DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to and the benefit of Indian Patent Application No. 202321040588, filed on Jun. 14, 2023.

FIELD OF THE INVENTION

The present invention relates to a stable pharmaceutical composition of a smoking cessation drug (Varenicline Tartrate) and its pharmaceutically acceptable salts thereof and process for the preparation thereof. This invention more particularly relates to a stable pharmaceutical composition comprising Varenicline or its pharmaceutically acceptable salts, and process for the preparation thereof wherein said composition employs a fluid bed processor for granulation and the composition is substantially free of undesirable nitrosamine impurities.

BACKGROUND OF THE INVENTION

Varenicline tartrate is a partial nicotinic agonist selective for a4ß2 nicotinic acetylcholine receptor subtypes, which is for use as an aid to smoking cessation. It blocks the ability of nicotine to activate a4ß2 receptors and thus to stimulate the central nervous mesolimbic dopamine system, which is responsible for its role in smoking cessation. It both reduces craving for and decreases the pleasurable effects of nicotine from cigarettes and other tobacco products.
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-dihydroxybutanedioate (1:1). Varenicline tartrate is highly soluble in water and is represented by the following formula as:

Varenicline formulations are commercially available in United States of America under the brand name of Chantix® Tablets, 0.5 mg and 1 mg and Tyrvaya® Nasal Spray, 0.03mg base/spray and are indicated for use as an aid to smoking cessation treatment.

In June 2021, Pfizer suspended worldwide distribution of Chantix® (varenicline tartrate tablets) after finding unacceptable levels of nitrosamines in certain Chantix® lots.

US Patent No. 6410550 generically discloses varenicline.

US patent No. 6890927 specifically discloses tartrate salt.

US patent No. 7265119, 6787549, and 6794388 disclose various crystalline polymorphic forms of varenicline tartrate, citrate and succinate salts.

US Patent application No. 20060057207 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.

US Patent application No. 20200276113 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.

US patent application No 20040235850 discloses various impurities of varenicline in drug substance and pharmaceutical compositions such as N-formyl varenicline and N-methyl varenicline.

US patent application No. 20100062046 discloses N-formylvarenicline and N-carboxyvarenicline as impurities in varenicline drug substance.

US patent application No. US20120093887 discloses stable amorphous coprecipitate comprising Varenicline tartrate with excipient selected from the group consisting of maltodextrin, lactose monohydrate and 2-hydroxypropyl-3-cyclodextrin, method for the preparation, pharmaceutical compositions, and method of treating thereof, it also discloses the ratio of varenicline with different excipients.

The FDA has been investigating the presence of nitrosamine impurities in certain drug products since 2018. The FDA is concerned about exposure to nitrosamine impurities above acceptable levels over long periods of time, which may increase the risk of cancer. The FDA became concerned about seven nitrosamine impurities that theoretically could be present in drug products: NDMA, NDEA, NMBA, NIPEA, NDIPA, NDBA, and NMPA. Five of these impurities (NDMA, NDEA, NMBA, NIPEA, and NMPA) have already been detected in drug substances or drug products.

On September 1, 2020, the U.S. Food and Drug Administration (FDA) issued Guidance for Industry: Control of Nitrosamine Impurities in Human Drugs to provide the agency’s current thinking on the issue of nitrosamine impurities in active pharmaceutical ingredients (APIs) and drug products. The Guidance describes what the FDA has learned from its investigation of nitrosamine impurities, the manufacturing conditions that have the potential to introduce these impurities, and the steps that manufacturers of APIs and drug products should take to prevent unacceptable levels of nitrosamine impurities. The Guidance also discusses risk assessment strategies to identify drugs that may be at risk for the presence of these impurities.

Nitrosamine describes a class of compounds having the chemical structure of a nitroso group bonded to an amine (R1N(-R2)-N=O). These compounds can form by a Nitrosation reaction between amines (secondary, tertiary, or quaternary amines) and nitrous acid (nitrite salts under acidic conditions). Nitrosamine impurities are known to be mutagenic and carcinogenic.

Nitrosamine impurities in varenicline can be generated by reagents, catalysts, solvents, or even starting materials can contribute to the formation of these impurities in varenicline. In addition, varenicline or its salts may produce these impurities upon interaction with different excipients in the formulation or during the process of preparation.

When formulations contain nitrosamine impurities, the stability of the formulations is decreased, the duration of the shelf life of the formulation is shortened, and the formulation is not safe for efficacious use. As a result, there is a unmet and significant need for the formulations of varenicline tartrate that are both extremely pure and stable, including free of undesirable level of Nitrosamine impurities with acceptable potency.

