, 20% or less, 10% or less, 5% or less. More preferably, the binder according to the present invention is present in an amount of about 0.01% to about 30% by weight of the composition. In some embodiment, a binder can also act as a stabilizer.
Various useful disintegrants and/or super-disintegrants include, but are not limited to croscarmellose sodium, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, povidone, crospovidone, polacrilin potassium, sodium starch glycolate, alginic acid, sodium alginate, calcium phosphate tribasic, docusate sodium, guar gum, low substituted hydroxypropyl cellulose (L-HPC), magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch and/or combinations thereof. The disintegrant according to the present invention can be used in intra-granular part or extra-granular or in both parts of the composition in any proportion. The amount of disintegrant according to the present invention ranges from 0 to about 40% by weight of the composition. Preferably, the amount of disintegrant according to the present invention ranges from 0 to about 20% by weight of the composition. In an embodiment, the disintegrant according to the present invention is present in an amount of about 40% or less, 30% or less, e.g. 20% or less, 10% or less. More preferably, disintegrant according to the present invention is present in an amount of about 0.01% to about 20% by weight of the composition. Pharmaceutically acceptable lubricants include stearic acid, zinc stearate, sucrose stearate, sodium benzoate, hydrogenated vegetable oil, calcium stearate, adipic acid, glyceryl palmitostearate, glycerine monostearate, medium-chain triglycerides, glyceryl behenate, sodium lauryl sulphate, sodium stearyl fumarate, magnesium lauryl sulphate, magnesium stearate, polyethylene glycol. The amount of lubricant according to the present invention ranges from 0 to about 20% by weight of the composition. Preferably, the amount of lubricant according to the present invention ranges from about 0.1% to about 5% by weight of the composition. In an embodiment, the lubricant according to the present invention is present in an amount of about 20% or less, e.g. 10% or less, 5% or less. More preferably, lubricant according to the present invention is present in an amount of about 0.01% to about 5% by weight of the composition.
Suitable surfactants according to the present invention are selected from ionic or non-ionic surfactants. Various useful surfactants include, but not limited to, sodium lauryl sulphate, polysorbates (e.g. polysorbate 20, polysorbate 40, polysorbate 60,
and polysorbate 80), cetrimide, cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol, cholesterol, polyethylene glycols, polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate, sorbitan fatty acid esters such as sorbitan monostearate, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate, polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether, polyoxyethylene castor oil, polyoxyethylene polyoxypropylene block copolymers, and combinations thereof. Commercially available surfactants such as SEPITRAP® 80 or SEPITRAP® 4000 may also be used. In an embodiment, the surfactant according to the present invention is present in an amount of about 30% or less, e.g. 20% or less, 10% or less, 5% or less, or 2% or less.
Suitable glidants include, but are not limited to, calcium silicate, magnesium silicate, magnesium trisilicate, stearic acid and its derivatives or esters like magnesium stearate, calcium stearate, and sodium stearate and the corresponding esters, sodium stearyl fumarate, talc, colloidal silicon dioxide, amorphous silicon dioxide, tribasic calcium phosphate, starch or mixtures thereof. The amount of glidant according to the present invention ranges from 0 to about 20% by weight of the composition. In an embodiment, the glidant according to the present invention is present in an amount of about 20% or less, e.g. 10% or less, 5% or less, 3% or less. More preferably, glidant according to the present invention is present in an amount of about 0.01% to about 5% by weight of the composition. The invention is further defined by reference to the following examples describing in detail methods for the preparation and testing of the pharmaceutical composition.
EXAMPLE-1 7V-nitroso-varenicline Impurity: Nitrosamines are potent carcinogens in animals and probable carcinogens in humans. Nitrates and/or nitrites are common nitrosating impurities that can be found at parts per million levels. The most probable reason is the interaction of secondary amines/tertiary amines with nitrite in acid conditions. N-nitroso-varenicline is formed via in-situ interaction of varenicline with nitrates and/or nitrites. Possible sources of nitrites and/or nitrates may include one or more of: a) API; b) intermediates; c) excipients; d) solvents; e)
manufacturing process, etc. Excipients used in the development of solid oral compositions such as disintegrants, diluents, binders, glidants, lubricants, and coating agents can carry trace levels of nitrate and/or nitrite impurities.
7V-nitroso-varenicline impurity and its impact on formulation:
The presence of nitrosamine impurities adversely affects the safety and shelf life of formulations. The present inventors intensively studied all the critical factors, which can be a cause of nitrosamines impurity in the formulation. The present inventors followed the following approaches:
In the first method, the present inventors performed all the experiments and determined their results without applying any control.
