US20030111088A1 - Device and method for treating combination dependencies - Google Patents

Device and method for treating combination dependencies Download PDF

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US20030111088A1
US20030111088A1 US10285016 US28501602A US2003111088A1 US 20030111088 A1 US20030111088 A1 US 20030111088A1 US 10285016 US10285016 US 10285016 US 28501602 A US28501602 A US 28501602A US 2003111088 A1 US2003111088 A1 US 2003111088A1
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nicotine
chamber
device
end
naltrexone
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US10285016
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Barbara Fox
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RECOVERY PHARMACEUTICALS Inc
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Addiction Therapies Inc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61JCONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J7/00Devices for administering medicines orally, e.g. spoons; Pill counting devices; Arrangements for time indication or reminder for taking medicine
    • A61J7/0015Devices specially adapted for taking medicines
    • A61J7/0038Straws
    • AHUMAN NECESSITIES
    • A24TOBACCO; CIGARS; CIGARETTES; SMOKERS' REQUISITES
    • A24FSMOKERS' REQUISITES; MATCH BOXES
    • A24F47/00Smokers' requisites not provided for elsewhere, e.g. devices to assist in stopping or limiting smoking
    • A24F47/002Simulated smoking devices, e.g. imitation cigarettes
    • AHUMAN NECESSITIES
    • A47FURNITURE; DOMESTIC ARTICLES OR APPLIANCES; COFFEE MILLS; SPICE MILLS; SUCTION CLEANERS IN GENERAL
    • A47GHOUSEHOLD OR TABLE EQUIPMENT
    • A47G21/00Table-ware
    • A47G21/18Drinking straws or the like
    • A47G21/183Drinking straws or the like with means for changing the flavour of the liquid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00Inhalators
    • A61M15/06Inhaling appliances shaped like cigars, cigarettes or pipes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61JCONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J15/00Feeding-tubes for therapeutic purposes
    • A61J15/0011Feeding-tubes for delivery of nourishment to the mouth; Mouth pieces therefor

Abstract

The present invention is directed to an oral medication delivery device and a method of using the device to reduce the incidence of tobacco smoking and/or treat a second dependency in a person. The device comprises a tubular chamber having a first end suitable for taking in liquid or gas from an external source and a second end suitable for the application of oral suction. The chamber contains nicotine, another drug, and a retainer for preventing release of the drugs from the first end of the chamber.

Description

    BACKGROUND OF THE INVENTION
  • 1. Field of the Invention [0001]
  • The field of the present invention is pharmacology. More specifically, the invention relates to methods and medication delivery devices for promoting smoking cessation and/or treating another dependency. [0002]
  • 2. Summary of the Related Art [0003]
  • Cigarette smoking is the leading cause of preventable disease and death in the United States. Each year, over 400,000 adults die from tobacco-related diseases ([0004] A Report of the Surgeon General, Rockville, Md.: Public Health Service (2000)). In addition to health risks facing smokers themselves, the annoyance and risks of second-hand smoke are receiving increased attention. Although airlines, workplaces, and restaurants often ban smoking, almost 88% of non-smokers have detectable blood levels of nicotine metabolites (Morbidity and Mortality Weekly, Nov. 5, 1999). Environmental tobacco smoke remains a preventable health hazard for smokers' co-workers and family members (A Report of the Surgeon General, Rockville, Md.: Public Health Service (2000)).
  • Unfortunately, 48 million adults in the United States, 24.7% of the population, continue to smoke. Despite public health initiatives, smoking prevalence among adults has not changed significantly throughout the 1990's ([0005] Morbidity and Mortality Weekly, Nov. 5, 1999). Although most smokers in the United States wish to stop smoking, and over one third of them attempt to give up smoking each year, only about 2.5% succeed (A Report of the Surgeon General, Rockville, Md.: Public Health Service (2000)).
  • Various techniques have been advanced to aid smoking cessation. The five major pharmacotherapies for treating tobacco dependence are nicotine gum (see, e.g., U.S. Pat. No. 3,845,217); nicotine transdermal patch (see, e.g., U.S. Pat. No. 4,915,950); nicotine nasal spray (see, e.g., AU 664 41); nicotine inhaler (see, e.g., U.S. Pat. Nos. 4,920,989 and 4,953,572); and sustained-release bupropion hydrochloride (see, e.g., Jorenby et al., [0006] N. Engl. J. Med., 340:685-91(1999)). Other examples of smoking cessation aids include nicotine nose drops (see, e.g., U.S. Pat. No. 4,579,858); nicotine lozenges (see, e.g., U.S. Pat. Nos. 4,806,35 and 5,549,906); smoke-free cigarettes (see, e.g., U.S. Pat. Nos. 4,284,089, 4,676,259, 4,736,755, 4,813,437, 5,284,163, and 6,041,789); compositions comprising nicotine metabolites (see, e.g. U.S. Pat. No. 5,869,505); and drinkable nicotine solutions (see, e.g., WO 99/55371).
  • Studies have shown that smokers using nicotine gum, patch, nasal spray, inhaled nicotine, or nicotine sublingual tablets are about 1.5 to 2 times more likely to stop smoking than smokers using no cessation aid, and evidence suggests that bupropion may be even more effective (see, Silagy et al., [0007] Cochrane Database Syst. Rev., No. 2, p.CD000146 (2000)). However, each of the existing smoking cessation aids has drawbacks, and none has proven fully effective.
  • For example, nicotine gum and lozenges can cause high localized nicotine concentration in the mouth, which tastes unappealing, and the gum may be difficult to chew. In addition, chewing gum or eating lozenges may appear unprofessional. Nicotine patches may irritate the skin, and some smokers are dissatisfied with the lack of rapid nicotine absorption from the patch. Nicotine nasal sprays may irritate the nose and throat. More importantly, none of these smoking cessation aids simulates the tactile sensations or hand-to-mouth behaviors that form an integral part of the smoker's addiction. [0008]
  • Studies have shown that sensory aspects affect smoking behavior and cigarette cravings as much as nicotine intake does. Indeed, smokers attempting to give up cigarettes have complained that, aside from experiencing nicotine withdrawal, they miss the sensations and hand-to-mouth behaviors associated with smoking (see, Rose, [0009] Ann. Rev. Med., 47:493-507 (1996)). In a study prepared for the American Lung Association, 41% of smokers reported that their most recent attempt to stop smoking was unsuccessful because they missed having something to hold or to do with their hands (Smoking Cessation Study, Yankelovich Partners, Jul. 27, 1998). Cigarette smoking involves a hand-to-mouth ritual that may be repeated over 70,000 times per year. Since smoking cessation requires giving up a highly ingrained habitual motion as well as giving up nicotine, an effective smoking cessation aid should address the behavioral components of smoking as well as providing nicotine replacement therapy. A smoking cessation aid should give the smoker the comfort of an oral and tactile ritual, while at the same time supplying nicotine. However, a smoking cessation device that is too similar to a conventional cigarette and provides oral sensations and tactile stimuli that too closely mimic tobacco smoking may not be ideal. A smoker using such a device might find it too easy to relapse into cigarette smoking (see, e.g., Schneider et al., Addiction, 91:1293-1306 (1996)). Thus, a smoking cessation aid that provides the synergistic combination of nicotine plus oral and tactile stimuli, while not too closely approximating a conventional tobacco cigarette, seems most desirable.
