(12) United States Patent (10) Patent No.: US 8,470,366 B2 Thakkar (45) Date of Patent: Jun

USOO8470366B2

(12) United States Patent (10) Patent No.: US 8,470,366 B2 Thakkar (45) Date of Patent: Jun. 25, 2013

(54) NICOTINE CONTAINING SOFT GELATIN (56) References Cited PASTILLES U.S. PATENT DOCUMENTS (76) Inventor: Jatin Thakkar, Maharashtra (IN) 4,967,773. A 1 1/1990 Shaw 5.488.962 A 2, 1996 Perfetti ck (*) Notice: Subject to any disclaimer, the term of this 8:32: f $38, RMonas ...... 424/464 patent is extended or adjusted under 35 6,280,761 B1 8, 2001 Santus U.S.C. 154(b) by 197 days. 6,344.222 B 1 2/2002 Cherukuri et al. 2004/O151771 A1 8, 2004 Gin 2005/OOO2993 A1 1/2005 Goggin et al. (21) Appl. No.: 13/029,163 2005.0034738 A1 2/2005 Whalen 2005.0053665 A1 3/2005 Ek et al. 1-1. 2005/O1235O2 A1 6/2005 Chan et al. (22) Filed: Feb. 17, 2011 2007/01224.56 A1* 5/2007 Lindberg ...... 424/439 2007/0202069 A1* 8/2007 Tamareselvy et al. ... 424.70.12 (65) Prior Publication Data 2007,0269386 A1 11/2007 Steen et al. 2007,0269492 A1 11/2007 Steen et al. US 2011 FO2OO67OA1 Aug. 18, 2011 2010, 0004294 A1 1/2010 Axelsson et al. (30) Foreign Application Priority Data FOREIGN PATENT DOCUMENTS GB 223O439 A 10, 1990 GB 2299756. A 10, 1996 Feb. 18, 2010 (IN) ...... 452AMUMA2010 WO 2009134947 A1 11 2009 (51) Int. Cl * cited by examiner A6 IK9/20 (2006.01) Primary Examiner — Blessing Fubara A6 IK36/81 (2006.01) (74) Attorney, Agent, or Firm — Mayback & Hoffman, P.A.: A 6LX3L/785 (2006.01) Gregory L. Mayback A6 IK3I/44 (2006.01) (57) ABSTRACT A 6LX3L/75 (2006.01) The present invention relates to soft pastilles for nicotine (52) U.S. Cl. replacement therapy, said pastille comprises about 0.05% to USPC ...... 424/465; 424/751; 424/78.15: 514/343; about 1% of nicotine active; about 5% to about 40% of gelling 514/57: 514/60 agent; about 30% to about 70% of plasticizer; about 0.05% to (58) Field of Classification Search about 10% of sweetener, 0.5% to about 30% of releasing USPC ...... 424/465, 751, 78.15, 78, 15: 514/343, agent; about 0.05% to about 2% of preservative; about 0.01% 514/57, 60 to 5% of flavoring agent; and about 5% to about 20% of water. See application file for complete search history. 13 Claims, No Drawings US 8,470,366 B2 1. 2 NCOTINE CONTAINING SOFT GELATIN A wide variety of nicotine cessation products and therapies PASTILLES are known. However, in most of the cases the mere replace ment of cigarettes with another nicotine source may not be CROSS-REFERENCE TO RELATED Sufficient to ensure Success in Smoking cessation therapy. The APPLICATIONS available nicotine cessation products include lozenges, gums, transdermal patches and the like. Lozenges and chewing This application claims the priority, under 35 U.S.C. S 119, gums provide oral delivery of nicotine, whereas transdermal of Indian patent application No. 452/MUM/2010, filed Feb. patch treatments deliver nicotine through the wearer's skin. 18, 2010; the prior application is herewith incorporated by Nicotine chewing gum containing nicotine polacrilex and reference in its entirety. 10 transdermal nicotine are two of the more popular forms of nicotine replacement available commercially. STATEMENT REGARDING FEDERALLY Nicotine gum is actually an ion-exchange resin that SPONSORED RESEARCH ORDEVELOPMENT releases nicotine slowly when the patient chews and the nico 15 tine present in the mouth is delivered directly to the systemic Not applicable. circulation by buccal absorption. However, much of the nico tine is retained in the gum through incomplete chewing or is FIELD OF THE INVENTION largely wasted through Swallowing, so that the systemic bio availability of nicotine from gum is low and averages only The present invention relates to pastilles. 