US 2011 0200670A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0200670 A1 Thakkar (43) Pub. Date: Aug. 18, 2011

(54) NICOTINE CONTAINING SOFT GELATIN A 6LX 3L/787 (2006.01) PASTILLES A636/8 (2006.01) A63L/78 (2006.01) (76) Inventor: Jatin Thakkar, Maharashtra (IN) A 6LX 3L/77 (2006.01) A6IP 25/34 (2006.01) (21) Appl. No.: 13/029,163 (52) U.S. Cl...... 424/465; 514/343; 424/78.15; 424/751; 514/60: 514/57 (22) Filed: Feb. 17, 2011 (57) ABSTRACT (30) Foreign Application Priority Data The present invention relates to soft pastilles for nicotine replacement therapy, said pastille comprises about 0.05% to Feb. 18, 2010 (IN) ...... 452AMUMA2010 about 1% of nicotine active; about 5% to about 40% of gelling O O agent; about 30% to about 70% of plasticizer; about 0.05% to Publication Classification about 10% of sweetener, 0.5% to about 30% of releasing (51) Int. Cl. agent; about 0.05% to about 2% of preservative; about 0.01% A6 IK 9/20 (2006.01) to 5% of flavouring agent; and about 5% to about 20% of A6 IK 3L/46.5 (2006.01) Water. US 2011/0200670 A1 Aug. 18, 2011

NCOTINE CONTAINING SOFT GELATIN 0010 A wide variety of nicotine cessation products and PASTILLES therapies are known. However, in most of the cases the mere replacement of cigarettes with another nicotine source may CROSS-REFERENCE TO RELATED not be sufficient to ensure Success in Smoking cessation APPLICATIONS therapy. The available nicotine cessation products include 0001. This application claims the priority, under 35 U.S.C. lozenges, gums, transdermal patches and the like. Lozenges S119, of Indian patent application No. 452/MUM/2010, filed and chewing gums provide oral delivery of nicotine, whereas Feb. 18, 2010; the prior application is herewith incorporated transdermal patch treatments deliver nicotine through the by reference in its entirety. wearer's skin. 0011 Nicotine chewing gum containing nicotine polac STATEMENT REGARDING FEDERALLY rilex and transdermal nicotine are two of the more popular SPONSORED RESEARCH ORDEVELOPMENT forms of nicotine replacement available commercially. 0012 Nicotine gum is actually an ion-exchange resin that 0002. Not applicable. releases nicotine slowly when the patient chews and the nico tine present in the mouth is delivered directly to the systemic FIELD OF THE INVENTION circulation by buccal absorption. However, much of the nico 0003. The present invention relates to pastilles. tine is retained in the gum through incomplete chewing or is 0004 Particularly, the present invention relates to soft pas largely wasted through Swallowing, so that the systemic bio tilles for nicotine replacement therapy. availability of nicotine from gum is low and averages only 30-40%. BACKGROUND OF THE INVENTION 0013 Furthermore, most commercially available products 0005. In the context of the present invention a soft pastille Such as chewing gums, lozenges for nicotine replacement in means a resilient preparation which is can be retained and Smoking cessation therapy do not specifically address the Sucked in the mouth. issue of taste masking and side effects of nicotine ingestion 0006 Nicotine is an alkaloid found in the plants belonging Such as nausea and burning sensation. Instead, they generally to family Solanaceae. Nicotine is a hygroscopic, oily liquid target providing a stable baseline level of nicotine in the which is miscible with water in its base form. Nicotine is blood. optically active and has two enantiomeric forms. The natu 0014. The following patents/patent applications disclose rally occurring form of nicotine is levorotatory. The dextroro compositions containing nicotine. tatory form ((+) nicotine) has only one-half the physiological (0015 U.S. Pat. No. 4,967,773 discloses a lozenge formed activity of (-) nicotine. It is therefore weaker in the sense that by compression of at least two mixed components, one of said a higher dose is required to attain the same effects. As nicotine components including lactose or a lactose containing Sub enters the body, it is distributed quickly through the blood stance and the other of said components comprising a carrier stream and can cross the blood-brain barrier. On an average it having nicotine or a nicotine derivative absorbed therein Such takes about ten seconds for the substance to reach the brain that there is no direct contact between the nicotine and the when inhaled. The half life of nicotine in the body is around lactose whilst together in the lozenge. two hours. 0016 GB2230439 discloses a lozenge which is a substi 0007 Nicotine is the main addictive ingredient in the tute for Smoking tobacco comprises a lozenge core which tobacco used in cigarettes, cigars, Snuff and other nicotine contains nicotine and/or a nicotine Substitute and a shell or containing products. It is generally known that active as well coating around the lozenge core. as passive Smoking of tobacco products, such as cigarettes, 0017 GB2299756 discloses pastilles containing nicotine cigars and pipe tobacco presents serious health risks to the in an acacia gum or gelatine base. user and those Subjected to secondary Smoke. It is also known (0018 U.S. Pat. No. 5.488,962 discloses chewing gum that the use of Smokeless forms of tobacco. Such as chewing formed into 3 g strips, characterized in that each strip contains tobacco, Spit tobacco and Snuff tobacco presents serious not more than 25 wt.% of a gum base and from 0.3-0.4 mg of health risk to the user. nicotine dispersed in the gum base. 0008. During Smoking a cigarette, nicotine is quickly 00.19 U.S. Pat. No. 6,183,775 discloses a controlled absorbed into the smoker's blood and reaches the brain within release lozenge consisting of (a) 50 to 99% of a soluble filler; ten seconds after inhalation. The quick uptake of nicotine (b) 0.5 to 30% of an insoluble film forming agent which is gives the consumer a rapid satisfaction or kick. The poison selected from the group consisting of a polyacrylate, ethyl ous, toxic, carcinogenic and addictive nature of Smoking has cellulose and mixtures thereof; (c) 0.5 to 30% of a swellable initiated efforts to search for methods, compositions and polymer which is selected from the group consisting of Xan devices which would help in breaking the habit of smoking than gum, guar gum, cellulose derivatives and mixtures cigarettes. thereof; and (d) nicotine or a salt or derivative of nicotine. 0009 Smokers and other tobacco users often try to quit the (0020 U.S. Pat. No. 6,280,761 discloses a nicotine lozenge potentially deadly habit. Although the damaging effects of consisting of nicotine, mannitol. Xylitol, mint flavor, ammo tobacco usage are well known, most individuals who are nium glycyrrhizinate, sodium carbonate, sodium bicarbon nicotine dependent have great difficulty in overcoming their ate, hydrogenated vegetable oil and magnesium Stearate. dependence on nicotine. The difficulty arises in part due to the 0021 U.S. Pat. No. 6,344.222 discloses a chewing gum highly addictive nature of nicotine and the strong nicotine composition for systemic, oral administration of nicotine withdrawal symptoms that can occur when one begins to constituent, said composition comprising a) a nicotine con deprive the body of the nicotine. Overcoming nicotine with stituent; b) a gum base matrix, said gum base matrix including drawal symptoms is a critical challenge for those attempting at least one hydrophilic polymer and at least one hydrophobic to conquer nicotine dependence. polymer; and c) a buffer. US 2011/0200670 A1 Aug. 18, 2011

