MXPA06004905A

MXPA06004905A - Transdermal analgesic systems having reduced abuse potential

Info

Publication number: MXPA06004905A
Application number: MXPA/A/2006/004905A
Authority: MX
Inventors: Robert Gale; Thomas Stein; Jay Audett
Original assignee: Jay Audett; Gale Robert M; Thomas Stein
Priority date: 2003-10-30
Filing date: 2006-05-02
Publication date: 2007-04-20

Abstract

A transdermal analgesic system having reduced potential for abuse, wherein the system provides for the controlled release of the antagonist at a rate sufficient to provide an abuse limiting release rate ratio of the antagonist to the analgesic when the dosage form is subject to abuse is disclosed.

Description

TRANSDERMAL ANALGESIC SYSTEMS THAT HAVE A POTENTIAL OF REDUCED ABUSE TECHNICAL FIELD The present invention describes a transdermal analgesic system that has a reduced potential for abuse. In particular, the invention describes a system for the transdermal administration of fentanyl and analogs thereof to a subject through intact skin over an extended period of time, wherein the system provides controlled release of the antagonist at a rate sufficient to provide a rate of release ratio that limits the abuse of the antagonist to the analgesic when the dosage form is abused (ie, the transdermal analgesic system).

BACKGROUND OF THE INVENTION The transdermal administration of narcotic analgesics, ie, opioids for the treatment of both acute and chronic pain, has been described in great detail. The following U.S. Patent Nos. 4,466,953 4,470,962; 4,588,580; 4,626,539; 5,006,342; 5,186,939; 5,310,559; 5,474,783 5,656,286; 5,762,952; 5,948,433; 5,985,317; 5,958,446; 5,993,849; 6,024,976 6,063,399 and 6,139,866 describe various ways of transdermally administering fentanyl and analogs thereof, such as alfentanil, carfentanil, lofentanil, remifentanil, sufentanil, trefentanil and the like, and are incorporated herein by reference. These patents describe that fentanyl can be administered from an ointment applied topically, cream or from a transdermal patch. The potential for abuse of narcotic analgesics by intranasal, oral or parenteral routes of administration is well known. The fun and abuse of opioids can take several different forms. For example, the medication can be used by a person, for which it is not intended, that is, fun, or in amounts and / or frequency greater than those prescribed, either by the originally prescribed route (for example, oral or transdermal). ) or by an alternate route (for example, parenteral, intravenous, or intranasal). In order to prevent the abuse of these substances, it has been proposed to provide dosage forms that combine the abusable substance with an amount of an antagonist for the abusable substance sufficient to eliminate the "rise" associated with the abuse of the substance without the elimination of other therapeutic benefits for which the drugs are intended to be administered. See, for example, U.S. Patent Nos. 3,773,955; 3,493,657; 4,464,378; 4,457,933; 4,626,539; 4,806,341; 4,935,428; 5,149,538; and 5,236,714; and international publication No. WO 01/58451 A1, all of which are incorporated herein by reference. See also, Talwin; Levine J.D., et al. "Potentiation of pentazocine analgesia by low-dose naloxone", J Clin Invest 1988; 82: 1574-1577; Crain SM, Shen F-K "Antagonist of excitatory opioid receptor function enhance morphine's analgesic potency and attenuate opioid tolerance / dependence liability", Pain 2000; 84: 121-131, which are incorporated herein for reference. U.S. Patent No. 5,236,714 describes the transdermal dosage forms for delivering narcotic and psychoactive substances, the dosage form having a reduced potential for abuse. The transdermal dosage forms comprise an analgesic reservoir comprising a narcotic and an antagonist, and delivery means through which the narcotic is released in the body. U.S. Patent No. 5,149,538 discloses a misused-resistive dosage form for the transdermal administration of opioids. The dosage form comprises an opioid, an antagonist for the opioid that is releasable upon ingestion or immersion in solvent, barrier means separating the opioid from the antagonist and delivery means for delivering the opioid. Despite having some success, the existing dosage forms have not been entirely satisfactory for reducing the abuse potential, since the narcotic can be extracted from the dosage form for injection, inhalation or ingestion; or the narcotic and antagonist may interact resulting in adverse physical and / or chemical interaction, such as ion exchange or undesired penetration of the antagonist into the narcotic deposit that results in the systemic delivery of the antagonist. On prolonged exposure to the skin, the antagonist produces a sensitizing response. In addition, existing dosage forms are not provided for the controlled release of the antagonist at a rate sufficient to provide a release rate relationship that limits the abuse of the antagonist to the narcotic when the dosage form is abused, for example, in the ingestion or substantial immersion of the system in a solvent. When such dosage forms are subjected to abuse, the antagonist can be isolated at a rate disproportionate to the rate of release of the analgesic from the dosage form, such that the effects of the analgesic opioid become blocked Insufficiently during abuse situations. .

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to the aforementioned needs in the art, and provides a transdermal analgesic system that has reduced abuse potential, without diminishing the therapeutic or beneficial effects of the analgesic when the system is applied to the skin, where the system provides a substantially minimized / negligible skin sensitization response of the antagonist exposure. In particular, the transdermal analgesic system of the present invention provides controlled release of the antagonist at a rate sufficient to provide - a rate of release ratio that limits the abuse of the antagonist to the analgesic when the dosage form is subjected to abuse. Additionally, the transdermal analgesic system of the present invention provides improved safety, for example, in the case of accidental ingestion of a system used by children or domestic pets. In one aspect, the invention relates to a transdermal system for the administration of an analgesic through the skin, the system having a reduced potential for abuse, comprising: (a) an analgesic reservoir comprising an analgesic, the analgesic being selected from the group consisting of fentanyl and analogs thereof; (b) an antagonist reservoir comprising an antagonist for said analgesic; (c) a barrier layer, said barrier layer separating said antagonist deposit from the analgesic deposit, the barrier layer being substantially impermeable to said analgesic and said antagonist, wherein the system (i) allows the release of the antagonist from the system in normal use but at sufficiently low levels in such a way that the analgesic effect of the analgesic in the presence of the liberated antagonist divided by the effect of the analgesic in the absence of the liberated antagonist, is greater than about 85%, and (ii) it provides release of the antagonist at a rate sufficient to provide a rate of release ratio that limits abuse of the antagonist to the analgesic when the dosage form is subjected to abuse, for example, during ingestion or substantial immersion of the system in the solvent.

In another aspect, the transdermal analgesic system of the invention comprises an analgesic reservoir comprising an amount of analgesic sufficient to induce and maintain analgesia in a human patient for a period of at least three days, wherein the analgesic is fentanyl or a analogue thereof and the analogue is selected from the group consisting of alfentanil, lofentanil, remifentanil, sufentanil and trefentanil. In preferred embodiments, the analgesic in fentanyl or sufentanil, more preferably, the basic form of fentanyl or sufentanil. In additional aspects, the transdermal analgesic system of the invention comprises an analgesic reservoir comprising a polymer matrix comprising about 1% by weight to about 20% by weight of the analgesic, and optionally a penetration enhancer. Preferably, the analgesic deposit comprises a single phase formulation free of undissolved components. In other aspects, the transdermal analgesic system of the The invention comprises an analgesic deposit comprising an aqueous gel comprising up to about 20% by weight of the analgesic, up to about 50% by weight penetration enhancer, and about 0.5 to about 10% by weight of the analgesic agent. gelation In additional aspects, the transdermal analgesic system of the invention further comprises means for controlling the rate of analgesic release disposed between the analgesic reservoir and the skin. In certain aspects, the means of controlling the analgesic release rate are less permeable to the analgesic than to the penetration enhancer. In additional aspects, the transdermal analgesic system of the invention comprises an antagonist reservoir comprising an antagonist in a form that is not releasable through the barrier layer., the antagonist is releasable from the system when ingested or immersed substantially in a solvent. Preferably, the antagonist deposit comprises the antagonist dispersed within a polymer, wherein the antagonist is substantially insoluble in the polymer of the antagonist deposit. In certain embodiments, the antagonist is dispersed in a matrix comprising a material that substantially prevents the release of the antagonist.; or the antagonist forms complex with an ionic resin. In additional embodiments, the antagonist deposit comprises the antagonist in a multiparticulate form, wherein each particle is individually coated with a material that substantially prevents the release of the antagonist. In additional embodiments, the antagonist reservoir comprises beads coated with the antagonist, wherein the beads may be formed of glass or an inert or non-dissolvable polymer, and furthermore wherein the coated beads are optionally coated with material or dispersed therein. material that substantially prevents the release of the antagonist. The antagonist is selected from the group consisting of naltrexone, methylnaltrexone, naloxone, nalbuphine, nalorphine, nalorphine dinicotinate, nalmefene, nadide, levalorphan, cyclozocine and pharmaceutically acceptable salts thereof. In preferred embodiments, the antagonist is present as a salt, preferably as a hydrochloride salt of an antagonist base. In additional aspects, the transdermal analgesic system of the invention comprises a barrier layer impermeable to the analgesic and the antagonist; wherein the barrier layer comprises a material that is insoluble in water, alcohol and organic solvents. The antagonist deposit is deposited on the distal surface of the skin of the barrier layer and the analgesic deposit is placed on the proximal surface of the skin of the barrier layer. In additional aspects, the transdermal analgesic system of the invention further comprises means for controlling the rate of release of the antagonist, wherein said means for controlling the release rate of the antagonist (i) allow the release of the antagonist from the system in normal use. but at sufficiently low levels such that the analgesic effect of the analgesic in the presence of the liberated antagonist divided by the effect of the analgesic in the absence of the liberated antagonist is greater than about 85%; and (ii) provide for the release of the antagonist at a rate sufficient to provide a release rate ratio that limits the abuse of the antagonist to the analgesic when the dosage form is abused, for example, in the ingestion or substantial immersion of the system in the solvent The means of controlling the rate of release of the antagonist are placed on the distal surface of the skin of the antagonist reservoir. In another aspect, the transdermal analgesic system of the invention, when the dosage form is abused, for example, during ingestion or immersion in a solvent for a period of time, substantially continuously provides a release rate ratio of the analgesic antagonist from about 0.075: 1 to about 30: 1; from about 0.25: 1 to about 20: 1; from about 0.5: 1 to about 16: 1; from about 0.5: 1 to about 14: 1; from about 0.75: 1 to about 12: 1; from about 1: 1 to about 10: 1; from about 1.5: 1 to about 8: 1; from about 2: 1 to about 6: 1; and from about 2: 1 to about 4: 1, where the immersion time period is up to about 1 minute to about 24 hours. In another aspect, the invention describes a transdermal system for administering an analgesic through the skin, the system having a reduced potential for abuse, comprising: (a) an analgesic reservoir comprising an amount of analgesic sufficient to induce and maintaining analgesia in a human patient for a period of at least three days, wherein the analgesic is fentanyl or an analog thereof and the analog is selected from the group consisting of alfentanil, lofentanil, remifentanil, sufentanil and trefentanil; (b) an antagonist reservoir comprising an antagonist for said analgesic, wherein the antagonist is a form that is not releasable through the barrier layer, the antagonist being releasable from the system upon ingestion or substantially immersed in a solvent, and further wherein the antagonist is selected from the group consisting of naltrexone, methylnaltrexone, naloxone, nalbuphine, nalorphine, nalorphine dinicotinate, nalmefene, nadide, levalorphan, cyclozocine and pharmaceutically acceptable salts thereof; (c) a barrier layer, said barrier layer separating the antagonist reservoir from the analgesic reservoir, the barrier layer being substantially impermeable to said analgesic and said antagonist; and (d) means for controlling the release rate of the antagonist positioned on the distal surface of the skin of the antagonist reservoir, wherein the means of controlling the release rate of the antagonist (i) allow the release of the antagonist from the system. in normal use but at sufficiently low levels such that the analgesic effect of the analgesic in the presence of the liberated antagonist divided by the effect of the analgesic in the absence of the liberated antagonist is greater than about 85%; and (ii) provide release of the antagonist at a rate sufficient to provide a rate of release ratio that limits the abuse of the antagonist to the analgesic when the dosage form is abused, for example, during ingestion or substantial immersion of the system in the solvent. These and other embodiments of the present invention will readily be in mind those of ordinary skill in the art in view of the description herein.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 illustrates a cross section through a perspective, schematic view of an embodiment of the transdermal analgesic system according to this invention. Figure 2 illustrates a cross-sectional view through another embodiment of this invention. Figure 3 illustrates a cross-sectional view through another embodiment of this invention. Figure 4 illustrates a cross-sectional view through another embodiment of this invention. Figure 5 illustrates a cross-sectional view through another embodiment of this invention. Figures 6, 7 and 8 illustrate the cumulative release of naltrexone from control media for the release of the Pluronic coated Solupor antagonist. Figures 9 and 10 illustrate the rate of release and cumulative release of naltrexone, respectively, from means of controlling the release of the antagonist Celgard 3401. Figures 11 and 12 illustrate the rate of release and cumulative release of naltrexone, respectively, of control means for the release of the impermeable LDPE antagonist. Figures 13 and 14 illustrate the rate of release and cumulative release of naltrexone, respectively of means controlling the release of the antagonist Celgard 3501. Figures 15 and 16 illustrate the rate of release and cumulative release of naltrexone, respectively, from media of control of the release of the continuous filament propylene antagonist. Figures 17 and 18 illustrate the effect of naltrexone on clinical signs induced by sufentanil in rats within 30 minutes after dosing. Figure 19 illustrates serum fentanyl concentrations after transdermal application of several fentanyl systems for 72 hours, over a period of 120 hours after application. Figure 20 illustrates concentrations of fentanyl in serum after transdermal application of various fentanyl systems for 72 hours, around a period of 120 hours after application. Figure 21 illustrates the concentrations of sufentanil in plasma after various treatments with sufentanil , up to 120 hours after the first administration.

DETAILED DESCRIPTION OF THE INVENTION SUMMARY The present invention describes a transdermal analgesic system having reduced abuse potential, without diminishing the therapeutic or beneficial effects of the analgesic when the system is applied to the skin. In particular, the system of the present invention is provided for controlled release of the antagonist at a rate sufficient to provide a rate ratio that limits the abuse of the antagonist to the analgesic when the dosage form is abused, wherein the system provides a response of substantially minimized / negligible skin sensitization of the antagonist exposure. The practice of the present invention will employ, unless otherwise indicated, conventional methods used by those skilled in the art in the development of pharmaceutical products. Such techniques are fully explained in the literature. See, for example, Gale, R., Chandrasekaran, S.K., Swanson, D. and Wright, J., "Use of Osmotically Active Therapeutic Agents in Monolithic Systems" J. Membrane Sci., 7 (1980), 319-331; Patini, G.A. and Chein, Y.W., Swarbrick, J. and Boylan, J.C., eds, Encyclopedia of Pharmaceutical Technology, New York; Marcel Dekker, Inc., 1999 and Gale, R., Hunt, J. and Prevo, M. Mathiowitz, E., ed, Encyclopedia of Controlled Drug Delivery Patches, Passive, New York; J Wiley & Sons, Inc. 1999. All patents, patent applications, and publications mentioned herein, whether supra or infra, are therefore incorporated by reference in their entirety.

