TRANSDERMAL PATCH

REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 62/693,087, filed July 2, 2018 and of U.S. Provisional Application No. 62/692,987, filed July 2, 2018, the entireties of which are incorporated by reference herein.

TECHNICAL FIELD

The present disclosure relates to transdermal dosage forms containing large amounts/high loads of active agent(s) and processes of manufacture thereof.

BACKGROUND

Transdermal dosage forms offer a favorable route of administration by providing a method of administering a drug for an extended period of time, while increasing patient compliance and decreasing extreme peaks and troughs in blood plasma. These dosage forms typically contain large amounts of active agent. In cases where the active agent is an active agent effective to treat pain such as an opioid, these high load transdermal dosage forms have a high potential for abuse.

Many different approaches have been proposed to prevent abuse of transdermal patches. In particular, U.S. Pat. No. 5,236,714 discloses a dosage form comprising an abusable substance formulated with an antagonist for the abusable substance. U.S. Pat. No. 5,149,538 discloses a transdermal patch comprising an opioid and an antagonist for the opioid that is releasable upon ingestion or solvent immersion, wherein the two reservoirs are separated by an impermeable barrier. U.S. Pat. Nos. 8,747,889, 8,790,689 and 7,182,955 disclose transdermal patch systems comprising an opioid and an antagonist to the opioid with different methods for release of the antagonist.

US Pub. No. 20040126323 discloses a transdermal system with an opioid layer and an antagonist layer comprising antagonist salt and base, with or without a barrier separating the opioid and antagonist layer.

There remains a need in the art for transdermal dosage forms having improved adhesion and processes of manufacture thereof.

SUMMARY OF THE INVENTION The disclosure is directed to processes for the manufacture of transdermal dosage systems for administering active agents to patients. The novel processes enable scalable manufacture of transdermal dosage systems with concomitant reduction in waste and cost of goods. The transdermal dosage systems include a skin contact layer (SCL) comprising a drug layer comprising the active agent(s). The drug layer optionally further comprises an antagonist. The dosage systems of the disclosure also comprise at least one adhesive strip located externally to the drug layer. Methods of manufacturing the described dosage form are described. Also described are methods of using the disclosed dosage systems.

The present invention also relates to a processes for manufacturing a transdermal dosage system for administering an active agent to a mammal, wherein the transdermal dosage system comprises:

a skin contact layer comprising a drug layer comprising an active agent and optionally a first antagonist of the active agent, the skin contact layer further comprising two adhesive skin contact strips, each adhesive strip located externally to the drug layer;

a second drug layer optionally comprising a second antagonist; and

a barrier impermeable to said active agent or the pharmaceutically acceptable salt thereof, and to said first and second antagonist, or the pharmaceutically acceptable salt thereof; wherein the skin contact layer and the second drug layer are separated from each other by said barrier.

The disclosure is also directed to transdermal dosage systems for administering active agents to patients. These dosage systems include a skin contact layer comprising a drug layer comprising the active agent. The drug layer optionally further comprises a first antagonist. The dosage systems of the disclosure also comprise at least one adhesive strip located externally to the drug layer. In the described dosage systems, the first-reservoir and the at least one adhesive strip are separated by a spacer having a width of at least about 0.2 mm. Methods of manufacturing the described dosage form are described. Also described are methods of using the disclosed dosage systems.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a schematic cross-section of a transdermal dosage system of the disclosure.

Figure 2 is a schematic cross-section of a transdermal dosage system of the disclosure.

Figure 3 is a schematic of one exemplary process of the disclosure.

Figure 4 is a schematic of one exemplary process of the disclosure.

DETAILED DESCRIPTION The terms "transdermal dosage form", "transdermal dosage system", "patch" and "dosage form", as used herein, are used interchangeably and refer to any dosage form that, when contacted with a patient's skin for a sufficient period of time, can transdermally deliver an effective amount of an active agent, such as a pharmaceutical agent, e.g., an opioid, through the patient's skin whether the type of transdermal dosage form is a polymer-matrix-type, drug-in-adhesive-type, or other form.

As used herein, the term "transmucosal" refers to buccal, nasally, sublingual, topical, rectal, and/or vaginal.

As used herein, the term "buccal administration" refers to a topical route of administration by which a composition is held or applied to the buccal area of the inner cheek.

As used herein, the term "chew" or "chewed" refers to a method of administration of a composition whereby said composition is chewed over a pre-defined period of time in the oral cavity without being swallowed.

A "patient" or "animal" or "human" is a mammal, and includes, but is not limited to, a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, and guinea pig. In some embodiments, the "patient" or "animal" or mammal is a human. As used herein, the terms "abuse resistant" and "abuse deterrent" are synonymous and shall mean any transdermal dosage form that when misused, inhibits or deters the abuser from achieving the non-therapeutic effects sought from misuse of the composition, formulation or dosage form, such as opioid induced euphoria. Abuse or misuse shall mean any means including but not limited to being administered buccally, nasally, sublingually, parenterally, rectally, and/or vaginally to an animal.

As used herein, the term "fentanyl" refers to the chemical compound N-Phenyl-N-(l-(2-phenylethyl)-4- piperidinyl) propanamide as either free base or a pharmaceutically acceptable salt. In some embodiments, the fentanyl is in the form of its free base.

As used herein, the term "naltrexone" refers to the chemical compound morphinan-6-one, 17 (cyclopropylmethyl) 4,5-epoxy3,14-dihydroxy-(5ct) as free base, co-crystal, or a pharmaceutically acceptable salt. In some embodiments, two forms of naltrexone are present in the transdermal dosage form. In one preferred embodiment, the naltrexone is in the form of its free base. In another preferred embodiment, the naltrexone is in the form of its HCI salt.

The term "biological effect" or "biological result" as used herein refers to a physical reaction in a patient. In some embodiments, the effect is analgesic, euphoria, respiratory, anti-depressive, or combinations thereof. As used herein, the terms "adverse agent" or "antagonist" or "antagonist to the active agent" refer to a pharmaceutical agent, drug, and/or antagonist that partially or completely prevents, negates, diminishes, delays or reverses at least one biological effect of the active agent present in the dosage form, e.g. euphoric effect, or produces one or more unpleasant physiological reactions, e.g., vomiting, nausea, diarrhea, bad taste, when absorbed in sufficient amount into the blood stream of a patient.

The phrase "pharmaceutically acceptable salt," as used herein, is a salt formed from an acid and a basic group. In some embodiments, the salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucoronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, glubionate and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono- , bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2- hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N, N, -di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as N, N,-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine; N-methyl- D-glucamine; and amino acids such as arginine, lysine, and the like. The list is not meant to be exhaustive but merely illustrative as a person of ordinary skill in the art would appreciate that other salts may be prepared.

As used herein, the phrase "active agent" refers to the drug which action is needed, intended or desired as the result of administration of the transdermal dosage form of the present invention. The active agent may be in any form which provides the desired biological effect, for example attenuation of pain. In addition to pharmaceutically acceptable salts, the active agent may be utilized in any solid state form such as amorphic or polymorphic form of the active agent. In some embodiments, the active agent is amorphous. In further embodiments, the active agent is crystalline. In further embodiments, the active agent includes one or more fentanyl polymorph and amorphic form described in US Patent Publication No. 2010/0076198. The term "active agent" therefore encompasses all amorphic forms or polymorphic forms existing under any possible crystal morphology. In further embodiments, the active agent such as fentanyl is in the form of a base. In further embodiments, the active agent such as fentanyl base is in amorphous form when formulated with excipients in the final transdermal dosage form. In further embodiments, the antagonist such as Naltrexone is in salt form such as HCI. In further embodiments, the antagonist such as Naltrexone salt is in micronized form. In further embodiments, the micronized Naltrexone salt is maintained in crystalline form within the transdermal dosage form. In further embodiments, the transdermal dosage form comprises crystalline ionic antagonist such as Naltrexone salt, admixed with povidone and silicone. In further embodiments, the antagonist such as Naltrexone is in base form. In further embodiments, the antagonist such as Naltrexone base is in amorphous form when formulated with excipients in the final transdermal dosage form. In further embodiments, the transdermal dosage form comprises amorphous antagonist in base form such as Naltrexone base in povidone.

