MXPA06004719A - Method and apparatus for reducing the incidence of tobacco use - Google Patents

Abstract

An apparatus for transdermally delivering a nicotine-based agent to a tobacco or nicotine user comprising a microprojection member (5) having a plurality of microprojections (10) that are adapted to pierce the stratum corneurn of the tobacco user, the microprojection member having a biocompatible coating (16) disposed thereon that includes a nicotine-based agent.

Description

YAPARATO METHOD TO REDUCE THE INCIDENCE OF TOBACCO USE CROSS REFERENCE WITH RELATED REQUESTS This application claims the benefit of the provisional application of E.U.A. No. 60 / 515,396, filed on October 28, 2003.

FIELD OF THE PRESENT INVENTION The present invention relates to a method and apparatus for reducing or eliminating an individual's habit of tobacco use, particularly smoking, and the related nicotine dependence that is created through the use of tobacco.

BACKGROUND OF THE INVENTION In recent years, with the recognition of the harmful effects of tobacco smoking, there have been numerous campaigns and programs by government agencies, various health groups, and other organizations interested in disseminating information about the adverse health effects that result from In addition, and as a result of this recognition of the harmful effects, there have been many programs related to attempts to reduce the incidence of smoking, however, the successes to achieve the reduction in the incidence of smoking have been relatively scarce. Currently known The present state of the art involves behavioral methods and also pharmacological methods.Approximately 80% or more of tobacco smokers who initially quit smoking after using some behavioral or pharmacological method to reduce without incidence the incidence to smoking , they usually relapse and return to the habit of smoking in its initial smoking ratio in approximately a period of one year. One method that is commonly used to reduce the incidence of smoking is based on nicotine-containing chewing gum, which is designed to reduce the symptoms of smoking abstinence. The reported success rate, although still relatively low, is approximately twice that of the other methods, which to date had been employed. There are numerous drawbacks and disadvantages related to the use of nicotine gum, including a bad taste and destruction of dental appliances. A further disadvantage is that nicotine gum causes gastrointestinal disturbance, which often reduces compliance. In addition, it has been found that nicotine-containing gum does not satisfy the anxiety that most smokers experience because of the different sensations in the throat and chest produced by nicotine in the smoke. Over the course of many years of tobacco smoking, these particular sensations have become an important and related part of the habit of smokers and give rise to the dependence to the smoke of the tobacco in the majority of the tobacco smokers. Passive transdermal delivery of nicotine-based agents has also been used to reduce the incidence of smoking. Delivery is usually achieved through a transdermal patch that is removably applied to the skin. As an example there are the transdermal patches used in the system marketed by GlaxoSmithKIine under the trade name NICODERM CQ®. As is known in the art, transdermal agent delivery systems generally rely on passive diffusion to deliver an agent, such as nicotine, while other active transdermal agent delivery systems rely on external energy sources, including electricity. (for example, iontophoresis) and ultrasound (for example, phonophoresis) to deliver the agent. Passive transdermal drug delivery systems are more common. Passive transdermal systems usually include a drug reservoir containing a high concentration of the agent. The reservoir is adapted to make contact with the skin, which allows the agent to diffuse through the skin and into the bodily tissues or bloodstream of an individual, such as a tobacco user.

As is known in the art, the flow of transdermal agent depends on the condition of the skin, the size and physical / chemical properties of the drug molecule, and the concentration gradient across the skin. Due to the low permeability of the skin for many agents, the transdermal delivery has had limited applications. This low permeability is mainly attributed to the stratum corneum, the outermost skin layer consisting of flat, dead cells, filled with keratin fibers (ie, keratinocytes) surrounded by lipid bilayers. This highly ordered structure of the lipid bilayers confers a relatively impermeable character to the stratum corneum. A common method for enhancing flow by diffusion of passive transdermal agent involves pre-treating the skin with, or co-delivering with the agent, a skin penetration enhancer. A penetration enhancer, when applied to a body surface through which the agent is delivered, improves the flow of the agent therethrough. However, the effectiveness of these methods to enhance the transdermal flow for many agents has been limited. An additional method to enhance the flow of transdermal agent is through the use of active transportation systems. As indicated, active transportation systems use an external energy source to help, and in most cases, enhance agent flow through the stratum corneum. Said improvement for the transdermal agent supply is referred to as "electrotransport". This mechanism uses an electrical potential, which results in the application of electrical current to aid in the transport of the agent through a body surface, such as the skin. There have also been many techniques and systems developed to penetrate or mechanically break the outermost layers of skin thus creating trajectories to the skin in order to enhance the amount of agent that is transdermally delivered. The first vaccination devices, known as scarifiers, generally included a plurality of teeth or needles that were applied to the skin to scrape or make small cuts in the area of application. The vaccine was applied either topically on the skin, as described in the U.S. patent. No. 5,487,726, or as a wetted liquid applied to the teeth of the scarifier, as described in the U.S. Patents. Nos. 4,453,926, 4,109,655, and 3,136,314. However, there are numerous disadvantages and drawbacks related to scarifiers. A serious disadvantage of using a scarifier to deliver an agent is the difficulty in determining the transdermal agent flow and the resulting dosage delivered. In addition, due to the elastic, flexible and deformable nature of the skin to fold and resist piercing, the tiny puncturing elements often do not uniformly penetrate the skin and / or become free of a liquid coating of an agent after the penetration in the skin.

