Composition to help stop smoking

FIELD OF THE INVENTION The present invention relates to compositions and methods for persons who wish to reduce their cigarette consumption or to seek socially acceptable consumption of nicotine instead.

Because of the well-known harmful effects of smoking and the general social attitude towards smoking, which results in a steady increase in non-smoking public areas, smokers are under great pressure to stop smoking or find a more socially acceptable alternative.

For those who are unable to give up smoking completely, various forms of nicotine replacement therapy are suggested.

Commercially available nicotine-containing chewing gum, which for some people satisfactorily replaces smoking. For many, nicotine chewing gum does not alleviate the feeling of wanting to smoke due to the progressive and low blood nicotine levels. Many have undesirable side effects such as nausea and loss of nutrition (Jarvis et al., 1982, British Medical Journal, Vol. 285, p. 537; Schneider, Comprehensive Therapy, Vol. 13, p. 32 (1987)].

Nicotine-containing nasal drops have been described (Russell et al., British Medical Journal, Vol. 286, p. 683 (1983); Jarvis et al., Brit. J. of Addiction, Vol. 82, p. 983 (1987)). However, the use of nasal drops is cumbersome and not suitable for use in the workplace or other public settings. Using nicotine nasal drops may also cause local nasal irritation. Difficulties of use include that the amount of nicotine administered cannot be determined.

The use of a skin patch for nicotine delivery through the skin has also been reported (Rose, Pharmacological Treatment of Tobacco Dependence (1986), pages 158-166, Harvard Univ. Press). Nicotine-containing skin patches can cause local irritation, and the absorption of nicotine is slow and can affect the blood flow to the skin.

In U.S. Patent Nos. 4,920,989 and 4,953,572, the use of an inhaled nicotine aerosol is sometimes associated with nicotine skin patch as a method of reducing smoking. With skin patches, nicotine absorption through the skin resulted in blood levels of nicotine similar to those achieved by smoking. The use of the nicotine aerosol alone provided significantly lower levels of nicotine in the blood than those achieved by smoking, but it created a sense of irritation in the respiratory tract of the user, thereby mimicking the smoking experience.

To ensure that the droplets of nicotine solution are delivered to the respiratory tract by oral inhalation to simulate smoking, i.e., are not deposited in the oral cavity, the aerosol droplets used were 10 microns or less in size.

Although respiratory tract irritation is somewhat desirable to mimic smoking, it is not easily controlled and the irritation may be so severe that it makes undesirable use of the nicotine aerosol.

Perkins et al., Behavior. Research Methods, Instruments and Computers (1986), Vol. 18, p. 420, and Psychopharm. (1989), Vol. 97, p. 529, described a nicotine aerosol spray as a way of administering nicotine. , in which nicotine was administered in controlled amounts to the subject to investigate the physiological effects of nicotine. Under the test conditions, a dilute solution of nicotine was used, which was given in multiple doses, giving 1.8 ml at rest over a period of 5 minutes, and sought a practical nicotine formulation for daily use, which is desirable for smoking cessation and smoking .

U.S. Patent 4,579,858 discloses a high-viscosity nicotine-containing composition that can be applied to the nose as a viscous tampon. The size of the surface of the nasal contact pad is limited, as indicated by the relatively low blood nicotine levels achieved with this nicotine delivery route.

There remains a need to provide a smoking substitute nicotine formulation that is convenient for the public to use while allowing the user to carry out long-term activity in the usual manner.

FIELD OF THE INVENTION The present invention relates to a nasal dosage form which assists in reducing or replacing a user's desire for smoking comprising a solution of nicotine or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable solvent, wherein the composition has a nicotine concentration of 10 to 40 mg / ml. and also contains a viscosity agent between 1 and 99 centipoise, other pharmaceutically acceptable additives which may be present.

The invention, which is illustrated by preferred embodiments, will be described with reference to the drawings; Figure 1 shows a person's nicotine blood level at various time intervals following administration of the nicotine-containing composition of the invention.

