DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10, Rule 13)

NICOTINEBILAYER 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 bi-layer oral film composition comprising Nicotine or its pharmaceutically acceptable salt thereof.

The present invention relates to novel Nicotine bi-layer oral film composition comprising sustained release drug layer and backing layer.

The present invention specifically relates to novel bi-layer oral film composition comprising Nicotine or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the bi-layer oral film provides sustained release of drug.

The present invention more specifically relates to process for the preparation of Nicotine bi-layer oral film.

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.

US 8,613,285 B2 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 which 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.

US 9,763,928 B2 discloses a 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.

US 11,311,623 B2 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.

None of the prior art references disclose novel nicotine bi-layer oral film composition of present invention. The inventors of the present invention provide composition of sustained release bi-layer oral film comprising Nicotine or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected. The inventors of present invention also provide a process for the preparation of Nicotine bi-layer oral film.

The prior art nicotine containing oral films, do not address the difficulty associated with maximizing absorption of the nicotine active through the oral mucosa. Thus, there remains a need in the art for a slower disintegrating oral film that disintegrates at a rate that maximizes the absorption of the nicotine active through the oral mucosa, which thereby effectively delivers a dose of nicotine active to a user in a sufficient amount to reduce or eliminate nicotine cravings associated with the cessation of tobacco usage.

Encapsulating nicotine using the spray drying method of present invention has several unique advantages compared to other encapsulation techniques like , liposomal encapsulation and freeze drying, methods. Spray-dried bi-layer films offer enhanced formulation flexibility and the potential for improved therapeutic outcomes.

The backing layer consists of water-insoluble polymers and excipients that are inert and classified as Generally Recognized As Safe (GRAS) for oral use, with FDA approval. After the sustained-release (SR) layer disintegrates, it gradually releases the drug due to the presence of specific polymers. The non-disintegrating backing layer further controls the release by preventing drug diffusion from the back side.

This bi-layer nicotine film design ensures that nicotine is delivered in a sustained manner. The backing layer eventually detaches and can be easily split or peeled off from the mouth. If the backing layer is accidentally swallowed, it poses no toxicity risk, as all its components are GRAS (Generally Recognized as Safe) and FDA-approved.
OBJECTIVE OF INVENTION
The main objective of the present invention is to provide a novel bi-layer oral film composition comprising Nicotine or its pharmaceutically acceptable salt thereof.

Another objective of the present invention is to provide a novel Nicotine bi-layer oral film composition comprising sustained release drug layer and backing layer.

Still another objective of the present invention is to provide a novel bi-layer oral film composition comprising Nicotine or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the bi-layer oral film provides sustained release of drug.

Still another objective of the present invention is to provide a process for the preparation of Nicotine bi-layer oral film using spray drying technique.

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

One embodiment of the present invention provides a novel Nicotine bi-layer oral film composition comprising sustained release drug layer and backing layer.

One embodiment of the present invention provides a novel bi-layer oral film composition comprising Nicotine or its pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the bi-layer oral film provides sustained release of drug.

One embodiment of the present invention provides a novel Nicotine bi-layer oral film composition comprising;
i. sustained release drug layer comprising retard polymers, antistatic agents, pH modifiers, thickeners, wetting agents/emulsifiers, plasticizers, film forming agents, disintegrants, flavoring agents, colorants and solvents,
ii. backing layer comprising backing layer polymers, opacifiers, plasticizer and solvents.

One embodiment of the present invention provides a novel Nicotine bi-layer oral film composition comprising;
i. sustained release drug layer comprising:
a) Nicotine or pharmaceutically acceptable salts in the range of 1% to 30% w/w,
b) retard polymers in the range of 1% to 40% w/w,
c) antistatic agents in the range of 1% to 20% w/w,
d) pH modifiers in the range of 1% to 20% w/w,
e) thickeners in the range of 10% to 50% w/w,
f) wetting agents/emulsifiers in the range of 0.1% to 10% w/w,
g) film forming agents in the range of 0.1% to 10% w/w,
h) plasticizers in the range of 1% to 20% w/w,
i) disintegrants in the range of 0.001% to 1% w/w,
j) flavoring agents in the range of 0.001% to 2% w/w,
k) colorants in the range of 0.001% to 1% w/w, and
l) solvents,
ii. backing layer comprising
a) backing layer polymers in the range of 10% to 50% w/w,
b) opacifiersin the range of 1% to 10% w/w,
c) plasticizer in the range of 1% to 20% w/w and
d) solvents.