The present inventors have surprisingly found that by employing the process of granulation in a fluid bed processor (FBP) with an aqueous binder solution comprised of maltodextrin and varenicline Tartrate in a particular concentration, resulted in Varenicline tablet compositions which are stable and substantially free of the nitrosamine impurities.

OBJECT OF THE INVENTION

It is an object of the present invention to provide a stable pharmaceutical composition comprising varenicline or its pharmaceutically acceptable salts thereof and other pharmaceutically acceptable excipients.

It is another object of the present invention to provide a stable pharmaceutical composition comprising varenicline or its pharmaceutically acceptable salts thereof and other pharmaceutically acceptable excipients wherein said composition is substantially free of undesirable nitrosamine impurities.

It is yet another object of the present invention to provide a stable pharmaceutical composition of varenicline or its pharmaceutically acceptable salts thereof comprising:
a) Varenicline or its pharmaceutically acceptable salts thereof, as an active ingredient;
b) Diluent;
c) Binder;
d) Disintegrant;
e) Lubricant; and
f) One or more pharmaceutically acceptable excipients.

It is another object of the present invention to provide a stable pharmaceutical composition of Varenicline comprising:
a) about 1.71 mg of Varenicline Tartrate;
b) about 114.29 mg of Microcrystalline cellulose;
c) about 7.50 mg of Maltodextrin;
d) about 4 mg of Croscarmellose sodium;
e) about 2.5 mg of stearic acid;
f) about 2.5 mg of barrier coating agent;
g) about 4.5 mg of film coating agent;
h) QS of Purified water, wherein said composition employs a fluid bed processor for granulation.

It is yet another object of the present invention to provide a stable pharmaceutical composition of Varenicline comprising:
a) about 0.3-10 mg of Varenicline Tartrate;
b) about 40-130 mg of Microcrystalline cellulose;
c) about 2-15 mg of Maltodextrin;
d) about 1-10 mg of Croscarmellose sodium;
e) about 1-7 mg of stearic acid;
f) about 1-10 mg of barrier coating agent;
g) about 2-10 mg of film coating agent;
h) QS of Purified water, wherein the granulation of the composition is done using a fluid bed processor.

It is another object of the present invention to provide a stable pharmaceutical composition of Varenicline comprising:
a) about 1.24% w/w of Varenicline Tartrate;
b) about 83.42% w/w of Microcrystalline cellulose;
c) about 5.47 %w/w of Maltodextrin;
d) about 2.91% w/w of Croscarmellose sodium;
e) about 1.82% w/w of stearic acid;
f) about 1.82% w/w of barrier coating agent;
g) about 3.28% w/w of film coating agent;
h) QS of Purified water, wherein the granulation of the composition is done using a fluid bed processor.

It is yet another object of the present invention to provide a stable pharmaceutical composition of Varenicline comprising:
a) about 0.5-5% w/w of Varenicline Tartrate;
b) about 40-90% w/w of Microcrystalline cellulose;
c) about 1-10 %w/w of Maltodextrin;
d) about 1-5% w/w of Croscarmellose sodium;
e) about 0.5-5% w/w of stearic acid;
f) about 1-10 % w/w of barrier coating agent;
g) about 1.5-7% w/w of film coating agent;
h) QS of Purified water, wherein the granulation of the composition is done using a fluid bed processor.

It is another object of the present invention to provide a process for preparation of a stable pharmaceutical compositions comprising;
a) Varenicline Tartrate as an active ingredient;
b) a Diluent which is Microcrystalline cellulose;
c) a Binder which is Maltodextrin;
d) a Disintegrant which is Croscarmellose sodium;
e) a Lubricant which is stearic acid; and
f) one or more pharmaceutically acceptable excipient.
wherein the process comprises the steps of:
a) Co-sifting of microcrystalline cellulose and croscarmellose sodium;
b) Maltodextrin was dissolved in water followed by addition of Varenicline Tartrate to the binder solution to make drug-binder solution.
c) Spraying of drug binder solution over the sifted material of step (a) in fluid bed processor (FBP) followed by drying;
d) The above blend was compressed into tablet followed by barrier coating and film coating.

SUMMARY OF THE INVENTION

The present invention provides a stable pharmaceutical composition comprising varenicline or its pharmaceutically acceptable salts thereof and process for the preparation thereof. The present invention provides a stable pharmaceutical composition of varenicline or its pharmaceutically acceptable salts thereof for oral administration, wherein said composition employs a fluid bed processor for granulation and the composition is substantially free of undesirable nitrosamine impurities.

