FIELD OF INVENTION:

The present invention relates to stable oral lozenges containing nicotine active which is bioequivalent to approved marketed lozenges as nicotine replacement therapy for reducing or stopping tobacco usage.

BACKGROUND AND PRIOR ART:

It is generally known that smoking of tobacco products, such as cigarettes, cigars and pipe tobacco presents serious health risks to the user and those subjected to secondary smoke. It is also known that the use of smokeless forms of tobacco, such as chewing tobacco, spit tobacco and snuff tobacco, presents serious health risks to the user. Furthermore, the use of tobacco products in public areas is increasingly either restricted or socially unacceptable. Consequently, smokers and other tobacco users often try to quit the potentially deadly habit. Others may be forced to cut back on the amount of tobacco used as employment and social settings increasingly restrict smoking and other tobacco use.

Although the damaging effects of tobacco usage are well known, most individuals who are nicotine dependent have great difficulty overcoming their dependence on nicotine, typically in cigarette form. The difficulty arises in part due to the highly addictive nature of nicotine and the strong nicotine withdrawal symptoms that can occur when one begins to deprive the body of the nicotine to which it has grown dependent. Indeed, overcoming nicotine withdrawal symptoms is a critical challenge for those attempting to conquer nicotine dependence.

Nicotine withdrawal symptoms, particularly nicotine cravings, may arise in several ways. For instance, studies have shown that following a quit attempt, smokers report moderate levels of steady nicotine craving throughout the day. This craving can prove too much for some, leading to relapse and a return to tobacco usage for some of those individuals attempting to quit. In addition to steady cravings, smokers may also experience episodic, or acute, cravings. These acute cravings may be provoked by a number of stimuli, such as exposure to smoking related cues, seeing smoking paraphernalia, being in proximity to others engaged in smoking, or inhaling second hand smoke. Such episodic cravings may also lead to relapse if effective coping measures are not employed by the individual.

In an attempt to assist those who wish to eliminate or reduce tobacco usage, efforts have been made to provide those in need with some level of nicotine craving relief. Historically, these efforts have focused on the activity and administration of nicotine itself. This nicotine replacement therapy (NRT) helps to combat the intense nicotine withdrawal symptoms encountered by many individuals upon quitting smoking or other tobacco usage. In recent years, NRT has been successfully commercialized in both the United States and elsewhere. Such commercial NRT offerings include nicotine gums (e.g. NICORETTE® brand gums sold in the United States by GlaxoSmithKline Consumer Healthcare) and nicotine transdermal patches (e.g., NICODERM® brand patches sold by GlaxoSmithKline Consumer Healthcare).

In addition to traditional gums and patch NRT offerings, more recently, nicotine containing lozenges have been introduced commercially both within and outside the United States. For example, NICORETTE®, brand lozenges offer individuals an alternative form of NRT.

U.S. Pat. No. 5, 110,605 to Acharya et al. relates to lozenge compositions which comprise polycarbophil and alginic acid components.

Nicotine containing lozenge formulations are disclosed in US Pat. No. 4,967,773 to Shaw; U.S. Pat. No. 5,549,906 to Santus; U.S. Pat. No.6, 183,775 to Ventouras and WO 2007/104575 to Axelsson et al. Similarly, U.S. Pat. Nos. 5,593,684; 5,721,257 and 5,362,496 (all to Baker et al.) disclose methods and therapeutic systems for smoking cessation, utilizing both transdermal nicotine delivery for obtaining baseline nicotine plasma levels, and transmucosal administration of nicotine to satisfy transient cravings.

W02005/023227A2, focusses on pharmaceutical formulations of nicotine wherein the nicotine is stabilized against degradation and which have a high content of stable nicotine in bioavailable form. Under the‘Prior art and problems thereof it is mentioned that the need for said pharmaceutical formulations "is not entirely achieved through nicotine formulations known in the art". As "traditional solid nicotine species" for use "in dosage forms such as gums and tablets" are mentioned "nicotine resin complex, nicotine b-cyclodextrin complex, and salts as e.g. nicotine bitartrate dihydrate". The solution offered by WO 2005/023227 A2 is to use as nicotine species "a cellulose carrier for administration of nicotine", in other words a "nicotine-cellulose matrix", more precisely a nicotine-cellulose matrix using "cellulose of non-seed organism origin" (e.g. obtained from algae).

