WO2025189277A1

WO2025189277A1 - Nicotine containing composition

Info

Publication number: WO2025189277A1
Application number: PCT/CA2025/050248
Authority: WO
Inventors: Yahia Gawad
Original assignee: Tjp Labs Inc
Current assignee: Tjp Labs Inc
Priority date: 2024-03-12
Filing date: 2025-02-26
Publication date: 2025-09-18
Anticipated expiration: 2026-09-12

Abstract

Disclosed is a composition comprising a pharmaceutically acceptable particle; a carboxylic acid group containing water soluble polymer coating the pharmaceutically acceptable particle; and nicotine, nicotine prodrug or a nicotine analog releasably bound to the water soluble polymer. Also disclosed is a process for the preparation of the composition, along with use of composition and a product containing the composition for delivery of nicotine, nicotine prodrug or nicotine analog to a subject in need thereof.

Description

NICOTINE CONTAINING COMPOSITION

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63/564,221 , filed March 12^th, 2024, titled, NICOTINE CONTAINING COMPOSITION. The contents of the U.S. Provisional Patent Application are hereby expressly incorporated herein by reference.

FIELD

[0002] The present disclosure relates to a composition containing nicotine, nicotine prodrug or nicotine analog, a carboxylic acid group containing water soluble polymer and a pharmaceutically acceptable particle.

BACKGROUND

[0003] Therapeutic uses of nicotine range from smoking cessation to treatment of inflammatory bowel diseases, and include many other clinical indications. Since the nicotine base is volatile and unstable, most nicotine clinical formulations employ nicotine salts or nicotine anchored to solid phases, mostly an ion exchange resins.

[0004] Nicotine Replacement Therapy (NRT) is a cornerstone of smoke cessations. NRT products available for smoke cessations include gums, transdermal patches, tablets, nasal sprays, oral inhalers, and film strips. The high failure rate of quitting attempts while consuming NRT products is mostly attributed to the different nicotine release profile of NRT products in comparison to smoking combustibles. Currently, most marketed NRT products fail during the acute stage of consuming these products for rescue craving, mostly due to the peak plasma nicotine levels occurring after the critical 10 minutes threshold which is delayed in comparison to smoking combustibles.

[0005] A long list of nicotine carriers have been documented, although cation exchange resins are the main nicotine carrier employed in commercial NRT products over the last 5 decades. Amberlite™ IRP 64 (known as polacrilex) is the most frequently employed nicotine carrier resin in NRT products, although other cation exchange resins have been proposed.

[0006] Polacrilex is a copolymer of methacrylic acid and divinylbenzene, and is considered a weak cation exchange resin. Resin particles with different particle size profiles have been produced by post manufacturing processing. Resins with mean particle size of 300 microns (range 50-1500) are most commonly employed for NRT. Polacrilex resin particles are porous and their surfaces are decorated with carboxylic acid groups. Polacrilex particles have ion replacement capacity of about 10meq (meq/gr of dry material) and are available with nicotine loading up to 40%.

[0007] Nicotine binding and release from polacrilex particles serve two fundamental functions; increases nicotine stability and control the rate of nicotine release. Nicotine release profile from various commercial polacrilex-containing NRT products is well documented and depends on several factors. These include particle size, the porous nature of the resin (nicotine is bound to the surface and inside of the resin particles), the amount of nicotine/gram of resin and the ionic environment of the binding sites. To a large extent, nicotine desorption from polacrilex depends on the diffusion of the fluid phase through the polymer phase and the electrolytic ion contents of the diffusing fluid.

[0008] The carboxylic acid group of polacrilex, as any other weakly-acidic cation exchange resin, desorbs its cargo more efficiently in acidic environment (high affinity to hydrogen). However, nicotine oral absorption is optimal at alkaline pH, hence nicotine release from polacrilex in the oral cavity and its mucosal absorption is a balancing act of the electrolytic environment.

[0009] According to most published literature, the residual amount of nicotine left on polacrilex after using the NRT products is, on average, 40% of its original nicotine loading. Innovations to manipulate the rate of nicotine release and increase the total released nicotine amount (to increases the chances of NRT success in smoke cession) are numerous. The scientific and patent literatures are full of implementations to optimize and speed up the release of nicotine from various NRT products and increase its mucosal absorption. [0010] Particularly interesting set of innovations are related to the employment of carbomers in NRT products. Carbomers are cross-linked acrylic acid copolymers with their carboxylic acid content range between 56-68%, depending on the degree of cross-linking. As a cross-linked polymer, carbomers are not soluble (in aqueous or non-aqueous solvents), as they form microgels in aqueous environment, and although their molecular weight cannot be determined (as they are not water soluble), they are frequently characterized as very high molecular weight polymers. Due to their water absorption and microgel formation, carbomers are strong mucoadhesives and have been employed in NRT products, either as mean to control the release of nicotine by binding nicotine or to increase its absorption by its mucoadhesive features or by holding high mount of fluids within the gel. These polymers have been employed with both nicotine salts and nicotine polacrilex.

[0011] Although nicotine binding to solid matrices have successfully addressed the issue of nicotine stability, the solid matrix role, particularly polacrilex, in determining the nicotine release profile is fundamental in commercial success. None of the current commercial NRT products that employ polacrilex has fulfilled the need for a truly rapid controlled nicotine release and its mucosal absorption. The very high failure rate of commercial NRT products urges the need to develop alternatives that offer nicotine release profile that simulates smoking combustibles, or at least help with rescue craving.

[0012] There is a need in the art for a composition that provides the consumer with a clinically useful alternative. In addition, there is a need in the art for a process for preparation of such a composition. Further, there is a need in the art for a product containing the composition disclosed herein. Moreover, there is a need in the art for a product, composition and/or a method of preparation of the composition for delivery of nicotine, nicotine prodrug or nicotine analog that addresses or mitigates at least some of the deficiencies of the state of the art, or to provide a useful alternative.

[0013] The background herein is included solely to explain the context of the disclosure. This is not to be taken as an admission that any of the material referred to was published, known, or part of the common general knowledge as of the priority date. SUMMARY

[0014] In one aspect, the specification relates to a composition comprising:

[0015] a pharmaceutically acceptable inert particle;

[0016] a carboxylic acid group containing water soluble polymer coating the pharmaceutically acceptable particle; and

[0017] nicotine, nicotine prodrug or a nicotine analog releasably bound to the water soluble polymer.

[0018] In one embodiment of the composition, the nicotine, nicotine prodrug or nicotine analog is bound to the water soluble polymer before coating the pharmaceutically acceptable particle with the water soluble polymer.

[0019] In a second embodiment of the composition, the nicotine, nicotine prodrug or nicotine analog is bound to the water soluble polymer after coating of the pharmaceutically acceptable particle with the water soluble polymer.

[0020] In a second aspect, the specification relates to a process for preparation of a composition having a pharmaceutically acceptable particle, a carboxylic acid group containing water soluble polymer, and nicotine, nicotine prodrug or a nicotine analog, the process comprising:

[0021] mixing the pharmaceutically acceptable particle with a carboxylic acid group containing water soluble polymer forming a polymer coated particle having a carboxylic acid group, and;

[0022] mixing the nicotine, nicotine prodrug or a nicotine analog with the coated particle to releasably bind the nicotine, nicotine prodrug or a nicotine analog to the carboxylic acid group of the polymer coated particle.

[0023] In a third aspect, the specification relates to a process for preparation of a composition having a pharmaceutically acceptable particle, a carboxylic acid group containing water soluble polymer, and nicotine, nicotine prodrug or a nicotine analog, the process comprising:

[0024] mixing the nicotine, nicotine prodrug or a nicotine analog with the carboxylic acid group containing water soluble polymer to releasably bind the nicotine, nicotine prodrug or a nicotine analog to the carboxylic acid group of the carboxylic acid group containing water soluble polymer, forming a nicotine, nicotine prodrug or nicotine analog bound carboxylic acid group containing water soluble polymer; and

[0025] mixing the nicotine, nicotine prodrug or nicotine analog bound carboxylic acid group containing water soluble polymer with the pharmaceutically acceptable particle to coat the pharmaceutically acceptable particle with the nicotine, nicotine prodrug or nicotine analog bound carboxylic acid group containing water soluble polymer.

[0026] In a fourth aspect, the specification relates to a composition as disclosed herein for use in the delivery of nicotine, nicotine prodrug or nicotine analog to a subject in need thereof.

[0027] In a fifth aspect, the specification relates to use of a composition as disclosed herein for delivery of nicotine, nicotine prodrug or nicotine analog to a subject in thereof.

[0028] In a sixth aspect, the specification relates to a method of preventing or treating a disease or condition, comprising providing a composition as disclosed herein to a subject in need thereof.

[0029] In a seventh aspect, the specification relates to a product comprising the composition as disclosed herein.

[0030] In an eighth aspect, the specification relates to use of the product as disclosed herein for delivery of nicotine, nicotine prodrug or nicotine analog to a subject in need thereof.

[0031] In a ninth aspect, the specification relates to a product as disclosed herein for use in the delivery of nicotine, nicotine prodrug or nicotine analog to a subject in need thereof.