30-40%. Particularly, the present invention relates to soft pastilles Furthermore, most commercially available products such for nicotine replacement therapy. as chewing gums, lozenges for nicotine replacement in Smok ing cessation therapy do not specifically address the issue of BACKGROUND OF THE INVENTION taste masking and side effects of nicotine ingestion Such as 25 nausea and burning sensation. Instead, they generally target In the context of the present invention a soft pastille means providing a stable baseline level of nicotine in the blood. a resilient preparation which is can be retained and Sucked in The following patents/patent applications disclose compo the mouth. sitions containing nicotine. Nicotine is an alkaloid found in the plants belonging to U.S. Pat. No. 4,967,773 discloses a lozenge formed by family Solanaceae. Nicotine is a hygroscopic, oily liquid 30 compression of at least two mixed components, one of said which is miscible with water in its base form. Nicotine is components including lactose or a lactose containing Sub optically active and has two enantiomeric forms. The natu stance and the other of said components comprising a carrier rally occurring form of nicotine is levorotatory. The dextroro having nicotine or a nicotine derivative absorbed therein Such tatory form ((+) nicotine) has only one-half the physiological that there is no direct contact between the nicotine and the activity of (-) nicotine. It is therefore weaker in the sense that 35 lactose whilst together in the lozenge. a higher dose is required to attain the same effects. As nicotine GB2230439 discloses a lozenge which is a substitute for enters the body, it is distributed quickly through the blood Smoking tobacco comprises a lozenge core which contains stream and can cross the blood-brain barrier. On an average it nicotine and/or a nicotine Substitute and a shell or coating takes about ten seconds for the substance to reach the brain around the lozenge core. when inhaled. The half life of nicotine in the body is around 40 GB2299756 discloses pastilles containing nicotine in an two hours. acacia gum or gelatine base. Nicotine is the main addictive ingredient in the tobacco U.S. Pat. No. 5.488.962 discloses chewing gum formed used in cigarettes, cigars, Snuff and other nicotine-containing into 3 g strips, characterized in that each strip contains not products. It is generally known that active as well as passive more than 25 wt.% of a gum base and from 0.3-0.4 mg of Smoking of tobacco products, such as cigarettes, cigars and 45 nicotine dispersed in the gum base. pipe tobacco presents serious health risks to the user and those U.S. Pat. No. 6,183,775 discloses a controlled release loz Subjected to secondary Smoke. It is also known that the use of enge consisting of (a) 50 to 99% of a soluble filler; (b) 0.5 to Smokeless forms of tobacco, such as chewing tobacco, Spit 30% of an insoluble film forming agent which is selected tobacco and snuff tobacco presents serious health risk to the from the group consisting of a polyacrylate, ethyl cellulose USC. 50 and mixtures thereof; (c) 0.5 to 30% of a swellable polymer During Smoking a cigarette, nicotine is quickly absorbed which is selected from the group consisting of Xanthan gum, into the Smoker's blood and reaches the brain within ten guar gum, cellulose derivatives and mixtures thereof, and (d) seconds after inhalation. The quick uptake of nicotine gives nicotine or a salt or derivative of nicotine. the consumer a rapid satisfaction or kick. The poisonous, U.S. Pat. No. 6,280.761 discloses a nicotine lozenge con toxic, carcinogenic and addictive nature of Smoking has ini 55 sisting of nicotine, mannitol. Xylitol, mint flavor, ammonium tiated efforts to search for methods, compositions and devices glycyrrhizinate, sodium carbonate, sodium bicarbonate, which would help in breaking the habit of Smoking cigarettes. hydrogenated vegetable oil and magnesium Stearate. Smokers and other tobacco users often try to quit the poten U.S. Pat. No. 6,344.222 discloses a chewing gum compo tially deadly habit. Although the damaging effects of tobacco sition for systemic, oral administration of nicotine constitu usage are well known, most individuals who are nicotine 60 ent, said composition comprisinga) a nicotine constituent; b) dependent have great difficulty in overcoming their depen a gum base matrix, said gum base matrix including at least dence on nicotine. The difficulty arises in part due to the one hydrophilic polymer and at least one hydrophobic poly highly addictive nature of nicotine and the strong nicotine mer; and c) a buffer. withdrawal symptoms that can occur when one begins to US2004151771 discloses a flavored a lozenge comprising deprive the body of the nicotine. Overcoming nicotine with 65 a sustained release wet matrix of ethylcellulose and a flavor drawal symptoms is a critical challenge for those attempting ing agent selected from