One embodiment of the present invention provides a process for the preparation of Nicotine or its pharmaceutically acceptable salt thereof bi-layer oral film.

One embodiment of the present invention provides a process for the preparation of Nicotine or its pharmaceutically acceptable salt thereof bi-layer oral film, wherein the process involves spray drying technology.

Yet another embodiment of the present invention provides a process for the preparation of bi-layer oral film comprising the steps of:
(a) preparing sustained drug layer,
(b) preparing backing layer, and
(c) degassing, layering and drying.

Yet another embodiment of the present invention provides a process for the preparation of bi-layer oral film comprising the steps of:
(a) preparing sustained release drug layer comprising steps of
i. adding retard polymer to isopropyl alcohol then mixed,
ii. adding antistatic agents and Nicotine or its pharmaceutically acceptable salt and mixed it properly until it gives clear solution,
iii. homogenizing and spray drying above solution,
iv. mixing nicotine encapsulated powder from step iii withfilm forming agents and thickners and adding water,
v. adding disintegrants and pH modifiers and mixing,
vi. adding pH modifiers, wetting agents/emulsifiers, plasticizers, flavoring agents and colorants andmixing,
vii. adding step vi to step v and mixing,
(b) preparing backing layer comprising;
i. adding backing layer polymers to solvents and mixing,
ii. adding opacifiers, plasticizers to solvent, and mixing,
iii. adding step ii solution to step I,
(c) degassing, layering and drying;
i. degassing both the slurry mixtures,
ii. layering backing layer and drying,
iii. layering drug layer over the backing layer 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 bi-layer oral film composition comprising Nicotine or its pharmaceutically acceptable salts as active ingredient, pharmaceutically acceptable excipients and its process of preparation.

One embodiment of the present invention provides a novel Nicotine bi-layer oral film composition comprising;
i. sustained release drug layer comprising retard polymers, antistatic agents,pH modifiers, thickeners, wetting agents/emulsifiers, plasticizers, film forming agents, disintegrants, flavoring agents, colorants and solvents,
ii. backing layer comprising backing layer polymers, opacifiers, plasticizer and solvents.

The sustained release drug layer of the bi-layer film of the present invention provides the drug release in sustained manner.

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

The Nicotine salt as used herein is in the form of solvates, hydrates thereof. For example hemihydrate, monohydrate, dihydrate and higher hydrates thereof.

The concentration of Nicotine base or its salts used in the present invention is in the range of 1% to 30% (w/w) of the total weight of the composition.
.

Retard polymers used alone or in combination in the compositions of the present invention include, but are not limited to hydroxypropyl methylcellulose, methylcellulose (MC), ethylcellulose (EC), methacrylic acid-ethyl acrylate copolymers, methacrylic acid and methacrylate based polymers, and a methylmethacrylate copolymer.

The concentration of Retard polymers used in the present invention is in the range of 1%(w/w) to 40%(w/w) of the total weight of the composition.

Antistatic-agents alone or in combination in the compositions of the present invention include, but are not limited to magnesium aluminometasilicate (Neusilin®), titanium dioxide, microcrystalline cellulose, maltodextrin and dicalcium phosphate.

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

Thickeners used alone or in combination in the compositions of the present invention include, but are not limited to hydroxypropylmethyl, cellulose methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, pullulan, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof.

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

Wetting agents/emulsifiers used alone or in combination in the compositions of the present invention include, but are not limited to polysorbate, tween, span, lecithin, sodium lauryl sulfate, castor oil derivatives, cetyl and palmityl alcohol, ethanol, hydrogenated vegetable oils, kolliphore RH 40 ((polyoxyl 40 hydrogenated castor oil, polyvinyl alcohol, simethicone, sorbitan ester, glyceryl monostearate, polyoxyethylene alkyl ethers, polyoxyethylene stearates, transcutol HP(diethylene glycol monoethyl ether), poloxamer, polyoxyethylene lauryl ether and polyoxyethylene sorbitan fatty acid esters.