[0032] In a tenth aspect, the specification relates to a method of preventing or treating a disease or condition, comprising providing a product as disclosed herein to a subject in need thereof. DESCRIPTION OF EXAMPLE EMBODIMENTS

[0033] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In addition, although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present invention, the typical materials and methods are described herein.

[0034] It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting. Any patent applications, patents, and publications are referred to herein to assist in understanding the aspects described. Each of these references is incorporated herein by reference in their entirety.

[0035] When introducing elements disclosed herein, the articles “a”, “an”, “the”, and “said” are intended to mean that there may be one or more of the elements.

[0036] The term "comprising" and its derivatives, as used herein, are intended to be open ended terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and/or steps. The foregoing also applies to words having similar meanings such as the terms, "including", "having" and their derivatives. It will be understood that any embodiments described as “comprising” certain components may also “consist of” or “consist essentially of,” these components, wherein “consisting of” has a closed- ended or restrictive meaning and “consisting essentially of” means including the components specified but excluding other components except for materials present as impurities, unavoidable materials present as a result of processes used to provide the components, and components added for a purpose other than achieving the technical effects described herein. For example, a composition defined using the phrase “consisting essentially of” encompasses any known acceptable additives, excipients, diluents, carriers, and the like, suitable for the composition described herein. Typically, a composition consisting essentially of a set of components will comprise less than 5% by weight, typically less than 3% by weight, more typically less than 1 % by weight of non-specified components.

[0037] It will be understood that any component defined herein as being included may be explicitly excluded from the claimed invention by way of proviso or negative limitation, such as any specific compounds or method steps, whether implicitly or explicitly defined herein.

[0038] In addition, all ranges given herein include the end of the ranges and also any intermediate range points, whether explicitly stated or not.

[0039] Finally, terms of degree such as "substantially", "about" and "approximately" as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies.

[0040] The abbreviation, “e.g.” is derived from the Latin exempli gratia, and is used herein to indicate a non-limiting example. Thus, the abbreviation “e.g.” is synonymous with the term “for example.” The word “or” is intended to include “and” unless the context clearly indicates otherwise.

[0041] The phrase “at least one of” is understood to be one or more. The phrase “at least one of...and...” is understood to mean at least one of the elements listed or a combination thereof, if not explicitly listed. For example, “at least one of A, B, and C” is understood to mean A alone or B alone or C alone or a combination of A and B or a combination of A and C or a combination of B and C or a combination of A, B, and C.

[0042] In one aspect, the specification relates to a composition comprising:

[0043] a pharmaceutically acceptable inert particle;

[0044] a carboxylic acid group containing water soluble polymer coating the pharmaceutically acceptable particle; and

[0045] nicotine, nicotine prodrug or a nicotine analog releasably bound to the carboxylic acid containing water soluble polymer.

[0046] The term, composition, as used herein is not particularly limited and should be understood by a person of skill in the art. The term composition referred to herein generally refers to combinations of ingredients, whether combined as a chemical union or physical mixture. The ingredients present can include physical and/or chemical substances, compounds and the like.

[0047] The term, pharmaceutically acceptable particle, is not particularly limited and should be understood by a person of skill in the art. In the context of the present specification, a pharmaceutically acceptable particle is a carrier that is useful in preparing a composition that is generally safe and non-toxic. The pharmaceutically acceptable particle is neither biologically adverse nor otherwise undesirable, and can include a carrier that is acceptable for use in a human.

[0048] In addition, the pharmaceutically acceptable particle is an inert particle that generally does not significantly interfere with the binding and release of nicotine, nicotine prodrug or nicotine analog from the carboxylic acid group containing water soluble polymer. As such, the pharmaceutically acceptable inert particles contain no surface functional groups that influence the binding between the carboxylic acid group containing water soluble polymer and nicotine, nicotine prodrug or nicotine analog. The reference to phrase - generally does not interfere - is intended to mean that the pharmaceutically acceptable particle does not bind to the nicotine, nicotine prodrug or nicotine analog. In one embodiment, for example and without limitation, the pharmaceutically acceptable particle does not chemically bind to the nicotine, nicotine prodrug or nicotine analog. In a second embodiment, for example and without limitation, the pharmaceutically acceptable particle does not interact with the nicotine, nicotine prodrug or nicotine analog to significantly reduce the rate of release of the nicotine, nicotine prodrug or nicotine analog from the carboxylic acid group containing water soluble polymer, when compared to the release of the nicotine, nicotine prodrug or nicotine analog from the carboxylic acid group containing water soluble polymer in the absence of the pharmaceutically acceptable particle. In a further embodiment, for example and without limitation, the pharmaceutically acceptable particle does not reduce the rate of release of the nicotine, nicotine prodrug or nicotine analog by 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5% or 1 % from the carboxylic acid group containing water soluble polymer, when compared to the release of the nicotine, nicotine prodrug or nicotine analog from the carboxylic acid group containing water soluble polymer in the absence of the pharmaceutically acceptable particle. [0049] The pharmaceutically acceptable particle used in accordance with the specification is such that a carboxylic acid group containing water soluble polymer can coat the pharmaceutically acceptable particle. In addition, in one embodiment, for example and without limitation, the pharmaceutically acceptable particle used in accordance with the specification allows releasable binding of the nicotine, nicotine prodrug or a nicotine analog to the carboxylic acid group containing water soluble polymer, as disclosed herein. In a further embodiment, for example and without limitation, the pharmaceutically acceptable particle allows for releasably binding of the nicotine, nicotine prodrug or a nicotine analog to the carboxylic acid group containing water soluble polymer either before or after coating of the carboxylic acid group containing water soluble polymer to the pharmaceutically acceptable particle, as disclosed herein. The pharmaceutically acceptable particle is selected such that the nicotine, nicotine prodrug or nicotine analog binds to the carboxylic acid group of the carboxylic acid group containing water soluble polymer under certain conditions and can be released from the carboxylic acid group containing water soluble polymer under a different set of conditions. This allows for control of the binding and release of the nicotine, nicotine prodrug or nicotine analog, such that the nicotine, nicotine prodrug or nicotine analog can be delivered at a point of interest, for instance, to a subject in need thereof, while at other times the pharmaceutically acceptable particle can help to provide stability and storage of the nicotine, nicotine prodrug or nicotine analog.

[0050] Various types of pharmaceutically acceptable particles can be used, based on the design and application requirements. In one embodiment, for example and without limitation, the pharmaceutically acceptable particle is porous particle. In another embodiment, for example and without limitation, the particle is nonporous. The porous particle can provide cavities within the pharmaceutically acceptable particle where the carboxylic acid group containing water soluble polymer have the nicotine, nicotine prodrug or nicotine analog attached to it. Nicotine, nicotine prodrug or nicotine analog attached within the porous structure help with a controlled extended release profile. The strength of the binding and release of nicotine, nicotine prodrug or a nicotine analog from the carboxylic acid group containing water soluble polymer depends on a number of factors, such as, the environment where the particle is used and the chemical structure of the particle. In one embodiment, for example and without limitation, the pharmaceutically acceptable particle can be a biodegradable particle. In another embodiment, for example and without limitation, the pharmaceutically acceptable particle can be a non-biodegradable. When a biodegradable particle is used, the biodegradable particle can disintegrate in a particular medium leading to release of the nicotine, nicotine prodrug or nicotine analog. In another further embodiment, the particle used is non-swellable in an aqueous environment, which can help in improved release of the nicotine, nicotine prodrug or a nicotine analog.

[0051] The size of pharmaceutically acceptable particle as disclosed herein is not particularly limited. In one embodiment, for example and without limitation, the pharmaceutically acceptable particle has a size of from about 1 pm to about 1000 pm, and all values and ranges in between. In another embodiment, for example and without limitation, the pharmaceutically acceptable particle has a size of from about 200 pm to about 750 pm, and all values and ranges in between. In a further embodiment, for example and without limitation, the pharmaceutically acceptable particle has a size of from about 250 pm to about 700 pm, and all values and ranges in between. In another further embodiment, for example and without limitation, the pharmaceutically acceptable particle has a size of from about 300 pm to about 650 pm, and all values and ranges in between.

[0052] The shape of the pharmaceutically acceptable particle is not particularly limited and should be known or can be determined based on design and application requirements by a person of skill in the art. In one embodiment, for example and without limitation, the pharmaceutically acceptable particle has a spherical shape. In a second embodiment, for example and without limitation, the pharmaceutically acceptable particle has a non-spherical shape.

[0053] The method for preparation of a pharmaceutically acceptable particle is not particularly limited. Different methods for preparation of the pharmaceutically acceptable particle are available to a person of skill in the art. Alternatively, pharmaceutically acceptable particle present in nature can be used. As such, the pharmaceutically acceptable particle can be a natural or a synthetic material.

[0054] In one embodiment, for example and without limitation, the pharmaceutically acceptable particle is a synthetic material. Non-limiting examples of a synthetic pharmaceutically acceptable particle include glass, ceramic, metal microspheres or polymer microparticles.

[0055] In a particular embodiment, for example and without limitation, the synthetic pharmaceutically acceptable particle is silicon dioxide.