In addition, due to the process of self-healing of the skin, the perforations or slits made in the skin tend to close after the removal of the piercing elements of the stratum corneum. In this way, the elastic nature of the skin acts to remove the liquid coating of active agent that has been applied to the tiny piercing elements after the penetration of these elements into the skin. In addition, the tiny slits formed by the piercing elements heal quickly after removal of the device, thus limiting the passage of liquid agent solution through the passages created by the piercing elements and in turn, limit the transdermal flow of said devices . Other systems and apparatuses that employ minute skin piercing elements to enhance the delivery of transdermal agent are described in the U.S. Patents. Nos. 5,879,326, 3,814,097, 5,279.54, ,250,023, 3,964,482, Reissue No. 25,637, and PCT Publication Nos. WO 96/37155, WO 96/37256, WO 96/17648, WO 97/03718, WO 98/11937, WO 98/00193, WO 97/48440, WO 97/48441, WO 97/48442, WO 98/00193, WO 99/64580, WO 98/28037, WO 987/29298, and WO 98/29365; all incorporated to the present in its entirety. The described systems and apparatuses employ perforating elements of various shapes, sizes and arrangements for piercing the outermost layer (ie, the stratum corneum) of the skin. The piercing elements described in these references generally extend perpendicularly from a thin, flat element, such as a pad or sheet. The perforating elements in some of these devices are extremely small, some have a microprojection length of only about 25-400 microns and a microprojection thickness of only about 5-50 microns. These tiny perforation / cutting elements thus make micro-slits / small micro-cuts in the stratum corneum to enhance the delivery of transdermal agent therethrough. The systems described generally also include a reservoir for containing the agent and also a delivery system for transferring the agent from the reservoir through the stratum corneum, such as, for example, through hollow teeth of the device itself. An example of such a device is described in WO 93/17754, which has a liquid agent reservoir. However, the reservoir must be pressurized to force the liquid agent through the tiny tubular elements and into the skin. The disadvantages of such devices include the complication and added expense for adding a pressurizable liquid reservoir and complications due to the presence of a pressure operated delivery system. As described in the patent application of E.U.A. No. 10 / 045,842, which is incorporated herein by reference in its entirety, it is also possible that the agent to be supplied is coated in the microprojections instead of being contained in a physical reservoir. This eliminates the need for a separate physical deposit and for developing a drug formulation or composition specifically for deposit. However, hitherto the coated microprojections have not been employed to transdermally deliver nicotine-based agents to users of tobacco or nicotine to reduce dependence thereon. Therefore, it is an object of the present invention to provide a transdermal delivery apparatus and method that substantially reduces or eliminates the aforementioned disadvantages and drawbacks related to the prior art nicotine-based delivery system delivery systems. It is another object of the present invention to provide a transdermal apparatus and method for the delivery of nicotine-based agents that substantially reduce or eliminate the incidence of tobacco and / or the use of nicotine. Another objective of the present invention is to provide a transdermal delivery apparatus having a coated microprojection arrangement that delivers nicotine-based agents at an effective dose in a bolus delivery.

BRIEF DESCRIPTION OF THE INVENTION In accordance with the above objectives and those to be mentioned and which will be apparent below, the apparatus for transdermally supplying nicotine-based agents to a user of tobacco or nicotine in accordance with this invention comprises a microprojection element having a plurality of microprojections that are adapted to pierce through the stratum corneum to the underlying epidermis and dermal layers of the nicotine user, the microprojection member has a biocompatible coating that has at least a nicotine-based agent thereon. Preferably, the nicotine-based agent is selected from the group consisting of nicotine base, nicotine salts and simple nicotine derivatives. As discussed in detail herein, after drilling through the stratum corneum, the coating containing the agent dissolves through body fluid (intracellular fluids and extracellular fluids, such as interstitial fluid) and is released into the skin layer. epidermis for systemic therapy (ie, bolus delivery). The advantages of this invention, therefore, include (i) effective transdermal bolus delivery of nicotine-based agents, (i) rapid administration or emergence of nicotine, and (ii) effective treatment for persistent anxiety during attempts to quit tobacco by administering small amounts of nicotine when necessary. The invention also provides a convenient and easy-to-use method for supplementing nicotine replacement therapy. Preferably, each of the microprojections has a length of less than 1000 microns, preferably less than 500 microns. In one embodiment of the invention, each microprojection has a length of less than 250 microns. The coating formulations that are employed to form the biocompatible coatings, preferably include at least one wetting agent and optionally, a hydrophilic polymer. Preferably, the coating formulations include at least one surfactant, including but not limited to sodium lauroanfoacetate, sodium dodecylsulfate (SDS), cetylpyridinium chloride (CPC), dodecyltrimethylammonium chloride (TMAC), benzalkonium chloride, polysorbates such as Tween 20 and Tween 80, other sorbitan derivatives such as sorbitan laurate, and alkoxylated alcohols such as laureth-4. The most preferred surfactants include Tween 20, Tween 80 and SDS. Preferred coating formulations further include at least one polymeric material having amphiphilic properties, including but not limited to cellulose derivatives, such as hydroxyethyl cellulose (HEC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose (MC) ), hydroxyethylmethylcellulose (HEMC), and ethylhydroxyethylcellulose (EHEC), as well as pluronics.

The coating formulations may further include a hydrophilic polymer. Preferably, the hydrophilic polymer is selected from the following group: polyvinyl alcohol, polyethylene oxide, poly (2-hydroxyethyl methacrylate), poly (n-vinyl pyrrolidone), polyethylene glycol and mixtures thereof, and similar polymers. In a further embodiment of the invention, the coating formulations and, therefore, the biocompatible coatings include a vasoconstrictor. Preferably, the vasoconstrictor is selected from the group consisting of amidefrine, cafaminol, cyclopentamine, deoxyapinephrine, epinephrine, felipresin, indanazoline, metizoline, midodrine, naphazoline, nordefrine, octodrin, omipresin, oxymetazoline, phenylephrine, phenylethanolamine, phenylpropanolamine, propyledexedrine, pseudoephedrine, tetrahydrozoline. , tramazoline, tuaminoheptano, thimazoline, vasopressin and xylometazoline. In a further embodiment of the invention, the coating formulations and, therefore, the biocompatible coatings, may further include a biocompatible carrier. Examples of biocompatible carriers include human albumin, biodesized human albumin, polyglutamic acid, polyaspartic acid, polyhistidine, pentosan polysulfate, polyamino acids, sucrose, trehalose, melezitose, raffinose and stachyose. The thickness of the biocompatible coating disposed in the microprojections is preferably less than 50 microns. In one embodiment of the invention, the thickness of the coating is less than 25 microns.

