MXPA06010686A - Means for transdermal administration of nicotine - Google Patents

Abstract

Devices for transdermal administration of nicotine, which provide for basic as well as additional user activatable administration of nicotine, as well as use of such devices.

Description

MEANS FOR THE TRANSDERMAL ADMINISTRATION OF NICOTINE TECHNICAL FIELD The present invention relates to devices for the transdermal administration of nicotine, especially to devices that provide both a basic administration of nicotine, and an administration of additional nicotine activable by the user. The present invention also relates to the use of said devices.

BACKGROUND OF THE INVENTION Dependence on and reduction of tobacco In recent years, with the recognition of the harmful effects of tobacco use, numerous campaigns and programs have been promoted by government agencies and various health groups and other interested organizations to disseminate information on the effects of smoking. adverse health resulting from smoking tobacco. In addition, and as a result of this recognition of harmful effects, many programs have been created aimed at reducing the incidence of smoking practice. Nicotine is an organic compound and is the main alkaloid of tobacco. Nicotine is the main addictive ingredient in tobacco used in cigarettes, cigars, powdered tobacco, etc. Nicotine is also an addictive drug, and smokers characteristically have a strong tendency to relapse after having successfully stopped smoking for a while. Nicotine is the second most widely used drug worldwide, after the caffeine in coffee and tea. The main problem related to the practice of smoking tobacco is related to the enormous implications on health. It is estimated that the diseases related to the practice of smoking produce three to four million deaths per year globally. According to the Cenlers of Disease Concern and Prevention, the practice of smoking cigarettes among adults (United States, 1995. MMWR 1997; 46: 1217-1220), is responsible for the deaths of approximately 500,000 people per year in the United States. as a result of tobacco consumption. In fact, excessive tobacco consumption is now recognized as one of the most important health problems in the world. The cruel consequence of smoking has urged many medical associations and health authorities to take very strong measures against the use of tobacco. Although tobacco use is declining in many developed countries today, it is hard to see how societies could break free of the second most widely used drug worldwide. The most advantageous thing that a chain smoker can do is reduce, or even preferably quit smoking completely. Experience shows, however, that the majority of smokers find it exremely difficult because, in most cases, the practice of smoking tobacco leads to a dependence disorder or burning desire to smoke. The World Health Organization has made a diagnostic study called Tobacco Dependence in its International Classification of Disorders. Other organizations, such as the American Psychiatric Association, call the dependency addiction to Nicoíina. It is generally accepted that these difficulties in eliminating tobacco consumption result from the fact that these heavy smokers are dependent on nicotine. The most important risk factors are, however, substances that are formed during the combustion of tobacco, such as carbon monoxide, illegal products, aldehydes, and hydrocyanic acid.

Effects of niciline The administration of nicotine can provide satisfaction and the usual time is the practice of smoking, indiscriminately smoking a cigarette, a cigar or a pipe. However, smoking poses health hazards and it is desirable, therefore, to formulate an all-important way of administering nicolina in a pleasant way that can be used to facilitate smoking cessation and / or used as a substitute for smoking. When a cigarette is smoked, nicotine is rapidly absorbed into the smoker's blood and reaches the brain about 10 seconds after inhalation. The rapid rise of nicotine provides the consumer with rapid satiation or impact. Salting then lasts the time of smoking the cigarette and for a period of time afterwards. The poisonous, toxic, carcinogenic and addictive nature of smoking has favored the modality of efforts to develop methods, compositions and devices that help to quit the habit of smoking cigarettes. Nicotine is an addictive harmful alkaloid of formula C5H4NC H7NCH3 derived from the tobacco plant. Nicolina is also used as an insecticide.

