Title:  Nicotine mucosal spray

United States Patent:  6,596,740

Issued:  July 22, 2003

Inventors:  Jones; Richard L. (10928-81 Street, Edmonton Alberta, CA T5H 1L5)

Appl. No.:  983554

Filed:  October 24, 2001

Abstract

A composition for administration to the nasal mucosa of a subject comprises a solution of nicotine or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable solvent. The composition has a nicotine concentration less than 10 mg/ml. The composition used alone assists in reduction of the desire of a subject to smoke tobacco. It also reduces the nasal symptoms associated with administration of higher concentrations of nicotine to the nasal mucosa.

SUMMARY OF THE INVENTION

The present invention provides novel methods and compositions for nicotine therapy. In one embodiment, the invention provides a composition for nasal administration of nicotine to a subject effective in increasing the nicotine plasma concentration of the subject to a level effective to assist the subject in quitting smoking and that results in reduced nasal symptoms as compared with other nicotine nasal sprays. Preferably, the composition results in minimal, and more preferably no nasal symptoms.

In a preferred embodiment, the invention provides a nicotine spray composition for administration to the nasal mucosa of a subject comprising a solution of nicotine or a pharmaceutically acceptable s It thereof in a pharmaceutically acceptable solvent, the solution having a nicotine concentration less than 10 mg/ml, preferably 1 to less than 9 mg/ml, more preferably from a out mg/ml, more preferably form about 5 to about 9.9 mg/ml. In a preferred embodiment of the invention, the pharmaceutically acceptable solvent is phosphate buffered saline. In another embodiment the pH of the solution is between about 5.0 and 8.0, more preferably between about 6.0 to 7.5 and most preferably about 7.0. The term "about" as used herein refers to +/-10% of the pH value.

In another embodiment, the invention provides a method that enables a subject to stop smoking and decreases the desire of a subject to smoke, the method comprising administering to the subject one source of an effective amount of nicotine, the source being in the form of a nicotine nasal spray composition that can be administered to the nasal mucosa of the subject, the composition comprising droplets having a size of about 10 or more microns and a solution of nicotine or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable solvent, said solution having a nicotine concentration less than 9 mg/m. In a particular embodiment, the nicotine solution has a pH in the range of about 5.0 to 8.0, preferably between about 6.0 to 7.5 and most preferably about 7.0.

In another embodiment, the nicotine nasal spray composition of the invention can be used to reduce nasal symptoms associated with the administration of nicotine to the nasal mucosa, the method comprising administering the composition of the invention to the nasal mucosa of a subject. In a preferred embodiment the nicotine nasal spray is in the form of droplets having a size of about 10 or more microns and is a solution of nicotine or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable solvent, the solution having a nicotine concentration less than 10 mg/ml and, preferably, a nicotine concentration in the range of about 5 mg/ml to less than 10 mg/ml. The term "about" as used herein refers to +/-10% of the concentration value.

Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The term "effective amount" means an amount effective, at dosages and for periods of time necessary to achieve the desired result A person skilled in the art would appreciate that the effective amount can vary depending on the age, sex, and weight of the subject. In the present invention when referring to an effective amount of nicotine for assisting a subject to stop smoking, the effective amount may vary depending on the degree the subject smoked (i.e. number of cigarettes per day).

The term "subject" means a human subject.

The term "increasing plasma nicotine concentration" is defined as increasing the plasma nicotine concentration above the baseline plasma nicotine concentration. The increase in plasma nicotine concentration can be assessed by methods well known in the art including the method described by Fayerabend and Russell and used herein (21).

The term "nasal symptoms" means the undesirable physiological symptoms caused by administering nicotine to the nasal mucosa of a subject, primarily rhinorrhea, sneezing, throat irritation, watery eyes and other less frequent symptoms (2).

The term "reducing nasal symptoms" means reducing the severity of one or more nasal symptoms experienced by a subject using a nicotine spray with a nicotine concentration of 10 mg/ml or more.

The term "reducing the desire to smoke tobacco" means providing a subject with an effective way of obtaining nicotine without resorting to smoking tobacco. A commonly used method for assessing the craving for nicotine can be found in the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) (see (1991) J. Am. Med. Assoc. 266:3133) This source uses a 4-point scale to rate nicotine craving from none (rating 0) to severe (rating 4). An effective nicotine replacement should result in at lease a 1-point decrease in the nicotine craving score.

The term "pharmaceutically acceptable salt" means an acid salt or a basic salt which is suitable for or compatible with the treatment of a subject. Pharmaceutically acceptable salts of nicotine are known to those skilled in the art and include nicotine tartrate and nicotine hydrogen tartrate

The term "pharmaceutically acceptable solvent" means a solvent that is physiologically tolerable at the dosage administered. Nicotine is soluble in water but an aqueous solvent should have it's pH adjusted with buffers and it's osmolarity adjusted into the physiological range. Those skilled in the art will know how to accomplish these adjustments.