The biocompatible coating provides a biologically effective amount of the nicotine-based agent and, if employed, a biologically effective amount of the vasoconstrictor. The biocompatible coating can be applied and dried in the microprojections using known coating methods. For example, the microprojections may be immersed or partially immersed in an aqueous coating solution. Alternatively, the coating solution can be sprayed onto the microprojections. Preferably, the spray has a droplet size of about 10-200 picoliters. Preferably, the size and placement of the drop is controlled precisely using printing techniques, so that the coating solution is deposited directly on the microprojections and / or on other "non-perforating" portions of the element having the microprojections. The method for transdermally delivering a nicotine-based agent to a nicotine user, according to one embodiment of the invention, comprises the steps of (i) providing a microprojection member having a plurality of microprojections that are adapted to pierce the stratum corneum of the nicotine user, (ii) coating the microprojection element with a coating formulation having at least one nicotine-based agent to form a biocompatible coating and (iii) applying the microprojection element to the user's skin of nicotine, whereby the microprojection elements perforate the stratum corneum of the nicotine user and supply the biocompatible coating and, therefore, the nicotine-based agent disposed therein.

BRIEF DESCRIPTION OF THE DRAWINGS Other features and advantages will be apparent from the following and more detailed description of the preferred embodiments of the invention, as illustrated in the accompanying drawings, in which the characters with similar reference generally refer to the same parts and / or elements in all views, and in which: Figure 1 is a perspective view of a portion of an example of a microprojection arrangement; Figure 2 is a perspective view of the microprojection arrangement shown in Figure 1 having a coating deposited on the microprojections, according to the invention; Figure 2A is a cross-sectional view of a simple microprojection taken along the line 2A-2A, according to the invention; Figure 3 is a side cross-sectional view of a microprojection arrangement having an adhesive reinforcement; Figure 4 is a side cross-sectional view of a retainer having a microprojection element disposed therein; and Figure 5 is a perspective view of the retainer shown in Figure 4.

DETAILED DESCRIPTION OF THE INVENTION Before describing the present invention in detail, it will be understood that this invention is not limited to particularly exemplified materials, methods or structures which, as such, may, of course, vary. Thus, although a number of materials and methods similar or equivalent to those described herein can be used in the practice of the present invention, the preferred materials and methods are described. It will also be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only and is not intended to be limiting. Unless otherwise defined, all the technical and scientific terms used in the present invention have the same meaning as commonly understood by one skilled in the art to which the invention pertains. In addition, all publications, patents and patent applications cited herein, whether supra or infra are hereby incorporated by reference in their entirety.

Finally, as used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, the reference to "a nicotine-based agent" includes two or more of said agents; the reference to "a microprojection" includes two or more of said microprojections and the like.

Definitions The terms "biologically active agent", "active agent" and "agent", as used herein, refer to a composition of matter or mixture containing a substance or drug, such as the nicotine-based agents described below, which are pharmacologically effective when administered in a therapeutically effective amount. The term "nicotine-based agent", as used herein, means and includes nicotine, a substance which is equivalent or approximating to nicotine, including any and all known compounds and / or compositions that produce a physiological effect similar to that of nicotine. of nicotine, or a mixture of them that produces an effect similar to that of nicotine. The term "nicotine-based agent" therefore includes, but is not limited to, nicotine base, nicotine salts and simple nicotine derivatives. Examples of pharmaceutically acceptable nicotine salts include, but are not limited to acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, levulinate, chloride, bromide, citrate, succinate, maleate, glycolate, gluconate, glucuronate, 3-hydroxyisobutyrate, 2- hydroxyisobutyrate, lactate, malate, pyruvate, fumarate, tartarate, tartronate, nitrate, phosphate, benzenesulfonate, methanesulfonate, sulfate, sulfonate, salicylate and double salts such as zinc chloride. Examples of simple nicotine derivatives include, but are not limited to amides, carbamates, mines, enamines, and N-acyloxyalkyloxycarbonyls. The aforementioned nicotine-based agents can also be in various forms, such as free bases, acids, charged or uncharged molecules, molecular complex components or non-irritant pharmacologically acceptable salts. The term "transdermal", as used herein, means the delivery of an agent in and / or through the skin for systemic therapy. The term "transdermal flow", as used herein, means the rate of transdermal delivery. The term "co-delivery", as used herein, means that a supplemental agent (s) is administered transdermally either before the agent is delivered, before and during transdermal flow of the agent, during transdermal flow. of the agent, during and after transdermal flow of the agent, and / or after transdermal flow of the agent. In addition, two or more nicotine-based agents can be coated onto the microprojections resulting in the co-delivery of the nicotine-based agents. It will be understood that more than one nicotine-based agent can be incorporated into the coating formulations and, therefore, into the biocompatible coatings of this invention and that the use of the terms "active agent" and / or "nicotine-based agent" does not in any way exclude the use of two or more of said agents. The term "biologically effective amount" or "biologically effective rate" will be used when the nicotine-based agent is a pharmaceutically active agent and refers to the amount or speed of the pharmacologically active agent necessary to achieve the therapeutic, often beneficial, result. wanted. The amount of active agent employed in the coatings of the invention will be that amount necessary to deliver a therapeutically effective amount of the active agent to obtain the desired therapeutic result. In practice, this will vary widely depending on the particular pharmacologically active agent that is delivered, the delivery site, the severity of the condition being treated, the desired therapeutic effect and the kinetics of dissolution and release for delivery of the agent from the coating to the tissues of the skin. The term "bolus supply" refers to the "release of the nicotine-based agent into the skin within a certain time".

