DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10, Rule 13)

NICOTINE ORAL FILM AND PROCESS FOR PREPARATION THEREOF

We, AAVISHKAR ORAL STRIPS PVT LTD,
a company incorporated under the company’s Act, 1956 having address at
Plot No. 109/3, Phase II, Sector 2, Lane 6, IDA Cherlapally, Hyderabad, Telangana State, India- 500051
&
RAPID DOSE THERAPEUTICS CORP.
1121, Walkers Line, Burlington ON
L7N 2G4, Canada.

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF INVENTION
The present invention relates to novel oral film composition comprising Nicotine or its pharmaceutically acceptable salt thereof.

The present invention specifically relates to novel oral film composition comprising Nicotine or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients.

The present invention more specifically relates novel oral film composition comprising Nicotine or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from film-forming agents, anti-caking agents, pH Modifiers, disintegrants, humectants, sweetners, surfactants/wetting agents, flavoring agents, colorants, preservatives and carriers.

The present invention more specifically relates to process for the preparation of Nicotine or its pharmaceutically acceptable salt thereof.

BACKGROUND OF INVENTION
Central nervous system (CNS) conditions, diseases, or disorders can be drug induced; can be attributed to genetic predisposition, infection or trauma; or can be of unknown etiology. They comprise neuropsychiatric disorders, neurological diseases and mental illnesses; and include neurodegenerative diseases, behavioral disorders, cognitive disorders and cognitive affective disorders. The clinical manifestations of several CNS conditions, diseases or disorders have been attributed to CNS dysfunction (i.e., disorders resulting from inappropriate levels of neurotransmitter release, inappropriate properties of neurotransmitter receptors, and/or inappropriate interaction between neurotransmitters and neurotransmitter receptors).

Nicotinic compounds, such as nicotine, are capable of affecting nicotinic acetylcholinergic receptors (nAChRs). Subtypes of nAChRs exist in both the CNS and the peripheral nervous system (PNS), but the distribution of subtypes is heterogeneous. For instance, certain subtypes which are predominant in vertebrate brain, others predominate at the autonomic ganglia, and others predominate at neuromuscular junction. Activation of nAChRs by nicotinic compounds results in neurotransmitter release.

The potential roles of nicotine in COVID-19 pathology have recently been offered , study stated that that nicotine itself, through its interaction with the nicotinic cholinergic system, as well as ACE2, may not only be of use in a variety of neuropsychiatric and neurodegenerative diseases, but may also be of potential use in COVID-19.

Nicotinic compounds, such as nicotine, are capable of affecting nicotinic acetylcholinergic receptors (nAChRs). Subtypes of nAChRs exist in both the CNS and the peripheral nervous system (PNS), but the distribution of subtypes is heterogeneous. For instance, certain subtypes which are predominant in vertebrate brain, others predominate at the autonomic ganglia, and others predominate at neuromuscular junction. Activation of nAChRs by nicotinic compounds results in neurotransmitter release.

US 9,675,548 B2 discloses rapidly dissolving, oral film preparations for rapid release of Nicotine in the oral cavity, in particular, rapidly dissolving oral films comprising a nicotine active which achieve good transbuccal absorption and provide nicotine craving relief to an individual are disclosed herein.

US 8,469,036 B2 discloses an orally disintegrable smokeless tobacco product comprising a film comprising cured tobacco having an average particle size of 250 µm or less and a water-soluble polymer.

US8,613,285B2 discloses an extruded bioactive product comprising a sheet made by extruding or hot melt shaping a nonaqueous composition comprising at least one thermoplastic polymer, an ion exchange resin and a bioactive agent other than tobacco, the composition not containing polycarbophil, the sheet comprising a matrix comprising the at least one thermoplastic polymer and an ion exchange resin and bioactive agent complex distributed in the matrix, the matrix being soluble in the mucosa of a user and resulting in sustained release of the bioactive agent to the user.

US 9,155,321 B2 discloses the smokeless tobacco composition includes a tobacco material and a lipid having a melting point of about 36° C. to about 45° C. An associated process is also provided. The process includes melting a lipid having a melting point of about 36° C. to about 45° C to form a molten lipid composition, mixing a tobacco material with the molten lipid composition to form a molten smokeless tobacco composition, and cooling the molten smokeless tobacco composition to form a solidified smokeless tobacco composition.

US9,763,928B2 disclosesa multi-layered pharmaceutical composition comprising two or more formulations with varying properties. In some embodiments, the pharmaceutical compositions provide combinations of different organoleptic properties within the same product. In certain embodiment, these combinations allow for a modified release profile of active ingredients as the user enjoys the pharmaceutical composition.

US11,311,623B2 discloses a nicotine delivery product comprising, or even consisting essentially of, a population of nicotine-loaded cation exchange resin particles, said population comprises at least 50% (w/w) particles having a size in the range of 90-300 micron which provides an improved nicotine stability to oral dosage forms comprising the nicotine delivery product.

Still there is a need for a rapidly dissolving oral film that effectively delivers a nicotine active to a user in a sufficient amount to reduce or eliminate the steady or acute nicotine cravings associated with quitting tobacco usage.

None of the prior art references disclose Oral film compositions of present application specifically. The inventors of the present invention provide composition of oral film comprising Nicotine or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from film-forming agents, anti-caking agents, pH Modifiers, disintegrants, humectants, sweetners, surfactants/wetting agents, flavoring agents, colorants, preservatives and carriers. The inventors of present invention also provide a process for the preparation of Nicotine or its pharmaceutically acceptable salt thereof oral film.

OBJECTIVE OF INVENTION
The main objective of the present invention is to provide a novel oral film composition comprising Nicotine or its pharmaceutically acceptable salt thereof.

Another objective of the present invention is to provide a novel oral film composition comprising Nicotine or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients.