essential oils, constituents of essential to conquer nicotine dependence. oils, and mixtures thereof, wherein, in an aqueous environ US 8,470,366 B2 3 4 ment, the matrix gradually releases the flavoring agent over a Accordingly, it is desirable to develop a palatable nicotine time period of at least 45 minutes. The active ingredient used containing formulation which is devoid of gums and which is nicotine releases the nicotine for prolong period of time in controlled US2005034738 discloses a chewing tobacco substitute manner without causing nausea, bad taste and burning sensa comprising a non-tobacco leaf-like material; an alkaline tion. chemical; and a nicotine compound capable of being absorbed orally. The nicotine compound used is nicotine SUMMARY OF THE INVENTION polacrilex. US2005.002993 discloses a confectionery product for It is an object of the present invention to provide a formu delivering at least one pharmaceutically active agent such as 10 lation which can be used by smokers either as a substitute for nicotine replacement agents which includes a hard outer cigarettes or the like or as an aid in giving up the Smoking shell and a core comprised of a core material which is or habit or for nicotine replacement in Smoking cessation forms a liquid-like to a gel-like Substance in the oral cavity therapy. and is capable of delivering pharmaceutically active agents to 15 It is another object of the present invention to provide a infected and/or irritated tissues of the throat. formulation which is designed to be held in the user's mouth US2005 1235.02 discloses an oral composition comprising and Sucked to release active ingredient into the buccal cavity a nicotine active, a polycarbophil component or a salt thereof in a user determined manner. and an alginic acid component or a salt thereof. It is still another object of the present invention to provide US2005.0053665 discloses a nicotine-containing pharma a formulation which provides maximum buccalabsorption of ceutical composition comprising nicotine and cellulose of nicotine. non-seed organism origin. Said composition can be in the It is yet another object of the present invention to provide a form of chewing gum, mouth spray, buccal Sachet, lozenge or formulation which is not associated with symptoms like nau a tablet. sea, hiccups or burning sensation. US2007269492 discloses a coated oral dosage forms for 25 It is a further object of the present invention to provide an the delivery of nicotine in any form to a subject by rapid oral formulation which releases the active ingredient for pro intraoral delivery of nicotine comprising at least one core, long period of time in a controlled manner. nicotine in any form and/or a nicotine mimicking agent, at In accordance with the present invention there is provided least one coating layer and optionally at least one additive. a soft pastille comprising: US2007269386 discloses a buffered pharmaceutical oral 30 a.nicotine active in an amount of about 0.05% to about 1% formulation comprising nicotine, characterized in that it is of the mass of the pastille; buffered with at least trometamol. The formulation can be in b. gelling agent in an amount of about 5% to about 40% of the form of a mouth spray, a capsule, a chewing gum, a the mass of the pastille; chewable tablet, a tablet, a melt tablet and a lozenge. International Publication No. WO/2009/134947 discloses 35 c. plasticizer in an amount of about 30% to about 70% of an oral lozenge composition comprising: a) a master granule the mass of the pastille; component comprising: at least one an alkaline buffering d. Sweetener in an amount of about 0.05% to about 10% of agent; at least one dissolution modifier; and at least one filler, the mass of the pastille; b) a nicotine polacrilex; and c) at least one alkaline buffering e. releasing agent in an amount of about 0.5% to about 30% agent. The dissolution modifier used is selected from the 40 of the mass of the pastille; group consisting of Xanthan gum, acacia, carbomer, car f.preservative in an amount of about 0.05% to about 2% of boxymethylcellulose, carrageenan and cellulose. the mass of the pastille; US20100004294 discloses a lozenge composition for g. flavouring agent in an amount of about 0.01% to 5% of achievement of a fast onset of action of nicotine after appli the mass of the pastille; and