0022 US2004151771 discloses a flavored a lozenge com 0035) Nicotine containing lozenges also possess disad prising a Sustained release wet matrix of ethylcellulose and a Vantages Such as person using Such lozenges is not com flavoring agent selected from essential oils, constituents of fortable to keep a hard product in the buccal cavity for essential oils, and mixtures thereof, wherein, in an aqueous prolong period. Another disadvantage is that lozenges environment, the matrix gradually releases the flavoring get break down into pieces followed by accidental swal agent over a time period of at least 45 minutes. The active lowing which in turn result in excessive transfer of nico ingredient used is nicotine tine in GI tract and causes nausea and burning sensation. 0023 US2005034738 discloses a chewing tobacco substi 0036. Accordingly, it is desirable to develop a palatable tute comprising a non-tobacco leaf-like material; an alkaline nicotine containing formulation which is devoid of gums and chemical; and a nicotine compound capable of being which releases the nicotine for prolong period of time in absorbed orally. The nicotine compound used is nicotine controlled manner without causing nausea, bad taste and polacrilex. burning sensation. 0024 US2005002993 discloses a confectionery product for delivering at least one pharmaceutically active agent Such SUMMARY OF THE INVENTION as nicotine replacement agents which includes a hard outer shell and a core comprised of a core material which is or 0037. It is an object of the present invention to provide a forms a liquid-like to a gel-like Substance in the oral cavity formulation which can be used by smokers either as a substi and is capable of delivering pharmaceutically active agents to tute for cigarettes or the like or as an aid in giving up the infected and/or irritated tissues of the throat. Smoking habit or for nicotine replacement in Smoking cessa 0025 US2005 1235.02 discloses an oral composition com tion therapy. prising a nicotine active, a polycarbophil component or a salt 0038. It is another object of the present invention to pro thereof and an alginic acid component or a salt thereof. vide a formulation which is designed to be held in the user's 0026 US20050053665 discloses a nicotine-containing mouth and Sucked to release active ingredient into the buccal pharmaceutical composition comprising nicotine and cellu cavity in a user determined manner. lose of non-seed organism origin. Said composition can be in 0039. It is still another object of the present invention to the form of chewing gum, mouth spray, buccal Sachet, loZ provide a formulation which provides maximum buccal enge or a tablet. absorption of nicotine. 0027 US2007269492 discloses a coated oral dosage 0040. It is yet another object of the present invention to forms for the delivery of nicotine in any form to a subject by provide a formulation which is not associated with symptoms rapid intraoral delivery of nicotine comprising at least one like nausea, hiccups or burning sensation. core, nicotine in any form and/or a nicotine mimicking agent, 0041. It is a further object of the present invention to at least one coating layer and optionally at least one additive. provide an oral formulation which releases the active ingre 0028 US2007269386 discloses a buffered pharmaceuti dient for prolong period of time in a controlled manner. cal oral formulation comprising nicotine, characterized in 0042. In accordance with the present invention there is that it is buffered with at least trometamol. The formulation provided a soft pastille comprising: can be in the form of a mouth spray, a capsule, a chewing gum, 0043 a.nicotine active in an amount of about 0.05% to a chewable tablet, a tablet, a melt tablet and a lozenge. about 1% of the mass of the pastille: 0029 International Publication No. WO/2009/134947 0044) b. gelling agent in an amount of about 5% to about discloses an oral lozenge composition comprising: a) a mas 40% of the mass of the pastille; ter granule component comprising: at least one an alkaline 0.045 c. plasticizer in an amount of about 30% to about buffering agent; at least one dissolution modifier; and at least 70% of the mass of the pastille; one filler; b) a nicotine polacrilex; and c) at least one alkaline 0046 d. Sweetener in an amount of about 0.05% to buffering agent. The dissolution modifier used is selected about 10% of the mass of the pastille: from the group consisting of Xanthan gum, acacia, carbomer, 0047 e. releasing agent in an amount of about 0.5% to carboxymethylcellulose, carrageenan and cellulose. about 30% of the mass of the pastille: 0030 US20100004294 discloses a lozenge composition 0.048 f. preservative in an amount of about 0.05% to for achievement of a fast onset of action of nicotine after about 2% of the mass of the pastille: application of the Solid dosage form to the oral cavity of a 0049 g. flavouring agent in an amount of about 0.01% Subject, comprising a nicotine-cellulose combination and one to 5% of the mass of the pastille; and or more pharmaceutically acceptable excipients. 0050 h. water in an amount of about 5% to about 20% 0031 Short comings and problems associated with the of the mass of the pastille, said pastille being capable of known nicotine containing compositions: being dissolved in the buccal cavity in about 5 to about 0032 Nicotine containing products in the form of 15 minutes, depending on the user's sucking pattern. chewing gums are associated with problems such as 0051 Typically, the nicotine active is selected from the disposal problem and chewing is very often Socially group consisting of nicotine polacrilex, tobacco plant extract unacceptable. containing nicotine, derivatives of nicotine, nicotine oil, nico 0033. Further, much of the nicotine is retained in the tine salts, nicotine cation exchanger, nicotine inclusion com gum through incomplete chewing or is largely wasted plex, nicotine bound to cellulose or starch micro-spheres, through Swallowing which in turn results in low sys metabolites of nicotine and combinations thereof. temic bioavailability (about 30 to 40%). 0.052 Preferably, the nicotine active is nicotine polacrilex 0034) Furthermore, chewing of chewing gum leads to or tobacco plant extract containing nicotine. breaking of polymer coating and result in excessive 0053 Typically, the gelling agent is selected from the release of nicotine in buccal cavity which in turn causes group consisting of gelatin, carrageenan and mixtures nausea, bad taste and burning sensation. thereof. US 2011/0200670 A1 Aug. 18, 2011