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

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, complexolHP (hydroxypropyl beta cyclodextrin), polyethyleneoxide, carrageenan, gelatin, dextrin, polyethylene oxide, starch, pectin, sodium alginate, guar gum, gum arabic, xanthan gum, glycerol monooleate, maltodextrin, tragacanth gum, pullulan, mannitol, sorbitol, sodium citrate dihydrate, polyvinyl alcohol, polyethylene glycol co-polymers, carboxylic acid containing polymers such as acrylic acid, methacrylic acid, 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 0.1% (w/w) to 10% (w/w) of the total weight of the composition.

Plasticizers used alone or in combination in the compositions of the present invention include, but are not limited to polyalkylene oxides, glycerine,glycerol, polyethylene glycols, polypropylene glycols, polyethylene-propylene glycols, organic plasticizers with low molecular weights, such as glycerol, glycerol monoacetate, glycerol diacetate, glycerol triacetate, triacetin, polysorbate, cetyl alcohol, propylene glycol, sorbitol, sodium diethylsulfosuccinate, triethyl citrate, glycerine, tributyl citrate and the like.

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

Disintegrant used alone or in combination in the compositions of the present invention include, but are not limited to cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, carboxymethyl starch,sodium starch glycolate, sodium carboxymethyl starch, potassium methacrylate-divinylbenzene copolymer, polyvinyl alcohols, amylose, cross-linked amylose, starch derivatives, microcrystalline cellulose and cellulose derivatives, alpha-, beta-and gamma-cyclodextrin and dextrin derivatives; an acrylic acid polymer such as cross-linked polymer available under the tradenamecarbopol®;a vinyl pyrrolidone polymer such as crosslinked polyvinylpyrrolidone or crospovidone; copolymers of vinyl pyrrolidone and vinyl acetate; or mixtures thereof.

The concentration of disintegrant used in the present invention is in the range of 0.001% (w/w) 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 present invention is in the range of 0.001% (w/w) to 2% (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, erythrosine, riboflavin, beta carotene, anthocyanidin, fuchsin, indigo-blue fuchsin, FDC Red, FDC yellow, orange Yellow S, quinoline yellow, indigo-blue acid blue (indigotine lake), light blue and sunset yellow.

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

Backing layer polymers used alone or in combination in the compositions of the present invention include, but are not limited to hydroxypropyl methylcellulose, hydroxypropryl cellulose, methylcellulose (MC), ethylcellulose (EC), methacrylic acid-ethyl acrylate copolymers, methacrylic acid and methacrylate based polymers, and a methylmethacrylate copolymer.

The concentration of backing layer polymers used in the present invention is in the range of 10% (w/w) to 50% (w/w) of the total weight of the composition.

Opacifiers used alone or in combination in the compositions of the present invention include, but are not limited tocalcium carbonate, titanium dioxide, talc, silicon dioxide and combinations thereof.

The concentration of opacifiers used in the present invention is in the range of 1% (w/w) to 10% (w/w) of the total weight of the composition.

Solvents 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, propylene glycol, polyethylene glycol.

The concentration of excipients used in the present invention are 0.1 % to 99% w/w of total weight of composition.

Advantages of Nicotine encapsulation via spray drying are as given below:
Cost-effective & Scalable
•Spray drying is relatively inexpensive and highly scalable, making it ideal for industrial production of nicotine formulations.
•Compared to freeze drying (which is expensive and time-consuming), spray drying is faster and cheaper.
Enhanced Stability
•Protects nicotine, which is volatile and sensitive to oxidation, from environmental factors (light, heat, and oxygen).
•Offers more stability than methods like liposomal encapsulation, which can be prone to leakage or degradation.
Improved Shelf Life
•Encapsulated nicotine in spray-dried microparticles tends to have a longer shelf life, maintaining potency and efficacy over time.
Flexibility in Carrier Materials
•Compatible with a variety of carriers (e.g., maltodextrin, gelatin, gum arabic, polyvinyl alcohol), enabling formulation versatility.
•Some other techniques, like nanoemulsion, require specific surfactants or emulsifiers, limiting formulation options