  • Among the existing smoking cessation aids, patches provide no oral or tactile stimulus, gum, lozenges, and drinkable solutions stimulate only the mouth, and nasal sprays stimulate only the airways. These aids lack the important synergistic combination of nicotine, oral stimulation, and hand-to-mouth behaviors that smokers desire. [0010]
  • Some existing smoking cessation aids, such as nicotine inhalers and various smoke-free cigarettes, do provide nicotine as well as some behavioral aspects of smoking. However, these products have major drawbacks. For example, U.S. Pat. No. 4,953,572 (Rose et al.) discloses a nicotine aerosol spray designed to simulate the sensations of inhaling tobacco smoke. The spray may be administered through inhalation from a hand-held nebulizer. However, the nicotine dose of the spray, which is limited by the volatility of the inhaler's nicotine base at room temperature, is low compared to that of tobacco smoke, and thus may be insufficient for many smokers. Additionally, such a spray may irritate the oral cavity. [0011]
  • U.S. Pat. No. 5,284,163 (Knudsen et al.) discloses a smoke-free cigarette substitute comprising a nicotine granulate in a tubular sleeve. The end of the sleeve contains a gum plug, which is bitten off and held in the mouth as chewing gum. When a person draws on the cigarette, nicotine granulate is pulled into the mouth and can be chewed into the gum, thus dispensing nicotine into the oral cavity. This product may possess the drawbacks of nicotine chewing gum described above. Also, as with any smoke-free cigarette, using it may approximate the behavioral aspects of smoking so closely that smoking cessation becomes more difficult. [0012]
  • U.S. Pat. Nos. 4,284,089 and 4,813,437 (Ray) disclose non-pyrolytic devices shaped like ordinary cigarettes and containing porous polymer plugs holding volatile liquid nicotine. Drawing on the device delivers nicotine vapors to a person's lungs. However, these devices are unable to deliver sufficient uniform doses of nicotine. Additionally, the vaporizable nicotine tastes unpleasant and is unstable, such that the devices have a very short shelf life. [0013]
  • U.S. Pat. No. 6,041,789 (Bankert et al.) addresses some of these problems with a non-pyrolytic cigarette substitute that delivers a nicotine-simulating vapor mixture with a cigarette-like taste and aroma. Instead of vaporizable nicotine, the device contains a volatile nicotinomimetic agonist and volatile palatability enhancing agents. However, this device does not actually deliver nicotine. Additionally, the cigarette-like structure, taste, and aroma may make the device so similar to a conventional cigarette that smokers using it as a cessation aid are likely to relapse. [0014]
  • Japanese Pat. No. 02190178 (Akimichi et al.) discloses a smoke-free tobacco “perfume solution” that may be vaporized and administered through a “tubular flexible casing.” However, the solution may present health risks due to the carcinogens and irritating particulates contained in tobacco. Additionally, as with other smoke-free cigarettes, using the device may approximate the actual tastes, smells, and motions of cigarette smoking so closely that smoking cessation is made more difficult. [0015]
  • U.S. Pat. No. 5,293,883 (Edwards) discloses a non-pyrolytic cigarette containing two tobacco-filled chambers, which house unburned and pre-burned tobacco, and a mouth filter that holds nicotine-filled ampules that release pure liquid nicotine into a person's mouth when the person breaks them open by biting or manually crushing the mouth filter. This device provides nicotine and a cigarette-like taste, but it may suffer from the drawbacks of liquid nicotine described above. Additionally, as discussed above, the device presents the health hazards of tobacco and may make smoking cessation more difficult by too closely approximating actual tobacco cigarettes. [0016]
  • Thus, a continuing need exists for new and improved smoking cessation aids to help reduce the ongoing public health hazards associated with cigarette smoking and second-hand smoke. Particularly needed is a smoking cessation aid that synergistically provides an easily controllable nicotine dose in a non-irritating form along with a delivery device that supplies the oral and tactile stimulation that smokers crave, without too closely approximating actual cigarette smoking. [0017]
  • Alcoholism is another prevalent addictive disorder that poses an enormous public health problem, costing an estimated $165 billion per year in the U.S. (see [0018] Substance Abuse: The Nation's Number One Health Problem, Schneider Institute for Health Policy, Brandeis University, Robert Wood Johnson Foundation (2001)). Approved pharmacotherapy treatments for alcoholism include disulfuram and naltrexone. Naltrexone is an opioid receptor antagonist that is believed to reduce the reinforcing properties of alcohol, thus leading to the extinction of drinking behavior and decreased craving (Sinclair, Alcohol Alcohol. 36:2-10 (2001)). Naltrexone also appears to affect the hypothalamic pituitary adrenal axis, and may thus have a more direct effect on alcohol craving (O'Malley et al., Psychopharmacol. (Berl) 160:19-29 (2002). Although published reports regarding the efficacy of naltrexone have been mixed (O'Malley et al., Psychiat. Ann. 25:681-688 (1995); Krystal et al., N. Engl. J. Med. 345:1734-1739 (2001)), naltrexone is the most effective medication currently available in the U.S. for treating alcoholism (Kranzler et al., Alcohol Clin. Exp. Res. 25:1335-1341 (2001)). A combination therapy of naltrexone and nicotine for smoking cessation also has been proposed (U.S. Pat. No. 6,004,970). Data indicate that the combination of nicotine and naltrexone does not pose any significant safety issues. Several clinical studies investigating the effect of naltrexone on smoking cessation (Sutherland et al., Psychopharmacol. (Berl), 120:418-425 (1995); Wewers et al., Psychopharmacol. (Berl), 140:185-190 (1998); Hutchison et al., Psychopharmacol. (Berl), 142:139-143 (1999); Wong et al., Addiction 94:1227-1237 (1999); King et al., Pharmacol. Biochem. Behav. 66:563-572 (2000)) found only small effects on smoking cessation, but found that the combination of naltrexone and nicotine was well-tolerated in patients.
  • Naltrexone is available in a solid oral dosage form for once daily dosing, and poor dosing compliance is believed to be a primary factor leading to relapse to drinking (Namkoong et al., [0019] J. Clin. Psychiatry 60:449-453 (1999)). An injectable sustained-release formulation of naltrexone, designed to deliver clinically effective levels of naltrexone for approximately one month, is also under development (DrugAbuse Sciences, Hayward, Calif.; Alkermes, Inc., Cambridge, Mass.). This depot formulation is intended to increase compliance and therefore efficacy of the naltrexone treatment. However, alcoholics may be reluctant to commit to such a depot product that interferes with the action of opiate analgesics. Several investigators have explored the use of naltrexone in association with different behavioral therapies (Sinclair, Alcohol Alcohol. 36:2-10 (2001); Carroll et al., Arch. Gen. Psychiatry 58:755-761 (2001); Anton et al., J. Clin. Psychopharmacol. 21:72-77 (2001); Preston et al., Drug Alcohol Depend., 54:127-135 (1999); Heinala et al., J. Clin. Psychopharmacol., 21:287-292 (2001)). In some of these studies, naltrexone has been used in novel ways, e.g., dosing in anticipation of heavy drinking (Sinclair, Alcohol Alcohol. 36:2-10 (2001)). A need exists for alternative dosing approaches to increase efficacy and improve patient compliance with naltrexone.