In the second methodology, the present inventor performed all the experiments and determined their results by applying all technical efforts to control the content of undesirable genotoxic nitrosamines impurity in the formulation. The present inventors carried out various testing on each excipient used in the development of formulations. The present inventors also carried out various testing on each process step during the manufacturing process to determine the impact of nitrosamine impurity. To screen trace levels of impurities in drug/formulation/excipients, the present inventors developed a highly sensitive analytical method capable of detecting this impurity at an even ppm level using a Liquid chromatography-mass spectrometry (LC-MS or LCMS-MS) instrument. The present inventors studied various factors such as: a) screening of raw materials such as drug substance and all excipients being used in the formulation to identify the major contributors for nitrates and/or nitrites impurities; b) identification of alternative sources of the same substance or excipients with negligible levels of nitrates and/or nitrites; c) identification of new excipients.
Approach 1: 7V-nitroso-varenicline impurity content in the formulation without any control: The content of Nitrosamines impurities was determined by the present inventors in:
1) Reference product (Chantix® film-coated tablets);
2) Test formulation was developed having the same qualitative excipients used in the reference product. The present inventors surprisingly found that both test and reference samples were found to have higher than permissible levels of N-nitroso-varenicline. Test and reference product data indicate that impurity is present in significantly large amounts. The results are as follows:
7V-nitroso-varenicline
content in Test
product 7V-nitroso-varenicline
content in Reference
product Permissible Limit
30 to 180 PPM 400 to 600 PPM Less than 20 PPM.
Preferably less than 15
PPM
The inventors also determined that certain excipients such as microcrystalline cellulose, croscarmellose sodium, and Opadry can be a major contributor of nitrates and/or nitrites impurities. The inventors determined that nitrate and/or nitrite-free excipients are also required for adequate control of nitrosamine impurity in the formulation.
Approach 2: 7V-nitroso-varenicline impurity content in the formulation while applying controls:
Extensive experimentation was carried out by the present inventors to reduce the level of the undesirable nitrosamine impurities in composition. As a result, it has been found that the nitrosamine impurity formed during the development of solid oral composition of varenicline can be reduced or substantially completely removed by the selection of suitable excipients, and the manufacturing process.
Further, some of the excipients like Polacrilin Potassium, colloidal silicon dioxide, and magnesium stearate exhibited less than 5 ppm. The quantitative compositions exhibited not more than 20 ppm of N-nitroso-varenicline impurity in compositions, accordingly were found acceptable.
The present inventors detected the presence of undesirable nitrate and/or nitrites in various excipients used in the manufacturing of varenicline tablets, which are a
potential cause of the formation of undesirable genotoxic nitrosamine impurities like TV-nitroso-varenicline. As per LCMS-MS analytical testing, excipients like Croscarmellose sodium (comprises a substantially high amount of nitrate and/or nitrite more than 230 ppm), Microcrystalline cellulose (more than 10 ppm), film coating (more than 10 ppm). The present inventors selected these excipient batches with content of nitrate and/or nitrite less than 10 ppm. More preferably, less than 5 ppm of nitrate and/or nitrite. More preferably, free from nitrate and/or nitrite.
EXAMPLE 2-4
Varenicline tablets were prepared by using the quantitative formula as given in
Table 1: (Quantity/Tablet (%w/w)).
TABLE 1
Ingredient Function 2 3 4
Varenicline or its salts thereof Active Ingredient 0.001-97 0.001-50 0.001-3C
Lactose /
Microcrystalline cellulose / Mannitol /
Xylitol / Dicalcium phosphate / Pre-
Gelatinized starch Diluent 1-95 5-95 10-95
Povidone / Hypromellose / Starch /
Microcrystalline cellulose /
Pre-Gelatinized starch Binder 0-30 0-20 0.1-10
Sodium starch glycolate /
Croscarmellose sodium / Crospovidone
/ Pre-Gelatinized starch /
Microcrystalline cellulose / L-HPC Disintegrant 0-20 0-10 0.1-10
Colloidal silicon dioxide / Talc / calcium silicate Glidant 0.1-5 0.1-2 0.1-2
Magnesium Stearate / Stearic acid / Sodium stearyl fumarate Lubricant 0.1-5 0.1-3 0.1-2
Preferred methods of manufacture: wet granulation, dry granulation, direct compression, and extrusion-spheronization.