cation of the Solid dosage form to the oral cavity of a Subject, 45 h. waterinanamount of about 5% to about 20% of the mass comprising a nicotine-cellulose combination and one or more of the pastille, said pastille being capable of being dis pharmaceutically acceptable excipients. solved in the buccal cavity in about 5 to about 15 min Short comings and problems associated with the known utes, depending on the user's Sucking pattern. nicotine containing compositions: Typically, the nicotine active is selected from the group Nicotine containing products in the form of chewing gums 50 consisting of nicotine polacrilex, tobacco plant extract con are associated with problems such as disposal problem taining nicotine, derivatives of nicotine, nicotine oil, nicotine and chewing is very often socially unacceptable. salts, nicotine cation exchanger, nicotine inclusion complex, Further, much of the nicotine is retained in the gum through nicotine bound to cellulose or starch micro-spheres, metabo incomplete chewing or is largely wasted through Swal lites of nicotine and combinations thereof. lowing which in turn results in low systemic bioavail 55 Preferably, the nicotine active is nicotine polacrilex or ability (about 30 to 40%). tobacco plant extract containing nicotine. Furthermore, chewing of chewing gum leads to breaking of Typically, the gelling agent is selected from the group polymer coating and result in excessive release of nico consisting of gelatin, carrageenan and mixtures thereof. tine in buccal cavity which in turn causes nausea, bad Preferably, the gelling agent is gelatin. taste and burning sensation. 60 Typically, the ratio of the gelling agent to plasticizer is in Nicotine containing lozenges also possess disadvantages the range of about 1:2.7 to about 1:3. Such as person using such lozenges is not comfortable to Typically, the plasticizer is selected from the group con keep a hard product in the buccal cavity for prolong sisting of glycerine, Sorbitol and mixtures thereof. period. Another disadvantage is that lozenges get break Preferably, the plasticizer is glycerine down into pieces followed by accidental swallowing 65 Typically, the releasing agent is selected from the group which in turn result in excessive transfer of nicotine in consisting of lecithin, oil, starch and mixtures thereof. GI tract and causes nausea and burning sensation. Preferably, the releasing agent is lecithin. US 8,470,366 B2 5 6 Typically, the Sweetener is at least one selected from the In accordance with one of the preferred embodiment of the group consisting of Stevia, aspartame, saccharin, Sucralose, present invention the nicotine active is nicotine polacrilex. Sucrose, dextrose and lactose. In accordance with another preferred embodiment of the Typically, the preservative is at least one selected from the present invention the nicotine active is tobacco plant extract group consisting of methyl paraben, propyl paraben, Sodium containing nicotine. methyl paraben and sodium propyl paraben. The gelling agent used for the preparation of soft pastille in Typically, the flavouring agents include, but are not limited accordance with the present invention is selected from the to menthol, Vanillin, peppermint, lemon, mint, strawberry, group consisting of gelatin, carrageenan and mixtures banana, pineapple, orange, raspberry and the like. thereof. In accordance with another aspect of the present invention 10 In accordance with the preferred embodiment of the there is also provided a process for the preparation of soft present invention gelatin is used as a gelling agent as the gel pastilles; said process comprising the following steps: obtained from gelatin is thermo-reversible. Because of a. introducing accurately weighed plasticizer selected from thermo-reversible property, after cooling the gelatin Solution the group consisting of glycerine, Sorbitol and combina the viscosity increases progressively and passes from a Sol to tions thereof and water in a reactor followed by addition 15 a gel. On the other hand, if the gel is heated, it dissolves and of gelling agent selected from the group consisting of once again becomes a solution. gelatin, carrageenan and mixtures thereof and releasing Typically, the plasticizer is selected from the group con agent selected from the group consisting of