In one aspect of the present invention, there is provided a stable pharmaceutical composition of varenicline comprising:
a) Varenicline or its pharmaceutically acceptable salts thereof, as an active ingredient;
b) Diluent;
c) Binder;
d) Disintegrant;
e) Lubricant; and
f) one or more pharmaceutically acceptable excipient, wherein said composition employs a fluid bed processor for granulation

In another aspect of the present invention, there is provided a stable pharmaceutical composition of Varenicline comprising:
a) about 1.71 mg of Varenicline Tartrate;
b) about 114.29 mg of Microcrystalline cellulose;
c) about 7.50 mg of Maltodextrin;
d) about 4 mg of Croscarmellose sodium;
e) about 2.5 mg of stearic acid;
f) about 2.5 mg of barrier coating agent;
g) about 4.5 mg of film coating agent;
h) QS of Purified water, wherein said composition employs a fluid bed processor for granulation

In yet another aspect of the present invention, there is provided a stable pharmaceutical composition of Varenicline comprising:
a) about 0.3-10 mg of Varenicline Tartrate;
b) about 40-130 mg of Microcrystalline cellulose;
c) about 2-15 mg of Maltodextrin;
d) about 1-10 mg of Croscarmellose sodium;
e) about 1-7 mg of stearic acid;
f) about 1-10 mg of barrier coating agent;
g) about 2-10 mg of film coating agent;
h) QS of Purified water, wherein said composition employs a fluid bed processor for granulation

In one aspect of the present invention, there is provided a stable pharmaceutical composition of Varenicline comprising:
a) about 1.24% w/w of Varenicline Tartrate;
b) about 83.42% w/w of Microcrystalline cellulose;
c) about 5.47 %w/w of Maltodextrin;
d) about 2.91% w/w of Croscarmellose sodium;
e) about 1.82% w/w of stearic acid;
f) about 1.82% w/w of barrier coating agent;
g) about 3.28% w/w of film coating agent;
h) QS of Purified water, wherein said composition employs a fluid bed processor for granulation

In another aspect of the present invention, there is provided a stable pharmaceutical composition of Varenicline comprising:
a) about 0.5-5% w/w of Varenicline Tartrate;
b) about 40-90% w/w of Microcrystalline cellulose;
c) about 1-10 %w/w of Maltodextrin;
d) about 1-5% w/w of Croscarmellose sodium;
e) about 0.5-5% w/w of stearic acid;
f) about 1-10 % w/w of barrier coating agent;
g) about 1.5-7% w/w of film coating agent;
h) QS of Purified water, wherein said composition employs a fluid bed processor for granulation

In yet one aspect of the present invention, there is provided a process for preparation of a stable pharmaceutical compositions comprising;
a) Varenicline Tartrate, as an active ingredient;
b) a Diluent which is Microcrystalline cellulose;
c) a Binder which is Maltodextrin;
d) a Disintegrant which is Croscarmellose sodium;
e) a Lubricant which is stearic acid; and
f) one or more pharmaceutically acceptable excipients,
wherein the process comprising the steps of:
a) Co-sifting of microcrystalline cellulose and croscarmellose sodium;
b) Maltodextrin was dissolved in water followed by addition of Varenicline Tartarate to the binder solution to make drug-binder solution.
c) spraying of drug binder solution over the sifted material of step (a) in fluid bed processor (FBP) followed by drying;
d) The above blend was compressed into tablet followed by barrier coating and film coating.

DETAILED DESCRIPTION OF THE INVENTION

Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.

Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.

The publications discussed herein are provided solely for their availability to the applicant prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

The term "varenicline" used throughout the specification refers to not only varenicline per se, but also its other pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.

The term “substantially free of” as used herein refers to the Varenicline tartrate compositions having less than 20 ppm of the total Nitrosamine impurities in the tablet dosage form.
The term “stable” as used herein refers to chemical stability of Varenicline in oral solid dosage form wherein there is no change in assay values and/or the total organic impurity is less than 3% and the total Nitrosamine impurities are less than 20 ppm, when the dosage form is kept at 25°C ± 2°C and 60% RH ± 5% RH and 30°C ± 2°C and 65% RH ± 5% RH for 12 months.