The present invention provides a convenient, inexpensive and effective alternative to nasal spray administration of an effective nicotine dose of smoking.

Further, nicotine-containing formulations and nasal sprays for nasal administration are provided.

The alternative smoking alternative provided by the present invention can be used to assist those who attempt to quit smoking or to use it indefinitely in order to avoid both unwanted side effects of smoking and other harmful effects on the person who is smoking. such as. the carcinogens of cigarettes and carbon monoxide. The use of the nicotine-containing composition and spray of the present invention does not limit the user's ability to work or perform other routine activities.

When a nicotine-containing solution is administered to the nasal mucosa, nicotine is delivered directly into the bloodstream. If this pathway is chosen as a replacement for smoking, sufficient nicotine delivery and absorption is required to achieve a rapid increase in blood nicotine levels similar to that achieved by smoking if we are to quit smoking. Previously available smoking replacement methods have often proved inadequate in this regard because of too small or too late increases in blood nicotine levels.

It is desirable that nasal administration of nicotine provide a sufficient nicotine dose over a sufficiently large area of ​​the nasal mucosa to produce the desired rapid increase in blood nicotine levels without producing a high local concentration of nicotine that would cause irritation of the mucous membrane and excess would like to get some of the dose applied out of the nose, thereby causing inconvenience and inconvenience to the user.

According to the present invention, nicotine or a pharmaceutically acceptable salt thereof is dissolved in a pharmaceutically acceptable solvent, e.g. phosphate buffer in physiological saline; and the pH is ca. It is adjusted in the range of 5 to 6.5 to achieve optimum absorption in the nasal mucosa. A pH of about 5.8 is preferred.

Pharmaceutically acceptable nicotine salts are known to those skilled in the art. These include nicotine tartrate and nicotine hydrogen tartrate.

Other pharmaceutically acceptable buffering agents are known to those skilled in the art.

A nicotine-containing composition of the present invention is added to the nasal cavity to aid retention in the nose, which is about 1 to about 5 minutes. It provides viscosity in the 1-99 centipoise band, preferably in the 10-20 centipoise band.

As known to those skilled in the art, various agents can be used to achieve the desired viscosity, including cellulose, substituted cellulose derivatives such as carboxymethylcellulose derivatives and methylcellulose, gum arabic and polyethylene glycol. The desired viscosity can also be achieved using an oil emulsion wherein the oily phase contains a suitable nasally applicable oil such as lanolin or beeswax. Of course, any viscosity enhancer used will necessarily be pharmaceutically acceptable and will be tolerated by the nasal mucosa.

The nicotine-containing composition of the present invention is injected into the nose by blowing micro droplets; this facilitates the deposition of droplets in the nose and minimizes inhalation of the nicotine formulation into the further airways.

The studies of Yu et al. , Pharmaceutical. Sci., Vol. 73, p. 344 (1984)] have shown that the droplet size of a spray blown into the nose or inhaled influences the location of the droplet deposition. These authors have shown that the majority of particles of 2-6 microns in size reach the end of the bronchus and the alreoli, while most droplets larger than 10 microns are expected to be deposited in the nose. a.

The nicotine-containing composition of the present invention may be delivered to the nose by any suitable nebulizing or spraying device that can be delivered to the nasal cavity for about 10 minutes. It produces a spray droplet size greater than 10 microns. For example, conventional venturi-type nebulizers, which are used for nasal meal suppression, or metered dose spray devices, such as P1, which can be used for nasal steroid application. These devices provide 98% of droplets larger than 16 microns and most droplets are approx. 100-200 microns. As will be readily apparent to those skilled in the art, the viscosity of the composition of the invention should be optimized according to the type of nebulizer used. For example, it has been observed by the inventors that when a venturi type nebulizer is used, the viscosity of the nicotine composition may not be approx. More than 10 centipoise. If a metered dose spray device is used, the viscosity of the formulation will be approx. Raised up to 30 centipoises to achieve proper droplet production, with increasing viscosity above this level, the result tends to be more fluid jet formation than aerosol formation. The composition viscosity for a particular type of sprayer can be readily determined by those skilled in the art.