0054 Preferably, the gelling agent is gelatin. 0.077 g. flavouring agent in an amount of about 0.01% 0055 Typically, the ratio of the gelling agent to plasticizer to 5% of the mass of the pastille; and is in the range of about 1:2.7 to about 1:3. 0078 h. water in an amount of about 5% to about 20% 005.6 Typically, the plasticizer is selected from the group of the mass of the pastille, consisting of glycerine, Sorbitol and mixtures thereof. said pastille is capable of being dissolved in the buccal cavity 0057 Preferably, the plasticizer is glycerine in about 5 to about 15 minutes, depending on the user's 0058 Typically, the releasing agent is selected from the Sucking pattern. group consisting of lecithin, oil, starch and mixtures thereof. 007.9 Typically, the nicotine active is selected from the 0059 Preferably, the releasing agent is lecithin. group consisting of nicotine polacrilex, tobacco plant extract 0060 Typically, the sweetener is at least one selected from containing nicotine, derivatives of nicotine, nicotine oil, nico the group consisting of Stevia, aspartame, saccharin, Sucral tine salts, nicotine cation exchanger, nicotine inclusion com ose, Sucrose, dextrose and lactose. plex, nicotine bound to cellulose or starch micro-spheres, 0061 Typically, the preservative is at least one selected metabolites of nicotine and combinations thereof. from the group consisting of methyl paraben, propyl paraben, 0080. In accordance with one of the preferred embodiment Sodium methyl paraben and Sodium propyl paraben. of the present invention the nicotine active is nicotine polac 0062 Typically, the flavouring agents include, but are not rilex. limited to menthol, Vanillin, peppermint, lemon, mint, Straw I0081. In accordance with another preferred embodiment berry, banana, pineapple, orange, raspberry and the like. of the present invention the nicotine active is tobacco plant 0063. In accordance with another aspect of the present extract containing nicotine. invention there is also provided a process for the preparation I0082. The gelling agent used for the preparation of soft of soft pastilles; said process comprising the following steps: pastille in accordance with the present invention is selected 0064 a. introducing accurately weighed plasticizer from the group consisting of gelatin, carrageenan and mix Selected from the group consisting of glycerine, Sorbitol tures thereof. and combinations thereof and water in a reactor fol I0083. In accordance with the preferred embodiment of the lowed by addition of gelling agent selected from the present invention gelatin is used as a gelling agent as the gel group consisting of gelatin, carrageenan and mixtures obtained from gelatin is thermo-reversible. Because of thereof and releasing agent selected from the group con thermo-reversible property, after cooling the gelatin Solution sisting of lecithin, oil, starch and combinations thereof the viscosity increases progressively and passes from a Sol to to form a first mixture; a gel. On the other hand, if the gel is heated, it dissolves and 0065 b. adding Nicotine active selected from the group once again becomes a solution. consisting of nicotine polacrilex, tobacco plant extract I0084 Typically, the plasticizer is selected from the group containing nicotine, derivatives of nicotine, nicotine oil, consisting of glycerine, Sorbitol and mixtures thereof. nicotine salts, nicotine cation exchanger, nicotine inclu I0085. In accordance with the preferred embodiment of the sion complex, nicotine bound to cellulose or starch present invention the plasticizer used is glycerine. micro-spheres, metabolites of nicotine and combina I0086. The critical parameter in the preparation of soft tions thereof to the mixture and mixing for about 30 to pastille in accordance with the present invention is the ratio of about 45 minutes at 1500 rpm to form a second mixture: the gelling agent to plasticizer. It is found that when the ratio 0066 c. incorporating adequate quantities of Sweetener, of gelling agent to glycerin is kept below 1:2.7, the formed flavouring agent, colour and preservative into the second mixture becomes hard and gets stuck in the nozzle while mixture to obtain a mass; transferring it into the die cavities in order to form pastilles. It 0067 d. collecting the mass in a container followed by is also found that when the ratio of gelling agent to glycerin is cooling and Solidification; kept above 1:3, the formed mixture becomes less viscous and 0068 e. transferring the solidified mass into a melter to results in formation of poor quality pastilles. obtain a melted mass; and I0087. Therefore, the ratio of gelling agent to glycerin for 0069 f. passing the melted mass through an injector the preparation of soft pastilles containing nicotine is kept in into the preformed cavities followed by cooling and the range of about 1:2.7 to about 1:3. blister packaging. I0088 Typically, the releasing agent is selected from the DETAILED DESCRIPTION OF THE INVENTION group consisting of lecithin, oil, starch and mixtures thereof. I0089. In accordance with the preferred embodiment of the 0070. In accordance with the present invention there is present invention the releasing agent used in the preparation provided a soft pastille comprising: of soft pastilles containing nicotine is lecithin. Lecithin used (0071 a.. nicotine active in an amount of about 0.05% to in the preparation of soft pastilles acts as a releasing agent or about 1% of the mass of the pastille; lubricating agent which prevent the friction (or Sticking) 0072 b. gelling agent in an amount of about 5% to about between the die wall and the pastilles. This in turn helps to 40% of the mass of the pastille; eject or remove the pastilles smoothly from the die cavity as 0073 c. plasticizer in an amount of about 30% to about well as from the final pack. 70% of the mass of the pastille; 0090 The sweetener used in the preparation of pastilles in 0074 d. Sweetener in an amount of about 0.05% to accordance with the present invention is at least one selected about 10% of the mass of the pastille: from the group consisting of Stevia, aspartame, Saccharin, 0075 e. releasing agent in an amount of about 0.5% to Sucralose. Sucrose, dextrose and lactose. about 30% of the mass of the pastille: 0091 Typically, the preservative is at least one selected (0076 f. preservative in an amount of about 0.05% to from the group consisting of methyl paraben, propyl paraben, about 2% of the mass of the pastille; Sodium methyl paraben and Sodium propyl paraben. US 2011/0200670 A1 Aug. 18, 2011