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
Nicotine Sustained Release Bilayer Film (Nicotine Bitartrate Dihydrate)
Name of the ingredient Strengths
SR Layer 1mg 2mg 3mg 4mg 5mg
Nicotine Bitartrate Dihydrate 3.333 6.667 10.000 13.333 16.667
Ethocel Standard 100 5.000 10.000 15.000 20.000 25.000
Titanium Di oxide 0.833 1.667 2.500 3.333 4.167
Nusilin 0.833 1.667 2.500 3.333 4.167
Sodium Bi carbonate 2.500 5.000 7.500 10.000 12.500
Tween 20 0.125 0.250 0.375 0.500 0.625
Tri ethyl Citrate 0.571 1.143 1.714 2.286 2.857
Sodium Starch Glycolate 0.014 0.029 0.043 0.057 0.071
Sodium Hydroxide 0.079 0.158 0.237 0.316 0.395
HPMC E15 4.000 8.000 12.000 16.000 20.000
Cinnamon Flavour 0.229 0.457 0.686 0.914 1.143
HPC 0.286 0.571 0.857 1.143 1.429
Pullulan 6.808 13.612 20.420 27.228 34.033
Lecithin 0.375 0.750 1.125 1.500 1.875
Erythrosin 0.014 0.029 0.043 0.057 0.071
IPA 0.200 0.400 0.600 0.800 1.000
Wtater 52.571 105.143 157.714 210.286 262.857
Total weight of each strip in mg 25.000 50.000 75.000 100.000 125.000
Backing layer
Ethyl cellulose (MP 50) 13.000 13.000 13.000 13.000 13.000
HPC 5.382 5.382 5.382 5.382 5.382
Talc 1.471 1.471 1.471 1.471 1.471
TiO2 1.471 1.471 1.471 1.471 1.471
Glcerol tri acetate 3.676 3.676 3.676 3.676 3.676
Solvent 143.910 143.910 143.910 143.910 143.910
Total Strip weight 25.00 25.00 25.00 25.00 25.00
Total weight of each bi layer strip in mg 50.000 75.000 100.000 125.000 150.000
Film Dimension (mm+/-1) 15x19 15x19 15x19 15x19 17x21

Example 2

Nicotine Sustained Release Bilayer Film (Nicotine Bitartrate Dihydrate)
Name of the ingredient Strengths
SR Layer 6mg 7mg 8mg 9mg 12mg
Nicotine Bitartrate Dihydrate 20.000 23.333 26.667 30.000 40.000
Ethocel Standard 100 30.000 35.000 40.000 45.000 60.000
Titanium Di oxide 5.000 5.833 6.667 7.500 10.000
Nusilin 5.000 5.833 6.667 7.500 10.000
Sodium Bi carbonate 15.000 17.500 20.000 20.000 20.000
Tween 20 0.750 0.875 1.000 1.000 1.000
Tri ethyl Citrate 3.429 4.000 4.571 4.571 4.571
Sodium Starch Glycolate 0.086 0.100 0.114 0.114 0.114
Sodium Hydroxide 0.474 0.553 0.632 0.632 0.632
HPMC E15 24.000 28.000 32.000 32.000 32.000
Cinnamon Flavour 1.371 1.600 1.829 1.829 1.829
HPC 1.714 2.000 2.286 2.286 2.286
Pullulan 40.841 47.648 54.453 54.454 54.454
Lecithin 2.250 2.625 3.000 3.000 3.000
Erythrosin 0.086 0.100 0.114 0.114 0.114
IPA 1.200 1.400 1.600 1.600 1.600
Wtater 315.429 368.000 420.571 473.143 630.857
Total weight of each strip in mg 150.000 175.000 200.000 210.000 240.000
Backing layer
Ethyl cellulose (MP 50) 13.000 13.000 26.000 52.000 104.000
HPC 5.382 5.382 10.764 21.528 43.056
Talc 1.471 1.471 2.942 5.884 11.768
TiO2 1.471 1.471 2.942 5.884 11.768
Glcerol tri acetate 3.676 3.676 7.352 14.704 29.408
Solvent 143.910 143.910 143.910 143.910 143.910
Total Strip weight 25.00 25.00 50.00 50.00 50.00
Total weight of each bi layer strip in mg 175.000 200.000 250.000 260.000 290.000
Film Dimension (mm+/-1) 17x21 17x21 18x28 18x28 18x28