Still another objective of the present invention is to providea novel oral film composition comprising Nicotine or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from film-forming agents, anti-caking agents, pH Modifiers, disintegrants, humectants, sweetners, surfactants/wetting agents, flavoring agents, colorants, preservatives and carriers.

Still another objective of the present invention is to provide a process for the preparation of Nicotine or its pharmaceutically acceptable salt thereof oral film.

SUMMARY OF INVENTION
Accordingly, the present invention provides a novel oral film composition comprising Nicotine or its pharmaceutically acceptable salt thereof.

One embodiment of the present invention provides a novel oral film composition comprising Nicotine or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients.

One embodiment of the present invention provides a novel oral film composition comprising Nicotine or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from film-forming agents, anti-caking agents, pH modifiers, disintegrants, humectants, sweetners, surfactants/wetting agents, flavoring agents, colorants, preservatives and carriers.

One embodiment of the present invention provides a novel oral film composition comprising Nicotine or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the Nicotine salt is selected from nicotine bitartrate, nicotine oil, nicotine tartrate, nicotine polacrilex, nicotine citrate and nicotine maleate.

Another embodiment of the present invention provides a novel oral film composition comprising:
a) 10% to 50% (w/w) of Nicotine or its pharmaceutically acceptable salt thereof,
b) 1% to 30% (w/w) of pH modifiers,
c) 10% to 50% (w/w) of film forming agents,
d) 0.01% to 5% (w/w) of surfactants,
e) 0.1% to 10% (w/w) of humectants, and
f) 0.1% to 90% (w/w) of other pharmaceutically acceptable excipients.

Another embodiment of the present invention provides a novel oral film composition comprising:
a) 10% to 50% (w/w) of Nicotine bitartrate,
b) 1% to 30% (w/w) of pH modifiers,
c) 10% to 50% (w/w) of film forming agents,
d) 0.1% to 30% (w/w) of surfactants/wetting agents,
e) 0.1% to 10% (w/w) of humectants,
f) 1% to 20% (w/w) of anti-caking agents,
g) 5% to 30% of film forming agents,
h) 1% to 30% of disintegrants,
i) 0.001% to 1% of preservatives, and
j) 0.1% to 90% (w/w) of other pharmaceutically acceptable excipients.

Another embodiment of the present invention provides a novel oral film composition comprising:
a) 10% to 50% (w/w) of Nicotine Polacrilex,
b) 1% to 30% (w/w) of pH modifiers,
c) 10% to 50% (w/w) of film forming agents,
d) 0.1% to 30% (w/w) of surfactants/wetting agents,
e) 0.1% to 10% (w/w) of humectants,and
f) 0.1% to 90% (w/w) of other pharmaceutically acceptable excipients.

One embodiment of the present invention provides a novel oral film composition comprising Nicotine or its pharmaceutically acceptable salt thereof wherein other pharmaceutically acceptable excipients are flavoring agents, colorants, and carriers.

Yet another embodiment of the present invention provides a process for the preparation of Nicotine or its pharmaceutically acceptable salt thereof.

Yet another embodiment of the present invention provides a process for the preparation oforal film comprising the steps of:
(a) soaking of polymer solution,
(b) preparing of aqueous phase,
(c) preparing coloring agent,
(d) preparing oil phase, and
(e) adding polymers.

Yet another embodiment of the present invention provides a process for the preparation of oral film comprising the steps of:
(a) preparing of aqueous phase,
(b) preparing coloring agent,
(c) preparing mixture,
(d) preparing oil phase, and
(e) adding polymers.

Yet another embodiment of the present invention provides a process for the preparation of oral film comprising the steps of:
(a) adding film-forming agents to water under continuous stirring,
(b) dissolving pH modifier in purified water and mixing with step (a) solution,
(c) adding Nicotine bitatrate to water under continuous stirring and adding pH modifier, ant-caking agent, sweetner, disintegrant and preservative to the drug solution,
(d) adding colorant to purified water slowly under continuous stirring and adding to step (c),
(e) adding surfactants/wetting agents, humectants, flavoring agents and mixing to ensure for uniform mixing,
(f) adding step (e) to step (c) under continuous stirring,
(g) adding pH modifier, film forming agentsto step (c) and mixing,
(h) deaerating the slurry, and
(i) layering and drying.

Yet another embodiment of the present invention provides a process for the preparation of oral film comprising the steps of:
(a) adding Nicotine Polacrilex to water under continuous stirring,
(b) dissolving colorants in purified water under continuous stirring and adding to step (a) solution,
(c) adding surfactants to water under continuous stirring,
(d) dissolving pH modifier in purified water and mixing with step (c) solution,
(e) adding step (d) to step (a) under continuous stirring,
(f) mixing surfactants/wetting agents, humectantsand flavoring agents and adding to step (a),
(g) adding film forming agents in purified under stirring and mixing step (a) solution,
(h) deaerating the slurry, and
(i) layering and drying.

DETAILED DESCRIPTION OF THE INVENTION
The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

The present invention provides novel oral film composition comprising Nicotine or its pharmaceutically acceptable salts as active ingredient, pharmaceutically acceptable excipients and its process of preparation.

The present invention provides novel oral film composition comprising Nicotine or its pharmaceutically acceptable salts as active ingredient, wherein the film is mono-layer film.

The Nicotine salt is selected from nicotine bitartrate, nicotine oil, nicotine polacrilex, nicotine tartrate, nicotine citrate and nicotine maleate.

The concentration of Nicotine base or its salts used in the present invention is in the range of 10% to 50% (w/w) of the total weight of the composition.

One embodiment of the present invention provides a novel oral film composition comprising Nicotine or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from film-forming agents, anti-caking agents, pH Modifiers, disintegrants, humectants, sweetners, surfactants, flavoring agents, colorants, preservatives and carriers.