US 9,763,929 & US9, 511,021 discloses a stable chewing gum for use in nicotine replacement therapy comprising a coated core, the core comprising: a compressible chewing gum base that is suitable for tableting at ambient temperature, nicotine active, at least one buffering agent in homogeneous mixture with the nicotine active, said at least one buffering agent comprising particles comprising a core of sodium bicarbonate and an outer layer of sodium carbonate and a binder.

Although NRT products, including nicotine containing lozenges, have gained public acceptance in many Western markets, there are still some obstacles to providing these products to many other areas of the globe. Some of these drawbacks include, for example, the high cost to manufacture NRT products and their lack of stability in more cost-effective packaging options.

A need therefore exists in the art to provide nicotine lozenges that is stable and which reduces some or all of the drawbacks of the current available NRT lozenges. SUMMARY OF THE INVENTION

In accordance with the above, the present invention provides stable nicotine lozenges for reducing or stopping tobacco usage which comprises;

a) Nicotine active in an amount ranging from 1% to 20% by weight of the composition;

b) Buffering agent in an amount ranging from 1% to 20% by weight of the composition;

c) Xanthum gum in an amount ranging from 1% to 10% by weight of the composition;

d) Hydroxypropyl methyl cellulose in an amount ranging from 5% to 15% by weight of the composition; together with other pharmaceutically acceptable excipients.

In another aspect, the present invention provides a process for preparation of nicotine containing lozenges comprising compressing by conventional method to lozenges of hardness ranging from 20N to 200N.

In yet another preferred aspect of the present invention, the lozenges are packed in simple, cost effective and lower moisture barrier packs of material selected from polyvinyl chloride (PVC), polyvinylidene chloride (PVDC) or poly-chloro-tri- fluoro-ethylene (PCTFE), that protects nicotine from degradation and oxidation on exposure to moisture.

The Nicotine lozenges of the present invention are stable, bioequivalent to traditional lozenges and thus useful as a tobacco replacement, and as a means to reduce or stop tobacco use.

DETAILED DESCRIPTION OF THE INVENTION:

The invention will now be described with reference to certain preferred and optional embodiments, so that the various aspects therein will be more clearly understood and appreciated. As used herein the term“nicotine active” refers to one or more compounds selected from nicotine; derivatives of nicotine, such as nicotine salts and nicotine complexes; tobacco extract or leaf; any compounds or compositions that produce a similar physiological effect as nicotine, such as lobeline; and the like or mixtures thereof.

The inventors of the present invention surprisingly found that the use of a combination of at least one buffer, xanthum gum and hydroxypropyl methyl cellulose provides not only bioequivalent lozenge containing nicotine active of the present invention to traditional lozenges but also significant advantages over the traditional lozenges in terms of stability.

In an embodiment, the present invention relates to stable nicotine lozenges for reducing or stopping tobacco usage which comprises;

a) Nicotine active in the amount ranging from 1% to 20% by weight of the composition;

b) Buffering agent in an amount ranging from 1% to 20% by weight of the composition;

c) Xanthum gum in an amount ranging from 1% to 10% by weight of the composition;

d) Hydroxypropyl methyl cellulose (HPMC) in an amount ranging from 5% to 15% by weight of the composition; together with other pharmaceutically acceptable excipients.

The nicotine actives of the present invention includes but is not limited to nicotine monotartrate, nicotine bitartrate, nicotine hydrochloride, nicotine dihydrochloride, nicotine sulfate, nicotine zinc chloride monohydrate, nicotine salicylate, nicotine oil, nicotine complexed with cyclodextrin, polymer resins such as nicotine polacrilex, or mixtures thereof. The nicotine active may be used in one or more distinct physical forms which include free base forms, encapsulated forms, ionized forms or spray-dried forms. In a preferred embodiment, the nicotine active is a nicotine resin complex such as nicotine polacrilex in an amount ranging from about 1 mg to about 50 mg, preferably from about 5mg to about 25mg; most preferably from about lOmg to about 20mg. The amount of nicotine (subtracting the amount of resin in the polacrilex complex) may vary from about lmg to about 20mg; preferably from about 2mg to about 8mg; most preferably from about 2mg to about 6mg; still most preferably from about 2mg to 4mg.

