MXPA06009535A - Abuse resistant opioid transdermal delivery device containing opioid antagonist microspheres - Google Patents

Abstract

The present invention provides abuse-resistant transdermal delivery devices containing an opioid agonist intended for analgesic purposes in pain patients.

Description

DEVICE OF TRANSDERMAL ADMINISTRATION OF OPIODDE RESISTANT TO ABUSE FIELD OF THE INVENTION The present invention relates to transdermal administration devices useful for the administration of opioid agonists while decreasing the potential for abuse. BACKGROUND OF THE INVENTION Prolonged-release opioid formulations are known in the art and provide a longer period of pharmacological effect that is commonly experienced after the administration of immediate-release opioid preparations. Such longer periods of efficacy achieved with sustained release formulations can provide many therapeutic benefits that are not achieved with the corresponding immediate release preparations. One approach to the prolonged release of the therapeutically active agent is the use of a transdermal delivery device such as the transdermal patch. Certain commercially available transdermal devices such as scopolamine or nitroglycerin, for example, contain a reservoir placed between an impermeable support and a face of the membrane and are generally adhered to the skin by means of a gel adhesive. In recent years, transdermal administration has been widely accepted in the management of chronic pain syndromes, for example, when analgesics are indicated for 24 hours. Transdermal administration devices in which the opioid analgesic is the active ingredient are known. Generally, a transdermal delivery device contains a therapeutically active agent (e.g., an opioid analgesic) in a reservoir or matrix and an adhesive that allows the transdermal device to adhere to the skin, allowing the passage of the active agent from the device through the Patient's skin Once the active agent has penetrated the skin layer, the drug is absorbed into the bloodstream where it can exert a desired pharmacotherapeutic effect such as analgesia. Examples of patents in this area include U.S. Patent No. 4,588,580 to Gale, which discloses transdermal delivery devices for the administration of fentanyl or its analgesically effective derivatives; U.S. Patent No. 5,908,846 to Bundgaard, which discloses a topical preparation of morphine derivatives together with a vehicle in the form of a transdermal patch; U.S. Patent No. 4,806,341 to Chien et al, which describes the transdermal administration of narcotic analgesics or opioid antagonists using a device containing a support layer, an adjoining layer of a solid polymer matrix containing narcotic morphine analgesics or antagonists Y permeability enhancers in the skin and an adhesive polymer; U.S. Patent No. 4,626,539 to Aunst et al., which discloses transdermal patches containing a gel, a lotion or cream composed of an opioid, a penetration enhancer, and a pharmaceutical carrier such as propylene glycol; and U.S. Patent Nos. 5,968,547; 6,231,886; and 6,344,212 to Reder et al., which describe transdermal delivery devices containing buprenorphine to provide prolonged pain management. All references cited herein, including the foregoing, are incorporated herein by reference in their entirety.

A commercially available opioid analgesic transdermal device commercialized in the United States is the Duragesic® patch containing fentanyl as the active agent (commercially available from Janssen Pharmaceutical). The 0 Duragesic® patch is adapted to provide analgesia for up to 48 to 72 hours.

A greater concern associated with the use of opioids is the abuse of said drugs and the diversion of these drugs from a patient in need of such treatment to an individual who is not a patient, for example to an individual who is not a patient for illicit uses. It has been recognized in the art that transdermal opioid formulations can be abused when the delivery device is adulterated (eg by chewing), breaking or extracting the drug) to release the opioid for its illicit use (for example for oral or parenteral use). Additionally, transdermal fentanyl administration devices "used" previously have been reported, which are subsequently used to abuse the surplus. U.S. Patent No. 5,236,714 to Lee et al. and U.S. Patent No. 5,149,538 to Granger et al., describe opioid agonists in transdermal delivery devices that purportedly have a lower abuse potential.

There remains a need for a transdermal opioid delivery device that has a lower potential for opioid abuse than does the device. 0 SUMMARY OF THE INVENTION It is an object of the present invention to provide a transdermal delivery device containing opioid analgesics and having a lower abuse potential.

, A further objective of the present invention is to provide a method of pain treatment with a transdermal administration device containing opioids, this device having a lower abuse potential.

In accordance with the above objectives and others, the present invention is directed in part to a transdermal administration device for the administration of an opioid analgesic comprising an analgesically effective amount of an opioid agonist and an opioid antagonist in substantially non-releasable form when the device of transdermal administration is applied topically and intact.

In certain formulations, the present invention is directed to a transdermal delivery device comprising a drug-containing layer, which contains an effective amount of an opioid agonist and a plurality of dispersed microspheres in the drug-containing layer, the microspheres they contain an opioid antagonist and are visually undetectable in the layer containing the drug.

In certain formulations, the present invention is directed to a transdermal delivery device comprising a support layer; and a layer containing the drug in contact with a surface of the support layer, the layer containing the drug, which contains an effective amount of an opioid agonist and a plurality of dispersed microspheres in the layer containing the drug, the microspheres comprise an opioid antagonist and a polymer selected from the group consisting of polyesters, polyethers, polyorthoesters, polysaccharides, cyclodextrins, chitosans, poly (S-caprolactones), polyanhydrides, albumin, combinations and copolymers thereof, the microspheres have an average size from about 1 to about 500 μm.

In certain formulations, the present invention is further directed to a transdermal delivery device comprising a support layer; and a layer containing the drug in contact with a surface of the support layer, the layer containing the drug comprises an effective amount of an opioid agonist and a plurality of scattered microspheres in the layer containing the drug, the microspheres contain a Opioid antagonist dispersed in a polymeric matrix, the microspheres have an average size from about 1 to about 500 μm. In certain formulations, the present invention is directed to a transdermal delivery device comprising a support layer; and a drug containing a layer connected to a surface of the support layer, the layer containing the drug contains an effective amount of an opioid agonist and a plurality of dispersed microspheres in the layer containing the drug, the microspheres have a size average from about 1 to about 500 μm and contain an opioid antagonist. In such a formulation, the size of the microspheres containing the antagonist will not readily separate from the opioid agonist in the event that an abuser attempts to abuse the opioid agonist that is in the transdermal device.

In certain formulations, the present invention is directed to a transdermal delivery device comprising a support layer; and a layer containing the drug in contact with a surface of the support layer, the layer containing the drug comprises an effective amount of an opioid agonist and a plurality of dispersed microspheres in the layer containing the drug. The microspheres consist essentially of an opioid antagonist and a polymer selected from the group consisting of polyesters, polyethers, polyorthoesters, polysaccharides, cyclodextrins, chitosans, poly (S-caprolactones), polyanhydrides, albumin, combinations and copolymers thereof.

In certain formulations, the present invention is further directed to a transdermal delivery device containing a support layer; and a layer containing the drug in contact with a surface of the support layer, the layer containing the drug comprises an effective amount of an opioid agonist and a plurality of dispersed microspheres in the layer containing the drug. The microspheres consist essentially of an opioid antagonist dispersed in a polymeric matrix.

In certain formulations, the layer containing an opioid agonist is selected from an adhesive layer, a matrix layer, a reservoir or a combination thereof.

In certain formulations, the antagonist is non-releasable or substantially non-releasable from the microspheres (and therefore not releasable or substantially non-releasable from the device) when the transdermal delivery device is applied topically and intact to the skin of the human patient . However, the antagonist is releasable from the microspheres when the transdermal delivery device is adulterated for example when chewing, wetting, piercing, breaking or, on the other hand, when it is subjected to any other treatment that alters the integrity of the microspheres.

In certain preferred formulations, the microspheres of the present invention that are dispersed in the matrix layer containing the opioid agonist, which have a visual appearance similar to the other components of the matrix layer (eg the opioid agonist, the / the polymer (s), etc.) so that the opioid agonist and the opioid antagonist can not be easily identified by visual inspection, thus increasing the difficulty in separating the opioid agonist from the antagonist.