The term "release of the nicotine-based agent in the skin within a certain time" means that most (eg, more than 50%) of the total dose delivered to the skin is actually delivered during that time. The term does not refer to the total time of use (which may be longer) or to the total amount of the coated agent in the microprojections. The term "biologically effective amount" or "biologically effective rate" will also be used when the nicotine-based agent is an immunologically active agent and refers to the amount or rate of the immunologically active agent necessary to stimulate or initiate the immunological result, with beneficial frequency, desired. The amount of the immunologically active agent employed in the coatings of the invention will be that amount necessary to supply an amount of the active agent necessary to obtain the desired immunological result. In practice, this will vary widely depending on the particular immunologically active agent that is delivered, the delivery site, and the dissolution and release kinetics for delivery of the active agent to the skin tissues. The terms "microprojections" and "microprotrusions", as used herein, refer to piercing elements that are adapted to pierce or cut through the stratum corneum to the underlying epidermal layer or layers of epidermis and dermis, of the skin of a living animal, particularly a mammal, and particularly a human being.

As discussed herein, in one embodiment of the invention, the microprojections have a projection length of less than 1000 microns. In a further embodiment, the microprojections have a projection length of less than 500 microns, preferably less than 250 microns. The microprojections preferably have a width and thickness of about 5 to 50 microns. The microprojections can also be formed in different configurations, such as needles, blades, pins, punctures and combinations thereof. The term "microprojection arrangement", as used herein, refers to a plurality of microprojections disposed in an arrangement for piercing the stratum corneum. The microprojection arrangement can be formed either by etching or puncturing a plurality of microprojections from a thin sheet and bending or flexing the microprojections out of the plane of the sheet to form a configuration, such as that shown in Figure 1 The arrangement of microprojections can also be formed in other known ways, such as by forming one or more strips having microprojections along one edge of each of the strip (s) as described in the US Pat. USA No. 6,050,988, which is incorporated herein by reference in its entirety. References to the area of the sheet or element and reference to some property by area of the sheet or element refer to the area limited by the circumference or outer edge of the sheet.

The term "solution" will include not only fully dissolved component compositions, but also suspensions of nicotine-based agents. The present invention, as described herein, provides an effective method and apparatus for reducing or eliminating an individual's habit of tobacco or nicotine use, particularly smoking, as well as the nicotine dependence associated with that habit. The reduction or elimination of tobacco use is done with or without behavioral intervention. This strategy expands the use of nicotine replacement therapy from an abrupt cessation of tobacco use to a gradual reduction. The gradual reduction of the number of smoked cigarettes or other nicotine products used during the replacement of nicotine with an alternative source, such as the coated microprojection element of the invention, helps reduce nicotine anxieties and abstinence thus facilitating reduction or elimination of tobacco use. As indicated above, the present invention comprises an apparatus and system for transdermal delivery of nicotine-based agents to a user of tobacco or nicotine. The system generally includes a microprojection element having a microprojection arrangement comprising a plurality of microprojections that are adapted to pierce through the stratum corneum to the underlying epidermis layer, or epidermis and dermis layers.

Preferably, the microprojections have a coating thereon which contains at least one biologically active agent, preferably a nicotine-based agent. By piercing through the stratum corneum layer of the skin, the coating containing the agent is dissolved by body fluid (intracellular fluids and extracellular fluids such as interstitial fluid) and released into the epidermis layer for systemic therapy (i.e. , bolus supply). In contrast, in a conventional passive patch, the coating containing the agent must diffuse into and through the stratum corneum to obtain the systemic delivery. In this way, said systems do not present a bolus supply. Preferably, the release of the nicotine-based agent towards the epidermis layer of the skin occurs 1 hour after the application of the microprojection arrangement. Preferably, the release of the nicotine-based agent towards the epidermis layer occurs 15 minutes after the application of the microprojection arrangement. Even preferably, the release of the nicotine-based agent towards the epidermis layer occurs within 5 minutes after the application of the microprojection arrangement. According to the invention, the kinetics of the solution and release of the coating will depend on many factors including the nature of the biologically active agent, the coating process, the thickness of the coating and the coating composition. (for example, the presence of coating formulation additives).