The active agent or salt thereof also may be in the form of a prodrug. Such prodrugs may include, without limitation, esters, carbamates sulfate, oximes, sulfamites, carbonates and other conventional "pro-drug" forms, which, when administered in such form, convert to the active agent in vivo. In some embodiment, the prodrugs are esters.

As used herein, the term "proximal" refers to the location of a component, when considered as a whole, at a position which is relatively near to a site for application of the transdermal dosage form. The term "proximal surface" refers to the surface of a component which, when considered as a whole, is relatively near to a site for application of the transdermal dosage form, as compared to other surfaces of the component. In certain embodiments, the proximal surface of a component can be either continuous or discontinuous.

As used herein, the term "distal" refers to the location of a component, when considered as a whole, at a position which is relatively distant from a site for application of the transdermal dosage form. The term "distal surface" refers to the surface of a component which, when considered as a whole, is relatively distant from a site for application of the transdermal dosage form, as compared to other surfaces of the component. In certain embodiments, the distal surface of a component can be either continuous or discontinuous.

As used herein, the term "external" or "externally located" refers to the location of a component, at a position which is at the same distance from a site for application of the transdermal dosage form relative to a component of reference, and closer to the side, end or outer edge of the transdermal dosage system.

As used herein, the term "central" or "centrally located" refers to the location of a component, when considered as a whole, at a position which is at equidistance to at least two edges of the transdermal dosage system, for example, when viewing from above. As used herein, the term "to encircle" or "encircling" a component refers to the location of a component, which is at the same distance from a site for application of the transdermal dosage form relatively to a component of reference, and which is external to said component at more than two axes.

As used herein, the term "final size" of a component, e.g. active strip, adhesive strip, non-skin contact strip, refers to the area of that component in the complete/final patch. When referring to the patch, the "final size" is the area of the complete/final patch.

As used herein, a "component" refers to a layer, a stratum, a reservoir, a coating, a sheet, a film, a deposit, a sediment, a residue and/or a cover.

As used herein, a "spacer" is meant to include a strip, channel, pore, orifice, opening, void, gap, hole, crack and/or slit which provides for a distance between two components. It may be a void or made up of an inactive ingredient, a barrier material or other.

The "percent weight" of an active agent and/or an antagonist in a drug layer (e.g., a drug-adhesive strip) as used herein, as measured by %w/w, is the percent of the weight of the active agent and/or an antagonist out of the total weight of the drug layer. The "sum percent weight" of the active agent and the antagonist in the drug layer, as used herein, and as measured by %w/w, is the percent of the sum weight of the active agent and the antagonist out of the total weight of the drug layer. The percent weight may be calculated as the active agent weight, the antagonist weight or the sum weight of the active agent and the antagonist, divide by the total weight of the drug layer and multiplied by 100.

As used herein, a "strip" is a formulation comprising either an active agent, antagonist, or both in any desired geometry and may be either continuous or discontinuous and may be disposed in a pattern.

As used herein, an "adhesive strip" is a formulation able to adhere to human skin and comprising one or more adhesives but substantially free of an active agent, antagonist, or both. The adhesive strip may have any desired geometry and may be either continuous or discontinuous and may be disposed in a pattern.

The phrase "treatment of pain" or "treating pain," as used herein, includes reduction of pain intensity, amelioration of pain or the cessation of pain in an animal.

The phrase "prevention of pain" or "preventing pain," as used herein, includes the avoidance of the onset of pain in an animal.

As used herein, the phrase "dispersed" unless otherwise specified refers to dispersed, mixed, and/or dissolved either homogenously and/or heterogeneously. As used herein, the term "opposed" as used with reference to two surfaces of a component refers to two surfaces which are generally facing in opposite directions regardless of whether one or both of the two surfaces are planar and/or parallel to each other.

As used herein, the terms "porous medium" and "porous material" are used interchangeably.

The term "drug layer" as used herein refers to a compartment, layer or strip (preferably a layer or strip) of a transdermal dosage system which contains one or more active or adverse agents. In some embodiments, a drug layer is a layer or strip of the transdermal dosage system. In one embodiment, said layer or strip forms part of a polymer-matrix type transdermal dosage form and in another embodiment, said layer or strip forms part of a drug-in-adhesive type transdermal dosage form.

The term "second drug layer" as used herein refers to a compartment, layer or strip of a transdermal dosage system which contains one or more active or adverse agents. In some embodiments, said second drug layer is a layer or strip of the transdermal dosage system. In one embodiment, said layer or strip forms part of a reservoir type transdermal dosage form, in another embodiment, said layer or strip forms part of a polymer-matrix type transdermal dosage form and in yet another embodiment, said layer or strip forms part of a drug-in-adhesive type transdermal dosage form.

A "drug-in-adhesive strip" or "drug-adhesive strip" as used herein is a strip containing both a drug (e.g. the active agent and/or an antagonist) and at least one adhesive. As used herein, the phrase "active agent- containing drug layer" or "active-containing drug layer" refers to a drug layer comprising the active agent.

"Room temperature" refers to a typical indoor temperature. In some embodiments, room temperature is about 15 to about 25 °C. In further embodiments, room temperature is about 20 °C.

The modifier "about" or "substantially" should be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression "from about 2 to about 4" also discloses the range "from 2 to 4." When used to modify a single number, the term "about" may refer to plus or minus 10% of the indicated number and includes the indicated number. For example, "about 10%" may indicate a range of 9% to 11%, and "about 1" means from 0.9-1.1.

The term "substantially free" of an active agent and/or antagonist as used herein refers to levels of a component, e.g., the active agent and/or the antagonist, that do not interfere with adhesion of the transdermal dosage form to the skin and are considered negligible or insignificant. In an embodiment, a component, e.g. a strip which is "substantially free" of an active agent and/or from an antagonist, as used herein, refers to a component that contains below a measureable amount of the active agent and/or the antagonist, and/or a "biologically insignificant" amount of the active agent and/or the antagonist. A "biologically insignificant" amount as used herein means that the amount of the active agent and/or the antagonist when administered to a human, does not have a significant biological/clinical/euphoric effect.

In some embodiments, the adhesives strips of the disclosure comprise 0.50% or less, 0.40% or less, 0.30% or less, 0.20% or less, 0.10% or less, or 0.05% or less by weight of an active agent and/or antagonist.

As used herein, "normal storage conditions" are storage/stability testing at 25°C ± 2°C/60% RH (relative humidity) ± 5% RH.

The term "resistant to transdermal absorption" as used herein refers to the tendency of a compound to cthe epidermis layer. In some embodiments, resistant to transdermal absorption means that no amount of a compound discussed herein crosses the epidermis layer. In other embodiments, "resistant to transdermal absorption" includes a "biologically insignificant" or negligible amount.

"Conformable" describes the ability of the transdermal dosage system to adapt in shape to the skin of the subject, e.g. patient. In some embodiments, the patch is flexible. When applied as instructed, the transdermal dosage system moves as the skin of the patient moves. In some embodiments, the transdermal dosage system does not become displaced from the patient as the skin moves or shifts.

As used herein, the term "micronized" refers to particles wherein the particles are about 10 pm or less in diameter. In other embodiments, D ₅ o is about 10 pm (microns) or less or Dio is about 5 pm or less or Dg ₀ is about 30 pm or less. In further embodiments Dso is about 10 pm or less and Dio is about 5 pm or less and Dgo is about 30 pm or less. A number of micronization techniques may be utilized to micronize one or more components of the transdermal dosage system including, without limitation, conventional jet mills. The particle size or particle size distribution may be determined using techniques in the art such as light diffraction methods such as devices of Malvern Instruments, mechanical sieve shaking method, or air jet sieve analyses.