In certain preferred formulations, the composition of the matrix layer inhibits the dissolution of the microspheres and the release of the opioid antagonist with topical application of the device on the intact skin of a human patient. In the present invention, the amount of antagonist released from a transdermal delivery device of the present invention that has been altered (eg, by chewing, wetting, piercing, breaking or being subjected to any other treatment that disrupts the integrity of the microspheres) ). is an amount that at least partially blocks the opioid agonist when administered (eg, orally, intranasally, parenterally or sublingually). Preferably, the euphoric effect of the opioid agonist will be attenuated or blocked, thereby reducing the tendency to misuse or abuse of the dosage form.

The physical / chemical characteristics of the polymers can be used to provide abuse resistance of the present invention. For example, the hydrolysis of poly (orthoester) is catalyzed by acid. Thus, abuse by oral intake of the opioid-containing portion in the transdermal delivery device, which contains microspheres comprising polyorthoester and opioid antagonist would result in degradation of the polymer and release of the opioid antagonist in the stomach acid environment . Additionally, the degradation of microspheres containing polysaccharides and proteins is catalyzed by enzymatic cleavage. Thus, abuse through oral ingestion of a transdermal delivery device of microspheres comprising dextrans would result in degradation of the polymer and release of the opioid antagonist in the gastrointestinal tract. In addition, an abuser could try to extract a transdermal formulation containing microspheres by immersing the complete formulation in diethyl ether. The microspheres would dissolve in the ether, releasing the antagonist, leaving the liquid unsuitable for abuse. In a further formulation, in the intraoral abuse scenario of a transdermal dosage form, the saliva would penetrate the transdermal formulation and dissolve the microspheres, releasing the antagonist and decreasing the value of the transdermal formulation for the abuser. In said formulation, the microspheres could contain a material such as starch which is degraded by salivary amylase.

In certain preferred formulations, a separate adhesive layer may be included in contact with the opposing matrix layer on the side of the matrix layer in contact with the support layer. In other preferred formulations, the matrix layer containing the opioid agonist and antagonist microspheres comprises a pharmaceutically acceptable polymer that also acts as a transdermal adhesive, and an additional adhesive layer is not needed to allow the transdermal device to adhere to the skin. of the patient. In certain preferred formulations, the adhesive layer used to glue the transdermal delivery device to the patient's skin comprises a pressure sensitive adhesive. In certain formulations, the transdermal delivery device further comprises a removable protective layer that is in contact with the adhesive or matrix layer and that is removed prior to application of the transdermal delivery device to the skin.

In preferred formulations, the transdermal delivery device provides effective pain management for a period of 2 to 8 days when used on the intact skin of a human patient.

In certain formulations, the transdermal delivery device is a transdermal patch, a transdermal plaster, a transdermal disk, a transdermal iontophoretic device, or the like.

The term "prolonged release" is defined for purposes of the present invention as the release of an opioid agonist from a transdermal delivery device to a cup in which blood concentrations (levels) (eg plasma) are reached and maintained within the therapeutic range but low toxic levels for at least 1 day and for example, for 2 and 8 days.

For purposes of the present invention, the term "opioid agonist" is interchangeable with the term "opioid" or "opioid analgesic" and includes the base of the opioid and pharmaceutically acceptable salts thereof. The present invention also contemplates the administration of a prodrug thereof (for example ethers or esters) which becomes an active agonist in the patient's device. The opioid agonist can be a complete agonist, a mixed agonist-antagonist or a partial agonist.

For purposes of the present invention, the term "opioid antagonist" includes the base of the antagonist and pharmaceutically acceptable salts thereof. The present invention also contemplates the administration of a prodrug thereof. Examples of opioid antagonists include, for example, nalorphine, nalorphine dinicotinate, naloxone, nalmefene, cyclazocine, levalorfan, naltrexone, nadide, cyclazocine, amifenazole and pharmaceutically acceptable salts thereof and mixtures thereof.

The term "effective analgesia" is defined for purposes of the present invention as a satisfactory reduction in, or elimination of pain as determined by a human patient or through the use of a recognized pain scale. In a preferred formulation, effective analgesia has no side effects, or has a tolerable level of side effects as determined in a human patient.

The term "microsphere" as used herein means solid (or semi-solid) particles that contain an active agent dispersed in a biocompatible polymer (matrix type) or covered by (microcapsules), which serve to render the antagonist non-releasable or substantially non-releasable. The term "substantially non-releasable" means that the antagonist could be released in a small amount, as long as the amount released does not affect or does not significantly affect the analgesic efficacy when the dosage form is administered transdermally, as planned.

The term "flow" refers to the rate of penetration of a chemical entity such as an opioid agonist or an opioid antagonist, through the skin of the individual.

The term "emulsion", for purposes of the present invention, means a stable dispersion of a liquid in a second immiscible liquid. With respect to emulsions, the term "continuous phase" means the external phase compared to the "dispersed phase" which is the internal phase. For example, if an emulsion is a "water in oil" emulsion (w / o), the oil is the continuous phase, while in an "oil in water" emulsion (o / w), water is the continuous phase.

The term "pharmaceutically acceptable salt" means any suitable, non-toxic salt of an antagonist or opioid agonist having therapeutic properties in a mammal, particularly a human. The preparation of such salts is known to those skilled in the pharmaceutical arts. Forms of useful salts of opioid agonists and opioid antagonists may include for example the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, citrate, tartrate, bitartrate, lactate, phosphate, maleate, fumarate, succinate, acetate, palmate, stearate, oleate, palmitate, napsylate, tosylate, methanesulfonate, succinate, laurate and valerate among others.

In certain formulations, the present invention is further directed to a method for preparing a transdermal administration device of an opioid agonist having a lower abuse potential, the method comprising incorporating a plurality of microspheres containing an opioid antagonist, as disclosed in present, within a transdermal opioid device.

In certain formulations, the present invention is further directed to a method of treating pain, which comprises applying a transdermal delivery device, described herein, to a patient in need of such therapy.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows a cross section of a formulation of a transdermal delivery device of the present invention. The device has a waterproof support layer 10, such as metal foil, plastic film, or a laminate of different materials. In contact with and under the support layer 10 is located a matrix layer containing both the opioid agonist and the microspheres 11 containing the polymer and the opioid antagonist. The matrix layer of this formulation acts as a reservoir for the opioid agonist and as an adhesive, allowing this transdermal delivery device to adhere to the skin of a human patient.

Figure 2 shows a cross section of a formulation of a transdermal delivery device of the present invention. The device is similar to the device shown in Figure 1 in that it has an impermeable support layer 13 and a matrix layer 15 in contact with or under the support layer 13. The matrix layer contains both the opioid agonist and microspheres 14 containing the polymer and the opioid agonist. This transdermal delivery device further has a separate adhesive layer 16 in contact with the matrix layer and in contact with certain portions of the support layer, allowing this transdermal delivery device to adhere to the skin of a human patient.

Figure 3 shows a cross section of a formulation of a transdermal delivery device of the present invention. The device has an impermeable support layer 17 and a matrix layer 18 in contact with and below the support layer 17. The matrix layer contains an opioid agonist and microspheres 20 containing the polymer and the opioid agonist. The matrix layer acts as an adhesive, allowing the transdermal delivery device to adhere to the skin of a human patient. The transdermal delivery device further has a removable protective layer 19 in contact with and below the matrix layer that is removed prior to the application of the transdermal delivery device.