The term “composition” as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amount, if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The term by “pharmaceutically acceptable” it is mean that the diluent, excipient or carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The terms “nitrosamine”, “N-nitroso-varenicline”, “(7,8,9,10-tetrahydro-8-nitroso-6,10-Methano-6H-pyrazino[2,3-h][3] benzazepine)” and “N-nitrosamine” are used interchangeably and should both be understood to refer to the following structure:

USFDA has identified seven nitrosamine impurities that theoretically could be present in drug products: N-nitrosodimethylamine (NDMA), Nnitrosodiethylamine (NDEA), N-nitroso-N-methyl-4-aminobutanoic acid (NMBA), N-nitrosoisopropylethyl amine (NIPEA), N-nitrosodiisopropylamine (NDIPA), N-nitrosodibutylamine (NDBA), and N-nitrosomethylphenylamine (NMPA). Five of them (NDMA, NDEA, NMBA, NIPEA, and NMPA) have actually been detected in drug substances or drug products.

More specifically “nitrosamine”, “(7,8,9,10-tetrahydro-8-nitroso-6,10-Methano-6H-pyrazino[2,3-h][3] benzazepine)”, “nitrosamine varenicline impurity”, “varenicline nitrosamine impurity” and “N-nitroso-varenicline” are used interchangeably herein.

In an embodiment, the present invention provides that the one or more pharmaceutically acceptable excipient(s) constituting the stable pharmaceutical compositions of varenicline are diluents, binders, disintegrants, glidants, lubricants and other suitable excipients.

Varenicline or its pharmaceutically acceptable salt is introduced to the inert carrier by techniques known to one skilled in the art such as drug layering, powder coating, extrusion/spheronization, spray dry process, fluid bed processor, roller compaction or dry/wet granulation. Preferably, Varenicline Tartrate is introduced by a method which is spraying a solution of varenicline Tartrate and a binder onto the inert carrier by using fluid bed processor (FBP) granulation technology.

The pharmaceutical compositions of the present invention comprise about 0.01 mg to about 100 mg of varenicline or its pharmaceutically acceptable salts thereof, preferably about 0.1 to about 50 mg, more preferably about 0.5 to about 1 mg.

In one aspect of the present invention, there is provided a stable pharmaceutical composition of varenicline or its pharmaceutically acceptable salts thereof comprising:
a) Varenicline Tartrate, as an active ingredient;
b) Diluent;
c) Binder;
d) Disintegrant;
e) Lubricant; and
f) one or more pharmaceutically acceptable excipient, wherein said composition employs a fluid bed processor for granulation

In another aspect of the present invention, there is provided a stable pharmaceutical composition of Varenicline comprising:
a) about 1.71 mg of Varenicline Tartrate;
b) about 114.29 mg of Microcrystalline cellulose;
c) about 7.50 mg of Maltodextrin;
d) about 4 mg of Croscarmellose sodium;
e) about 2.5 mg of stearic acid;
f) about 2.5 mg of barrier coating agent;
g) about 4.5 mg of film coating agent;
h) QS of Purified water, wherein said composition employs a fluid bed processor for granulation.

In yet another aspect of the present invention, there is provided a stable pharmaceutical composition of Varenicline comprising:
a) about 0.3-10 mg of Varenicline Tartrate;
b) about 40-130 mg of Microcrystalline cellulose;
c) about 2-15 mg of Maltodextrin;
d) about 1-10 mg of Croscarmellose sodium;
e) about 1-7 mg of stearic acid;
f) about 1-10 mg of barrier coating agent;
g) about 2-10 mg of film coating agent;
h) QS of Purified water, wherein said composition employs a fluid bed processor for granulation.

In one aspect of the present invention, there is provided a stable pharmaceutical composition of Varenicline comprising:
a) about 1.24% w/w of Varenicline Tartrate;
b) about 83.42% w/w of Microcrystalline cellulose;
c) about 5.47 %w/w of Maltodextrin;
d) about 2.91% w/w of Croscarmellose sodium;
e) about 1.82% w/w of stearic acid;
f) about 1.82% w/w of barrier coating agent;
g) about 3.28% w/w of film coating agent;
h) QS of Purified water, wherein said composition employs a fluid bed processor for granulation.

In another aspect of the present invention, there is provided a stable pharmaceutical composition of Varenicline comprising:
a) about 0.5-5% w/w of Varenicline Tartrate;
b) about 40-90% w/w of Microcrystalline cellulose;
c) about 1-10 %w/w of Maltodextrin;
d) about 1-5% w/w of Croscarmellose sodium;
e) about 0.5-5% w/w of stearic acid;
f) about 1-10 % w/w of barrier coating agent;
g) about 1.5-7% w/w of film coating agent;
h) QS of Purified water, wherein said composition employs a fluid bed processor for granulation.