In an embodiment, the transdermal dosage form of the disclosure, when contacted with an animal's skin, allows for the transdermal administration of fentanyl, but either (a) allows for the transdermal administration of only an amount of naltrexone that is ineffective for inhibiting the analgesic effect of the fentanyl, or (b) does not allow for the transdermal administration of the naltrexone. However, if the transdermal dosage form of the disclosure is used to deliver fentanyl via a route other than transdermal, such as buccal, nasal, oral, parenteral, rectal and/or vaginal, or if the transdermal dosage form is subjected to abuse or misuse, then the naltrexone, present in sufficient amounts to counter the effect of fentanyl, inhibits the euphoric effect of the fentanyl. In some embodiments, the transdermal dosage form will inhibit the euphoric effect of fentanyl if used other than transdermally whether before or after it is used by an animal or human for treating or preventing pain. The transdermal dosage form of the disclosure is also tamper-resistant in that if an abuser attempts to extract or separate fentanyl from the transdermal dosage form, and self-administer it via another route, such as, but not limited to, oral, parenteral, nasal, or buccal, rectal or vaginal, i.e., a route of administration that can result in a quick euphoric rush, the abuser would self-administer an amount of naltrexone along with the fentanyl, the amount of naltrexone being effective to inhibit the euphoric effect of the opioid.

In one embodiment of the present disclosure, there is provided a transdermal dosage form having reduced potential for abuse comprising fentanyl and more than one naltrexone layers.

In one embodiment, a transdermal dosage form comprises fentanyl, a first naltrexone component, and a second naltrexone component. In one embodiment, the drug layer comprises naltrexone in the form of a pharmaceutically acceptable salt, and the second drug layer comprises naltrexone in the form of a pharmaceutically acceptable base. In one embodiment, the drug layer comprises naltrexone in the form of a pharmaceutically acceptable salt and fentanyl and the second drug layer comprises naltrexone in the form of a pharmaceutically acceptable base. In one embodiment the present disclosure is directed to an abuse deterrent transdermal dosage forms wherein the drug layer and second drug layer are separated by a barrier.

In another embodiment of the transdermal dosage form, the drug layer has a proximal and distal surface; the second drug layer is disposed distal to the drug layer and the barrier is interposed between the drug layer and second drug layer. The dosage form may also include a backing layer located distal to the second drug layer. In another embodiment, the backing layer is permeable to the naltrexone of the second drug layer.

In another embodiment, the proximal surface of the drug layer has an area of about 5 to about 150 cm ² . In another embodiment, the surface area of the dosage form is about 5 to about 60 cm ² . In another embodiment, the surface area of the dosage form is about 25 to about 35 cm ² or about 100 to about 125 cm ² . In another embodiment, the transdermal dosage form releases about 10 to about 100 pg of fentanyl per hour to skin. In another embodiment, the transdermal dosage form releases about 12.5, 25, 50, 75 or 100 pg of fentanyl per hour to skin. Any amount of active is possible, for example the transdermal dosage form may contain anywhere from 0.1 to 500 mg of fentanyl. In one embodiment, the transdermal dosage form comprises fentanyl base or alkaloid in an amount of about 1 to about lOmg.

In another embodiment, the disclosure relates to a transdermal dosage system for administering an active agent through the skin, wherein a drug layer comprises the active agent such as fentanyl formulated in amorphous form while the drug layer further comprises Naltrexone HCI in crystalline form and a second drug layer comprises naltrexone base formulated in amorphous form. When fentanyl is used as the active agent, release of naltrexone from one or both of the layers can inhibit the euphoric effect of the opioid. In some embodiments, the transdermal dosage form will inhibit the euphoric effect of fentanyl if the device is used other than transdermally whether before or after the device is used by an animal or human for treating or preventing pain.

Release of naltrexone from the system, when used transdermally, is controlled so that antagonist levels are sufficiently low while maintaining fentanyl's effect. In some embodiments, the fentanyl's effects are maintained for more than about two days. In other embodiments, the fentanyl's effects are maintained for more than about three days.

Referring now to Figure 1, in one embodiment, the present disclosure comprises a transdermal dosage form comprising:

a drug layer 120, comprising fentanyl and a naltrexone salt optionally comprising a polymeric material and optionally in the form of a continuous, planar component in the form of a slab;

a second drug layer 140 comprising naltrexone in free base form; and a barrier layer 130.

The drug layer has a proximal surface 115, which may be a skin-contacting surface and is optionally covered with a release liner 110, and a distal surface 125 which is opposed to the proximal surface 115. The barrier 130 is disposed between the distal surface 125 of the drug layer 120 and the second drug layer 140. A backing 150 is disposed adjacent to the second drug layer 140 at a location which provides an outer surface 155 of the dosage form. In some embodiments, a permeable backing layer 150 is adjacent to the second drug layer 140. In other embodiments, a structured release liner 110 is located proximal to the drug layer 120 and functions to protect the surface of the skin-contacting drug layer 120 prior to use of the dosage form.

The following relates to Figures 1 and 2 and the disclosure in general.

The fentanyl will be present in an amount such that the dosage form delivers a therapeutically effective amount for the condition being treated. This amount will vary according to the type of fentanyl used, the condition to be treated, the amount of time the composition is allowed to remain in contact with the skin of the subject, and other factors known to those of skill in the art. For example, information on dosing and the amount of fentanyl present in a transdermal dosage form is set forth in U.S. Published Patent Application No. 2003/0026829 each of which are incorporated by reference herein in their entirety for all purposes. In one embodiment, the amount of fentanyl present in the transdermal dosage form of the disclosure is greater than about 0.01 wt-%, based on the total weight of the composition of the fentanyl component. In another embodiment, the amount of fentanyl present in the transdermal dosage form of the disclosure is greater than about 1.0 wt-%, based on the total weight of the composition of the fentanyl component. In another embodiment, the amount fentanyl present in the transdermal dosage form of the disclosure is less than about 40 wt-%, based on the total weight of the composition of the fentanyl component. In another embodiment, the amount of fentanyl present in the transdermal dosage form of the disclosure is less than about 20.0 wt-%, based on the total weight of the fentanyl.

The analgesically effective amount of fentanyl present in the transdermal dosage form typically ranges from about 0.01 to about 50 mg/cm ² in one embodiment, from about 0.05 to about 15mg/cm ² in another embodiment, and from about 0.05 to about 5.0mg/cm ² in another embodiment. It is well within the purview of one skilled in the art to readily determine the analgesically effective amount of fentanyl needed for a particular indication.

For the purpose of abuse deterrence, the drug layer in the transdermal dosage system of the present disclosure includes amounts of the active agent required to reach efficacy, as well as an appropriate amount of an antagonist, leading to a relatively high drug load of at least about 5.00 % (%w/w), at least about 6.00 % (%w/w), at least about 7.00% (%w/w), at least about 8.00% (%w/w), at least about 9.00% (%w/w), at least about 10.00% (%w/w), at least about 12.00% (%w/w) at least about 15.00% (%w/w) or at least about 20.00% (%w/w) in the drug layer.

In one embodiment, the naltrexone free base and naltrexone salt are present in an amount sufficient to inhibit at least one biological effect of fentanyl. In a further embodiment, the naltrexone free base and naltrexone salt are provided in a total amount sufficient to inhibit the euphoric effect of fentanyl when the transdermal dosage form is subjected to abuse or misuse.

Depending on the type of abuse, the transdermal patch is capable of containing a sufficient amount of naltrexone to blunt or block at least one biological effect of the fentanyl or to cause at least one unpleasant side effect in a patient or animal when the patch is subjected to abuse or misuse. This amount can vary according to the amount and type of fentanyl in the dosage form. The amount may be included in each layer individually or combined in second drug layer 140 and drug layer 120 depending on desired effect and form of the formulation.

In certain embodiments, naltrexone can be dispersed, mixed and/or dissolved in a polymeric material, including but not limited to, the polymeric materials which are suitable for incorporation into the fentanyl containing drug layer.

In one embodiment of the present disclosure, the dosage form is provided such that the naltrexone is not absorbed to any biologically significant degree into a blood stream when administered transdermally. In other embodiments, the dosage form is provided such that the ratio of naltrexone to fentanyl in the dosage form is from about 1:10 to about 10:1. In other embodiments, the dosage form is provided such that the ratio of naltrexone to fentanyl in the dosage form is more than 3:1. In another embodiment of the present disclosure, there is provided a transdermal dosage form having reduced potential for abuse comprising naltrexone to fentanyl weight ratio of about 4:1. The transdermal dosage form of the present disclosure would also have stability, adhesive properties as required by pharmaceutical regulatory approval.