Figure 4 shows a cross section of a formulation of a transdermal delivery device of the present invention. The device is similar to the device shown in Figure 3, in that it has an impermeable support layer 21 and a matrix layer 22 in contact with and below the support layer 21. The matrix layer contains an opioid agonist and microspheres. containing the polymer and the opioid antagonist. Additionally, the transdermal delivery device has an adhesive layer 23 in contact with and below the matrix layer 22, allowing the transdermal delivery device to adhere to the skin of the human patient. This transdermal delivery device further has a removable protective layer 24 in contact with and below the adhesive layer that is removed prior to application of the transdermal delivery device.

Figure 5 depicts an in vitro release of naltrexone from the microspheres prepared according to Example 1.

DETAILED DESCRIPTION OF THE INVENTION Certain devices prepared and used according to the present invention contain an opioid antagonist dispersed in microspheres. In certain formulations, the amount of opioid antagonist incorporated within the microspheres ranges from about 1% by weight to about 90% by weight, or from about 5% by weight to about 70% by weight, or from about 10% by weight. 30% up to 50% by weight of the microsphere (including the active).

In the present invention, the opioid antagonist is incorporated within the microspheres for use in the transdermal delivery devices to render the opioid antagonist non-releasable or substantially non-releasable with topical application to the intact skin of a transdermal delivery device that contains antagonist microspheres. Preferably, the microspheres comprise a polymeric substance.

Suitable polymers that can be used to form opioid-containing antagonist microspheres include soluble, insoluble, biodegradable and non-biodegradable polymers. The use of pharmaceutically acceptable non-toxic polymers is preferred.

Physicochemical characteristics of the polymers can be selected to provide greater abuse resistance of the present invention. For example, the hydrolysis of polyorthoester is catalyzed by acid. Thus, abuse via oral intake of the opioid-containing portion of the transdermal delivery device, which contains polyorthoester microspheres comprising an opioid antagonist would result in degradation of the polymer and release of the opioid antagonist in the acidic environment of the stomach. The degradation of microspheres comprising polysaccharides and proteins is catalyzed by enzymatic cleavage. Thus, for example, abuse via oral intake of the opioid-containing portion of the transdermal delivery device, which contains dextran microspheres would result in degradation of the polymer and release of the opioid antagonist in the gastrointestinal tract.

The polymers that can be used for the microspheres containing the opioid antagonist of the present invention can generally be classified into three types, for example, natural, semi-synthetic and synthetic, based on their origins. Natural biodegradable polymers can also be classified into proteins and polysaccharides.

Representative polymers derived from natural sources include proteins such as zaina, modified zaina, casein, gelatin, gluten, albumin, fetuin, orosomucoid, glycoproteins, collagen, synthetic polypeptides and elastin. Synthetic biodegradable polypeptides include, for example, poly- (N-hydroxyalkyl) -L-asparagine, poly- (N-hydroxyalkyl) -L-glutamine, and copolymers of N-hydroxyalkyl-L-asparagine and N-hydroxyalkyl-L-glutamine with other amino acids, for example, L-alanine, L-lysine, L-phenylalanine, L-valine, L-tyrosine and the like.

Polysaccharides (eg, cellulose, dextrans, polyhyaluronic acid, lipopolysaccharides), acrylic polymers and metracrylic esters and alginic acid can also be used. Natural, synthetically modified (ie semi-synthetic) polymers include alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters and nitrocelluloses among others.

Semi-synthetic biodegradable polymers are produced by modifying natural polymers to produce polymers that have altered physical and chemical properties such as thermogelling properties, mechanical strength and degradation rates. Examples of biodegradable, semi-synthetic polymers suitable for use in the present invention include modified chitosan complexes, Chitosan sulfate chondroitin / A complexes. and soluble water, phosphorylated chitosan (P-chitosan) and combinations thereof such as, for example, alginate-chitosan.

The lack of immunogenicity and more reproducible and predictable physical-chemical properties make synthetic biodegradable polymers preferable to natural polymers for drug administration uses. These polymers can be non-toxic and biodegradable and the delivery devices have been prepared from these polymers. Therefore, synthetic biodegradable polymers may be particularly suitable for the microspheres of the present invention.

Non-limiting examples of synthetic biodegradable polymers include: polyesters, polyethers, polyorthoesters, polyvinyl alcohols, polyamides, polycarbonates, polyacrylamides, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinyl pyrrolidone, polyglycolides, polysiloxanes , polylactides, polyurethanes and copolymers thereof. Non-limiting examples of polyesters include polylactic acid, polyglycolic acid, polylactide-co-glycolide, poly (e-caprolactone), polydioxanone, poly (ethylene terephthalate), poly (malic acid), poly (tartronic acid), polyphosphazenes, polyorthoester, poly (valeric acid), poly (butyric acid), polyhydroxybutyrate, polyhydroxyvalerate, polyanhydride and copolymers of monomers used to synthesize any of the polymers mentioned above, for example polylactic-co-glycolic acid or the polyhydroxybutyrate copolymer with hydroxyvaleric acid (Biopol ® by Zeneca). Copolymers of lactic and glycolic acids, for example, polylactic-co-glycolic acid (PLGA), have been widely studied for their use in drug delivery devices such as microspheres.

In certain formulations, the polymer (e.g., PLGA) can have a molecular weight of from about 1 KD to about 100 KD or greater, from about 5 KD to about 60 KD or from about 10 KD to about 40 KD. KD In certain formulations, a portion of PLGA (eg, from 10% to up to 90%) may have a molecular weight of less than 20 KD or less than 15 KD and the corresponding remaining portion (eg, from 90% to 10% ) may have a weight greater than 25 KD or greater than 35 KD.

The poly (e-caprolactone) can be used in preparing microspheres for use in the present invention. The degradation rate of poly (e-caprolactone) is much slower than that of polyglycolic acid or polylactic-co-glycolic acid. Poly (e-caprolactone) has an exceptional ability to form mixtures with many other polymers. Poly (e-caprolactone) copolymers can be used to control the permeability and mechanical properties of drug delivery devices.

The polyethers and polyorthoesters can be further used in preparing microspheres for use in the present invention. These polymers have been incorporated in multiblock for block polymers that have different rates of degradation, mechanical strength, porosity, diffusivity and inherent viscosity. Examples of polyethers include polyethylene glycol and polypropylene glycol. An example of a multiblock copolymer is poly (ether ester amide). Additionally, triblock copolymers of polyorthoesters with various polyethylene glycol contents are useful for their stability in water / oil emulsions (w / o) and have greater efficacy than the polyorthoester when used in preparing microspheres. Other useful block copolymers include diblock copolymers of polylactic acid-glycolic acid) and polyethylene glycol (PEG), triblock copolymers of PEG-PLGA-PEG, copolymers of PLGA and polylysine, and polyestereter block copolymers.

In certain formulations, the microspheres useful for practicing the present invention are spherically formed and from about up to about 500 microns, from about 1 to about 300 microns, from about 1 micron to about 10 microns. 200 microns, from around 1 to around 100 microns, from around 300 up to 500 microns, from 200 to 500 microns, from 100 to 500 microns, from 125 to 200 microns or from 50 to 100 microns in diameter. The size of the microsphere may depend on the type of polymer used. In certain formulations, rather than spherical, the microspheres may be formed irregularly, where the diameter is considered to be the largest cross-section of the microsphere.

In certain formulations, the microspheres used in the present invention comprise an opioid antagonist in an amount of from about 5% to up to 70% by weight of the microsphere (including the active).