Definitions In describing the present invention, the following terminology will be used according to the definitions set forth below. The singular forms "un", "one" and "the or" include plural referents unless the context clearly indicates otherwise. Thus, for example, the reference to "a polymer" includes a single polymer as well as a mixture of two or more different polymers, the reference to "a penetration enhancer" includes a single penetration enhancer as well as two or more enhancers of different penetration in combination, and the like. As used herein, the terms "analgesic" and "drug" are used interchangeably and refer to fentanyl and a fentanyl analog. As used herein, the term "a fentanyl analogue" (formerly referred to as "analog") refers to extremely potent and effective analgesics such as alfentanil, carfentanil, lofentanil, remifentanil, sufentanil, trefentanil, and the like. As used herein, the term "substantially prevents release of the antagonist from the system" involves a transdermal analgesic system wherein the amount of antagonist that is released from the system in normal use or during casual contact or incidental exposure to water does not substantially reduce the analgesic effect of the drug in the transdermal analgesic system, such as in the case where the amount of antagonist released from the system in normal use is sufficiently low such that the analgesic effect of the drug in the presence of the released antagonist divided by the effect of the drug in the absence of the released antagonist (for example, in a system where there is no antagonist or where no antagonist is released in normal use) is greater than about 85%, such as greater than about 90%, greater than about 95%, greater than about 98%, greater than about 99%, greater than about 99.5%, close to 100%, 100%, and / or greater than 100%. "Analgesic effect", as used in this context, refers to therapeutic and / or pharmacokinetic effects, as determined by any clinical, in vitro, in vivo, pharmacokinetic, or conventional pharmacodynamic method. It will be appreciated that, for some drug / antagonist combinations, the co-administration of a small amount of antagonist and drug can actually increase the analgesic effect of the drug. It is understood that the term "substantially prevents release of the system antagonist" refers to that includes those transdermal analgesic systems where the amount of antagonist that is released from the system in normal use or during casual contact or during incidental exposure to water increases the effect drug analgesic. It is also understood that the term "substantially prevents the release of the antagonist from the system" means that it includes those transdermal analgesic systems in which the amount of antagonist that is released from the system in normal use does not increase the analgesic effect of the drug but in which the amount of antagonist that can be released from the system during casual contact and / or during incidental exposure to water does not increase the analgesic effect of the drug. It is also understood that the term "substantially prevents the release of the antagonist from the system" refers to including those transdermal analgesic systems where the amount of antagonist that is released from the system in normal use or during casual contact or during incidental exposure to water is not Increases the analgesic effect of the drug. The term "substantially prevents the release of the antagonist from the system", as used herein additionally or alternatively, involves a transdermal analgesic system wherein the minimum amount of antagonist is released from the system in casual contact or incidental exposure to water, such that there is minimal contact of the antagonist with the skin, in this way the skin sensitization response of the antagonist exposure is substantially minimized. Illustratively, the term "substantially prevents the release of the antagonist from the system" refers to including the transdermal analgesic systems wherein the total amount of the antagonist that is released from the system in normal use or in casual contact or in incidental exposure to water divided by the amount of drug that is released from the system under the same conditions is less than 20%, such as less than about 20%, less than 10%, less than about 10%, less than 5%, less than about 5%, less than 2%, less than about 2%, less than 1% , less than about 1%, close to zero, and / or zero. As an additional illustration, the term "substantially prevents release of the antagonist from the system" refers to including transdermal analgesic systems wherein the release rate of the antagonist from the system and delivery to the subject is less than about 6 micrograms / kg. / hour, such as less than about 5 micrograms / kg / hour, less than about 4 micrograms / kg / hour, less than about 3 micrograms / kg / hour, less than 2 micrograms / kg / hour, less closely of 1 microgram / kg / hour, less than about 0.5 microgram / kg / hour, less than about 0.3 microgram / kg / hour, less than about 0.2 microgram / kg / hour, and / or less than about 0.1 microgram / kg / hour. As an additional illustration, the term "substantially prevents release of the antagonist from the system" means that it includes the transdermal analgesic systems wherein the rate of release of the antagonist from the system and delivery to the subject divided by the drug release rate of the drug. system and supply to the subject is less than about 10%, such as less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5% , less than about 4%, less than about 3%, less than about 2%, less than about 1%, less about 0.5%, less about 0.2%, close to zero, and / or zero. As a further illustration, the term "substantially prevents the release of the antagonist from the system" refers to the inclusion of transdermal analgesic systems wherein the rate of release of the antagonist from the system and delivery to the subject is such that the peak concentration of the antagonist serum of the subject (ie, during the course of the use of the transdermal analgesic system) is less than about 1000 pg / ml, such as less than about 800 pg / ml, less than about 700 pg / ml, less than about 600 pg / ml, less than about 500 pg / ml, less than about 400 pg / ml, less than about 300 pg / ml, less than about 200 pg / ml, less than about 100 pg / ml ml, less than about 90 pg / ml, less than about 80 pg / ml, less than about 70 pg / ml, less than about 60 pg / ml, less than about 50 pg / ml, less close of 40 pg / ml, less than about 30 pg / ml, less than about 20 pg / ml, less than about 10 pg / ml, close to zero, and / or zero. Additionally or alternatively, the term "substantially prevents release of the antagonist from the system" refers to including the transdermal analgesic systems wherein the rate of release of the antagonist from the system and delivery to the subject is such that the peak concentration of the antagonist in the serum of the subject (ie, averaged over the course of the use of the transdermal analgesic system) does not exceed the need for drug antagonism, for example, such that the average concentration of the antagonist in the subject's serum (ie, the average over the course of use) of the transdermal analgesic system) is less than about 1000 pg / ml, such as less than about 800 pg / ml, less than about 700 pg / ml, less than about 600 pg / ml, less than about 500 pg / ml, less than about 400 pg / ml, less than about 300 pg / ml, less than about 200 pg / ml, less than about 100 pg / ml, less than about 90 pg / ml, lower - of about 80 pg / ml, less than about 70 p g / ml, less than about 60 pg / ml, less than about 50 pg / ml, less than about 40 pg / ml, less than about 30 pg / ml, less than about 20 pg / ml, lower of about 10 pg / ml, close to zero, and / or zero. It should be understood that, when the term "substantially prevents the release of the antagonist from the system" is said to include transdermal analgesic systems that satisfy a particular condition, this condition should be considered to be satisfied, for example, if more than about 90% of transdermal analgesic systems used in a population of subjects satisfy the condition, such as in cases where more than about 95% of the transdermal analgesic systems used in a population of subjects satisfy the condition, in cases where more than about 97% of the transdermal analgesic systems used in a population of subjects satisfy the condition, in cases where more than about 98% of the transdermal analgesic systems used in a population of subjects satisfy the condition, in cases where more than about 99% of the transdermal analgesic systems used in a population of subjects satisfy the condition, and / or in cases where close to 100% of the transdermal analgesic systems used in a population of subjects satisfy the condition. As used herein, the term "incidental exposure to water" refers to a exposure of short period of time to high humidity or brief exposure to liquid water, such as during rain, perspiration, and the like.

As used herein, the term "subsaturated system" refers to the system wherein the concentration of the analgesic is below its solubility limit. The analgesic reservoir comprises a single phase polymer composition, free of undissolved components, wherein the analgesic and all other components are present in concentrations no greater than, and preferably less than, their saturation concentrations in the reservoir. As used herein, the term "single phase polymer composition" refers to a composition in which the analgesic and all other components are solubilized in a polymer and are present in concentrations no greater than, and preferably less than, their concentrations saturation in the tank such that there are no undissolved components present in the composition over a substantial portion of the administration period; wherein all the components in combination with the polymer form a single phase. As used herein, the term "component" refers to an element within the analgesic reservoir, which includes, but is not limited to, an analgesic as defined above, additives, penetration enhancers, stabilizers, feints, diluents, plasticizers. , tackifier, pigments, carriers, inert fillers, antioxidants, excipients, gelling agents, anti-irritants, vasoconstrictors and the like. As used herein, "analgesic release control means" refers to means for modulating the rate of release of the analgesic, such as speed control membranes generally known in the art. As used herein, the term "antagonist release control means" refers to means for controlling the release rate of the antagonist and substantially minimizing the skin sensitization response of the antagonist exposure. The means of controlling the release of the antagonist modulate the entry of solvent into the antagonist reservoir, thereby modulating the release of the antagonist during the abuse while allowing the release of the antagonist at a rate sufficient to inhibit the abuse. The means of controlling the release of the antagonist include physical media such as a layer, a membrane, a film, a coating, a sheet, a reservoir, including, but not limited to, a speed control layer, a membrane of speed control, a porous or microporous membrane, an impermeable film where release is controlled through the edge of the patch. The means of controlling the release of the antagonist also include chemical means and can be osmotically managed, they can be concentration dependent, or they can depend on the size and characteristics of the materials forming the means for controlling the release of the antagonist. In certain embodiments, the means of controlling the speed of the antagonist is incorporated into the antagonist reservoir where the rate of release is governed by the osmotic triggering mechanism cited in Gale, et al., (Gale, R., Chandrasekaran, SK , Swanson, D. and Wright, J., "Use of Osmotically Active Therapeutic Agents in Monolithic Systems", J. Membrana Sci., 7 (1980), 319-331). The rate of antagonist release is controlled by factors such as the amount of antagonist within the antagonist reservoir, the particle size of the antagonist, the osmotic pressure of the antagonist salt, and the physical characteristics of the polymer matrix of the antagonist reservoir . The "DURAGEIC® fentanyl patch" is used interchangeably with the "DUROGESIC ™ fentanyl patch" and refers to a fentanyl patch as discussed above (see also Physicians Desk Reference, 56th Edition, 2002, pages 1786-1789 ). As used herein, the term "abuse of a transdermal analgesic system" refers to the use of a transdermal analgesic system different from that indicated by the labeling of the product., including devices against alteration or misuse of the system, subjecting the system to diversion, ingestion, or substantial immersion of the system in a solvent for intravenous administration, oral administration, and the like. As used herein, the term "Cmax (ng / ml)" refers to peak blood, plasma or serum concentration of the analgesic, ie, fentanyl or the analogue thereof. As used herein, the term "standardized Cmax (ng / ml-cm2)" refers to the Cma? (ng / ml) per unit area (cm2) of the active analgesic system's delivery area, for example, the area of the analgesic reservoir.

As used herein, the term "normalized Cmax (ng / ml- (mg / h))" refers to the Cmax (ng / ml) divided by the rate of the analgesic administered (mg / h). As used herein, the term "steady state analgesic flow" refers to the analgesic flow (in vitro and in vivo) in the range of 1 to 20 μg / h-cm 2 over a substantial portion of the administration period. As used herein, the term "bioavailability" refers to the rate and degree to which the active ingredient or active radical is absorbed from a pharmacological product and becomes available at the site of action. The speed and degree are established by pharmacokinetic parameters, such as the area under the blood, plasma or serum concentration curve of the drug-time (AUC) and the peak plasma or serum concentration (Cmax) of the drug. Two different products are considered to be "bioequivalent" if they produce substantially the same pharmacokinetic effects when studied under similar experimental conditions. Bioequivalence can be demonstrated through several methods in vivo and in vitro. These methods, in descending order of preference, include pharmacokinetic, pharmacodynamic, and clinical studies. In particular, bioequivalence is demonstrated using pharmacokinetic measurements such as the area under the blood concentration curve, plasma or drug-time serum (AUC) and peak concentration in blood, plasma or serum (Cmax) of the drug, using criteria statistics as described in more detail below. They are considered to be two different "pharmacologically equivalent" products if they produce substantially the same therapeutic effects when studied under similar experimental conditions, as demonstrated by various in vivo and in vitro methods, as described in more detail below. The therapeutic effects depend on several factors, such as drug potency, drug solubility and diffusivity in the skin, skin thickness, drug concentration within the skin application site, concentration of the drug in the drug reservoir , and the like, as described in more detail below. In general, pharmacological equivalence is demonstrated using measurements such as the peak concentration in blood, plasma or serum of the drug normalized for the drug rate administered (ie, Cmax normalized as defined above) and the peak concentration in blood, plasma or standardized drug serum per unit area of the active drug delivery area of the system (ie, Cmax standardized as defined above). When comparing two different products whose rate of drug administration is proportional to the size of the transdermal analgesic system, the bioequivalence or pharmacological equivalence can be established either by normalization of the peak concentration in blood, plasma or serum of the drug (Cmax) to the rate of drug administered (normalized Cmax), or by standardization of the peak concentration in blood, plasma or serum of the drug (Cma?) per unit area of the active drug delivery area of the system (Cma? standardized). However, when comparing two different products having different drug administration rates per unit area, it is necessary to normalize the peak concentration in blood, plasma or serum of the drug (Cma?) In the bases of the drug rate administered for establish bioequivalence or pharmacological equivalence.

PREFERRED MODALITY OF THE INVENTION The present invention provides an analgesic system for the transdermal delivery of fentanyl and analogs thereof for analgesic purposes, to a subject through intact skin over an extended period of time, the system has a reduced potential for abuse and a sensitizing response to substantially minimized / negligible skin of the antagonist exposure. In particular, the transdermal analgesic system of the present invention is provided for the controlled release of the antagonist at a rate sufficient to provide a rate of release rate that limits the abuse of the antagonist to the analgesic when the dosage form is abused. In this regard, the transdermal analgesic system of the invention provides for the release of the antagonist at a rate sufficient to block the opioid effects of the analgesic during abuse situations.