In another embodiment, the ratio of naltrexone to fentanyl released from the dosage form when the dosage form is tampered with, e.g., chewed, extracted, mechanically violated, is at least 1:5, 1:4, 1:3, 1:2, or 1:1. In another embodiment, the ratio of naltrexone to fentanyl released from the dosage form when the dosage form is tampered with, e.g., chewed, extracted, mechanically violated, is at least 1:1 at time points between 5 min. to 4 hours.

In some embodiments, the proximal surface 115 has a release liner 110 which is removed to reveal a skin contacting surface which should be sufficiently conformable when placed on a skin surface so as to make intimate contact with at least a portion of the skin surface. In one embodiment, substantially all of the polymeric material of the proximal surface of the drug layer 120 will make intimate contact with the skin surface of a patient. Suitable release liners include conventional release liners comprising a known sheet material such as a polyester web, a polyethylene web, a polypropylene web, or a polyethylene-coated paper coated with a suitable fluoropolymer or silicone based coating. The release liner that has been coated with the drug layer 120 can be dried and laminated onto a barrier component 130 using conventional methods.

In one embodiment, the drug layer 120 comprises a polymeric material, fentanyl as free base and naltrexone HCI. Suitable polymeric materials or matrices for use in the first antagonist or adverse agent component include, but are not limited to, acrylates, natural rubbers, polyisobutylenes, polyisoprenes, styrenic block copolymers, polyvinylethers, silicone polymers, polyurethanes, and polyurethane-ureas. In one embodiment, the fentanyl or naltrexone is preferably dispersed substantially homogeneously throughout a polymeric material. In one embodiment, the fentanyl or naltrexone is dissolved in the polymeric material. In another embodiment, fentanyl is substantially in amorphous form. In another embodiment, the naltrexone includes a crystalline form substantially dispersed throughout the polymeric material.

In certain embodiments, the polymeric matrix is a pressure sensitive adhesive (PSA). Suitable pressure- sensitive adhesives include those suitable for use as the polymeric material of the layer. Additionally, pressure-sensitive adhesives not typically suitable for direct skin contact can be suitable for use as the polymeric material of the transdermal dosage system described herein, for example with fentanyl and/or naltrexone. In some embodiments, pressure-sensitive adhesives for use in the dosage forms of the disclosure include acrylates, polyisobutylenes, silicone polymers, and mixtures thereof. Examples of useful polyisobutylene pressure-sensitive adhesives are described in U.S. Pat. No. 5,985,317, the disclosure of which is incorporated herein by reference in its entirety for all purposes. Examples of useful acrylate and silicone polymer pressure-sensitive adhesives, and mixtures thereof, are described in U.S. Pat. No. 5,474,783, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

Acrylate polymers and copolymers may include pressure-sensitive adhesives. Examples of suitable monomers for use in acrylate copolymers include alkyl acrylates, such as isooctyl, 2-ethylhexyl, n-butyl, ethyl, methyl, and dimethylhexyl, and alkyl methacrylates, such as lauryl, isodecyl, and tridecyl. Monomers containing functional groups, such as carboxylic acid, hydroxy, amide, and amino may also be incorporated into an acrylate copolymer. Examples of suitable monomers containing functional groups include acrylic acid, hydroxyalkyl acrylates containing 2 to 4 carbon atoms in the hydroxyalkyl group, acrylamide, N-vinyl-2-pyrrolidone, vinyl acetate, and alkoxyethyl acrylates.

Acrylate copolymers may optionally further comprise a substantially linear macromonomer copolymerizable with the other monomers. Suitable macromonomers include polymethylmethacrylate, styrene/acrylonitrile copolymer, polyether, and polystyrene macromonomers. Examples of useful macromonomers and their preparation are described in U.S. Pat. No. 4,693,776 (Krampe et al.), the disclosure of which is incorporated herein by reference in its entirety for all purposes.

Other polymer materials of the drug layer may include but are not limited to polyethylene; polypropylene; ethylene/propylene copolymers; ethylene/ethylacrylate copolymers; ethylene/vinyl acetate copolymers; silicone elastomers, especially the medical-grade polydimethylsiloxanes; neoprene rubber; polyisobutylene; chlorinated polyethylene; polyvinyl chloride; vinyl chloride-vinyl acetate copolymer; polymethacrylate polymer (hydrogel); polyvinylidene chloride; poly(ethylene terephthalate); butyl rubber; epichlorohydrin rubber; ethylene-vinyl alcohol copolymer; ethylene-vinyloxyethanol copolymer; silicone copolymers, for example, polysiloxane-polycarbonate copolymers, polysiloxane- polyethyleneoxide copolymers, polysiloxane-polymethacrylate copolymers, polysiloxane-alkylene copolymers (e.g., polysiloxane-ethylene copolymers), polysiloxane-alkylenesilane copolymers (e.g., polysiloxane-ethylenesilane copolymers), and the like; cellulose polymers, for example methyl or ethyl cellulose, hydroxypropyl methylcellulose, and cellulose esters; polycarbonates; polytetrafluoroethylene; and combinations thereof. In one embodiment, the polymer matrix has a glass-transition temperature below room temperature. The polymer can, but need not necessarily, have a degree of crystallinity at room temperature. Cross-linking monomeric units or sites can be incorporated into the polymers. For example, cross-linking monomers can be incorporated into polyacrylate polymers. The cross-linking monomers provide sites for cross-linking the polymer matrix after microdispersing the active agent into the polymer. Known cross-linking monomers for polyacrylate polymers include, but are not limited to, polymethacrylic esters of polyols such as butylene diacrylate and dimethacrylate, trimethylol propane trimethacrylate, and the like. Other monomers that provide cross-linking sites include ally I acrylate, allyl methacrylate, diallyl maleate, and the like. In one embodiment the polymer matrix does not allow any, or any detectable amount, of naltrexone to diffuse out of it, particularly in those instances in which the fentanyl can penetrate a patient's skin.

The drug layer can also comprise a porous medium, such as a woven fabric, porous or microporous film, or other open, mesh-like material, wherein at least a portion of the pores contain active agent or adverse agent. The fentanyl or naltrexone can be present within the pores in any form, including but not limited to a liquid, a gel or a solid, such as a solid crystalline or powdered material. For example, the fentanyl or naltrexone can be mixed with a carrier, such as a viscous liquid, semi-solid or gel material. Examples of suitable materials for incorporation into the fentanyl or naltrexone component include, but are not limited to, microporous films formed by extruding polyethylene or polypropylene with mineral oil as described in U.S. Pat. No. 4,539,256, the disclosure of which is incorporated herein by reference in its entirety.

Each of the layers comprising fentanyl or naltrexone may comprise a number of additional components. Additional components of the drug layer can include skin penetration enhancers, drug solubilizers, plasticizers, anti-oxidants, colorants, bittering agent and the like.

The drug layer will typically comprise a skin penetration enhancer. Examples of excipients useful as skin penetration enhancers or solubilizers in transdermal drug delivery systems include C8-C24 fatty acids such as isostearic acid, octanoic acid, and oleic acid; C8-C24 fatty alcohols such as oleyl alcohol and lauryl alcohol; lower alkyl esters of C8-C24 fatty acids such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate; monoglycerides of C8-C24 fatty acids such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate; monoglycerides of C8-C24 fatty acids such as glyceryl monolaurate; tetraglycol (tetrahydrofurfuryl alcohol polyethylene glycol ether); tetraethylene glycol (ethanol, 2,2'- (oxybis(ethylenoxy))diglycol); polyethylene glycol; propylene glycol; N,N-dimethyldodecylamine-N-oxide; terpenes, such as d-limonene, menthol, and terpineol.

The skin penetration enhancers, drug solubilizers, plasticizers, and other additives can be dispersed or mixed, optionally substantially uniformly, or optionally dissolved in the composition. Where the additive is a penetration enhancer, it is present in an amount that enhances fentanyl permeation through the skin compared to a like composition not containing the penetration enhancer(s) when this phenomenon is measured using a standard skin penetration model, such as set forth in U.S. Pat. No. 5,585,111, the disclosure of which is herein incorporated by reference in its entirety. In one embodiment, the total amount of penetration enhancer and solubilizer is less than about 40% by weight based on the total weight of the composition. In another embodiment, the total amount of penetration enhancer and solubilizer is less than about 30% based on the total weight of the composition.