In certain formulations, the opioid antagonist can be loaded into the microspheres via microencapsulation. The microencapsulation techniques to be used in accordance with the present invention are described in U.S. Patent Nos. 3,161,602; 3,396,117; 3,270,100; 3,405,070; 3,341,466; 3,567,650; 3,875,074; 4,652,441; 5,100,669; 4,438,253; 4,391,909; 4,145,184; 4,277,364; 5,288,502 and 5,665,428. In addition, the microspheres can be prepared by evaporation of the solvent as described for example in, E. Mathiowitz, et al., J. Scanning Microscopy, 4, 329 (1990); L.R. Beck, et al., Fertile. Steril., 31, 545 (1979); and S. Benita, et al, J. Pharm. Sci. 73, 1721 (1984); or by hot melt microencapsulation, as described for example in E. Mathowitz, et al., Reactive Polymers 6, 275 (1987); or by spray drying. The microspheres can be prepared by any method known in the art including but not limited to coacervation, phase separation, solvent evaporation, spray drying, spray solidification, pan coating, fluidized bed coating and the like.

For purposes of the present invention, a microcapsule can be functionally described as a small container enclosing the contents with a film. The film can be a synthetic, semi-synthetic or natural polymer, as described above, and can control the release (or provide non-release) of the contents. The rate of release of the contents from a microcapsule is determined primarily by the chemical structure and the thickness of the film of the capsule and the size of the microcapsule. In microcapsule formulations, small solid particles of opioid antagonist can be coated with a coating consisting of an organic polymer, hydrocolloid, sugar, wax, fat, metal or inorganic oxide.

In certain formulations, the opioid antagonist is incorporated into the microspheres using an oil / water emulsion (o / w), a water / oil emulsion (w / o), an oil / oil emulsion (o / o), an oil emulsion / water / oil (o / w / o), an oil / water / water emulsion (o / w / w), a water / oil / water emulsion (w / o / w) or a water / oil / oil emulsion (w / o / w) / o / o) or similar.

In certain formulations, the opioid antagonist is incorporated into the microspheres by microemulsification of a fixed oil and an aqueous solution of the water-soluble opioid antagonist. This emulsion is of the "water in oil" type. When the emulsion is of the "water in oil" type, the oil is the continuous phase or the external phase and the water is the internal phase or "dispersed" in the opposite way to the "oil in water" device, where the water is the phase keep going.

In certain preferred formulations, the opioid antagonist can be incorporated into the microspheres via a multi-phase emulsification device such as w / o / w. The opioid antagonist can be incorporated into the multi-phase microspheres prepared by the solvent evaporation technique from multiple emulsion. In this technique, the opioid antagonist is incorporated into the biodegradable polymer microspheres by an emulsification process. The device is suitable for water insoluble and soluble opioid antagonists. The microspheres of the present invention can be multiphasic polymeric microspheres in which the opioid antagonist is dispersed in oily droplets in a polymeric matrix. The microspheres can be prepared by a solvent evaporation technique from a multiple emulsion described in U.S. Patent No. 5,288,501, this patent describes a solvent evaporation technique from a multiple emulsion where the drug is protected within an oily droplet and contact with the polymer, organic solvent and other potentially denaturing agents is avoided.

Multiple emulsions are devices in which the droplets of the dispersed phase in oil contain in turn dispersed aqueous droplets consisting of a liquid identical to that of the continuous aqueous phase. These are emulsions of emulsions with a high capacity to trap the drug, protection of the trapped drug, ability to introduce incompatible substances within the same device and prolongation of the release.

Anyone within a variety of fixed oils can be used to prepare the microspheres, including safflower, soybean, peanut, cottonseed, sesame, cod liver oil, among others. In certain preferred formulations, soy, sesame and safflower oil are used. The oil phase may consist of isohexadecane or liquid paraffin. The concentration of oil influences the stability of the emulsion. Preferably, the stability is optimal with a percentage of oil in a range of 20-30% w / w of the total emulsion.

In the multiple emulsion process, the organic phase can be prepared by preparing an emulsion containing the opioid antagonist and a polymeric material. Preferably, the opioid antagonist is dispersed in an organic polymer solution in methylene chloride or ethyl acetate. The resulting primary w / o emulsion is then dispersed in an external aqueous phase to form a second emulsion comprising microspheres containing the opioid antagonist in the polymeric matrix material (i.e., emulsification in the external phase). The subsequent steps of the process are similar to the o / w method. The step of dissolving the drug in the internal aqueous phase is eliminated. In addition, a higher theoretical drug load is achieved because the internal drug phase consists only of solid particles and not a drug solution.

In yet another formulation, an o / w emulsion process can be used to incorporate the opioid antagonist into the microspheres. For the o / w dispersion method, the opioid antagonist is dispersed in the polymer phase followed by emulsification in the external aqueous phase. Then, the microspheres are separated from the external aqueous phase by wet screening followed by washing and drying by desiccator.

In certain formulations, the present invention utilizes encapsulation techniques that allow solid or liquid substances to be encapsulated by polymers. In certain preferred formulations, the opioid antagonist has a crystalline form. The crystalline opioid antagonist particles can be formed by solid state crystallization by exposure to solvent vapors. The crystalline form can decrease the water content of the preparation, thus preserving the stability of the opioid antagonist. The crystal can be encapsulated in a fixed oil, and mixed with a solution of polymer and solvent in dispersion oil. U.S. Patent No. 6,287,693 to Savoir discloses stable particles of crystalline organic compounds that are formed into microspheres to achieve storage stability. Alternatively, any suitable method can be used to produce crystalline particles of organic compounds.

The stability and release characteristics of the emulsion devices are influenced by a number of factors such as the composition of the emulsion, the size of the droplet, viscosity, phase volumes and pH. The effectiveness of the opioid antagonist encapsulation can be optimized by minimizing the migration of the drug from the polymer by altering the volume, temperature and chemical composition of the extraction medium (chilling solution) during the encapsulation process. The purpose of the chiller solution is to remove most of the organic solvent from the microspheres during the process.

The cooling liquid can be pure water, an aqueous solution or any other suitable liquid, the volume, quantity and type thereof depends on the solvents in the emulsion phase. The volume of the coolant is in the order of 10 times the saturated volume (ie 10 times the volume of cooler needed to fully absorb the volume of the solvent in the emulsion). The volume of the cooler can vary from about 2 to about 20 times the saturated volume.

After cooling, the microspheres are separated from the aqueous chilling solution by, for example, decanting or filtration with a sieving column. Various other separation techniques can be used.

The residual solvent in the microspheres accelerates the degradation process, thus reducing its conservation time. Therefore, the microspheres are preferably washed with water or a solvent miscible therewith to further remove the residual solvent, preferably at a level of from 0.2 to less than 2.0% or less. Aliphatic alcohols such as methanol, ethanol, propanol, butanol, and isomers of the foregoing are preferred for use in washing solutions. Ethanol is the most preferred.

Alternatively, the removal of the solvent can be achieved by evaporation. In formulations where the solvent evaporation method is used, the polymer can be dissolved in a volatile organic solvent. The opioid antagoma is dispersed or dissolved in a solution of the selected polymer and a volatile organic solvent such as methylene chloride, the resulting solution or dispersion is suspended in an aqueous solution containing a surface active agent such as polyvinyl alcohol, and is used a temperature gradient to remove the solvent.

The solvent evaporation method may involve dissolving the opioid antagonist and the polymer in a co-solvent device. However, alternative methods that omit the incorporation of unacceptable organic solvents can be used. The resulting emulsion is stirred until most of the organic solvent evaporates, leaving solid microspheres. The solution can be loaded with the opioid antagonist and suspended in 200 ml of vigorously stirred distilled water containing 1% (w / v) polyvinyl alcohol. After 4 hours of stirring, the organic solvent is evaporated from the polymer and the resulting microspheres can be washed with water and dried overnight in a lyophilizer.

In formulations where the spray drying method is used, the polymer can be dissolved in methylene chloride. Suspend a known amount of drug (where the opioid antagonist is insoluble) or co-dissolve (where the opioid antagonist is soluble) in the polymer solution. Then, the solution of the dispersion is spray dried. This method is used for small microspheres between 1-10 microns.