Referring now to Figures 1-4, a preferred embodiment of the transdermal analgesic system according to this invention comprises a patch 1, means for controlling the release of antagonist 2, an antagonist deposit 3 wherein the distal surface of the skin of the antagonist deposit is disposed in the means for controlling the release of the antagonist 2, an impermeable barrier layer 4 wherein the antagonist deposit 3 is disposed on the distal surface of the skin of the barrier layer 4, a reservoir of analgesic 5 disposed on the proximal surface of the skin of the barrier layer 4, wherein at least the surface that contacts the skin 6 of the analgesic deposit 5 is adhesive, and a removable protective layer 7. In preferred embodiments, the analgesic deposit 5 is formed of a pharmaceutically acceptable adhesive. Referring now to Figure 2, the transdermal analgesic system of the invention further comprises means for controlling the speed of the analgesic 8 disposed on the surface that makes contact with the skin of the analgesic deposit 6, wherein at least the surface that makes contact with the skin of the means of controlling the speed of the analgesic 8 is adhesive. Referring now to Figure 3, the analgesic deposit 5 is formed of a material that does not have suitable adhesive properties. In this embodiment of a transdermal analgesic system of the invention, it comprises a patch 1, wherein the surface that makes contact with the skin of the analgesic deposit 6 can be formulated with an adhesive coating 9. The analgesic deposit 5 is a polymeric composition of a single phase in which the analgesic and all other components are present in concentrations no greater than, and probably less than, their saturation concentrations in the analgesic reservoir 5. This produces a composition in which no undissolved components are present. Referring now to Figure 4, the transdermal analgesic system of the invention further comprises means for controlling the speed of the analgesic 8 disposed on the surface that contacts the skin of the analgesic reservoir 6, wherein at least the surface that makes contact with the skin of the means of controlling the speed of the analgesic 8 is adhesive. The means of controlling the release of antagonist 2 substantially prevents the release of the antagonist from the system during the securing of the system to a human patient for a period of up to about 7 days; substantially minimizing the skin sensitization response of the antagonist exposure; and providing release of the antagonist at a rate sufficient to provide a rate ratio that limits the abuse of the antagonist to the analgesic when the dosage form is abused, for example during ingestion or substantial immersion of the system in the solvent. The antagonist release control means 2 modulates the water / solvent entry into the antagonist reservoir, thus modulating the release of the antagonist during abuse while allowing the release of an antagonist at a rate sufficient to limit abuse. The means for controlling the release of the antagonist include physical media such as a membrane, a film, a coating, a sheet, a reservoir, including but not limited to, a speed control membrane, a porous or microporous membrane. , a waterproof film where the release is controlled through the edge of the patch. Antagonist release control means also include chemical means and can be osmotically activated, they can be concentration dependent, or they can depend on the size and characteristics of the materials forming the antagonist release control means. In certain embodiments, the means controlling the speed of the antagonist are incorporated into the antagonist reservoir where the rate of release is governed by the osmotic triggering mechanism cited in Gale., et al. The rate of antagonist release is controlled by factors such as the amount of antagonist within the antagonist reservoir, the particle size of the antagonist, the osmotic pressure of the antagonist salt, and the physical characteristics of the polymer matrix from the reservoir of the antagonist. antagonist. In preferred embodiments, the means of controlling the release of antagonist 2 can be a monolithic or a multilaminate layer comprising a material that substantially prevents release of the antagonist from the antagonist reservoir during incidental exposure to moisture. In particular, the means of controlling the release of the antagonist 2 comprises a breathable or occlusive material comprising fabric, porous, microporous material, non-woven fabric of continuous filament, non-woven fabric, hydrolyzed, microfiltration, or waterproof material comprising acetate. polyvinyl, polyvinylidene chloride, polyethylene, polypropylene, polyurethane, polyester, ethylene vinyl acetate (EVA), polyethylene terephthalate, polybutylene terephthalate, rayon (synthetic textile fibers produced by forcing a cellulose solution through fine swaths and solidifying the resulting filaments), wood pulp, hydrolyzed polyester, paper products! coated, aluminum sheet, and the like, and a combination thereof. In preferred embodiments, the antagonist release control means comprises low density polyethylene (LDPE) materials, medium density polyethylene (MDPE) or high density polyethylene (HDPE) materials, and the like. In preferred embodiments, the release control means is a single LDPE layer. In further preferred embodiments, the antagonist release control means comprises a microporous layer selected from the group consisting of Solupor microporous ultra high density polyethylene (UHDPE) materials / film (Solupor ™ manufactured by DSM Desotech, Denmark), microporous polypropylene (Celgard ™ film manufactured by Celgard, Inc., Charlotte, NC), RoTrac polyester porous capillary membranes (OYPHEN GmbH, Germany), hydrolyzed polyester, polypropylene or polyethylene. The microporous layer can further be modified with surfactants such as polyethylene oxide-polypropylene oxide block copolymers Pluracare (BASF, Wyandotte, Ml) or hydrophilic polymers such as polyvinylpyrrolidone to provide additional control over the release of the antagonist as discussed with greater detail later. The means of controlling the release of the antagonist have a thickness of about 0.012 mm (0.5 mil) to about 0.125 mm (5 mil); preferably from 0.025 mm (1 mil) to about 0.1 mm (4 mil); more preferably from 0.0375 mm (1.5 mil) to about 0.0875 mm (3.5 mil); and even more preferably from 0.05 mm (2 mil) to about 0.0625 mm (2.5 mil). The transdermal analgesic system according to this invention comprises an antagonist reservoir 3, wherein the distal surface of the skin of the antagonist reservoir is disposed in the antagonist 2 release control means. The antagonist reservoir can have the same Size that the other layers of the patch or the antagonist can be inserted from the edge of the die-cut patch. Antagonist deposit 3 can be formed of standard materials such as those known in the art. For example, the antagonist reservoir is formed of a hydrophobic, lipophilic and / or non-polar polymeric material, such as, ethylene ketene copolymers, ethylene-vinyl acetate copolymer (EVA), low density polyethylene (LDPE), polyethylene high density (HDPE), medium density polyethylene (MDPE), thermoplastic elastomers of styrene block copolymer, and the like. In preferred embodiments, the antagonist deposit 3 is formed from EVA, ethylene ketene copolymers, as described in greater detail below. As discussed above, the deposit of antagonist 3 comprises an antagonist in a substantially non-releasable form when the transdermal analgesic system is used as recommended and / or during exposure to water (eg, perspiration, rain, high humidity etc.) , the antagonist is releasable from the analgesic system when the analgesic system is abused, that is, when it is ingested or immersed substantially in a solvent. Preferably, the antagonist is present in a form that is substantially impermeable to the skin to which the transdermal analgesic system of the invention is applied. The antagonist deposit comprises an antagonist dispersed within a polymer, wherein the antagonist is substantially insoluble in the polymer of the antagonist deposit. In preferred embodiments, the antagonist is present as a salt, preferably as a hydrochloride salt of an antagonist base. The low solubility of the antagonist in the skin and the polymer has several advantages, substantially minimizes undesirable interactions between the antagonist and the analgesic, improves the stability / shelf life of the transdermal analgesic system, and substantially minimizes the skin sensitization response of the exposure of the antagonist. In certain embodiments, the antagonist is dispersed in a matrix comprising a polymeric material that substantially prevents release of the antagonist, preferably a thermoformable material; or the antagonist forms complex with an ionic resin. In further embodiments, the antagonist deposit comprises the antagonist in a multiparticulate form, wherein each particle is individually coated with a polymeric material that substantially prevents release of the antagonist, wherein the polymeric material is preferably a thermoformable material. In further embodiments, the antagonist reservoir comprises beads coated with the antagonist, wherein the beads can be formed of glass or an inert or non-dissolvable polymer, and further wherein the coated beads are optionally coated with a polymeric material or dispersed therein. which substantially prevents the release of the antagonist, wherein the polymeric material is preferably a thermoformable material. The antagonist is selected from the group consisting of naltrexone, methylnaltrexone, naloxone, nalbuphine, nalorphine, nalorphine dinicotinate, nalmefene, nadide, levalorphan, cyclozocine, and pharmaceutically acceptable salts thereof. Preferably, the antagonist is present as a salt. As discussed above, the antagonist deposit comprises the antagonist dispersed within a polymer. Preferably, the antagonist is dispersed in a matrix comprising a thermoformable material that substantially prevents the release of the antagonist. Alternatively, the antagonist is present in a multiparticulate form, wherein each particle is individually coated with a polymeric material that substantially prevents release of the antagonist. Preferably, the polymeric material that substantially prevents release of the antagonist is hydrophobic, i.e., substantially prevents release of the antagonist during normal use, minimizes the amount of antagonist during incidental / casual exposure to solvents (moisture, eg, perspiration, during a rain), and when the dosage form is subjected to abuse, for example, during ingestion or immersion in a solvent, it releases the antagonist in amounts that limit abuse. Preferably, the polymeric material has a low melting point to allow processing of the antagonist in the solid phase and to prevent degradation of the antagonist. Examples of a polymeric material that substantially prevents release of the antagonist include, but are not limited to, polyethylene, polyoxyethane, polyvinyl acetate, polymethyl acrylate, polyethyl acrylate, polystyrene polymers and copolymers, and mixtures thereof.; polystyrene copolymers such as styrenic block copolymers (SIS, SBS, SEBS), ethylene copolymers such as polyethylene-ketene copolymers, ethylene-vinyl acetate copolymer (EVA), ethylene-methyl acrylate copolymers (EMA), copolymer ethylene-acrylic acid, ethylene-ethylacrylate copolymer, and the like, and combinations thereof. In additional embodiments, the antagonist complexes with an ionic queen. Examples of ionic resins include, but are not limited to, sulfonated polystyrene resins, and the like. Preferably the resin contains a sulfonic acid functionality which when neutralized with the antagonist base forms the sulfonate salt of the antagonist. In further embodiments, the antagonist deposit comprises beads coated with the antagonist, wherein the beads or beads can be formed of glass, metals or an inert or non-dissolvable polymer, and further wherein the coated beads are optionally coated with polymeric material or dispersed therein which substantially prevents the release of the antagonist, as described above. The beads may be in any configuration, size or shape, but preferably they are small in size, preferably less than 10 microns. Examples of an inert or non-soluble polymer include, but are not limited to, polymethyl methacrylate, polycarbonate and polystyrene. The deposit of antagonist 3 comprises an amount of the antagonist sufficient to counteract the analgesic and euphoric effects of the analgesic when the transdermal analgesic system is abused. Preferably, the antagonist reservoir comprises about 0.2 to about 15 mg / cm2 of the antagonist; more preferably from about 0.6 to about 5 mg / cm2 of the antagonist; and even more preferably about 0.75 to about 1.5 mg / cm 2 of the antagonist. Preferably, the antagonist deposit comprises from about 20 to about 70% by weight of the antagonist; more preferably about 40 to about 65% by weight of the antagonist; even more preferably from about 50 to about 60% by weight of the antagonist; and even more preferably from about 52 to about 56% by weight of the antagonist. In preferred embodiments, the antagonist is in the salt form and preferred antagonists are naltrexone, methylnaltrexone, naloxone, nalbuphine, nalorphine, nalorphine dinicotinate, nalmefene, nadide, levalorphan and cyclozocine. Preferably, the antagonist is substantially insoluble in the polymer that forms the deposit of antagonist 3. In particular, the material that forms the deposit of antagonist 3 has a solubility for the antagonist of about 0 wt% to about 1 wt% of the total composition of the polymer; more preferably about 0% by weight to about 0.8% by weight; and even more preferably from about 0% by weight to about 0.5% by weight of the total polymer composition. The antagonist tank 3 has a thickness of about 0.0125 mm (0.5 mil) to about 0.1 mm (4 mil); preferably from about 0.015 mm (0.6 mil) to about 0.0875 mm (3.5 mil); more preferably from 0.025 mm (1 mil) to about 0.08 mm (3.3 mil); and even more preferably from about 0.025 mm (1 mil) to about 0.075 (3 mil). The transdermal analgesic system according to this invention comprises an impermeable barrier layer 4 wherein the antagonist reservoir 3 is placed on the distal surface of the skin of the barrier layer 4, and an analgesic reservoir 5 is placed on the surface proximal of the skin of the barrier layer 4. The barrier layer 4 is impermeable to the antagonist and the analgesic; and comprises a material that is insoluble in water, alcohol and organic solvents. The barrier layer 4 comprises a polymer such as polyolefin laminates (Dow Chemical, Midland, Ml), acrylonitrile copolymer films (BAREX, BP Chemicals, Koln, Germany), polyethylene naphthalene (PEN), polyethylene terephthalate (PET), polyimide, polyurethane, polyethylene, metallized films and glass-lined films where these films may include ethylene copolymers such as ethylene-vinyl acetate copolymer (EVA), and combinations thereof. In preferred embodiments, the barrier layer comprises polyester such as PET laminated to a polymer such as polyurethane, polyethylene, and ethylene copolymers. In preferred embodiments, the barrier layer comprises polyester such as PET laminated to ethylene copolymers such as ethylene-vinyl acetate copolymer (EVA). The barrier layer as a multilaminate layer has a thickness of about 0.075 mm (0.3 mil) to about 0.125 mm (5 mil); preferably from 0.025 mm (1 mil) to about 0.1 mm (4 mil); more preferably from 0.0625 mm (1.5 mil) to about 0.0875 mm (3.5 mil); and even more preferably from 0.025 mm (1 mil) to about 0.05 mm (2 mil). The laminated polyethylene or EVA layer of the preferred PET-PE laminates improves the adhesion of the antagonist deposit to the reinforcement, and serves to prevent easy removal of the antagonist deposit from the system by the abuser. The analgesic deposit 5 is placed on the proximal surface of the skin of the barrier layer 4, wherein at least the surface that contacts the skin 6 of the analgesic deposit 5 is adhesive. The analgesic reservoir 5 can be formed from the standard materials as is known in the art. For example, the analgesic deposit is formed of hydrophobic and / or lipophilic polymeric material, such as hydrophobic polyurethane, ethylene-vinyl acetate copolymer (EVA) and the like. In preferred embodiments, the analgesic deposit 5 is formed of a pharmaceutically acceptable pressure sensitive adhesive, preferably a polyacrylate-based adhesive or a styrenic block copolymer, as described in greater detail below. In preferred embodiments, the pressure sensitive adhesive has zero shear viscosity greater than 1-109 poises at 25 ° C, as determined by the time-temperature superposition principle of dynamic viscosity curves at various temperatures. This requirement serves to prevent the adhesive cold flow, and the corresponding increased probability for the analgesic-antagonist exchange at the edge of the system. The adhesive analgesic deposit 5 of the adhesive coating 9 is formed of standard pressure sensitive adhesives known in the art. Examples of pressure sensitive adhesives include, but are not limited to, polyacrylates, polysiloxanes, polyisobutylene (PIB), polyisoprene, polybutadiene, styrenic block polymers, and the like. Examples of styrenic block copolymer based adhesives include but are not limited to, styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene copolymer (SBS), styrene-ethylenebutene-styrene copolymers (SEBS), and analogs di-block thereof. The acrylic polymers comprise a copolymer or terpolymer comprising at least two or more exemplary components selected from the group comprising acrylic acids, alkyl acrylates, methacrylates, copolymerizable secondary monomers or monomers with functional groups. Examples of monomers include, but are not limited to, acrylic acid, methacrylic acid, methoxyethyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-etilhexii methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl methacrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, tert- butylaminoethyl acrylate, tert-butylaminoethyl methacrylate, methoxyethyl acrylate, methoxyethyl methacrylate, and the like. Additional examples of suitable acrylic adhesives suitable in the practice of the invention are described in Satas, "Acrylic Adhesives," Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed., Pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989). Acrylic adhesives are commercially available (National Starch and Chemical Corporation, Bridgewater, NJ; Solutia, MA). Additional examples of polyacrylate-based adhesives are as follows, identified as product numbers, manufactured by National Starch (Product Bulletin, 2000): 87-4098, 87-2287, 87-4287, 87-5216, 87-2051, 87 -2052, 87-2054, 87-2196, 87-9259, 87-9261, 87-2979, 87-2510, 87-2353, 87-2100, 87-2852, 87-2074, 87-2258, 87-9085 , 87-9301 and 87-5298. Acrylic polymers comprise entangled or non-interlaced polymers. The polymers are entangled by known methods to provide the desired polymers. In preferred embodiments, the adhesive is a polyacrylate adhesive having a glass transition temperature (Tg) of less than -10 ° C, more preferably having a Tg of about -20 ° C to about -35 ° C. . The molecular weight of the polyacrylate adhesive, expressed in average weight (MW), generally ranges from 25,000 to 10,000,000, preferably from 50,000 to about 3,000,000 and more preferably from 100,000 to 1,000,000 before any of the entanglement reactions. In the interlaced the MW approaches infinity, as is known by those involved in the technique of polymer chemistry. Transdermal analgesic systems comprise analgesic deposits comprising a component, including an analgesic with a concentration greater, equal, or less than the saturation concentration. As discussed above, in preferred embodiments the analgesic deposit 5 comprises a single phase polymeric composition, free of undissolved components, containing an amount of analgesic sufficient to induce and maintain analgesia in a human for at least three days. The analgesic is selected from the group consisting of fentanyl and analogs thereof, such as alfentanil, carfentanil, lofentanil, remifentanil, sufentanil, trefentanil, and the like. In preferred embodiments the analgesic reservoir comprises about 0.05 to about 1.75 mg / cm 2 of analgesic; preferably about 0.07 to about 1.50 mg / cm2 of analgesic; preferably from about 0.08 to about 1.25 mg / cm2 of analgesic; more preferably from about 0.09 to about 1.0 mg / cm 2 of analgesic; more preferably from about 0.1 to about 0.75 mg / cm 2 of analgesic; and even more preferably from about 0.12 to about 0.5 mg / cm 2 of analgesic. The analgesic should be soluble in the reservoir forming polymer 3 in a form that is as discussed below. In preferred embodiments, the analgesic is in the base form and the preferred analgesics are fentanyl or sufentanil. In particularly preferred embodiments, the analgesic reservoir comprises about 0.05 to about 1.75 mg / cm2 of fentanyl; preferably from about 0.07 to about 1.50 mg / cm2 or fentanyl; preferably from about 0.08 to about 1.25 mg / cm2 of fentanyl; more preferably from about 0.09 to about 1.0 mg / cm2 of fentanyl; more preferably from about 0.1 to about 0.75 mg / cm2 of fentanyl; and even more preferably from about 0.12 to about 0.5 mg / cm2 of fentanyl; where fentanyl is in a base form and is completely dissolved. In further preferred embodiments, the analgesic reservoir comprises from about 0.05 to about 1.75 mg / cm2 of sufentanil; preferably from about 0.07 to about 1.50 mg / cm2 of sufentanil; preferably from about 0.08 to about 1.25 mg / cm2 of sufentanil; more preferably from about 0.09 to about 1.0 mg / cm2 of sufentanil; more preferably from about 0.1 to about 0.5 mg / cm2 of sufentanil; and more preferably from about 0.12 to about 0.5 mg / cm2 of sufentanil; where sufentanil is in a base form and is completely dissolved. The material forming the analgesic reservoir 5 has a solubility for the analgesic from about 1% by weight to about 25% by weight of the total polymer composition; preferably from about 2% by weight to about 15% by weight; more preferably from about 4% by weight to about 12% by weight of the total polymer composition; and even more preferably from about 6% by weight to about 10% by weight of the total polymer composition. The reservoir 5, with or without the adhesive coating 9, has a thickness of about 0.0125 mm (0.5 mil) to about 0.1 mm (4 mil); preferably from about 0.025 mm (1 mil) to about 0.0875 mm (3.5 mil); more preferably from 0.0375 mm (1.5 mil) to about 0.075 (3 mil); and even more preferably from about 0.04 mm (1.6 mil) to about 0.05 mm (2 mil). In preferred embodiments, the analgesic is fentanyl, preferably in the base form, wherein the material forming the deposit 5 has a solubility for fentanyl of from about 1% by weight to about 25% by weight of the total composition of the composition. polymer; preferably from about 3% by weight to about 15% by weight; more preferably from about 5% by weight to about 12% by weight; and even more preferably from about 7% by weight to about 10% by weight of the total polymer composition. The reservoir 5, with or without the adhesive coating 9, has a thickness of about 0.0125 mm (0.5 mil) to about 0.1 mm (4 mil); preferably about 0.025 mm (1 mil) to about 0.075 mm (3 mil); more preferably from 0.0375 mm (1.5 mil) to about 0.0625 (2.5 mil); and even more preferably from about 0.04 mm (1.6 mil) to about 0.05 mm (2 mil). In further preferred embodiments, the analgesic is sufentanil, preferably in the base form, wherein the material forming the deposit 5 has a solubility for sufentanil from about 1% by weight to about 25% by weight of the composition total of the polymer; preferably from about 3% by weight to about 15% by weight; more preferably from about 5% by weight to about 12% by weight; and even more preferably from about 7% by weight to about 10% by weight of the total polymer composition. The reservoir 5, with or without the adhesive coating 9, has a thickness of about 0.0125 mm (0.5 mil) to about 0.1 mm (4 mil); preferably from about 0.025 mm (1 mil) to about 0.075 mm (3 mil); more preferably from 0.0375 mm (1.5 mil) to about 0.0625 (2.5 mil); and even more preferably from about 0.04 mm (1.6 mil) to about 0.05 mm (2 mil). In further embodiments, the analgesic deposit 5 optionally may contain additional components such as additives, penetration enhancers, stabilizers, inks, diluents, plasticizers, tackifiers, pigments, carriers, inert fillers, antioxidants, excipients, gelling agents. , anti-irritants, vasoconstrictors and other materials as are generally known for the transdermal technique, with the proviso that said materials are present below the concentration of saturation in the reservoir. Examples of penetration enhancers include, but are not limited to, esters of glycerin fatty acids, such as capric, caprylic, dodecyl, oleic acids; fatty acid esters of isosorbide, sucrose, polyethylene glycol, caproyl lactic acid; lauret-2; laureth-2 acetate, laureth-2 benzoate, laureth-3-carboxylic acid; lauret-4; laureth-5 carboxylic acid; olet-2; glyceryl pyroglutamate oleate; glyceryl oleate; N-lauroyl sarcosine; N-myristoyl sarcosine; N-octyl-2-pyrrolidone; lauraminopropionic acid; propylene glycol-4-lauret-2; propylene glycol-4-lauret-5-dimethyl lauramide, lauramide diethanolamine (DEA). Preferred enhancers include, but are not limited to, lauryl pyroglutamate (LP); glyceryl monolaurate (GML), glyceryl monocaprylate; glyceryl monocaprate; glyceryl monooleate (GMO), and sorbitan monolaurate. Additional examples of suitable penetration enhancers are described, for example, in the US patent. Nos: 5,785,991; 5,843,468; 5,882,676; and 6,004,578. In certain embodiments, the analgesic reservoir comprises diluent materials capable of rapidly reducing viscosity, increasing viscosity, and / or hardening the matrix structure, such as polymethyl methacrylate or polybutyl methacrylate (ELVACITE, manufactured by ICI Acrylics, for example, ELVACITE. 1010, ELVACITE 1020, ELVACITE 20), high molecular weight acrylates, ie, acrylates having an average molecular weight of at least 500,000, and the like. In certain embodiments, particularly with styrenic block copolymer adhesive systems, a plasticizer or tackifier is incorporated into the adhesive composition to improve the adhesive characteristics. Examples of suitable tackifiers include, but are not limited to, aliphatic hydrocarbons; aromatic hydrocarbons; hydrogenated esters; polyterpenes, hydrogenated wood resins; tackifying resins such as ESCOREZ, aliphatic hydrocarbon resins produced from cationic polymerization of petrochemical feedstock, turpentine ester tackifiers, and the like; mineral oil and combinations thereof. The tackifier used must be compatible with the polymer mixture. For example, styrenic block copolymers can be formulated with rubber-compatible tackifying thickeners, compatible end block resins such as polymethyl styrene, or plasticizers such as mineral oil. In general, the polymer is about 5-50% of the total composition of the adhesive, the tackifier is about 30-85% of the total composition of the adhesive, and the mineral oil is about 2-40% of the total adhesive composition. The patch 1 further comprises means for controlling the speed of the analgesic 8 disposed on the surface that makes contact with the skin of the analgesic deposit 6, wherein at least the surface that makes contact with the skin of the means for controlling the Analgesic speed 8 is adhesive. The means of controlling the speed of the analgesic 8 is composed of a polymeric material such as ethylene-vinyl acetate (EVA), polyvinyl chloride (PVC), ethylene-ethyl acrylate copolymer, ethylene butylacrylate copolymer, polyisobutylene (PIB) ), polyethylene (PE) such as low density polyethylene (LDPE), medium density polyethylene (MDPE), high density polyethylene (HDPE), and the like, and a combination thereof; The polymeric materials can be plasticized. In preferred embodiments, the means of controlling the speed of the analgesic adhere to the skin with an acrylic, silicone, or PIB adhesive material. The means of controlling the speed of the analgesic have a thickness of about 0.012 mm (0.5 mil) to about 0.125 mm (5 mil); preferably from 0.025 mm (0.6 mil) to about 0.1 mm (4 mil); more preferably from 0.0625 mm (0.8 mil) to about 0.0875 mm (3.5 mil). The patch 1 further comprises a removable protective layer 7. The protective layer 7 is composed of a polymeric material which can optionally be metallized. Examples of the polymeric materials include, polypropylene, polystyrene, polyimide, polyethylene, polyethylene terephthalate, polybutylene terephthalate, paper, and the like, and a combination thereof. In preferred embodiments, the protective layer comprises a siliconized polyester sheet. Referring now to Figure 5 a preferred embodiment of the transdermal analgesic system for this invention comprises a patch 11, means for controlling the release of antagonist 12, an antagonist reservoir 13 wherein the distal skin surface of the antagonist reservoir is disposed in the means for controlling the release of the antagonist 12, an impermeable barrier layer 14 wherein the antagonist reservoir 13 is disposed on the distal surface of the skin of the barrier layer 14, a bag formed of the impermeable barrier layer 14, an analgesic reservoir 15, means controlling the speed of the analgesic 18, and an amine resistant contact adhesive layer 19, covered by a removable protective layer 17. The impermeable barrier layer 14 is configured to provide a central volume which contains an analgesic deposit 15 in the form of a gel having dissolved analgesic and suspended therein. Although the preferred embodiments of this invention utilize an amine-resistant in-line adhesive as shown in Figure 5, other means may be employed to maintain the system in the skin. Such means include a peripheral ring of adhesive outside the path of the skin system analgesic, in which case the adhesive does not need to be resistant to the amine. In this way the use of superimposed layers of adhesive or other fastening means such as buckles, belts, and elastic arm bands are also contemplated. The elements 11, 12, 13, 14, 15, 16, 17, 18 and 19 can be made from materials similar to those used in the corresponding elements of Figures 1-4 while the analgesic tank 15 includes both aqueous and non-aqueous systems. aqueous and is preferably a material based on acrylic, silicone or polyisobutylene, which can be plasticized and contains penetration enhancers, in which the analgesic is dissolved and dispersed. A general formulation for the barrier 13, the analgesic reservoir 15 and the means that control the analgesic rate of the transdermal analgesic system illustrated in Figure 5 is as described in the U.S. Pat. No. 4,588,580, which is hereby incorporated by reference. A wide variety of materials that can be used for the manufacture of several layers of the transdermal analgesic systems according to this invention have been described above. Therefore, this invention contemplates the use of materials different from those specifically described herein, including those that can be known in the art with the ability to perform the necessary functions.