Depending on the profile of the release kinetics, it may be necessary to keep the microprojections coated in perforating relation with the skin for extended periods. This can be done by anchoring the microprojection element to the skin using adhesives or by the use of anchored microprojections, as described in PCT publication WO 97/48440, which is hereby incorporated by reference in its entirety. Referring now to Figure 1, one embodiment of a microprojection member 5 is shown for use with the present invention. As illustrated in Figure 1, the microprojection member 5 includes a microprojection arrangement 7 having a plurality of microprojections 10. The microprojections 10 preferably extend substantially at a 90 ° angle from the sheet 12, which includes openings 14. According to the invention, the sheet 12 can be incorporated into a delivery patch, which includes a reinforcement 15 for the sheet 12, and can additionally include adhesive 16 to adhere the patch to the skin (see Figure 3). In this embodiment, the microprojections 10 are formed by etching or puncturing a plurality of microprojections 10 from a thin sheet of metal 12 and flexing the microprojections 10 out of the plof the sheet 12. The microprojection element 5 can be manufactured from various metals, such as stainless steel, titanium, nickel and titanium alloys, or similar biocompatible materials, such as polymeric materials. Preferably, the microprojection element 5 is made of titanium. The microprojection elements that can be employed with the present invention include, but are not limited to, the elements described in the U.S.A. Nos. 6,083,196, 6,050,988 and 6,091,975, which are hereby incorporated by reference in their entirety. Other microprojection elements that may be employed with the present invention include elements formed by etching with silicon acid using silicon chipplate etching techniques or by plastic molding using acid-etched micromoldes, such as the elements described in the US Pat. USA No. 5,879,326, which is incorporated herein by reference in its entirety. Referring now to Figure 2, the microprojection member 5 is shown having microprojections 10 which include a biocompatible coating 16. According to the invention, the coating 16 can partially or completely cover each microprojection 10. For example, the coating 16 can be in a dry pattern coating on the microprojections 10. The coating 10 can also be applied before or after the microprojections 10 are formed. According to the invention, the coating 16 can be applied to the microprojections 10 through a variety of known methods. Preferably, the coating is applied only to those portions of the microprojection member 5 or microprojections 10 that pierce the skin (e.g., tips 18). One such coating method comprises the dip coating. The dip coating can be described as a means for coating the microprojections by partially or totally submerging the microprojections 10 in a coating solution. Through the use of a partial immersion technique, it is possible to limit the coating 16 only to the tips 18 of the microprojections 10. Another coating method comprises the roll coating, which employs a roller coating mechanism which likewise limits the coating. coating 16 to the tips 18 of the microprojections 10. The roller coating method is described in the US patent application No. 10 / 099,604 (Pub. No. 2002/0132054) which is incorporated by reference in its entirety herein. As discussed in detail in the aforementioned application, the roller coating method described provides a smooth coating that does not easily detach from the microprojections 10 during skin piercing. The smooth cross-section of microprojection tip coating is further illustrated in Figure 2A. According to the invention, the microprojections 10 may further include means adapted to receive and / or improve the volume of the coating 16, such as openings (not shown) grooves (not shown), surface irregularities (not shown) or similar modifications, wherein the means provide a greater surface area on which a larger amount of coating can be deposited. Another coating method that can be employed within the scope of the present invention comprises spray coating. In accordance with the invention, the spray coating may encompass the formation of an aerosol suspension of the coating composition. In one embodiment, an aerosol suspension having a droplet size of about 10 to 200 picoliters is sprinkled onto the microprojections 10 and then dried. The pattern coating can also be used to coat the microprojections 10. The pattern coating can be applied using a dispensing system to place the liquid deposited on the microprojection surface. The amount of liquid deposited is preferably in the range of 0.1 to 20 nanoliters / microprojection. Examples of liquid dispensers with suitable metering accuracy are described in U.S. Pat. Nos. 5,916,524; 5,743,960; 5,741,554 and 5,738,728, which are fully incorporated by reference herein. Microprojection coating solutions can also be applied using inkjet technology using solenoid valve dispensers, optional fluid motive media and placement means which are generally controlled by the use of an electric field. Another liquid dispensing technology of the printing industry or similar liquid dispensing technology that is known in the art can be used to apply the pattern coating of this invention. According to the invention, the coating formulations applied to the microprojection element for forming solid coatings can comprise aqueous and non-aqueous formulations having at least one nicotine-based agent. In accordance with the invention, the active agent can be dissolved with a biocompatible carrier or suspended within the carrier. Preferably, the nicotine-based agent comprises a nicotine base, nicotine salts and simple nicotine derivatives. More preferably, the nicotine-based agent is a nicotine salt. There are several advantages related to the use of a salt instead of the base. First, it is expected that the use of a nicotine salt results in a reduction or elimination of a deposit in the skin compared to the nicotine base. Another advantage is that the form of nicotine in salt is expected to result in better chemical stability of the nicotine and better stability of the chemical composition of the coating during storage compared to the nicotine base. An additional advantage is that the nicotine form in salt is expected to reduce or eliminate the characteristic bad odor of the nicotine base.