The buffering agent is an alkaline buffering agent which include but is not limited to sodium carbonate, sodium bicarbonate (Effer soda 12), potassium phosphate, potassium carbonate and potassium bicarbonate, or mixtures thereof in an amount of from about 1 mg to about 60 mg.

In an embodiment, the total amount of buffer present in the composition of the present invention varies from about 20 mg to about 30 mg.

In an embodiment, the ratio of nicotine active to total buffer is from about 1 :20 to about 20: 1 by total weight.

In another embodiment, the ratio of nicotine polacrilex to total buffer is from about 3: 1 to about 1 :3 by total weight, preferably from about 2: 1 to about 1 :2 by total weight of the composition.

The pharmaceutically acceptable excipients are selected from diluents, taste masking agents, antioxidants, glidants, colorants or any combinations thereof.

Suitable diluents include, but are not limited to maltitol, maltose, fructose, glucose, trehalose, sorbitol, sucrose, sugar, mannitol, xylitol, isomalt, dextrose, maltodextrin, dextrates, dextrin, erythritol, lactitol, polydextrose and mixtures thereof in an amount ranging from about 500 mg to about 1,100 mg per lozenge, preferably from about 750 mg to about 1,000 mg per lozenge. The taste masking agent include, but are not limited to intensive sweetening agents and/or flavorants. Suitable intensive sweetening agents include, but are not limited to, aspartame, acesulfame K, cyclamate and salts thereof, glycyrrhizin and salts thereof, neohesperidine, sucralose, saccharin and salts thereof, thaumatin or mixtures thereof.

Suitable taste masking agents/ flavorants include, but are not limited to, menthol, peppermint, wintergreen, sweet mint, spearmint, vanillin, chocolate, coffee, cinnamon, clove, tobacco, citrus and fruit flavors andor mixtures thereof. When present, taste masking agents are present in an amount from about 1 mg to about 50 mg per lozenge, or from about 10 mg to about 20 mg per lozenge.

In yet another preferred aspect, the present invention discloses Stable nicotine lozenges for reducing or stopping tobacco usage comprising;

a) Nicotine polacrilex in the amount ranging from 1% to 10% by weight of the composition;

b) Buffering agent in an amount ranging from 1% to 10% by weight of the composition;

c) Xanthum gum in an amount ranging from 1% to 10% by weight of the composition;

d) Hydroxypropyl methyl cellulose (HPMC) in an amount ranging from 5% to 15% by weight of the composition; together with other pharmaceutically acceptable excipients.

In yet another embodiment, the nicotine lozenges of the present invention are prepared by conventional process and then are compressed by traditional tableting compression techniques to a hardness of from about 20N to about 200 N, or from about 30 N to about 150 N, or from about 50 N to about 100 N. In an embodiment, the Lozenges of the present invention have a total weight per lozenge of between about 100 mg to about 2,000 mg, or between about 500 mg and about 1500 mg, or between about 1,000 mg and about 1,300 mg. In one embodiment, the total weight per lozenge is about 1,200 mg.

In yet another embodiment, the lozenges are packed in simple, cost effective, low moisture barrier packs of material selected from polyvinyl chloride (PVC), polyvinylidene chloride (PVDC) or poly-chloro-tri-fluoro-ethylene (PCTFE- ACLAR), such that the lozenges remain stable for a longer period of time without degradation or oxidation.

In another embodiment, the present invention provides stable lozenges containing the nicotine active for reducing or stopping tobacco usage packed in PVC/ACLAR Blister package without degradation or oxidation.

The lozenges of the present invention are stable at a temperature of about 40°C and relative humidity of 75% for a period of at least 6 months, or for at least 12 months, or for at least 24 months in the saidPVC/ACLAR Blister package.

In an embodiment, the stability of the lonzeges of the present invention is partly attributed to, however not limiting the theory, the use of HPMC in the composition. Nicotine when exposed to water in the presence of HPMC, HPMC having more affinity towards water will prevent nicotine exposure to water thereby resulting in less oxidation or degradation of nicotine and consequently less impurity generation.