Drug Administration The present invention provides a transdermal analgesic system having reduced abuse potential, without diminishing the therapeutic or beneficial effects of the analgesic when the system is applied to the skin. As discussed above, the transdermal analgesic system comprises an antagonist in a substantially non-releasable form when the system is used as recommended and / or during an accidental exposure to water, the antagonist being released from the system when the analgesic system is abused, is say, when ingested or immersed substantially in a solvent. In particular, the system of the present invention is provided for the controlled release of the antagonist at a rate sufficient to provide a rate of release rate that limits the abuse of the antagonist to the analgesic when the dosage form is abused. The transdermal analgesic system substantially prevents the release of the antagonist from the system during the securing of the system to a human patient for a period of up to about 7 days. Additionally, the system of the invention provides for the release of the antagonist at a rate sufficient to provide a rate of release rate that limits the abuse of the antagonist to the analgesic when the dosage form is abused, for example, during substantial ingestion or immersion of the drug. system in the solvent, as described in more detail below. In the application to the skin, the analgesic in the analgesic deposit (5, 15) of the transdermal system (1, 11) diffuses into the skin where it is absorbed into the bloodstream to produce a systemic analgesic effect. The onset of analgesia depends on several factors, such as analgesic potency, solubility and diffusivity of the analgesic in the skin, thickness of the skin, concentration of the analgesic within the skin application site, concentration of the analgesic in the depot. analgesic, and the like (see, for example, US Patent No. 4,588,580 for a discussion of permeabilities and relative potencies of fentanyl and analogs thereof). The concentration of the analgesic within the skin application sites is also significant when establishing an upper limit on the size of the transdermal analgesic system and, vice versa, the lower limit on the usable administration rate as described in the international application No. WO 200274286, which is incorporated herein in its entirety for reference. When continuous analgesia is desired, the spent transdermal analgesic system must be removed and a fresh system applied to a new location. For example, the transdermal analgesic system can be removed sequentially and replaced with a fresh system at the end of the administration period to provide chronic pain relief. Because the absorption of the analgesic from the fresh transdermal analgesic system in the area of the new application usually occurs substantially at the same rate as the absorption by the body of the residual analgesic within the site of previous application of the transdermal analgesic system, the levels of blood will remain substantially constant. Additionally, it is contemplated that doses may be increased over time and that the concurrent use of other analgesics may be presented to deal with breakthrough pain. In preferred embodiments, the invention provides a transdermal analgesic system that exhibits a normalized Cmax ranging from about 3.3 to about 82.5 ng / ml- (mg / h), preferably from about 6.6 to about 50 ng / ml- ( mg / h), more preferably from about 13 to about 40 ng / ml- (mg / h), and even more preferably from about 20 to about 35 ng / ml- (mg / h), and a Cmax standardized ranges from about 0.001 to about 0.2 ng / ml-cm2, preferably from about 0.005 to about 0.15 ng / ml-cm2, more preferably from about 0.008 to about 0.1 ng / ml-cm2, and even more preferably from about 0.01 to about 0.08 ng / ml-cm2. The transdermal analgesic system comprises a transdermal analgesic system of about 0.5 to about 150 cm2; preferably from about 2 to about 100 cm2; more preferably from about 4 to about 50 cm2, and even more preferably from about 10 to about 20 cm2. During administration on the skin the transdermal analgesic system exhibits a steady state analgesic flow from about 0.1 to about 20 μg / h-cm2; preferably from about 0.75 to about 10 μg / h-cm2; preferably from about 1 to about 8 μg / h-cm 2; more preferably from about 1.5 to about 5 μg / h-cm 2; more preferably from about 2 to about 3 μg / h-cm 2; and even more preferably from about 1 to about 2.5 μg / h-cm2. The steady state administration rates obtainable according to this invention range from about 0.1 to about 500 μg / h; preferably from about 1 to about 300 μg / h; more preferably from about 2 to about 250 μg / h; and even more preferably from about 5 to about 200 μg / h. In further preferred embodiments, the invention provides a transdermal fentanyl system that exhibits a normalized Cmax ranging from about 3.3 to about 82.5 ng / ml- (mg / h), preferably from about 10 to about 62 ng / ml- (mg / h), more preferably from about 16 to about 41 ng / ml- (mg / h), and even more preferably from about 20 to about 35 ng / ml- (mg / h); and a Cma? standardized which ranges from about 0.01 to about 0.2 ng / ml-cm2, preferably from about 0.02 to about 0.15 ng / ml-cm2, more preferably from about 0.03 to about 0.1 ng / ml-cm2, and yet more preferably from about 0.04 to about 0.08 ng / ml-cm2. The transdermal fentanyl system is from about 1 to about 150 cm2; preferably from about 2 to about 125 cm2; more preferably from about 4 to about 100 cm2; more preferably from about 5 to about 75 cm2, and even more preferably from about 5 to about 50 cm2. During administration on the skin, the transdermal fentanyl system exhibits a steady state analgesic flow from about 1 to about 10 μg / h-cm 2; preferably from about 1.5 to about 8 μg / h-cm2; more preferably from about 2 to about 5 μg / h-cm 2; and even more preferably from about 2 to about 3 μg / h-cm 2. The steady state administration rates obtainable for a transdermal fentanyl system according to this invention vary from about 1 to about 300 μg / h; preferably from about 2 to about 250 μg / h; and more preferably from about 5 to about 200 μg / h. In additional preferred embodiments, the invention provides a transdermal sufentanil system exhibiting a Cma? normalized which ranges from about 0.04 to about 10 ng / ml- (mg / h), preferably from about 1 to about 8 ng / ml- (mg / h), and more preferably from about 2 to about 5.5 ng / ml- (mg / h), and even more preferably from about 2.5 to about 5 ng / ml- (mg / h), and a standardized Cmax ranging from about 0.001 to about 0.05 ng / ml -cm2, preferably from about 0.005 to about 0.04 ng / ml-cm2, more preferably from about 0.0075 to about 0.025 ng / ml-cm2, and more preferably from about 0.01 to about 0.02 ng / ml-cm2 . The transdermal sufentanil system comprises a transdermal analgesic system of about 0.5 to about 40 cm2; preferably from about 1 to about 35 cm2; and more preferably from about 2 to about 30 cm2. In the administration on the skin, the transdermal sufentanil system exhibits a steady state analgesic flow from about 0.1 to about 10 μg / h-cm2; preferably from about 0.5 to about 8 μg / h-cm2; more preferably from about 0.75 to about 6 μg / h-cm2; more preferably from about 1 to about 5 μg / h-cm 2; and even more preferably from about 1 to about 2.5 ng / h-cm2. The steady state administration rates obtainable for a sufentanil system according to this invention range from about 0.1 to about 200 μg / h; preferably from about 0.25 to about 150 μg / h; more preferably from about 0.5 to about 100 μG / h; more preferably from about 0.75 to about 50 μg / h; and even more preferably from about 1 to about 40 μg / h. The administration is maintained for at least three days, and up to 7 days, with the 3-4 day regimen being considered preferable. In preferred embodiments, at least 3%, but not more than 40%, of the total amount of the analgesic in the system is administered for approximately the first 24 hours of use; at least 6%, but not more than 50%, of the total amount of the analgesic is administered during approximately the first 48 hours of use; and at least 10%, but not more than 75%, of the total amount of the analgesic is administered during the administration period. In preferred embodiments, the transdermal analgesic system is a fentanyl system wherein at least 5%, but not more than 40%, of the total amount of the analgesic in the system is administered for approximately the first 24 hours of use; at least 15%, but not more than 50%, of the total amount of the analgesic is administered during approximately the first 48 hours of use; and at least 25%, but not more than 75%, of the total amount of the analgesic is administered during the administration period. In alternative embodiments, the transdermal analgesic system is a sufentanil system wherein at least 3%, but not more than 40% of the total amount of the analgesic in the system is administered for approximately the first 24 hours of use; at least 6%, but not more than 50%, of the total amount of the analgesic is administered for approximately 48 hours of use; and at least 10%, but not more than 75%, of the total amount of the analgesic is administered during the administration period. As discussed at the outset, the transdermal analgesic system of the invention provides for release of the antagonist at a rate sufficient to provide a rate of release rate that limits the abuse of the antagonist to the analgesic when the dosage form is abused, for example in the ingestion or substantial immersion of the system in the solvent. In this regard, the transdermal analgesic system of the invention provides for the release of the antagonist at a rate sufficient to block the opioid effects of the analgesic during abuse situations. As discussed at the beginning, and as illustrated in the examples, the release rate of the antagonist is controlled by varying the concentration of the antagonist within the antagonist reservoir, the particle size of the antagonist salt, the selection of the media that they control the release of the appropriate antagonist, and the processing condition involved in the formation of the transdermal analgesic system. As used herein, "a rate of release ratio" refers to the ratio of a rate of release of the antagonist to the analgesic over a given period of time measured using appropriate standard techniques. In this regard, the present invention provides a transdermal analgesic system wherein the ratio of the amount of the antagonist released (ie, cumulative release) when the patch is abused to the amount of the analgesic released (ie, cumulative release) when abused. of the patch is from about 0.075: 1 to about 30: 1, from about 0.25: 1 to about 20: 1; from about 0.5: 1 to about 16: 1; from about 0.5: 1 to about 14: 1; from about 0.75: 1 to about 12: 1; from about 1: 1 to about 10: 1; from about 1.5: 1 to about 8: 1; from about 2: 1 to about 6: 1; and from about 2: 1 to about 4: 1, where the period of time of abuse, eg, ingestion or substantial immersion of the system in a solvent, is up to 1 minute to about 24 hours, the release based in a standardized test method (e.g., in vitro and in vivo extraction methods) as described in more detail below. If either of the test methods satisfies the release rate relationship that limits the abuse of the antagonist to the analgesic, it considers that it satisfies the requirement that release rate relationships are limiting of the abuse. Examples of in vitro extraction methods are described in greater detail in the following examples. In general, the transdermal analgesic system is placed in a standard extraction medium / solution, equilibrated to the target temperature and agitated. Examples of standard extraction media include, but are not limited to, aqueous medium such as distilled water, saline, aqueous medium containing appropriate pH regulating agents to provide a pH of about 1 to 14 (eg, aqueous medium). containing phosphate pH regulator at pH 6.5), an aqueous solvent similar to saliva; organic solvents such as alcohol (for example, methanol, ethanol, isopropyl alcohol and the like), dimethylfuran, methylene chloride, chloroform, carbon tetrachloride, ether, acetone, benzene, toluene, hexane, pentane, dimethylformamide, formaldehyde, acetate ethyl, methyl ethyl ketone; and common household materials such as, nail varnish remover, rubbing alcohol, glycerin, mineral spirits, turpentine, vodka, cooking oil, vinegar, gasoline, kerosene, dry cleaning fluid and the like and mixtures thereof. The volume of the medium is adjusted to be below the solubility limit of the analgesic and the antagonist. The extraction temperature can be varied within the range of the ambient temperature to near the boiling temperature, for example, 25 ° C, 50 ° C and 75 ° C. The aliquots of the extraction medium are stirred at various time points, for example, 0, 2, 5, 15, 60 and 120 minutes, and diluted with the corresponding unused extraction medium. Samples are analyzed for antagonist and analgesic content by HPLC. If either one of the test methods satisfies the rate of release ratio that limits the abuse of the anatagonist to the analgesic in any of the media / extraction solution mentioned above, it is considered to satisfy the requirement that release rate relationships are limiting. of abuse. Examples of in vivo extraction methods are described in greater detail in the following examples. In general, transdermal analgesic systems are placed in the oral cavity of animals, for example, mice, rats, pigs, cats, dogs, primates (monkeys), humans, and the like for a predetermined period, for example, close to 1 minute to about 2 hours. At the end of the test period, the transdermal analgesic systems are removed from the oral cavity and allowed to air dry. The transdermal analgesic systems are analyzed for residual analgesic and antagonist contents using standard extraction procedures followed by reverse phase HPLC analysis. In certain aspects, the rate of release of the antagonist in phosphate buffered pH medium is controlled by membrane selection or modification of the surfactant of the means for controlling the release of the antagonist. In general, the lower release of the antagonist is provided by the polyethylene film and the faster release of the antagonist is provided by the Celgard membrane. The transdermal analgesic systems wherein the analgesic is fentanyl, the antagonist is naltrexone, and the means of controlling the release of the antagonist comprise modified Pluronic Solupor materials, the release rate ratio of naltrexone to fentanyl is at least 2: 1 . The transdermal analgesic systems wherein the analgesic is sufentanil, the higher potency of sufentanil requires a faster rate of antagonist release. These faster rates can be provided by an appropriate selection of antagonist release control means such as the use of Celgard 3501, various nonwoven materials, and exposed antagonist deposits where the rate of release is controlled by the quality of antagonist within the antagonist reservoir and the particle size of the antagonist. In some embodiments, the present invention provides a transdermal analgesic system wherein the ratio of the amount of antagonist administered during use to the amount of analgesic administered during use is less than 1: 1000, and preferably 1: 10,000, depending on the analgesic. and the antagonist used, the concentration of the antagonist in the antagonist reservoir and the selection of the means for controlling the release of the antagonist. In additional aspects, the present invention provides a transdermal analgesic system wherein the amount of antagonist administered during use is 0.1% or less, 168 hours after administration. Preferably, the amount of antagonist released when the transdermal analgesic system is abused is 70% or more after 1, 2, 4, 8 or 24 h of abuse activities. A preferred embodiment of this invention is a transdermal analgesic system that is bioequivalent to the DURAGESIC® fentanyl system. In particular, a monolithic fentanyl system according to the invention produces substantially the same pharmacokinetic effects (as measured by the area under the curve drug concentration in blood, plasma or serum - time (AUC) and peak concentration of drug in plasma or serum (Cma?)) compared to the DURAGESIC® transdermal fentanyl system, when studied under similar experimental conditions, as described in more detail below. In additional preferred embodiments, a transdermal analgesic system of this invention is pharmacologically equivalent to the DURAGEIC® fentanyl system. In particular, a monolithic sufentanil system according to the invention produces substantially the same therapeutic effects as compared to the DURAGEIC® transdermal fentanyl system, when studied under similar experimental conditions, as described in more detail below. In general, the standard bioequivalence study is conducted in a crossover manner on a small number of volunteers, usually with 24 to 36 normal healthy adults. The single doses of the test product containing the drug, for example, the transdermal fentanyl system according to the invention, and the reference product, for example the DURAGEIC® / DUROGESIC ™ fentanyl system, are administered and the blood levels, plasma or serum of the drug are measured over time. The characteristics of these concentration-time curves, such as the area under the curve drug concentration in blood, plasma or serum-time (AUC) and peak concentration in blood, plasma or serum of the drug (Cma?). they are examined by statistical procedures as described in more detail below. In general, two statistical tests of a tail are carried out using the log-transformed parameter (AUC and Cmax) of the bioequivalence study. The two tests of a queue are carried out at a level 0.05 of importance and the confidence interval of 90% is computed. The test and the formulation / reference composition are considered to be bioequivalent if the confidence interval around the ratio of the mean value (test / reference product) for a pharmacokinetic parameter is not less than 80% at the lower end and no more than 125 % in the upper end. Two different products are generally considered "pharmacologically equivalent" if they produce substantially the same therapeutic effects when studied under similar experimental conditions, as demonstrated by several in vivo and in vitro methods as described above. The therapeutic effects depend on several factors, such as drug potency, drug solubility and diffusivity in the skin, skin thickness, concentration of the drug within the skin application site, concentration of the drug in the drug reservoir , and the like, as described in more detail below. In general, pharmacological equivalence is demonstrated using measurements such as the peak concentration in blood, plasma or serum of the drug normalized for the drug rate administered (ie, Cmax normalized as defined above) and the peak concentration in blood, plasma or standardized drug serum per unit area of the active drug delivery area of the system (ie, Cma? standardized as defined above). When comparing two different products whose drug administration rate is proportional to the size of the transdermal analgesic system, there is no difference if the peak concentration in blood, plasma or serum of the drug (Cma?) is normalized for the speed of the drug administered, or standardized per unit area of the active drug delivery area of the system, in order to establish the bioequivalence or pharmacological equivalence. However, when comparing two different products that have different drug delivery rates per unit area, it is necessary to normalize the peak concentration in blood, plasma or serum of the drug (Cma?) Based on the drug rate administered for the drug. establish bioequivalence or pharmacological equivalence.