  • Cigarette smoking is much more common in alcoholics than in the general population, with as many as 80-95% of alcoholics being smokers (Hays et al., [0020] Ann. Behav. Med. 21:244-250 (1999); Daeppen et al., Alcohol Alcohol. 35:171-175 (2000)). This high percentage of co-morbidity reflects overlapping biochemical mechanisms of alcohol and nicotine in the central nervous system, which seem to result in even greater dependency on both drugs (Almeida et al., Neuropharmacol. 39:2740-2755 (2000); Narahashi, et al., Alcohol Clin. Exp. Res. 25:152S-156S (2001)). Traditionally, there has been some reluctance to treat alcohol and nicotine dependence concurrently. There is evidence that smoking can increase the likelihood that alcoholics will stop drinking, possibly due to the reinforcing activity of nicotine, and the ability of the hand and mouth behaviors of smoking to provide a substitute for drinking (Narahashi et al., Alcohol Clin. Exp. Res. 25:152S-156S (2001); Palfai et al., J. Abnorm. Psychol. 109:96-105 (2000); Schmidt et al., Alcohol 24:111-5 (2001)). However, increased awareness of the harm caused by smoking has led to an increased interest in treating nicotine and alcohol dependence concurrently (Saxon et al., J. Subst. Abuse Treat. 14:333-337 (1997); Hurt et al., Alcohol Clin. Exp. Res., 18:867-872 (1994); Kalman et al., J. Subst. Abuse Treat. 20:233-238 (2001)). Thus, a need exists for new products that provide combination therapy for smoking and alcoholism.
  • SUMMARY OF THE INVENTION
  • The present invention solves the foregoing problems by providing a medication delivery device that provides nicotine along with another drug in non-irritating solution form, and offers oral and tactile stimulation. The combination formulation is particularly useful for administering nicotine and naltrexone to treat patients who are smokers and also suffer from another dependency, such as alcoholism. [0021]
  • Accordingly, one aspect of the invention provides an oral medication delivery device. The device includes a tubular chamber having a first end suitable for taking in a liquid from an external source and a second end suitable for oral application of suction. Nicotine and a second drug other than nicotine are contained within the tubular chamber. A retainer prevents release of the nicotine, second drug, or liquid from the first end of the chamber. When oral suction is applied to the second end of the chamber, liquid enters the chamber from the external source through the first end of the chamber, and then the liquid, the nicotine, and the second drug are delivered through the second end of the chamber. [0022]
  • In some embodiments, the tubular chamber of the device approximates the size and shape of a conventional cigarette. In other embodiments, the tubular chamber approximates the size and shape of a conventional drinking straw. In certain embodiments, the retainer is fixed proximal to the first end of the chamber. In other embodiments, the retainer is transportable toward the second end of the chamber with the nicotine, second drug, and liquid when suction is applied to the second end of the chamber. [0023]
  • In some embodiments, the second drug is naltrexone. In certain embodiments, the tubular chamber contains from about 4 milligrams to about 25 milligrams of naltrexone. In particular embodiments, the tubular chamber contains from about 4 milligrams to about 12 milligrams of nicotine. In specific embodiments, the nicotine is selected from the group consisting of levo nicotine, dextro nicotine, racemic mixtures thereof, and pharmaceutically acceptable salts thereof. [0024]
  • In some embodiments, the nicotine and the second drug are in the form of coated particles of powdered drug. In particular embodiments, the drug particles are coated to enhance palatability. In certain embodiments, the nicotine and the second drug are incorporated in spheres comprising at least one material selected from the group consisting of sugar, starch, acacia, sodium alginate, carbomer, cellulose, dextrotes, ethyl cellulose, methyl cellulose, and povidone. In some embodiments, a solution of nicotine and the second drug is formed when the liquid enters the chamber and contacts the nicotine and the second drug. In specific embodiments, the solution is a suspension. [0025]
  • Another aspect of the invention provides a method for reducing the incidence of tobacco smoking and alcohol consumption by a person. The method includes orally administering nicotine and naltrexone to the person using an oral delivery device. The device includes a tubular chamber having a first end suitable for taking in a liquid from an external source and a second end suitable for oral application of suction. Nicotine and naltrexone are contained within the tubular chamber. A retainer prevents release of nicotine, naltrexone, or liquid from the first end of the chamber. In the method, oral administration includes application of oral suction by the person to the second end of the chamber. Upon the application of oral suction, the liquid enters the chamber from the external source through the first end of the chamber, and then the liquid and the nicotine and naltrexone are delivered through the second end of the chamber into the mouth of the person. [0026]
  • In some embodiments of the method, a single dose of nicotine and naltrexone administered to the person includes from about 4 milligrams to about 12 milligrams of nicotine and from about 4 milligrams to about 25 milligrams of naltrexone. In certain embodiments, the total daily dose of nicotine administered to the person is from about 4 milligrams to about 144 milligrams of nicotine. In particular embodiments, the total daily dose of naltrexone administered to the person is from about 4 milligrams to about 300 milligrams of naltrexone. In some embodiments, a solution of nicotine and naltrexone is formed when the liquid enters the chamber and contacts the nicotine and naltrexone. In specific embodiments, the solution has an acidic pH. [0027]
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 is a diagrammatic representation of a frontal view of a nicotine delivery device of the invention that approximates the shape and size of a conventional drinking straw. [0028]
  • FIG. 2 is a diagrammatic representation of a frontal view of a nicotine delivery device of the invention that approximates the shape and size of a conventional cigarette. [0029]
  • FIG. 3 is a graphic representation illustrating plasma levels of nicotine observed in subjects following administration of a single dose of nicotine using a straw-like nicotine delivery device according to certain embodiments of the invention containing 4 mg, 8 mg, or 12 mg of nicotine, as compared to nicotine plasma levels observed for nicotine gum (2 mg or 4 mg), nasal spray, inhaler, and patch (60 min.) formulations. [0030]
  • FIG. 4 is a graphic representation illustrating plasma levels of nicotine observed over time in subjects following administration of a single dose of 8 mg nicotine or repeated doses of 8 mg nicotine every 1.5 hours using a straw-like nicotine delivery device according to certain embodiments of the invention.[0031]
  • DETAILED DESCRIPTION
  • The patents, published patent applications, and literature references cited herein are hereby incorporated by reference to the same extent as if each were specifically and individually indicated to be incorporated by reference. Any inconsistency between these publications and the present disclosure shall be resolved in favor of the present disclosure. [0032]
  • The present invention provides smoking cessation methods and smoking cessation aids that deliver a nicotine solution through a tubular device to a user. Combination therapies are also provided that deliver a second drug along with nicotine to treat a second dependency. For example, a second drug is provided to treat alcoholism as well as promoting smoking cessation. The second drug is not nicotine. The advantage of delivering nicotine, alone or in combination with another drug, through a tubular device is that the oral and tactile sensations experienced by the user approximate the ingrained hand-to-mouth behaviors associated with smoking and other dependencies, such as drinking. Thus, the device of the present invention offers oral and manual focus, which helps to alleviate cravings by providing an object to manipulate and chew. [0033]
  • As shown in FIG. 1, the device of the invention may approximate a conventional drinking straw in size and shape. Alternatively, as shown in FIG. 2, the device may approximate a conventional cigarette in size and shape. Referring to the figures, the device comprises an elongated tubular chamber [0034] 10, with a first end 12 adapted for drawing in air or liquid from an external source and a second end 14 adapted for the application of oral suction, and that the dimensions of the device are similar to the dimensions of a conventional drinking straw or a conventional cigarette. In some embodiments, as shown in FIG. 1, the device approximates a conventional drinking straw in shape and size. In certain embodiments, the chamber 10 is from about 13 to about 20 centimeters long, with a diameter of from about 4 to about 8 millimeters. In some instances, the chamber 10 is from about 15 to about 17 centimeters long, with a diameter of from about 6 to about 7 millimeters. Alternatively, as shown in FIG. 2, the device approximates a conventional cigarette in shape and size. In at least some such embodiments, the chamber 10 is from about 7 to about 11 centimeters long, with a diameter of from about 7 to about 10 millimeters. For example, the chamber 10 is from about 8 to about 10 centimeters long, with a diameter of about 8 millimeters. Examples of the tubular delivery devices of the present invention include, without limitation, devices such as those disclosed in U.S. Pat. No. 5,718,681 (Manning) and U.S. Pat. Nos. 5,780,058, 5,985,324, 5,989,590, 6,024,721, and 6,106,845 (Wong et al.).
