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Title:  Nicotine lozenge

United States Patent:  6,280,761

Inventors:  Santus; Gian Carlo (Milan, IT)

Assignee:  Pharmacia AB (Helsingborg, SE)

Appl. No.:  644971

Filed:  May 15, 1996

Abstract

A method for smoking cessation therapy is described that utilizing an improved nicotine lozenge to satisfy transient craving. The lozenge contains nicotine, a nonnutritive sweetener and an absorbent excipient.

DESCRIPTION OF THE PREFERRED EMBODIMENT

 The Lozenge

The present invention provides for lozenges used to deliver nicotine to a patient for reducing his craving for nicotine and for smoking cessation therapy, and methods of using nicotine lozenges for this purpose, including but not limited to the embodiments and methods described below. The nicotine lozenge of the present invention comprises any lozenge, tablet, or capsule formulation that delivers nicotine to the buccal cavity, comprising nicotine dispersed in an absorbent excipient and a nonnutritive sweetener.

A. Nicotine

Nicotine is a heterocyclic compound that exists in both a free base and a salt form. The free base is extremely volatile and is absorbed readily through mucous membranes and intact skin. The major problems reported for products based on nicotine free base originate from the volatility of the nicotine, its acrid, burning taste, the irritant sensation of the mucous membranes, and the decomposition of nicotine in the presence of oxygen. Previously, these problems have been alleviated, in part, through the use of nicotine's salt form, i.e., an acid addition salt or metal salt.

Surprisingly, the lozenges described herein can be produced from either the free base or a pharmaceutically acceptable acid addition salt thereof, or any combination thereof. In the exemplary embodiment, nicotine, i.e., the free base form of nicotine, is used.

Regardless of the formulation used, the lozenge contains fairly low doses of nicotine, preferably between 0.5 and 5 mg, and most preferably from 0.5 to 2.0 mg, to avoid accidental overdosage by swallowing the lozenge intact. High doses are not required because the purpose of the nicotine lozenge is to provide a transient blood level peak of nicotine.

B. The Absorbent Excipient

According to the compositions and methods described herein, the nicotine is dispersed in an absorbent excipient. Absorbent excipients are pharmaceutically acceptable substances that are capable 1) of reducing the volatility of the nicotine, for example, through absorption or by the incorporation of nicotine, such as in an inclusion complex, and 2) of being compressed into a lozenge or tablet. Suitable absorbent excipients include, but are not limited to, mannitol; cyclodextrins, including .alpha., .beta., and .gamma.-cyclodextrin, as well as derivatives of cyclodextrins, such as trimethyl-.beta.-cyclodextrin, dimethyl-.beta.-cyclodextrin, hydroxyethyl-.beta.-cyclodextrin, and hydroxypropyl-.beta.-cyclodextrin; silica preparations, such as the synthetic silica formulation marketed under the trade name syloid.TM. by W. R. Grace Limited of North Dale House, North Circular Road, London; cellulosic materials, such as Avicel microcellulose manufactured by FMC Corporation; and other conventional binders and fillers used in the food industry, such as acacia powder, gelatin, gum arabic, and sorbitol.

According to some embodiments, the absorbent excipient will serve more than one role in the lozenge formulation. For example, mannitol can function as both a nonnutritive sweetener and an absorbent excipient. Similarly, the absorbent excipient can serve as a flavorant, buffering agent, lubricant, or other component of the lozenge.

The absorbent excipient is typically present in an amount between about 5 and 25% by weight (wt %), preferably in an amount between about 5 and 20 wt %, and more preferably in an amount between about 5 and 15 wt %.

In a preferred embodiment, the absorbent excipient comprises mannitol or .beta.-cyclodextrin.

C. The Nonnutritive Sweetener

The lozenge will also contain a nonnutritive sweetener. Since nicotine has an acrid, burning taste, the choice of a sweetener for a nicotine lozenge can be critical, for many patients do not find the taste of nicotine palatable in lozenge form. Typically, a nonnutritive sweetener or combination of sweeteners will be utilized in the lozenges described herein.

A nonnutritive sweetener is a synthetic or natural sugar substitute whose sweetness is higher than or comparable to sucrose. Table I lists examples of nonnutritive sweeteners and their relative sweetness values.