In certain formulations, a hot melt encapsulation method is used. By using this method, the polymer can be melted first and then mixed with solid drug particles that have been sieved to less than 50 microns. The mixture is suspended in a non-miscible solvent and with constant stirring, is heated to 5 ° C above the melting point of the polymer. Once the emulsion is stabilized, it cools until the polymer particles solidify. The resulting microspheres are washed by decanting with petroleum ether to provide a free-flowing powder. This technique is used for polyesters, polyanhydrides and polymers with high melting points and different molecular weights. The typical performance of the microspheres in this process is about 80-90%. The resulting microspheres have an encapsulated structure.

To create microspheres containing an opioid antagonist, an organic or oil phase (discontinuous) and an aqueous phase can be combined. The organic and aqueous phases are largely or substantially immiscible, with the aqueous phase constituting the continuous phase of the emulsion. The organic phase includes the active agent and the wall-forming polymer, i.e., the polymer matrix material. The organic phase is prepared by dispersing the active opioid antagonist in the organic solvent (s). Preferably, the organic and aqueous phases are combined under the influence of a mixing means, preferably a static mixer.

Opioid antagonists useful in the present invention include, but are not limited to, nalorphine, nalorphine dinicotinate, naloxone, nalmefene, cyclazocine, levalorfan, naltrexone, nadide, cyclazocine, amifenazole and pharmaceutically acceptable salts thereof and mixtures thereof. Preferably, the opioid antagonist is an orally bioavailable antagonist, for example, naltrexone or a pharmaceutically acceptable salt thereof. By using a bioavailable antagonist, the transdermal device will prevent both oral and parenteral abuse.

After the formation of the microspheres containing the opioid antagonist, the microspheres are incorporated into a transdermal delivery device containing an opioid agonist. Preferably, the microspheres are included in a transdermal delivery device so that they are substantially indistinguishable from the preparation volume containing the opioid agonist (e.g., the microspheres can be embedded in the matrix of the matrix delivery device). In certain formulations, the opioid agonist has a form that can be absorbed through the human skin, i.e., the opioid agonist can be administered effectively through the transdermal route. In some formulations, it may be necessary to further provide an absorption enhancer to facilitate transdermal absorption.

In the transdermal delivery devices of the present invention, the opioid agonist is available for absorption, passing through pores in the intact surface of the skin, typically at less than 50 nm to provide prolonged therapeutic levels over a longer period of time . Transdermal delivery devices that are prepared in accordance with the present invention can release the opioid agonist according to the first-order pharmacokinetics (eg, where the plasma concentrations of the opioid agonist increase over a specific period of time) or according to with zero order pharmacokinetics (for example, when plasma concentrations are maintained at relatively constant levels in a specific period of time) or with zero order and first order pharmacokinetics. Opioid agonists that can be selected for use in transdermal delivery devices of the present invention include any opioid agonist, mixed opioid agonist-antagonist, or partial agonist, including, but not limited to: alfentanil, allylprodin, alphaprodin, anileridin, benzinophil, bezitramide , buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocin, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimetheptanol, dimethylthiambutene, dioxafethylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypetidine, isomethadone, ketobemidone, levorphanol, levofenacilmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopona, morphine, mirofin, narcein, nicomorphine, norlevorphanol, normetadoma, nalorphine, nalbufen, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pent azocine, fenadoxone, fenomorphane, phenazocine, phenoperidine, piminodine, piritramide, profeptazine, promedol, properidin, propoxyphene, remifentanil, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, mixtures thereof and the like. In preferred formulations, the opioid agonist is selected from the group consisting of transdermally administrable forms of fentanyl, buprenorphine, sufentanil, hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, dihydrocodeine, tramadol, pharmaceutically acceptable salts of the same and mixtures thereof. Any type of transdermal delivery device can be used in accordance with the methods of the present invention, provided that the (a) pharmacokinetic and pharmacodynamic response (s) are obtained for at least a period of one day, such as, for example, from 2 to 8 days. Preferably, transdermal delivery devices include, for example, transdermal patches, transdermal plasters, transdermal disks, and the like. In a preferred formulation, the transdermal drug delivery device of the present invention is a patch, usually in the range from about 1 to 30 square centimeters, preferably 2 to 10 square centimeters. The term "patch", as used herein, includes any product having a support membrane and a surface with a pressure-sensitive adhesive face that allows adhesion to the patient's skin. Said products can be provided in various sizes and configurations such as tapes, bandages, sheets and the like. In the transdermal delivery device of the present invention, the opioid agonist is preferably dispersed along a matrix (such as, for example, a polymer matrix). In such a matrix device, the release of the opioid agonist can be controlled predominantly by diffusion of the opioid agonist out of the polymer or by erosion of the polymer to release the opioid agonist, or by the combination of these two mechanisms. When the diffusion of the opioid agonist is faster than the erosion of the polymer, the release of the drug is controlled by diffusion.

When the erosion of the polymer is faster than the diffusion of the opioid agonist, the release of the drug is controlled by the erosion of the polymer. If the delivery device is prepared with a polymer that undergoes supercifial erosion, the release of the drug can be controlled by varying the amount of drug loaded in the device and / or by varying the geometric dimension of the delivery device. Generally, the polymers used in the polymer matrix of the transdermal delivery device are those capable of forming thin walls or coatings, through which the opioid agonist can pass at a controlled rate. Examples of such polymers for use in the preparation of polymeric matrices include: polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethylacrylate copolymers, ethylene vinyl acetate copolymers, silicones, rubber, homopolymers, copolymers or synthetic block polymers similar to rubber, polyacrylic esters and copolymers thereof, polyurethanes, polyisobutylene, chlorinated polyethylene, polyvinylchloride, vinyl chloride-vinyl acetate copolymer, polymethacrylate (hydrogel) polymer, polyvinylidene chloride, poly (ethylene terephthalate), ethylene copolymer vinyl alcohol, ethylene-vinyl oxyethanol copolymer, silicones, including silicone copolymers, such as polysiloxane-polymethacrylate copolymers, cellulose polymers (for example, ethyl cellulose and cellulose esters), polycarbonates, polytetrafluoroethylene and mixtures thereof.

Preferred materials for use in the preparation of the polymer matrix are silicone elastomers of the general polydimethylsiloxane structures (eg, silicone polymers). Preferred silicone polymers are those which crosslink and which are pharmaceutically acceptable. For example, preferred materials for use in the preparation of the polymer matrix layer include silicone polymers that are crosslinkable copolymers, having dimethyl and / or dimethylvinyl siloxane units that can be crosslinked using an appropriate peroxide catalyst. Likewise, the preferred polymers are those consisting of block copolymers based on styrene and 1,3-dienes (particularly linear styrene-isoprene block copolymers of styrene-butadiene block copolymers), polyisobutylenes, acrylate-based polymers and / or methacrylate. In certain formulations, the polymer matrix includes a pharmaceutically acceptable crosslinking agent. Suitable crosslinking agents include, for example, tetrapropoxysilane, among others. Certain formulations of the present invention include a polymer matrix layer having an opioid agonist with interspersed microspheres of opioid antagonists. Preferably, for the opioid antagonist to become bioavailable, the integrity of the microspheres must be altered. The combination of microsphere with polymeric matrix prevents the release of the opioid antagonist from the microspheres embedded in the matrix in an intact device. The release of opioid antagonist from the microspheres can also be prevented by means of polymer coatings on the microspheres.