  • Materials for making the tubular chamber [0035] 10 of the present invention may include, without limitation, paper, plastic such as propylene/styrene copolymers, polypropylene, high density polyethylene, low density polyethylene, ethylene vinyl acetate copolymer, and the like.
  • The tubular chamber [0036] 10 of the device of the present invention contains nicotine 16 that will be delivered to the user. The nicotine 16 may be in any useful form, such as levo nicotine, dextro nicotine, or a racemic mixture thereof. Pharmaceutically acceptable salt forms of nicotine are also suitable for use in the present invention. Nonlimiting examples of such suitable salt forms of nicotine include the dihydrochloride, sulfate, bitartrate, salicylate, hydrogen tartrate, and hemisulfate salts. Nicotine and its salt forms are commercially available, for example, from Sigma-Aldrich, St. Louis, Mo. The term “nicotine” as used herein also includes analogs of nicotine having a similar pharmacological effect to nicotine itself.
  • In some embodiments, the nicotine [0037] 16 is a granulate. The term “granulate” means that the nicotine is in the form of a particulate such as grains or beads. In certain embodiments, the size of the grains or beads is small enough not to be felt as separate particles in the mouth, for example, less than about 200 micrometers in diameter.
  • In some embodiments, the nicotine granulate comprises particles of powdered nicotine which have been coated according to standard techniques known in the art (see, e.g., Deasy, [0038] Crit Rev. Ther. Drug Carrier Systems, 8:39-89 (1991)). The term “powdered” means composed of fine particles. Glatt Air Technique (Ramsay, N.J.) and Particle and Coating Technologies, Inc. (St. Louis, Mo.) provide particle coating services. Suitable coatings include, without limitation, hydroxy propyl cellulose, sugar, starch, polymer, resin, gum, wax, and fat. In certain embodiments, the diameter of the nicotine particles before coating is less than about 200 micrometers, for example, from about 20 to about 100 micrometers, or from about 40 to about 60 micrometers.
  • In some embodiments, the nicotine granulate comprises particles of powdered nicotine that are incorporated into microspheres, which may be coated as described above. Suitable materials for the microspheres include, without limitation, sugar, starch, acacia, sodium alginate, carbomer, cellulose, dextrotes, ethyl cellulose, methyl cellulose, povidone, and mixtures thereof. For example, the microspheres may comprise a degradable composition. The microspheres have a diameter of between about 300 micrometers and about 1000 micrometers, for example, between about 500 micrometers and about 600 micrometers. U.S. Pat. No. 5,939,100 (Albrechtson et al.) discloses further examples of nicotine microspheres. [0039]
  • In certain embodiments, the coating on the nicotine particles or microspheres is designed to mask the taste of the nicotine, and thus enhance palatability. In some instances, the coating is formulated such that most, but not all, of the nicotine taste is masked. The advantage of such a formulation is that enough of the nicotine taste is masked that the nicotine particles are palatable, but enough nicotine taste remains that the user is aware that nicotine is being ingested. Thus, in some embodiments, the formulation may comprise both coated and uncoated particles. The coating on the particles or microspheres also may be designed to achieve other functions, including, but not limited to, preventing clumping and preventing water absorption. [0040]
  • In certain embodiments, a single dose of nicotine [0041] 16 from the device of the present invention contains a therapeutically effective amount of nicotine. The term “single dose” means the quantity of nicotine 16 provided in the chamber 10 and delivered to the user upon application of oral suction to the second end 14 of the chamber 10. The term “therapeutically effective amount” means an amount sufficient to reduce a smoker's need for nicotine from burnt tobacco. This amount can be determined by the user's physician. An advantage of the smoking cessation devices of the invention is their ability to deliver a large dose of nicotine when necessary, or a smaller dose of nicotine when appropriate. In certain embodiments, from about 1 milligram to about 40 milligrams of nicotine are provided by the device. Useful amounts include from about 1 milligram to about 5 milligrams, from about 4 milligrams to about 12 milligrams, from about 4 milligrams to about 20 milligrams, from about 5 milligrams to about 15 milligrams, from about 5 milligrams to about 20 milligrams, and from about 20 milligrams to about 40 milligrams of nicotine provided by the device in a single dose. A smoker attempting to stop smoking may use the device of the present invention from about 1 to about 12 times per day, for example, from about 5 to about 12 times per day, such that a total daily dose of from about 1 milligram to about 480 milligrams, for example, from about 5 milligrams to about 480 milligrams, of nicotine is delivered, depending on perceived need. Useful total daily doses include from about 1 milligram to about 60 milligrams, from about 4 milligrams to about 144 milligrams, from about 4 milligrams to about 240 milligrams, from about 5 milligrams to about 180 milligrams, from about 5 milligrams to about 240 milligrams, and from about 240 milligrams to about 480 milligrams of nicotine. The term “total daily dose” means the quantity of nicotine delivered to the user during a 24-hour period.