The advantage of the current lozenges compared to traditional formulations is their ability to remain stable for longer periods of time in less expensive packaging. Nicotine is a moisture sensitive molecule and requires precaution when handling and packaging. Moisture leads to oxidation of nicotine and often results in the generation of oxide impurities when nicotine products are packaged in simple and lower moisture barrier packs such as PVC/PVDC/Duplex as compared to Triplex/Zymax/Alu-Alu or some specially designed desiccant coated HDPE container. High moisture barrier options are available at high cost and contribute to the overall product cost. These costs are prohibitive when attempting to make NRT products available to consumers with less financial means.

In another embodiment, the nicotine lozenges of the present invention although vary in dissolution profile are however bioequivalent to currently approved and marketed traditional lozenges, such as NICORETTE® or NIQUITIN® or NIC ABATE® lozenges. This is significant because this provides formulators more leeway in designing dosage forms with specific dissolution profiles that are still bioequivalent to traditional lozenges.

In an embodiment, the Lozenges of the present invention may be bioequivalent to traditional lozenges such as NICORETTE® Original 4 mg lozenges.

In an embodiment, the nicotine lozenges of the present invention are useful as a tobacco replacement, and as a means to reduce or stop tobacco use. The compositions may be used as a total or partial replacement of tobacco, and may be used concurrently with tobacco as part of a planned tobacco reduction program, e.g., while reducing tobacco usage prior to outright quitting tobacco usage. A user may consume a lozenge of the present invention at set intervals throughout the day as part of a tobacco quit regime. Alternatively, a user may consume a lozenge of the present invention intermittently in response to an acute nicotine craving. The user may consume a lozenge of the present invention at both predetermined intervals as well as intermittently throughout the day to assist with craving relief.

In yet another embodiment, the present invention relates to methods of reducing tobacco usage, comprising administering therapeutic effective amount of nicotine lozenge of the present invention to a person in need thereof. The present invention also relates to a method of reducing nicotine withdrawal symptoms comprising administering therapeutic dosage of nicotine lozenge of the present invention to a person in need of such relief. "Need" is intended to include a person's desire to reduce tobacco usage or nicotine withdrawal symptoms, respectively. "Reducing" nicotine withdrawal symptoms or tobacco usage includes eliminating nicotine withdrawal symptoms or tobacco usage.

Examples:

Example 1: Composition

Example 2: Preparation of Nicotine Containing Lozenges

Sifting 1 : Mannitol, Xanthum Gum, HPMC, Nicotine Polacrilex and sorbitol are sifted and passed through #24 sieve and collected in polybags.

Blending 1 : The contents of the sifting 1 are loaded into the blender and mixed for 5 to 20 minutes.

Sifting 2 : Effer Soda 12, Colloidal anhydrous silica, Aspartame, Emerald green spectra Flecks, Peppermint flavour and Menthol are sifted and passed through #24 sieve and collected in polybags.

Blending 2: The contents of the sifting 2 are loaded into the blender and mixed with contents of Blending 1 for 5 to 30 minutes.

Lubrication: Magnesium stearate was mixed with the contents of sifting 2 for 5 to 10 minutes.

Compression: The above lubricated blend was pressed into Lozenges.

Example 3: Package Stability of Lozenges

Lozenges were stored in the Blisters at 40°C and 75% relative humidity. At various time points, samples were withdrawn from the packaging and analyzed for the degradation products (impurities). Determination of degradation products was carried out by reversed phase HPLC. All the related substances i.e. cotinine, myosmine, ( G S,2' S)-Nicotine- 1 '-N-oxide, (TR,2' S)-Nicotine- 1 '-N-oxide, pseudooxynicotine, and nornicotine/anatabine were well separated from each other and other excipients. The method is stability indicating and completely validated for all parameters like specificity, linearity, precision, accuracy, robustness and solution stability. The LOD/LOQ values for all the compounds were also established. Stability results for PVC/ACLAR are shown in Table 1 below.

It was observed during stability studies that impurities are well below the normal limits.

One skilled in the art will appreciate readily that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those objects, ends and advantages inherent herein. Changes therein and other uses which are encompassed within the spirit of the invention as defined by the scope of the claims will occur to those skilled in the art.