Preferably, the transdermal delivery device of the present invention comprises a support layer made of a pharmaceutically acceptable material that is impermeable to the opioid agonist. The support layer preferably serves as a protective coating for the opioid agonist and may also provide a support function. Examples of suitable materials for making the support layer are: polyethylene films, polypropylene, polyvinylchloride, polyurethane, high and low density polyesters such as polyethylene phthalate, metal foils, sheet metal laminates of said appropriate polymer films and fabrics. textiles .. Preferably, the materials used for the backing layer are laminates of said polymer films with a metal foil such as aluminum foil. The support layer may have any suitable thickness that provides the desired protection and support functions. A suitable thickness will be, for example, from 10 to 200 microns. In certain alternative formulations, the transdermal delivery device of the present invention may have microspheres contained in a reservoir. In said reservoir device, the opioid agonist and the microspheres of the opioid antagonist are dispersed in a reservoir (eg, a reservoir of liquid or gel), and the rate limiting the biodegradable membrane is located in the flow path of the reservoirs. drugs, thereby limiting the flow of the opioid agonist into the skin. Said device can provide a constant release rate of the opioid agonist, but serves to prevent the release of the opioid antagonist. A transdermal delivery device using a reservoir device may also have a support layer and, optionally, a removable protective layer, as described above with the array device.

Preferred transdermal devices used in accordance with the methods of the present invention, include, more preferably, an adhesive layer for adhering the delivery device to the skin of the patient for a desired period of administration, such as, for example, from 2 to 8. days. If the adhesive layer of the delivery device fails to provide adequate adhesion for the desired period, contact between the delivery device and the skin can be maintained by, for example, attaching the delivery device to the patient's skin with an adhesive tape. , as for example, a surgical tape. It is not relevant for the purposes of the present invention if the adhesion of the delivery device to the skin of the patient is achieved only by means of the adhesive layer of the delivery device or by the use of an external source of adhesion, such as surgical tape. , as long as the administration device adheres to the patient's skin for the required period. However, in all cases, the adhesive must allow the patch to firmly adhere to the patient's skin in need of treatment, but it ld not adhere as strongly to the patient when the patch is removed. The adhesive layer can be selected from any adhesive known in the art that is pharmaceutically compatible with the delivery device. The adhesive is preferably hypoallergenic. Examples of adhesives include: an adhesive polyacrylic polymer, an acrylate copolymer (eg, polyacrylate) or an adhesive polyisobutylene polymer. Other useful adhesives include silicones, polyisoalkylenes, rubbers, vinyl acetates, polybutadiene, styrene-butadiene (or isoprene) -styrene block copolymer rubber, acrylic rubber, and natural rubber; high molecular weight vinyl-based materials, such as polyvinyl alkyl ether; polyvinyl acetate, cellulose derivatives such as methylcellulose, carboxymethyl cellulose and hydroxypropyl cellulose; polysaccharides such as pullullan, dextrin and agar; and polyurethane elastomers and polyester elastomers. While many of these adhesives are virtually interchangeable, some combinations of a specific opioid analgesic and a specific adhesive may provide slightly better properties. In some formulations, the adhesive is a pressure sensitive contact adhesive, which is preferably hypoallergenic. In certain formulations, the transdermal drug delivery material provides the adhesive and matrix functions that the drug contains. In certain formulations with a separate adhesive layer, the drug will be distributed throughout the layers (with the exception of the support layer), according to its relative affinity with the different environments offered by the different layers. The matrix "layer" may consist of more than one simple sub-layer, with opioid loading in the different layers adjusted to optimize their administration characteristics and microspheres containing the opioid antagonist dispersed throughout them. In such formulations, the matrix containing the drug has direct contact with the skin and the transdermal delivery device is adhered to the skin by a peripheral adhesive or by the matrix itself. In certain formulations, the transdermal delivery device of the present invention optionally includes an agent that serves to enhance impregnation. Agents that serve to enhance impregnation are compounds that promote the penetration and / or absorption of the opioid agonist through the skin into the bloodstream of the patient. Due to these agents that serve to increase impregnation, almost any drug, to a certain extent, can be administered transdermally. The agents that serve to increase the impregnation, are generally characterized to be of the group of monovalent aromatic, aliphatic or linear cycloaliphatic or branched alcohols of 4-12 carbon atoms; aromatic or cycloaliphatic aldehydes or ketones of 4-10 carbon atoms; carbon cycloalkanoyl amides Cto-20; aliphatic, cycloaliphatic and aromatic esters; N, N-di-low alkyl sulfides; unsaturated oils, terpenes and glycol silicates. A non-limiting list of agents that serve to increase impregnation includes polyethylene glycols, surfactants and the like. The impregnation of the opioid agonist can also be increased by occlusion of the delivery device after application at the desired site in the patient with, for example, an occlusive bandage. The impregnation can also be increased by the removal of the beauty from the application site, such as cutting, shaving or by the use of a depilatory agent. Another way to increase impregnation is by applying heat to the adhesion site of the patch, such as with an infrared lamp. Other ways to increase the impregnation of the opioid agonist include the use of iontophoretic means. In certain formulations, the transdermal delivery device includes a softening agent to modify the skin at the time of adhesion, so as to promote absorption of the drug. Suitable softening agents include: higher alcohols such as dodecanol, undecanol, octanol, ethers of carboxylic acids, where the alcohol component can also be a polyethoxylated alcohol, diesters of dicarboxylic acids, such as di-n-butyladapate and triglycerides, particularly medium chain triglycerides of caprylic / capric acids or coconut oil. Other examples of softening agents are multivalent alcohols, such as, for example, levulinic acid, caprylic acids, glycerol and 1,2-propanediol, which can also be etherified by polyethylene glycols.