  • In certain embodiments, such a dosing regimen provides a blood level of nicotine of at least about 5 nanograms of nicotine per milliliter of blood, with a maximum peak of about 60 nanograms of nicotine per milliliter of blood. For example, the blood level of nicotine in the user of the device is from about 10 nanograms to about 50 nanograms of nicotine per milliliter of blood. In particular embodiments, the user's blood level of nicotine is about 20 nanograms of nicotine per milliliter of blood. [0042]
  • In some embodiments, blood levels of nicotine are measured by gas chromatography with nitrogen phosphorous detection as described, for example, by Jacob et al., [0043] J. Chromatography, 222: 61-70 (1981). The dosing frequency may be adjusted so as to achieve a steady state concentration of nicotine in the blood. In at least some embodiments, the steady state blood levels of nicotine fall within the blood level ranges described above. The quantities of nicotine described above are sufficient to deliver a therapeutically effective amount of nicotine into the user's metabolism, even after first-pass absorption by the liver. It will be understood by those skilled in the art that the doses and blood levels of nicotine will vary according to the preferences, metabolism, and former smoking habits of the individual user of the smoking cessation aid of the present invention.
  • In one device encompassed by the present invention, the nicotine granulate is delivered to the user as a nicotine solution. The term “solution,” as used herein, refers to a liquid into which the nicotine is dissolved, or a suspension or emulsion of nicotine in a liquid. Delivery of nicotine as a solution provides several advantages. Swallowing the solution provides the oral stimulation that smokers crave. However, the solution does not irritate the oral cavity as does nicotine gum. Additionally, nicotine in solution form is absorbed in the body more slowly than nicotine from a nasal spray. Such slow absorption allows for less frequent dosing and provides less potential for abuse. Finally, delivery of liquid along with the nicotine prevents high local concentrations of nicotine, which may result in cramping, for example, when a nicotine capsule is swallowed. [0044]
  • In some devices, the first end [0045] 12 of the chamber 10 is placed in contact with an external source of liquid and the user applies oral suction to the second end 14 of the chamber 10. According to one method of the invention, a liquid is drawn into the first end 12 of the chamber 10 from the external source. The liquid then forms a suspension of the nicotine 16 granulate as it is drawn through the chamber 10, and the suspension is delivered through the second end 14 of the chamber 10 into the user's mouth. Some or all of the nicotine 16 granulate also may dissolve in the liquid, such that the nicotine 16 is delivered as a solution. WO 99/55371 (Westman et al.) discloses non-limiting nicotine solutions whose properties may be desirable for use with the present invention.
  • In at least some embodiments, the external source of liquid to be drawn into the tubular chamber [0046] 10 of a device of the invention is a beverage. Sometimes, the beverage contains a flavoring, which helps to make the nicotine solution palatable. This is less crucial where the nicotine taste has already been masked by coating the particles of the nicotine granulate. The term “palatable” means that the taste of the solution is tolerable to the user. The beverage may comprise, but is not limited to, coffee, soda, sugar, fruit juice, carbonation, or ethyl alcohol, such as wine, beer, or hard liquor. In some instances, the beverage does not contain solids such as pulp. In certain embodiments, to be palatable, the nicotine solution has an acidic pH. The term “acidic pH” means a pH of less than about 6.9. For example, the nicotine solution has a pH of less than about 5.5, or a pH from about 2.0 to about 4.0. Flavorings such as coffee, alcohol, and fruit juice may be used to regulate the pH of the nicotine solution. For example, lime juice, cranberry juice, grapefruit juice, orange juice, tonic water, soda, and wine have pH's from about 2.0 to about 4.0, and beer, seltzer water, coffee, and have pH's less than about 6.9.
  • An advantage of the devices of the present invention is their compatibility with beverages that are acidic, as the majority of popular beverages are. Existing smoking cessation devices, such as nicotine gum and nicotine inhalers, may not be used in combination with acidic beverages because an alkaline environment is required for buccal absorption of the nicotine delivered by such devices. Acidic beverages must be avoided for a period of about one hour surrounding each use of a smoking cessation device relying on buccal absorption of nicotine. Thus, smokers attempting to use such devices to give up smoking must also avoid consuming a majority of beverages much of the time. In contrast, patients using nicotine delivery devices of the invention, through which nicotine is orally ingested, may consume acidic beverages whenever they choose. [0047]
  • The tubular chamber [0048] 10 of the device of the present invention may comprise two or more lumens. The multiple lumens provide a plurality of smaller cross-sectional flow paths, which help to optimize the flow velocity and flow volume of the liquid from the external source, thus assuring rapid, uniform, and complete delivery of the nicotine 16 contained within the chamber 10. The nicotine 16 may be contained in one of the lumens, or in multiple lumens. The multiple lumens may be of identical size or of different sizes.
  • Alternatively, the chamber [0049] 10 of the device of the present invention contains a preformulated solution of nicotine 16 such as, for example, a nicotine suspension. About 1 milliliter to about 40 milliliters of nicotine solution may be provided in the chamber. For example, from about 1 milliliter to about 10 milliliters, or from about 1 milliliter to about 5 milliliters, of solution are provided. Single doses of nicotine, total daily doses of nicotine, and nicotine blood levels are as described above for the nicotine granulate.
  • In another method of the invention, the user applies oral suction to the second end [0050] 14 of the chamber 10 of the device, such that a gas such as air is drawn through the first end 12 of the chamber 10 into the device. As the air is drawn into the chamber 10, the nicotine 16 solution contained in the chamber 10 is delivered through the second end 14 of the chamber 10 into the user's mouth.
  • Alternatively, the user places the first end [0051] 12 of the chamber 10 in contact with an external source of a liquid and applies oral suction to the second end 14 of the chamber 10, such that the liquid is drawn into the first end 12 of the chamber 10 from the external source. As the liquid is drawn through the chamber 10, it is mixed with the solution of nicotine 16 contained in the chamber 10, and the mixture is delivered through the second end 14 of the chamber 10 into the user's mouth. The external source of liquid often is a beverage, as described above for the device in which the chamber 10 contains a nicotine 16 granulate. In certain embodiments, the beverage comprises flavorings and pH ranges as described above.
  • The nicotine [0052] 16 solution contained within the chamber 10 may itself contain the flavorings described above. In some embodiments, the solution is pre-formulated to fall within the aforementioned pH levels through use of an acid such as, for example, carbonic acid, citric acid, acetic acid, tartaric acid, maleic acid, ascorbic acid, adipic acid, or combinations thereof. Such pre-formulation to optimize flavoring and pH is especially desirable if the user will be drawing air, rather than liquid, through the first end of the chamber, such that the nicotine 16 solution contained in the chamber 10 is delivered without any liquid from an external source that might enhance palatability.
  • The chamber [0053] 10 of the device of the present invention further contains a retainer 18 for preventing release of nicotine 16 from the first end 12 of the chamber 10. The term “retainer” refers to a disc, float, plug, or other restriction that blocks the diameter of the chamber 10 such that the nicotine 16 contained within the chamber 10 cannot be released from the first end 12 of the chamber 10. The retainer 18 allows gas or liquid from an external source to enter the first end 12 of the chamber 10, but prevents release of nicotine 16 from the first end 12 of the chamber 10. The retainer 18 also discourages release from the first end 12 of the chamber 10 of liquid drawn into the chamber 10 from an external source or contained within the chamber 10 as part of a pre-formulated solution of nicotine 16.