                             TABLE I
                     Nonnutritive Sweeteners
        Sweetener     Sweetness1    Sweetener   Sweetness1
        Saccharin         400-500      Invert sugar     1.1-1.2
        Cyclamate          30-40        Palantinose     0.4-0.5
        Aspartame         100-200     Xylitol           1.0
        Acesulfame          200          Sorbitol        0.5-0.6
        Monellin               2500        Mannitol        0.4-0.6
        Neohesperidine    1000        Maltitol        0.7-0.9
        Palatinit                 0.4-0.5     --                --
    1 Sucrose = 1.0


Thus, the nonnutritive sweetener should have a relative sweetness value between about 0.4 and 2500, as compared with sucrose, more typically between about 0.4 and 500, preferably between about 0.4 and 200, and more preferably, between about 0.4 and 2. See Makinen (1988) Oral Health 78: 57-66, which is incorporated herein by reference.

In a preferred embodiment, the nonnutritive sweetener is also noncariogenic. The cariogenicity of a substance is dependent upon its susceptibility to fermentation by Streptococcus mutans and other oral microorganisms. Dental researchers have long recognized that fermentable sweeteners such as sucrose, glucose, starch, and corn syrup are

1 Sucrose =1.0 cariogenic or caries causing. The polyol nonnutritive sweeteners, such as xylitol, sorbitol, fructose, invert sugar, palantinose, mannitol, maltitol, palatinit, and ammonium glycyrrhizinate, however, are generally not fermented to any significant degree and are less cariogenic than sucrose. See Olinger presented at the Interphex-USA Conference/Exhibition, New York; May 8-11, 1990.

More specifically, the ability of xylitol to inhibit the development of new caries has been demonstrated in numerous in vitro and in vivo studies. For example, field trials of oral products containing xylitol have suggested that substitution of sucrose by xylitol in products such as chewing gum may aid in prevention of dental caries (see Soderling, E., and Scheinin, A., Proc. Finn. Dent. Soc. 1991, 87(2), 217-229). Studies have also revealed that when xylitol-containing confections are consumed as part of a normal diet, in conjunction with accepted oral hygiene practices, new caries incidence is reduced by about 50% to as high as 80%. See Olinger supra.

Moreover, the literature suggests that nonnutritive sweeteners, and particularly xylitol, may be useful as a sugar substitute for weight control, (see U.S. Pat. No. 3,717,711), which is clearly a major concern for people who are quitting smoking. In addition, xylitol as been shown to prolong gastric emptying and decrease food intake in humans. See Shafer et al. (1987) Am. J. Clin. Nutr. 45: 744-47. Likewise, because xylitol is not metabolized as a sugar, it has value for use with people who must restrict their sugar intake, such as diabetics (see Maukinen, K., Oral Health 1988, 78(9), page 60).

Xylitol also has a cooling effect when it dissolves in the mouth, due to its negative heat of solution. Xylitol's heat of solution is -36.6 cal/g, compared to -28.9 cal/g for mannitol, -26.6 cal/g for sorbitol, and -4.3 cal/g for sucrose (see Olinger, P. M., presented at the Interphex-USA Conference/Exhibition, New York; May 8-11, 1990). Therefore, xylitol is an excellent choice for a sweetener and excipient in a lozenge that needs to be held in the mouth for an extended period of time, and that needs to be taken frequently every day for maximum therapeutic effect.

Frequently a combination of nonnutritive sweeteners will be used. According to one embodiment, a sweetener with temporal sensory properties similar to that of sucrose (i.e., an appearance time of about 4 seconds and an extinction time of 13 seconds, e.g., some of the polyol sweeteners, saccharin, cyclamate and aspartame) will be combined with a sweetener whose sweetness develops slower or persists longer. For example, ammonium glycyrrhizinate, a nonnutritive sweetener with a slight licorice taste, has a taste onset or appearance time of about 16 seconds for ammonium glycyrrhizinate and a taste persistence or extinction time of 69 seconds. Dubois and Lee (1983) Chem. Sens. 7: 237-248. Other examples of nonnutritive sweeteners with temporal sensory properties different than that of sucrose include, but are not limited to, neohesperidine dihydrochalcone (appearance time of 9 seconds and an extinction time of 40 seconds) and stevioside (appearance time of 4 seconds and an extinction time of 22 seconds).