In certain formulations, a solvent for the opioid agonist is included in the transdermal delivery device of the present invention. Preferably, the solvent dissolves the opioid agonist to a sufficient degree, thus preventing complete salt formation. A non-limiting list of suitable solvents includes those with at least one acidic group. Monoesters of dicarboxylic acids such as monomethylglutarate and monomethyladipate are particularly suitable. Other pharmaceutically acceptable compounds that can be included in the transdermal delivery device of the present invention include agents that serve to increase viscosity, such as cellulose derivatives, natural or synthetic gums, such as guar gum and the like. In certain formulations of the present invention, the transdermal delivery device further includes a removable protective layer. The removable protective layer is removed prior to application, and may consist of materials used for the production of the support layer described above, as long as they are removable, such as, for example, by a silicone treatment. Other examples of removable protective layers are paper treated with polytetra-fluoroethylene, allophane, polyvinyl chloride and the like. Generally, the removable protective layer is in contact with the adhesive layer, and provides a convenient means to maintain the integrity of the adhesive layer until the desired period of application. In the art of transdermal delivery devices it is understood that, in order to maintain a desired flow rate for a desired dosage period, it is necessary to include a "surplus" of active agent in the transdermal delivery device in an amount that is substantially greater than the amount to be administered to the patient during the desired period. For example, to maintain the desired flow rate for a period of three days, it is considered necessary to include in the transdermal delivery device much more than would otherwise be 100% of a three-day dose of the active agent. The remainder of the active agent remains in the transdermal delivery device. Only that portion of the active agent leaving the transdermal delivery device becomes available for skin absorption. The term "surplus" means, for the purposes of the present invention, the amount of opioid analgesic in the transdermal delivery device that is not administered to the patient. The surplus is necessary to create a sufficient concentration gradient, whereby the active agent will migrate from the transdermal delivery device through the skin of the patient to produce a sufficient therapeutic effect. Preferably, the transdermal delivery device of the present invention is used to prolong the dosage, releasing the opioid agonist constantly or intermittently to the patient, while the opioid antagonist within the microspheres remains non-releasable or substantially non-releasable. Non-opioid analgesics that can be included in combination with the opioid agonist are, for example, acetaminophen, phenacetin and nonsteroidal anti-inflammatory agents. Suitable non-steroidal anti-inflammatory agents include; aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprocine, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucilloxic acid, indomethacin, sulindac, tolmetin, zomepirac, thiopinaco, zidometacin, acemetacin, fentiazaco, clidanaco, oxpinaco, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, pharmaceutically acceptable salts thereof and mixtures thereof . Other non-steroidal anti-inflammatory agents include: cox-2 inhibitors such as celecoxib, DUP-697, flosulide, meloxicam, 6-MNA, L-745337, rofecoxib, nabumetone, nimesulide, NS-398, SC-5766, T-614, L-768277, GR-253035, JTE-522, RS-57067 -000, SC-58125, SC-078, PD-138387, NS-398, flosulide, D-1367, SC-5766, PD-164387, etoricoxib, valdecoxib, parecoxib, pharmaceutically acceptable salts thereof and mixtures thereof . Other active agents that can be combined with the opioid agonist can be, for example, antiemetic / antiviral agents such as chlorpromazine, perphenazine, triflupromazine, prochlorperazine, triethylperazine, metoclopropramide, cyclizine, meclizine, scopolamine, diphenhydramine, buclizine, dimenhydrate and trimethobenzamide.; 5-HT3 receptor agonists such as ondasetron, granisetron and dolasetron; antianxiety agents such as meprobamate, benzodiazepines, buspirone, hydroxyzine, doxepin and the like. It is contemplated that previously known transdermal delivery devices can be modified, including in the matrix, reservoir and / or adhesive layers, microspheres containing opioid antagonists as described above, so as to diminish the abuse potential of said devices. For example, transdermal delivery devices for use in accordance with the present invention may use certain aspects described in U.S. Patent No. 5,240,711 to Hille, et. to the.; U.S. Patent No. 5,225,199 to Hidaka et. to the.; U.S. Patent No. 4,588,580 to Gale et. al, U.S. Patent No. 5,069,909 to Sharma et. to the.; U.S. Patent No. 4,806,341 to Chien et. to the.; U.S. Patent No. 5,026,556 to Drust et. to the.; and McQuinn, R. L. et. al, "Sustained Oral Mucosal Delivery in Human Volunteers "J. Controlled Reléase; (34) 1995 (243-250) The present invention also relates to transdermal dosage forms described herein, using different active agent / antagonist (ie, non-opioid) combinations, for prevent abuse of the active agent For example, when a benzodiazepine is used as an active agent in the transdermal dosage form of the present invention, a non-releasable benzodiazepine antagonist can be formulated in the transdermal dosage form. an active agent in the transdermal dosage form of the present invention, a non-releasable barbiturate antagonist can be formulated in the transdermal dosage form When an amphetamine is used as an active agent in the transdermal dosage form of the present invention, a Non-releasable amphetamine antagonist can be formulated in the transdermal dosage form. benzodiazepines "refers to benzodiazepines and drugs that are derived from benzodiazepine capable of depressing the central nervous system. Benzodiazepines include, but are not limited to: alprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, methylphenidate and mixtures thereof. Benzodiazepine antagonists that can be used in the present invention include, but are not limited to, flumazenil. Barbiturates refer to sedative-hypnotic drugs derived from barbituric acid (2,4,6, -trioxohexahydropyrimidine). Barbiturates include, but are not limited to: amobarbital, aprobotal, butabarbital, butalbital, methohexital, mephobarbital, metarbital, pentobarbital, phenobarbital, secobarbital and mixtures thereof.

Barbiturate antagonists that can be used in the present invention include, but are not limited to amphetamines, as described herein. Stimulants refer to drugs that stimulate the central nervous system. Stimulants include, but are not limited to amphetamines, such as amphetamine, dextroamphetamine, dextroamphetamine-resin complex, dextroamphetamine, methamphetamine, methylphenidate, and mixtures thereof. Stimulating antagonists that can be used in the present invention include, but are not limited to, benzodiazepines, as described herein. The present invention also relates to transdermal dosage forms described herein, which utilize adverse agents other than antagonists, to prevent abuse of the active agent. The term "adverse agent" refers to any agent that can create an unpleasant effect with administration in a releasable form. Examples of adverse agents other than antagonists include emetics, irritants and those that produce bitterness. Emetics include, but are not limited to ipecac and apomorphine. Irritants include, but are not limited to: capsaicin, capsaicin analogues and mixtures thereof. Capsaicin analogues include: resiniferatoxin, denatonium benzoate; tiniatoxin, heptanoylisobutylamide, heptanoyl guaiacilamide, other isobutylamides or guaiacylamides, dihydrocapsaicin, homovainillyloctylester, nonanoyl vanillylamide and mixtures thereof.

Agents that produce bitterness include, but are not limited to, essential oils; aromatic flavorings; oleoresins; extracts derived from plants, leaves, flowers; fruit flavors; sucrose derivatives; chlorosucrose derivatives; quinine sulfate; denatonium benzoate; and combinations thereof.

The following examples are not intended to limit the invention in any way.

EXAMPLE 1 Using the procedure described in this example, multiple batches of microspheres loaded with naltrexone were prepared using polymers Lactide / Glycolide (65:35) of different molecular weights (40 KD), 40 KD with 0.01% calcium chloride, 50:50 mixture of 40 KD and low molecular weight (around 10 KD) and 11 KD). The microspheres loaded with naltrexone were made using a solvent extraction from double emulsion of water-in-oil-in water (w / o / w) / evaporation technique. In this process, naltrexone was dissolved in phosphate buffered saline (PBS) (pH 7.4) containing 0.05% polyvinyl alcohol (PVA) (w / v) as an emulsifier, and mixed with ethyl acetate which Contains polylactic acid-co-glycolide (PLGA). The emulsification was carried out by sonication for 15 seconds. The resulting emulsion was then injected in PBS (pH 7.4) containing 0.05% (w / v) PVA as an emulsifier, to produce a double w / o / w emulsion. The dispersion was then stirred at a constant temperature for 30 minutes. In order to extract the ethyl acetate from the first emulsion within the external phase, a second buffer solution (pH 7.4) containing 0.05% (w / v) PVA at a rate of 3 ml was continuously added. /minute. The temperature of the second emulsion throughout the solvent extraction / evaporation phase was kept constant, using a low temperature chiller. The resulting naltrexone loaded microspheres were collected by vacuum filtration and washed three times with PBS. The microspheres were then dried under vacuum overnight and stored at 4C.

The load of naltrexone for the microspheres is set forth below in Table 1.

TABLE 1 Polymer Naltrexone charge the complete microsphere 40KD 42.2% 40KD and 0.01% Calcium chloride 42.3% Mix 50:50 of 40KD and low molecular weight 39.3% (to the O KD) 11 KD 28, 8% EXAMPLE 2 The microsphere prepared in Example 1 was exposed to simulated extraction conditions to determine the degree of in vitro release of naltrexone from the microspheres. The extractions were performed using 0.5N NaCl, phosphate buffer pH 6.5. The sample size was 100 mg microspheres and the release of naltrexone was measured at 0.5, 1 and 4 hours. The results are set forth in Table 2 and Figure 5. TABLE 2 H KD 42.3 mg as 2.4% 3.5% 5.9% Base Based on the amount of antagonist released from any given microsphere formulation, the antagonist amount loaded into the microspheres can be adjusted to obtain the release of the desired amount with the adulteration.

EXAMPLE 3 (Prophetic) The microspheres are prepared as described below: Naltrexone is mixed with required amounts of gelatin, Tween 80 and water and heated, then the mixture is dispersed in a mixture of aluminum monostearate, Span 80 and Soybean oil to form a microemulsion The microemulsion is homogenized by a microfluidizer, then the microemulsion is dispersed in PLGA-acetonitrile solution, then the acetonitrile is removed from the emulsion by evaporation under atmospheric pressure, thus forming microspheres containing naltrexone for be incorporated into the transdermal delivery device.