A solubility enhancer may also be included. In one embodiment, the solubility enhancer is present in an amount more than 2%. In another embodiment, it is present is in an amount of between 2.5 to 3.5%. In one embodiment, polyvinylpyrrolidone (PVP) is used.

In some embodiments comprising fentanyl and naltrexone in the drug layer, the fentanyl and naltrexone are dispersed homogeneously throughout the polymeric material, or are optionally dissolved within the polymeric material. The proximal or skin-contacting surface 115 should be sufficiently conformable when placed on a skin surface so as to make intimate contact with at least a portion of the skin surface. In one embodiment, substantially all of the polymeric material at the proximal surface 115 will make intimate contact with the skin surface.

In one embodiment, the drug layer and second drug layer each have a thickness of no less than about 10pm. In another embodiment, the drug layer has a thickness of no less than about 20pm. In another embodiment, the drug layer has a thickness of no less than about 50pm. In another embodiment, the drug layer has a thickness of no greater than about 250pm. In another embodiment, the drug layer has a thickness of no greater than about 200pm. In another embodiment, the drug layer has a thickness of no greater than about 150pm.

The barrier layer 130, as shown in Figure 1, is substantially continuous and is adjacent to the distal surface of the drug layer 120 on one side and the second drug layer 140 on the other side. The barrier layer is impermeable to naltrexone and fentanyl; and comprises a material which is insoluble in water, alcohol and organic solvents. The barrier layer comprises a polymer such as polyolefin laminates (Dow Chemical, Midland, Ml), acrylonitrile copolymer films (BAREX, BP Chemicals, Koln, Germany), polyethylnapthalene (PEN), polyethylene terephthalate (PET), polyimide, polyurethane, polyethylene, metallized films and glass coated films where these films can include ethylene copolymers such as ethylene-vinyl acetate copolymer (EVA), and combinations thereof. In some embodiments, the barrier layer comprises polyester such as PET laminated to a polymer such as polyurethane, polyethylene, and ethylene copolymers. In other 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 0.075mm (0.3 mil) to about 0.125mm (5 mil); optionally 0.025mm (1 mil) to about 0.1 mm (4 mil); optionally 0. 0625mm (1.5 mil) to about 0.0875mm (3.5 mil); and optionally 0.025mm (1 mil) to about 0.05mm (2 mil). The polyethylene or EVA laminated layer of the PET-PE laminates improves the adhesion of the naltrexone to the backing, and serves to prevent the facile removal of the second drug layer from the system by the potential abuser.

In some embodiments, the backing is laminated to the surface of the second drug layer, optionally using heat, pressure and/or an additional tie component to ensure adequate contact between the second drug layer and backing. In some embodiments, the backing is non-sticking and hydrophobic.

Any device known to those skilled in the art for transdermally delivering a therapeutic agent, particularly an opioid, to an animal can be used for the transdermal dosage form of the disclosure. For example, the transdermal dosage form can be a polymer-matrix type transdermal dosage form, a drug-in-adhesive type transdermal dosage form or a mixture thereof. The transdermal dosage form is designed so that when contacted with the animal's skin, an analgesically effective amount of fentanyl is transdermally administered to the animal while naltrexone either remains in the transdermal dosage form and is not administered to the animal or is administered to the animal in an amount insufficient to inhibit the analgesic effect of the fentanyl.

The transdermal dosage forms of the disclosure can be made in the form of an article such as a tape, a patch, a sheet, a dressing or any other form known to those skilled in the art. Generally, the dosage form will be in the form of a patch of a size suitable to deliver a preselected amount of fentanyl through the skin.

In one embodiment, the dosage form will have a surface area that is 5cm ² or greater. In another embodiment, the dosage form will have a surface area that is 10cm ² or greater. In another embodiment, the dosage form will have a surface area of 100 cm ² or less. In another embodiment, the dosage form will have a surface area of 40 cm ² or less.

Dosage forms of the present disclosure are typically packaged individually in a foil-lined pouch for storage. Dosage forms of the present disclosure may alternatively be provided in a rolled or stacked form suitable for use with a dispensing apparatus. An optional tie component, heat, and/or pressure may be used to connect the skin-contacting component with the barrier component. In addition, the skin-contacting component compositions may be directly coated onto the barrier component and subsequently dried and laminated to a release liner.

One skilled in the art will appreciate that it may be preferred to vary the order of lamination steps depending on the types and thickness of the components comprising the dosage form.

According to the methods of the disclosure, in one embodiment the transdermal dosage form is contacted with the skin of the patient and fentanyl is released by the transdermal dosage form and becomes absorbed through the skin. Once absorbed into the patient, the fentanyl is provided in an analgesically effective amount. The transdermal dosage form can provide sustained and continuous delivery of an analgesically effective amount of fentanyl. In another embodiment, on administration over the skin, the transdermal dosage form exhibits a steady state drug flux of about 1 to about 10pg/cm ² /hr. In one embodiment, the transdermal dosage form exhibits a steady state drug flux of about 1 to about 8 pg/cm ² /hr. In one embodiment, the transdermal dosage form exhibits a steady state drug flux of about 1 to about 5 pg/cm ² /hr. In one embodiment, the transdermal dosage form exhibits a steady state drug flux of about 2 to about 3 pg/cm ² /hr.

In one embodiment, the transdermal dosage form exhibits a nominal flux (i.e., the average amount of fentanyl delivered to the systemic circulation per hour acaverage skin) depending on the dosage loaded within the transdermal dosage form. In some embodiments, the transdermal dosage form exhibits a nominal flux of about 12.5 mcg/hr. In one embodiment, the transdermal dosage form exhibits a nominal flux of about 50 mcg/hr. In one embodiment, the transdermal dosage form exhibits a nominal flux of about 75 mcg/hr. In one embodiment, the transdermal dosage form exhibits a nominal flux of about 100 mcg/hr.

In one embodiment of the present disclosure, the method of treating pain with any one of the transdermal dosage forms described herein, wherein said transdermal dosage form can provide a ratio of naltrexone to fentanyl released, or alternatively absorbed into a blood stream, from about 1:10 to about 10:1 when the transdermal dosage form is used in an inappropriate manner. For example, an abuser may attempt to extract the fentanyl from the transdermal dosage form with a solvent, such as a liquid or gas. In certain embodiments, the dosage form, when tampered with in such a manner, will release both naltrexone and fentanyl. In certain embodiments, the ratio of naltrexone to fentanyl released from a transdermal dosage form when tampered with is about is 1:5, 1:4, 1:3, 1:2, or 1:1. In other embodiments, the method of treating pain comprises applying to the skin of a human subject a transdermal dosage form as described herein, wherein said dosage from comprises a ratio of naltrexone to fentanyl from about 1:10 to about 10:1. In other embodiments, the ratio of naltrexone to fentanyl released into the plasma is about is 1:5, 1:4, 1:3, 1:2, or 1:1.

The present disclosure is also directed to a kit comprising at least one transdermal dosage form of the disclosure. In one embodiment, the transdermal dosage form is present in a container, e.g., a box. In another embodiment, the kit further comprises a set of instructions directing the use of the transdermal dosage form to treat a patient, e.g., for pain. In one embodiment, the instructions may be a printed label affixed to or printed on the container. In another embodiment, the instructions may comprise a printed sheet inserted into the container or into the packaging which contains the container. The instructions may also state that the transdermal dosage form and/or its usage are designed to reduce abuse, misuse or diversion of the transdermal dosage form.

Skin adhesion is known to be critical to the safety and efficacy of transdermal dosage systems, wherein the therapeutic benefit is directly correlated to proper and complete patch adhesion to the skin. The addition of a drug (e.g. an active agent and/or antagonist) to a pressure sensitive adhesive may influence the adhesive properties and appearance of a transdermal patch. Active agents and/or antagonists, when added to the blend may interfere with the adhesive properties of the system in a dose dependent manner, resulting in inferior adhesion of the dosage system to patients' skin. Fentanyl and other drug or therapeutic agent having a low melting point form examples of active agents which interfere with adhesion in a dose dependent matter.