  • The retainer [0054] 18 may be fixed proximal to the first end 12 of the chamber 10. “Proximal to” the first end 12 of the chamber 10 means toward or at the first end 12 of the chamber 10. Alternatively, the retainer 18 may be transportable toward the second end 14 of the chamber 10. For example, the retainer 18 is transported toward the second end 14 of the chamber 10 as the user applies oral suction to the second end 14 of the chamber 10. Gas or liquid from an external source is drawn through the first end 12 of the chamber 10 into the device, and the nicotine 16 solution in the chamber 10 is delivered into the user's mouth. As it is drawn toward the second end 14 of the chamber 10 behind the nicotine 16 solution, the transportable retainer 18 assures that all of the nicotine 16 in the chamber 10 is cleanly delivered through the second end 14 of the chamber 10 into the user's mouth. The second end 14 of the chamber 10 is constructed such that the retainer 18 itself is blocked from entering the user's mouth. For example, the diameter at the second end 14 of the chamber 10 may be smaller than the diameter elsewhere in the chamber 10 and smaller than the diameter of the retainer 18, such that the retainer 18 may pass from the first end 12 of the chamber 10 to the second end 14 of the chamber 10, but cannot pass through the second end 14 of the chamber 10 into the user's mouth. The diameter at the second end 14 of the chamber 10 may be made smaller than the diameter elsewhere in the chamber 10 by a crimping of the chamber 10, a series of dimples in the circumference of the chamber 10, or a continuous indentation in the circumference of the chamber 10 at the second end 14 of the chamber 10. A transportable retainer 18 is particularly useful when the device is prefilled with liquid, i.e., contains a pre-formulated solution of nicotine 16.
  • The retainer [0055] 18 may comprise a restriction and a plug. The term “restriction” means that the diameter near the first end 12 of the chamber 10 is smaller than the diameter elsewhere in the chamber 10 and smaller than the diameter of the plug, such that the plug is contained within the chamber 10 and prevents release of nicotine 16 through the first end 12 of the chamber 10. The restriction may result from, for example, a crimping of the chamber 10, a series of dimples in the circumference of the chamber 10, or a continuous indentation in the circumference of the chamber 10 near the first end 12 of the chamber 10.
  • The retainer [0056] 18 may alternatively comprise a particle barrier with apertures or slits that allow liquid to pass through the barrier when oral suction is applied to the second end 14 of the chamber 10. A cap may be placed over the first end 12 of the chamber 10 prior to use to avoid any possible loss of nicotine 16 or entry of contaminants through the particle barrier apertures or slits. The apertures must be small enough that nicotine 16 cannot pass through them and be released from the first end 12 of the chamber 10. The slits are easier to manufacture and seal the chamber 10 more completely prior to use than the apertures do. Alternatively, the barrier is made from a material such as fine mesh or porous paper that will retain the nicotine 16 in the chamber 10 but requires no barrier apertures or slits to allow liquid to be drawn into the chamber 10. Sometimes, for ease in construction, the barrier is cone-shaped and located all the way at the first end 12 of the chamber 10.
  • Alternatively, the retainer [0057] 18 comprises a one-way plug or valve. The plug or valve seals the first end 12 of the chamber 10 at atmospheric pressure. However, when suction is applied to the second end 14 of the chamber 10, the plug is deformed and permits liquid from an external source to flow around the plug and into the chamber 10 through the first end 12 of the chamber 10. In certain embodiments, the plug has a density of less than one, such that it is drawn toward the second end 14 of the chamber 10 when suction is applied to the second end 14 of the chamber 10 and the nicotine 16 contained within the chamber 10 is delivered into the mouth of the user. When suction is removed from the second end 14 of the chamber 10, the plug relaxes, seals the chamber 10, and remains stationary. Transportation of the plug all the way to the second end 14 of the chamber 10 indicates that the entire dose of nicotine 16 contained within the chamber 10 has been delivered.
  • The retainer [0058] 18 alternatively comprises a cylindrical body with at least one protrusion on its exterior surface. Liquid from an external source is drawn through or around the retainer 18 and into the chamber 10, but the protrusions prevent nicotine 16 solution from leaking through or around the sides of the retainer 18 and out of the first end 12 of the chamber 10. The protrusions are fins, ridges, or rings which act as a seal for the chamber 10 and also create friction or drag between the retainer 18 and the chamber 10, which allows time for the liquid from the external source to mix with the nicotine 16 after passing through or around the retainer 18.
  • The retainer [0059] 18 of the present invention may be made from, for example, thermoplastic materials or low or high density foam materials such as, without limitation, ethylene vinyl acetate copolymers, polyolefins such as polyethylene, polypropylene, and the like, or closed cell foam. Alternatively, the retainer 18 may comprise, for example, a compressible plug of bonded fibers. The fibers may be polymeric fibers, such as polyolefin fibers with or without a polyester core, polyester, cellulose acetate, nylon, felt, or cotton. In certain embodiments, the uncompressed fiber plug has a diameter slightly larger than the diameter of the chamber 10. Thus, after insertion in the chamber 10, the plug seals and prevents the release of nicotine 16 from the chamber 10, but still allows liquid to be drawn into the chamber 10 when oral suction is applied to the second end 14 of the chamber 10.
  • In some embodiments, the chamber [0060] 10 of the device of the present invention also contains a removable end cap 20 or seal located at the second end 14 of the chamber 10. The removable end cap 20 or seal prevents the nicotine 16 granulate or pre-formulated nicotine 16 solution contained within the chamber 10 from being released through the second end 14 of the chamber 10 during shipping and storage of the device. Before using the device, the user removes the end cap 20 or seal from the second end 14 of the chamber 10 so that the nicotine 16 granulate or pre-formulated nicotine 16 solution contained within the chamber 10 may be delivered through the second end 14 of the chamber 10 into the user's mouth. Materials for making the end cap 20 or seal of the present invention may include, without limitation, paper, foil, plastic such as propylene/styrene copolymers, polypropylene, high density polyethylene, low density polyethylene, ethylene vinyl acetate copolymer, and the like.
  • In some instances, the device, itself, may comprise a flavoring, such that it tastes pleasant for chewing as, before, or after the nicotine dose has been delivered. The flavoring may be, for example, sugar, cinnamon, spearmint, peppermint, wintergreen, bubble gum, fruit, chocolate, anise, nut, coffee, tobacco, or combinations thereof. Sometimes, the flavoring is selected from the group consisting of spearmint, peppermint, wintergreen, and cinnamon. [0061]
  • The device as described in detail above provides the novel synergistic combination of oral and tactile stimulation along with a controlled dose of nicotine in non-irritating solution form. Smokers attempting to stop smoking may use the device as an aid that can satisfy nicotine needs and at the same time prevent cigarette cravings by providing a substitute for the hand-to-mouth behavioral component of smoking. The synergistic combination of the present invention provides an important new method for reducing the incidence of tobacco smoking in smokers who appreciate the health risks of smoking and wish to stop. [0062]
  • In some alternative embodiments, the device as described herein contains another drug along with nicotine in the tubular chamber [0063] 10. As a non-limiting example, the additional drug is naltrexone. The nicotine/naltrexone combination device is useful for treating alcoholics who are also smokers. The combination treatment promotes decreased alcohol consumption as well as smoking cessation. The nicotine promotes smoking cessation and also improves compliance with naltrexone. The nicotine/naltrexone tubular delivery device may improve the efficacy of naltrexone even beyond the expected improvement due to increased compliance. Alcohol dependence, like tobacco dependence, involves situational craving and ritualized manual and oral behaviors that accompany drug delivery (Weinstein et al., Alcohol Clin. Exp. Res., 22:1376-1381 (1998); Tiffany et al., Addiction 95:S145-153 (2000)). A tubular oral nicotine/naltrexone delivery device as described herein provides an effective substitute for the hand and mouth behaviors associated with drinking as well as smoking. In addition, the increased frequency of dosing with this delivery device, as compared to once-daily or depot formulations of naltrexone, encourages alcoholics to become more actively involved in their treatment, and thus be more likely to focus on and achieve recovery.