Thus, in a preferred formulation, the lozenge will contain a nonnutritive, noncariogenic sweetener, such as xylitol, sorbitol, fructose, invert sugar, palantinose, mannitol, maltitol, and palatinit, either alone or in combination with other nonnutritive sweeteners. More preferably, xylitol, either alone or in combination with a nonnutritive sweetener having an extinction time longer than that of sucrose, such as ammonium glycyrrhizinate, neohesperidine dihydrochalcone, or stevioside, will be used. In an exemplary embodiment, the nonnutritive sweetener will comprise xylitol and ammonium glycyrrhizinate.

The nonnutritive sweetener is typically present in an amount between about 50 and 90 wt %, preferably in an amount between about 70 and 90 wt %, and more preferably in an amount between about 80 and 90 wt %.

D. Other Ingredients

The lozenge preferably is a buffered formulation in order to aid in buccal absorption of nicotine. A preferred formulation is at a pH of about 6-11, and preferably at a pH of about 7-9. Preferred buffered formulations will include sodium carbonate, sodium bicarbonate, sodium phosphate, calcium carbonate, magnesium hydroxide, potassium hydroxide, magnesium carbonate, aluminum hydroxide, and other substances known to those skilled in the art, as well as combinations of the aforementioned substances. In a most preferred formulation, the lozenge will contain sodium carbonate and bicarbonate as buffering agents.

The buffering agent(s) should be present in an amount sufficient to adjust the pH of the lozenge to between 6 and 11, typically, between about 0.1 and 25% by weight (wt %), preferably in an amount between about 0.1 and 10 wt %, and more preferably in an amount between about 0.1 and 5 wt %.

In addition, the lozenge may contain a flavorant, for example, a candy taste, such as chocolate, orange, vanilla, and the like; essential oils such as peppermint, spearmint and the like; or other flavor, such as aniseed, eucalyptus, 1-menthol, carvone, anethole and the like, to mask the taste of nicotine. See Hall et al. Food Technol. 14: 488 (1960); 15: 20 (1961); 19: 151 (1965); 24: 25 (1970); 26: 35 (1972); 27: 64 (1973); 27: 56 (1973); 28: 76 (1974); 29: 70 (1974) 31: 65 (1977); 32: 60 (1978); and 33: 65 (1979), each of which is incorporated herein by reference. It may also contain tobacco flavor in order to reproduce some of the sensation of smoking for the user. A small amount of colloidal silica (less than about 1 wt %) typically is added to tablets containing tobacco flavor to aid in manufacturing.

Magnesium stearate and/or hydrogenated vegetable oil may also be added to the formulation as lubricants. Typically, the lubricant will be present in an amount between about 0.1 and 25 wt %, preferably in an amount between about 0.1 and 10 wt %, and more preferably in an amount between about 0.1 and 5 wt %.

The lozenges described herein may also contain a variety of other additives. For example, pharmacologically active ingredients such as sodium monofluorophosphate, sodium fluoride, dextranase, mutanase, hinokitiol, allantoin, aminocaproic acid, tranexamic acid, azulene, vitamin E derivatives, sodium chloride and the like can be added at need. More specifically, since the effects of xylitol and fluoride on dental hygiene are additive, the former can significantly enhance the efficacy of traditional fluoride treatments. Thus, according to one embodiment, fluoride, and more particularly sodium monofluorophosphate or sodium fluoride will be incorporated into a lozenge formulation having xylitol as a nonnutritive sweetener.

In addition, the lozenge may be colored with conventional, pharmaceutically acceptable food coloring agents. Other additives that may be incorporated within the lozenges described herein include, but are not limited to, preservatives, antimicrobial agents, and antioxidants.

E. The Method of Manufacture

The method of manufacture of these lozenges may be any suitable method known in the art, including but not limited to, the addition of a nicotine compound to premanufactured tablets; cold compression of an inert filler, a binder, and either pure nicotine or a nicotine-containing substance (as described in U.S. Pat. No. 4,806,356, herein incorporated by reference); and encapsulation of nicotine or a nicotine compound. See U.S. Pat. No. 5,135,753, herein incorporated by reference, for examples of methods of manufacture of various nicotine lozenges, sublingual tablets, and gelatin capsules. In a preferred embodiment, the lozenges are formed using direct compression. See Example 4 for a discussion of the manufacturing process in which the nicotine is dispersed in mannitol.