Film-forming agents used alone or in combination in the compositions of the present invention include, but are not limited to hydroxypropyl methylcellulose grades, hydroxy propyl cellulose, hydroxy propyl cellulose LV, low-substituted hydroxypropyl cellulose, sodium carboxy methyl cellulose, polyvinyl alcohol, polyvinyl acetate, hydroxyethyl cellulose (HEC), methylcellulose (MC), ethylcellulose (EC), polyvinyl pyrrolidone (copovidone), cyclodextrin and its derivatives, polyethyleneoxide, carrageenan, gelatin, dextrin, starch, pectin, sodium alginate, guar gum, gum arabic, xanthan gum, glycerol monooleate, maltodextrin, tragacanth gum, pullulan, mannitol, sorbitol, sodium citrate dihydrate, polyethylene glycol co-polymers, carboxylic acid containing polymers such as acrylic acid, methacrylic acid, methacrylic acid copolymer, esterified poly acrylic acid polymers, such as polyacrylic acid polymers lightly crosslinked with a polyalkenylpolyethers; methacrylate polymers; maleic acid copolymers; methacrylic acid-ethyl acrylate copolymers, methacrylic acid and methacrylate based polymers, and a methylmethacrylate copolymer.

The concentration of film-forming agents used in the present invention is in the range of 10% to 50% (w/w) of the total weight of the composition.

Anti-caking agents used alone or in combination in the compositions of the present invention include, but are not limited to mannitol, microcrystalline cellulose, maltodextrin, zein silicon dioxide, calcium silicate, sodium aluminosilicate, cellulose, talc and starch.

The concentration of anti-caking agents used in the present invention is in the range of 1% to 20% (w/w) of the total weight of the composition.

pH modifiers used alone or in combination in the compositions of the present invention include, but are not limited to meglumine, citric acid, sodium carbonate, sodium citrate dihydrate, trisodium citrate dihydrate, ascorbic acid, acetic acid, tartaric acid, citric acid monohydrate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium phosphate dibasic, sodium phosphate tribasic, disodium phosphate dibasic, potassium citrate, potassium phosphate dibasic, potassium phosphate tribasic, tricalcium phosphate, calcium carbonate, calcium phosphate, carbonated calcium phosphate, magnesium carbonate, sodium hydroxide, magnesium hydroxide, potassium hydroxide, aluminium hydroxide, and combinations thereof.

The concentration of pH modifiers used in the present invention is in the range of 1% to 30% (w/w) of the total weight of the composition.

Disintegrantsused alone or in combination in the compositions of the present invention include, but are not limited to croscarmellose cellulose, crospovidone and sodium starch glycollate.

The concentration of disintegrants used in the present invention is in the range of 1% to 30% (w/w) of the total weight of the composition.

Humectants used alone or in combination in the compositions of the present invention include, but are not limited to glycerin, hyaluronic acid, propylene glycol, polyethylene glycol and sorbitol.

The concentration of humectants used in the present invention is in the range of 0.1% to 10% (w/w) of the total weight of the composition.

Sweetners used alone or in combination in the compositions of the present invention include, but are not limited to natural and artificial sweeteners, monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose, dextrose, mannose, galactose, fructose, levulose, sucrose, high fructose corn syrup, maltose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, corn syrup solids, and sucralose, the potassium salt of 3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2,2-dioxide (acesulfame-K), L-aspartyl-L-phenylalanine methyl ester (aspartame), L-alpha-aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamide hydrate, methyl esters of L-aspartyl-L-phenylglycerin and L-aspartyl-L-2,5,dihydrophenylglycine, L-aspartyl-2,5-dihydro-L-phenylalanine, L-aspartyl-L-(1-cyclohexyen)-alanine, stevia, steviosides, monellin, neotame, alitame, sorbitol, mannitol, saccharin sodium.

The concentration of sweetners used in the present invention is in the range of 0.1% to 10% (w/w) of the total weight of the composition.

Surfactants/wetting agents used alone or in combination in the compositions of the present invention include, but are not limited to polysorbate, tween, span, sodium lauryl sulfate, castor oil derivatives, cetyl and palmityl alcohol, hydrogenated vegetable oils, polyvinyl alcohol, diethylene glycol monoethyl ether(transcutol hp), polyoxyl 40 castor oil (kolliphorerh 40), simethicone, sorbitan ester, glycerine, glyceryl monostearate, glycerol tri acetate, glycerol oleate,polyoxyethylene alkyl ethers, polyoxyethylene stearates, poloxamer, polyoxyethylene lauryl ether and polyoxyethylene sorbitan fatty acid esters.

The concentration of surfactants/wetting agents used in the present invention is in the range of 0.1% to 30% (w/w) of the total weight of the composition.

Preservatives used alone or in combination in the compositions of the present invention include, but are not limited to potassium sorbate, calcium sorbate, sodium benzoate and calcium propionate.

The concentration of preservativesused in the present invention is in the range of 0.001% to 1% (w/w) of the total weight of the composition.

Flavouring agents used alone or in combination in the compositions of the present invention include, but are not limited to natural and artificial flavors. These flavorings may be chosen from synthetic flavor oils and flavoring aromatics, and/or oils, oleo resins and extracts derived from plants, leaves, flowers, fruits and so forth, and combinations thereof. Non-limiting flavor oils include: spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, and oil of bitter almonds. Also useful are artificial, natural or synthetic fruit flavors such as vanilla, chocolate, coffee, cocoa and citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and the like. These flavorings can be used individually or in combination. Commonly used flavors include mints such as peppermint, winter mint flavor, eucalyptol, menthol bold flavors, artificial vanilla, cinnamon derivatives, and various fruit flavors, whether employed individually or in combination. Flavorings such as aldehydes and esters including cinnamylacetate, cinnamaldehyde, citral, diethylacetal, dihydrocarvyl acetate, eugenyl formate, p-methylanisole, and the like may also be used. Further examples of aldehyde flavorings include, but are not limited to acetaldehyde (apple); benzaldehyde (cherry, almond); cinnamaldehyde (cinnamon); citral, i.e., alpha citral (lemon, lime); neral, i.e. beta citral (lemon, lime); decanal (orange, lemon); ethyl vanillin (vanilla, cream); heliotropine, i.e., piperonal (vanilla, cream); vanillin (vanilla, cream); alpha-amyl cinnamaldehyde (spicy fruity flavors); butyraldehyde (butter, cheese); valeraldehyde (butter, cheese); citronellal (modifies, many types); decanal (citrus fruits); aldehyde C-8 (citrus fruits); aldehyde C-9 (citrus fruits); aldehyde C-12 (citrus fruits); 2-ethyl butyraldehyde (berry fruits); hexenal, i.e. trans-2 (berry fruits); tolyl aldehyde (cherry, almond); veratraldehyde (vanilla); 12,6-dimethyl-5-heptenal, i.e. melonal (melon); 2 dimethyloctanal (greenfruit); and 2-dodecenal (citrus, mandarin); cherry; anis flavour; grape; mixtures thereof; and the like, the concentration of flavouring agents used in the range of 0.1% to 10% (w/w) of the total weight of the composition.