Nicotine replacement products One way to reduce tobacco use is to provide nicotine in a different way or form than smoking, and some products have been developed to meet this need. The use of nicotine-containing formulations is usually the dominant treatment for tobacco dependence. The successes in reducing the incidence of tobacco use have been relatively poor using the products known today. The current state of the art implies solutions related to behavior as well as pharmacological solutions. More than 80% of tobacco smokers who quit smoking initially after using a behavioral or pharmacological solution to reduce only the incidence of tobacco use, generally relapse and return to smoking with their original tobacco consumption rate. of about a period of time of one year. As an aid to those who want to quit smoking, there are several ways and forms of nicotine replacement products available in the market, such as nicotine gum. Various methods and means for decreasing the desire to smoke have been described, comprising the operation of administering nicotine or one of its derivatives to the subject, as described in the US Pat. Number 5,810,018 (oral nicolina spray), in the U.S. patent. Number 5,939,100 (microspheres containing nicolin), and in the US.U.A. Number 4,967,763 (pills that contain nicofine). The use of nasal drops containing nicoiin has been reported (Russell et al, British Medical Journal, Vol. 286, page 683 (1983), Jarvis ef al, Bri. J. of Addiction, Vol, 82, P. 983 (1987). )). Nasal drops, however, are difficult to administer and are not convenient to be used in the work or in other public situations. There are known modes of administering nicoin by direct application in the nasal cavity by spraying, by documents US 4,579,858, DE 32 41 437 and WO 93/127 64. However, local nasal irritation can be produced with the use of nasal formulations. with nicotine. The difficulty of administration also gives rise to the inability to predict the dose of nicotine administered.

Also, inhalation devices reminiscent of a cigarette for aspiration of nicotine vapors are known, as suggested in US 5,167,242. A successful approach to reduce the incidence of smoking is based on a chewing gum that contains nicoin and that is designed to reduce the symptoms that occur when quitting. The reported success rate is approximately twice that of a placebo. A product that is used successfully as a substitute for smoking and / or as an aid to stop smoking and that is based on nicotine, is Nicoretfe chewing gum (registered trademark). This product was one of the first nicotine substitute products that was approved by the Food and Drug Administration (FDA) and is one of the most useful nicofine substitutes. Nicorette chewing gum has been in the market in approximately 60 countries for several years. In this chewing gum the nicoin is present in the form of a complex with a nonsoluble cation exchanger (polacrilex) which is dispersed in the gum base. Nicotine is slowly released from the chewing gum when chewed and reaches plasma levels similar to those found when smoking a cigarette after approximately 30 minutes, depending on the chewing technique, ie slow or active chewing. Patents related to this product are, for example, US patents. UU Numbers 3,877,468; 3,901, 248 and 3,845,217.

Iransdermic nicinin patches The use of skin patches for the transdermal administration of nicotine was reported many years ago (Rose, in Pharmacologic Treatment or Tobacco Dependence, (1986), pages 158 to 166, Harvard Univ. Press). A large number of patents have been issued concerning devices for the transdermal administration of nicotine, for example the U.S. patent. Number 5,120,546 which describes a transdermal delivery system in which nicotine is complexed with a cyclo compound, the patenie of E.U.A. Number 5,230,896 which describes a transdermal administration system in which an acrylic polymer adhesive is used, the patent of E.U.A. Number 4,943,435 which describes a fransdermic patch for supplying nicoinin for periods of 12 to 24 hours, which makes use of a supply diaphragm conlrol membrane, the country of E.U.A. Number 4,915,950 which describes a method for the manufacture of transdermal administration devices for nicotine-containing compounds, by which nicotine is printed on an adsorbent textile layer, the U.S. patent. Number 5,533,995 which describes a transdermal device in which the transport of nicotine within the device is controllable using a system of internal electrodes, the patenie of E.U.A. Number 5,135,753 which describes a fransdermic device for administering nicoin in combination with a pellet containing nicoin, the patent of E.U.A. Number 5,721, 257 which describes a transdermal device for administering nicotine in combination with a nasal spray for the administration of nicofine, the document WO 0164149 which describes the use of a device for the transdermal administration of nicotine in combination with heat, and the WO document No. 9600111 which describes the transdermal administration of a drug, for example, nicoin, utilizing electrical impulses.

PREVIOUS TECHNIQUE AND ITS PROBLEMS Means are known to obtain a basal level of nicoin in plasma essentially essential, with nicotine reinforcement supplements when the patient so wishes. These methods also involve the use of two different dosage forms for the supply of nicotine, which are to be used in combination. For this purpose, for example, a nicotine patch in combination with a nicotine lozenge (see US Patent Number 5,135,753) or a nicotine patch in combination with a nicofine nasal spray (see US Pat. 5,721, 257). For the convenience of the user, there is a need to provide a single-dose form of administration, which can provide an essentially constant basal plasma nicotine level and also the administration of additional reinforcing nicofine doses as desired by a patient / user. The present invention relates to a solution to the problems detected, which creates a unitary device that takes into account a transdermal supply of basic nicotine and also a supply of additional fransdermic nicoinine acivable by the user. It is highly desirable in light of the above-mentioned problems to develop means and methods for the administration of nicotine to provide satisfaction to a person who urgently desires nicotine or to create a sense of the satiety of smoking without smoking, which can also avoid problems associated with nicotine. means and methods of the prior art. With respect to this, the present invention addresses this need and interest.