Examples of pharmaceutically acceptable nicotine salts include, without restriction, acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, levulinate, chloride, bromide, citrate succinate, maleate, glycolate, gluconate, glucuronate, 3-hydroxisobutyrate, 2-hydroxyisobutyrate, lactate, malate, pyruvate, fumarate, tartarate, tartronate, nitrate, phosphate, benzenesulfonate, methanesulfonate, sulfate, sulfonate, salicylate and double salts such as zinc chloride. Examples of simple nicotine derivatives include, without restriction, amides, carbamates, imines, enamines and N-acyloxyalkyloxycarbonyls. Preferably these derivatives are reversible and will be degraded or metabolized to nicotine and introduced into the body. Even more preferably, the nicotine-based agent is a nicotine salt that exhibits low volatility. The use of this type of salt is expected to result in optimum stability of the chemical composition of the coating during storage. The solid coating is obtained by drying a formulation on the microprojection as described in the patent application of E.U.A. No. 2002/0128599. A number of factors affect the volatility of the compounds. These include temperature, atmospheric pressure and vapor pressure of the compound. The volatilization process depends on the time. Additionally, ionized compounds exhibit a much lower volatility compared to non-ionized forms. For example, acetic acid has a boiling point of 118 ° C while sodium acetate is essentially non-volatile. During the drying process, all volatiles, including water, are removed almost completely. If a volatile compound in equilibrium between its ionized and non-ionized forms is present in solution, only the non-ionized form disappears at the moment in which the drying process takes place and the ionized form remains in solution. In a solid coating in a microprojection arrangement, the active agent is typically present in an amount of less than about 2 mg per unit dose. With the addition of excipients and counterions, the total mass of the solid coating is less than 4 mg per unit dose. The microprojection arrangement is usually arranged in an adhesive backing, which is attached to a disposable polymeric retainer ring. This assembly is typically packaged individually in a bag or in a polymeric housing. In addition to the assembly, this package contains an atmosphere (usually inert) that refers to a volume of at least 3 ml. This large volume (compared to that of the coating) acts as a receiver for any volatile component. For example, at 20 ° C, the amount of acetic acid present in a 3 ml atmosphere as a result of its vapor pressure would be around 0.15 mg. This amount is typically that which would be present in the solid coating if the acetic acid were used as counter-ion. Additionally, the components of the assembly such as the adhesive probably act as additional receptors for volatile components. As a result, during its long-term storage, it is likely that the concentration of any volatile component present in the coating will change dramatically. These conditions are atypical of the packaging of pharmaceutical products where large amounts of additives are present. The nicotine base also has some volatility and, if present in the formulation, will be affected in the same way by these procedures. The selection of a nicotine salt having a low volatility is based on the pKa of nicotine as well as on the pKa and melting point of the acid counter ion. As is well known in the art, nicotine itself is a liquid at room temperature and exhibits some volatility. The smell of the nicotine base is certainly very strong and this odor (which is partly due to the volatile degradants) is greatly reduced by salification. The majority, if not all nicotine salts have a higher melting point than nicotine itself. Additionally, if salification of nicotine is achieved with an acidic compound having a pKa greater than 4, a fraction of the acid and / or nicotine is free and the counterion will slowly evaporate and / or migrate into system components, which will result in the poor stability of the system. Examples of volatile counterions include, without restriction, acetic acid, propionic and butyric acid. A more preferred embodiment is directed to nicotine salts with low volatility, where the counterion is a strong acid. A strong acid is defined as an acidic compound having at least one pKa less than about 2. Examples of such acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfonic acid, sulfuric acid, maleic acid, phosphoric acid, benzenesulfonic acid and methanesulfonic acid. In another more preferred embodiment, the acid counterion is a weak acid with low volatility. Said compound is defined as an acid compound having at least one pKa greater than about 2 and melting point greater than about 50 ° C. Examples of such acids include citric acid, succinic acid, glycolic acid, gluconic acid, glucuronic acid, lactic acid, malic acid, pyruvic acid, tartaric acid, tartronic acid, fumaric acid and salicylic acid. According to the invention, nicotine and counterion can be combined in various stoichiometric amounts. Excess of counterions (such as free acid or as a salt) can be added to nicotine to control pH. It is also possible to use mixtures of different counterions. The coating formulation containing a nicotine-based agent should preferably be water-based. After drying, as described in the patent application of the U.S.A. 2002/0128599 (World Publication WO 02/094368), the formulation is substantially free of water, although residual water up to 0% p may be present. Optionally the nicotine-based agent could be formulated in non-aqueous formulations. Examples of solvents that can be used include ethanol, IPA, chloroform, ether, petroleum ether, kerosene, and other volatile solvents. Additives for formulations (wetting agents, viscosity enhancing agents) can also be added to the formation. After drying, the formulation is substantially free of volatile solvent although it may be present in residual solvent in up to 10% p. The concentration of the nicotine-based agent in the coating formulation is preferably in the range of 5-80% p, more preferably in the range of about 10-70% p. Even more preferably, the concentration of the nicotine-based agent in the coating formulation is in the range of about 20-60% p of the coating formulation. The concentration of the nicotine-based agent in the solid coating (s) is preferably up to 99% p. More preferably, the concentration of the nicotine-based agent in the solid coating (s) is on the scale of about 30-70% p. According to the invention, the nicotine-based agent used in the present invention requires that the total amount of the agent coated on the microprojections of a microprojection arrangement be sufficient to effectively deliver it on the scale of approximately 0.02-2.0 mg of the agent to a nicotine user. According to the invention, quantities within this scale can be coated on a microprojection arrangement of the type shown in Figure 1 having an area of up to 10 cm2 and a microprojection density of up to 2000 microprojections per cm2. In accordance with the invention, the coating formulations preferably include at least one wetting agent. As is known in the art, wetting agents can generally be described as amphiphilic molecules. When a solution containing the wetting agent is applied to a hydrophobic substrate, the hydrophobic groups of the molecule agglutinate to the hydrophobic substrate, while the hydrophilic portion of the molecule remains in contact with the water. As a result, the hydrophobic surface of the substrate is not coated with hydrophobic groups of the wetting agent, making it susceptible to wetting by the solvent. Wetting agents include surfactants as well as polymers that exhibit amphiphilic properties. In one embodiment of the invention, the coating formulations include at least one surfactant. According to the invention, the surfactant agent (s) can be zwitterionic (s), amphoteric (s), cationic (s), anionic (s) or non-ionic (s). Examples of surfactants include sodium lauroamphoacetate, sodium dodecylisulfate (SDS), cetylpyridinium chloride (CPC), dodecyltrimethyl ammonium chloride (TMAC), benzalkonium chloride, polysorbates such as Tween 20 and Tween 80, other sorbitan derivatives such as laurate sorbitan and alkoxylated alcohols such as laureth-4. More preferred surfactants include Tween 20, Tween 80 and SDS.

Applicants have discovered that the use of the aforementioned surfactants at the desired scales provides maximum wetting and above the critical concentration of micelles.