Colorant used alone or in combination in the compositions of the present invention include, but are not limited to titanium dioxide, riboflavin, beta carotene, anthocyanidin, fuchsin, indigo-blue fuchsin, orange Yellow S, quinoline yellow, indigo-blue acid blue (indigotine lake), light blue and sunset yellow, the concentration of colorant used in the range of 0.01% to 10% (w/w) of the total weight of the composition.

Carriers used alone or in combination in the compositions of the present invention include, but are not limited to water, methanol, ethanol, propanol, or low alkyl alcohols such as isopropyl alcohol, or acetone. Other suitable solvents may comprise dimethyl acetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, ethoxydiglycol, propylene glycol, polyethylene glycol.

The present invention is illustrated in detail but not limiting to, the following examples. 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.

Example 1:

Name of the Ingredient Function Quantity mg/ Strip
1mg 2mg 3mg 4mg 5mg
Nicotine as Nicotine Bi tartrate Active 3.647 7.294 10.941 14.588 18.235
Sodium bicarbonate pH modifier 4.500 9.000 13.500 10.000 12.500
Pullulan# Thickener 2.957 5.914 8.871 8.466 10.580
Mannitol Anti-caking agent 2.000 4.000 6.000 6.990 8.738
Hydroxy Propyl methyl cellulose 5cps Polymer 1.733 3.466 5.199 4.500 5.625
Methacrylic acid Copolymer Co Polymer 1.575 3.150 4.725 4.000 5.000
Cross linked sodium carboxyl
methyl cellulose Disintegrant 1.500 3.000 4.500 3.150 3.938
Glycerol Humectant 1.375 2.750 4.125 3.020 3.775
Winter mint flavor Flavor 1.125 2.250 3.375 3.000 3.750
Titanium Di oxide Coloring agent 1.000 2.000 3.000 3.000 3.750
Meglumine pH modifier 1.000 2.000 3.000 2.000 2.500
Sucralose Sweetener 0.750 1.500 2.250 2.000 2.500
Menthol Bold crystals Flavor 0.500 1.000 1.500 1.500 1.875
Polysorbate 80 Surfactant 0.475 0.950 1.425 1.500 1.875
Glycerol Tri acetate Wetting agent 0.375 0.750 1.125 1.038 1.298
Eucalyptol Flavor 0.260 0.520 0.780 0.950 1.188
Sodium hydroxide pH modifier 0.158 0.316 0.474 0.158 0.198
Glycerol oleate Wetting agent 0.050 0.100 0.150 0.100 0.125
Potassium sorbate Preservative 0.020 0.040 0.060 0.040 0.050
Purified Water Carrier Qs* Qs* Qs* Qs* Qs*
Theoretical strip weight in mg 25.000 50.000 75.000 70.000 87.500
Film Dimension(mm)+/-1 15x19 15x19 15x19 15x19 17x21
Thickness (µ)+/-10 µ 180 µ 200 µ 220 µ 240 µ 260 µ

Example 2:

Name of the Ingredient Function Quantity mg/ Strip
6mg 7mg 8mg 9mg 12mg
Nicotine as Nicotine Bi tartrate Active 21.882 25.529 29.176 32.823 43.764
Sodium bicarbonate pH modifier 15.000 17.500 20.000 22.500 30.000
Pullulan# Thickener 12.699 14.813 16.932 19.046 25.398
Mannitol Anti-caking agent 10.485 12.233 13.980 15.728 20.970
Hydroxy Propyl methyl cellulose 5cps Polymer 6.750 7.875 9.000 10.125 13.500
Methacrylic acid Copolymer Co Polymer 6.000 7.000 8.000 9.000 12.000
Cross linked sodium carboxyl
methyl cellulose Disintegrant 4.725 5.513 6.300 7.088 9.450
Glycerol Humectant 4.530 5.285 6.040 6.795 9.060
Winter mint flavor Flavor 4.500 5.250 6.000 6.750 9.000
Titanium Di oxide Coloring agent 4.500 5.250 6.000 6.750 9.000
Meglumine pH modifier 3.000 3.500 4.000 4.500 6.000
Sucralose Sweetener 3.000 3.500 4.000 4.500 6.000
Menthol Bold crystals Flavor 2.250 2.625 3.000 3.375 4.500
Polysorbate 80 Surfactant 2.250 2.625 3.000 3.375 4.500
Glycerol Tri acetate Wetting agent 1.557 1.817 2.076 2.336 3.114
Eucalyptol Flavor 1.425 1.663 1.900 2.138 2.850
Sodium hydroxide pH modifier 0.237 0.277 0.316 0.356 0.474
Glycerol oleate Wetting agent 0.150 0.175 0.200 0.225 0.300
Potassium sorbate Preservative 0.060 0.070 0.080 0.090 0.120
Purified Water Carrier Qs* Qs* Qs* Qs* Qs*
Theoretical strip weight in mg 105.000 122.500 140.000 157.500 210.000
Film Dimension(mm)+/-1 17x21 17x21 17x21 18x28 18x28
Thickness (µ)+/-10 µ 280 µ 300 µ 320 µ 340 µ 380 µ