Definitions As used herein, the terms "basic transdermal administration of nicotine in any form" and the like refer to the transdermal nicofine transport provided by a part of the claimed device, which delivers nicotine continuously during the period of the intended application of the claimed device on the skin. In the sense in which they are used herein, the terms "additional transdermal administration of nicoin in any form" and the like, refer to the transdermal nicotine transportion provided by a part of the claimed device administering additional nicotine by user activation, in addition to the amount provided by the part of the claimed device that provides the fransdermal administration of basic nicotine in any form.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic drawing of the embodiment according to example 1. Figure 2 is a schematic drawing of the embodiment according to example 2. Figure 3 is a schematic drawing of the embodiment according to example 3 Figure 4 is a schematic drawing of the embodiment according to example 4. Figure 5 is a schematic drawing of the embodiment according to example 5. Figure 6 is a schematic drawing of the embodiment according to the example 6 DETAILED DESCRIPTION OF THE INVENTION In view of the above-mentioned disadvantages known in the art when attempting to administer nicotine to a subject to provide different nicofine delivery rates, the present invention creates new conception devices for the basic and transdermal administration of nicoinine and for the additional combined administration Irididemic of nicoin activable by the user. Additionally, the present invention facilitates the use of nicotine for the manufacture of a device, and creates a method to help quit smoking, in situations of transient absences, and / or to reduce the urge to smoke or otherwise use material. which contains an abacus, and / or to handle situations suitable for the treatment with nicoin, being selected the symptoms of the group consisting of Alzheimer's disease, Crohn's disease, Parkinson's disease, Toureiie syndrome, ulcerative colitis, and control of body weight after smoking cessation, by means of Iransdermic administration of nicoin with dispositional device. The transdermal nicotine administration method can also be practiced in combination with means for the supply of nicolin selected from the following: mouth sprays, nasal sprays, transdermal patches, inhalation devices, pills, tablets, etc., and in combination with methods of parenteral, subcutaneous, intravenous, recial, vaginal and transmucosal administration, including the use of tobacco.

Categorization of transdermal devices Means for the transdermal administration of nicotine in any form can be classified in many different ways. Said extensive transdermalization arrangements in the present invention can be broadly classified into four main groups, as follows: - depot type devices, in which the drug is placed in a liquid or gel and delivered to the skin through a supply rate regulating membrane; - devices of the matrix type, in which the drug is placed inside a non-adhesive polymeric maferial, typically a hydrogel or a soft polymer; - disposiíivos of the drug type in adhesive, in which the drug is placed deníro of an adhesive polymer; - Devices of the multi-stratified type, which are similar to the devices of the drug type in adhesive, but which incorporate an additional layer of pressure-sensitive adhesive to cover the entire device and fix it to the skin. A membrane may also be incorporated into the disposed of a microfiluted type.

User-readable nicofine administration The means for modifying the transdermal flow of pharmaceutically active substances can be classified in many different ways.

One of the classifications is shown in accordance with Table 1. Since many of the means listed in Table 1 can be designed so that they are both activatable and deactivatable by the user, their use for administration may be very appropriate. Additional transdermal nicotine in the present invention. Means especially suitable for acivation and deacylation by the user, and preferred for use in the transdermal administration of additional nicotine according to the present invention, include, but are not limited to, the following: iontophoresis (including also electromigration and electroosmosis), sonophoresis, microneedles, jet injection, and combinations thereof.

TABLE 1 Means for Modifying Transdermal Administration The means of Table 1 are known in the art as such.