Manufacturing methods Transdermal analgesic systems are manufactured as follows. The antagonist deposit and the analgesic deposits are manufactured according to known methodology, as described in more detail below.

Antagonist reservoir The antagonist reservoir can be formed through dry blending of an antagonist, preferably an antagonist salt, with a polymeric material, preferably a thermoformable material, with high shear and temperature using equipment such as sigma paddle mixers. or extruders, whether in a batch or continuous mode. The extrudate is calendared to the desired thickness between release liners, followed by lamination at elevated temperature to a barrier film and / or analgesic rate control means. In the case of a semi-continuous process, a polymeric material (for example, the ethylene-vinyl acetate copolymer (28% by weight VA)) is added to a feed hopper of a continuous co-kneader or screw extruder. double (Coperion Buss Kneader, Stuttgart, Germany) at a speed of about 22.67 kg per hour. An antagonist, preferably an antagonist salt (eg, naltrexone hydrochloride dihydrate) is added to a second hopper at a rate of 26.62 kg per hour. The extruder is operated to produce extrudates at a constant speed of approximately 0.45 kg per minute. After leaving the extruder, the polymer-drug mixture is calendered to a desired thickness (about 0.03 mm (1.2 mil)) between the barrier layer (e.g., polyester / EVA) and the release liner (polyester film). siliconized). The trilaminate structure is wound on feed roll rollers for further processing. Parameters such as antagonist loading, thickness of the antagonist reservoir, membrane selection for the analgesic rate control means, and modification of the surfactant of the analgesic rate control means can be varied to achieve target release rate of antagonist to the analgesic for a variety of abuse circumstances, as illustrated in the examples below. In preferred embodiments, the surfactants are coated onto the membrane materials by forming the analgesic rate control means using techniques such as dip coating, gravure coating, and the like.

Analgesic deposit Transdermal analgesic systems are manufactured according to known methodology. A solution of the polymeric analgesic deposit material, as described above, is added to a double planetary mixer, followed by the addition of desired amounts of the analgesic, preferably fentanyl, more preferably fentanyl base, and optionally, a penetration enhancer. Preferably, the material of the polymeric analgesic deposit is an adhesive polymer, which is solubilized in an organic solvent, for example, ethanol, ethyl acetate, hexane, and the like. The mixer is then closed and activated for a period of time to achieve acceptable uniformity of the ingredients. The mixer is attached via connectors to a suitable molding nozzle located at one end of a film molding / drying line. The mixer is pressurized using nitrogen to feed the solution to the molding die. The solution is emptied as a wet film onto a moving siliconised polyester strip. The strip is pulled through lines and a series of furnaces is used to evaporate the pouring solvent to acceptable residual limits. The dried analgesic deposit film is then laminated to a selected barrier and the laminate is wound on advancement roller rollers. In another method, the analgesic reservoir can be formed using dry blending and thermal film formation using equipment known in the art. Preferably, the materials are dry mixed and extruded using a slot die followed by calendering to an appropriate thickness. Parameters such as analgesic loading, analgesic deposit thickness, analgesic selections, material selections and manufacturing procedures may vary for the preparation of analgesic deposits of the present invention, as illustrated in the following examples.

Transdermal analgesic system In subsequent operations, the intermediate containing the analgesic deposit and the intermediate containing the antagonist deposit are laminated and the individual transdermal systems are die cut, separated and packaged in units using suitable bag stock material. The intermediate containing the antagonist deposit can be laminated immediately after drying the intermediate containing the analgesic deposit. Transdermal analgesic systems are packaged in cardboard boxes using conventional equipment.

Experimental Below are examples of specific embodiments for carrying out the present invention. The examples are given for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Efforts have been made to ensure accuracy with respect to the numbers used (eg, temperatures, temperatures, etc.), but some errors and experimental deviations must be taken into account. Specific examples of various transdermal analgesic systems of the invention that are capable of administering fentanyl and analogs thereof for extended periods of time will be described in the examples set forth below. Transdermal analgesic systems comprise analgesic deposits comprising an analgesic in a concentration greater than or equal to or lower than the saturation concentration. The analgesic adhesive deposit systems wherein the analgesic reservoir comprises a single phase formulation of free undissolved components containing an amount of fentanyl at the subsaturation concentration are currently considered preferable according to our invention. In the following examples all percentages are by weight unless otherwise indicated.

EXAMPLE 1 Monolithic transdermal analgesic deposits are prepared according to Figure 1 containing 1.5 mg / cm2 of fentanyl base. A polyacrylate adhesive (National Starch 87-2287, -100 g) is solubilized in a solvent (ethyl acetate, 128 ml). Fentanyl base is added to the polyacrylate adhesive solution in amounts sufficient to generate a mixture containing 4% by weight of fentanyl in the adhesive solution and stirred to dissolve the analgesic. The solution is molded to a removable protective liner such as a siliconized polyester film, and the solvent is evaporated to provide a deposit layer with a thickness of 0.05 mm (2 mil). Similarly, monolithic transdermal analgesic deposits are prepared using the polyacrylate adhesive (National Starch 87-4287, 100 g), as described above.

EXAMPLE 2 The monolithic transdermal analgesic deposits are prepared as described in Example 1 with the following exceptions.

The materials are mixed dry, in the absence of ethyl acetate, and extruded using a slot die followed by calendering to an appropriate thickness.

EXAMPLE 3 The monolithic transdermal analgesic deposits are prepared according to Figure 1 as follows. A polyacrylate adhesive (National Starch 87-2287, 500 g) and glyceryl monolaurate (GML, 10 g) are dissolved in a solvent (ethyl acetate, 640 ml). The fentanyl base is added to the polyacrylate adhesive solution in amounts sufficient to generate a mixture containing 4% by weight of fentanyl in the adhesive solution and stirred to dissolve the analgesic. The solution is molded to a removable protective liner such as a siliconized polyester film, and the solvent is evaporated to provide a deposit layer with a thickness of 0.045 mm (1.8 mil). Analgesic transdermal systems contain 0.35 mg / cm2 of fentanyl base. Similarly, transdermal analgesic deposits are prepared using the polyacrylate adhesive (National Starch 87-4287, 100 g), as described above.

EXAMPLE 4 The monolithic transdermal analgesic deposits are prepared as described in Example 3 with the following exceptions.

EXAMPLE 5 The monolithic transdermal analgesic deposits are prepared which respectively comprise 0.25, 0.5, 0.75, 1.0 and 1.1 mg each of sufentanil, by 2.54 cm2, in a polyacrylate adhesive (National Starch 87-4287), as described in the example 1 previous Similarly, monolithic transdermal analgesic deposits are prepared using the polyacrylate adhesive (National Starch 87-2287, 100 g), as described above.

EXAMPLE 6 Monolithic transdermal analgesic deposits are prepared containing 0.25, 0.5, 0.75, 1.0 and 1.1 mg each of sufentanil, and penetration enhancers (1 mg) comprising lauryl pyroglutamate, glycerol monolaurate, glycerol monocaprylate and monocaproate monocaproate. glycerol, respectively by 2.54 cm2 as described in example 5.

EXAMPLE 7 The transdermal analgesic reservoir described above in Examples 1-6 is laminated to the PET side of the PET / EVA barrier layer (eg, as depicted in Figure 1) to provide an intermediate containing the reservoir transdermal analgesic EXAMPLE 8 The transdermal analgesic reservoir described above in Examples 1-6 is coated with an adhesive coating followed by PET face lamination of the PET / EVA barrier layer (e.g., as depicted in Figure 3) to provide an intermediate that contains the transdermal analgesic deposit.

EXAMPLE 9 The transdermal analgesic reservoir described above in Examples 1-6 is laminated to an analgesic speed control membrane followed by PET face lamination of the PET / EVA barrier layer (e.g., as shown in FIG. figure 2) to provide an intermediate containing the transdermal analgesic reservoir.

EXAMPLE 10 The transdermal analgesic reservoir described above in Examples 1-6 is laminated to a membrane for controlling the speed of the analgesic. The surface near the skin of the analgesic speed control membrane is coated with an adhesive coating followed by lamination to the PET face of the PET / EVA barrier layer (eg, as shown in Figure 4). ) to provide an intermediate containing the transdermal analgesic reservoir.

EXAMPLE 11 Intermediates containing the antagonist deposit are prepared as follows. A thermoformable polymer (460 g), such as the ethylene-octene copolymer Engage®, (DuPont-Dow Elastomers, Midland, Ml), is placed inside the container of a high torque mixer. The vessel is heated (150 ° C) and the polymer pellets are mixed until the polymer pellets are sufficiently chewed to provide a melt (10 minutes). The antagonist (naltrexone hydrochloride USP, 540 g) is added to the mixing vessel, and the mixture is stirred for about 30 minutes. The polymer in the molten state is emptied from the mixing vessel and extruded between two moving webs: a top layer of 0.05 mm (2 mil) of polyester / EVA film (the EVA side to the material in the molten state) and a 0.075 mm (3 mil) lower layer of siliconized polyester film. The three-layer film structure is passed through calendering rolls to size the antagonist deposit disposed in the barrier layer of about 0.025 mm (1 mil) in thickness. The movement band is taken in the form of a roller at the end of the extrusion line. In a second step through the line, the mixed intercalation is removed and a microporous polyethylene film (SOLUPOR, DSM Solutech, Heerlan, The Netherlands) is hot rolled to the exposed antagonist reservoir using a calender. The microporous membrane provides the means of controlling the release of the antagonist to the final transdermal analgesic system. The resulting structure is taken in the form of a roll as an intermediate product comprising the antagonist reservoir disposed in the means or control layer of the release of the antagonist. The intermediate containing the antagonist deposit described above is laminated to the adhesive film containing the analgesic leaving the drying ovens described in Examples 1-6 above, providing a six layer film laminate: a release liner, a analgesic deposit; optionally containing a speed control membrane, a barrier layer (polyester, EVA), an antagonist reservoir (polyethienooctene-naltrexone HCl) and the control means of antagonist release (microporous polyethylene). The total thickness of the film is about 0.2 mm (8 mil). The six-fold film is die cut to transdermal analgesic systems corresponding to the analgesic delivery areas from 1 cm2 to 44 cm2. In systems containing fentanyl, the charge ratio of fentanyl to naltrexone in the final systems is 1: 2; and the delivery rates of fentanyl are from about 12.5 to about 100 μg / h depending on the area of the system. In systems containing sufentanil, the loading ratio of sufentanil to naltrexone in the final systems is 1: 4-16, and the delivery rates of sufentanil are from about 1.5 to about 12 μg / h depending on the system area .