In yet another aspect of the present invention, there is provided a process for preparation of a stable pharmaceutical compositions comprising;
a) Varenicline Tartrate, as an active ingredient;
b) Diluent which is Microcrystalline cellulose;
c) Binder which is Maltodextrin;
d) Disintegrant which is Croscarmellose sodium;
e) Lubricant which is stearic acid; and
f) one or more pharmaceutically acceptable excipients,
wherein the process comprising the steps of:
a) co-sifting of microcrystalline cellulose and croscarmellose sodium;
b) Maltodextrin was dissolved in water followed by addition of varenicline tartrate to the binder solution to make drug-binder solution.
c) spraying of drug binder solution over the sifted material of step (a) in fluid bed processor (FBP) followed by drying;
d) The above blend was compressed into tablet followed by barrier coating and film coating.

The pharmaceutical composition of the present invention may be developed in the form of a capsule, a tablet, a caplet and a mini-tablet. Preferably the dosage form is in the form of a tablet.

Diluents increase the bulk of a solid pharmaceutical composition. Exemplary diluents for solid compositions include, but are not limited to, microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, mannitol, polymethacrylates, potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc. The preferred diluent is Microcrystalline Cellulose. The fillers or diluents may be used in the range of about 40% w/w to about 90% w/w, preferably about 45% w/w to about 88% w/w, more preferably about 55% w/w to about 85% w/w of the total weight of stable oral pharmaceutical composition.

Solid pharmaceutical compositions that are compressed may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Exemplary binders for solid pharmaceutical compositions include, but are not limited to, acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate, polyvinylpyrrolidone (PVP K30 or PVP K 90) and starch. The preferred binder is Maltodextrin. The suitable maltodextrin grades which can be used are Glucidex 9 (Dextrose equivalent 8-10), Glucidex 12D (Dextrose equivalent 11-14) & Glucidex 17D (Dextrose equivalent 15-18).

The binders may be used in the range of about 1% w/w to about 20% w/w, preferably about 4% w/w to about 15% w/w, more preferably about 5% w/w to about 10% w/w of the total weight of stable oral pharmaceutical composition.

Disintegrants increase the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach, for example. Exemplary disintegrants include, but are not limited to, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate and starch. The preferred disintegrant is Croscarmellose sodium. The disintegrants may be used in the range of about 0.5% w/w to about 10% w/w, preferably about 1.5 % w/w to about 7% w/w, more preferably about 2% w/w to about 5% w/w of the total weight of stable oral pharmaceutical composition.

Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Exemplary excipients that may function as glidants include, but not limited to, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.

A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Exemplary lubricants include, but are not limited to, magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate. The lubricant may be used in the range of about 0.5% w/w to about 10% w/w, preferably about 1 % w/w to about 7% w/w, more preferably about 1.5% w/w to about 5% w/w of the total weight of stable oral pharmaceutical composition.

The barrier coating consists of Opadry clear 04K59023 (Mixture of Hypromellose and triacetin); and optional film coating of Opadry white 03F180011 (Mixture of Hypromellose, titanium dioxide and polyethylene glycol) and Opadry blue 03F505152 (Mixture of Hypromellose, polyethylene glycol, titanium dioxide, talc, FD&C Blue indigo carmine, FD&C blue brilliant blue aluminium lake, iron oxide yellow). The barrier coating may be present in the amount of 1% w/w to about 10% w/w and film coating may be present in amount of 1.5% w/w to about 7% w/w of the total weight of the composition.

An aspect of the present invention provides a stable pharmaceutical composition comprising varenicline as an aid to smoking cessation treatment.

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.

In a preferred embodiment, the granulation of the composition is done using a Fluid Bed Processor (FBP) equipment. The fluid bed granulation process (also known as agglomeration) involves suspending particles in an air stream and spraying a liquid from the top of the system down onto the fluidized bed (top-down spray). Particles in the path of the spray get slightly wet and become sticky. The sticky particles collide with other particles in the bed of material and adhere to them to form granules. In another embodiment, the granulation of the composition is done using a Fluid Bed Processor (FBP) equipment using a bottom-up spray (Wurster coating process).

In a preferred embodiment, the stable composition of Varenicline Tartrate is prepared by a process which comprises the steps of:
a) co-sifting of microcrystalline cellulose and croscarmellose sodium;
b) Dissolving of Maltodextrin in water followed by addition of varenicline tartrate to the binder solution to make drug-binder solution.
c) spraying of drug binder solution over the sifted material of step (a) in fluid bed processor (FBP) followed by drying;
d) compressing the blend obtained above into a tablet followed by barrier coating and film coating of the same.

The solid pharmaceutical compositions of the present invention is substantially free of undesirable nitrosamine impurities after 12 month of stability.