lecithin, oil, sisting of glycerine, Sorbitol and mixtures thereof. starch and combinations thereof to form a first mixture; In accordance with the preferred embodiment of the b. adding Nicotine active selected from the group consist present invention the plasticizer used is glycerine. ing of nicotine polacrilex, tobacco plant extract contain The critical parameter in the preparation of soft pastille in ing nicotine, derivatives of nicotine, nicotine oil, nico accordance with the present invention is the ratio of the gel tine salts, nicotine cation exchanger, nicotine inclusion ling agent to plasticizer. It is found that when the ratio of complex, nicotine bound to cellulose or starch micro gelling agent to glycerin is kept below 1:2.7, the formed spheres, metabolites of nicotine and combinations 25 mixture becomes hard and gets stuck in the nozzle while thereof to the mixture and mixing for about 30 to about transferring it into the die cavities in order to form pastilles. It 45 minutes at 1500 rpm to form a second mixture; is also found that when the ratio of gelling agent to glycerin is c. incorporating adequate quantities of Sweetener, flavour kept above 1:3, the formed mixture becomes less viscous and ing agent, colour and preservative into the second mix results in formation of poor quality pastilles. ture to obtain a mass; 30 Therefore, the ratio of gelling agent to glycerin for the d. collecting the mass in a container followed by cooling preparation of soft pastilles containing nicotine is kept in the and solidification; range of about 1:2.7 to about 1:3. e. transferring the Solidified mass into a melter to obtain a Typically, the releasing agent is selected from the group melted mass; and consisting of lecithin, oil, starch and mixtures thereof. f. passing the melted mass through an injector into the 35 In accordance with the preferred embodiment of the preformed cavities followed by cooling and blisterpack present invention the releasing agent used in the preparation aging. of soft pastilles containing nicotine is lecithin. Lecithin used in the preparation of soft pastilles acts as a releasing agent or DETAILED DESCRIPTION OF THE INVENTION lubricating agent which prevent the friction (or Sticking) 40 between the die wall and the pastilles. This in turn helps to In accordance with the present invention there is provided eject or remove the pastilles smoothly from the die cavity as a soft pastille comprising: well as from the final pack. a.nicotine active in an amount of about 0.05% to about 1% The Sweetener used in the preparation of pastilles in accor of the mass of the pastille; dance with the present invention is at least one selected from b. gelling agent in an amount of about 5% to about 40% of 45 the group consisting of Stevia, aspartame, saccharin, Sucral the mass of the pastille; ose, Sucrose, dextrose and lactose. c. plasticizer in an amount of about 30% to about 70% of Typically, the preservative is at least one selected from the the mass of the pastille; group consisting of methyl paraben, propyl paraben, Sodium d. Sweetener in an amount of about 0.05% to about 10% of methyl paraben and sodium propyl paraben. the mass of the pastille; 50 The flavouring agents employed in the preparation of pas e. releasing agent in an amount of about 0.5% to about 30% tilles of the present invention include, but are not limited to of the mass of the pastille; menthol, Vanillin, peppermint, lemon, mint, strawberry, f.preservative in an amount of about 0.05% to about 2% of banana, pineapple, orange, raspberry and the like. the mass of the pastille; In accordance with another aspect of the present invention g. flavouring agent in an amount of about 0.01% to 5% of 55 there is also provided a process for the preparation of soft the mass of the pastille; and pastilles; said process comprising the following steps: h. waterinanamount of about 5% to about 20% of the mass First step is introducing accurately weighed plasticizer of the pastille, selected from the group consisting of glycerine, Sorbitol and said pastille is capable of being dissolved in the buccal cavity combinations thereofand waterina reactor. To this accurately in about 5 to about 15 minutes, depending on the user's 60 weighed gelling agent selected from the group consisting of Sucking pattern. gelatin, carrageenan and mixtures thereof