EXAMPLE 12 Intermediates containing the antagonist deposit are prepared as follows. A thermoformable polymer (460 g), such as the ethylene-octane copolymer Engage®, (DuPont-Dow Elastomers, Midland, Ml), is placed inside the container of a high torque mixer. The vessel is heated (150 ° C) and the polymer pellets are mixed until the polymer pellets are sufficiently plasticized to provide a melt (10 minutes). The antagonist (naltrexone hydrochloride USP, 540 g) is added to the mixing vessel, and the mixture is stirred for about 30 minutes. The polymer in the molten state is emptied from the mixing vessel and extruded between two moving webs: a top layer of 0.075 mm (3 mil) of fluoropolymer release liner film (polyester film coated with fluorocarbon diacrylate) and a lower layer of 0.075 mm (3 mil) of siliconized polyester film. The three-layer film structure is passed through calender rolls to size the antagonist deposit disposed in the barrier layer to about 0.025 mm (1 mil) in thickness. The moving band is taken in the form of a roller at the end of the extrusion line. In a second passage through the line, one of the siliconized intercalation is removed and a microporous polyethylene film (SoluPor, Solutech, Denmark) is hot-rolled to the exposed antagonist reservoir using a calender. The microporous membrane provides the means of controlling the release of the antagonist for the final transdermal analgesic system. The resulting structure is taken as a roll as an intermediate product comprising the antagonist deposit. In the third step through the line, the siliconized interlayer is removed and an adhesive layer is laminated to the exposed antagonist deposit using a laminator, which provides a four-layer film laminate: the adhesive layer, the barrier layer, the antagonist deposit (polyethyleneoctane-naltrexone HCl) and antagonist release control means (microporous polyethylene). The four-ply film is die-cut into corresponding individual units to form forming, filling and sealing system (FFS) areas of 10, 20, 30 and 40 cm2. Intermediates containing the analgesic deposit are prepared as follows. The fentanyl base (1.4 kg) is suspended in purified water (5 I, USP) in a container. Ethanol (25 kg, USP) and water (65 l, USP) are mixed in a pressure vessel of 151.4 I, the solution is stirred, and allowed to cool to room temperature. Fentanyl suspension is added to the ethanol solution, using water (4 I, USP) to wash the vessel quantitatively. In a separate vessel, hydroxyethyl cellulose (2 kg, QP 100,000 [HEC], NF) is suspended with water (4 I). The hydroxymethyl cellulose suspension is added with mixing to the fentanyl mixture in the 151.4 I mixer. The remaining hydroxyethyl cellulose is washed using water (2 I) and added to the large mixing vessel. The vessel is immediately stirred at 100 cycles / minute until the gelling of mixtures of the analgesic deposit. The pressure vessel provided by the fentanyl gel is attached to a multibill gel placement arrangement mounted on a bagging machine (formed, filled and sealed) Bodolay (FFS). A composite laminate of the protective liner (removable PET-slicona film), adhesive layer (silicone adhesive film, 0.039 mm), and analgesic release rate control means (an EVA film (9% VA), 0.051 mm) is laid on the equipment used to build the shape filling sealing systems. The analgesic deposit is dosed onto the protective liner / adhesive layer / analgesic release rate control means such that the gel contacts the analgesic release control means. The barrier layer (PET / EVA) is laid in such a way that it covers the gel. The EVA component of the barrier layer makes contact with the analgesic release control membrane. The perimeter of the construction is hot rolled, forming the analgesic portion of the system that forms the peripheral sealing systems with 245 mg of reservoir gel per 10 cm2 of the area of active drug release from the system. The film is cut with die in individual units corresponding to the analgesic delivery areas of 10 to 40 cm2 to form the intermediate containing the analgesic deposit. The adhesive surface of the intermediate containing the antagonist reservoir is laminated onto the barrier layer of the intermediate containing the analgesic reservoir to form the transdermal analgesic system having a formant, filled and sealed analgesic reservoir (FFS). In systems containing fentanyl, the charge ratio of fentanyl to naltrexone in the final systems is 0.5 to 4, and fentanyl delivery rates are from about 12.5 to about 100 μg / h depending on the area of the system.

EXAMPLE 13 The intermediate containing the antagonist reservoir described in Example 11 is laminated to the analgesic reservoir described in Examples 9 and 10 above, providing an eight layer film laminate: release liner, adhesive layer, analgesic speed control membrane , analgesic deposit (analgesic-adhesive layer), barrier layer (EVA polyester), antagonist deposit (polyethyleneoctene-naltrexone HCl) and antagonist release control means (microporous polyethylene).

The eight-fold film is die cut to individual transdermal analgesic systems corresponding to the analgesic delivery areas of 5.5 to 44 cm2. In systems containing fentanyl, the charge ratio of fentanyl to naltrexone in the final systems is 1: 2, and the delivery rates of fentanyl are from about 12.5 to about 100 μg / h depending on the area of the system. In systems containing sufentanil, the loading ratio of sufentanil to naltrexone in the final systems is 1: 4-16, and the delivery rates of sufentanil are from 1.5 to about 12 μg / h depending on the area of the system.

EXAMPLE 14 A thermoformable polymer, polyolefin elastomer (460 g), such as Engage® ethylene-octene copolymer, (DuPont-Dow Elastomers, Midland, MI.), Is mixed in the molten state (88-100 ° C) with hydrochloride Naltrexone dihydrate (690 g) for about 1.5 to 2.5 hours. The mixture is extruded between the differential release liners, calendered to a thickness of 0.025 mm (1 mil) to form an antagonist reservoir. The antagonist deposit is laminated to the PE side of a PET-PE barrier film (Mediflex 1203, Mylan, St, Albans, VT), at 0-100 ° C, 4.99 kg / cm2 gauge, 121.9 cm / min . The remaining release liner is removed and the barrier layers are laminated at 60 ° C, 2.67 kg / cm 2 gauge, 121 cm / min. The antagonist release control means, for example, Solupor 10P05A, Pluronic modified Solupor, Celgard microporous polypropylene (grades 3401 and 3501), continuous filament polypropylene, and polyethylene film are laminated to the antagonist reservoir between 4.21 and 6.32 kg / cm2 gauge, 121.9 cm / min. The PET face of the intermediate containing the antagonist deposit described above is laminated to the adhesive film containing the analgesic leaving the drying ovens described in Examples 1-6 above, at 731.5 cm / min, 25 ° C, 4.92 kg / cm2 gauge. The liner is replaced with a slot release liner to allow easy removal of the liner system, and die cut to the desired dimensions, 5.5 to 44 cm2.

EXAMPLE 15 A thermoformable polymer, such as the ethylene-vinyl acetate copolymer Elvax® 210, (1.61 kg, 28% vinyl acetate, DuPont de Nemours, Wilmington, DE.), Is mixed in the molten state (77-88 °). C) with naltrexone hydrochloride dihydrate (1.89 kg) for about 1.5 to 2.5 hours. The mixture is extruded between the differential release liners, and calendered (0.031 mm) to form an antagonist reservoir. The antagonist deposit is laminated to the EVA face of a PET-EVA barrier film (Scotchpac 9733, 3M, Minneapolis, MN), at 80-85 ° C, 4.92-6.32 kg / cm2 gauge, 121.9-579.12 cm / min. The remaining release liner is removed and the antagonist release rate control means, the microporous polyethylene (e.g., Solupor 10P05A, or Solubor modified with Pluronic), are laminated to the antagonist reservoir between 80-85 ° C, 3.51 -3.79 kg / cm2 gauge, 121.9-731.5 cm / min. The PET face of the intermediate containing the antagonist deposit described above is laminated to the adhesive film containing the analgesic leaving the drying ovens described in Examples 1-6 above, at 731.5 cm / min, 25 ° C, 4.92 kg / cm2 gauge. The liner is replaced with a slot release liner to allow easy removal of the liner system, and die cut in individual transdermal analgesic systems corresponding to the analgesic delivery areas of 5.5 to 44 cm2.

EXAMPLE 16 The intermediate that confers the analgesic deposit described in the previous examples is prepared with the following exceptions. The means for controlling the release of the antagonist are prepared as follows. The Pluronic F108NF solutions (0.5, 1.0 and 2.0% by weight) are prepared in a solvent (3% water, 97% ethanol). Solupor 10P05A material is coated with Pluronic solutions and dried at room temperature overnight, providing coating weights of 35 μg / cm2, 50 μg / cm2, and 90 μg / cm2, for Pluronic solutions of 0.5, 1.0 and 2% by weight, respectively. These means for controlling the release of the antagonist, ie the membranes modified with surfactant, are laminated to the antagonist reservoir as described in the previous examples. EXAMPLE 17 The intermediate containing the antagonist deposit described in the previous examples is prepared with the following exceptions. Antagonist release control means (a membrane filled with salt that forms pores in situ during exposure to water) are prepared as follows. The ethylene-vinyl acetate copolymer (EVA) with 28% vinyl acetate monomer (Elvax 210, E.I. DuPont de Nemours, Wilmington, DE) is added to the hopper of a criomolino (10 kg). The criomolino is then filled to the mark with liquid nitrogen and the top is sealed. The mill is activated for about 10 minutes and the polymer pellets are milled to an average particle size of about 0.05 mm, and dried (using a stream of hot air) to obtain the ground polymer. Sodium chloride spray, with approximately 2% magnesium sulfate, (National Formulary, about 10 kg) is added to the hopper of a V mixer. The ground polymer (10 kg) is then added to the hopper. The hopper is activated to spin for approximately 15 minutes, to obtain a powder mix that is a consistent mixture of the polymer and sodium chloride. The powder mix is continuously fed to the addition port of a single screw extruder, the heating sections are preheated to approximately 110 ° C. At the end of the extruder, a flexible clamping nozzle is attached which has been adjusted to an output thickness of about 0.25 mm (1 mil). The extruder is operated to produce a film that is fed to the rollers of a three roll calender. The clamping point of the roller is adjusted to produce a continuous film that comes out of the calender that has a thickness of about 0.03 mm (1.5 mil). The film is wound onto feed roll rollers for additional manufacturing use. These antagonist release control means, ie the salt-containing film is laminated to the antagonist reservoir as described in the previous examples. The final systems are cut with a die and packaged. During the immersion of said systems in water, the sodium chloride layer rapidly desorbs the water-soluble salt. The resulting film forms a microporous membrane in situ that provides a release rate ratio of the antagonist to analgesic of at least 2: 1 and up to 20: 1.

EXAMPLE 18 Intermediates containing the antagonist deposit as described in Examples 11-17 are manufactured using an alternative continuous process. A gravimetric or volumetric feeder is used to feed the thermoplastic polymer into a twin screw extruder, the alternative single screw extruder ("co-kneader") or continuous mixer. The antagonist is fed in a similar manner into the molten polymer and mixed, and extruded in a calender in the laminate of the intermediate antagonist reservoir. Alternatively, the mixture is extruded in a yarn or bar, cut into pellets (approximately 5-10 mm) and subsequently extruded in a second stage.

EXAMPLE 19 The intermediate containing the antagonist deposit described in Examples 11-18 is prepared with the following exception. The intermediate antagonist reservoir is coated by extrusion directly to the EVA face of the barrier layer in a cold roll and the antagonist speed control layer is laminated in the same process step.

EXAMPLE 20 Systems manufactured according to examples 11-19 are used to study the release of naltrexone from the system during immersion in water at room temperature, i.e. room temperature. The transdermal analgesic systems are immersed in distilled water. After the selected time intervals, the systems are moved to a fresh extraction medium. This operation is repeated for a total time of 24 hours. The naltrexone released during this test procedure equals the rate and degree of fentanyl released as determined after performing a similar test procedure to measure the release of the opioid. These systems release naltrexone to fentanyl in a ratio of 2: 1 around at least one hour of immersion in water.

EXAMPLE 21 The systems manufactured according to examples 11-20 are used to study the release of naltrexone from the system in the immersion in an aqueous medium with regulated pH containing phosphate pH regulator with a pH of 6.5 at room temperature, i.e. room temperature or boiling temperature. The volume of the medium is adjusted below the solubility limit of the antagonist and the analgesic. The rate of release of the antagonist into the pH regulated phosphate medium is controlled by means of membrane selection or modification of the surfactant of the antagonist release control means. Figures 6-16 illustrate release rate profiles for various transdermal analgesic systems described in the previous examples. Figures 6, 7 and 8 illustrate the cumulative release of naltrexone from control media of release of the Solupor antagonist coated with Pluronic. Figures 9 and 10 illustrate the rate of release and cumulative release of naltrexone, respectively, of release control means from the Celgard 3401 antagonist. Figures 11 and 12 illustrate the rate of release and cumulative release of naltrexone, respectively, of control means for releasing the impermeable LDPE antagonist. Figures 13 and 14 illustrate the rate of release and cumulative release of naltrexone, respectively, from means of controlling the release of the antagonist Celgard 3501. Figures 15 and 16 illustrate the rate of release and cumulative release of naltrexone, respectively, from media of control of release of the continuous filament propylene antagonist. Each of Figures 9-16 illustrates data from experiments in triplicate (# 1, 2 and 3) and average data.

EXAMPLE 22 Extraction studies An intact, unused transdermal analgesic system (100 μg / h, 42 cm2) is placed in medium / standard extraction solution (approximately 300 ml) equilibrated at the target temperature. Examples of standard extraction media used include common household materials such as distilled water, vodka, rubbing alcohol, cooking oil, vinegar / water mixture and acetone. An aliquot of the extraction medium (1 ml) is removed at 0, 2, 5, 15, 60 and 120 minutes and diluted with unused extraction medium (5 ml). The samples are analyzed for naltrexone and fentanyl content by HPLC. The extractions are conducted at 25 ° C and repeated at 50 ° C and 75 ° C (where possible). The rate of release rate of the antagonist to analgesic ranges from about less than 0.1: 1 to about 3.6: 1.

EXAMPLE 23 The transdermal systems manufactured in Example 11 adhere to a section of human epidermis that has previously been excised from the underlying dermal tissue using techniques known to those skilled in the art. The system / skin intercalation is placed in a Franz diffusion cell. The number of replicated samples is 12. The entire apparatus is immersed in a thermoset water bath at 32 ° C. The cell receptor compartment is filled with an aqueous phosphate pH regulator at a pH of 6.5. The receiving compartment is sampled at selected intervals over a period of three days. Solutions for fentanyl and naltrexone are analyzed using sensitive HPLC assay techniques. Using the concentration of fentanyl / naltrexone, the diffusion area, the sample volume and the sampling time interval, the fentanyl / naltrexone flow is calculated. The results show that after a transient onset period, the mean fentanyl flux is about 2 μg / h-cm2, while the naltrexone flux has a value below the detection limit of the assay (ie «0.1 μg / h-cm2).

EXAMPLE 24 Awareness studies The systems are prepared as follows: Male hairless guinea pigs (Charles River laboratories, Boston, MA) are used to assess the sensitization potential of a 48-hour dermal application of a transdermal system (2.5 cm2). The transdermal system is composed of a skin adhesive (NS Duro-Tak 87-2287 or NS Duro-Tak 87-4287), a barrier film, a polymer with (transdermal analgesic system) and without (transdermal placebo system) naltrexone HCl , and a porous reinforcement layer. The guinea pigs are divided into the following six groups: TABLE 1 Naltrexone HCl nominal concentration per system = 3.44 mg During the induction period, animals in groups 1-5 receive nine topical inductions to the dorsal skin area about 21 days (3 applications per week) of their respective test or control articles. Each application is used for approximately 48 hours except for the DNCB (positive control), which is used for 24 hours. Before each skin application and after the removal of the system, the skin sites are cleaned with a scouring pad with alcohol and dried with a gauze pad. The margins of the application sites on the skin are marked with a skin marker after removing the system. For groups 1-4, sites with skin irritation are evaluated 2 ± 0.5 hours after the removal of the first induction, and 2 ± 0.5 and 24 ± 1 hours after the removal of the system for the last induction. For group 5, after the removal of the first and last induction applications, the sites are evaluated for primary and cumulative skin irritation, respectively, 2 ± 0.5 and 24 ± 1 hours after removal of the skin. system. Within approximately 10 to 14 days after the last induction application, each guinea pig is challenged according to the treatment presented in Table 1. Each topical application is used for approximately 48 hours except for DNCB (positive control), which is use for 24 hours. All application sites are marked to denote irritation approximately 2 ± 0.5, 24 + 1, and 48 ± 1 hours after the removal of the challenge item. All scores are conducted using a modified Draize scale (0-4 for erythema and 0-4 for edema). The responses are defined as positive for sensitization if the combined erythema and edema scores are > 2 to 48 hours after the challenge. The mean irritation scores for systems with the transdermal antagonist system (Adhesive 2287) after the first and last induction applications are similar without evidence of cumulative irritation and the transdermal system is categorized as a mean irritant. The mean irritation scores for the transdermal antagonist system (Adhesive 4287) after the first and last induction applications are similar without evidence of cumulative irritation and the transdermal system is categorized as a mild irritant. No evidence of sensitization is observed in any of the guinea pigs induced and challenged with the transdermal placebo system or the transdermal antagonist system. The transdermal systems are classified by category, having a weak sensitization potential. A sensitization response occurs in all guinea pigs induced and challenged with the positive control, DNCB, confirming that a response can be produced in this model. The manufacturer of acrylate skin adhesives also conducts safety tests on each adhesive, including a Buehier sensitization study. The data supports the safe use of each adhesive. A GLP study conducted in conscious hairless guinea pigs reveals that naltrexone gel injected intradermally or applied topically has a potential moderate to strong sensitization to contact under the conditions of the study. A second LPG study is conducted in conscious hairless guinea pigs with transdermal placebo and antagonist systems. No evidence of sensitization is observed in any of the guinea pigs induced and challenged with transdermal placebo systems or transdermal antagonist systems. This classifies the transdermal systems into categories having a weak sensitization potential. A sensitization response occurs in all guinea pigs induced and challenged with the positive control, DNCB, confirming that a response can be produced in this model (the details of the study are presented later). Additional safety data on the acrylate skin adhesives used in these studies are available from the manufacturer. The data support the safe use in a clinical study of sensitization of transdermal systems with and without naltrexone in the reinforcement.