The method of analysis for detection of Nitrosamine impurities is provided by USFDA under the title “Liquid Chromatography-High Resolution Mass Spectrometry (LC-ESI-HRMS) Method for the Determination of Varenicline Nitroso-Drug Substance Related Impurity (NDSRI) in Chantix™ Drug Product and Varenicline Drug Substance” has been employed for testing of the Varenicline tartrate tablets of the invention. This method is published on USFDA’s website and can be accessed using the weblink: https://www.fda.gov/media/151470/download.

It should be appreciated that the invention can be embodied / aspects in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will convey the scope of the invention to those skilled in the art. Other features and embodiments of the invention will become apparent from the following examples, which are given for illustration of the invention rather than for limiting its intended scope.

The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.
Example -1
Table -1
S. No. Name of Ingredients Std. Qty. in mg/tab
1 Varenicline Tartrate 1.7
2 Microcrystalline cellulose 114.2
3 Croscarmellose Sodium 4
4 Maltodextrin 7.5
5 Stearic Acid 2.5
6 Opadry clear 2.5
7 Isopropyl Alcohol q.s.
8 Methylene Chloride q.s.
9 Opadry Blue/White 4.5
10 Water q.s.
Qs: Quantity sufficient

Example-2
Table-2
S. No. Name of Ingredients Std.Qty.in mg/tab
1 Varenicline tartrate 0.3-10
2 Microcrystalline cellulose 40-130
3 Croscarmellose Sodium 1-10
4 Maltodextrin 2-15
5 Stearic Acid 1-7
6 Opadry clear 1-10
7 Isopropyl Alcohol q.s.
8 Methylene Chloride q.s.
9 Opadry Blue/White 2-10
10 Water q.s.
Qs: Quantity sufficient

Example 3:
Table-3
S. No. Name of Ingredients % W/W
1 Varenicline Tartrate 0.5-5
2 Microcrystalline cellulose 40-90
3 Croscarmellose Sodium 1-5
4 Maltodextrin 1-10
5 Stearic Acid 0.5-5
6 Opadry clear 1-10
7 Isopropyl Alcohol q.s.
8 Methylene Chloride q.s.
9 Opadry Blue/White 1.5-7
10 Water q.s.
Qs: Quantity sufficient
Manufacturing process for example 1:
1) Sifting of Intra Granular material:
1.1) Microcrystalline cellulose and croscarmellose sodium were co-sifted through sieve size 18.
2) Granulation:
2.1) Preparation of Drug Binder Solution:
2.1.1) Maltodextrin was dissolved in purified water under constant stirring till clear solution was obtained.
2.1.2) Varenicline Tartrate was added under continuous stirring to the step no. 2.1.1 till clear solution was obtained.
2.2) Top spray Granulation:
2.2.1) The sifted material of step no. 1.1 was loaded in fluid bed processor (FBP).
2.2.2) The solution of step 2.1.2 was sprayed on the loaded material of 2.2.1 with optimum spray rate and dried subsequently.
3) The dried granules were sifted/milled through mechanical sifter/co-milled and lubricated with Stearic acid.
4) The granules of step 3 were compressed into tablet.
5) The tablets were barrier coated with opadry clear solution and onto this film coating was done with opadry Blue/white as per the strength of tablet.
The formulations of the invention exemplified in Example 1 were evaluated for stability at conditions of 25°C ± 2°C and 60% RH ± 5% RH, 40°C ± 2°C and 75%RH ± 5% RH for initial and 6M and 12M (months).

Stability Study: Example 1 at 25°C ± 2°C and 60%RH ± 5% RH for initial, 6M and 12M (months):
Table-4
Sr.No Tests Specification Station
1. Description Light blue, capsular biconvex, film coated tablets, debossed with ‘VC’ on one side and ‘1’ on other side. Initial 6M 12M
Complies
@ Complies
@ Complies
@
2. Water content (By K.F. Titration, w/w) Not more than 7.0% 4.2 3.5 3.7
3. Dissolution (By HPLC)

Not less than 80 % (Q) of the labeled amount of Varenicline (C13H13N3) is dissolved in 15 minutes. Min:95
Max:99
Avg:97 Min:100
Max:102
Avg:101 Min:98
Max:101
Avg:99
4. Organic Impurities (w/w, By HPLC)
i)DP1
ii)Varenicline N-Methyl impurity
iii) Varenicline N-formyl impurity
iv) Specified unidentified degradation product at RRT 0.88
v) Specified unidentified degradation product at RRT 0.91
vi) Specified unidentified degradation product at RRT 0.93
vii) Specified unidentified degradation product at RRT 0.95
viii) Any unspecified degradation Product
ix)Total degradation Products Not more than 1.0%
Not more than 1.0%
Not more than 1.0%