and releasing agent Typically, the nicotine active is selected from the group selected from the group consisting of lecithin, oil, starch and consisting of nicotine polacrilex, tobacco plant extract con combinations thereof are added to form a first mixture. taining nicotine, derivatives of nicotine, nicotine oil, nicotine To this first mixture, Nicotine active selected from the salts, nicotine cation exchanger, nicotine inclusion complex, 65 group consisting of nicotine polacrilex, tobacco plant extract nicotine bound to cellulose or starch micro-spheres, metabo containing nicotine, derivatives of nicotine, nicotine oil, nico lites of nicotine and combinations thereof. tine salts, nicotine cation exchanger, nicotine inclusion com US 8,470,366 B2 7 8 plex, nicotine bound to cellulose or starch micro-spheres, Nicotine Polacrilex contain 20% Nicotine; 1 mg of Nicotine metabolites of nicotine and combinations thereof is added Polacrilex=0.2 mg of Nicotine and the resulted mixture is mixed for about 30 to about 45 Testing: minutes at 1500 rpm to form a second mixture. A Stability Data: In next step, adequate quantities of Sweetener, flavour, 5 I Temperature: 25°C.i.2° C.; Relative Humidity: 60+5% colour and preservative are incorporated into the second mix ture to obtain a mass. The obtained mass is then collected in TABLE NO. 1 a container followed by cooling and solidification of the Time Assay/uniformity of mass. The solidified mass is transferred into a melter to obtain interval Average Weight Uniformity of content 90% to 115% a melted mass. Month (+7.5%) (in mg) Weight) (+7.5%) of Label Claim Finally, the melted mass is passed through an injector into O 1509.22 Complies 110.43% the preformed cavities followed by cooling and blister pack 3 1SOO.87 Complies 108.72% aging. 6 1SO3.42 Complies 106.98% 9 1SOO.S1 Complies 104.23% Following examples illustrate the invention, but is not 15 12 1SO1.92 Complies 102.49% intended to limit the scope of the present invention. 18 1502.51 Complies 101.31% 24 1506.92 Complies 99.56% Example 1 A Soft pastille in accordance with the present invention was II Temperature: 30° C.i.2°C.; Relative Humidity: 65+5% prepared with the following composition. TABLE NO. 2 Time Assay/uniformity of interval Average Weight Uniformity of content 90% to 115% Each pastille (1500mg) contains: 25 Month (+7.5%) (in mg) Weight (+7.5%) of Label Claim Nicotine from Nicotine poliacrilex (1 mg = 5 mg): 5 mg O 1509.22 Complies 110.43% Gelatin (bloom strength 250): 299 mg 3 1509.55 Complies 107.67% Glycerine: 971.7 mg 6 15O1.97 Complies 105.12% Water: 170 mg 9 1509.60 Complies 103.89% Lecithin: 37.3 mg 12 1506.87 Complies 100.32% Flavour: 3.8 mg 30 Sucralose: 1.4 mg Colour: 4 mg Methyl paraben: 2.4 mg III] Temperature: 40° C.i.2°C.; Relative Humidity: 75+5% Propyl paraben: 1.2 mg TABLE NO. 3 35 Time Assay/uniformity of Example 2 interval Average Weight Uniformity of content 90% to 115% Month (+7.5%) (in mg) Weight (+7.5%) of Label Claim O 1509.22 Complies 110.43% 40 3 1508.34 Complies 106.21% Each pastille (1500mg) contains: 6 1SOS.43 Complies 103.68% Nicotine from Nicotine poliacrilex (1 mg = 5 mg): 5 mg Gelatin (bloom strength 170): 315 mg Glycerine: 950 mg From the above stability data it is found that the product of Water: 188 mg this invention is stable. Lecithin: 30.3 mg 45 Flavour: 2.8 mg B Dissolution Study User Defined: Sucralose: 2ng Each of the 10 subjects was instructed to hold and suck the Colour: 4 mg pastille of the present invention. The time required to com Methyl paraben: 2.4 mg pletely dissolve the pastille in the mouth was recorded by Propyl paraben: 1.2 mg each of the subjects. 50 The results are provided in Table No. 4

Example 3 TABLE NO. 4 Subject Dissolution time min. 55 Each pastille (1500mg) contains: 8 12 Nicotine from Nicotine poliacrilex (1 mg = 5 mg): 5 mg 10 Gelatin (bloom strength 100): 343 mg 5 Glycerine: 970 mg 10 Water: 150 mg 9 Lecithin: 25.6 mg 60 15 Methyl paraben: 2.4 mg 9 Propyl paraben: 1.2 mg 10 Spearmint: 1.5 mg 1 13 Menthol: 1.3 mg Sucralose: 1.5 mg Colour: 4 mg 65 From the results (as shown in Table No. 4) it was found that the time require to dissolve the pastille of the present inven tion is in between 5 to 15 minutes depending upon individu als rate of Sucking the pastille. The average dissolution time was found to be 10 Minutes.