[0056] In another particular embodiment, for example and without limitation, the polymer microparticle is a pharmaceutical grade synthetic polymer microparticle, as employed in clinical applications. Such pharmaceutical grade synthetic polymer microparticle includes biodegradable, non-biodegradable or a combination of biodegradable and non-biodegradable pharmaceutical grade synthetic polymer microparticle. Non-limiting examples of non-biodegradable pharmaceutical grade synthetic polymer microparticle include polymethylmethacrylate (PMMA), acrolein, glycidyl methacrylate, or epoxy polymers. Non-limiting examples of biodegradable pharmaceutical grade synthetic polymer microparticle include lactides, glycolides, or their copolymers, for example and without limitation, poly anhydrides, or poly alkyl cyanoacrylates.

[0057] In one embodiment, for example and without limitation, the pharmaceutically acceptable particle is a natural material. Non-limiting examples of a natural pharmaceutically acceptable particle can include a pharmaceutical grade natural polymer microparticle. Such a pharmaceutical grade natural polymer microparticle can include a natural biodegradable, biocompatible, and bioadhesive particle or a modified one. Non-limiting examples of pharmaceutical grade natural polymer microparticles can include proteins (such as, for example and without limitation, albumin, gelatin, or collagen), carbohydrates, cellulose, starch, flour, agarose or other powdered carbohydrates and chemically modified carbohydrates (such as, for example and without limitation, polydextran or polystarch).

[0058] The carboxylic acid group containing water soluble polymer as used herein is not particularly limited and the term should be understood by a person of skill in the art. A carboxylic acid functional group has the formula R-C(=O)OH, where -C(=O)OH represents the carboxylic acid functional group and R represents the remaining chemical moiety, which in the present application can be the polymeric chain. In the context of the present specification, the carboxylic acid group can be present in the ionic form (-C(=O)O^_), which allows ionic interaction between the carboxylic acid group with the protonated nicotine, nicotine prodrug or nicotine analog, as disclosed herein.

[0059] A synthetic polymer is a substance or material consisting of very large molecules called macromolecules, composed of many subunits called monomers. Polymers are formed via polymerization of many small molecules, known as monomers. The monomers in formation of a polymer can be the same, leading to a homopolymer, or different, leading to a co-polymer. In addition, a polymer can be linear or branched, where a linear polymer is a continuous chain with each monomer unit coupled to another monomer unit along the chain, while branched polymer have a branched structure, with one or more substituent side chains or branches.

[0060] The term, water soluble polymer, as used herein is not particularly limited and should be understood by a person of skill in the art. Water soluble polymer, as used herein, relate to polymers that dissolve or disperse in water, with each polymer chain chemically and physically separate from the other chains in solution and can lead to a change in the physical properties of the aqueous system surrounding these polymers. Water-soluble polymers are molecules made out of monomer units that dissolve in water to form a clear solution and have a defined molecular weight that could be measured by various analytical means. In one embodiment, for example and without limitation, the water soluble polymer in accordance with the specification is a charged water soluble polymer. The charge present on the water soluble polymer in accordance with the specification is one or more negative charges due to the presence of the carboxylic acid functional group that leads to formation of the carboxylate anion (-C(=O)O^_), as disclosed herein.

[0061] A carboxylic acid group containing water soluble polymer as used herein relates to a water soluble polymer that has carboxylic acid functional groups present on the polymer. In one embodiment, for example and without limitation, the carboxylic acid group containing water soluble polymer can mean that each polymer unit is completely solubilized once added to water and is not cross-linked to other polymer molecules in the same solution to any degree of cross-linking.

[0062] In one embodiment, for example and without limitation, the carboxylic acid group containing water soluble polymer is a negatively charged water soluble polymer. In another embodiment, for example and without limitation, the negatively charged water soluble polymer has a combination of protonated or deprotonated carboxylic acid functional groups. The number of carboxylic acid functional group in the water soluble polymer is not particularly limited, and will depend upon the design and application requirements. In a further embodiment, for example and without limitation, the carboxylic acid functional group in the water soluble polymer is present in more than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% of the total monomer units, depending upon the monomer unit selected to form the carboxylic acid group containing water soluble polymer.

[0063] Non-limiting examples of carboxylic acid containing water soluble polymer can include a natural polymer, synthetic polymer or a modified natural polymer. The natural polymer used is not particularly limited, and in one embodiment, for example and without limitation, can include collagen, gelatin, gluten or oligonucleotides. The synthetic polymer or modified natural polymer used is not particularly limited, and in one embodiment, for example and without limitation, can include polyacrylic acid (PAA), polymethacrylic acid, poly(acrylic-co-methacrylic) acid, aromatic polyanhydrides (such as, for example and without limitation, styrene maleic anhydride), aliphatic polyanhydride (such as, for example and without limitation, polymaleaic acid), polylactic acid, poly(L-glutamic acid), alginate, pectin, starch based polyanion, dextran based polyanion or polyitaconic acid. In another further embodiment, for example and without limitation, the carboxylic acid group containing water soluble polymer is polyacrylic acid.

[0064] The size and weight of the carboxylic acid group containing water soluble polymer is not particularly limited and can vary depending on the design and application requirements. In one embodiment, for example and without limitation, the carboxylic acid group containing water soluble polymer has a molecular weight of from about 20 kDa to about 3500 kDa, and all molecular weights and ranges in between. In another embodiment, for example and without limitation, the water soluble polymer has a molecular weight of from about 100 kDa to about 1000 kDa, and all molecular weights and ranges in between. In a further embodiment, for example and without limitation, the water soluble polymer has a molecular weight of from about 200 kDa to about 800 kDa, and all molecular weights and ranges in between. In a still further embodiment, for example and without limitation, the water soluble polymer has a molecular weight of about 20 kDa, 30 kDa, 40 kDa, 50 kDa, 60 kDa, 70 kDa, 80 kDa, 90 kDa, 100 kDa, 110 kDa, 120 kDa, 130 kDa, 140 kDa, 150 kDa, 160 kDa, 170 kDa, 180 kDa, 190 kDa, 200 kDa, 210 kDa, 220 kDa, 230 kDa, 240 kDa, 250 kDa, 260 kDa, 270 kDa, 280 kDa, 290 kDa, 300 kDa, 310 kDa,

320 kDa, 330 kDa, 340 kDa, 350 kDa, 360 kDa, 370 kDa, 380 kDa, 390 kDa, 400 kDa, 410 kDa, 420 kDa, 430 kDa, 440 kDa, or 450 kDa, and all molecular weights and ranges in between.

[0065] The method of preparation of the carboxylic acid group containing water soluble polymer coating is not particularly and should be known or can be determined by a person of skill in the art. Different methods of preparation are available and known for polymerization that may be used depending upon the carboxylic acid group containing water soluble polymer being synthesized.

[0066] The carboxylic acid group containing water soluble polymer is coated onto the pharmaceutically acceptable particle, as disclosed herein. The process for coating of the pharmaceutically acceptable particle with the carboxylic acid group containing water soluble polymer is not particularly limited, and can be determined by a person of skill in the art. In one embodiment, for example and without limitation, the pharmaceutically acceptable particle is stirred in a solution containing the carboxylic acid group containing water soluble polymer, allowing the carboxylic acid group containing water soluble polymer to coat the pharmaceutically acceptable particle. In another embodiment, for example and without limitation, the pharmaceutically acceptable particle is fluidized in a fluid bed and a solution containing the carboxylic acid group containing water soluble polymer is sprayed on the particles in a fluidizing chamber, allowing the carboxylic acid group containing water soluble polymer to coat the pharmaceutically acceptable particle. In one embodiment, for example and without limitation, the carboxylic acid group containing water soluble polymer completely coats onto the pharmaceutically acceptable particle. In another embodiment, for example and without limitation, the carboxylic acid group containing water soluble polymer partially coats the pharmaceutically acceptable particle. The coating of the pharmaceutically acceptable particle leads to a polymer coated particle that has carboxylic acid functional groups that can bind with the nicotine, nicotine prodrug or nicotine analog, as disclosed herein.

[0067] The terms, nicotine, nicotine prodrug or nicotine analog as used herein is not particularly limited and should be known or understood by a person of skill in the art. Nicotine has the structure as shown below having two nitrogen atoms, with the nitrogen on the pyrrolidine moiety being more basic the pyridine nitrogen. As the p a of the pyrrolidine moiety is higher than the p _a of the pyridinium ion (and also higher than the p a of the carboxylic acid), the tertiary amine (nitrogen on pyrrolidine moiety) is protonated in the presence of carboxylic acid, leading to a nicotine cation. This leads to an ionic bond between the carboxylate anion and the nicotine cation.

[0068] The term, prodrug, as used herein is not particularly limited and should be known or understood by a person of skill in the art. A prodrug is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a subject or patient, to produce nicotine (or a nicotine anion). Prodrugs include compounds wherein a part of the molecule is bonded to any group that, when administered to a mammalian subject, cleaves to form the desired species. Prodrugs of nicotine may be prepared by modifying functional groups present in the nicotine in such a way that the modifications are cleaved in vivo to generate nicotine. As such, prodrugs of nicotine that can be protonated by the carboxylic acid on the water soluble polymer, and hence bind to the carboxylic acid containing water soluble polymer, are contemplated within the scope of the present specification.