Manufacturing procedure for example 1 and 2

1. Soaking of Polymer solution:

1.1 Take required quantity of purified water and add slowly Methacrylic acid copolymer (Acry coat L100) under continuous stirring.
1.2 Take small quantity of purified water and dissolve weighed quantity of Sodium hydroxide pellets and ensure the solubility of Pellets.
1.3 Add step 2 to step 1 slowly under continuous stirring for 45min and ensure the uniform mixing
2. Preparation of Aqueous Phase:

2.1 Take required Quantity of Purified water and add weighed quantity of Nicotine Bi tatrate under continuous stirring at 500RPM for 10min and ensure the solubility.
2.2 Add Meglumine, Mannitol, Sucralose, Cross-linked sodium carboxyl methyl cellulose and Potassium sorbate to step 2.1 under continuous stirring for 10 min at 500RPM and ensure the solubility of each ingredient.

3. Preparation of Coloring agent:

3.1 Take required quantity of Purified water and add Titanium Di oxide slowly under continuous stirring for 10 min at 500RPM and added to above step 2.2 slowly.

4. Preparation of Oil Phase:

4.1 Take SS vessel and add Tween 80, Glycerol, Glycerol tri acetate, Glycerol oleate, winter mint flavor, Menthol bold crystals and Eucalyptol flavor and mix for 15 min at 500RPM and ensure the uniform mixing of each ingredient, than add to to Aqueous phase under continuous stirring for 30 min at 500RPM ensure the mixing of both phases.

5. Addition of Polymers

5.1 Add weighed quantity of Sodium bi carbonate Slowly to the above step 2 Under continuous slow stirring (Note: avoide the Foam generation during the addition)
5.2 Add hydroxy propyl methyl cellulose, Pullulan under stirring for 45 min at 1000RPM and ensure the solubility of both polymers.
5.3 Add above Soaked Polymer (Step-1) slowly with High speed mixing for 30min and ensure the uniform mixing of polymer.
Note: The complete Formulation process should be done in the presence of Sodium vapor lamp

6. DEAERATION

The above slurry was applied to negative vacuum pressure to remove the air present in it.

7. Layering and Drying

The Degassing slurry was layered and dried

Results

S.No Parameter Specification
1. Description White Colored, Rectangular/Oval shape/ Hexagone transparent Strips.
2. Moisture Content (w/w) Not more than 3.0 – 10.0%
3. Disintegation Not more than 5 minutes
4 Drug Release Not less than 90% within 5 min

Example 3:
Name of the Ingredient Function 1mg 2mg 3mg 4mg 5mg
Pullulan Thickener 8.678 17.355 26.036 26.611 43.393
Nicotine as Nicotine Polacrilex Active 5.374 10.750 16.121 21.494 26.868
Diethylene glycol monoethyl ether(Transcutol HP) Surfactant 1.250 2.500 3.750 2.500 6.250
Polyoxyl 40 castor oil (Kolliphore RH 40) Surfactant 1.250 2.500 3.750 2.500 6.250
Polysorbate 80 Surfactant 0.023 0.045 0.068 0.045 0.113
Akrysol K-140 Co Surfactant 0.225 0.450 0.675 0.450 1.125
Meglumine pH modifier 0.200 0.400 0.600 0.400 1.000
Sorbitol Humectant 1.250 2.500 3.750 2.500 6.250
Titanium dioxide Colorant 0.750 1.500 2.250 1.500 3.750
Winter mint flavor Flavor 2.250 4.500 6.750 4.500 11.250
Sodium Hydroxide pH modifier 1.250 2.500 3.750 2.500 6.250
Glycerin Wetting agent 2.500 5.000 7.500 5.000 12.500
Purified Water Carrier Qs* Qs* Qs* Qs* Qs*
Theoretical strip weight in mg 25.000 50.000 75.000 70.000 125.000
Film Dimension(mm)+/-1 15x19 15x19 15x19 15x19 17x21
Thickness (µ)+/-10 µ 180 µ 200 µ 220 µ 240 µ 260 µ

Example 4:
Name of the Ingredient Function 6mg 7mg 8mg 9mg 12mg
Pullulan Thickener 52.072 60.751 53.222 78.108 104.144
Nicotine as Nicotine Polacrilex Active 32.242 37.616 42.988 48.363 64.484
Diethylene glycol monoethyl ether
(Transcutol HP) Solubililzer 7.500 8.750 5.000 11.250 15.000
Polyoxyl 40 castor oil (Kolliphore RH 40) Solubililzer 7.500 8.750 5.000 11.250 15.000
Polysorbate 80 Surfactant 0.136 0.159 0.090 0.204 0.272
Akrysol K-140 Co Surfactant 1.350 1.575 0.900 2.025 2.700
Meglumine pH modifier 1.200 1.400 0.800 1.800 2.400
Sorbitol Humectant 7.500 8.750 5.000 11.250 15.000
Titanium dioxide Colorant 4.500 5.250 3.000 6.750 9.000
Winter mint flavor Flavor 13.500 15.750 9.000 20.250 27.000
Sodium Hydroxide pH modifier 7.500 8.750 5.000 11.250 15.000
Glycerin Wetting agent 15.000 17.500 10.000 22.500 30.000
Purified Water Carrier Qs* Qs* Qs* Qs* Qs*
Theoretical strip weight in mg 150.000 175.000 140.000 225.000 300.000
Film Dimension(mm)+/-1 17x21 17x21 17x21 18x28 18x28
Thickness (µ)+/-10 µ 280 µ 300 µ 320 µ 340 µ 380 µ

Manufacturing procedure for Example 3 and 4:

1. Preparation of Aqueous Phase:

1.1 Take required Quantity of Purified water and add weighed quantity of Nicotine Polacrilex under continuous stirring at 500RPM for 10min and ensure the solubility.
2. Preparation of Coloring agent:

2.1 Take required quantity of Purified water and add Titanium Di oxide slowly under continuous stirring for 10 min at 500RPM and added to above step 1.1slowly.