The active ingredient According to the invention, the claimed device comprises nicofine in any form. It is expected that the term includes nicotine, 3- (1-methyl-2-pyrrolidinyl) -pyridine in its base form, including also synthetic nicotine and nicofine extracts from tobacco plants, or parts of complexes, such as generic Nicofiana. alone or in combination. The nicoinine in any form is selected from the group consisting of a nicotine salt, the free nicotine base form, a nicotine derivative, such as a nicotinic base cationic exchanger, a nicofine or nicotine inclusion complex with any non-nicotine linkage. covalent nicotine bound to zeolites; Nicofine bound to cellulose or nicofine bound to starch microspheres; and mixtures of spheres substances. Numerous salts of nicoin are known and can be used, for example, the salts shown in Table 2 below.

TABLE 2 Useful acids for the formation of nicotine salts Molar Ratio * of Acidomicotine Acid Formic Acid Propionic Butyric 2-Methyl butyric 3-Methyl butyric Valricoic Lauricco Palmitic Tartaric Citric Malic Oxalic Benzoic Gentisic Gálico Phenyl acetic Salicylic Phthalic Pyric Sulfosalicylic Tannic Pectic Alginate Hydrochloric Chloroplaminic Silicotungstic Pyruvic Glutamic Aspartic * recommended for production. The aforementioned cationic monomer is preferably a polyacrylate. The aforementioned inclusion complex is preferably a complex with a cyclodextrin, such as β-cyclodextrin.

The above-mentioned nicoinic salt is preferably a tartrate, a hydrogenated form, a citrate, a maleate or a hydrochloride. The form of nicoine provided by the basic administration may be a different form of nicoine than is provided by additional administration.

Additional additives Additional additives may optionally be added to a device according to the present invention. Optional additives preferably comprise one or more additives selected from the group consisting of stabilizers, enhancers and anti-irritants. The stabilizers may be selected from the group consisting of antioxidants, including vitamin E, ie, tocopherol, ascorbic acid, sodium pyrosulfite, or butylated hydroxy-luene (BHT), butylated hydroxyanisole, edetic acid, and edeinate salts; and preservatives including citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, and sorbic acid. Preferred embodiments comprise an antioxidant as a stabilizer, and even more preferably vitamin E and / or buffered hydroxy-luene (BHT). The potentiates can be selected from the group consisting of: alcohols, fales such as short-chain alcohols, for example elanol, etc., long-chain fatty alcohols, for example, lauryl alcohols, etc., and polyalcohols, for example propylene glycol, glycerin, etc. . - amides, such as amides with long aliphatic chains, or aromatic amides such as N, N-dielyl-m-ololumide; - amino acids; - azone and azonic compounds; - essential oils, ie complete essential oils or their constituents, such as 1-carvone, 1 -mentone, ele; - fatty acids and fatty acid esters, such as oleic acid, lauric acid, etc., additional esters of fatty acids, such as isopropyl myristate, and various esters of lauric acid and oleic acid, etc .; - macrocyclic compounds, such as cyclopenfadecanone and cyclodexyrins; - phospholipid compounds and phosphate compounds, such as phospholipids; - Compounds of 2-pyrrolidone; and - various compounds, such as sulfoxides, such as dimethyl sulfoxides, and fatty acid ethers, such as Laurey-9 and polyoxylauryl ether. The combinations of enhancers of different groups can prove to be useful and efficient. An example of a useful anti-irritant is vitamin E.

EXAMPLES The follo examples are illustrative and not limiting. The numbers in parentheses refer to the corresponding numbers in the figures.