[0069] The term, nicotine analog, as used herein is not particularly limiting and should be known or understood by a person of skill in the art. An analog is a chemical compound that is structurally similar to another compound but differs slightly in certain aspects, such as, by replacement of one or more atoms by an atom of a different element. The nicotine analog used in accordance with the specification is not particularly limited. In addition, a number of nicotine analogs are known in the field, such as, disclosed in Cai et al., J. Biol. Chem., 2012, 287(51 ) (incorporated herein by reference).

[0070] The nicotine, nicotine prodrug or a nicotine analog as disclosed herein are releasably bound to the carboxylic acid containing water soluble polymer, disclosed herein. The binding of the nicotine, nicotine prodrug or a nicotine analog to the carboxylic acid containing water soluble polymer is chemical in nature. The presence of the carboxylic acid functional group on the water soluble polymer leads to protonation of the nicotine, nicotine prodrug or a nicotine analog, forming a carboxylate anion

(-C(=O)O^_) and a cation of nicotine, nicotine prodrug or nicotine analog, leading to ionic interaction between the species (carboxylate anion and cation of nicotine, nicotine prodrug or nicotine analog).

[0071] The strength of binding between the carboxylate anion present on the water soluble polymer and the cation of nicotine, nicotine prodrug or nicotine analog depends upon a number of factors, including the specific polymer used and the medium the two species are present in. Under suitable conditions, such as, for example and without limitation, in an oral cavity of a user, the cation of the nicotine, nicotine prodrug or nicotine analog disassociates from the carboxylic acid containing water soluble polymer, and leads to release of the nicotine, nicotine prodrug or nicotine analog in the oral cavity. As such, presence of ions or pH modulating agents can further facilitate release of the nicotine, nicotine prodrug or nicotine analog from the composition.

[0072] The extent of binding of the nicotine, nicotine prodrug or nicotine analog to the carboxylic acid group containing water soluble polymer is not particularly limited, and can be varied depending on design and application requirements.

[0073] The process for binding of the nicotine, nicotine prodrug or a nicotine analog to the carboxylic acid containing water soluble polymer is not particularly limited, and can be determined by a person of skill in the art. In one embodiment, for example and without limitation, the nicotine, nicotine prodrug or nicotine analog is bound to the carboxylic acid containing water soluble polymer after the carboxylic acid containing water soluble polymer has been coated on the pharmaceutically acceptable particle. In a second embodiment, for example and without limitation, the nicotine, nicotine prodrug or nicotine analog is bound to the carboxylic acid containing water soluble polymer before the carboxylic acid containing water soluble polymer is coated on the pharmaceutically acceptable particle. [0074] In a second aspect, the specification relates to a process for preparation of a composition having a pharmaceutically acceptable particle, a carboxylic acid group containing water soluble polymer, and nicotine, nicotine prodrug or a nicotine analog, the process comprising:

[0075] mixing the pharmaceutically acceptable particle with a carboxylic acid group containing water soluble polymer forming a polymer coated particle having a carboxylic acid group, and;

[0076] mixing the nicotine, nicotine prodrug or a nicotine analog with the coated particle to releasably bind the nicotine, nicotine prodrug or a nicotine analog to the carboxylic acid group of the polymer coated particle.

[0077] The step of mixing the carboxylic acid group containing water soluble polymer with the pharmaceutically acceptable particle for forming a polymer coated particle having a carboxylic acid group is not particularly limited and should be understood by a person of skill in the art. The carboxylic acid containing water soluble polymer and the pharmaceutically acceptable particle are selected to allow for binding the nicotine, nicotine prodrug or nicotine analog to the carboxylic acid of the polymer coated particle. In one embodiment, for example and without limitation, the polymer coated particle having a carboxylic acid group is a polyacrylic acid coated particle and the active ingredient is nicotine. Mixing of the carboxylic acid group containing water soluble polymer and the pharmaceutically acceptable particle is carried out under conditions to allow the carboxylic acid containing water soluble polymer to coat the pharmaceutically acceptable particle. In one embodiment, for example and without limitation, the entire pharmaceutically acceptable particle is covered by the carboxylic acid containing water soluble polymer. In a second embodiment, for example and without limitation, multiple layers of the carboxylic acid containing water soluble polymer coat and cover the pharmaceutically acceptable particle. In one embodiment, for example and without limitation, the medium selected allows for such coating without having a detrimental effect on the carboxylic acid containing water soluble polymer, and also ensuring that the coating of the carboxylic acid containing water soluble polymer retains on the pharmaceutically acceptable particle. In one embodiment, for example and without limitation, once the polymer coated particle having the carboxylic acid is formed, it can be separated from the medium before the next step of mixing the polymer coated particle having the carboxylic acid with nicotine, nicotine prodrug or nicotine analog is carried out.

[0078] Once the polymer coated particle having the carboxylic acid group is formed, the nicotine, nicotine prodrug or nicotine analog can be added. The step of mixing the polymer coated particle having the carboxylic acid with the nicotine, nicotine prodrug or nicotine analog for forming the composition is not particularly limited and should be understood by a person of skill in the art. In one embodiment, for example and without limitation, the polymer coated particle having a carboxylic acid group is a polyacrylic acid coated particle and the active ingredient is nicotine. In such an embodiment, the polymer coated particle having a carboxylic acid group and nicotine are mixed under conditions where the polymer coated particle having a carboxylic acid group has a negative charge (from deprotonation of the carboxylic acid substituents) and the nicotine is protonated (due to the basic nature of the molecule), leading to ionic interaction and bonding between the polymer coated particle having a carboxylic acid group and the nicotine, and thereby forming the composition. In a further embodiment, the step of mixing the polymer coated particle having a carboxylic acid group and the nicotine, nicotine prodrug or nicotine analog can be performed in a medium that allows the ionic bonding between the polymer- coated particle having a carboxylic acid group and the nicotine, nicotine prodrug or nicotine analog to take place. The medium selected is not particularly limited and can be varied depending on the pharmaceutically acceptable particle, carboxylic acid containing water soluble polymer, and nicotine, nicotine prodrug or nicotine analog selected.

[0079] In a third aspect, the specification relates to a process for preparation of a composition having a pharmaceutically acceptable particle, a carboxylic acid group containing water soluble polymer, and nicotine, nicotine prodrug or a nicotine analog, the process comprising:

[0080] mixing the nicotine, nicotine prodrug or a nicotine analog with the carboxylic acid group containing water soluble polymer to releasably bind the nicotine, nicotine prodrug or a nicotine analog to the carboxylic acid group of the carboxylic acid group containing water soluble polymer, forming a nicotine, nicotine prodrug or nicotine analog bound carboxylic acid group containing water soluble polymer; and [0081] mixing the nicotine, nicotine prodrug or nicotine analog bound carboxylic acid group containing water soluble polymer with the pharmaceutically acceptable particle to coat the pharmaceutically acceptable particle with the nicotine, nicotine prodrug or nicotine analog bound carboxylic acid group containing water soluble polymer.

[0082] The difference between second and third aspects of the specification relate to the timing of binding of the nicotine, nicotine prodrug, or nicotine analog to the carboxylic acid. In the second aspect, the nicotine, nicotine prodrug or nicotine analog is bound to the carboxylic acid group of the water soluble polymer after coating of the pharmaceutically acceptable particle with the carboxylic acid water soluble polymer. In contrast, in the third aspect, the nicotine, nicotine prodrug or nicotine analog is bound to the carboxylic acid group of the water soluble polymer before coating of the pharmaceutically acceptable particle with the carboxylic acid water soluble polymer. In both cases, the selection of the pharmaceutically acceptable particle, carboxylic acid group containing water soluble polymer, and nicotine, nicotine prodrug or nicotine analog allows for disassociation of the nicotine, nicotine prodrug or nicotine analog from the carboxylic acid moiety on the water soluble polymer, leading to release of the nicotine, nicotine prodrug or nicotine analog in the medium at the point of delivery of interest.

[0083] As noted above, in accordance with the third aspect of the specification, the step of binding of the nicotine, nicotine prodrug or nicotine analog to the carboxylic acid moiety of the carboxylic acid group containing water soluble polymer takes place before the coating step. The step of binding of the nicotine, nicotine prodrug or nicotine analog to the carboxylic acid moiety of the carboxylic acid group containing water soluble polymer is not particularly limited and should be understood by a person of skill in the art. Similar to the second aspect of the specification, the step of mixing the nicotine, nicotine prodrug or nicotine analog and the carboxylic acid group containing water soluble polymer is carried out under conditions and in a medium that allows for deprotonation of the carboxylic acid moiety (forming the carboxylate anion species) and protonation of the nicotine, nicotine prodrug or nicotine analog (forming the cation species), and leading to ionic interaction and ionic bonding between two species. Binding of the deprotonated carboxylic acid group containing water soluble polymer with the protonated nicotine, nicotine prodrug or nicotine analog leads to formation of the nicotine, nicotine prodrug or nicotine analog bound carboxylic acid group containing water soluble polymer, which can then be separated, mixed or to which can be added with the pharmaceutically acceptable polymer to form the composition.