3. Preparation of Aqueous Phase:

3.1 Take required quantity of purified water and add slowly (Akrysol K-140), Transcutol HP under continuous stirring.
3.2 Take small quantity of purified water and dissolve weighed quantity of Sodium hydroxide pellets and ensure the solubility of Pellets and add to step 3.1
3.3 Add the step 3 to step 1 under continuous stirring for 10 min at 500RPM and ensure the solubility of both phases.
4. Preparation of S mix:

4.1 Take required Quantity of Transcutol HP and Kolliphore RH40 under Magnetic stirring at Heating process Temperature 40°C RPM for 10min and ensure the solubility than added to Aqueous phase.
5. Preparation of Oil Phase:

5.1 Take SS vessel and add Polysorbate 80, Glycerol, Sorbitol, meglumine, winter mint and mix for 15 min at 500RPM and ensure the uniform mixing of each ingredient, than add to Aqueous phase under continuous stirring for 30 min at 500RPM ensure the mixing of both phases.

6. Addition of Polymers

6.1 Add Pullulan to the aqueous phase under stirring for 45 min at 1000RPM and ensure the solubility of polymer.

7. DEAERATION

The above slurry was applied to negative vacuum pressure to remove the air present in it.

8. Layering and Drying

The Degassing slurry was layered and dried

Results

S.No Parameter Specification
1. Description White Colored, Rectangular/Oval shape/ Hexagone transparent Strips.
2. Moisture Content (w/w) Not more than 3.0 – 10.0%
3.. Disintegration Not more than 5 minutes
4 Drug Release Not less than 90% within 5 min

Applicant has done stability studies of oral films of the present application and the data is given below:

S.No Tests Specification 40°C ± 2°C / 75 % ± 5 % RH
Initial 1 month 3 month 6 months
1. Description White to Off white coloured rectangular shaped dried oral strips. Complies Complies Complies Complies
2. Identification (By HPLC) a. Nicotine Bitartarate Dihydrate The retention time of the peak in the test solution corresponds to the chromatogram of the standard solution as obtained in the assay. Complies Complies Complies Complies
3. Average Weight (mg) & Weight Variation 70.00 ± 10 % (Between 63.00 to 77.00 ) 70.41 mg 70.48 mg 72.03 mg 72.26 mg
4. Moisture content (% w/w) Between 3.00 to 8.00 5.62 % 5.72 % 5.98 % 6.06 %
5. Disintegration time Not more than 60 seconds 40 seconds 38
seconds 30
seconds 27
Seconds
6. Assay : Each Strip Contains
a) Nicotine as
(Nicotine Bitartrate Dihydrate) 4mg Not less than 90.0% and Not more than110.0% 109.20 % 108.68 % 107.25 % 106.25 %
7. Dissolution by HPLC Not less than 70.0% 99.93 % 99.32 % 98.45 % 98.23 %
8. Microbial Count:

a) Total Aerobic Microbial Count b) Total Yeast and mould Count Pathogens:
i) Escherichia coli
ii) Salmonella
iii) Pseudomonas aeruginosa
iv) Staphylococcus aureus

Not more than 10,000 cfu/g
Not more than 100 cfu/g

Should be absent/ g Should be absent/ 25g Should be absent/ g
Should be absent/ g

30 cfu/g

<10 cfu/g

Absent/g Absent/25g Absent/g Absent/g NA NA

58 cfu/g

2 cfu/g

Absent/g Absent/25g Absent/g Absent/g

S.No Tests Specification 25°C ± 2°C / 60 % ± 5 % RH
Initial 3 month 6 months 9 months
1. Description White to Off white coloured rectangular shaped dried oral strips. Complies Complies Complies Complies
2. Identification (By HPLC) a. Nicotine Bitartarate Dihydrate The retention time of the peak in the test solution corresponds to the chromatogram of the standard solution as obtained in the assay. Complies Complies Complies Complies
3. Average Weight (mg) & Weight Variation 70.00 ± 10 % (Between 63.00 to 77.00 ) 70.41 mg 71.03 mg 71.22 mg 71.58 mg
4. Moisture content (% w/w) Between 3.00 to 8.00 5.62 % 5.88 % 6.05 % 6.23 %
5. Disintegration time Not more than 60 seconds 40 seconds 35
seconds 28
seconds 25
Seconds
6. Assay : Each Strip Contains
a) Nicotine as
(Nicotine Bitartrate Dihydrate) 4mg Not less than 90.0% and Not more than110.0% 109.20 % 108.35 % 107.21 % 106.25 %
7. Dissolution by HPLC Not less than 70.0% 99.93 % 99.44 % 99.12 % 98.72 %
8. Microbial Count:

a) Total Aerobic Microbial Count b) Total Yeast and mould Count Pathogens:
i) Escherichia coli
ii) Salmonella
iii) Pseudomonas aeruginosa
iv) Staphylococcus aureus

Not more than 10,000 cfu/g
Not more than 100 cfu/g

Should be absent/ g Should be absent/ 25g Should be absent/ g
Should be absent/ g