The transdermal dosage form of the current disclosure includes an active-containing drug layer including at least one adhesive. This type of drug-in-adhesive patch, wherein the layer serves both as a drug reservoir and as an adhesive component with no separate or additional adhesive component or layer is acceptable in the art (Tapash K. Ghosh et al. eds., 1997). However, for the purpose of abuse deterrence, for example, the drug-in-adhesive layer in the transdermal dosage system of the present disclosure can include both the amount of the active agent required to reach efficacy, and an effective amount of an antagonist, leading to a high drug load in the active agent-containing/drug-adhesive strip. The resulting decrease in adherence of the drug-adhesive layer led the inventors of the present disclosure to include separate adhesive strips in the same layer (the skin-contact layer) as the active agent-containing strip, adjacent to, and externally to the active agent-containing strip. In an embodiment, the adhesive strips are laminated to the same barrier and on the same side as the drug-adhesive strip as shown in Fig 2 (layer B). In some embodiments the adhesive strips have about the same width as the drug-adhesive strip. This new design maintains direct contact of the active-containing reservoir with the skin, while also assuring appropriate adherence of the transdermal dosage system to the skin over the administration period.

In addition, transdermal dosage systems may change during storage or while adhered to the skin. For example, cold flow may occur during storage or administration periods, wherein the active agent and/or antagonist creeps beyond the boundaries of the drug layer comprising the active agent. Migration of an active agent and/or antagonist into the adhesive strips is undesired as it may reduce the concentration of the active agent and/or antagonist in the active-containing drug layer, thus reducing the delivery of the active agent to the patient and/or compromising the abuse deterrent activity and thereby compromising the efficacy and safety of the transdermal dosage system. In addition, migration of the drug into the adhesive strips may compromise adhesion. Thus, the addition of adhesive strips adjacent to the active-containing drug layer /drug-adhesive strip, created a new and unexpected concern that the active agent and/or antagonist would migrate to the sidewise adhesive strips, potentially compromising treatment efficacy and/or safety.

Surprisingly, it has now been found that the physical separation of the active-containing drug layer (drug- adhesive strip) and the adhesive strips, reduces and/or prevents the migration of the active agent and/or antagonist from the drug-adhesive strip to the adhesive strips, wherein the drug-adhesive strip and the side adhesive strips are laminated onto one layer, e.g. a barrier layer or backing layer, however not in contact with each other. In an embodiment, the active-containing drug layer (drug-adhesive strip) is positioned on said layer, e.g. a barrier layer or backing layer, at a distance of about 0.2mm to about 5mm, about 0.3mm to about 3mm, or about 0.4mm to about 2.5mm, or about 0.5mm to about 2.0mm, or about 0.6mm to about 1.8mm, or about 0.7mm to about 1.6mm, or about 0.8mm to about 1.2mm, about 0.9mm to about 1.1mm or about 1.0mm from the adhesive strips.

In some embodiments of the transdermal dosage form, the drug layer and the at least one adhesive strip are positioned on a layer selected from a barrier layer and a backing layer and wherein the spacer is a void between the drug layer and the at least one adhesive strip. In some embodiments the layer is a barrier layer. In other embodiments the layer is a backing layer, for example in a single drug layer patch.

With the addition of a spacer between the adhesive strips and the drug-adhesive strip, the adhesive strip remains substantially free of the active agent and the antagonist, specifically fentanyl and naltrexone, for at least about 24 hours, at least about 48 hours, at least 72 hours, at least about one month, at least about three months, at least about six months or at least about 1 year of storage/shelf life.

Similarly, with the addition of a spacer between the adhesive strips and the drug-adhesive strip, the adhesive strip contains about 0.50% or less, 0.40% or less, 0.30% or less, 0.20% or less, 0.10% or less, or 0.05% or less by weight of each of the active agent and the antagonist, specifically fentanyl and naltrexone, for at least 3 hours, at least 24 hours, at least 36 hours, at least 48 hours or at least 72 hours after transdermal administration.

Thus, the present invention provides an improved transdermal dosage system, including a transdermal dosage system having a high drug load (including an active agent or active agent and an antagonist), which preserves its efficacy and intended dosage over the time of administration and/or storage. At least one adhesive strip, e.g. two adhesive strips or one continuous adhesive strip, is included in the skin contact layer to provide proper adhesion during administration. The at least one adhesive strip is separated from the drug-adhesive strip by a spacer, e.g. void or barrier, which reduces or prevents the migration of the active agent from the central drug layer to the adhesive strips. The spacer may have a width of about 0.2mm to about 5mm, about 0.3mm to about 3mm, or about 0.4mm to about 2.5mm, or about 0.5mm to about 2.0mm, or about 0.6mm to about 1.8mm, or about 0.7mm to about 1.6mm, or about 0.8mm to about 1.2mm, about 0.9mm to about 1.1mm or about 1.0mm. For example, the spacer may have a width of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6,

2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5mm. In an embodiment, the transdermal dosage system of the present invention is a transdermal dosage system for administering an active agent to a human comprising a skin contact layer, including a first drug- adhesive strip comprising the active agent and optionally a first antagonist, and at least one adhesive strip, wherein the at least one adhesive strip is located externally to the drug layer; and optionally a second drug layer including a second antagonist, wherein the drug layer and the at least one adhesive strip are separated by a spacer, wherein the spacer has a width of about 0.2mm to about 5mm, about 0.3mm to about 3mm, or about 0.4mm to about 2.5mm, or about 0.5mm to about 2.0mm, or about 0.6mm to about 1.8mm, or about 0.7mm to about 1.6mm, or about 0.8mm to about 1.2mm, about 0.9mm to about 1.1mm or about 1.0mm. For example, the spacer may have a width of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6,

3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5mm.

In an embodiment, the at least one adhesive strip is two adhesive strips positioned externally and on two opposite sides of the drug layer. In an embodiment, the at least one adhesive strip is one continuous adhesive strip encircling the drug layer.

In an embodiment, the at least one adhesive strip is substantially free of each of the active agent and the antagonist. In an embodiment, the at least one adhesive strip remains substantially free of the each of the active agent and the antagonist, for at least 3 hours, at least 24 hours, at least 36 hours, at least 48 hours or at least 72 hours after transdermal administration of the dosage system to a human. In an embodiment, the at least one adhesive strip remains substantially free of each of the active agent and the antagonist, for at least about 24 hours, at least about 48 hours, at least about 72 hours, at least about one month, at least about three months, at least about six months or at least about 1 year of shelf life in normal storage conditions.

In an embodiment, the at least one adhesive strip contains about 0.50% or less, about 0.40% or less, about 0.30% or less, about 0.20% or less, about 0.10% or less, or about 0.05% or less by weight of each of the active agent and the antagonist, after at least 3 hours, at least 24 hours, at least 36 hours, at least 48 hours or at least 72 hours after transdermal administration of the dosage system to a human. In an embodiment, the at least one adhesive strip contains about 0.50% or less, about 0.40% or less, about 0.30% or less, about 0.20% or less, about 0.10% or less, or about 0.05% or less by weight of each of the active agent and the antagonist, after at least about 24 hours, at least about 48 hours, at least about 72 hours, at least about one month, at least about three months, at least about six months or at least about 1 year of shelf life in normal storage conditions.

In an embodiment, the percent increase of the area of the patch is not more than about 0.50%, not more than about 0.42%, not more than 0.12% or not more than about 0.09% after about 6 months of shelf life in normal storage conditions.

In an embodiment, the sum percent weight of the active agent and the first antagonist in the drug- adhesive strip is at least about 5.00 % (%w/w), at least about 6.00 % (%w/w), at least about 7.00% (%w/w), at least about 8.00% (%w/w), at least about 9.00% (%w/w), at least about 10.00% (%w/w), at least about 12.00% (%w/w) at least about 15.00% (%w/w) or at least about 20.00% (%w/w) of the weight of the drug layer. In an embodiment, the ratio between the sum weight of the active agent and the first antagonist of the active agent, and the area of the drug layer, is 0.6-1.8 mg/cm ² , 0.7-1.7 mg/cm ² , 0.8-1.6 mg/cm ² , 0.9- 1.5 mg/cm ² , 1.0 and 1.4 mg/cm ² , 1.1 and 1.3 mg/cm ² or about 1.2 mg/cm ² .