EXAMPLE 1 (which is illustrated schematically in figure 1) Basic administration from the matrix side and additional administration from the ontophoretic part A device in the ransdermal patch format consists of two different administration systems of nicolin: A system in which the transdermal nicotine dose is delivered from a compartment (11). ) of polymeric matrix. The mechanism for the transdermal administration of nicotine for this system is passive diffusion along a concentration gradient. The supply rate is governed by the properties of the matrix polymers and by the concentration of the loaded nicoin in the matrix. The nicotine in the matrix is in its neutral base form. Another system in which the transdermal dose of nicotine is supplied from a compartment, in which the mechanism of nicotine transport is ionophoresis, ie the driving force is provided by an electric current (12, 13). In this system, charged nicofine is charged posti ively in the drug compartment (12) provided with an electrode (anode). The system is completed by means of a second compartment (13) equipped with an eiecírod? (cathode) in which negatively charged compensation ions are charged, preferably chloride ions, but other biocompatible negatively charged ions may also be used. The electrodes (14) are preferably of the silver-silver chloride type. A disposable battery (14) capable of generating a current of up to 0.5 mA / cm2 corresponding to the area of the drug compartment in contact with the skin is connected to the electrodes. When the ionophoretic system is activated, the dermal leg at the point of application complemented the electrical circuit. The rate of nicotine delivery for this system is governed by the magnitude of the electric current between the electrodes (14). The two above systems are arranged side by side in a device in the form of a thin patch of 20 to 50 cm2 in area. The device is fixed at the point of application by means of an adhesive layer covering the bottom of the device. The device is reinforced by a flexible nonwoven material that provides structural support. Directly below the non-woven material, a thin layer of aluminum is arranged, which acylates as a barrier for the diffusion of nicofine through the reinforcement material of the device. The device is also provided with an activation button (15) to initiate the passage of the electric current of the ionloforphic system. The passive diffusion system provides a basic dose of nicotine. The user can activate the iontophoretic system by pressing the acuplication button (15), and thus release an additional dose of nicotine. The deactivation of the ionophoretic system is performed by a timer function. Alternately, the user can deacitate at any time the additional administration of nicotine by pressing the activation button (15) a second time.

EXAMPLE 2 (illustrated schematically in Figure 2) Basic administration from the deposit side and additional administration from the microneedle part. A device in the transdermal patch format consists of two different systems of administration of nicoin: A system in which the ransdermic dose of nicoin is delivered from a reservoir compartment through a membrane (21) of rate control. The mechanism for the transdermal administration of nicolin for this system is passive diffusion along a concentration gradient. The supply rate is governed by the properties of the supply diaphragm conirol membrane and by the concentration of nicoine loaded in the compartment. The nicoíina in the maíriz esfá in its neuíra base form. Another system in which the transdermal dose of nicoin is supplied from a reservoir compartment coated on one side with microneedles that have the function of puncturing the stratum corneum of the skin, thus increasing the rate of transdermal administration of nicoin (22). ). The microneedles are suspended at a short distance from the surface of the skin and the user can activate the system by pressing on the poserior layer of the patch to bring the microneedles into contact with the skin. The speed of supply is governed by the properties of the microneedles and by the concentration of nicofine loaded in the compartment. The nicotine in the microneedle reservoir compartment is in its neu- rior base form. The two above systems are arranged side by side in a thin patch-like device of 20 to 50 cm2 in area. The device is reinforced by a flexible non-woven material, which provides structural support. Directly below the non-woven material, a thin layer of aluminum is arranged which acts as a barrier for the diffusion of nicotine through the reinforcing material of the device. The device is fixed at the point of application by means of an adhesive layer covering the bottom of the device. The immediate area surrounding the microneedle part of the device consists of a semirigid flexure polymer (23) that allows the microneedles to be deformed by bending by contacting and undoing contact with the stratum corneum (24) when the user presses on the layer. of reinforcement of the device, directly by the microneedles. The passive diffusion system provides a basic dose of nicotine. The user can activate an additional dose of nicotine by pressing on the strengthening layer, so that the microneedles puncture the horn (24) of the skin and channel the nicoinine through the stratum corneum (24) to the underlying tissue.

EXAMPLE 3 (shown schematically in Figure 3) Basic management from the matrix part and additional administration from the ultrasonic part. A device in the transdermal patch format consists of two different nicotine delivery systems: A system in which the transdermal dose of nicotine is delivered from a compartment (31) of polymeric matrix. The mechanism for the transdermal administration of nicoin for this system is passive diffusion along a gradient of concentration. The supply rate is governed by the properties of the polymers of the maíriz and the concentration of nicoíina loaded in the mafriz. The nicoíina in the maíriz is in its neutra base form. Another system in which the transdermal dose of nicotine is supplied from a compartment (32) of polymeric matrix, in which the mechanism of nicotine transport is sonophoresis, ie an ultrasonic device (33) causes the heating of the skin and a reversible disorder of the esoteric process of the cornea. The nicotine supply slab for this system is governed by the intensity of the ulfronic vibrations. The nicotine in the matrix is in its neutral base form.