[0084] The step of mixing the nicotine, nicotine prodrug or nicotine analog bound carboxylic acid group containing water soluble polymer with the pharmaceutically acceptable particle is not particularly limited and should be understood by a person of skill in the art, or can be determined based on non- inventive routine experimentation. The mixing is carried out under conditions and medium that leads to formation of the composition, and avoids, or inhibits dissociation of the nicotine, nicotine prodrug or nicotine analog from the carboxylic acid group containing water soluble polymer.

[0085] The step of coating the pharmaceutically acceptable particle with the carboxylic acid group containing water soluble polymer or the nicotine, nicotine prodrug or nicotine analog bound carboxylic acid group containing water soluble polymer in accordance with the second or third aspects of the specification is not particularly limited. In one embodiment, for example and without limitation, the step of mixing to coat the pharmaceutically acceptable particle is carried out in a solution containing 1 %, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%, and all values and ranges based on the values disclosed herein, of the carboxylic acid group containing water soluble polymer (whether with or without the nicotine, nicotine prodrug or nicotine analog). This can result in a single layer or multiple layers of carboxylic acid group containing water soluble polymer (whether with or without the nicotine, nicotine prodrug or nicotine analog) on the pharmaceutically acceptable particle.

[0086] The extent of loading on the nicotine, nicotine prodrug or nicotine analog on the particles is not particularly limited and can be varied depending on the design and application requirements. The extent of loading will depend upon the extent of carboxylic acid moieties present in the water soluble polymer, and calculated based on the carboxylic acid moieties bound to the nicotine, nicotine prodrug or nicotine analog divided by the total number of carboxylic acid moieties present in the water soluble polymer. In one embodiment, for example and without limitation, the particles have nicotine, nicotine prodrug or nicotine analog loading of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or higher, including all values in between and ranges based on these values.

[0087] In one embodiment, for example and without limitation, the rate of release of the nicotine, nicotine prodrug or nicotine analog from the composition is not particularly limited, and can be varied depending on design and application requirements. In a particular embodiment, for example and without limitation, the nicotine, nicotine prodrug or nicotine analog, the pharmaceutically acceptable particle and the carboxylic acid group containing water soluble polymer are selected to allow for a high initial release of the nicotine, nicotine prodrug or nicotine analog, thereby providing an high bolus dose of the nicotine, nicotine prodrug or nicotine analog, followed by gradual release of the nicotine, nicotine prodrug or nicotine analog. In another embodiment, for example and without limitation, the initial rate of release of the nicotine, nicotine prodrug or nicotine analog from the composition is about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or higher from the composition within 10 minutes in a targeted medium at a specified temperature. In a further embodiment, for example and without limitation, the targeted medium is saliva or simulated saliva and the temperature is about 37°C or body temperature.

[0088] The nicotine, nicotine prodrug or nicotine analog, the pharmaceutically acceptable particle and the carboxylic acid containing waters soluble polymer can be selected to control the amount of nicotine, nicotine prodrug or nicotine analog remaining bonded to the composition after the initial release of the nicotine, nicotine prodrug or nicotine analog, and which will be slowly released in the environment. In one embodiment, for example and without limitation, the amount of nicotine, nicotine prodrug or nicotine analog bonded to the composition is about 25%, 30%, 35%, 40%, or 45%, between 15 to 30 minutes after the initial release of the nicotine, nicotine prodrug or nicotine analog in the environment.

[0089] The composition disclosed herein allows for retaining the nicotine, nicotine prodrug or nicotine analog as part of the composition providing stability upon storage, while under certain conditions allows for delivery of the nicotine, nicotine prodrug or nicotine analog at a point of interest. In one embodiment, for example and without limitation, nicotine is bound to the carboxylic acid group of the water soluble polymer and when placed in medium, such as, for example and without limitation, a saliva of a human, can lead to significant weakening of the interaction between the nicotine and the carboxylic acid group containing water soluble polymer, thereby leading to high release of the nicotine from the composition, and delivery to the human subject.

[0090] The composition as disclosed herein can contain other ingredients, including for example, pharmaceutically acceptable salts, pharmaceutically acceptable excipients, pharmaceutically acceptable carriers, pH regulating agents or buffering agents that help with and control the rate of release of the nicotine, nicotine prodrug or nicotine analog from the composition, and delivery to a subject in need thereof.

[0091] The term, pH regulating agent, as used herein is not particularly limiting and should be known to a person of skill in the art. pH regulating agents refer to agents that actively adjust and regulate the pH value of the solution to which they have been added or are to be added. Hence, pH regulating agents may be acids and bases, including acidic buffering agents and alkaline buffering agents.

[0092] The term, buffering agent, as used herein is not particularly limiting and should be known or understood by a person of skill in the art. The term, buffering agents, can be used interchangeably with, buffer, and refers to agents for obtaining a buffer solution. Buffering agents include acidic buffering agents, i.e. for obtaining a buffer solution with an acidic pH, and alkaline buffering agents, i.e. for obtaining a buffer solution with an alkaline pH.

[0093] In a fourth aspect, the specification relates to a composition as disclosed herein for use in the delivery of nicotine, nicotine prodrug or nicotine analog to a subject in thereof. In addition, in a fifth aspect, the specification relates to the use of a composition as disclosed herein for delivery of nicotine, nicotine prodrug or nicotine analog to a subject in need thereof.

[0094] The use as disclosed herein is not particularly limited and should be understood by a person of skill in the art. The objective is delivery of nicotine, nicotine prodrug or nicotine analog to a subject in need thereof. The subject is also not particularly limited, and can be varied depending on application requirements. In one embodiment, for example and without limitation, the subject is human. [0095] In a sixth aspect, the specification relates to a method of preventing or treating a disease or condition, comprising providing a composition as disclosed herein to a subject in need thereof.

[0096] The terms, preventing, treating, disease and condition are used broadly herein and are not particularly limited, and should be understood by a person of skill in the art. Preventing can involve averting or stopping onset of a disease or condition. In one embodiment, for example and without limitation, the method can involve nicotine replacement therapy as treating a condition.

[0097] In a seventh aspect, the specification relates to a product comprising the composition as disclosed herein. In addition, in an eighth aspect, the specification relates to use of the product as disclosed herein for delivery of nicotine, nicotine prodrug or nicotine analog to a subject in need thereof. Further, in a ninth aspect, the specification relates to a product as disclosed herein for use in the delivery of nicotine, nicotine prodrug or nicotine analog to a subject in need thereof.

[0098] The term, product, as used herein is not particularly limited and should be understood by a person of skill in the art. In one embodiment, for example and without limitation, the product can include gums, transdermal patches, tablets, film strips, pouch, lozenges, spray, drops, cream and the like. The method of preparation of such products should be known to or can be determined by a person of skill in the art.

[0099] In a tenth aspect, the specification relates to a method of preventing or treating a disease or condition, comprising providing a product as disclosed herein to a subject in need thereof. The method as disclosed herein is not particularly limited and involves providing the product having the composition to a subject in need thereof. In one embodiment, for example and without limitation, the composition includes inert particles such as silicon dioxide or cellulose as the pharmaceutically acceptable particle, nicotine, polyacrylic acid as the carboxylic acid group containing water soluble polymer, and the product is to for nicotine replacement therapy (NRT).

EXAMPLES

[00100] The above disclosure generally describes the present invention. A more complete understanding can be obtained by reference to the following specific Examples. These Examples are described solely for purposes of illustration and are not intended to limit the scope of the invention. Changes in form and substitution of equivalents are contemplated as circumstances may suggest or render expedient. Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the constructs of the present invention and practice the claimed methods. The following working examples therefore, specifically point out the typical aspects of the present invention and are not to be construed as limiting in any way in the remainder of the disclosure. Although specific terms have been employed herein, such terms are intended in a descriptive sense and not for purposes of limitation.

[00101 ] Example 1 :

[00102] Borosilcate glass particles (size of 10 micron-100 micron) were added to a Polyacrylic acid polymer solution of 10% (molecular weight of 20kd-450kD) containing 0.4 Molar sodium Chloride at room temperature. The particles were coated for 1 hour and then separated from the solution, washed with distilled water to remove excess polymer and dried in oven at 45°C for 2 hours. The coated particles were added to a nicotine solution (2%-50%) and stirred for 30 minutes, then removed for solution, washed off with Distilled water and dried in an oven for 2 hours at 45°C. The nicotine loaded particles were included in a composition containing a buffering system, spacers and excipient to formulate a fast dissolving tablet.

[00103] Example 2:

[00104] A 10% solution of carboxymethyl cellulose (degree of substitution of 0.4-1.5) was spray coated onto Polyethylene particles (size 5-50 micron) using horizontal fluid bed coating process. The coated particles where then dip coated into a nicotine solution (20-40%) for 30 minutes, washed of excess nicotine and oven dried at 45°C temperate for 3 hours. The nicotine coated particles were used in a formulation with a buffer system, excipient in an oral pouch for nicotine replacement therapy.

[00105] Example 3:

[00106] Silicon dioxide particles (size of 10-100 micron) were spray coated with a solution of Styrene maleic anhydride copolymer (molecular weight 40-120kD) in acetone while the coating chamber saturated with 50% humidity and left in the same humidity level for 2 hours at 60°C till all the anhydride groups are hydrolysed. The coated particles placed in nicotine solution and dried as in example 2. The nicotine coated particles were used in a formulation with a buffer system, excipient, electrolytes, flavoring agent, sucralose and anti-caking agent and employed in a pouch for nicotine replacement therapy at 4mg nicotine per pouch.