0092. The flavouring agents employed in the preparation Example 3 of pastilles of the present invention include, but are not lim ited to menthol, Vanillin, peppermint, lemon, mint, Straw I0121 Each pastille (1500 mg) contains: berry, banana, pineapple, orange, raspberry and the like. 0.122 Nicotine from Nicotine poliacrilex (1 mg 5 mg): 5 0093. In accordance with another aspect of the present ng invention there is also provided a process for the preparation I0123 Gelatin (bloom strength 100): 343 mg of soft pastilles; said process comprising the following steps: (0.124 Glycerine: 970 mg 0094. First step is introducing accurately weighed plasti (0.125 Water: 150 mg cizer selected from the group consisting of glycerine, Sorbitol 0.126 Lecithin: 25.6 mg and combinations thereof and water in a reactor. To this I0127. Methyl paraben: 2.4 mg accurately weighed gelling agent selected from the group I0128 Propyl paraben; 1.2 mg consisting of gelatin, carrageenan and mixtures thereof and I0129. Spearmint: 1.5 mg releasing agent selected from the group consisting of lecithin, I0130 Menthol: 1.3 mg oil, starch and combinations thereof are added to form a first I0131 Sucralose: 1.5 mg mixture. I0132) Coluor: 4 mg 0095 To this first mixture, Nicotine active selected from Nicotine Polacrilex contain 20% Nicotine; 1 mg of Nicotine the group consisting of nicotine polacrilex, tobacco plant Polacrilex=0.2 mg of Nicotine extract containing nicotine, derivatives of nicotine, nicotine (0.133 Testing: oil, nicotine salts, nicotine cation exchanger, nicotine inclu I0134) A Stability Data: sion complex, nicotine bound to cellulose or starch micro spheres, metabolites of nicotine and combinations thereof is I Temperature: 25°C.i.2° C.; Relative Humidity: 60+5% added and the resulted mixture is mixed for about 30 to about 0135) 45 minutes at 1500 rpm to form a second mixture. 0096. In next step, adequate quantities of Sweetener, fla TABLE NO. 1 Vour, colour and preservative are incorporated into the second Time Assay/uniformity of mixture to obtain a mass. The obtained mass is then collected interval Average Weight Uniformity of content 90% to 115% in a container followed by cooling and solidification of the Month (+7.5%) (in mg) Weight) (+7.5%) of Label Claim mass. The solidified mass is transferred into a melter to obtain O 1509.22 Complies 110.43% a melted mass. 3 1SOO.87 Complies 108.72% 6 1SO3.42 Complies 106.98% 0097 Finally, the melted mass is passed through an injec 9 1SOO.S1 Complies 104.23% tor into the preformed cavities followed by cooling and blister 12 1SO1.92 Complies 102.49% packaging. 18 1502.51 Complies 101.31% 0098. Following examples illustrate the invention, but is 24 1506.92 Complies 99.56% not intended to limit the scope of the present invention. Example 1 II Temperature: 30° C.i.2°C.; Relative Humidity: 65+5% 0099. A soft pastille in accordance with the present inven tion was prepared with the following composition. 0.136 Each pastille (1500 mg) contains: 0100 Nicotine from Nicotine poliacrilex (1 mg 5 mg): 5 TABLE NO. 2 ng Time Assay/uniformity of 0101 Gelatin (bloom strength 250): 299 mg interval Average Weight Uniformity of content 90% to 115% 0102 Glycerine: 971.7 mg Month (+7.5%) (in mg) Weight (+7.5%) of Label Claim (0103 Water: 170 mg O 1509.22 Complies 110.43% 0104 Lecithin: 37.3 mg 3 1509.55 Complies 107.67% 0105 Flavour: 3.8 mg 6 15O1.97 Complies 105.12% 0106 Sucralose: 1.4 mg 9 1509.60 Complies 103.89% 0107 Colour: 4 mg 12 1506.87 Complies 100.32% 0108 Methyl paraben: 2.4 mg 0109 Propyl paraben; 1.2 mg III] Temperature: 40° C.i.2°C.; Relative Humidity: 75+5% Example 2 0.137 0110. Each pastille (1500 mg) contains: 0111 Nicotine from Nicotine poliacrilex (1 mg 5 mg): 5 TABLE NO. 3 ng 0112 Gelatin (bloom strength 170): 315 mg Time Assay/uniformity of 0113 Glycerine: 950 mg interval Average Weight Uniformity of content 90% to 115% 0114 Water: 188 mg Month (+7.5%) (in mg) Weight (+7.5%) of Label Claim 0115 Lecithin: 30.3 mg O 1509.22 Complies 110.43% 0116 Flavour: 2.8 mg 3 1508.34 Complies 106.21% 0117 Sucralose: 2 mg 6 1SOS.43 Complies 103.68% 0118 Colour: 4 mg 0119 Methyl paraben: 2.4 mg From the above stability data it is found that the product of 0120 Propyl paraben; 1.2 mg this invention is stable. US 2011/0200670 A1 Aug. 18, 2011