In an embodiment, the active agent is at least one opioid agonist, e.g. fentanyl or a pharmaceutically acceptable salt thereof. In another embodiment, the active agent is other than an opioid agonist. In an embodiment, the transdermal dosage system comprises a second drug layer comprising a second antagonist. In an embodiment, the first and second antagonists are independently selected from naltrexone, methylnaltrexone, naloxone, nalbuphine, nalorphine, nalorphine dinicotinate, nalmefene, nadide, levallorphan, or cyclozocine or a pharmaceutically acceptable salt thereof. In an embodiment, the drug layer comprises an active agent and a first antagonist, wherein the transdermal dosage system comprises a second drug layer including a second antagonist, and wherein the skin contact layer and the second drug layer are separated from each other by a barrier that is impermeable to the active agent and the first and second antagonists. In an embodiment, the active agent is at least one opioid agonist, e.g. fentanyl or a pharmaceutically acceptable salt thereof. In an embodiment, the first and second antagonists are independently selected from naltrexone, methylnaltrexone, naloxone, nalbuphine, nalorphine, nalorphine dinicotinate, nalmefene, nadide, levallorphan, or cyclozocine or a pharmaceutically acceptable salt thereof.

In preferred embodiments of the transdermal dosage system described hereinabove, the drug layer comprises at least one adhesive, which may be a pressure sensitive adhesive. Non-limiting examples of PSA include acrylic base adhesives and silicone based adhesives. The present invention also provides a new, highly efficient process for manufacturing a transdermal dosage system which includes a skin contact layer including a drug layer comprising an active agent and optionally a first antagonist of the active agent, and further comprises at least one adhesive skin contact strip located externally to the drug layer; a second drug layer optionally comprising a second antagonist; and a barrier impermeable to said active agent or the pharmaceutically acceptable salt thereof, and to said first and second antagonist, or the pharmaceutically acceptable salt thereof; wherein the skin contact layer and the second drug layer are separated from each other by said barrier; the process including the steps of: manufacturing a wet blend for each of said drug layer, said at least one adhesive strips and said second drug layer; coating each of the wet blends onto a release liner to form at least one drug layer laminate, at least one adhesive laminate and at least one second drug layer laminate; laminating the drug layer laminate, the at least one adhesive laminate and the second drug layer laminate to said barrier to form a combined laminate; and die-cutting the combined laminate to its final size to form a patch.

The process may further include a step of laminating the second drug layer laminate to a backing layer prior to laminating the drug layer laminate and the at least one adhesive laminate to the barrier. Alternatively, the process may further include a step of laminating the drug layer laminate to a backing layer prior to laminating the second drug layer laminate and the at least one adhesive laminate to the barrier.

In an embodiment, the at least one adhesive laminate is two adhesive laminates. In an embodiment, the two adhesive laminates are laminated to the barrier concurrently. In an embodiment, the two adhesive laminates and the drug layer laminate are laminated to the barrier concurrently. In an embodiment, the two adhesive laminates are laminated to the barrier externally to the drug layer laminate at two opposing sides. In an embodiment, the two adhesive laminates are laminated to the barrier so that a spacer having a width of about 0.2mm to about 5mm, about 0.3mm to about 3mm, or about 0.4mm to about 2.5mm, or about 0.5mm to about 2.0mm, or about 0.6mm to about 1.8mm, or about 0.7mm to about 1.6mm, or about 0.8mm to about 1.2mm, about 0.9mm to about 1.1mm or about 1.0mm is formed between the drug layer laminate and each of the two adhesive laminates. For example, the two adhesive laminates are laminated to the barrier so that the spacer has a width of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5mm. In an embodiment, the two adhesive laminates and the drug layer laminate are die-cut to their final size after lamination to the barrier. In an embodiment, the second drug layer laminate is die-cut to its final size after lamination to the barrier. In an embodiment, the two adhesive laminates, the drug layer laminate and the second drug layer laminate are die-cut to their final size concurrently.

The present invention also provides a new, highly efficient process for manufacturing a transdermal dosage system that includes a skin contact layer including a drug layer comprising an active agent and further comprises at least two adhesive skin contact strips, each adhesive strip located externally to the drug layer; a second drug layer comprising a second active agent; and a barrier to said agents; wherein the skin contact layer and the second drug layer are separated from each other by said barrier. The process includes the steps of: manufacturing a wet blend for each of said drug layer, said adhesive strips and said second drug layer; laminating the second drug layer wet blend to said barrier; coating the drug layer and adhesive strips wet blends to a release liner and laminating to said barrier to form a combined laminate; and die-cutting the combined laminate to its final size to form a patch.

In an embodiment, the at least two adhesive laminate is two adhesive laminates. In an embodiment, the two adhesive laminates are laminated to the barrier externally to the drug layer laminate at two opposing sides. In an embodiment, the two adhesive laminates are laminated to the barrier so that a spacer having a width of about 0.2mm to about 5mm, about 0.3mm to about 3mm, or about 0.4mm to about 2.5mm, or about 0.5mm to about 2.0mm, or about 0.6mm to about 1.8mm, or about 0.7mm to about 1.6mm, or about 0.8mm to about 1.2mm, about 0.9mm to about 1.1mm or about 1.0mm is formed between the drug layer laminate and each of the two adhesive laminates. For example, the two adhesive laminates are laminated to the barrier so that the spacer has a width of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5mm. In an embodiment, the two adhesive laminates and the drug layer laminate are die-cut to their final size after lamination to the barrier. In an embodiment, the second drug layer laminate is die-cut to its final size after lamination to the barrier. In an embodiment, the two adhesive laminates, the drug layer laminate and the second drug layer laminate are die-cut to their final size concurrently. In some embodiments of the process described herein, the drug layer further comprises at least one adhesive, for example a PSA, which may be silicone based PSA. In some embodiments, the drug layer comprises a first antagonist. In some embodiments, the second drug layer comprises a second antagonist. In some embodiments the active agent is at least one opioid agonist. In various embodiments of the process, the active agent is fentanyl or a pharmaceutically acceptable salt thereof. In other embodiments, the active agent is other than an opioid agonist.

In some embodiments of the process described herein, the first antagonist is in salt form. In some embodiments the second antagonist is in free base form and the free base may be in amorphous form. In some embodiments, first antagonist and the second antagonist are the same antagonist and the second antagonist is in free base form. In some embodiments, first antagonist and the second antagonist are the same antagonist and the first antagonist is in salt form and the second antagonist is in free base form.

In some embodiments of the process described herein, the transdermal dosage form further comprises a permeable backing layer distal to the second drug layer. In some embodiments, the proximal surface of the drug layer comprises a release liner. In some embodiments, the drug layer comprises one or more skin penetration enhancer, which may be polyvinylpyrrolidone. In some embodiments, polyvinylpyrrolidone is present in an amount of about 2.5 to 3.5%, by weight based on the total weight of the transdermal dosage system. In some embodiments, the drug layer includes a silicone or an acrylic adhesive.

In some embodiments of the process described herein, the second drug layer of the transdermal dosage system allows for greater release of the second antagonist in the presence of an organic solvent than in the presence of water.

In some embodiments of the process described herein, the first antagonist and the active agent are in a homogenous mixture. In some embodiments, the first antagonist and the second antagonist are independently naltrexone, methylnaltrexone, naloxone, nalbuphine, nalorphine, nalorphine dinicotinate, nalmefene, nadide, levallorphan, cyclozocine or a pharmaceutically acceptable salt thereof. In some embodiments, the first antagonist and the second antagonist are both naltrexone or a pharmaceutically acceptable salt thereof.

In some embodiments, the active agent is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dihydromorphone, dihydroisomorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl, heroin, hydrocodone, hydromorphone, hydromorphodone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, pantopon, papaveretum, paregoric, pentazocine, phenadoxone, phendimetrazine, phendimetrazone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, propylhexedrine, sufentanil, tilidine, tramadol, a pharmaceutically acceptable salt thereof, a prodrug thereof, a derivative thereof and a mixture of any two or more thereof. In some embodiments, the active agent is fentanyl, alfentanil, carfentanil, lofentanil, remifentanil, sufentanil, trefentnanil, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a derivative thereof, or a mixture of any two or more thereof. In some embodiments, the active agent is fentanyl or a pharmaceutically acceptable salt thereof.

In some embodiments of the process described herein, the drug layer further comprises at least one adhesive, which may be a pressure sensitive adhesive. In some embodiments the PSA is a silicone base adhesive.