The term "one source" when referring to "one source of nicotine" as used herein means a single form of nicotine other than, or in addition to tobacco smoke and does not include multiple alternative sources for nicotine, for example, the use of a nicotine patch, a nicotine nasal spray, nicotine lozenges or other form. However in the context of the application, it should be understood that a subject may, at least on occasion, be smoking tobacco in addition to administering the one source of nicotine in accordance with the methods and uses of the present invention.

DETAILED DESCRIPTION

The present invention provides a convenient, inexpensive and effective way to increase the nicotine plasma levels in a subject by administration of an effective amount of nicotine by nasal spray to a subject. In a preferred embodiment the present invention assists subjects in quitting tobacco smoking. In another embodiment, the invention provides a convenient, inexpensive, and effective way to increase nicotine plasma levels in a subject as an alternative to tobacco smoking by administering a nicotine nasal spray composition to a subject.

Nicotine-containing compositions and nasal strays suitable for nasal administration, and delivery of the nicotine to the nasal mucosa of a subject are also provided. Preferably, the nicotine compositions are suitable to be formed into a nasal spray composition and administered by nasal spray. "Suitable for nasal administration and delivery" as used herein refers to any form of the nasal spray composition that can be delivered so. A person skilled in the art would be familiar with suitable preparation forms. Preferably, the nicotine nasal spray composition suitable for nasal administration is in a form and is delivered by a nebulizer or atomizer that generates droplet sizes of about 10 or greater microns, more preferably about 10-200 microns, most preferably about 10-100 microns.

The smoking alternative provided by the present invention may be used to assist those attempting to stop tobacco smoking or may be used indefinitely as circumstances dictate as a substitute for tobacco smoking which avoids both the undesired side effects of tobacco smoking on other people in the vicinity of the smoker and also the deleterious effects on the smoker of other substances such as carcinogens and carbon monoxide in tobacco smoke. When the nicotine-containing solution is applied to the nasal mucosa, nicotine can be absorbed directly into the bloodstream if a smoking substitute is to be provided by this means, sufficient nicotine must be applied and absorbed to give a rapid increase in blood nicotine comparable to that achieved by tobacco smoking if the craving to smoke is to be eliminated, either in the short term as a tobacco substitute or in the long term as a smoking cessation aid. Previously available smoking substitutes often fail in this regard due to a too small or too delayed increase in blood nicotine levels.

It is desirable that nasal administration of nicotine provides a sufficient dose of nicotine to a sufficiently large area of the nasal mucosa to give the desired rapid increase in blood nicotine level without providing a local nicotine concentration so high that it causes mucosal irritation and without requiring the delivery of such a large volume of nicotine-containing composition that a portion of the administered dose runs from the nose, causing annoyance and inconvenience to the user.

In accordance with the present invention, nicotine or a pharmaceutically acceptable nicotine salt is dissolved in a pharmaceutically acceptable solvent, such as phosphate-buffered saline, and is adjusted to pH in the range of about 5.0 to 8.0, preferably 6.0-7.5 and most preferably to a pH of about 7.0.

In accordance with a preferred embodiment of the invention, a composition having a nicotine concentration of less than 10 mg/ml, dissolved in phosphate buffered saline at a pH of about 7.0 is employed. The composition is delivered to the nose by a spray device which preferably delivers about 0.05 ml of the composition per activation of a suitable pump-type nasal spray atomizer in the form of a spray having droplets of about 10 microns or more in diameter.

The nicotine composition of the invention may also optionally contain one or more of a flavouring agent such as menthol, and preserving agent such as benzoic acid or an antioxidant such as ascorbic acid Suitable flavourings and preservatives acceptable in foods and pharmaceuticals will be known to those skilled in the art, as well as suitable concentrations of these agents.

The nicotine-containing composition of the present invention is applied to the nose as a spray of droplet size selected to favour deposition of the droplets in the nose and minimise inhalation of the nicotine composition into the airways beyond the nose where irritation of the upper respiratory tract can result in immediate and severe symptoms.

Studies by Yu et al (20) have shown that droplet size of a spray delivered into the nose or inhaled through the mouth influences the location of droplet deposition These authors showed that, during inhalation, droplets of 2 to 6 microns largely reach the terminal bronchi and alveoli, whereas a majority of droplets greater than 10 microns is required to localise delivery to the nasal mucosa.

The nicotine-containing composition of the invention may be applied to the nose by any suitable atomiser or spray device which produces a spray of droplet size greater than about 10 microns. For example, conventional venturi-type atomisers such as are used for nasal decongestants or metered dose spray devices may be employed. These devices produce 98% of droplets greater than 16 microns and a majority of droplets are approximately 100 to 200 microns.

When the nasal spray of the invention is used, nicotine is not drawn into the user's airways beyond the nose, thus avoiding respiratory irritation and allowing the use of higher nicotine concentrations, permitting bloods nicotine levels to be boosted into the range which reduces nicotine withdrawal symptoms without concomitant irritation.