EXAMPLE 25 Study of skin irritation A study of GLP skin irritation in conscious male hairless guinea pigs (strain IAF: HA-HO-hr) is conducted to evaluate the irritation potential of various transdermal analgesic systems containing sufentaniol after a single topical application of 72 hours. Two transdermal systems (having a thickness of 0.025 mm (1.0 mil) and 0.05 mm (2.0 mil) composed of a skin adhesive (NS Duro-Tak 87-4287) that confers a sufentanil base, and a reinforcement layer are tested (as described in Example 11) The in vitro flux of sufentanil base of both systems is approximately 0.60 μg / cm2 / hr Each of the six guinea pigs has a system of each thickness applied to areas of intact dorsal skin for 72 hours (± 1) hours.The sites were marked for erythema, eschar, and edema in 30-40 minutes, 24 (± 1) hours after removing the test items. mark, using the Draize scale of 0-4 for erythema and 0-4 for edema, primary irritation indices (Plls) are calculated, mild irritation is observed after application of all systems, no changes occur in the clinical condition The systems can be used in a human clinical study of application unique with a period of use of up to 72 hours.

EXAMPLE 26 Miniature pigs of the Yucatan race are used to assess potential systemic toxicity following the intra-oral administration of a transdermal analgesic system. The transdermal system is composed of a skin adhesive (NS Duro-Tak 87-4287) with fentanyl, a barrier layer, a polymer with naltrexone HCl, and a porous reinforcement layer (as described in example 14). The transdermal analgesic systems, with naltrexone HCl in the booster, contain approximately 8.8 mg of fentanyl per system and 35.2 mg of naltrexone HCl (0.4 mg / cm2 in a 22 cm2 system). Miniature pigs of the healthy female Yucatan breed are used, obtained from S &S Farms (Ranchita CA), weighing 19-27 kg, and at least 6 months old. The pigs are identified by cuts in the ears. Five animals are sedated and anesthetized with approximately 4 mg / kg Telazol® and isoflurane (for each cannulation), respectively, and the systems are placed in their oral cavities for 1-30 minutes. The anesthesia is discontinued and the animals are allowed to recover. The animals are monitored closely to observe the clinical signs. Transdermal analgesic systems are removed from the oral cavity and allowed to air dry. The residual drug analyzes are performed in the five transdermal antagonist systems administered. As tabulated in Table 2, both fentanyl and naltrexone are released from the patch into the oral cavity. The release rate ratio of naltrexone to fentanyl is from about 6: 1 to about 8: 1. Fentanyl toxicity is not observed in four of the five dosed animals.

TABLE 2 Pigs dosed with the transdermal antagonist system EXAMPLE 27 Study of sufentanil / naltrexone ratio in rats Groups of male rats (CRL: CD® (SD) IGSBR) are administered the following test agents intravenously via a tail vein: naltrexone hydrochloride alone, sufentanil alone, or naltrexone hydrochloride followed immediately by sufentanil. The objective of the study is to determine the doses of naltrexone that could effectively antagonize the profile of the severe opioid effect induced by a preselected intravenous dose of sufentanil (18.75 μg / kg). The dose groups are summarized in the following table.

TABLE 3 1 = (μg / kg iv) Following the injection of the test agents, the animals are observed for clinical signs. Naltrexone is effective in blocking opioid-induced effects of sufentanil in dose ratios of naltrexone: sufentanil of 4: 1, 8: 1, and 16: 1. The duration of naltrexone antagonism is comparable in each of the three dose ratios and appear at the end as long as the clinical signs persist in the sufentanil control group (generally 1-2 hours). The dose ratio of naltrexone: sufentanil 1: 1 is less effective in blocking clinical signs induced by sufentanil, but in this dose ratio the clinical signs are generally less severe and last less than in the sufentanil control group. Naltrexone (300 μg / kg) administered alone to rats (N = 3) produces no apparent effects. Figures 17 and 18 illustrate the effect of naltrexone on clinical signs induced by sufentanil in rats (within 30 minutes after dosing).

EXAMPLE 28 Evaluation of transdermal systems with contact sensitization potential in healthy subjects The contact sensitization potential of the components of the transdermal analgesic system in healthy subjects is conducted using several patches of transdermal antagonists as described in example 11 above: System A: transdermal analgesic system (placebo) with naltrexone (44 cm2); and System B: transdermal analgesic system (placebo) (44 cm2). A secondary objective is to demonstrate non-quantifiable serum naltrexone concentrations. The study is a simple, double blind, randomized study with phases of induction, rest and challenge. In the present study, 240 subjects receive system A and 60 subjects receive system B. System A (the transdermal placebo analgesic system with naltrexone) contains a polyester release liner, a polyacrylate adhesive and a laminated polyester reinforcement to a polyethylene film with a naltrexone-polyethylene layer. System B (transdermal placebo analgesic system without naltrexone) contains a polyester release liner, a polyacrylate adhesive, and a polyester reinforcement laminated to a polyethylene film with a polyethylene layer.

During the induction phase, each subject receives either system A or system B, for a total of nine consecutive systems applied to the same skin site for a total of 21 days. If the application site has to be changed due to severe skin reactions from a previous application of the system, a different site in the same arm is used to continue with the 21 day application plan. Each system is used continuously for two or three days (48 or 72 hours) ± 4 hours. The system is applied to skin sites on the outside of the upper arm. Immediately after the removal of each induction phase system, and 24 hours after the removal of the last induction phase system, the application site is assessed for topical reactions using a standard grading scale. During the resting phase, which begins after the induction phase, there is no application for two weeks. During the challenge phase, which begins after the resting phase, two systems (one A and one B) are applied to the untreated skin sites on the outside of the upper arm not used in the induction phase and It is used for 48 hours. After removal of the challenge phase transdermal analgesic systems, skin sites are assessed for topical irritation and sensitization reactions at 0.5, 24, 48, and 72 hours after removal. Any questionable sensitization reaction is confirmed by a new challenge that is applied to new sites 24 hours after the removal of the first challenge phase systems. Two systems (one A and one B) are applied to foot sites! no treatment on the outside of the upper arm not used in the induction phase (or upper chest if necessary) in the 24-hour assessment of the first challenge and used for 48 hours. These are removed and additional assessments are made at 0.5, 24, 48 and 72 hours after the removal. After the removal of each induction phase system, the application site is assessed for topical reactions and adhesion, using standard graduation scales. Blood samples are taken for analysis of naltrexone concentrations before system application on day 1 and before system removal on days 17, 19 and 22. Serum is removed from blood samples using standard procedures . The serum samples are analyzed using a validated method of liquid chromatography-tandem mass spectrometry (LC / MS / MS). The lower limit of quantification is approximately 5 pg / ml. Transdermal analgesic systems demonstrate acceptable levels of adhesion and irritation. No evidence of sensitization is observed. The concentration of naltrexone in most serum samples is below quantifiable limits. Consequently, there is no evidence of systemic administration of naltrexone.

EXAMPLE 29 Activity Studies The primary objective of this study is to evaluate the concentrations of naltrexone in serum after the application of a transdermal analgesic placebo system with the naltrexone system under various conditions (normal activity, bathing and physical exercise). The secondary objective is to evaluate the residual naltrexone in the systems used after a period of use of 4 hours under various conditions (normal activity, bathing and physical exercise). The study is a randomized study, simple center, open, a period of 3 to 4 hours, two sequences and crossed. The subjects are randomly assigned to one of the two treatment sequences. All three periods take place on the same day. During each period, each subject uses a new transdermal analgesic placebo system with the naltrexone system (44 cm2) for 4 hours and is engaged in normal activity; in hard physical activity (20 minutes, room temperature), or take a hot bath (10 minutes at approximately 40 ° C). First is the normal activity while the order of the other two activities is random. Blood samples are collected for the determination of naltrexone concentrations in serum before the first application of the system, then at 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 hours after the application of the system. During exercise and bathing activities, an additional blood sample is taken following the completion of the activity. The serum samples are analyzed for the determination of naltrexone concentration using a validated method of liquid chromatography-tandem mass spectrometry (LC / MS / MS). The lower limit of quantification is approximately 5 pg / ml. The adherence of each transdermal analgesic system is assessed just before the removal of the system. Each site of the skin to which the system is applied is monitored for topical reactions (including erythema, edema, pustules, papules and itching) approximately 15 minutes, one hour, and 16-24 hours after removal. The residual naltrexone in the systems used is measured after the system is removed. The method of analysis for naltrexone in used systems is carried out as follows. The systems are first weighed, removed from the protective liners and placed on nylon wire mesh, then rolled and placed in the extraction vessel. Extraction is carried out using an organic solvent with stirring, followed by dilution with a mixture of organic solvent / water. Naltrexone is measured using reverse phase HPLC with UV detection. The percentage of loss of naltrexone content of the transdermal system averages about 2-3% during normal activity and hard physical activity. During bathing activity, the percentage of loss of naltrexone content of the transdermal system averages about 23%. The concentration of naltrexone in most serum samples is below quantifiable limits. Consequently, there is no evidence of systemic administration of naltrexone. Additionally, transdermal analgesic systems demonstrate acceptable levels of adhesion and irritation. No evidence of sensitization is observed.

EXAMPLE 30 Bioequivalence study Fentanyl flux studies in vivo are conducted using various systems of transdermal fentanyl - transdermal analgesic system as described in example 14, and DUROGESIC ™ fentanyl system, and the comparative pharmacokinetic parameters are tabulated in Tables 4A-4B and later. The pharmacokinetic parameters of the transdermal analgesic systems are evaluated as follows. A single center study, randomized, single application, open, two treatments, two sequences, two periods, crossed using transdermal systems, each for 72 hours application: Treatment Durogesic ™ 50 μg / h; and treatment B (transdermal fentanyl system with naltrexone (50 μg / h of fentanyl) is performed to evaluate the pharmacokinetic parameters of the systems after the single application. Subjects are randomly assigned to one of the two treatment sequences (at least 14 subjects per treatment sequence). Subjects use two transdermal fentanyl systems sequentially for two 72-hour periods of use on a skin site on the outside of the upper arm. There is a minimum washing period of at least 14 days and no more than 21 days between treatments. The washing period begins with the removal of the study system. The study system is used for 72 hours. Each subject receives a bolus of naloxone (0.5 mg) followed by continuous infusion of naloxone (0.2 mg / h) since the opioid antagonist starts 15 minutes before the application of the system and during the application and up to 4 hours after the removal of the system. Each subject then receives naltrexone tablets of 50 mg in 6 and 20 hours after the removal of the system. At the programmed time points for both treatments (pre-dose and 2), 3, 5, 8, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 73, 74, 76, 80, 84, 96, 108 and 120 hours after the application of the system), blood samples are collected from each subject for the determination of serum fentanyl concentrations. The serum samples are analyzed for the determination of the concentration of fentanyl using a validated method of liquid chromatography-tandem mass spectrometry (LC / MS / MS). Topical skin irritation and adhesion of the system are assessed at the programmed time points. The results of the in vivo study are tabulated in Tables 4A-4B and 5. Figure 19 illustrates the concentrations of fentanyl in serum after transdermal application of several fentanyl systems - one application of the inventive transdermal analgesic system (50 μg. / h, 22 cm2); and DUROGESIC ™ fentanyl system (50 μg / h, 20 cm2), up to 120 hours after the first administration. Descriptive statistical data are calculated for the pharmacokinetic parameters of fentanyl for each treatment. The characteristics of these concentration-time curves, such as the area under the curve of drug concentration in serum-time (AUC), time at maximum concentration (Tmax) and the peak concentration in blood, plasma or serum (Cmax) of the drug, are examined by statistical procedures as described above. A mixed effect analysis of the variance model (ANOVA) that includes the treatment, period, sequence, fixed effects and random effect of the sequence within the subject is used for the analysis of fentanyl pharmacokinetic parameters (AUC¡nf and Cma transformed log., statistical methods for the average bioavailability (Design and Analysis of Bioavailability and Bioequivalence Studies, S. Chow and J. Liu (eds), Marcel Dekker, New York, NY, 1992, pp. 70-125) of least-squares of the average parameters and their 90% confidence intervals (Schuirmann DJ, A comparison of the two one-sided tests procedure and the power approach for assessing the equivalent of average bioavailability, J. Pharmacokinet, Biopharm, 1987, 15 : 657-680) are calculated.The lower and upper links of the 90% confidence intervals are compared for 80% and 125%, respectively.A non-parametric Wilcoxon sum sum test is performed in Tmax and AUC ac Fractional mumulative of fentanyl. A level of importance of 0.05 is used for these tests. The test and the formulation / reference composition are considered to be bioequivalent if the confidence interval that is around the ratio of the mean value (test / reference product, ie, treatment A / treatment B) to a pharmacokinetic parameter is not less than 80% at the lower end and no more than 125% at the upper end. The results of the statistical analysis of the transformed pharmacokinetic parameters log (PK) are tabulated in Tables 4A-4B and 5.

TABLE 4A Comparative pharmacokinetic parameters (PK) for the analgesic system containing transdermal fentanyl and fentanyl system DUROGESIC ™ TABLE 4B Pharmacokinetic parameters of the medium (% CVa) for transdermal fentanyl systems a = percentage of coefficient of variation TABLE 5 Analysis of bioequivalence of pharmacokinetic parameters (n = 26) Thus, as the results tabulated above and illustrated in FIG. 19 warn, the transdermal fentanyl-containing analgesic systems of the present invention comprising naltrexone are bioequivalent products to the saturated, speed-controlled furanyl DUROGESIC ™ system. In particular, the transdermal analgesic system according to the invention displays the dynamic pharmacokinetic parameters comparable to the transdermal DUROGESIC ™ fentanyl system: the 90% confidence interval for the Cma? transformed average log and the average ratios of the test formulation against the reference formulation fall within the range of 80% to 120%.

EXAMPLE 31 Fentanyl flux studies in vivo are conducted using several transdermal fentanyl systems - transdermal antagonist system as described in Example 15, and DUROGESIC ™ fentanyl system, with the following exceptions. Serum samples collected at 76 hours and before 76 hours post-application are also analyzed for naltrexone concentration (Treatment B) using a validated method of liquid chromatography-tandem mass spectrometry (LC / MS / MS).

TABLE 6A Comparative pharmacokinetic parameters (PK) for the analgesic system containing transdermal fentanyl and fentanyl system DUROGESIC ™ TABLE 6B Summary of average pharmacokinetic parameters (% CVa) a = percentage of coefficient of variation TABLE 7 Bioequivalence analysis of pharmacokinetic parameters (n = 28) Thus, as is evident from the results tabulated above and illustrated in Figure 20, the transdermal analgesic system of the present invention comprising a drug reservoir comprising fentanyl, are bioequivalent products to the saturated speed controlled DUROGESIC ™ fentanyl system . In particular, the transdermal analgesic system according to the invention displays dynamic pharmacokinetic parameters comparable to the transdermal DUROGESIC ™ fentanyl system: the 90% confidence interval for the Cma? transformed average log and the average ratios of the test formulation against the reference formulation fall within the range of 80% to 120%. Additionally, the concentration of naltrexone in the serum samples is below the detectable levels, indicating that there is no systemic absorption of naltrexone from the transdermal analgesic systems.

EXAMPLE 32 Pharmacokinetic Studies for Systems Containing Transdermal Sulfenyl A simple, randomized, open center study, three treatments, two sequences, three periods, crossed in healthy subjects using IV administration and transdermal systems, is performed to estimate the amount of sufentanil absorbed from two analgesic systems containing transdermal sufentanil of different thicknesses compared to the administration of intravenous sufentanil, and to compare the pharmacokinetic parameters of the two transdermal sufentanil systems. The following treatments are administered during this study: treatment A: continuous IV sufentanil infusion that delivers 100 μg of sufentanil at a rate of 10 μg / h (10 hours of infusion); treatment B: analgesic system containing transdermal sufentanil (6 mg, 20 cm2, 0.05 mm thickness of adhesive, approximately 10 μg / h, 72 hours of application); and treatment C: analgesic system containing transdermal sufentanil (3 mg, 20 cm2, 0.025 mm adhesive thickness, 10 μg / h, 72 hours of application). The subjects are randomly assigned to one of the two treatment sequences. Each subject receives an infusion of IV continuous sufentanil at 10 μg / h for 10 hours in the first period. Following with this, each subject receives two transdermal systems of 72 hours, one system during period 2 of treatment and one during period 3 of treatment, in the sites of the skin without treatment on the outside of the upper arm. There is a minimum washing period of at least 6 days and no more than 14 days between treatments. The washing period begins with the removal of the transdermal applications or completion of the IV infusion. Each subject receives 50 mg naltrexone tablets because the opioid antagonist initiates 14 hours before system application / IV infusion initiation. Subjects continue to receive the 50 mg naltrexone tablets twice daily during the IV system / infusion application and 24 hours after system removal / IV infusion completion. At the scheduled time points after IV infusion / system application, blood samples are collected for the determination of sufentanil concentrations in plasma. During IV treatment in pre-dose and 0.5, 1, 2, 3, 5, 8, 10, 10.5, 11, 12, 14, 18, 22, 26, 30, 34, 38 and 48 hours after the initiation of The infussion. During each transdermal treatment in pre-dose and 0.5, 1, 2, 3, 5, 8, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 73, 74, 78, 84 , 96, 108 and 120 hours after the application of the system. The plasma samples are analyzed for the determination of the sulfenyl concentration using a validated method of liquid chromatography - tandem mass spectrometry (LC / MS / MS). The residual sulfenyl content in the systems is measured using reverse phase HPLC with UV detection. Topical skin irritation and adherence of the system are assessed for transdermal treatments. Adverse events, blood pressure, temperature, heart rate and breathing speed are monitored. The results of the study are tabulated in Table 8. Figure 21 illustrates the concentrations of sufentanil in plasma after several treatments with sufentanil, up to 120 hours after the first administration. The descriptive statistical data are calculated for the pharmacokinetic parameters of sufentanil for each treatment (A, B or C) according to the statistical methods described in the previous examples.