[00107] Examples 4 - 11 :

[00108] Particles of microcrystalline cellulose (MCC, PH102) were coated with Polyacrylic acid (PAA) polymer using a fluid bed coater. The particles were first screened through a 200pm sieve and then fluidized in a Wurster Coater. PAA polymers of two different sizes were used (240Kd and 450Kd) and were applied from 10% aqueous solutions. Calculations were done to reach a theoretical coating buildup level of 3% or 5% (w/w).

[00109] The PAA-coated particles were briefly dried in the fluid bed and then screened again through the 200pm sieve. The filtered particles were returned to the coater and nicotine solution is applied. Nicotine was diluted with purified USP Water and the processing temperature was kept below 45°C (113°F). The finished product was screened through the 200pm screen.

[00110] The final coated particles were further processed as two sets; one set was washed with distilled water (Examples 4-7) and the other set was washed with 0.4M organic acid (Examples 8-11). After the relevant wash, both sets were dried in oven at 40°C and the nicotine contents were measured using established HPLC methodology. Results are listed in Table 1.

Table 1 shows the nicotine content of different PAA polymers prepared.

[00111 ] Examples 12 - 19: [00112] Particles of microcrystalline cellulose (MCC, PH102) were coated with PAA polymers using the same fluid bed coater. The particles were screened and fluidized in a Wurster Coater as detailed in Examples 4-7. Two PAA polymers of different sizes were used (240Kd or 450Kd). The theoretical calculations of the spraying solution were done to achieve a polymer build up of 3% or 5% and a fixed amount of nicotine (20%). The particles were sprayed with a solution of nicotine already reacted with the PAA polymer. This process was successful with the lower molecular weight polymer (240Kd). However, the attempts of using the 450Kd PAA in the presence with nicotine in solution was not successful, as the solution viscosity was too high to allow adequate fluid spraying and the attempts were aborted. The coated particles were screened as in Examples 4-7.

[00113] Two sets of the final particles coated with the 240Kd PAA polymer already reacted with nicotine are processed further; one set was washed with distilled water (Examples 12 and13) and the other set was washed with 0.4M organic acid (Examples 16 and 17). Both sets were dried in oven at 40°C and the nicotine contents were measured using established HPLC methodology. The results of nicotine measurements are listed in Table 2.

Table 2 shows the nicotine content of different PAA polymers prepared.

[00114] Example 20:

[00115] Particles of microcrystalline cellulose (MCC, PH102) coated with 450Kd PAA at 3 and 5% level of Examples 6 and 7 above. The polymer coated particles were screened through the 200pm screen and coated with an alcohol solution of nicotine in a drum coater to achieve a theoretical level of 25%. The coated particles were dried in an oven at temperature of 40°C without washing step. The coated particles were screened through the 200pm screen and the nicotine contents of the particles were determined using HPLC established methodology. Nicotine contents were 24.34% and 24.64% for the 3% and 5% polymer coat level respectively.

[00116] Example 21 :

[00117] Particles of microcrystalline cellulose (MCC, PH102) were screened through a 200pm sieve and coated with an alcoholic solution of PAA in a drum coater. The PAA used has a molecular weight of 60Kd and calculations were done for a polymer build up level of 5% (W/W). The coated articles were washed with distilled water and dried in an oven at 70°C. The coated particles were screened through a 200pm sieve and coated with an alcoholic solution of nicotine. Calculations were done to a nicotine level of 10%. The coated particles were washed in distilled water and dried at temperature of 40°C in a convection oven. The particles were screened through the 200pm screen and the nicotine contents of the particles were determined using HPLC established methodology. Measured nicotine contents were 9.6%.

[00118] Example 22:

[00119] Particles of microcrystalline cellulose (MCC, PH102) were screened through a 200pm sieve and coated in a drum coater by mixing the particles with an alcohol solution of PAA polymer and nicotine. The PAA polymer used was 60Kd polymer and calculations were done to a polymer coating level of 5% and nicotine of 20% (W/W). The particles were dried in an oven at 40°C. The coated particles were screened through a 200pm sieve and nicotine contents were determined using HPLC established methodology. The measured nicotine contents of the particles were 18.33%.

[00120] Example 23 - 26:

[00121] Bentonite particles (Volclay NF-BC-670) were coated with PAA using a fluid bed coater. The particles were screened through a 200pm sieve and fluidized in a Wurster Coater. The coating solution contains the PAA polymer and nicotine. Two PAA polymers of different sizes were used (80Kd and 240Kd) and theoretical calculations were done to achieve a polymer coating level build up of either 3% or 5%, each with a theoretical 20% nicotine level. The PAA-nicotine solutions were diluted in absolute alcohol to reach the targeted levels. Since the spraying pressure of nicotine plays a significant role in achieving the theoretical goals, the spraying pressure was decreased. The coated particles are screened through a 200pm sieve and the nicotine contents of the coated particles are measured in using established HPLC methodology. The measured nicotine is in Table 3.

Table 3 shows the nicotine content of different PAA polymers prepared.

[00122] Example 27:

[00123] D-Mannitol particles were screened through a 200pm sieve. Using a drum coater, the D-Mannitol particles were coated with a solution containing polyacrylic acid polymer (PAA) of an average molecular weight of 80Kd. Calculations were done to reach a polymer coating level of 5% (W/W). The coated particles were dried in an oven at 80°C. The dried particles screened through a 200pm sieve and coated with an alcoholic nicotine solution. Calculations were done to achieve a theoretical nicotine level of 15%. The particles were dried in an oven at 40°C. The coated particles were screened through a 200pm sieve and the nicotine contents were determined using HPLC established methodology. The measured nicotine contents of the particles were 12.6%.

[00124] Example 28:

[00125] Sodium carbonate particles were screened through a 200pm sieve. Using a drum coater, the particles were coated with a solution containing polyacrylic acid (PAA) polymer with a molecular weight of 80Kd. Calculations were done to reach a polymer coating level of 5% (W/W). The coated particles were dried in an oven at 80°C. The dried particles screened through a 200pm sieve and coated with an alcoholic nicotine solution. Calculations were done to achieve a theoretical nicotine level of 15%. The particles were dried in an oven at 40°C. The coated particles were screened through a 200pm sieve and the nicotine contents were determined using HPLC established methodology. Measured nicotine contents were 13.19%.

[00126] Example 29:

[00127] Dibasic calcium phosphate particles (Fujicalin, Fuji Chemical Industries Co.) were screened through a 200pm sieve. Using a drum coater, the particles were coated with a solution containing polyacrylic acid (PAA) polymer with a molecular weight of 80Kd. Calculations were done to reach a polymer coating level of 10% (W/W). The coated particles were dried in an oven at 80°C. The dried particles screened through a 200pm sieve and coated with an alcoholic nicotine solution. Calculations were done to achieve a theoretical nicotine level of 20%. The particles were dried in an oven at 40C. The coated particles were screened through a 200pm sieve and the nicotine contents were determined using HPLC established methodology. Measured nicotine contents were 17.44%

[00128] Example 30:

[00129] Dibasic calcium phosphate particles (Fujicalin, Fuji Chemical Industries Co.) were screened through a 200pm sieve. Using a drum coater, the particles were coated with a solution containing both polymer and nicotine. The polyacrylic acid (PAA) polymer used had a molecular weight of 80Kd. Calculations were done to reach a polymer coating level of 10% (W/W) and a nicotine level of 20% (W/W). The coated particles were dried in an oven at 40°C. The dried particles were screened through a 200pm sieve and the nicotine contents were determined using HPLC established methodology. The measured nicotine contents were 16.67%.

[00130] Example 31 :

[00131] The polymer coating and nicotine binding of Example 30 was repeated except porous styrene-divinyl benzene (DVB) resin particles was used instead of the dibasic calcium phosphate particles. The nicotine contents were determined using the same HPLC established methodology. The measured nicotine contents were 15.84%. REFERENCES

[00132] American Psychiatric Association. Task Force on DSM-IV. Diagnostic and statistical manual of mental disorders: DSM-IV-TR. 4th ed. Washington: American Psychiatric Association; 2000.

[00133] Health Canada. Canadian Tobacco Use Monitoring Survey (CTUMS). Summary of annual results for 2011 . Available from: www.hc-sc.qc. ca/hc-ps/tobac- tabac/research-recherche/stat/ ctums-esutc 2011/ann summary-sommaire- eng.php.

[00134] Pirie K, Peto R, Reeves GK et al. The 21st century hazards of smoking and benefits of stopping: a prospective study of one million women in UK. Lancet 2013; 381 :133-41.

[00135] Lin Li, Ron Borland, K. Michael Cummings, Andrew Hyland, Michael Le Grande, Geoffrey T. Fong, Ann McNeill. Non-cigarette combustible tobacco use and its associations with subsequent cessation of smoking among daily cigarette smokers: findings from the International Tobacco Control Four Country Smoking and Vaping Surveys (2016-20). Addiction. 2022;1-9. DOI: 10.1111/add.16023.