0138 BI Dissolution Study User Defined: 0.145) A variety of methods have been reported to assess 0.139. Each of the 10 subjects was instructed to hold and the craving for nicotine, which include but are not limited to, suck the pastille of the present invention. The time required to the nicotine craving test specified by the Diagnostic and Sta completely dissolve the pastille in the mouth was recorded by tistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) (see (1991) J. Am. Med. Assoc. 266:3133); the each of the subjects. Shiffman-Jarvik Craving Subscale (see O'Connell and Mar 0140. The results are provided in Table No. 4 tin (1987) J. Consult. Clin. Psychol. 55:367-371 and Steur and Wewers (1989) ONF 16:193-198, also describing a par TABLE NO. 4 allel visual analog test); West et al. (1984) Br. J. Addiction 79:215-219; and Hughes et al. (1984) Psychopharmacology Subject Dissolution time min. 83:82-87, each of which is expressly incorporated herein by 1 8 reference. 2 12 3 10 0146. As described in the J. Am. Med. Assoc. 266:3133, at 4 5 page 3135, nicotine withdrawal symptoms, specified by the 5 10 DSM-III-R, are scored based on the following symptoms: 6 9 nicotine craving, irritability, frustration, anger, anxiety, diffi 7 15 8 9 culty concentrating, and restlessness. Severity of each Symp 9 10 tom is rated as (O) none, (1) slight, (2) mild, (3) moderate, or 10 13 (4) severe. A mean combined withdrawal symptom score is calculated for each patient as the average of the individual symptom scores. 0141 From the results (as shown in Table No. 4) it was 0.147. In the context of the present invention, nicotine found that the time require to dissolve the pastille of the craving scale as taught in DSM-III-R, has been employed for present invention is in between 5 to 15 minutes depending assessment of craving of the Subjects. upon individual’s rate of Sucking the pastille. The average 0.148. According to this scale, a subject is asked to rate his dissolution time was found to be 10 Minutes. craving for nicotine, as well as his level of irritability, frus 0142 C Determination of Nicotine Craving: tration, anger, anxiety, difficulty in concentrating and rest lessness. Severity of each symptom is then rated on a scale 0143. As nicotine craving is considered to be the most between 0 and 4, wherein 0 is none; 1 is slight: 2 is mild; 3 is consistent and most severe factor in preventing a person from moderate; and 4 is severe. The mean combined withdrawal quitting Smoking. Ultimately, the Smoker's active involve symptom score is calculated for the Subject as the average of ment with timely self-assessment of the craving is very cru all of the symptom scores. cial for the efficacy of a Smoking cessation program. 0149 CI: A randomized double blind, placebo controlled 0144. Nicotine craving depends upon daily stress patterns, trial of nicotine soft gelatin pastille prepared in accordance sleep and eating habits, body weight, previous Smoking levels with the present invention was carried out in 20 subjects who and the like. Thus, the desire or need for pastilles (comparable were addicted to cigarette Smoking. to the desire to Smoke cigarettes) typically will vary during 0150 Group A: 10 subjects who received nicotine soft any given day and from day to day, as well as from patient to gelatin pastille Pastille containing 2 mg of nicotine and patient. Group B: 10 subjects who received placebo.