According to another embodiment, an in situ inclusion complex is created with nicotine and .beta.-cyclodextrin using a kneading technique. Specifically, a small amount of a nicotine-water solution is added to cyclodextrin and kneaded or mixed. See Szezetli in Cyclodextrins and Their Inclusion Complexes, Akademiai Kiado: Budapest, 1992; p. 109; herein incorporated by reference. This method of forming the nicotine-cyclodextrin inclusion complex is preferred as it minimizes the use of solvents or diluents and thus, eliminates a purification step in the manufacturing process. See also Example 5 for discussion of use of the kneading technique with nicotine and .beta.-cyclodextrin.

A further embodiment of the present invention provides for the production of inclusion complexes of both the nicotine and the flavorant. This embodiment is employed, for example, when an essential oil, or other volatile flavorant, such as carvone or menthol, is used in the lozenge formulation. As in the case of the nicotine inclusion complexes described herein, incorporation of the flavorant into cyclodextrin decreases the volatility of the flavorant and increases formulation stability. In addition, as the flavorant is slowly released from the complex during lozenge administration, the flavorant will "last" longer and thus, offset the acrid taste of the nicotine for longer periods of time.

According to this embodiment, a mixture of the nicotine and the flavorant, and optionally water, is added to the cyclodextrin and kneaded. Alternatively, the nicotine inclusion complex and the flavorant inclusion complex can be prepared separately and then mixed prior to lozenge formulation.

According to another embodiment, a portion of the nonnutritive sweetener, preferably xylitol, is utilized to hard coat the nicotine lozenge. Traditional pan coating techniques can be employed. Typically, weight increases of approximately 35% can be accomplished in less than three hours. See, e.g., Olinger supra.

The lozenges may be packaged in such a manner as to aid in maintaining nicotine stability. Preferred packaging methods include strip lamination in a foil-like material such as Barex.RTM., or packaging in blisters using a Teflon-like material such as Aclar.RTM.. See also, Hunt et al. (1991) U.S. Pat. No. 5,077,104.

As noted above, nicotine is a volatile substance. Others have reported a short shelf-life for nicotine lozenges due to evaporation of the nicotine, particularly when the ambient temperature is above 15oC. See Belcher et al. (1989) Brit. J. Med. 298: 570. The lozenges described herein, however, are stable for extended periods of time at elevated temperatures, as shown below in Table 2. See Example 6 for a discussion of the assay procedure used to determine stability.

                                     TABLE 2
                         Nicotine Lozenge Stability Data
    Temperature  Time               Nicotine  Degradation Dissolution
     Dissolution
    (oC.) (month) Appearance   mg/loz.   products   test 5 min. test 10
     min.
        --      Initial    White      1.001      <0.1%       89.7%       99.8%
        35         1     Unchanged    0.996      <0.1%       90.3%      100.0%
        35         2     Unchanged    0.998      <0.1%       88.7%      100.0%
        35         3     Unchanged    1.000      <0.1%       92.2%       99.6%
       R.T.        1     Unchanged    1.000      <0.1%       93.1%       99.8%
       R.T.        2     Unchanged    0.986      <0.1%       95.3%       99.9%
       R.T.        3     Unchanged    1.000      <0.1%       94.5%      100.1%

The lozenges described herein will typically have a weight of between about 70 and 1000 mg and will contain fairly low doses of nicotine, preferably less than 5 mg, and most preferably from 0.5 to 2.0 mg.

III. Method of Use

The present invention further provides a method of using nicotine lozenges to provide periodic transient blood level peaks of nicotine as an aid in reducing symptoms of craving of nicotine. Typically, the lozenges described herein will be used ad libitum by the patient to alleviate cravings for nicotine as they arise. Thus, this method provides for a means for the patient to self-titrate his administration needs.

More specifically, nicotine cravings depend, in part, upon daily stress patterns, sleep and eating habits and body weight, previous smoking levels, and the like. Thus, the desire or need for lozenges (comparable to the desire to smoke cigarettes) typically will vary during any given day and from day to day, as well as from patient to patient. The methods described herein allow the patient to consume lozenges in the amounts and at the times when he most feels the craving for nicotine. As nicotine craving is considered by some to be the most consistent and most severe factor in preventing a person from quitting smoking, this ability to self-titrate and thus, stave off the craving for nicotine will increase the efficacy of a smoking cessation program.