[00136] Hammond D, McDonald PW, Fong GT et al. Do smokers know how to quit? Knowledge and perceived effectiveness of cessation assistance as predictors of cessation behavior. Addiction 2004; 99:1042-8.

[00137] Michael McEwan, David Azzopardil , Nathan Galel , Oscar M. Camachol , George Hardiel , Ian M. Fearon, James Murphy. A Randomised Study to Investigate the Nicotine Pharmacokinetics of Oral Nicotine Pouches and a Combustible Cigarette. European Journal of Drug Metabolism and Pharmacokinetics (2022) 47:211-221.

[00138] David Azzopardil , James Ebajemitol , Michael McEwanl , Oscar M. Camachol , Jesse Thissenl , George Hardiel , Richard Voisine, Gavin Mullard, Zvi Cohen, James Murphy. A randomised study to assess the nicotine pharmacokinetics of an oral nicotine pouch and two nicotine replacement therapy products. Nature (2022) 12:6949.

[00139] Stacey McCaffrey, Jennifer Lewis. Elizabeth Becker, Andrea Vansickel, Elsa Larson, Mohamadi Sarkar. Six-Week Actual Use Study to Evaluate the Impact of Oral Tobacco-Derived Nicotine Pouches on Cigarette Smoking and Smokeless Tobacco Product Use Behaviors. Research Square, 05 Oct 2021 . DOI: https://doi.Org/10.21203/rs.3.rs-951433/v1 https://doi.org/10.21203/rs.3.rs- 951433/vl

[00140] Manpreet Sukhija, Reena Srivastava, Aditya Kaushik. Pharmacokinetic characterization of three novel 4-mg nicotine lozenges. International Journal of Clinical Pharmacology and Therapeutics, Vol. 56 No. 3/2018 (113-119).

[00141] Saul Shiffmana, Edward J. Coneb, August R. Buchhalterb, Jack E. Henningfieldb, Jeffrey M. Rohaya, Joe G. Gitchellb, John M. Pinneyb, Tommy Chau. Rapid absorption of nicotine from new nicotine gum formulations. Pharmacology, Biochemistry and Behavior 91 (2009) 380-384.

[00142] Jha P, Ramasundarahettige C, Landsman V et al. 21 st-century hazards of smoking and benefits of cessation in the United States. N Engl J Med 2013; 368:341-50.

[00143] Cornuz J, Willi C. Nonpharmacological smoking cessation interventions in clinical practice. Eur Respir Rev 2008; 17:187-91.

[00144] US patent publication number US 2002/0016469 A1 to HUGHES Lyn, published on Feb 7, 2002, filed Jun 20, 2001 , titled: Anhydrous purification of nicotine using an ion exchange resin, filed ;

[00145] US patent publication number US 2002/0164398 A1 to JOHNSON et al., published on Nov 7, 2002, filed Dec 17, 2001 , titled: Method and product for accelerating absorption of medicaments through oral mucosa;

[00146] US patent publication number US 2006/0275344 A1 to MODY et al., published on Dec 7, 2006, filed May 18, 2005, titled: Flavoring of drug-containing chewing gums;

[00147] US patent publication number US 20090253754A1 to SELMIN et al., published on Oct 8, 2009, filed Dec 4^th, 2008, titled: Fast dissolving films and coatings for controlled release of flavors, active pharmaceutical ingredients, food substances, and nicotine; [00148] US patent publication number US 2010/0004294 A1 to NICONOVUM AB, published on Jan 7^th, 2010, filed September 16^th, 2007, titled: Stable Lozenge Compositions Providing Rapid Release of Nicotine;

[00149] US patent publication number US 2010/0124560 A1 to

MCNEIL AB, published on May 20, 2010, filed Nov 14^th, 2008, titled: Multi portion intra-oral dosage form and use thereof ;

[00150] US patent publication number US 2013/0280179 A1 to NIELSEN BRUNO PROVSTGAARD etal., published on Oct 24, 2013, filed Dec 21 , 2010, titled: Chewing Gum Composition Comprising Cross-Linked Polyacrylic Acid;

[00151] US patent publication number US 2015/0020818 A1 to ALTRIA CLIENT SERVICES INC., published on Jan 22^nd, 2015, filed July 17^th, 2014, titled: Methods and Systems for Incorporating Nicotine into Oral Products;

[00152] US patent publication number US 2016/0113868 A1 to GLAXOSMITHKLINE LLC., published onApr 28, 2016, filed May 9^th, 2014, titled: Nicotine lozenge formulation;

[00153] US patent publication number US 2018/0353438 A1 to AMAPHASE LTD., published on Dec 13^th, 2018, filed May 30^th, 2018, titled: Exothermic topical devices for delivering pharmaceuticals and cosmetics to the skin;

[00154] US patent publication number US 2021/0106516 A1 to FERTIN PHARMA AS., published on April 15, 2021 , filed Oct 11 , 2019, titled: Ion-Exchange Composition With Water-Soluble Mucoadhesive Polymers;

[00155] US patent publication number US 2021/0386662 A1 to MODORAL BRANDS INC., published on Dec 16, 2021 , filed Aug 27, 2021 , titled: Snuff composition;

[00156] US patent publication number US 2022/0304373 A1 to NICOVENTURES TRADING LTD. et al., published on Sep 29, 2022, filed Jun 9, 2022, titled: Fibrous fleece material;

[00157] US patent publication number US 2022/0087997 A1 to

FERTIN PHARMA AS et al., published on Mar 24, 2022, filed Sep 22, 2020, titled: Oral Antagonist Compositions For Nicotine Burning Relief; [00158] US patent publication number US 2022/0151292 A1 to NCP NEXTGEN AS, published on May 19, 2022, filed Nov 16, 2020, titled: Nicotine pouch composition;

[00159] US patent publication number US 2023/0346768 A1 to

FERTIN PHARMA AS, published on Nov 2, 2023, filed July 7, 2023, titled: Nicotine tablet;

[00160] US Patent number US 3,901 ,248 A to LEO AB., issued on Aug 26, 1975, filed Aug 15, 1974, titled: Chewable smoking substitute composition;

[00161] US Patent number US 6,166,044 to MAYO FOUNDATION, issued on Dec 26, 2000, filed Mar 23, 1999, titled: Colonic delivery of nicotine to treat inflammatory bowel disease;

[00162] US Patent number US 6,238,689 B1 to MAYO FOUNDATION, issued on May 29, 2001 , filed July 16, 1997, titled: Intestinal absorption of nicotine to treat nicotine responsive conditions;

[00163] US Patent number US 9,585,967 B2 to FRANZ ALEXANDER, issued on Mar 7, 2017, filed Dec 10, 2009, titled: Nicotine-containing product;

[00164] US Patent number US 9,629,832 B2 to NICONOVUM USA INC., issued on Apr 25, 2017, filed Apr 28, 2014, titled: Physically and chemically stable nicotine-containing particulate material;

[00165] US Patent number US 9,707,175 B2 to FERTIN PHARMA A/S, issued on July 18, 2017, filed Dec 21 , 2010, titled: Chewing gum composition comprising cross-linked polyacrylic acid;

[00166] US Patent number US 9,801 ,408 B2 to FERTIN PHARMA AS, issued on Oct 31 , 2017, filed Apr 24, 2014, titled: Nicotine delivery product and method for producing it;

[00167] US Patent number US 10,881 ,134 to ALTRIA CLIENT SERVICES LLC., issued on Jan 5, 2021 , filed Nov 19, 2018, titled: Use of pectin or other anionic polymers in the stabilization and controlled release of nicotine in oral sensorial tobacco products or nicotine containing non-tobacco oral sensorial products;

[00168] US Patent number US 11 ,399,562 B2 to NCP NEXTGEN AS, issued on Aug 2, 2022, filed Jun 5, 2020, titled: Oral pouched product; [00169] US Patent number US 11 ,759,419 B2 to FERTIN PHARMA AS, issued on Sep 19, 2023, filed Oct 11 , 2019, titled: Compressed nicotine lozenge;

[00170] PCT patent publication number WO 1995030411 A1 to KOREA RES. INST. CHEM. TECH., published on Nov 16, 1995, filed May 9, 1995, titled: Transdermal drug delivery system having ionic polymer networks;

[00171] PCT patent publication number WO 1997028801 A1 to MAYO FOUNDATION et al., published on Aug 14, 1997, filed Feb 9, 1996, titled: Colonic delivery of nicotine to treat inflammatory bowel disease;

[00172] PCT patent publication number WO 2001058951 A3 to STICHTING TECH WETENSCHAPP, published on Aug 16, 2001 , filed Feb 9, 2001 , titled: Watersoluble ligand-binding proteins and analogs of ligand-gated ion channels, crystals thereof and their use for screening ligands of ligand-gated ion channels;

[00173] PCT patent publication number W02008140371 A1 to MCNEIL AB, published on Nov 20, 2008, filed Apr 21 , 2008, titled: Oral nicotine formulation buffered with amino acid;

[00174] PCT patent publication number WO2012083947 A1 to FERTIN PHARMA AS, published on June 28, 2012, filed Dec 21 , 2010, titled: Chewing gum composition comprising cross-linked polyacrylic acid;

[00175] PCT patent publication number WO2021071902 A1 to BRILLIAN PHARMA INC., published on Apr 15, 2021 , filed Oct 7, 2020, titled: Micronized drug resinate-based pharmaceutical compositions and methods of preparation thereof;

[00176] PCT patent publication number WO2022100806 A1 to FERTIN PHARMA AS, published on May 19, 2022, filed Nov 16, 2021 , titled: Solid oral nicotine formulation;

[00177] EP Patent number EP1803443 B1 to NICONOVUM AB, published on July 4, 2007, filed Dec 19, 2003, titled: A nicotine-containing particulate material with acrystalline cellulose.