Manufacturing process
Preparation of Drug Layer-
Step 1- Used required amount of isopropyl alcohol then added Ethocel standard 100 then mixed for 20minutes. After that Neusilin and Titanium dioxide were added, then added Nicotine Bitartare Dihydrate and mixed it properly until it gives clear solution, then homogenized it in 10K RPM in IKA homogenizer. Then spray dry it. (InletTemperature 70°c, Outlet temperature 50°c, Inlet High temperature80°c, Outlet temperature 60°C, Feed pump speed 3.0ml/minute).
Step 2- Take Nicotine Encapsulated powder from step 1, HPMC E15, Pullulan and HPC mixed properly. Then usedrequired amount of water and added it slowly and mixed it for 30minutes, RPM 1200. Then added Sodium starch glycolate and mixed for 10minutes. After that slowly added sodium bicarbonate and mixed for 10minute.
Step3- Usedrequired amount of water then added sodium hydroxide, Tween 20, Tri ethyl citrate, Lecithin, Cinnamon flavor and Erythrosin and mixed it properly. Each step mixed for 5minutes for proper mixing, RPM-1000.
Step 4- Then added Step 3 to step 2 and mixed for 15minutes, RPM-1200.
Preparation of Backing Layer-
Step 1- Usedrequired amount of Isopropyl alcohol and then added Ethyl cellulose MP50, then mixed for 20minutes, RPM 1200. Make sure solution should be clear.
Step 2 – Usedrequired amount of isopropyl alcohol then added HPC and mixed for 30minutes, RPM-1200, and make sure solution should be clear.
Step 3- Then added step 2 to step 1 and mixed for 15minutes, RPM 1200.
Step4- Usedrequired amount of isopropyl alcohol then added talc, titanium dioxide, and glycerol triacetate, and mixed for 10minutes then added to step 3 and mixed for 10minutes, RPM 1200.
Degassing, Layering and Drying
Degassing both the slurry mixtures. After that layered backing layer and dry it at 50°c. After that, layer Drug layer over the backing layer and dry it at 60°c. After drying, desired shape was obtained by print impose by using novel machine there after cutting the layer according shape as oval /rectangular/square shapes with dimension (15 mm to 30 mm length and 19 to 30 mm width)

Results:
Nicotine BI Tartarate Film
Thickness of Film
Release studies

Nicotine Bitartarate
( 1 mg, 2mg, 3mg and 4 mg) 100 to 200 µ 15 min- Not more than 35%
30 min- In between 35% to 55%
60 min- - In between 50 % to 75%
120 min Not less than 75%

Nicotine Bitartarate
(5 mg, 6 mg and 7 mg) 200 and 250 µ 15 min- Not more than 35%
30 min- In between 35 % to 55%
60 min- In between 55 % to 85%
120 min Not less than 85%
Nicotine Bitatarate
( 8, 9 and 12 mg) 300 µ to 400 µ 15 min- Not more than 45%
30 min- In between 45 % to 65%
60 min- In betwwen 65% to 85%
120 min Not less than 85%