When the nasal spray of the present invention is used, nicotine does not enter the user's airway above the nasal passages, thereby avoiding airway irritation and allowing the use of higher nicotine concentrations that provide elevated blood nicotine levels similar to those achieved with smoking without the associated irritation. .

As will be readily apparent to those skilled in the art, the concentration of nicotine in the composition of the invention and the volume of the nasal composition may be varied to provide the desired dose of nicotine to the user. The amount used should be chosen so that it is well retained in the nose and does not leak out. The nicotine concentration should not be high enough to cause undesirable local irritation when used in the required amounts.

It has been observed by the inventors that the composition of the invention is from about 0.03 to about. It may be administered in an amount of 0.08 ml per nostril, with the formulation remaining properly in the nose. The concentration of nicotine in the nasal mucosa is approx. It is well tolerated in the concentration range of 10-40 mg / ml when used in accordance with the present invention. To approximate the amount of nicotine in the blood (i.e., 1 mg) by smoking a cigarette (Russel et al., Supra), approx. 2 nicotine should be administered nasally. For example, if a spraying device is used that releases 0.03 ml of nicotine formulation per press and the formulation is nicotine at a concentration of 20 mg / ml, 0.6 mg of nicotine is released at a single pressure and three times the application takes approx. 2 mg of nicotine.

According to a preferred embodiment of the present invention, a composition having a viscosity of about 1 to about 10% is used. 10 centipoise and nicotine concentration ca. Dissolved in physiological saline containing 20 mg / ml phosphate buffer, pH 5.8. The formulation is delivered to the nose by a spray device, which may release 0.03 mL of the formulation, sometimes in the form of a spray, with droplets of at least 10 microns in diameter.

The composition of the invention may, if desired, contain one or more flavoring agents, e.g. menthol and a preservative such as benzoic acid or an antioxidant such as.

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- 10 ascorbic acids. Suitable flavoring and preservatives suitable for use in food and pharmaceutical formulations are known to those skilled in the art and the appropriate concentrations of these agents are known.

The use of the nicotine-containing formulations of the present invention as a nasal spray according to the present invention has been found to be well tolerated by human users with minimal side effects in the form of mild and transient rhinitis.

Experience with the use of the nicotine-containing nasal spray of the present invention allows smokers to function effectively for at least three years in a non-smoking environment without withdrawal symptoms or nicotine starvation.

The following examples are provided by way of illustration only and are not necessarily limited to the invention.

First example

Nicotine (98-100% free base, Catalog # 3876, Sigma Chemical Co., St. Louis, Mo.) was dissolved in phosphate buffered saline (PBS: 0.175 g Na).₂HP0₄/ 100 mL, 1.21 g NaH₂PO₄/ 100 ml; 0.292 g NaCl / 100 ml) to give a nicotine concentration of 20 mg / ml. The solution had a pH of 5.8 and an osmolarity of 290 mOsm. Carboxymethyl cellulose was added to achieve a viscosity of 5 centipoise. The solution was sterilized by filtration through a 0.2 micron filter and 10 ml of the sterilized solution was placed in a conventional venturi-type nebulizer.

The nebulizer was used by administering 2.4 mg nicotine nasally to a subject for approx. In 5 seconds, • · ». * ·· · 'four times pressure (2 pressures into each nostril). Blood samples were collected from the vein of said cubital arm at various time intervals after nicotine administration (time 0

First and blood nicotine concentrations according to Feyerabend and Russell [J. Pharm. Pharmacol., Vol. 32, pp. 178-181. (1980)]. The results are shown in Figure 1.

The blood nicotine concentrations achieved were similar to those resulting from smoking a cigarette, and peak values ​​were approximately. It was measured 15 minutes after dosing, slightly later than after smoking.

Although only preferred embodiments of the invention have been described and illustrated, the present invention is not limited to the features of these embodiments, but includes all variations and modifications within the scope of the claims.