30 cfu/g

<10 cfu/g

Absent/g Absent/25g Absent/g Absent/g NA 50 cfu/g
1 cfu/g

Absent/g Absent/25g Absent/g Absent/g

Stability data for Examples 3 & 4
S.No Tests Specification 40°C ± 2°C / 75 % ± 5 % RH
Initial 1 months 3 months 6 months
1. Description White to Off white coloured rectangular shaped dried oral strips. Complies Complies Complies Complies
2. Identification (By HPLC) a. Nicotine Polacrilex The retention time of the peak in the test solution corresponds to the chromatogram of the standard solution as obtained in the assay. Complies Complies Complies Complies
3. Average Weight (mg) & Weight Variation 70.00 ± 10 % (Between 63.00 to 77.00) 70.41 mg 70.55 mg 71.20 mg 71.50 mg
4. Moisture content (% w/w) Between 3.00 to 8.00 4.42 % 4.48 % 4.60 % 4.70 %
5. Disintegration time Not more than 60 seconds 30 Seconds
29 Seconds 25 Seconds 24 seconds
6. Assay : Each Strip Contains
a) Nicotine as
(Nicotine Polacrilex) 4 mg Not less than 90.0% and Not more than110.0% 106.8 % 106.1% 105.0 % 104.6%
7. Dissolution by HPLC NLT 70.0% of the labelled amount of Nicotine Polacrilex 4 mg is dissolved in 30 minutes 99.9 % 98.8 % 96.7 % 95.4%
8. Microbial Count:

a) Total Aerobic Microbial Count b) Total Yeast and mould Count Pathogens:
i) Escherichia coli
ii) Salmonella
iii) Pseudomonas aeruginosa
iv) Staphylococcus aureus

Not more than 10,000 cfu/g
Not more than 100 cfu/g

Should be absent/ g Should be absent/ 25g Should be absent/ g
Should be absent/ g

40 cfu/g <10 cfu/g

Absent/g Absent/25g Absent/g Absent/g NA NA
50 cfu/g

2 cfu/g

Absent/g Absent/25g Absent/g Absent/g

S.No Tests Specification 25°C ± 2°C / 60 % ± 5 % RH
Initial 3 months 6 months 9 months
1. Description White to Off white coloured rectangular shaped dried oral strips. Complies Complies Complies Complies
2. Identification (By HPLC) a. Nicotine Polacrilex The retention time of the peak in the test solution corresponds to the chromatogram of the standard solution as obtained in the assay. Complies Complies Complies Complies
3. Average Weight (mg) & Weight Variation 70.00 ± 10 % (Between 63.00 to 77.00 ) 70.40 mg 71.03 mg 72.25 mg 72.40 mg
4. Moisture content (% w/w) Between 3.00 to 8.00 4.42 % 4.52 % 4.60 % 4.68 %
5. Disintegration time Not more than 60 seconds 30 Seconds 27 Seconds 25
seconds 20
Seconds
6. Assay : Each Strip Contains
a) Nicotine as
(Nicotine Polacrilex) 4 mg Not less than 90.0% and Not more than110.0% 106.8 % 106.1% 105.8 % 105.0 %
7. Dissolution by HPLC Not less than 70.0% 99.93 % 99.44 % 99.12 % 98.72 %

As per the above results the film products of the present invention complies with all specifications.

,CLAIMS:WE CLAIM:

1. A novel oral film composition comprising Nicotine or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from film-forming agents, anti-caking agents, pH modifiers, disintegrants, humectants, sweetners, surfactants/wetting agents, flavoring agents, colorants, preservatives and carriers.

2. The composition as claimed in claim 1, wherein Nicotine salt is selected from nicotine bitartrate, nicotine oil, nicotine polacrilex, nicotine tartrate, nicotine citrate and nicotine maleate, present in the range of 10% to 50% (w/w) of the total weight of the composition.

3. The composition as claimed in claim 1, wherein film-forming agents selected from hydroxypropyl methylcellulose grades, hydroxy propyl cellulose, hydroxy propyl cellulose LV, low-substituted hydroxypropyl cellulose, sodium carboxy methyl cellulose, polyvinyl alcohol, polyvinyl acetate, hydroxyethyl cellulose (HEC), methylcellulose (MC), ethylcellulose (EC), polyvinyl pyrrolidone (copovidone), cyclodextrin and its derivatives, polyethylene oxide, carrageenan, gelatin, dextrin, starch, pectin, sodium alginate, guar gum, gum arabic, xanthan gum, glycerol monooleate, maltodextrin, tragacanth gum, pullulan, mannitol, sorbitol, sodium citrate dihydrate, polyethylene glycol co-polymers, carboxylic acid containing polymers such as acrylic acid, methacrylic acid, methacrylic acid copolymer, esterified poly acrylic acid polymers, such as polyacrylic acid polymers lightly crosslinked with a polyalkenylpolyethers; methacrylate polymers; maleic acid copolymers; methacrylic acid-ethyl acrylate copolymers, methacrylic acid and methacrylate based polymers, and a methylmethacrylate copolymer, the concentration of film-forming agents used in the range of 10% to 50% (w/w) of the total weight of the composition.

4. The composition as claimed in claim 1, wherein anti-caking agents selected from mannitol, microcrystalline cellulose, maltodextrin, zein silicon dioxide, calcium silicate, sodium aluminosilicate, cellulose, talc and starch, the concentration of anti-caking agents used in the range of 1% to 30% (w/w) of the total weight of the composition.

5. The composition as claimed in claim 1, whereinpH modifiers are selected meglumine, citric acid, sodium carbonate, sodium citrate dihydrate, trisodium citrate dihydrate, ascorbic acid, acetic acid, tartaric acid, citric acid monohydrate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium phosphate dibasic, sodium phosphate tribasic, disodium phosphate dibasic, potassium citrate, potassium phosphate dibasic, potassium phosphate tribasic, tricalcium phosphate, calcium carbonate, calcium phosphate, carbonated calcium phosphate, magnesium carbonate, sodium hydroxide, magnesium hydroxide, potassium hydroxide, aluminium hydroxide, and combinations thereof, the concentration of pH Modifiers used in the range of 1% to 30% (w/w) of the total weight of the composition.

6. The composition as claimed in claim 1, wherein disintegrants selected fromcroscarmellose cellulose, crospovidone and sodium starch glycollate, the concentration of disintegrants used in the range of 1% to 30% (w/w) of the total weight of the composition.