(CMC). Wetting is also noticeable at concentrations as low as about an order of magnitude below CMC. Preferably, the concentration of the surfactant is on the scale of about 0.001-2% p of the coating solution formulation. In a further embodiment of the invention, the coating formulations include at least one polymeric material or polymer having amphiphilic properties. Examples of the noted polymers include, without restriction, cellulose derivatives such as hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose (MC), hydroxyethylmethylcellulose (HEMC), or ethylhydroxyethylcellulose (EHEC), as well as pluronics. In one embodiment of the invention, the concentration of the polymer having amphiphilic properties preferably is in the range of about 0.01-20% p, more preferably in the range of 0.03-10% p of the coating formulation. Even more preferably, the concentration of the wetting agent is in the range of 0.1-5% p of the coating formulation. As will be observed by one skilled in the art, the observed wetting agents can be used separately or in combinations.

In accordance with the invention, the coating formulations may further include a hydrophilic polymer. Preferably the hydrophilic polymer is selected from the following groups: polyvinyl alcohol, polyethylene oxide, poly (2-hydroxyethyl methacrylate), poly (n-vinyl pyrrolidone), polyethylene glycol and mixtures thereof, and similar polymers. As is well known in the art, the observed polymers increase the viscosity. The concentration of the hydrophilic polymer in the coating formulation is preferably in the range of about 0.01-20% p, more preferably in the range of about 0.03-10% p of the coating formulation. Even more preferably, the concentration of the wetting agent is on the scale of about 0.1-5% p of the coating formulation. In accordance with the invention, the coating formulations can further include a biocompatible carrier such as those described in the application of E.U.A. co-pending No. 10 / 127,108, which is incorporated herein by reference in its entirety. Examples of biocompatible carriers include human albumin, biodesigned human albumin, polyglutamic acid, polyaspartic acid, polyhistidine, pentosan polysulfate, polyamino acids, sucrose, trehalose, melezitose, raffinose and stachyose. The concentration of the biocompatible carrier in the coating formulation is preferably in the range of about 2-70% p, more preferably in the range of about 5-50% p of the coating formulation. Even more preferably, the concentration of the wetting agent is in the range of about 10-40% p of the coating formulation. The coatings of the invention may also include a vasoconstrictor such as those described in the application of E.U.A. co-pending No. 10 / 674,626 and 60 / 514,433, which are incorporated by reference herein in their entirety. As stated in the co-pending requests observed, the vasoconstrictor is used to control bleeding during and after the application of the microprojection element. Preferred vasoconstrictors include, without restriction, amidefrin, cafaminol, cyclopentamine, deoxypinephrine, epinephrine, felipresin, indanazoline, metizoline, midodrine, naphazoline, norphedrine, octodrin, ornipressin, oxymetazoline, phenylephrine, phenylethanolamine, phenylpropanolamine, propylhexedrine, pseudoephedrine, tetrahydrozoline, tramazoline, tuaminoheptane , thimazoline, vasopressin, xylometazollna, and mixtures of these. More preferred vasoconstrictors include epinephrine, naphazoline, tetrahydrozoline, indanazoline, metizoline, tramazoline, tlmazoline, oxymetazoline and xylometazoline. The concentration of the vasoconstrictor, if employed, is preferably in the range of about 0.1% p to 10% p of the coating. In still another embodiment of the invention, the coating formulations include at least one "path paten modulator" such as those described in the application of E.U.A. co-pending No. 09 / 950,436, which is incorporated by reference herein in its entirety. As established in the co-pending application observed, the trajectory paten modulators avoid or diminish the natural healing processes of the skin, thus avoiding the closure of the trajectories or micro-indentations formed in the stratum corneum by the arrangement of elements of microprojection. Examples of path-length modulators include, without restriction, osmotic agents, (e.g., sodium chloride), and zwitterionic compounds (e.g., amino acids). The term "pathway patency modulator" as defined in the co-pending application also includes antiinflammatory agents such as betamethasone 21-phosphate disodium salt, triamcinolone acetonite 21-disodium phosphate, hydrocortamate hydrochloride, hydrocortisone 21-phosphate disodium salt, disodium salt of methylprednisolone 21-phosphate, sodium salt of methylprednisolone 21 -succinate, disodium parametasone phosphate and sodium salt of prednisolone 21 -succinate and anticoagulants such as citric acid, citrate salts (eg, sodium citrate), dextrin sulfate sodium, aspirin and EDTA. According to the invention, the coating formulations can also include a non-aqueous solvent such as ethanol, chloroform, ether, propylene glycol, polyethylene glycol and the like, dyes, pigment, inert fillers, penetration enhancers, excipients and other conventional pharmaceutical or pharmaceutical components. transdermal devices known in the art.

Other known formulation adjuvants can also be added to the coating formulations as long as they do not adversely affect the necessary solubility and viscosity characteristics of the coating formulation and the physical integration of the dry coating. Preferably, the coating formulations have a viscosity of less than about 500 centipoise and greater than 3 centipoise to effectively coat each microprojection 10. More preferably, the coating formulations have a scale viscosity of about 3- 200 centipoise. According to the invention, the desired coating thickness depends on the density of the microprojections per unit area of the sheet and the viscosity and concentration of the coating composition, as well as the chosen coating method. Preferably, the coating thickness is less than 50 microns. In one embodiment, the coating thickness is less than 25 microns, more preferably less than 10 microns as measured from the microprojection surface. Even more preferably, the coating thickness is in the range of about 1 to 10 microns. In all cases, once a coating has been applied, the coating formulation is dried on the microprojections 10 by various means. In a preferred embodiment of the invention, the coated element 5 is dried under ambient temperature conditions. However, various temperatures and humidity levels can be used for the coating formulation on the microprojections. Additionally, the coated element 5 can be heated, lyophilized, freeze-dried or similar techniques used to remove water from the coating. Referring now to Figures 4 and 5, for storage and application, the microprojection member 5 is preferably suspended in a retainer ring 40 by adhesive tabs 6, as described in co-pending US Application No. 09 / 976,762 ( Pub. No. 2002/0091357), which is incorporated by reference herein in its entirety. After the placement of the microprojection element 5 in the retaining ring 40, the microprojection element 5 is applied to the skin of the patient. Preferably, the microprojection member 5 is applied to the skin using an impact applicator, as described in copending application No. 09 / 976,798, which is hereby incorporated by reference herein in its entirety. As will be appreciated by one skilled in the art, the present invention can also be employed with the transdermal drug delivery system and apparatus described in copending application No. 60 / 514,433.