  • Naltrexone is safe in a broad range of doses. Typically, naltrexone is administered to alcoholics at a dose of 50 mg/day in a single daily dose (Krystal, et al., [0064] N. Engl. J. Med. 345:1734-1739 (2001); Anton et al., J. Clin. Psychopharmacol. 21:72-77 (2001); Heinala et al., J. Clin. Psychopharmacol. 21:287-292 (2001)). However, opioid dependent patients usually receive 100 mg/day three times per week (Carroll et al., Arch. Gen. Psychiatry 58:755-761 (2001); Preston et al., Drug Alcohol Depend. 54:127-135 (1999)), and doses as high as 250 mg/day have been tested in the treatment of gambling (Kim et al. Biol. Psychiatry 49:914-921 (2001)). In at least some instances, a total daily dose of between about 4 mg and about 300 mg naltrexone is administered. Naltrexone is well-suited for combination with nicotine in a multidose dosage form. Naltrexone has a plasma half-life of 4 hours (Meyer et al., J. Clin. Psychiatry, 45:15-19 (1984)), so dosing at between about 5 to about 10 times per day is expected to maintain active plasma levels. As explained above with respect to nicotine dosing, those of skill in the art will understand that the particular dosing schedule for an individual patient can be determined by a physician. In evaluating dosages of naltrexone, the physician can monitor patients for accumulation of the major metabolite of naltrexone, 6β-naltrexol, which is also pharmacologically active and has a half life of 12 hours (Meyer et al., J. Clin. Psychiatry, 45:15-19 (1984)).
  • In some embodiments, a delivery device as described herein contains nicotine in amounts as described above, and from about 4 milligrams to about 25 milligrams of naltrexone. Useful amounts include from about 6 milligrams to about 20 milligrams, from about 8 milligrams to about 15 milligrams, from about 8 milligrams to about 12 milligrams, and from about 6 milligrams to about 10 milligrams of naltrexone provided by the device in a single dose. In certain embodiments, a patient attempting to stop smoking and/or drinking alcohol is instructed to use the device from about 1 to about 12 times per day, for example, from about 5 to about 10 times per day, such that a total daily dose of from about 4 milligrams to about 300 milligrams, for example, from about 20 milligrams to about 200 milligrams, of naltrexone is delivered. Useful total daily doses include from about 40 milligrams to about 100 milligrams, from about 60 milligrams to about 100 milligrams, and from about 60 milligrams to about 200 milligrams of naltrexone. Such a dosing regimen provides naltrexone blood levels of at least about 2 nanograms of naltrexone per milliliter of blood, with a maximum peak of about 60 nanograms of naltrexone per milliliter of blood. For example, a blood level of between about 5 ng and about 40 ng of naltrexone per milliliter of blood is achieved. In certain embodiments, a peak blood level of about 30 nanograms of naltrexone per milliliter of blood is achieved. In at least some embodiments, the dosage regimen is adjusted to achieve steady state blood levels of naltrexone. Naltrexone levels are measurable using high pressure liquid chromatography. [0065]
  • The following nonlimiting examples further illustrate certain embodiments of the present invention: [0066]
  • EXAMPLE 1: SAFETY AND PHARMACOKINETICS STUDY
  • 1. Device [0067]
  • Nicotine is administered orally using a straw-like smoking cessation device of the invention as shown in FIG. 1. The chamber [0068] 10 is a plastic drinking straw. The retainer 18 is a filter at the first end 12 of the straw. The user places the first end 12 of the device in a glass of apple juice and applies oral suction to the second end 14 of the device, such that the juice and nicotine 16 are delivered into the user's mouth.
  • The nicotine [0069] 16 in the device is in the form of coated sugar spheres of nicotine bitartrate having a diameter of approximately 500 micrometers. The nicotine spheres are prepared by spraying nicotine bitartrate dihydrate with a binder onto sugar spheres and applying a film coating. Using a Wurster processing unit, particles are suspended in air using a controlled airflow system and a coating suspension is added at a controlled rate via a pneumatically atomized nozzle. As atomized droplets of the coating solution contact the particles, they spread and coalesce on the particle surface. Excess moisture from the applied liquid evaporates in the apparatus, leaving a coated dry substance. Mixing of the coating suspension occurs throughout the manufacturing process to ensure uniformity of the suspension.
  • 2. Administration [0070]
  • On day one, following overnight abstinence from smoking, healthy adult smokers who wish to give up smoking receive a single dose of nicotine or placebo. Smokers are assigned to each dosage group in a double blind, randomized manner, as is well known in the art. The following data are collected before dosing, every thirty minutes for the first two hours after dosing, and every hour for the following six hours: plasma levels of nicotine and cotinine, vital signs, adverse events, and patient's assessment of cigarette cravings. Baseline and endpoint clinical chemistry, hematology, urinalysis, and ECG are also monitored. [0071]
  • On day eight, again following overnight abstinence from smoking, the same subjects receive the same dose of nicotine or placebo. The dose is repeated periodically throughout the day. The following data are collected as described above before the first dosing and one hour after each dose is administered: plasma levels of nicotine and cotinine, vital signs, adverse events, and patient's assessment of cigarette cravings. Baseline and endpoint clinical chemistry, hematology, urinalysis, and ECG are also monitored. The data are used to evaluate the safety and pharmacokinetics of nicotine delivery by the smoking cessation device. [0072]
  • EXAMPLE 2: EFFICACY STUDY
  • In a double blind study, three hundred healthy adult smokers who wish to give up smoking use the smoking cessation device as described in Example 1 to deliver nicotine or placebo over a ten week period. Each device contains 5-10 mg of nicotine or placebo. Subjects are instructed to use the device as needed for smoking urges, but not to exceed 12 doses per day. Patients are concurrently enrolled in a counseling program to provide behavioral support for smoking cessation. Smoking abstinence data are collected during the last eight weeks of treatment, serving as the primary endpoint. Abstinence is defined as four weeks of continuous abstinence from smoking during the study period. Subjects have weekly clinic visits for monitoring plasma levels of nicotine and cotinine, vital signs, adverse events, and patient's assessment of cigarette cravings. Baseline and endpoint clinical chemistry, hematology, urinalysis, and ECG are also monitored. [0073]
  • EXAMPLE 3: PHARMACOKINETICS AND SAFETY STUDY
  • A placebo-controlled double blind trial was performed with three doses of nicotine (4 mg, 8 mg, and 12 mg) or placebo delivered using a straw-like delivery device as described in Example 1. There were 6 subjects per treatment group. In Part A of the study, subjects received a single dose, and in Part B, the same subjects received 8 doses of nicotine, one dose every 1.5 hours. Apple juice was used as the beverage for delivering nicotine from the straw-like device. [0074]
  • As shown in FIG. 3, delivery of nicotine using the straw-like device generated plasma levels of nicotine comparable to or greater than plasma levels observed for marketed nicotine replacement products (Schneider et al., [0075] Clin. Pharmacokinet. 40:661-684 (2001)). As shown in FIG. 4, peak plasma levels were achieved between 1 and 2 hours post dosing, with nicotine levels in most subjects already increased 15 minutes after dosing. The kinetics were very similar to those of nicotine gum. Repeated dosing with nicotine every 1.5 hours led to continuous increases in plasma nicotine over the 10.5 hour sampling period. In both the single dose and repeated dose parts of the study, the lowest plasma levels of nicotine were observed in the 4 mg dose group, with higher plasma levels observed in the 8 mg and 12 mg dose groups.