Not more than 0.5%

Not more than 0.5%

Not more than 0.5%

Not more than 0.5%

Not more than 0.5%

Not more than 2.5% ND
BLQ
BLQ

0.00

0.00

0.01

ND

0.03

0.1 ND
BLQ
BLQ

0.01

0.02

0.01

0.04

0.03

0.1 ND
0.1
BLQ

ND

ND

0.02

0.08

0.03

0.2
5. Assay (By HPLC, w/w)
Not less than 90.0% and not more than 110.0% of the labeled amount of Varenicline (C13H13N3). 100.8 100.3 99.4
6. Microbial enumeration tests
i)Total viable aerobic microbial count
ii) Total combined molds and yeast count
Tests for specified microorganisms
Escherichia Coli
Not more than 103 cfu/g
Not more than 102 cfu/g

Absent
< 10 cfu/g
< 10 cfu/g

Absent
< 10 cfu/g
< 10 cfu/g

Absent
< 10 cfu/g
< 10 cfu/g

Absent
7. Nitrosamine Impurities by LC-MS:
i) N-Nitroso-Varenicline(VRN-5000)
ii) VRN-5-1600

iii) VRN-6-1600

iv) Total Nitrosamine impurities

Not more than 18.5ppm
Not more than 5.26ppm
Not more than 5.26ppm
Not more than 18.5ppm

2.6ppm

1.93ppm

0.60ppm

5.1ppm

2.6ppm

0.05ppm

0.07ppm

2.7ppm

1.0ppm

ND

0.02ppm

1.0ppm

Stability Study: Example 1 at 30°C ± 2°C and 65%RH ± 5% RH for initial, 6M and 12M (months).
Table-5
Sr.No Tests Specification Station
1. Description Light blue, capsular biconvex, film coated tablets, debossed with ‘VC’ on one side and ‘1’ on other side. Initial 6M 12M
Complies
@ Complies
@ Complies
@
2. Water content (By K.F. Titration, w/w) Not more than 7.0% 4.2 3.6 3.9
3. Dissolution (By HPLC)

Not less than 80 % (Q) of the labeled amount of Varenicline (C13H13N3) is dissolved in 15 minutes. Min:95
Max:99
Avg:97 Min:100
Max:103
Avg:102 Min:98
Max:101
Avg:99
4. Organic Impurities (w/w, By HPLC)
i)DP1
ii)Varenicline N-Methyl impurity
iii) Varenicline N-formyl impurity
iv) Specified unidentified degradation product at RRT 0.88
v) Specified unidentified degradation product at RRT 0.91
vi) Specified unidentified degradation product at RRT 0.93
vii) Specified unidentified degradation product at RRT 0.95
viii) Any unspecified degradation Product
ix)Total degradation Products Not more than 1.0%
Not more than 1.0%
Not more than 1.0%

Not more than 0.5%

Not more than 0.5%

Not more than 0.5%

Not more than 0.5%

Not more than 0.5%

Not more than 2.5% ND
BLQ
BLQ

0.00

0.00

0.01

ND

0.03

0.1
ND
BLQ
BLQ

0.02

0.04

0.05

0.10

0.03

0.3 ND
0.1
BLQ

0.03

0.08

0.07

0.15

0.03

0.5
5. Assay (By HPLC, w/w)
Not less than 90.0% and not more than 110.0% of the labeled amount of Varenicline (C13H13N3). 100.8 99.7 98.7
6. Microbial enumeration tests
i)Total viable aerobic microbial count
ii) Total combined molds and yeast count
Tests for specified microorganisms
Escherichia Coli
Not more than 103 cfu/g
Not more than 102 cfu/g

Absent
< 10 cfu/g
< 10 cfu/g

Absent
< 10 cfu/g

< 10 cfu/g

Absent
< 10 cfu/g
< 10 cfu/g

Absent
7. Nitrosamine Impurities by LC-MS:
i) N-Nitroso-Varenicline(VRN-5000)
ii) VRN-5-1600

iii) VRN-6-1600

iv) Total Nitrosamine impurities

Not more than 18.5ppm
Not more than 5.26ppm
Not more than 5.26ppm
Not more than 18.5ppm

2.6ppm

1.93ppm

0.60ppm

5.1ppm

1.4ppm

0.03ppm

0.06ppm

1.4ppm

0.3ppm

ND

ND

0.3ppm

ND: Not Detected; BLQ: Below Limit of Quantification; cfu: Colony forming unit

All the physical and chemical parameters were found satisfactory and the initial, 6M and 12M stability data at 25°C ± 2°C and 60% RH ± 5% RH and 30°C ± 2°C and 65% RH ± 5% RH was found to be satisfactory.