EXAMPLES 5-8: (Quantity/Tablet (%w/w)) TABLE 2
Ingredients 5 6 7 8
Varenicline tartrate 0.5-1 0.814 0.814 0.814
Microcrystalline cellulose 68.70 69.18 35.06
Anhydrous dibasic calcium phosphate 0.1-80 22.38 22.38 22.38
Lactose
- - 35.07
Croscarmellose sodium 0.1-10 1.9 - -
Polacrilin Potassium
- 1.42 -
Colloidal silicon dioxide 0.1-2 0.48 0.48 0.48
Magnesium stearate 0.1-2 0.95 0.95 0.95
Film-Coating 0.1-6 4.7 4.7 4.7
Preparation Method: i) Varenicline, diluent, and other optional excipients such as one or more binders, disintegrants, and glidants were sifted through a suitable sieve in suitable proportion; ii) The sifted blend of step i) was mixed for a suitable time; iii) Co-milling the blend of step ii) in a suitable blender; iv) Co-shifted the lubricant through a suitable sieve; v) Lubricated the blend of step iii) with a lubricant of step iv); and vi) Compressed the final blend of step v) using suitable punches and dies.
Results:
Dissolution: The dissolution profile of tablet compositions prepared using quantitative compositions, was measured in 500 ml of 0.01 N Hydrochloric acid, using the USP I apparatus (basket) at a temperature of 37±0.5°C and a rotation speed of 100 revolutions per minute. The quantitative composition exhibited not less than 80% of drug release within 15 minutes, accordingly dissolution profiles were found acceptable.
EXAMPLES 9-10: (Quantity/Tablet (%w/w)) TABLE 3
Ingredients 9 10
Anhydrous dibasic calcium phosphate 62.1 63.4
Varenicline tartrate 0.8 0.8
Binder or Stabilizer
(Povidone/Hypromellose/Starch/
Maltodextrin) 8.1 8.3
Purified Water q.s q.s
Microcrystalline cellulose 17.9 18.3
Colloidal silicon dioxide 0.5 0.48
Low substituted Hydroxypropyl Cellulose 4.8 4.9
Magnesium Stearate 1.0 1.0
Coating
Film-Coating (non-aqueous) 4.8 3.0
Two batches were prepared for 0.5mg and lmg strengths using the same quantitative % w/w formulation. Preparation Method: i) one or more suitable diluent (such as anhydrous calcium phosphate) was sifted through a suitable sieve in a suitable proportion; ii) diluent of step i) was granulated using a binder solution containing varenicline, diluent, and a suitable solvent such as water; iii) one or more other optional excipients such as one or more diluent, disintegrant, and glidants were sifted through a suitable sieve in suitable proportion; iv) the sifted blend of step iii) was mixed with granules of step ii) for a suitable time; v) co-shifted the lubricant through a suitable sieve and the blend of step iv) was lubricated with a lubricant; vi) the lubricated blend of step v) was coated with a suitable coating solution; vii) the final blend of step vi) was compressed using suitable punches and dies. Results:
1. Dissolution: The dissolution profile of tablet compositions prepared using quantitative composition was measured in 500 ml of 0.01 N Hydrochloric acid, using the USP I apparatus (basket) at a temperature of 37±0.5°C and a rotation speed of 50 revolutions per minute. The quantitative composition exhibited not less than 80% of drug release within 15 minutes, accordingly dissolution profiles were found acceptable.
2. Other Results:
Test parameters
Example 9-10
(0.5mg & lmg)
Water Content (by KF)
2.7 & 2.6
Assay
101.3 & 99.4
Dissolution
99
1.2 & 1.5
N-Nitroso-varenicline Impurity
3. Content of N-Nitroso-Varenicline Impurity: The content of N-nitroso-varenicline impurity in the pharmaceutical composition was analyzed using the LCMS-MS method which comprised the steps of: a) tablet compositions
comprising varenicline or its salts thereof and at least one or more pharmaceutically acceptable excipients were taken in a suitable quantity (such as 20); b) the average weight of the tablet compositions were calculated; c) the tablet compositions were crushed to obtain fine powder and optionally homogenized; d) powder sample was weighed and transferred about equivalent to 2 mg varenicline into a clean, dry 15 ml of the centrifuge tube; e) 2 ml of diluent (mixing of water and methanol in the ratio of 80:20 (v/v)) was added, mixed well and centrifuged the solution for a suitable time (10-15 minutes); and f) the solution was filtered with 0.22 um nylon filter, the 4 drops were discarded and the solution was collected into sampler vial and then injected for analyzed. 4. Effect of Film-Coating: The present inventors have surprisingly found that film-coating also has a substantial impact on the content of undesirable N-nitroso-varenicline impurity in the final composition. Based on their extensive research, the present inventors have found that compositions prepared with the use of aqueous-based film-coating material resulted in very high content of N-nitroso-varenicline impurity, which was not safe for human administration. In fact, the content of N-nitroso-varenicline was found at about 200 ppm in composition prepared with the use of aqueous-based film-coating material. The present inventors performed multiple experiments and surprisingly found that film-coating compositions devoid of water and with an alcohol-based coating material (more particularly isopropyl alcohol) were able to result in compositions with very less amount of undesirable N-nitroso-varenicline impurity. These results were surprising and unexpected and resulted in tablet compositions that were safe for human use.