The two previous systems are arranged side by side in a thin patterned device of 20 to 50 cm2 in area. The device is fixed at the point of application by means of an adhesive layer that covers the bottom of the device. The device is also provided with an activation button (34) to initiate the ultrasonic vibrations. The passive diffusion system provides a basic dose of nicotine. The user can activate the sonophoral system by pressing the accumulation knob (34), thus releasing an additional dose of nicoin. The desacfivation of the sonoporélico system is done by means of a timer function. Alternatively, the user can deactivate the additional administration of nicoin at any time by pressing the activation button (34) a second time.

EXAMPLE 4 (which is illustrated schematically in Figure 4) Basic administration from the part of mairiz that shares space with the ionophoretic part that provides an additional administration. A device in the transdermal patch format consisting of two different nicoinine delivery systems: A system in which the transdermal nicotine dose is delivered from a compartment, in which the mechanism of nicotine transport is iontophoresis, i.e. Drive force is provided by an electric current. In this system, positively loaded nicoin is loaded into the drug compartment (41) provided with an electrode (anode). The system is completed by a second compartment (42) provided with an electrode (cathode) in which charged negatively charged compensation elements are charged. This compartment also contains the neural base nicofine of the diffusion system, which is detailed below. A battery (43) supplies the necessary electrical power. The supply rate of nicoin for this system is governed by the magnitude of the electric current between the electrodes. Another system in which the Iransdermic dose of nicolin is supplied from a compartment (42) of polymeric matrix. This compartment contains both nicoin, in its neutral base form, and the negative charge compensation ions necessary for the ionophoretic system. The mechanism for the transdermal administration of nicotine for this system is passive diffusion along a gradient of concentration. The supply of nicoin is governed by the properties of the matrix polymers and by the concentration of nicotine charged in the matrix. The two above systems are arranged side by side in a thin patch-like device of 20 to 50 cm2 in area. The device is fixed to the point of application by means of an adhesive layer which covers the bottom of the device. The device is reinforced by a non-rigid flexible material, which provides spherical support. Directly below the unaltered material, a thin layer of aluminum is arranged which acts as a barrier to the diffusion of nicoinine through the reinforcing material of the device. The device is also provided with an activation button (44) to initiate the electrical actuation current of the iontophoretic system. The passive diffusion part, located in the iontophoretic cathodic compartment (42), provides a basic dose of nicotine. The user can activate the iontophoretic system by pressing the activation button (44), thus releasing an additional dose of positively charged nicotine from the iontophoretic anodic compartment (41). The deactivation of the iontophoretic system is performed by a timer function. Alternatively, the user can deactivate at any time the additional administration of nicotine by pressing the activation button (44) a second time.

EXAMPLE 5 (illustrated schematically in Figure 5) Basic administration from the deposit side and additional administration from the iontophoretic part, the two parts can be applied individually to the skin. A device in the transdermal patch format consisting of two different nicotine delivery systems: A system in which the transdermal dose of nicotine is delivered from a reservoir compartment through a supply rate conrol membrane (51). The mechanism for the Iransdermic administration of nicoin for this system is passive diffusion along a concentration gradient. The supply rate is governed by the properties of the membrane (51) of control of delivery rate and by the concentration of nicotine loaded in the compartment. The nicotine in the maíriz is in its neutral base form. Another system in which the transdermal dose of nicofine is delivered from a compartment, in which the mechanism of transport of nicoin is ionophoresis, ie the driving force is provided by an electric current. In this system, positively charged nicoin is loaded in a drug compartment (52) provided with an electrode. The system was completed by a second compartment equipped with an electrium in which negatively charged compensation ions are charged (53). A battery (54) supplies the necessary electrical power. The supply of nicoin for this system is governed by the magnitude of the electric current flowing between the electrodes. The two anterior systems are arranged side by side in a thin patch-like device of 20 to 50 cm2 in area. The device is fixed to the point of application by means of an adhesive layer covering the bottom of the device. The device is reinforced by a flexible non-woven material, which provides structural support. Directly below the non-woven material, a thin layer of aluminum is arranged which acts as a barrier for the diffusion of nicofine through the reinforcing material of the device. The two systems are separated by a perforation (55) in the device, which makes it possible to separate one system from another for individual positioning of the two parts on the body. The iontophoretic part of the device is also provided with an activation button (56) to initiate the electric impulse current of the iontophoretic system. The passive diffusion system provides a basic dose of nicotine. The user can activate the iontophoretic system by pressing the activation button (56), thus releasing an additional dose of nicotine. The deactivation of the ionophoretic system is carried out by a timer function. Alternately, the user can deactivate at any time the additional administration of nicoin by pressing the second (56) of acfivation a second time.