TABLE 8 Summary of average pharmacokinetic parameters (% CV) TABLE 6C Comparative pharmacokinetic parameters (PK) for the analgesic system containing transdermal sufentanil The present invention is described and characterized by one or more of the following aspects and / or features, either individually or in combination with one or more other aspects and features: A transdermal system for the administration of an analgesic through of the skin, the system having a reduced potential for abuse, comprising: (a) an analgesic deposit comprising an analgesic, the analgesic being selected from the group consisting of fentanyl and analogues thereof; (b) an antagonist reservoir comprising an antagonist for said analgesic; (c) a barrier layer, said barrier layer separating said antagonist reservoir from the analgesic reservoir, the barrier layer being substantially impermeable to said analgesic agent and said antagonist, wherein system (i) substantially prevents the release of the antagonist from the antagonist. system during the assurance of the system to a human patient for a period of up to approximately 7 days; and (ii) provides release of the antagonist at a rate sufficient to provide a rate of release ratio that limits the abuse of the antagonist to the analgesic when the dosage form is abused, for example, in the ingestion or substantial immersion of the system in the solvent. The transdermal analgesic system of the invention comprises an analgesic reservoir comprising an amount of analgesic sufficient to induce and maintain analgesia in a human patient for a period of at least three days, wherein the analgesic is fentanyl or an analogue thereof and the analog is selected from the group consisting of alfentanil, lofentanil, remifentanil, sufentanil and trefentanil. In preferred embodiments, the analgesic is fentanyl or sufentanil, more preferably, the base form of fentanyl or sufentanil. The analgesic deposit comprises a polymer matrix comprising about 1% by weight to about 20% by weight of the analgesic, and optionally a penetration enhancer. The analgesic reservoir may comprise a single phase formulation free of undissolved components; or an aqueous gel comprising up to about 20% by weight of the analgesic, about 50% by weight of the penetration enhancer, and about 0.5 to about 10% by weight of the gelling agent. Additionally, the transdermal analgesic system of the invention further comprises analgesic release control means positioned between the analgesic reservoir and the skin. In additional aspects, the transdermal analgesic system of the invention comprises an antagonist reservoir comprising an antagonist in a form that is not releasable through the barrier layer, the antagonist being releasable from the system when the dosage form is abused, for example, when ingested or substantially immersed in a solvent. Preferably, the antagonist deposit comprises the antagonist dispersed within a polymer, wherein the antagonist is substantially insoluble in the polymer of the antagonist deposit. The antagonist is selected from the group consisting of naltrexone, methylnaltrexone, naloxone, nalbuphine, nalorphine, nalorphine dinicotinate, nalmefene, nadide, levalorphan, cyclozocine and pharmaceutically acceptable salts thereof. In preferred embodiments, the antagonist is present as a salt, preferably as a hydrochloride salt of an antagonist base. In additional aspects, the transdermal analgesic system of the invention comprises a barrier layer impermeable to the analgesic and the antagonist; wherein the barrier layer comprises a material that is insoluble in water, alcohol and organic solvents. The antagonist reservoir is placed on the distal surface of the skin of the barrier layer and the analgesic reservoir is placed on the proximal surface of the skin of the barrier layer. In additional aspects, the transdermal analgesic system of the invention further comprises means for controlling the rate of release of the antagonist, wherein the means of controlling the release rate of the antagonist substantially prevents the release of the antagonist from the system during the assurance of the system to a patient human for a period of up to about 7 days; and provides release of the antagonist at a rate sufficient to provide a rate of release ratio that limits the abuse of the antagonist to the analgesic when the dosage form is subjected to abuse, for example, in the ingestion or substantial immersion of the system in the solvent. The means of controlling the rate of release of the antagonist are placed on the distal surface of the skin of the antagonist reservoir. In another aspect, the transdermal analgesic system of the invention, when the dosage form is abused, for example, during ingestion or immersion in a solvent for a period of time, substantially continuously provides a release rate ratio of the analgesic antagonist of at least about 0.5: 1 to about 20: 1; preferably from 1: 1 to about 16: 1; more preferably from about 1.5: 1 to about 8: 1; and even more preferably from about 2: 1 to about 4: 1; where the immersion time period is up to about 1 minute to about 24 hours. In another aspect, the invention relates to a transdermal system for the administration of an analgesic through the skin, the system having a reduced potential for abuse, comprising: (a) an analgesic reservoir comprising a sufficient amount of analgesic for inducing and maintaining analgesia in a human patient for a period of at least three days, wherein the analgesic is fentanyl or an analogue thereof and the analog is selected from the group consisting of alfentanil, lofentanil, remifentanil, sufentanil and trefentanil; (b) an antagonist reservoir comprising an antagonist for said analgesic, wherein the antagonist is a form that is not releasable through the barrier layer, the antagonist being releasable from the system upon ingestion or substantially immersed in a solvent, and further wherein the antagonist is selected from the group consisting of naltrexone, methylnaltrexone, naloxone, nalbuphine, nalorphine, nalorphine dinicotinate, nalmefene, nadide, levalorphan, cyclozocine and pharmaceutically acceptable salts thereof; (c) a barrier layer, said barrier layer separating the antagonist reservoir from the analgesic reservoir, the barrier layer being substantially impermeable to said analgesic and said antagonist; and (d) means for controlling the release rate of the antagonist positioned on the distal surface of the skin of the antagonist reservoir, wherein said means for controlling the release rate of the antagonist substantially prevents the release of the antagonist from the system during the assurance of the system to a human for a period of up to about 7 days, and wherein also the means of controlling the rate of release of the antagonist provide for the release of the antagonist at a rate sufficient to provide a speed ratio that limits the abuse from the antagonist to the analgesic when the dosage form is subjected to abuse, for example, in the ingestion or substantial immersion of the system in the solvent. The exemplary embodiments described above are intended to be illustrative in all respects, rather than restrictive, of the present invention. In this way, the present invention is susceptible to many variations in the detailed implementation that can be derived from the description contained herein by a person skilled in the art. All variations and modifications are considered to be within the scope and essence of the present invention.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A transdermal system for administering an analgesic through the skin, the system having a reduced potential for abuse, comprising: (a) a reservoir analgesic comprising an analgesic, the analgesic being selected from the group consisting of fentanyl and analogs thereof; (b) an antagonist reservoir comprising an antagonist for said analgesic; (C) a barrier layer, said barrier layer separating said reservoir antagonist reservoir analgesic, the barrier layer being substantially impermeable to said analgesic and to said antagonist, wherein the system (i) permits the release of antagonist system in normal use but at levels sufficiently low such that the analgesic effect of analgesic effect in the presence of antagonist released divided by the effect of the analgesic in the absence of antagonist released, is greater than about 85%, and (ii) provides release antagonist at a rate sufficient to provide a rate of release ratio that limits the abuse of the antagonist to the analgesic when the dosage form is abused.

2. The system according to claim 1, further characterized in that the system (i) allows the release of the antagonist from the system in normal use but at sufficiently low levels such that the analgesic effect of the analgesic in the presence of the antagonist released divided by the effect of the analgesic in the absence of antagonist released, is greater than about 85%, and (ii) provides at a velocity sufficient release of the antagonist to provide a ratio of release rate limiting abuse antagonist to the analgesic in the Ingestion or substantial immersion of the system in the solvent.

3. The system according to any of the preceding claims, further characterized in that it comprises means for controlling the rate of release of the antagonist.

4. The system according to claim 3, further characterized in that the means of controlling the release rate of the antagonist (i) allow the release of the antagonist from the system in normal use but at sufficiently low levels in such a way that the effect analgesic analgesic in the presence of antagonist released divided by the effect of the analgesic in the absence of antagonist released, is greater than about 85%, and (ii) provides at a velocity sufficient release of the antagonist to provide a ratio of release rate which limits the abuse of the antagonist to the analgesic in the ingestion or substantial immersion of the system in the solvent.

5. The system according to any of claims 3 and 4, further characterized in that the means for controlling the release rate of the antagonist are placed on the distal surface of the skin of the antagonist deposit.

6. - The system according to any of claims 3-5, further characterized in that the means for controlling the rate of release of the antagonist are selected from a group consisting of a layer, a membrane, a film, a coating, a sheet , and a deposit in the antagonist deposit.

7. The compliance system cpn any of claims 3-6, further characterized in that the means for controlling the rate of release of the antagonist are selected from a group consisting of a speed control layer, a control membrane of speed, a porous membrane and a microporous membrane.

8. The system according to any of the preceding claims, further characterized in that the analgesic deposit comprises an amount of analgesic sufficient to induce and maintain analgesia in a human patient for a period of at least three days.

9. The system according to any of the preceding claims, further characterized in that the deposit of analgesic comprises an amount of dissolved fentanyl or analog thereof sufficient to induce and maintain analgesia for 3-7 days.

10. The system according to any of the preceding claims, further characterized in that the analgesic deposit comprises a single phase formulation free of undissolved components.

11. - The system according to any of the preceding claims, further characterized in that the analgesic deposit is formed of an adhesive polymer.

12. The system according to any of the preceding claims, further characterized in that the analgesic deposit comprises a polymer having a solubility for fentanyl and analogs thereof of about 1% by weight to about 25% by weight.

13. The system according to any of the preceding claims, further characterized in that the deposit comprises about 0.05 to about 1.75 mg / cm2 of fentanyl or analogs thereof.

14. The system according to any of the preceding claims, further characterized in that the analgesic deposit also comprises a penetration enhancer.

15. The system according to any of the preceding claims, further characterized in that the analgesic deposit comprises a polymer matrix comprising from about 5% by weight to about 50% by weight of the analgesic, and optionally a penetration enhancer .

16. The system according to any of the preceding claims, further characterized in that the analgesic deposit comprises an aqueous gel comprising up to about 1% by weight of analgesic, to about 25% by weight of penetration enhancer, and of 1-10% gelling agent.

17. The system according to any of the preceding claims, further characterized in that the deposit of analgesic comprises a penetration enhancer and wherein the system further comprises means of controlling the rate of release of the analgesic placed between the deposit of analgesic and the skin, wherein said means of controlling the rate of release are less permeable to the analgesic than the penetration enhancer.

18. The system according to any of the preceding claims, further characterized in that the antagonist reservoir is arranged adjacent the distal surface of the skin of the barrier layer and the analgesic reservoir is disposed adjacent to the proximal surface of the barrier. skin barrier layer.

19. The system according to any of the preceding claims, further characterized in that said antagonist deposit comprises the antagonist dispersed within a polymer.

20. The system according to any of the preceding claims, further characterized in that the system exhibits a standardized Cmax of about 0.01 to about 0.2 ng / ml-cm2.

21. The system according to any of the preceding claims, further characterized in that the system exhibits a normalized Cmax of about 3.3 to about 82.5 ng / ml- (mg / h).

22. The system according to any of the preceding claims, further characterized in that the system exhibits a steady-state analgesic flow in vivo of about 0.1 to about 10 μg / h-cm2.

23. The system according to any of the preceding claims, further characterized in that it is bioequivalent to the transdermal fentanyl system DURAGESIC®.

24. The system according to any of the preceding claims, further characterized in that it is pharmacologically equivalent to the transdermal fentanyl system DURAGESIC®.

25. The system according to any of the preceding claims, further characterized in that the analgesic is an analogue of fentanyl and the analog is selected from the group consisting of alfentanil, lofentanil, remifentanil, sufentanil and trefentanil; and the antagonist is selected from the group consisting of naltrexone, methylnaltrexone, naloxone, nalbuphine, nalorphine, nalorphine dinicotinate, nalmefene, nadide, levalorphan, cyclozocine and pharmaceutically acceptable salts thereof. 26.- The system according to any of claims 1-24, further characterized in that the analgesic is fentanyl and in the ingestion or immersion of the system in a solvent for a period of time, the system substantially provides a release rate ratio of the antagonist to the analgesic from about 0.5: 1 to about 20: 1. 27. The system according to any of claims 1-25, further characterized in that the analgesic is sufentanil and in the ingestion or immersion of the system in a solvent for a period of time, the system substantially provides a rate of release rate from the antagonist to the analgesic of at least about 4: 1. 28. The system according to any of the preceding claims, further characterized in that the antagonist is naltrexone. 29. The system according to any of the preceding claims, further characterized in that the antagonist reservoir comprises a sufficient amount of analgesic to induce and maintain analgesia in a human patient. 30. The system according to any of claims 1-24, 26, and 28-29, further characterized in that the analgesic deposit comprises a single phase polymer composition free of undissolved components containing a polyacrylate adhesive having sufficient solubility for fentanyl to contain fentanyl dissolved in an amount sufficient to induce and maintain analgesia in a human for at least three days. 31. The system according to claim 30, further characterized in that said system also comprises means for controlling the release rate of the antagonist arranged on the distal surface of the skin of the antagonist deposit, wherein the means of control of the rate of release of the antagonist (i) allows the release of the antagonist from the system in normal use but at sufficiently low levels such that the analgesic effect of the analgesic in the presence of the liberated antagonist divided by the effect of the analgesic in the absence of the antagonist released, greater than about 85%, and (ii) provide a ratio of the release rate of the antagonist to the analgesic from about 0.5: 1 to about 20: 1 in the ingestion or immersion of the system in a solvent by a time frame. 32. The system according to any of claims 30 and 31, further characterized in that (a) the analgesic deposit comprises about 0.05 to about 1.75 mg / cm2 of fentanyl base; (b) the antagonist reservoir comprises about 0.2 to about 15 mg / cm 2 of the antagonist dispersed in a polymer or copolymer selected from the group consisting of polyolefin, polyethylene polyoxydene, polyvinyl acetate, polymethyl acrylate, polyethyl acrylate, poliesfireno, polyethyleneoctane copolymers, ethylene-vinyl acetate copolymer (EVA), ethylene-methyl acrylate (EMA) copolymers, ethylene-acrylic acid copolymer, and ethylene-ethylacrylate copolymer; (c) the barrier layer comprises a polyester laminated to a polymer selected from the group consisting of copolymers of polyurethane, polyphenylene and ethylene; and (d) the means of controlling the release rate of the antagonist is a microporous layer selected from the group consisting of microporous ultra high density polyethylene (UHDPE), microporous polypropylene, polyester capillary pore membrane, hydrolyzed polyester, polypropylene and polyethylene. 33. The system according to any of claims 1-25 and 27-29, further characterized in that the analgesic deposit comprises an analgesic deposit comprising a single-phase polymer composition free of undissolved components containing an adhesive of polyacrylate having sufficient solubility for sufentanil to contain sufentanil dissolved in an amount sufficient to induce and maintain analgesia in a human for at least three days. 34. The system according to claim 33, further characterized in that it comprises means for controlling the release rate of the antagonist arranged "on the distal surface of the skin of the antagonist deposit, wherein said means for controlling the speed of antagonist release (i) allow release of the antagonist from the system in normal use but at sufficiently low levels such that the analgesic effect of the analgesic in the presence of the liberated antagonist divided by the effect of the analgesic in the absence of the antagonist released, be greater than about 85%, and (ii) provide a ratio of the release rate of the antagonist to the analgesic of at least about 4: 1 in the ingestion or immersion of the system in a solvent for a period of time. The system according to any of claims 33 and 34, further characterized in that (a) the analgesic deposit comprises about 0.05 at rca of 1.75 mg / cm2 of sufentanil base; (b) the antagonist reservoir comprises about 0.2 to about 15 mg / cm 2 of the antagonist dispersed in a polymer or copolymer selected from the group consisting of polyolefin, polyethylene, polyoxyethane, polyvinyl acetate, polymethyl acrylate, polymethyl acrylate , polyethylene acrylate, polystyrene, polyethylene octane copolymers, ethylene-vinyl acetate copolymer (EVA), ethylene-methyl acrylate (EMA) copolymers, ethylene-acrylic acid copolymer, and ethylene-ethylacrylate copolymer; (c) the barrier layer comprises a polyester laminated to a polymer selected from the group consisting of copolymers of polyurethane, polyethylene and ethylene; and (d) the means of controlling the release rate of the antagonist is a microporous layer selected from the group consisting of microporous ultra high density polyethylene (UHDPE), microporous polypropylene, polyester capillary pore membrane, hydrolyzed polyester, polypropylene and polyethylene. 36. The system according to claim 35, further characterized in that the system exhibits a standardized Cmax of about 0.001 to about 0.05 ng / ml-cm2. 37. The system according to claim 35, further characterized in that the system exhibits a normalized Cmax from about 0.04 to about 10 ng / ml- (mg / h).