Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
2001-01-12
2002-11-12
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S487000, C424S447000, C424S448000, C424S449000, C424S443000
Reexamination Certificate
active
06479076
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a new method for transdermal nicotine delivery which is particularly useful as a smoking-cessation aid in the treatment of addition to cigarette smoking.
Nicotine is the most widely used additive drug. Nicotine is more addictive than heroin, cocaine and alcohol. Every year, 30% of the smokers try to get rid of the habit but only about 3% succeed. In the United States alone there are 50 million smokers, each consuming an average of 10,000 cigarettes a year. This is estimated to cause 420,000 deaths due to lung and heart diseases and cancer. There are at present 1.1 billion smokers in the whole world and the World Health Organization has indicated that by the year 2020 tobacco related illness will be the cause of around 10% of all diseases affecting mankind and will be responsible for 14% of all deaths. The use of tobacco products produces a yearly loss of 200 billion dollars to the economy.
In Israel the problem is quite severe. Recent data shows that 28% of adults and 18% of youngsters (below 18 years old) are smokers. It is estimated that every year 10,000 people die due to the smoking habit and another 1,400 die due to passive smoking. Life insurance companies charge approximately double premium payments to smokers as compared to non-smokers. For a one million shekel life insurance policy ($=4 shekel) a 50 year old man will pay 6,690 shekel if he is a smoker and only 3,540 shekel if he is not.
Nicotine is by itself a moderately toxic material but in the case of cigarette smoking it is not the direct killer. The high temperature at the tip of the cigarette converts tobacco into 4,000 compounds. Of these, 400, including nicotine and carbon monoxide, are toxins, and another 40 are carcinogens (C&EN Nov. 28, 1994). Delivery of these products to the lungs is very effective since they are in the form of an extremely fine aerosol, and only 5-10 seconds after inhaling the nicotine arrives to the brain, dopamine is released and produces a quick pleasurable feeling.
Breaking the addiction to cigarette smoking can be aided by delivering the drug to the body in small controlled quantities, not through the lungs but through the skin, in the form of nicotine containing patches. Other less used presentations currently marketed deliver nicotine via mucous tissues; these are in the form of chewing gum, nicotine inhalers and nicotine nasal sprays. In all cases the use of Nicotine Replacement Treatment (NRT) is designed to satisfy the craving for the drug without generating the toxic and carcinogenic materials related to smoking.
There are many reports in the literature that these methods are helpful in considerably increasing the percentage of successful smoking cessation. However, each of the pharmacological methods available at present have certain problems:
Nicotine patch (Transdermal Nicotine System).—The most popular patches come in 3 sizes containing 7, 14 and 21 mg of nicotine. The smoker starts with the 21 mg patch for several weeks and then goes over to the 14 mg. patch for another few weeks. Weaning is completed by using the 7 mg. patch. The patches have proven to be effective and studies show that they double the odds of being abstinent at 6 and 12 months as compared to placebo patches. The main problems related to the use of patches are mild to moderate dermatological reactions in a significant proportion of patients. Patches occlude the area of the skin where they are applied. Allergenic reactions may be produced. The patches are quite expensive and this deters their use by a large part of the population.
Nicotine gum (nicotine polacrilex).—In this device the nicotine is bound to an ion-exchange resin and incorporated into a gum base. For its proper performance the gum has to be alternatively chewed and parked in the mouth until complete depletion of the nicotine. Two forms of this device are available, containing 2 or 4 mg of nicotine. A smoker will have to chew one gum approximately every two hours in order to attenuate the nicotine craving during the treatment period. The side effects may be: sore throat, sore jaw, nausea and vomiting. It is not recommended to use it with dentures, and there are indications that Mercury may be leached out from fillings.
Nicotine nasal spray.—This consists of a nicotine solution contained in a small bottle fitted for insertion into the nostril. By pressing the pump mechanism in the bottle, a fine spray of nicotine (0.5 mg) is released into the nostril. The patient squirts once in each nostril for a total of 1 mg of nicotine. Typically, a patient will use 13 to 20 doses per day. The long term effectiveness of the nasal spray has been shown in clinical tests. The most common side-effects are: nasal and sinus irritation, funny nose, watery eyes, throat irritation, sneezing and coughing. This device is expensive, and its use is very limited.
Nicotine inhaler.—This is a nicotine (10 mg) impregnated plug, that is inserted into a cigarette-like tube or mouthpiece. The patient puffs on the mouthpiece, the air becomes saturated with nicotine and is then inhaled by the user. The nicotine is absorbed mainly via the buccal mucosa. Adverse effects reported are mild mouth and throat irritation and coughing. The use of this device is not very popular.
The present invention consists of an improved transdermal nicotine delivery system which overcomes the problems related to the use of patches, gum, nasal spray and inhaler during smoking-cessation treatments, wherein topical application of the compositions on the skin will provide a slow and sustained release of nicotine so as to maintain the desired level in the blood of the patient and thus alleviate his craving for the drug. This is accomplished by the incorporation of uncrosslinked, water-insoluble N-vinylpyrrolidone copolymers in the compositions. The terms N-vinylpyrrolidone and vinylpyrrolidone are interchangable in this text.
The preferred system consists of an alcoholic gel containing nicotine and a copolymer together with excipients useful for improving the viscosity and texture of the gel and eliminating irritation. The gel is packed in an aluminum can provided with a dosifying pump which delivers an exact amount of gel every time the actuator is pressed. The gel is uniformly distributed over a small area of skin by means of a cap which is part of the package. Upon deposition on the skin as a thin layer, the gel dries quickly leaving an invisible film of polymer containing nicotine from which the drug leaches out gradually into the skin.
The patient can regulate the quantities applied according to his own needs. For instance, if every actuation of the pump delivers a quantity of gel containing 8 mg of nicotine, the user can start the treatment by applying 3 doses (24 mg) and go down gradually as he needs and less nicotine to complete the smoking-cessation treatment. This possibility of flexible dosage is very important since the nicotine-craving of the smoker varies according to his own individual physical and psychological status at different times.
The use of transdermal nicotine in this form may also be useful, as a dopamine release agent, in the treatment of other conditions such as attention deficit hyperactive disorder (ADHD), attention deficit disorder (ADD), Tourette's syndrome, schizophrenia, Parkinson's disease, anxiety and depression.
The use of water-soluble polyvinylpyrrolidone in conjunction with other medicaments has been disclosed in a number of patents. Thus, U.S. Pat. No. 3,972,995 discloses a buccal dosage form in which the water-soluble homopolymer functions as a binder in an adhesive layer. U.S. Pat. No. 3,214,338 discloses a topical ointment in which the water-soluble homopolymer is added to an emulsifiable polyvinyl acetate powder. U.S. Pat. No. 3,803,300 discloses a film-forming ointment containing water-soluble vinylpyrrolidone homopolymer or copolymers. U.S. Pat. No. 3,287,222 discloses the use of the homopolymer as a water-soluble plasticizer in an impregnating solution for a synthetic fiber medical dres
Amster Rothstein & Ebenstein
Fubara Blessing
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