While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments.
WE CLAIM:
1. An immediate-release solid oral pharmaceutical composition comprising
a) a compound of the formula I:
or its pharmaceutical^ acceptable salts thereof; and b) at least one or more pharmaceutical^ acceptable excipients, wherein the composition comprises less than 20 ppm of the compound represented by formula II:
.
wherein the content of the compound represented by formula II is analyzed
by the LCMS-MS method. The pharmaceutical composition as claimed in claim 1, wherein the content of the compound of formula II is less than 10 ppm.
The pharmaceutical composition as claimed in claim 1, wherein the compound of formula II is N-nitroso-varenicline and the salt of compound I is tartrate. The pharmaceutical composition as claimed in claim 1, wherein one or more pharmaceutically acceptable excipients are selected from the group consisting of diluent, binder, disintegrant, surfactant, stabilizer, glidant, and lubricant. The pharmaceutical composition as claimed in claim 1, wherein the diluent comprises one or more of lactose, mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch, and dicalcium phosphate.
a) about 0.01% to 15% by weight of varenicline tartrate;
b) from about 40% to about 95% by weight of diluent selected from the group consisting of microcrystalline cellulose; anhydrous calcium phosphate and combinations thereof;
c) from about 0.01% to about 10% by weight of binder selected from the group consisting of povidone; hypromellose; starch; maltodextrin and combinations thereof;
d) from about 0.01 % to about 10% by weight of disintegrant selected from the group consisting of low-substituted hydroxypropyl cellulose; croscarmellose sodium; crospovidone; and combinations thereof;
e) from about 0.01 % to about 1 % by weight of glidant selected from the group consisting of talc; colloidal silicon dioxide; and combinations thereof;
f) from about 0.01% to about 1% by weight of lubricant selected from the group consisting of sodium stearyl fumarate; magnesium stearate; and combinations thereof; and
g) optional film-coating;
wherein the composition comprises less than 15 ppm of the N-nitroso-varenicline and is stable when stored at 40°C and 75% relative humidity for at least 6 months and the content is analyzed by the LCMS-MS method and the composition release not less than 80% of drug release within 15 minutes in 500 ml of 0.01 N Hydrochloric acid, using USP I apparatus (basket) at a temperature of 37±0.5°C and a rotation speed of 50 revolutions per minute.
7. A process for preparing a pharmaceutical composition as claimed in claim 6, the process comprises:
a) analyzing the content of nitrates and/or nitrites in each excipient; and
b) if excipients meet pre-set specifications for the amount of the nitrates and/or nitrites, then continuing to process the final composition; or
c) if the composition does not meet said pre-set specifications for the amount then further purifying or using other excipients free of nitrates and/or nitrites or having content within pre-set specifications;
wherein the pre-set specification includes less than 20 ppm of the nitrates and/or nitrites in each excipient.
8. The pharmaceutical composition as claimed in claim 6, wherein the content of
N-nitroso-varenicline is measured using the process comprises the steps of:
a) calculating the average weight of the 20 tablet compositions;
b) crushing the tablet compositions to obtain fine powder and homogenizing the sample;
c) weighing and transferring about powder sample equivalent to 2 mg varenicline into a clean, dry centrifuge tube;
d) adding 2 ml of diluent (mixing of water and methanol in the ratio of 80:20(v/v));
e) mixing well and centrifuging the solution for about 10-15 minutes; and
f) filtering the solution with 0.22 um nylon filter, discarding the 4 drops and collecting the solution into a sampler vial, and then injecting.
9. The pharmaceutical composition as claimed in claim 6, wherein the method of analyzing the content of the N-nitroso-varenicline comprises determining the content of the impurity by LCMS-MS method with a suitable mobile phase such as 0.1% formic acid in water (mobile phase 1) and 0.1% formic acid in methanol (mobile phase 2) using suitable a column such as Phenomenex kinetex F5 100 Al50 x 4.6 2.6(x, and flow rate 0.7 ml/minute.
10. The pharmaceutical composition as claimed in claim 6, consists of:
a) less than 10 ppm of the N-nitroso-varenicline;
b) varenicline tartrate;
c) dibasic calcium phosphate;
d) microcrystalline cellulose;
e) low substituted hydroxypropyl cellulose;
f) colloidal silicon dioxide;
g) magnesium stearate;
h) optionally one or more other pharmaceutically acceptable excipients and
i) optional non-aqueous film-coating.