US 8,470,366 B2 11 12 Group withdrawal symptom score: 3.54 Group withdrawal symptom score: 3.58 (Arithmetic mean of the averages of the individual with (Arithmetic mean of the averages of the individual with drawal symptoms) drawal symptoms) From the observations as shown in the table No. 5& 6 it was From the observations as shown in the table No. 7&8 it was found that the placebo group reported significantly more found that the placebo group reported significantly more severe withdrawal symptoms than the nicotine Subjects. severe withdrawal symptoms than the nicotine Subjects. C II: Another randomized double blind, placebo con DOverall Compliance and Tolerance Study: trolled trial of nicotine Soft gelatin pastille prepared in accor DI: An independent study was undertaken to compare the dance with the present invention was carried out in 20 sub effect of the existing nicotine lozenges and the pastilles of the jects who were addicted to tobacco chewing. 10 present invention on specific parameters related to the overall Group A: 10 subjects who received nicotine soft gelatin pas compliance and tolerance. tille Pastille containing 4 mg of nicotine The study was carried out on 10 subjects (addicted to Group B: 10 subjects who received placebo cigarette Smoking) who were divided in to groups of 5 each. 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 O 1 Irritability 1 2 1 O 3 1 2 O 2 3 Frustration 1 3 2 3 1 2 3 1 1 2 Anger 3 1 2 2 1 1 1 2 3 2 Anxiety 1 2 1 2 1 O 1 1 1 1 Difficulty in 2 1 2 1 3 2 3 2 2 2 concentrating Restlessness 1 3 2 3 2 2 1 2 2 1 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 Group I: 5 subjects were administered the pastilles pastille (Arithmetic mean of the averages of the individual with- 40 containing 2 mg of nicotine of the present invention while drawal symptoms) Subjects of Group II were administered nicotine lozenges. 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

US 8,470,366 B2 15 16 During the study period, there were 2 phases. In the first The invention claimed is: phase, the Subjects were encouraged to Substitute Smoking/ 1. A soft pastille comprising: tobacco chewing by pastille consumption; in the second a.nicotine active in an amount of about 0.05% to about 1% phase (i.e. once the Subject has Switched to pastille consump of the mass of the pastille; tion without the need for Smoking) the Subjects were encour b. gelling agent in an amount of about 5% to about 40% of aged to taper down the frequency of pastille consumption for the mass of the pastille; attaining the ultimate goal of Successful quitting. The dura c. plasticizer in an amount of about 30% to about 70% of tion of the first phase and the second phase was varied from the mass of the pastille; Subject to subject depending on the response shown by the d. Sweetener in an amount of about 0.05% to about 10% of Subject. 10 the mass of the pastille; e. releasing agent in an amount of about 0.5% to about 30% A Subject is said to have Successfully quit Smoking in this of the mass of the pastille; context when he/she no longer Smokes or consumes nicotine f.preservative in an amount of about 0.05% to about 2% of through any other means which also include the pastilles of the mass of the pastille; the present invention. 15 g. flavouring agent in an amount of about 0.01% to 5% of Group 1: the mass of the pastille; and All the subjects completed the study. All of the subjects h. waterinanamount of about 5% to about 20% of the mass Successfully quit Smoking after participation for a period of 1 of the pastille, said pastille being capable of being dis week to 3 weeks of the study period. As the study progressed, solved in the buccal cavity in about 5 to about 15 min the initial dosing frequency was gradually tapered in conso utes, depending on the user's Sucking pattern; and nance with the craving of each of the Subjects. a ratio of the gelling agent to the plasticizer being in a range Group 2: of about 1:2.7 to about 1:3. One of the subjects abruptly discontinued the study on 4" 2. The pastille as claimed in claim 1, wherein the nicotine day from the commencement of the study. Right from the first active is selected from the group consisting of nicotine polac week of the study period, the subjects were constantly 25 rilex, tobacco plant extract containing nicotine, nicotine oil, encouraged to Substitute Smoking by pastille consumption. nicotine salts, nicotine cation exchanger, nicotine inclusion (First Phase). complex, nicotine bound to cellulose or starch micro-spheres, Out of the remaining 4 subjects, 3 Successfully quit Smok and combinations thereof. ing after participating for a period of 3 to 5 weeks while the 3. The pastille as claimed in claim 1, wherein the nicotine remaining one continued consuming pastilles without Smok 