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

2 mg

S.No Tests Specification 40°C ± 2°C / 75 % ± 5 % RH
Initial 1 month 3 month 6 months
1. Description Bilayer with one side in blue colour and other side in white colour, oval 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 75.00 ± 10 % (Between 67.50 to 82.5 ) 75.10 mg 75.20 mg 75.50mg 75.64 mg
4. Moisture content (% w/w) Between 3.00 to 8.00 4.10 % 4.20 % 4.28 % 4.32 %
5. Disintegration time Not more than 60 seconds 42 Seconds 38
seconds 30
seconds 26
Seconds
6. Assay : Each Strip Contains
a) Nicotine Bilayer as (Nicotine Bitartrate Dihydrate) 2 mg Between 90.0% to 110.0% of the label claim 103.5 % 103.0 % 102.1 % 101.8 %
7. Dissolution by HPLC
a. 5 Minutes NMT 60.0% of the labelled amount of Nicotine Bitartarate Dihydrate 4mg is dissolved in 5 minutes 52.0 % 51.9 % 50.8 % 50.5 %
b.10 Minutes Between 60.0% to 70.0% dissolved in 10 minutes 65.1% 64.8 % 63.5% 62.8 %
c. 20 minutes Between 70.0% to 85.0% dissolved in 20 minutes 75.5% 75.1% 74.1 % 73.8 %
d. 30 minutes NLT 85.0% of the labelled amount of Nicotine Bitartarate Dihydrate 4mg is dissolved in 30minutes 95.8 % 95.1 % 94.1 % 93.8 %
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

60 cfu/g <10 cfu/g Absent/g Absent/25g Absent/g Absent/g NA NA 70 cfu/g 5 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
1. Description Bilayer with one side in blue colour and other side in white colour, oval shaped dried oral Strips 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
3. Average Weight (mg) & Weight Variation 75.00 ± 10 % (Between67.50 to82.5 ) 75.10 mg 75.15 mg 75. 35mg
4. Moisture content (% w/w) Between 3.00 to 8.00 4.10 % 4.15 % 4.25%
5. Disintegration time Not more than 60 seconds 42 seconds 36
Seconds 33
seconds
6. Assay : Each Strip Contains
b) Nicotine Bilayer as
(Nicotine Bitartrate Dihydrate) 2 mg Not less than 90.0% and Not more than110.0% 103.5% 102.9 % 102.6%
7. Dissolution by HPLC
a. 5 Minutes NMT 60.0% of the labelled amount of Nicotine Bitartarate Dihydrate 4mg is dissolved in 5 minutes 55.0% 53.8 % 52.9 %
b.10 Minutes Between 60.0% to 70.0% dissolved in 10 minutes 65.1% 62.8% 61.8 %
c. 20 minutes Between 70.0% to 85.0% dissolved in 20 minutes 75.5% 74.6% 73.6%
d. 30 minutes NLT 85.0% of the labelled amount of Nicotine Bitartarate Dihydrate 4mg is dissolved in 30 minutes 95.8% 94.9% 94.1%
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

60 cfu/g <10 cfu/g

Absent/g Absent/25g Absent/g NA 80 cfu/g 6 cfu/g

Absent/g Absent/25g Absent/g

4 mg

S.No Tests Specification 40°C ± 2°C / 75 % ± 5 % RH
Initial 1 month 3 month 6 months
9. Description Bilayer with one side in blue colour and other side in white colour, oval shaped dried oral Strips Complies Complies Complies Complies
10. 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
11. Average Weight (mg) & Weight Variation 125.00± 10 % (Between 112.50 to 137.5 ) 125.02 mg 125.21 mg 125.66 mg 125.77 mg
12. Moisture content (% w/w) Between 3.00 to 8.00 4.30 % 4.32 % 4.42 % 4.52 %
13. Disintegration time Not more than 60 seconds 48 Seconds 45
seconds 40
seconds 35
Seconds
14. Assay : Each Strip Contains
a) Nicotine as
(Nicotine Bitartrate Dihydrate) 4mg Between 90.0% to 110.0% of the label claim 101.2 % 100.7 % 99.8 % 99.4 %
15. Dissolution by HPLC
a. 5 Minutes NMT 60.0% of the labelled amount of Nicotine Bitartarate Dihydrate 4mg is dissolved in 5 minutes 48.2 % 48.7 % 50.9 % 51.6 %
b.10 Minutes Between 60.0% to 70.0% dissolved in 10 minutes 62.4 % 62.8 % 63.8 % 64.5 %
c. 20 minutes Between 70.0% to 85.0% dissolved in 20 minutes 73.5 % 74.1% 76.1 % 77.7 %
d. 30 minutes NLT 85.0% of the labelled amount of Nicotine Bitartarate Dihydrate 4mg is dissolved in 30minutes 97.5 % 98.8 % 97.8 % 99.8 %
16. 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