EXAMPLE 6 (which is illustrated schematically in Figure 6) Basic management from the matrix part and additional multilevel administration from the iontophoretic part. A device in the transdermal patch format consists of two different nicolin delivery systems: A system in which the transdermal nicolin dose is delivered from a compartment (61) of a polymeric matrix. The mechanism for the transdermal administration of nicofine for this system is passive diffusion along a concentration gradient. The supply rate is governed by the properties of the polymers of the maize and by the concentration of nicotine charged in the maize. The nicoíina in the malriz is in its neutral base form. Another system in which the transdermal dose of nicotine is supplied from a compartment in which the mechanism of nicotine transport is iontophoresis, ie the driving force is provided by an electric current. In this system, charged nicofine is charged posiively in the drug compartment (62) provided with an electrode (anode). The system is completed by a second compartment (63) provided with an electrode (cathode) in which charged compensation ions are negatively charged. A battery (64) supplies the necessary electrical power. The supply rate of nicoin for this system is governed by the magnitude of the electric current between the electrodes. The two previous systems are arranged side by side in a thin patch device of 20 to 50 cm2 in area. The device is fixed to the point of application by means of an adhesive layer covering the bottom of the device. The device is reinforced by a flexible non-woven material, which provides structural support. Directly below the non-woven material, a thin layer of aluminum is arranged which acts as a barrier for the diffusion of nicotine through the reinforcement material of the device. The passive diffusion system provides a basic dose of nicotine. The device is also provided with a set of buttons (65, 66, 67) for activating the electric impulse current of the iontophoretic system. The user can activate the iontophoretic system by pressing one of the activation buttons (65, 66, 67), thus releasing an additional dose of nicotine. The amount of nicotine in the additional dose varies from low to high, depending on the button that the user presses. Each button corresponds to a preset dose level. The deacivation of the iontophoretic system is carried out by a timer function. Alternatively, the user can deactivate at any time the additional administration of nicotine by pressing the same activation button a second time.

Additional Modes Other combinations of the media described herein are useful and are readily contemplated to obtain basic administration and additional administration of nicoin, respectively, other than those described in the examples. The present device should preferably be occlusive. The present device can supply nicoine for a predefined period, preferably 12, 16, 24 or 48 hours. The part (at least one) that provides the basic transdermal administration and the part (at least one) that provides the additional transdermal administration operable by the user can be combined in different ways. For example, said parts may have at least one specific characteristic in common, for example a common adhesive layer and / or a common drug reservoir. Said parts may also be combined so that they do not have any characteristic in common.

Claims (15)

NOVELTY OF THE INVENTION CLAIMS

1. - A device for the transdermal administration of nicotine in any form, characterized in that it comprises at least a first part, which provides a basic administration of nicotine in any form, and at least a second part that provides an additional administration of nicofine in any form, the second part being activated by the user.

2. The device for the transdermal administration according to claim 1, further characterized in that the first part (at least one) that provides the basic administration is / are (a) an ransdermal patch (s), preferably of the Type of deposit, type of matrix, type of drug in adhesive and / or of the multi-siatic type, preferably of the type of drug in adhesive or of the type of deposit, or combinations of these two types.

3. The device for the transdermal administration according to any of the preceding claims, further characterized in that the second part (at least one) that provides the additional administration comprises (n) means for delivery by iontophoresis, sonophoresis, jet injection. and / or puncture by microneedles.

4. - The device for transdermal administration according to claim 3, further characterized in that the second part (at least one) that provides the additional administration comprises (n) means for iontophoretic administration.

5. The device for transdermal administration according to any of the preceding claims, further characterized in that the first part (at least one) and the second part (at least one) have at least one characteristic in common.

6. The device for the transdermal administration according to any of claims 1 to 5, characterized in that the first part (at least one) and the second part (at least one) are separable from each other and / or can be applied individually.