30 active is nicotine polacrilex or tobacco plant extract contain ing nicotine. ing (Phase 2) till the final week of the study period. However, 4. The pastille as claimed in claim 1, wherein the gelling the frequency of the pastille consumption at the end of the agent is selected from the group consisting of gelatin, carra study period was only 2 pastilles per day. geenan and mixtures thereof. Group 3: 35 5. The pastille as claimed in claim 1, wherein the gelling One of the five subjects Successfully quit Smoking at the agent is gelatin. end of 4" week of the study period. Another one quit smoking 6. The pastille as claimed in claim 1, wherein the plasticizer altogether; however he continued the consumption of pas is selected from the group consisting of glycerine, Sorbitol tilles at a frequency of 2 pastilles per day till the end of the and mixtures thereof. study period (Phase 2). Still another subject also quit Smoking 40 7. The pastille as claimed in claim 1, wherein the plasticizer during the study period but his pastilles consumption fre is glycerine. quency was 8 per day as reported on the last day of the study 8. The pastille as claimed in claim 1, wherein the releasing period. Out the of remaining 2 subjects, one subject reported agent is at least one selected from the group consisting of that his Smoking frequency during the study period came lecithin, oil and starch. down to 6 a day but he still continued with pastille consump 45 9. The pastille as claimed in claim 1, wherein the releasing tion with a frequency of 2 pastille per day (Phase 1). agent is lecithin. Group 4: 10. The pastille as claimed in claim 1, wherein the Sweet One of the total five subjects successfully quit Smoking at ener is at least one selected from the group consisting of the end of eight weeks of the study period. Stevia, aspartame, saccharin, Sucralose. Sucrose, dextrose and During Phase 1, out of the 5 subjects, 2 could completely 50 lactose. switch to the Phase 2 (Pastille only). The frequency of 2 of the 11. The pastille as claimed in claim 1, wherein the preser subjects who switched to Phase 2 was 10 pastilles (2 mg) per Vative is at least one selected from the group consisting of day as reported on the last day of the study period. methyl paraben, propyl paraben, Sodium methyl paraben and The two subjects who could not switch to phase 2 of the Sodium propyl paraben. study reported reduction in frequency of tobacco chewing to 55 12. The pastille as claimed in claim 1, wherein the flavour just 2 times a day along with pastille consumption frequency ing agent is at least one selected from the group consisting of of 2 pastilles (2 mg) per day. menthol, Vanillin, peppermint, lemon, mint, strawberry, While considerable emphasis has been placed herein on the banana, pineapple, orange and raspberry. specific ingredients of the preferred formulation, it will be 13. A process for the preparation of soft pastilles; said appreciated that many additional ingredients can be added 60 process comprising the following steps: and that many changes can be made in the preferred formu a. introducing accurately weighed plasticizer selected from lation without departing from the principles of the invention. the group consisting of glycerine, Sorbitol and combina These and other changes in the preferred formulation of the tions thereof and water in a reactor followed by addition invention will be apparent to those skilled in the art from the of gelling agent selected from the group consisting of disclosure herein, whereby it is to be distinctly understood 65 gelatin, carrageenan and mixtures thereof and releasing that the foregoing descriptive matter is to be interpreted agent selected from the group consisting of lecithin, oil, merely as illustrative of the invention and not as a limitation. starch and combinations thereof to form a first mixture US 8,470,366 B2 17 18 wherein a ratio of the gelling agent to the plasticizer is in a range of about 1:2.7 to about 1:3: b. adding Nicotine active selected from the group consist ing of nicotine polacrilex, tobacco plant extract contain ing nicotine, nicotine oil, nicotine salts, nicotine cation 5 exchanger, nicotine inclusion complex, nicotine bound to cellulose or starch micro-spheres, and combinations thereof to the mixture and mixing for about 30 to about 45 minutes at 1500 rpm to form a second mixture; c. incorporating adequate quantities of Sweetener, flavour 10 ing agent, colour and preservative into the second mix ture to obtain a mass; d. collecting the mass in a container followed by cooling and solidification; e. transferring the Solidified mass into a melter to obtain a 15 melted mass; and f. passing the melted mass through an injector into the preformed cavities followed by cooling and blisterpack aging.