TABLE 5

Results of withdrawal symptoms in participants of group A

Participant volunteer

1 (Age: 2 (Age: 3 (Age: 4 (Age: 5 (Age: 6 (Age: 9 (Age: 10 (Age: 42, 61, 37, 26, 31, 48, 7 (Age: 8 (Age: 43, 52, Withdrawal Sex: Sex: Sex: Sex: Sex: Sex: 29, 23, Sex: Sex: symptoms M) M) M) M) M) M) Sex: F) Sex: F) M) M)

Craving 2 2 O 1 3 2 1 2 1 1 Irritability O 1 2 1 2 1 2 3 2 2 Frustration 3 2 2 O 1 2 2 4 2 1 Anger O 3 1. 3 1 2 1 1 2 2 Anxiety 1 O 1. 2 1 3 O 1 O 2 Difficulty in 1 1 O 1 2 O 2 O 1 1 concentrating Restlessness 4 1 3 2 1 2 3 2 3 3 Average 1.57 1.43 129 1.43 1.57 1.71 1.57 1.86 1.57 1.71 US 2011/0200670 A1 Aug. 18, 2011

Group withdrawal symptom score: 1.57 (Arithmetic mean of the averages of the individual with drawal symptoms)

TABLE 6 Results of withdrawal symptoms in participants of group B Participant volunteer 1 (Age: 2 (Age: 4 (Age: 5 (Age: 6 (Age: 8 (Age: 9 (Age: 10 (Age: 25, 39, 3 (Age: 24, 64, 28, 7 (Age: 42, 36, 29, Withdrawal Sex: Sex:: 57, Sex: Sex: Sex: 34, Sex: Sex: Sex:: symptoms M) F) Sex: M) M) M) M) Sex: F) M) M) M)

Craving 4 3 4 4 3 4 4 3 Irritability 4 4 3 4 4 4 3 4 Frustration 3 4 3 4 3 4 2 4 Anger 4 3 4 4 4 3 4 3 Anxiety 3 2 4 3 4 4 3 4 Difficulty in 2 4 3 4 4 3 4 4 concentrating Restlessness 4 3 4 4 3 4 4 3 Average 3.43 3.29 3.57 3.86 3.57 3.71 3.43 3.57 3.43 3.57

Group withdrawal symptom score: 3.54 (Arithmetic mean of the averages of the individual with drawal symptoms) 0151. From the observations as shown in the table No. 5& 6 it was found that the placebo group reported significantly more severe withdrawal symptoms than the nicotine Subjects. 0152 C II: Another randomized double blind, placebo controlled trial of nicotine soft gelatin pastille prepared in accordance with the present invention was carried out in 20 Subjects who were addicted to tobacco chewing. Group A: 10 subjects who received nicotine soft gelatin pas tille Pastille containing 4 mg of nicotine Group B: 10 subjects who received placebo

TABLE 7 Results of withdrawal symptoms in participants of group A Participant volunteer 1 (Age: 2 (Age: 3 (Age: 4 (Age: 5 (Age: 6 (Age: 7 (Age: 8 (Age: 9 (Age: 10 (Age: 57, 29, 31, 22, 41, 62, 45, 47, 36, 54, Withdrawal Sex: Sex: Sex: Sex: Sex: Sex: Sex: Sex: Sex: Sex: symptoms M) M) M) M) M) M) M) M) M) M)

Craving 2 O 1 1 O 3 1 2 Irritability 1 2 1 O 3 1 2 O Frustration 1 3 2 3 1 2 3 1 Anger 3 1 2 2 1 1 1 2 Anxiety 1 2 1 2 1 O 1 1 Difficulty in 2 1 2 1 3 2 3 2 concentrating Restlessness 1 3 2 3 2 2 1 2 Average 1.57 1.71 1.57 1.71 1.57 1.57 1.71 1.42 1.57 1.71

Group withdrawal symptom score: 1.61 (Arithmetic mean of the averages of the individual with drawal symptoms) US 2011/0200670 A1 Aug. 18, 2011

TABLE 8 Results of withdrawal Symptoms in participants of group B Participant/volunteer 1 (Age: 2 (Age: 4 (Age: 5 (Age: 6 (Age: 7 (Age: 8 (Age: 9 (Age: 10 (Age: 46, 33, 3 (Age: 37, 42, 54, 50, 38, 56, 32, Withdrawal Sex: Sex:: 28, Sex: Sex: Sex: Sex: Sex: Sex: Sex:: symptoms M) M) Sex: M) M) M) M) M) M) M) M) Craving 4 4 3 4 4 4 4 3 4 4 Irritability 3 2 4 4 3 3 3 4 4 4 Frustration 4 4 4 4 4 2 4 4 3 3 Anger 4 3 3 2 4 4 4 4 2 4 Anxiety 2 4 4 4 3 4 2 4 4 3 Difficulty in 4 4 4 3 3 4 4 3 4 4 concentrating Restlessness 4 3 4 4 4 3 4 4 4 4 Average 3.57 3.43 3.71 3.57 3.57 3.43 3.57 3.71 3.57 3.71