EXAMPLE 4 (Prophetic) A transdermal patch is prepared in accordance with the disclosure in WO 96/19975 to LTS GMBH, published on July 4, 1996, with the addition of naltrexone containing microspheres, prepared according to Example 1, according to follow: The following are homogenized: 1,139 g of a polyacrylate solution at 47.83 w / w% with a self-crosslinking acrylate copolymer, containing 2-ethylhexylacrylate, vinyl acetate, acrylic acid (solvent: ethyl acetate: heptane: isopropanol: toluene : acetylacetonate in the ratio 37: 26: 26: 4: 1), 100 g of levulinic acid, 150 g of oleyl oleate, 100 g of polyvinylpyrrolidone, 150 g of ethanol, 200 g of ethyl acetate and 100 g of buprenorphine base. The mixture is stirred for 2 hours and then visually examined to confirm that all solids have dissolved. Evaporation loss is controlled by the method of replenishing and compensating the solvent with the addition of ethyl acetate, if required. Then, the mixture is combined with the naltrexone microspheres prepared as described above in Example 1. This mixture is then transferred to a transparent 420 mm wide polyester sheet. The solvent is removed by drying with hot air. Then, the sealing film is covered with a polyester sheet. A surface of 16 cm is cut with the help of the appropriate cutting tool.

Although the invention has been described and illustrated with reference to certain preferred formulations therein, those skilled in the art will appreciate that the modifications can be made without departing from the spirit and scope of the invention. It is contemplated that such variations are within the scope of the appended claims.

Claims (25)

1. TRANSDERMAL DELIVERY DEVICE CHARACTERIZED because the delivery device comprises: a drug-containing layer comprising an effective amount of an opioid agonist and a plurality of dispersed microspheres in the drug-containing layer, the * 0 microspheres comprising an opioid antagonist already) be visually indiscernible in the drug-containing layer; or b) in an average size of 1 to 500 μm in diameter.

2. Transdermal delivery device according to alternative a) of Claim 1, CHARACTERIZED in that the microspheres have an average size of 1 to 500 μm in diameter.

3. Transdermal delivery device according to alternative b) of Claim 1, CHARACTERIZED in that the microspheres have an average size of 1 to 300 μm in diameter.

4. Transdermal delivery device according to Claim 1, CHARACTERIZED in that the plurality of microspheres comprise the opioid antagonist dispersed in a polymeric matrix.

5. Transdermal delivery device according to Claim 1, CHARACTERIZED in that the microspheres further comprise a polymer selected from the group consisting of polyesters, polyethers, poly (orthoesters), polysaccharides, cyclodextrins, chitosans, poly (S-caprolactones), polydrides, albumin, combinations and copolymers thereof and mixtures thereof.

6. Transdermal delivery device according to Claim 1, CHARACTERIZED in that the microspheres consist essentially of the opioid antagonist and a polymer selected from the group consisting of polyesters, polyethers, poly (orthoesters), polysaccharides, cyclodextrins, chitosans, poly (S-caprolactones), polydrides, albumin, combinations and copolymers thereof.

7. Transdermal delivery device according to Claim 1, CHARACTERIZED in that the microspheres essentially consist of the antagonist 1 or opioid dispersed in a polymeric matrix.

8. Transdermal delivery device according to Claim 1, CHARACTERIZED in that the microspheres have an average size of 300 to 500 microns, of 200 to 500 microns, of 125 to 200 microns, of 50 to 100 microns, of 1 to 200 microns, of 1 to 100 microns or 100 to 500 microns in diameter.

^ 9. Transdermal delivery device according to claim 1, CHARACTERIZED because the opioid antagonist becomes releasable if the transdermal delivery device is chewed, soaked, punctured, ruptured or exposed to any other treatment that disrupts the integrity of the microspheres.

10. Transdermal delivery device according to Claim 1, CHARACTERIZED because the effect of the opioid agonist is at least partially blocked when the delivery device is chewed, milled or dissolved in a solvent, or is exposed to any other treatment that disrupts the integrity of the microspheres, and administered orally, intranasally, parenterally or sublingually.

11. Transdermal delivery device according to Claim 1, CHARACTERIZED because the opioid antagonist is in the form of stable crystalline particles.

12. Transdermal delivery device according to Claim 1, CHARACTERIZED in that the microspheres are dispersed uniformly within the drug layer.

13. Transdermal delivery device according to Claim 1, CHARACTERIZED in that the opioid agonist is selected from the group consisting of fentanyl, sufentanil, buprenorphine, hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, dihydrocodeine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof.

14. Transdermal delivery device according to Claim 1 or 13, CHARACTERIZED because the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, diprenorphine, nalmexone, ciprenorphine, alazocine, oxylorphan, cyclophane, nalorphine, nalbuphine, buprenorphine butorphanol, cyclazocine , pentazocine, levallorphan, pharmaceutically acceptable salts thereof, and mixtures thereof; and preferably is naltrexone or a pharmaceutically acceptable addition salt thereof.

15. Transdermal delivery device according to Claim 1, CHARACTERIZED in that the opioid analgesic is in an amount effective to provide analgesia for a period of time from 2 to 8 days upon being adhered to the skin of a human patient.

16. Transdermal delivery device according to Claim 1, CHARACTERIZED in that the drug-containing layer is a matrix layer, and the matrix preferably comprises a material selected from the group consisting of polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethylacrylate copolymers, copolymers ethylene vinyl acetate, silicones, gums, homo-synthetic rubber-type, co-or block polymers, polyacrylic esters and copolymers thereof, polyurethanes, polyisobutylene, chlorinated polyethylene, chloruropolivinyl, vinyl chloride-vinyl acetate copolymer, polymethacrylate polymer (hydrogel) , polyvinylidene chloride, poly (ethylene terephthalate), ethylene-vinyl alcohol copolymer, ethylene-vinyloxyethanol copolymer, silicones (e.g., silicone copolymers such as polysiloxane-polymethacrylate copolymers), cellulose copolymers (e.g., ethyl cellulose) , and cellulose esters), polycarbonates, polytetrafluoroethylene and m ezclas of the same.

17. Transdermal delivery device according to Claim 4, CHARACTERIZED because the matrix is selected from silicone polymers, silicone polymers that are crosslinkable, copolymers with dimethyl and / or dimethylvinyl siloxane units which may crosslink, block copolymers based on styrene and 1,3-dienes, polyisobutylenes, polymers based on acrylate and / or methacrylate.

18. Transdermal delivery device according to Claim 16, CHARACTERIZED in that it further comprises an adhesive layer adjacent to, and in contact with, the matrix layer and permeable to the therapeutically active agent.

19. Transdermal delivery device according to Claim 1, CHARACTERIZED in that the drug-containing layer is an adhesive layer and / or reservoir layer.

20. Transdermal delivery device according to Claim 25, CHARACTERIZED in that the reservoir layer further comprises a speed controlling membrane layer superimposed on the reservoir layer and substantially coextensive therewithin; and preferably further comprising an adhesive layer adjacent to, and in contact with, the membrane layer and permeable to the therapeutically active agent.

21. Transdermal delivery device according to Claim 18, CHARACTERIZED in that it further comprises a protective layer adhered to the adhesive layer and removable therefrom for use of the transdermal delivery device.

22. Transdermal delivery device according to claim 1, CHARACTERIZED because the transdermal delivery device is a device selected from the group consisting of a transdermal patch, a transdermal plaster, a transdermal disk and a transdermal iontophoretic device.

23. The use of a transdermal delivery device according to claim 1 to produce a medicament useful for the treatment of pain.

24. The use of a transdermal delivery device according to claim 1 for preparing a medicament useful for preventing the abuse of an opoid agonist.

25. The use of a transdermal delivery device according to any one of Claims 1-22 for preparing a medicament useful for providing analgesia.