To study the impact of Maltodextrin’s dextrose equivalent (DE) on physico-chemical properties on example 1:

Table 6: Physical Parameter of Example 1

Batch No. Maltodextrin Grade Hardness
(N) Thickness
(mm) Disintegration Time(Sec)
Core tablets
VNLT/FD000092/007 Glucidex 9 95-110 3.33-3.36 30-40
VNLT/FD000092/006 Glucidex 12D 90-105 3.30-3.36 30-45
VNLT/FD000092/008 Glucidex 17D 92-104 3.32-3.36 15-30
Coated tablets
VNLT/FD000092/007 Glucidex 9 100-110 3.42-3.46 45-65
VNLT/FD000092/006 Glucidex 12D 92-101 3.40-3.44 45-55
VNLT/FD000092/008 Glucidex 17D 94-108 3.38-3.43 35-45

Observation:
Based on the physical observation, the developmental batches of different grades of maltodextrin (with Glucidex 9, 12D & 17D) physical parameter (hardness, thickness and Disintegration time) are found satisfactory and comparable. There is no impact observed with different grades on physical parameters.

Physical Parameter of Varenicline Tablets 1mg after exposure of 7 days of example 1:
Developmental trial batches manufactured using Glucidex 9, Glucidex 12D & Glucidex 17D were kept in the proposed sealed 56’s count 40 cc HDPE bottle (without desiccant) at 25°C/60% RH, 30°C/65% RH, 40°C/75% RH & 50?/80% RH for 7 days to evaluate the physical parameter of samples.
Table 7: Dissolution Comparison with stress study data of example 1
Developmental trial batches manufactured using Glucidex 9, Glucidex 12D & Glucidex 17D were kept in the proposed sealed HDPE bottle (without desiccant) at 7 days at 50?/80%RH and dissolution data were generated.
Dissolution: 0.01N HCL, USP Type I (Basket), 100 RPM, 500 ml
Batch No. VNLT/FD000092/007 VNLT/FD000092/006 VNLT/FD000092/008
Time (min) Initial 7 days Initial 7 days Initial 7 days
5 99 97 97 96 100 98
10 98 97 97 96 99 98
15 98 97 97 96 100 98
20 98 97 97 96 100 98
30 98 97 97 96 100 97

Observations:
From the above dissolution data, formulations consisting of maltodextrins Glucidex 9 & Glucidex 17D which is having different DE values shows no significant changes in the stress study condition.

,CLAIMS:We claim:
1. A stable pharmaceutical composition comprising: a) Varenicline or pharmaceutically acceptable salts thereof b) binder and pharmaceutically acceptable excipients.

2. The stable pharmaceutical composition as claimed in claim 1, the binder is selected from the group consisting of acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate, polyvinylpyrrolidone, starch or combination thereof

3. The stable pharmaceutical composition as claimed in claim 2, wherein the binder is maltodextrin.

4. The stable pharmaceutical composition according to claim 1, wherein the composition further comprises diluents, binders, disintegrants, lubricants and film coating agents.

5. The stable pharmaceutical composition according to claim 1, wherein the composition comprises varenicline tartrate.

6. The stable pharmaceutical composition according to claim 1, wherein the composition comprises other excipients selected from microcrystalline cellulose, croscarmellose sodium, stearic acid or combination thereof

7. The stable pharmaceutical composition comprising: a) about 1.24% w/w of Varenicline Tartrate; b) about 83.42% w/w of Microcrystalline cellulose; c) about 5.47 %w/w of Maltodextrin; d) about 2.91% w/w of Croscarmellose sodium; e) about 1.82% w/w of Stearic acid; f) and pharmaceutically acceptable excipient thereof.

8. The stable pharmaceutical composition as claimed in claim 8, wherein the composition is prepared by a) co-sifting of microcrystalline cellulose and croscarmellose sodium; b) dissolving maltodextrin in water and adding varenicline tartrate to make drug-binder solution c) spraying of drug binder solution on material of step (a) in fluid bed processor and drying to obtain the blend and d) compressing the blend to obtain tablet.

9. The stable pharmaceutical composition in any of the preceding claims is prepared by using wet granulation.

10. The stable pharmaceutical composition in any of the preceding claims wherein the composition is substantially free of undesirable nitrosamine impurities.