Group withdrawal symptom score: 3.58 (Arithmetic mean of the averages of the individual with TABLE 10-continued drawal symptoms) 0153. From the observations as shown in the table No. 7& Group II 8 it was found that the placebo group reported significantly more severe withdrawal symptoms than the nicotine Subjects. Subjects 0154 D Overall Compliance and Tolerance Study: 0155 DI: An independent study was undertaken to com Parameter Subject 1 Subject 2 Subject 3 Subject 4. Subject 5 pare the effect of the existing nicotine lozenges and the pas tilles of the present invention on specific parameters related to Burning ------the overall compliance and tolerance. sensation 0156 The study was carried out on 10 subjects (addicted Palatability -- to cigarette Smoking) who were divided into groups of 5 each. 0157 Group I: 5 subjects were administered the pastilles 0159. In case of Group I, from the observations as pro pastille containing 2 mg of nicotine of the present invention vided in Table 9, it was found that all the subjects reported while subjects of Group II were administered nicotine loz better mouth-feel effect (palatability), the reason being, the engeS. pastilles of the present invention unlike the lozenges were soft 0158 The observations are provided in Table 9 & 10 given below: and flexible without any hard edges. Furthermore, the pas tilles were elastic in nature and did not cause any local irrita TABLE 9 tion in the oral mucosa. Still furthermore, none of the subjects reported nausea, headache and burning sensation which are Group I very often observed in case of nicotinelozenges on account of Subiects abrupt rupture in the mouth cavity, which in turn suddenly caused sharp increase in the Nicotine levels. As regards to the Parameter Subject 1 Subject 2 Subject 3 Subject 4. Subject 5 other parameters like hiccups, only one patient reported Nausea minor hiccup. Headache Hiccups -- 0160. As regards to Group II, all of the subjects except one Burning reported discomfort with hardness and edges of the lozenges. sensation Furthermore, each of the Subjects also reported burning sen Palatability ------sation. Severe to moderate headache and nausea was reported On a scale of 1 to 5, +: presence & -: absence by all the subjects. Furthermore, hiccups with moderate severity were also reported in 3 of the subjects. TABLE 10 0.161 DIII: Another independent study was undertaken to compare the effect of the existing nicotine lozenges and the Group II pastilles of the present invention on specific parameters Subiects related to the overall compliance and tolerance. Parameter Subject 1 Subject 2 Subject 3 Subject 4. Subject 5 0162 The study was carried out on 10 subjects (addicted to tobacco chewing) who were divided in to groups of 5 each. Nausea ------Headache ------Group I: 5 subjects were administered the pastilles pastille Hiccups ------containing 4 mg of nicotine of the present invention while Group II were administered nicotine lozenges. US 2011/0200670 A1 Aug. 18, 2011

(0163 The observations are provided in Table 11 & 12 given below: TABLE 13-continued TABLE 11 Group description Dose Frequency Group I Group 3 Subjects who smoke more than 20 4 mg 10 per day cigarettest day on average. Subiects Group 4 Subjects with tobacco chewing addiction 4 mg 10 per day Parameter Subject 1 Subject 2 Subject 3 Subject 4. Subject 5

Nausea -- -- 0170 Almost all the subjects had a history of more than 2 Headache years of cigarette?tobacco chewing addiction. In view of this, Hiccups -- Burning the subjects were observed for a period of 3 months. sensation 0171 During the study period, there were 2 phases. In the Palatability ------first phase, the Subjects were encouraged to Substitute Smok ing/tobacco chewing by pastille consumption; in the second On a scale of 1 to 5, +: presence & -: absence phase (i.e. once the Subject has Switched to pastille consump tion without the need for Smoking) the Subjects were encour TABLE 12 aged to taper down the frequency of pastille consumption for Group II attaining the ultimate goal of Successful quitting. The dura tion of the first phase and the second phase was varied from Subiects Subject to Subject depending on the response shown by the Parameter Subject 1 Subject 2 Subject 3 Subject 4. Subject 5 Subject. 0172 A subject is said to have successfully quit smoking Nausea ------Headache ------in this context when he/she no longer Smokes or consumes Hiccups ------nicotine through any other means which also include the Burning ------pastilles of the present invention. sensation (0173 Group 1: Palatability 0.174 All the subjects completed the study. All of the sub jects successfully quit Smoking after participation for a period 0164. In case of Group I, from the observations as pro of 1 week to 3 weeks of the study period. As the study vided in Table 11, it was found that out of 5 two subjects progressed, the initial dosing frequency was gradually reported minor nausea. Further, all the subjects reported bet tapered in consonance with the craving of each of the Sub termouth-feel effect (palatability). Still furthermore, none of jects. the Subjects reported headache and burning sensation while (0175 Group 2: only one participant reported minor hiccup. 0176 One of the subjects abruptly discontinued the study 0.165. As regards to Group II, all of the subjects reported on 4" day from the commencement of the study. Right from discomfort with hardness and edges of the lozenges. Further the first week of the study period, the subjects were constantly more, each of the Subjects also reported moderate to severe encouraged to Substitute Smoking by pastille consumption. nausea, burning sensation and hiccups. (First Phase). 0166 It was found out that the pastilles of the present 0177 Out of the remaining 4 subjects, 3 successfully quit invention offered improved tolerance (interms of symptoms) smoking after participating for a period of 3 to 5 weeks while and compatibility as compared to the known lozenges from the remaining one continued consuming pastilles without the market. Thus the product of the present invention provides smoking (Phase 2) till the final week of the study period. better patient compliance. However, the frequency of the pastille consumption at the end 0167 E Smoking Cessation Study: of the study period was only 2 pastilles per day. 0168 A study was carried out in 20 subjects addicted to (0178 Group 3: cigarette Smoking and/or tobacco chewing. After initial inter 0179. One of the five subjects successfully quit smoking at views for collection of the patient details, based on the aver the end of 4" week of the study period. Another one quit age number cigarettes Smoked by each of the Subjects, the Smoking altogether; however he continued the consumption dose and frequency of the pastille administration was of pastilles at a frequency of 2 pastilles per day till the end of decided. Accordingly, the following table shows the groups in the study period (Phase 2). Still another subject also quit which all the subjects were divided into along with the respec Smoking during the study period but his pastilles consump tive dose and frequency of the pastilles administered to each tion frequency was 8 per day as reported on the last day of the of the groups. study period. Out the of remaining 2 subjects, one subject 0169. For subjects who had a history of obsessive tobacco reported that his Smoking frequency during the study period chewing, pastilles with high nicotine content were given. came down to 6 a day but he still continued with pastille consumption with a frequency of 2 pastille per day (Phase 1). TABLE 13 0180 Group 4: Group description Dose Frequency 0181. One of the total five subjects successfully quit Smoking at the end of eight weeks of the study period. Group 1 Subjects who Smoke on average 10 1 mg 10 per day cigarettes day 0182 During Phase 1, out of the 5 subjects, 2 could com Group 2 Subjects who Smoke on average 20 2 mg 10 per day pletely switch to the Phase 2 (Pastille only). The frequency of cigarettes day 2 of the subjects who switched to Phase 2 was 10 pastilles (2 mg) per day as reported on the last day of the study period. US 2011/0200670 A1 Aug. 18, 2011