  • The 4 mg and 8 mg doses of nicotine in the straw-like delivery device were well tolerated. The adverse events observed, lightheadedness, nausea, and vomiting, were those expected for a nicotine product. Nausea and vomiting were seen only with the 12 mg dose. Occasional increases in vital sign measurements were seen, but these were neither dose nor time dependent, and were not sustained. There were no clinically significant changes in clinical chemistry, hematology, urinalysis or ECG values. [0076]
  • Over the course of the repeat dosing session, craving for cigarettes decreased in all subjects receiving nicotine. There was no net effect on craving in the placebo group. [0077]
  • EXAMPLE 4: NICOTINE/NALTREXONE DEVICE
  • A straw-like nicotine/naltrexone delivery device is prepared as described for the nicotine delivery device in Example 1. Naltrexone coated sugar spheres are prepared using the techniques described for preparing the nicotine coated sugar spheres in Example 1, but using naltrexone hydrochloride instead of nicotine bitartrate. The naltrexone coated sugar spheres are prepared to have a strength of approximately 10 mg naltrexone HCl per 150-200 mg loose coated sugar spheres. The naltrexone coated sugar spheres are combined with nicotine coated sugar spheres to prepare a nicotine/naltrexone delivery device similar to the device described in Example 1, but containing naltrexone as well as nicotine. Each device contains 8 mg nicotine and 10 mg naltrexone. [0078]
  • Patients diagnosed as alcoholics and smokers are instructed to use the device throughout the day as needed to administer a dose of nicotine and naltrexone in response to cravings for either tobacco or alcohol. Patients are instructed not to exceed one dose every 1.5 hours or 10 doses per day. Patients are monitored for progress toward cessation of smoking and/or drinking alcohol, i.e. for changes in smoking and/or alcohol consumption levels. [0079]
  • EQUIVALENTS
  • While the foregoing invention has been described in some detail for purposes of clarity and understanding, it will be appreciated by one skilled in the art from a reading of this disclosure that various changes in form and detail can be made without departing from the scope of the invention and the attached claims. [0080]

Claims (20)

    What is claimed is:
  1. 1. An oral medication delivery device comprising:
    (a) a tubular chamber having a first end suitable for taking in a liquid from an external source and a second end suitable for oral application of suction;
    (b) nicotine and a second drug contained within the tubular chamber; and
    (c) a retainer in the tubular chamber for preventing release of the nicotine, second drug, or liquid from the first end of the chamber,
    wherein the liquid enters the chamber from the external source through the first end of the chamber, and then the liquid, the nicotine, and the second drug are delivered through the second end of the chamber, when oral suction is applied to the second end of the chamber.
  2. 2. The device of claim 1, wherein the tubular chamber approximates the size and shape of a conventional cigarette.
  3. 3. The device of claim 1, wherein the tubular chamber approximates the size and shape of a conventional drinking straw.
  4. 4. The device of claim 1, wherein the retainer is fixed proximal to the first end of the chamber.
  5. 5. The device of claim 1, wherein the retainer is transportable toward the second end of the chamber with the nicotine, second drug, and liquid when suction is applied to the second end of the chamber.
  6. 6. The device of claim 1, wherein the second drug is naltrexone.
  7. 7. The device of claim 6, wherein the tubular chamber contains from about 4 milligrams to about 25 milligrams of naltrexone.
  8. 8. The device of claim 1, wherein the tubular chamber contains from about 4 milligrams to about 12 milligrams of nicotine.
  9. 9. The device of claim 1, wherein the nicotine is selected from the group consisting of levo nicotine, dextro nicotine, racemic mixtures thereof, and pharmaceutically acceptable salts thereof.
  10. 10. The device of claim 1, wherein the nicotine and the second drug are in the form of coated particles of powdered drug.
  11. 11. The device of claim 10, wherein the drug particles are coated to enhance palatability.
  12. 12. The device of claim 1, wherein the nicotine and the second drug are incorporated in spheres comprising at least one material selected from the group consisting of sugar, starch, acacia, sodium alginate, carbomer, cellulose, dextrotes, ethyl cellulose, methyl cellulose, and povidone.
  13. 13. The device of claim 1, wherein a solution of nicotine and the second drug is formed when the liquid enters the chamber and contacts the nicotine and the second drug.
  14. 14. The device of claim 13, wherein the solution is a suspension.
  15. 15. A method for reducing the incidence of tobacco smoking and alcohol consumption by a person, the method comprising orally administering nicotine and naltrexone to the person using an oral delivery device, the device comprising:
    (a) a tubular chamber having a first end suitable for taking in a liquid from an external source and a second end suitable for oral application of suction;
    (b) nicotine and naltrexone contained within the tubular chamber; and
    (c) a retainer in the tubular chamber for preventing release of the nicotine, naltrexone, or liquid from the first end of the chamber,
    wherein oral administration comprises application of oral suction by the person to the second end of the chamber, wherein the liquid enters the chamber from the external source through the first end of the chamber, and then the liquid and the nicotine and naltrexone are delivered through the second end of the chamber into the mouth of the person.
  16. 16. The method of claim 15, wherein a single dose of nicotine and naltrexone administered to the person includes from about 4 milligrams to about 12 milligrams of nicotine and from about 4 milligrams to about 25 milligrams of naltrexone.
  17. 17. The method of claim 15, wherein the total daily dose of nicotine administered to the person is from about 4 milligrams to about 144 milligrams of nicotine.
  18. 18. The method of claim 15, wherein the total daily dose of naltrexone administered to the person is from about 4 milligrams to about 300 milligrams of naltrexone.
  19. 19. The method of claim 15, wherein a solution of nicotine and naltrexone is formed when the liquid enters the chamber and contacts the nicotine and naltrexone.
  20. 20. The method of claim 19, wherein the solution has an acidic pH.
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