Lower concentrations of nicotine cause less rhinorrhea thus permitting the dose, although it is smaller than that from 10 mg/ml, longer access to the nasal mucosa with more efficient nicotine uptake into the blood. Using an NNS with nicotine concentrations less than 10 mg/ml, preferably 1 to less than 10 mg/ml, more preferably from about 5 to about 9 mg/ml, results in plasma nicotine levels similar to those observed from use of 10 mg/ml NNS (see Example 1) Use of an NNS with nicotine concentrations less than 10 mg/ml, preferably 1 to less than 10 mg/ml, more preferably from about 5 to about 9 mg/ml can, therefore, be an effective way of treating a disorder such as addiction to nicotine from cigarette smoking or of decreasing a subject's desire to smoke cigarettes. It will be appreciated that a NNS having a nicotine concentration of 1 mg/ml could be effective, but is not preferred where a subject is trying to stop smoking or decrease a desire to smoke, as the spray volume required to generate a suitable plasma nicotine level would not be convenient, and would be impractical and socially undesirable. Thus a suitable concentration of nicotine solution should be selected that is both convenient and socially desirable.

The inventors have found that in a preferred embodiment, the composition of the invention can be applied in a volume of about 0.05 ml to 0.10 ml per nostril with good retention of the composition in the nose. A nicotine concentration of less than 10 mg/ml, preferably 1 to less than 10 mg/ml, more preferably from about 5 to about 9 mg/ml is well tolerated by the nasal mucosa and reduces the nasal symptoms, primarily rhinorrhea and sneezing, observed when using solutions of higher nicotine concentration In order to approximate the dose of nicotine delivered to the blood by smoking one cigarette, (approximately 1 mg (Russell et al. (10)) about 2 mg nicotine should be delivered to the nose. If, for example, an atomiser delivering about 0.03 ml. nicotine composition per squeeze is employed, and the composition has a concentration of 20 mg/ml nicotine, one squeeze delivers 0.06 mg nicotine and three applications will deliver approximately 2 mg nicotine.

A method of increasing the plasma nicotine concentration of a subject involves administering to the nasal mucosa of a subject, a nicotine spray with a nicotine concentration of less than 10 mg/ml, preferably 1 to less than 10 mg/ml, more preferably from about 5 to about 9 mg/ml and with a pH in the range of 5.0 to 8.0, preferably 6.0 to 7.5 and most preferably about 7.0. Preferably, the nicotine spray is the sole source of nicotine for the subject.

A method of reducing nasal symptoms, primarily rhinorrhea and sneezing associated with using a nicotine spray with concentration is of nicotine of 10 mg/ml or greater involves administering as a sole source of nicotine, nicotine spray with a nicotine concentration of less than 10 mg/ml, preferably 1 to less than 10 mg/ml, more preferably from about 5 to about 9 mg/ml and with a pH in the range of 5.0 to 8.0, preferably 7.0, to the nasal mucosa of a subject. The inventors have unexpectedly found that administering a nicotine spray in accordance with this preferred embodiment results in similar blood plasma nicotine levels as from a nicotine spray with a nicotine concentration of 10 mg/ml.

A method of reducing the desire of a subject to, smoke tobacco or of providing a smoker with a substitute for smoking tobacco involves administering to the nasal mucosa of a subject, once source of an effective amount of nicotine in the form of a nicotine spray with a nicotine concentration of less than 10 mg/ml, preferably 1 to less than 10 mg/ml, more preferably from about 5 to about 9 mg/ml and with a pH in the range of 5.0 to 8.0, preferably 6.0 to 7.5 and most preferably about 7.0.

The methods can be effective in treating heavy smokers, those who consume more than one package of about 20 cigarettes per day (Fagerstrom score of 7 or more), or light smokers, those who smoke less than 1 package of about 20 cigarettes per day (Fagerstrom score of less than 7). The inventors have found that a nicotine nasal spray with a nicotine concentration of 10 mg/ml or more, does not benefit light smokers as much as it does heavy smokers is light smokers are not as inclined to suffer through the nasal symptoms caused by the nicotine and are likely to quit using the nasal spray before quitting smoking entirely. Heavy smokers seem more inclined to suffer through the nasal symptoms and may benefit more from a spray with a concentration of 10 mg/ml or more. However, a nicotine nasal spray in accordance with the preferred embodiments will be of benefit to both heavy smokers and light smokers since the resultant blood nicotine level is similar to that obtained from a NNS of 10 mg/ml yet the nasal irritation is less.

Other uses of the composition of the invention may be evident to those skilled in the art upon reading the present description. For instance, the compositions of the invention can be used where increasing the plasma nicotine levels is indicated or desired, such as in various neurological diseases such as Parkinson's and Alzheimer's, and can be used to relieve a smoker's desire for nicotine in environments where smoking is prohibited, such as in commercial aircraft.

Claim 1 of 14 Claims

What is claimed is:

1. A method for reducing nasal symptoms associated with the administration of nicotine to the nasal mucosa of a subject comprising administering to the subject one source of an effective amount of nicotine, said source being in the form of a nicotine nasal spray composition that can be administered to the nasal mucosa of the subject, the composition comprising droplets having a size of about 10 microns or more and a solution of nicotine or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable solvent, said solution having a nicotine concentration of 1 mg/ml to less than 9 mg/ml.

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