0183 The two subjects who could not switch to phase 2 of 7. The pastille as claimed in claim 1, wherein the plasticizer the study reported reduction in frequency of tobacco chewing is glycerine. to just 2 times a day along with pastille consumption fre 8. The pastille as claimed in claim 1, wherein the ratio of quency of 2 pastilles (2 mg) per day. gelling agent to plasticizer is in the range of about 1:2.7 to 0184 While considerable emphasis has been placed about 1:3. herein on the specific ingredients of the preferred formula 9. The pastille as claimed in claim 1, wherein the releasing tion, it will be appreciated that many additional ingredients agent is at least one selected from the group consisting of can be added and that many changes can be made in the lecithin, oil and starch. preferred formulation without departing from the principles of the invention. These and other changes in the preferred 10. The pastille as claimed in claim 1, wherein the releasing formulation of the invention will be apparent to those skilled agent is lecithin. in the art from the disclosure herein, whereby it is to be 11. The pastille as claimed in claim 1, wherein the Sweet distinctly understood that the foregoing descriptive matter is ener is at least one selected from the group consisting of to be interpreted merely as illustrative of the invention and not Stevia, aspartame, saccharin, Sucralose. Sucrose, dextrose and as a limitation. lactose. 1. A Soft pastille comprising: 12. The pastille as claimed in claim 1, wherein the preser a.nicotine active in an amount of about 0.05% to about 1% Vative is at least one selected from the group consisting of of the mass of the pastille; methyl paraben, propyl paraben, Sodium methyl paraben and b. gelling agent in an amount of about 5% to about 40% of Sodium propyl paraben. the mass of the pastille; 13. The pastille as claimed in claim 1, wherein the flavour c. plasticizer in an amount of about 30% to about 70% of ing agent is at least one selected from the group consisting of the mass of the pastille; menthol, Vanillin, peppermint, lemon, mint, strawberry, d. Sweetener in an amount of about 0.05% to about 10% of banana, pineapple, orange and raspberry. the mass of the pastille; 14. A process for the preparation of soft pastilles; said e. releasing agent in an amount of about 0.5% to about 30% process comprising the following steps: of the mass of the pastille; a. introducing accurately weighed plasticizer selected from f.preservative in an amount of about 0.05% to about 2% of the group consisting of glycerine, Sorbitol and combina the mass of the pastille; tions thereof and water in a reactor followed by addition g. flavouring agent in an amount of about 0.01% to 5% of of gelling agent selected from the group consisting of the mass of the pastille; and gelatin, carrageenan and mixtures thereof and releasing h. waterinanamount of about 5% to about 20% of the mass agent selected from the group consisting of lecithin, oil, of the pastille, starch and combinations thereof to form a first mixture; said pastille being capable of being dissolved in the buccal b. adding Nicotine active selected from the group consist cavity in about 5 to about 15 minutes, depending on the user's ing of nicotine polacrilex, tobacco plant extract contain Sucking pattern. ing nicotine, derivatives of nicotine, nicotine oil, nico 2. The pastille as claimed in claim 1, wherein the nicotine tine salts, nicotine cation exchanger, nicotine inclusion active is selected from the group consisting of nicotine polac complex, nicotine bound to cellulose or starch micro rilex, tobacco plant extract containing nicotine, derivatives of spheres, metabolites of nicotine and combinations nicotine, nicotine oil, nicotine salts, nicotine cation exchanger, nicotine inclusion complex, nicotine bound to thereof to the mixture and mixing for about 30 to about cellulose or starch micro-spheres, metabolites of nicotine and 45 minutes at 1500 rpm to form a second mixture; combinations thereof. c. incorporating adequate quantities of Sweetener, flavour 3. The pastille as claimed in claim 1, wherein the nicotine ing agent, colour and preservative into the second mix active is nicotine polacrilex or tobacco plant extract contain ture to obtain a mass; ing nicotine. d. collecting the mass in a container followed by cooling 4. The pastille as claimed in claim 1, wherein the gelling and solidification; agent is selected from the group consisting of gelatin, carra e. transferring the Solidified mass into a melter to obtain a geenan and mixtures thereof. melted mass; and 5. The pastille as claimed in claim 1, wherein the gelling f. passing the melted mass through an injector into the agent is gelatin. preformed cavities followed by cooling and blister 6. The pastille as claimed in claim 1, wherein the plasticizer packaging. is selected from the group consisting of glycerine, Sorbitol and mixtures thereof.