7. The device for transdermal administration according to any of the preceding claims, further characterized in that the nicotine form is selected from the free base of nicoin, a nicofine salt, such as an rtartrate, a hydrogen tartrate, a citrate, a maleate or hydrochloride; a nicotine inclusion complex, as a complex with a cyclodexyrin; a cationic exchanger of nicoíina, íal like nicotine with poliacrilato, or nicotine with any noncovalenie bond, nicoíina united to zeoliías, nicoíina joined to cellulose, or nicoíina united to microspheres of starch, and mixtures of these forms.

8. - The device for the transdermal administration according to claim 7, further characterized in that the nicotine form is nicotine free base.

9. The device for the transdermal administration according to any of claims 7 or 8, further characterized in that the part (at least one) that provides the basic nicotine administration is (are) provided for the administration of nicotine in another form different from that used by the part (at least one) that provides (n) the additional administration of nicotine.

10. The device for the transdermal administration according to any of the preceding claims, further characterized in that it supplies nicolina during a predefined period preferably of 12, 16, 24 or 48 hours.

11. The device according to any of the preceding claims, further characterized in that it further comprises: one or more stabilizers, preferably selected from the group consisting of antioxidants including vitamin E, ie tocopherol, ascorbic acid, sodium pyrosulfite, butylated hydroxytoluene ( BHT), butylated hydroxyanisole, edetic acid and edetate salts; and preservatives including citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, and sorbic acid; and more preferably vitamin E and / or butylated hydroxytoluene (BHT); and / or because it additionally comprises one or more substances that enhance the transdermal penetration, preferably a compound selected from the group consisting of alcohols, such as short-chain alcohols, for example elanol and similar alcohols, long-chain fatty alcohols, for example lauryl alcohols. and the like, and polyalcohols, for example propylene glycol, glycerin; amides, such as amides with long aliphatic chains, or aromatic amides such as N, N-dethyl-m-toluamide; amino acids; azone and azonic compounds; essential oils, i.e. essential oils or their constituents, such as 1-carvone, 1-menthone and similar compounds; fatty acids and esters of fatty acids, such as oleic acid, lauric acid and the like, additional esters of the fatty acids, such as isopropyl mirisols, and various esters of lauric acid and oleic acid; macrocyclic compounds, such as cyclopentadecanone and cyclodextrins; phospholipid compounds and phosphate compounds, such as phospholipids; 2-pyrrolidone compounds; and various compounds, such as sulfoxides, such as dimethyl sulfoxides, and fatty acid ethers, such as Laureth-9 and polyoxylauryl ether; and / or because it additionally comprises one or more substances that reduce irritant reactions, preferably vitamin E.

12. The device according to any of the preceding claims, further characterized in that it is occlusive. 13.- Use of nicotine for the manufacture of a device to help smoking cessation, in periods of transient abstinence, and / or reduce the urge to smoke or otherwise use material containing tobacco, and / or to handle appropriate situations for nicotine delivery, being selected from the group consisting of Alzheimer's disease, Crohn's disease, Parkinson's disease, Touretie's syndrome, ulcerative colitis and weight control when smoking cessation, such device being in accordance with any of claims 1 to 12. 14. A method to help smoking cessation, in periods of withdrawal, and / or reduce the urge to smoke or otherwise use tobacco that contains tobacco, and / or to handle situations suitable for smoking cessation. the treatment with nicofine, being selected the group's symptoms consist of Alzheimer's disease, Crohn's disease, Parkinson's disease, Tourelle syndrome, ulcerative colitis and weight control upon cessation of smoking, by transdermal administration of nicotine with a device according to any of claims 1 to 12. 15.- A method to help smoking cessation, in periods of absenteeism transient, and / or reduce the urgency of smoking or otherwise using tobacco-containing material, and / or to handle situations suitable for nicotine trafficking, such situations being selected from the group consisting of Alzheimer's disease, Crohn's disease, Parkinson's disease, Toureiie syndrome, ulcerative colitis and weight control upon smoking cessation, by transdermal administration of nicotine with a device according to any of claims 1 to 12 in combination with selected means of mouth sprays, nasal sprays, patches transdermal, inhalation devices, pills, iableies, and medium parenteral methods, subcutaneous methods, iniravenous methods, rectal methods, vaginal methods and methods of transportations to mucous membranes, including the use of tobacco.