EXAMPLES The following examples are provided to enable those skilled in the art to understand more clearly and to practice the present invention. They should not be considered as restrictive of the scope of the invention but as representative illustrations of it.

EXAMPLE 1 An aqueous solution containing 40% p of nicotine acid tartrate was prepared. Sufficient fluorescein was added to the solution to generate a concentration of 0.001 M. This agent was used to evaluate the quality of the coating after drying. A strip of thin titanium sheet was prepared by washing the surface with acetone and drying. Five microliters of the coating solution (or formulation) was applied and dried for four hours at room temperature. The quality of the coating was very poor when viewed under a fluorescent microscope, demonstrating the poor moisturizing properties of the nicotine solution. When 0.1% p of hydroxyethylcellulose (NATROSOL® 250 HHX PHARM, HERCULES Int. Lim., Holland, determined molecular weight: 1890000, Mn 1050000) was added to the same coating solution, the coating improved markedly.

EXAMPLE 2 A solution is prepared of 30% p of nicotine HCl in water. To this solution is added 0.1% p hydroxyethylcellulose and 0.1% p of the Tween 20 surfactant. The coating solution is then applied to the microprojections using the coating methods described in US Publication No. 2002/0132054. The coating is evaluated and found to be well distributed through the projections. The coated and dried projections of the 2 cm 2 device are found to contain about 300 micrograms of nicotine HCl. When the device is applied in humans using the applicator described in United States publication 2002/0123675, a supply of more than 70% of the nicotine contained in the projections is achieved.

EXAMPLE 3 An aqueous solution consisting of 5% p of nicotine base, 5% p hydroxypropylmethylcellulose (HPMC, Methocel E5 premium LV EP JP, Dow Chemical Company, Midland Ml) and 0.2% p Tween 20 is prepared. The coating solution is then applies to microprojections using the coating methods described in U.S. Publication No. 2002/0132054. The coating is evaluated and found to be distributed through the projections. The coated and dried projections of a 2 cm2 device are found to contain about 400 micrograms of nicotine base. The application of the device to the skin results in the essentially immediate delivery of 300 micrograms of nicotine base to the user.

From the above description one skilled in the art can easily elucidate that the present invention, among other things, provides an effective and efficient means to transdermally deliver nicotine-based agents to a tobacco user to substantially reduce or eliminate the habit of use to the tobacco user. tobacco. As will be appreciated by one skilled in the art, the present invention provides many advantages. Among the advantages are: • effective bolus transdermal supply of nicotine-based agents; • rapid administration or appearance of nicotine effect; • effective treatment for persistent anxiety during attempts to stop smoking by administering small amounts of nicotine when needed; and • a convenient method of providing a nicotine booster therapy employing a patch system. Without deviating from the essence of the scope of this invention, one skilled in the art can make various changes and modifications to the invention to adapt it to various uses and conditions. As such, these changes and modifications are appropriately, equitably and intended to be within the full range of equivalence of the following claims.

Claims (14)

NOVELTY OF THE INVENTION CLAIMS

1. An apparatus for transdermally supplying nicotine-based agents to a nicotine user, comprising a microprojection element having a plurality of microprojections that are adapted to pierce the stratum corneum of said nicotine user, said microprojection element includes a coating biocompatible that has at least one nicotine-based agent.

2. The apparatus according to claim 1, further characterized in that said nicotine-based agent is selected from the group consisting of nicotine base, nicotine salts and simple nicotine derivatives.

3. The apparatus according to claim 1, further characterized in that each of said microprojections has a length of less than about 1000 microns.

4. The apparatus according to claim 3, further characterized in that each of said microprojections has a length of less than about 500 microns.

5. The apparatus according to claim 4, further characterized in that each of said microprojections has a length of less than about 250 microns.

6. - The apparatus according to claim 1, further characterized in that said biocompatible coating further includes at least one wetting agent.

7. The apparatus according to claim 1, further characterized in that said biocompatible coating further includes a hydrophilic polymer.

8. The apparatus according to claim 1, further characterized in that said biocompatible coating further includes a surfactant.

9. The apparatus according to claim 1, further characterized in that said biocompatible coating further includes an amphiphilic polymer.

10. The apparatus according to claim 1, further characterized in that said biocompatible coating further includes a vasoconstrictor.

11. The apparatus according to claim 1, further characterized in that said biocompatible coating further includes a biocompatible carrier.

12. The apparatus according to claim 1, further characterized in that said biocompatible coating has a thickness of less than about 50 microns.

13. - The apparatus according to claim 1, further characterized in that said biocompatible coating has a thickness of less than about 25 microns.

14. The apparatus according to claim 1, further characterized in that it also includes an applicator having a contact surface, wherein said microprojection element is releasably mounted on said applicator by means of a retainer and wherein said applicator, once activated , puts said contact surface in contact with said microprojection element in such a manner that said microprojection element strikes the stratum corneum of the nicotine user with a power of at least 0.05 joules per cm2 of the microprojection element in 10 milliseconds or less.