50 cfu/g 10 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. Description Bilayer with one side in blue colour and other side in white colour, oval shaped dried oral Strips Complies Complies Complies
10. 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
11. Average Weight (mg) & Weight Variation 125.00± 10 % (Between 112.50 to 137.5 ) 125.02 mg 125.22 mg 125. 45mg
12. Moisture content (% w/w) Between 3.00 to 8.00 4.30 % 4.35 % 4.37 %
13. Disintegration time Not more than 60 seconds 48 seconds 45
Seconds 40
seconds
14. Assay : Each Strip Contains
a) Nicotine as
(Nicotine Bitartrate Dihydrate) 4mg Not less than 90.0% and Not more than110.0% 101.2 % 100.8 % 100.3%
15. Dissolution by HPLC
a. 5 Minutes NMT 60.0% of the labelled amount of Nicotine Bitartarate Dihydrate 4mg is dissolved in 5 minutes 48.2 % 49.6 % 49.9 %
b.10 Minutes Between 60.0% to 70.0% dissolved in 10 minutes 62.4 % 63.3% 65.8 %
c. 20 minutes Between 70.0% to 85.0% dissolved in 20 minutes 74.5 % 75.6% 77.2 %
d. 30 minutes NLT 85.0% of the labelled amount of Nicotine Bitartarate Dihydrate 4mg is dissolved in 30 minutes 97.5 % 98.0% 98.5%
16. 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
8 cfu/g