[00178] All publications, patents and patent applications cited above are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. [00179] Although preferred embodiments of the invention have been described herein in detail, it will be understood by those skilled in the art that variations may be made thereto without departing from the spirit of the invention or the scope of the appended claims.

Claims

WE CLAIM:

1 . A composition comprising: a pharmaceutically acceptable inert particle; a carboxylic acid group containing water soluble polymer coating the pharmaceutically acceptable particle; and nicotine, nicotine prodrug or a nicotine analog releasably bound to the water soluble polymer.

2. The composition of claim 1 , wherein the pharmaceutically acceptable particle is a non-porous particle.

3. The composition of claim 1 , wherein the pharmaceutically acceptable particle is a porous particle.

4. The composition of any one of claims 1 to 3, wherein the pharmaceutically acceptable particle is a biodegradable particle.

5. The composition of any one of claims 1 to 3, wherein the pharmaceutically acceptable particle is a non-biodegradable particle.

6. The composition of any one of claims 1 to 5, wherein the pharmaceutically acceptable particle is substantially non-swellable in an aqueous environment.

7. The composition of any one of claims 1 to 6, wherein the pharmaceutically acceptable particle have a particle size of from about 1 pm to about 800 pm.

8. The composition of any one of claims 1 to 7, wherein the pharmaceutically acceptable particle is glass, ceramic, a metal microsphere or a polymer microparticle.

9. The composition of any one of claims 1 to 8, wherein the carboxylic acid functional group in the carboxylic acid containing water soluble polymer is present in more than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% of the total monomer units forming the carboxylic acid containing water soluble polymer.

10. The composition of any one of claims 1 to 9, wherein the carboxylic acid group containing water soluble polymer is a non-cross-linked linear polymer or copolymer.

11. The composition of any one of claims 1 to 9, wherein the carboxylic acid containing water soluble polymer is polyacrylic acid.

12. The composition of any one of claims 1 to 11 , wherein the carboxylic acid group containing water soluble polymer has a molecular weight of from about 20 kDa to about 3500 kDa, and all molecular weights and ranges in between.

13. The composition of any one of claims 1 to 12, wherein nicotine is releasably bound to the carboxylic acid group containing water soluble polymer.

14. The composition of any one of claims 1 to 12, wherein the nicotine prodrug is releasably bound to the carboxylic acid group containing water soluble polymer.

15. The composition of any one of claims 1 to 12, wherein the nicotine analog is releasably bound to the carboxylic acid group containing water soluble polymer.

16. The composition of any one of claims 1 to 15, wherein the carboxylic acid group containing water soluble polymer is coated on the pharmaceutically acceptable particle before binding of the nicotine, nicotine prodrug or nicotine analog to the carboxylic acid group containing water soluble polymer.

17. The composition of any one of claims 1 to 15, wherein the nicotine, nicotine prodrug or nicotine analog is releasably bound to the carboxylic acid group containing water soluble polymer before the carboxylic acid group containing water soluble polymer is coated on the pharmaceutically acceptable particle.

18. A process for preparation of a composition having a pharmaceutically acceptable particle, a carboxylic acid group containing water soluble polymer, and nicotine, nicotine prodrug or a nicotine analog, the process comprising: mixing the pharmaceutically acceptable particle with a carboxylic acid group containing water soluble polymer forming a polymer coated particle having a carboxylic acid group, and; mixing the nicotine, nicotine prodrug or a nicotine analog with the coated particle to releasably bind the nicotine, nicotine prodrug or a nicotine analog to the carboxylic acid group of the polymer coated particle.

19. The process of claim 18, wherein the step of mixing to coat the pharmaceutically acceptable particle is carried out in a solution containing 1 %, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%, of the carboxylic acid group containing water soluble polymer.

20. The process of claim 18 or 19, wherein a single layer or multiple layers of the carboxylic acid group containing water soluble polymer coats the pharmaceutically acceptable particle.

21. A process for preparation of a composition having a pharmaceutically acceptable particle, a carboxylic acid group containing water soluble polymer, and nicotine, nicotine prodrug or a nicotine analog, the process comprising: mixing the nicotine, nicotine prodrug or a nicotine analog with the carboxylic acid group containing water soluble polymer to releasably bind the nicotine, nicotine prodrug or a nicotine analog to the carboxylic acid group of the carboxylic acid group containing water soluble polymer, forming a nicotine, nicotine prodrug or nicotine analog bound carboxylic acid group containing water soluble polymer; and mixing the nicotine, nicotine prodrug or nicotine analog bound carboxylic acid group containing water soluble polymer with the pharmaceutically acceptable particle to coat the pharmaceutically acceptable particle with the nicotine, nicotine prodrug or nicotine analog bound carboxylic acid group containing water soluble polymer.

22. The process of claim 21 , wherein the step of mixing to coat the pharmaceutically acceptable particle is carried out in a solution containing 1 %, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%, of the nicotine, nicotine prodrug or nicotine analog bound carboxylic acid group containing water soluble polymer.

23. The process of claim 21 or 22, wherein a single layer or multiple layers of the nicotine, nicotine prodrug or nicotine analog bound carboxylic acid group containing water soluble polymer coats the pharmaceutically acceptable particle.

24. The process of any one of claims 18 to 23, wherein the composition has a nicotine, nicotine prodrug or nicotine analog loading of 40%, 45%, 50%, 55%, 60%, or higher.

25. The process of any one of claims 18 to 24, wherein the initial rate of release of the nicotine, nicotine prodrug or nicotine analog is about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or higher from the composition within 10 minutes in a targeted medium at a specified temperature

26. The process of any one of claims 18 to 25, wherein the amount of nicotine, nicotine prodrug or nicotine analog bonded to the composition is about 25%, 30%, 35%, 40%, or 45%, between 15 to 30 minutes after the initial release of the nicotine, nicotine prodrug or nicotine analog in the environment.

27. The process of any one of claims 18 to 26, wherein the pharmaceutically acceptable particle is a non-porous particle.

28. The process of any one of claims 18 to 26, wherein the pharmaceutically acceptable particle is a porous particle.

29. The process of any one of claims 18 to 28, wherein the pharmaceutically acceptable particle is a biodegradable particle.

30. The process of any one of claims 18 to 28, wherein the pharmaceutically acceptable particle is a non-biodegradable particle.

31. The process of any one of claims 18 to 30, wherein the pharmaceutically acceptable particle is non-swellable in an aqueous environment.

32. The process of any one of claims 18 to 31 , wherein the pharmaceutically acceptable particle have a particle size of from about 1 pm to about 800 pm.

33. The process of any one of claims 18 to 32, wherein the pharmaceutically acceptable particle is glass, ceramic, a metal microsphere or a polymer microparticle.

34. The process of any one of claims 18 to 33, wherein the carboxylic acid functional group in the carboxylic acid containing water soluble polymer is present in more than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% of the total monomer units forming the carboxylic acid containing water soluble polymer.

35. The process of any one of claims 18 to 34, wherein the carboxylic acid group containing water soluble polymer is a non-crosslinked linear polymer or copolymer.

36. The process of any one of claims 18 to 34, wherein the carboxylic acid group containing water soluble polymer is polyacrylic acid.

37. The process of any one of claims 18 to 36, wherein the carboxylic acid group containing water soluble polymer has a molecular weight of from about 20 kDa to about 3500 kDa, and all molecular weights and ranges in between.

38. The process of any one of claims 18 to 37, wherein nicotine is releasably bound to the carboxylic acid group containing water soluble polymer.

39. The process of any one of claims 18 to 37, wherein the nicotine prodrug is releasably bound to the carboxylic acid group containing water soluble polymer.

40. The process of any one of claims 18 to 37, wherein the nicotine analog is releasably bound to the carboxylic acid group containing water soluble polymer.

41. Use of a composition as defined in any one of claims 1 to 17 for delivery of nicotine, nicotine prodrug or nicotine analog to a subject in need thereof.

42. A composition as defined in any one of claims 1 to 17 for use in the delivery of nicotine, nicotine prodrug or nicotine analog to a subject in need thereof.

43. A method of preventing or treating a disease or condition, comprising providing a composition as defined in any one of claims 1 to 17 to a subject in need thereof.

44. A product comprising the composition as defined in any one of claims 1 to 17.

45. Use of a product for delivery of nicotine, nicotine prodrug or nicotine analog comprising the composition as defined in any one of claims 1 to 17 to a subject in need thereof.

46. A product comprising the composition as defined in any one of clams 1 to 17, for use in the delivery of nicotine, nicotine prodrug or nicotine analog to a subject in need thereof.

47. A method of preventing or treating a disease or condition, comprising providing a product comprising the composition as defined in any one of claims 1 to 17 to a subject in need thereof.