7. The composition as claimed in claim 1, wherein humectants selected from glycerin, hyaluronic acid, propylene glycol, polyethylene glycol and sorbitol, the concentration of humectants used in the range of 0.1% to 10% (w/w)of the total weight of the composition.

8. The composition as claimed in claim 1, wherein sweeteners are selected fromnatural and artificial sweeteners, monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose, dextrose, mannose, galactose, fructose, levulose, sucrose, high fructose corn syrup, maltose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, corn syrup solids, and sucralose, the potassium salt of 3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2,2-dioxide (acesulfame-K), L-aspartyl-L-phenylalanine methyl ester (aspartame), L-alpha-aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamide hydrate, methyl esters of L-aspartyl-L-phenylglycerin and L-aspartyl-L-2,5,dihydrophenylglycine, L-aspartyl-2,5-dihydro-L-phenylalanine, L-aspartyl-L-(1-cyclohexyen)-alanine, stevia, steviosides, monellin, neotame, alitame, sorbitol, mannitol, saccharin sodium, the concentration of sweetners used in the range of 0.1% to 10% (w/w) of the total weight of the composition.

9. The composition as claimed in claim 1, wherein surfactants/wetting agents are selected frompolysorbate, tween, span, sodium lauryl sulfate, castor oil derivatives, cetyl and palmityl alcohol, hydrogenated vegetable oils, polyvinyl alcohol, diethylene glycol monoethyl ether (transcutol hp), polyoxyl 40 castor oil (kolliphorerh 40), simethicone, sorbitan ester, glycerine, glyceryl monostearate, glycerol tri acetate, glycerol oleate, polyoxyethylene alkyl ethers, polyoxyethylene stearates, poloxamer, polyoxyethylene lauryl ether and polyoxyethylene sorbitan fatty acid esters, the concentration of surfactants used in the range of 0.1% to 30% (w/w) of the total weight of the composition.

10. The composition as claimed in claim 1, wherein preservatives are selected from potassium sorbate, calcium sorbate, sodium benzoate and calcium propionate, the concentration of preservatives used in the range of 0.001% to 1% (w/w) of the total weight of the composition.

11. The composition as claimed in claim 1, wherein flavouring agents are selected from synthetic flavor oils and flavoring aromatics, oleo resins and extracts derived from plants, leaves, flowers, fruits, and combinations thereof,winter mint flavor, menthol, spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, eucalyptol cedar leaf oil, oil of nutmeg, oil of sage, and oil of bitter almonds, vanilla, chocolate, coffee, cocoa and citrus oil, lemon, orange, grape, lime and grapefruit, apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, cinnamylacetate, cinnamaldehyde, citral, diethylacetal, the concentration of flavouring agents used in the range of 0.1% to 10% (w/w) of the total weight of the composition.

12. The composition as claimed in claim 1, wherein colorant is selected from titanium dioxide, riboflavin, beta carotene, anthocyanidin, fuchsin, indigo-blue fuchsin, orange Yellow S, quinoline yellow, indigo-blue acid blue, light blue and sunset yellow, the concentration of colorant used in the range of 0.01% to 10% (w/w) of the total weight of the composition.

13. The composition as claimed in claim 1, wherein carriers are selected from water, methanol, ethanol, propanol, or low alkyl alcohols such as isopropyl alcohol, or acetone. Other suitable solvents may comprise dimethyl acetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, ethoxydiglycol, propylene glycol, polyethylene glycol.

14. The composition as claimed in claim 1, oral film composition comprising:
a) 10% to 50% (w/w) of Nicotine bitartrate,
b) 1% to 30% (w/w) of pH modifiers,
c) 10% to 50% (w/w) of film forming agents,
d) 0.1% to 30% (w/w) of surfactants/wetting agents,
e) 0.1% to 10% (w/w) of humectants,
f) 1% to 20% (w/w) of anti-caking agents,
g) 5% to 30% of film forming agents,
h) 1% to 30% of disintegrants,
i) 0.001% to 1% of preservatives, and
j) 0.1% to 90% (w/w) of other pharmaceutically acceptable excipients.

15. The composition as claimed in claim 1, oral film composition comprising:
a) 10% to 50% (w/w) of Nicotine Polacrilex,
b) 1% to 30% (w/w) of pH modifiers,
c) 10% to 50% (w/w) of film forming agents,
d) 0.1% to 30% (w/w) of surfactants/wetting agents,
e) 0.1% to 10% (w/w) of humectants, and
f) 0.1% to 90% (w/w) of other pharmaceutically acceptable excipients.

16. The process for the preparation of oral film comprising as claimed in claim 14, comprising the steps of:
(a) adding film-forming agents to water under continuous stirring,
(b) dissolving pH modifier in purified water and mixing with step (a) solution,
(c) adding Nicotine bitatrate to water under continuous stirring and adding pH modifier, ant-caking agent, sweetner, disintegrant and preservative to the drug solution,
(d) adding colorant to purified water slowly under continuous stirring and adding to step (c),
(e) adding surfactants/wetting agents, humectants, flavoring agents and mixing to ensure for uniform mixing,
(f) adding step (e) to step (c) under continuous stirring,
(g) adding pH modifier, film forming agents to step (c) and mixing,
(h) deaerating the slurry, and
(i) layering and drying.

17. The process for the preparation of oral film comprising as claimed in claim 15, comprising the steps of:
(a) adding Nicotine Polacrilex to water under continuous stirring,
(b) dissolving colorants in purified water under continuous stirring and adding to step (a) solution,
(c) adding surfactants to water under continuous stirring,
(d) dissolving pH modifier in purified water and mixing with step (c) solution,
(e) adding step (d) to step (a) under continuous stirring,
(f) mixing surfactants/wetting agents, humectants and flavoring agents and adding to step (a),
(g) adding film forming agents in purified under stirring and mixing step (a) solution,
(h) deaerating the slurry, and
(i) layering and drying.