Absent/g Absent/25g Absent/g

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

,CLAIMS:WE CLAIM:
1. A novel Nicotine bi-layer oral film composition comprising sustained release drug layer and backing layer.
2. The composition as claimed in claim 1, whereinNicotine bi-layer oral film composition comprising;
i. sustained release drug layer comprising retard polymers, antistatic agents, pH modifiers, thickeners, wetting agents/emulsifiers, plasticizers, film forming agents, disintegrants, flavoring agents, colorants and solvents,
ii. backing layer comprising backing layer polymers, opacifiers, plasticizer and solvents.
3. The composition as claimed in claim 2, wherein the Nicotine salt is selected from nicotine bitartrate, nicotine polacrilex, nicotine bitartarate dihydride, nicotine oil, 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 1% to 30% (w/w) of the total weight of the composition.
4. The composition as claimed in claim 2, wherein retard polymers selected from hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, methacrylic acid-ethyl acrylate copolymers, methacrylic acid and methacrylate based polymers, and a methylmethacrylate copolymer, the concentration of retard polymers used in the present invention is in the range of 1% (w/w) to 40% (w/w) of the total weight of the composition.
5. The composition as claimed in claim 2, wherein antistatic-agent alone or in combination in the compositions of the present invention include, but are not limited to magnesium aluminometasilicate (Neusilin®), titanium dioxide, microcrystalline cellulose, maltodextrin and dicalcium phosphate, the concentration of antistatic-agent used in the present invention is in the range of 1 % (w/w) to 20% (w/w) of the total weight of the composition.
6. The composition as claimed in claim 2, wherein pH modifiers are selected from 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% (w/w) to 20% (w/w) of the total weight of the composition.
7. The composition as claimed in claim 2, wherein thickeners are selected from hydroxypropyl methyl, cellulose methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, pullulan, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof, the concentration of thickeners used in the present invention is in the range of 10% (w/w) to 50% (w/w) of the total weight of the composition.
8. The composition as claimed in claim 2, wherein wetting agents/emulsifiers are selected frompolysorbate, tween, span, lecithin, sodium lauryl sulfate, castor oil derivatives, cetyl and palmityl alcohol, ethanol, hydrogenated vegetable oils, kolliphore RH 40, polyoxyl 40 hydrogenated castor oil, polyvinyl alcohol, simethicone, sorbitan ester, glyceryl monostearate, polyoxyethylene alkyl ethers, polyoxyethylene stearates, transcutol HP(diethylene glycol monoethyl ether), poloxamer, polyoxyethylene lauryl ether and polyoxyethylene sorbitan fatty acid esters, the concentration of wetting agents used in the present invention is in the range of 0.1% (w/w) to 10% (w/w) of the total weight of the composition.
9. The composition as claimed in claim 2, wherein film-forming agents are 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, methylcellulose, ethylcellulose, polyvinyl pyrrolidone, carrageenan, gelatin, dextrin, polyethylene oxide, starch, pectin, sodium alginate, guar gum, gum arabic, xanthan gum, glycerol monooleate, maltodextrin, tragacanth gum, pullulan, mannitol, sorbitol, sodium citrate dihydrate, acrylic acid, methacrylic acid, 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 0.1% (w/w) to 10% (w/w) of the total weight of the composition.
10. The composition as claimed in claim 2, wherein plasticizers are selected from polyalkylene oxides, glycerine,glycerol, polyethylene glycols, polypropylene glycols, polyethylene-propylene glycols, glycerol monoacetate, glycerol diacetate, glycerol triacetate, triacetin, polysorbate, cetyl alcohol, propylene glycol, sorbitol, sodium diethyl sulfosuccinate, triethyl citrate, tributyl citrate, the concentration of plasticizers used in the present invention is in the range of 1% (w/w) to 20% (w/w) of the total weight of the composition.
11. The composition as claimed in claim 2, wherein disintegrants are selected from cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, carboxymethyl starch, sodium starch glycolate, sodium carboxymethyl starch, potassium methacrylate-divinylbenzene copolymer, polyvinyl alcohols, amylose, cross-linked amylose, microcrystalline cellulose or mixtures thereof, the concentration of disintegrant used in the present invention is in the range of 0.001% (w/w) to 1% (w/w) of the total weight of the composition.
12. The composition as claimed in claim 2, whereinflavouring agents 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 present invention is in the range of 0.001% (w/w) to 2% (w/w) of the total weight of the composition.
13. The composition as claimed in claim 2, wherein colorantsare selected from titanium dioxide, erythrosine, riboflavin, beta carotene, anthocyanidin, fuchsin, indigo-blue fuchsin, FDC Red, FDC yellow, orange yellow S, quinoline yellow, light blue and sunset yellow, the concentration of colorants used in the present invention is in the range of 0.001% (w/w) to 1% (w/w) of the total weight of the composition.
14. The composition as claimed in claim 2, wherein backing layer polymers are selected from hydroxypropyl methylcellulose, hydroxypropryl cellulose, methylcellulose, ethylcellulose, methacrylic acid-ethyl acrylate copolymers, methacrylic acid and methacrylate based polymers, and a methylmethacrylate copolymer, the concentration of backing layer polymers used in the present invention is in the range of 10% (w/w) to 50% (w/w) of the total weight of the composition.
15. The composition as claimed in claim 2, wherein opacifiers are selected fromcalcium carbonate, titanium dioxide, talc, silicon dioxide and combinations thereof, the concentration of opacifiers used in the present invention is in the range of 1% (w/w) to 10% (w/w) of the total weight of the composition.
16. The composition as claimed in claim 2, wherein solvents are selected from water, methanol, ethanol, propanol, isopropyl alcohol, acetone, dimethyl acetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, propylene glycol and polyethylene glycol.
17. The process for the preparation of bi-layer oral film as claimed in claim 2, comprising the steps of:
(a) preparing sustained release drug layer comprising steps of
i. adding retard polymer to isopropyl alcohol then mixed,
ii. adding antistatic agents and Nicotine or its pharmaceutically acceptable salt and mixed it properly until it gives clear solution,
iii. homogenizing and spray drying above solution,
iv. mixing nicotine encapsulated powder from step iii withfilm forming agents and thickners and adding water,
v. adding disintegrants and pH modifiers and mixing,
vi. adding pH modifiers, wetting agents/emulsifiers, plasticizers, flavoring agents and colorants andmixing,
vii. adding step vi to step v and mixing,
(b) preparing backing layer comprising;
i. adding backing layer polymers to solvents and mixing,
ii. adding opacifiers, plasticizers to solvent, and mixing,
iii. adding step ii solution to step I,
(c) degassing, layering and drying;
i. degassing both the slurry mixtures,
ii. layering backing layer and drying,
iii. layering drug layer over the backing layer and drying.

Dated this Thirteenth (13th) day of May, 2025

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883