A variety of methods can be utilized to assess the craving for nicotine, including but not limited to, the nicotine craving test specified by the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) (see (1991) J. Am. Med. Assoc. 266: 3133); the Shiffman-Jarvik Craving Subscale (see O'Connell and Martin (1987) J. Consult. Clin. Psychol. 55: 367-371 and Steur and Wewers (1989) ONF 16: 193-198, also describing a parallel visual analog test); West et al. (1984) Br. J. Addiction 79: 215-219; and Hughes et al. (1984) Psychopharmacology 83: 82-87, each of which is expressly incorporated herein by reference.

A preferred nicotine craving scale comprises that specified in DSM-III-R. Supra. According to this scale, a subject is asked to rate the severity of his craving for nicotine on a scale between 0 and 4, wherein 0 is none; 1 is slight; 2 is mild; 3 is moderate; and 4 is severe. Using the compositions and methods described herein, the subject should attain at least a one unit, and preferably at least a two unit, decrease in his craving for nicotine as measured by the protocol set forth in DSM-III-R from 2 to 30 minutes after administration of the nicotine lozenge. More preferably, the maximum reduction in craving for nicotine will occur from about 2 to 10 minutes after administration of the nicotine lozenge.

The Shiffman-Jarvik Craving Scale is a six-item, forced-choice, self-report tool that measures cigarette craving. Each item has seven possible responses which correspond to scores ranging from 1 (no craving) to 7 (high craving). A mean score is obtained to determine the respondent's level of craving. A craving typical score measured 48 hours after the initiation of a smoking cessation program is between about 4 and 5; while a two-week follow-up craving scale will typically be between about 3 and 4. Using the compositions and methods described herein, the subject should attain at least a one unit, and preferably at least a two unit, decrease in his craving for nicotine as measured by the protocol set forth in the Shiffman-Jarvik Craving Scale from 2 to 30 minutes after administration of the nicotine lozenge. More preferably, the maximum reduction in craving for nicotine will occur from about 2 to 10 minutes after administration of the nicotine lozenge.

The "craving questionnaire" craving scale employs a five item questionnaire that asks subjects to rate how much they had been missing their cigarettes, how difficult it had been to be without cigarettes, how much they had been aware of not smoking, how preoccupied they had been with thinking about cigarettes, and how much they had craved their cigarettes. The subject responds to each question with a number between 1 and 3, where 1 is low and 3 is high. The ratings are combined to give a single craving score. According to this craving scale, a combined score of between about 9 and 12 is typical. Using the compositions and methods described herein, the subject should attain at least a three unit, and preferably at least a four unit, decrease in his craving for nicotine as measured by the protocol set forth for use with this craving questionnaire from 2 to 30 minutes after administration of the nicotine lozenge. More preferably, the maximum reduction in craving for nicotine will occur from about 2 to 10 minutes after administration of the nicotine lozenge.

Of course, the lozenges can also be used according to a dosage pattern prescribed by a physician. The dosage pattern will vary with the indication. For example, in addition to use in smoking cessation or reduction therapy, the nicotine lozenges described herein can be used for the treatment of Alzheimer's Disease, ulcerative colitis and related conditions, and diseases associated with reduced central cholinergic function, loss of cholinergic neurons, significant reduction in nicotine receptor binding, neurodegenerative dementia, or cognition and memory impairment. See Masterson (1991) U.S. Pat. No. 5,069,904; Wesnes and Warburton (1984) Psychopharmacology 82: 147-150; and Warburton et al. (1986) Psychopharmacology 89: 55-59.

The lozenge should be administered without holding any other substance, such as food or beverage, in the mouth. It is particularly important that acidic substances or beverages such as fruits, coffee, tea, or fruit juices are not consumed immediately or concurrently with the nicotine lozenge, in order to insure that a basic environment is maintained within the mouth.

The lozenge is preferably held from 2-10 minutes in the mouth as it dissolves completely and releases nicotine into the mouth, and the dissolved nicotine solution is held in the mouth for as long as possible so that the nicotine is absorbed through the buccal mucosa.

Claim 1 of 3 Claims

What is claimed is:

1. A nicotine lozenge consisting of 1 mg nicotine, 200 mg mannitol, 1309 mg xylitol, 20 mg mint flavor, 15 mg ammonium glycyrrhizinate, 5 mg sodium carbonate, 15 mg sodium bicarbonate, 25 mg hydrogenated vegetable oil, and 10 mg magnesium stearate.


____________________________________________
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