The current invention also provides a transdermal dosage system manufactured by the process described above, wherein the sum percent weight of the active agent and the antagonist in the drug layer is at least about 5.00 % (%w/w), at least about 6.00 % (%w/w), at least about 7.00 % (%w/w), at least about 8.00% (%w/w), at least about 9.00% (%w/w), at least about 10.00% (%w/w), at least about 12.00% (%w/w) at least about 15.00% (%w/w) or at least about 20.00% (%w/w) of the weight of the drug layer.

The current invention also provides a transdermal dosage system manufacture by the described above, wherein the ratio between the sum weight of the active agent and the first antagonist of the active agent, and the area of the drug layer, is between 0.6-1.8 mg/cm ² , between 0.7-1.7 mg/cm ² , 0.8-1.6 mg/cm ² , between 0.9-1.5 mg/cm ² , between 1.0 and 1.4 mg/cm ² , between 1.1 and 1.3 mg/cm ² or about 1.2 mg/cm ² .

The current invention also provides a transdermal dosage system manufacture by the described above, wherein the drug layer and the at least one adhesive strip are separated by a spacer, wherein the spacer has a width of about 0.2mm to about 5mm, about 0.3mm to about 3mm, or about 0.4mm to about 2.5mm, or about 0.5mm to about 2.0mm, or about 0.6mm to about 1.8mm, or about 0.7mm to about 1.6mm, or about 0.8mm to about 1.2mm, about 0.9mm to about 1.1mm or about 1.0mm. For example, the spacer may have a width of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5mm.

In some embodiments of the process described herein the at least one adhesive strip is substantially free of each of the active agent and the antagonist. In some embodiments, the at least one adhesive strip remains substantially free of each of the active agent and the antagonist, for at least 3 hours, at least 24 hours, at least 36 hours, at least 48 hours or at least 72 hours after transdermal administration of the dosage system to a human. In some embodiments, the at least one adhesive strip contains about 0.50% or less, about 0.40% or less, about 0.30% or less, about 0.20% or less, about 0.10% or less, or about 0.05% or less by weight, of each of the active agent and the antagonist, after at least 3 hours, at least 24 hours, at least 36 hours, at least 48 hours or at least 72 hours after transdermal administration of the dosage system to a human. In some embodiments, the at least one adhesive strip remains substantially free of each of the active agent and the antagonist, for at least about 24 hours, at least about 48 hours, at least about 72 hours, at least about one month, at least about three months, at least about six months or at least about 1 year of shelf life in normal storage conditions. In some embodiments, the at least one adhesive strip contains about 0.50% or less, about 0.40% or less, about 0.30% or less, about 0.20% or less, about 0.10% or less, or about 0.05% or less by weight, of each of the active agent and the antagonist, for at least about 24 hours, at least about 48 hours, at least about 72 hours, at least about one month, at least about three months, at least about six months or at least about 1 year of shelf life in normal storage conditions. In some embodiments, the percent increase of the area of the patch is not more than about 0.50%, not more than about 0.42%, not more than 0.12% or not more than about 0.09% after about 6 months of shelf life in normal storage conditions.

EXAMPLES

Example 1: Quantitative Composition and Manufacture of a Transdermal Dosage System Comprising Fentanyl and Naltrexone

The transdermal dosage system as depicted in Figures 1 and 2 was manufactured in a four step process. For each of the first three steps, a wet blend was coated onto an in-process release liner, dried and laminated to another release liner or a barrier film, resulting in one of the three separate intermediate adhesive laminates. During the last two steps of the manufacturing process, each of the intermediate laminates was die-cut to the appropriate size for each patch strength (see Table 1) and assembled into the final dosage form. Materials and system layout are provided in Table 1.

Table 1

Example la : Manufacture of the skin contact active laminate (Laver B)

Naltrexone hydrochloride suspension was prepared in three silicone adhesives, Bio-PSA ^® 7-4301 Bio- PSA ^® 7-4302 and Bio-PSA ^® 7-4202. Bio-PSA ^® 7-4301 and Bio-PSA ^® 7-4202 were mixed in a mixer bowl. The mixture was cooled to approximately 20°C and naltrexone hydrochloride and Bio-PSA ^® 7-4302 were added. The mixture was homogenized to form a uniform suspension. In a separate mixer bowl, fentanyl and povidone solution were prepared in a mixed solvent of ethanol and ethyl acetate, heated to approximately 50°C and mixed to form a clear, viscous solution. The final wet blend was prepared by adding the naltrexone hydrochloride suspension to the mixer bowl containing fentanyl and povidone K90 solution and mixing at a low speed for a minimum of 4 hours.

The final wet blend was transferred to four glass containers. The containers were placed in jar rollers and rotated at a slow speed to remove air bubbles and to keep the naltrexone hydrochloride crystals uniformly suspended.

To form Skin Contact Layer Active Laminate Strips of coat weight, the final wet blend was coated to a fluoropolymer coated polyester in-process release liner (Scotchpak™ 9755) in a continuous coater with slot-die coating knife and three-zone drying ovens at 0.3 meter/min web speed and zone temperatures (zone 1: ~65°C, zone 2: ~85°C and zone 3: ~109°C) and laminated to a fluoropolymer coated polyester in- process release liner (Scotchpak™ 9744). Using a rotary die press, the product was die-cut into individual active strips.

Example lb : Manufacture of the skin contact adhesive laminate (Laver B)

Duro-Tak ^® 87-4287 (acrylic PSA) and ethyl acetate were loaded into a mixer bowl and mixed for approximately 30 min. Titanium dioxide was added to the mixer bowl and homogenized to form a uniform suspension.

To form Skin Contact Layer Adhesive Laminates of 105 GSM (grams per square meter) coat weight, wet blend was coated onto an in-process polyester release liner with a fluoropolymer coating (Scotchpak™ 1022) in the continuous coater with slot-die coating knife and three-zone drying ovens at 0.3 meter/min web speed and zone temperature (zone 1: ~65°C, zone 2: ~85°C and zone 3: ~109°C) and laminated to an in-process silicone coated polyester release liner (SG4130). Using a rotary die press, the product was die-cut into individual adhesive strips.

Example lc : Manufacture of the second drug active laminate (Laver D)

A 3 kg wet blend was prepared by charging naltrexone base, Povidone K90, ethyl acetate and ethyl alcohol to a 3 kg glass container. Heat and mix at 55°C for about 1 hour until a clear solution is formed. Duro- Tak ^® 387-2510, Brij ^® CS20-SO-MH and Bio-PSA ^® 7-4302 were added and mixed. The procedure was repeated to prepare six 3 kg wet blends. The six 3 kg wet blends were transferred to a 10 gallon mixer bowl and mixed until uniform. The wet blend was transferred from the 10 gallon mixer to six 3 kg containers. The 3 kg containers were placed onto a roller and rolled to remove air bubbles. In-process testing was performed: Description, Blend CU and Viscosity. To form Second Drug Layer Adhesive Laminates of 105 GSM coat weight, the wet blend was coated onto release liner Scotchpak™ 9755 in the continuous coater with slot-die coating knife and three zone drying ovens at 0.3 meter/min web speed and zone temperature (zone 1: ~65°C, zone 2: ~85°C and zone 3: ~109°C) and laminated to Barrier film Scotchpak™ 9735 to form the Second Drug Intermediate Laminate. In a Slitter machine, wide laminate was slit from the coater to a narrower laminate. In a Converter machine, the release liner (Scotchpak™ 9755) was removed and the drug-adhesive layer was laminated to silicone coated elastic polyester fabric KOB051 backing. Using a rotary die press, the product was die- cut into individual second drug layer patches.

Example Id: Integration of the second drug active laminate, skin contact active laminate and skin contact adhesive laminate

The second drug layer patch was placed on a vacuum board with the barrier film (Scotchpak™ 9735) facing up. One release liner (SG4130) was removed from the skin contact adhesive strip. The adhesive layer was adhered to the right side of the second drug patch. One release liner (Scotchpak™ 9755) was removed from the skin contact central active strip. The adhesive layer was adhered to the center of the second drug layer. One release liner (SG4130) was removed from a second skin contact adhesive strip. The adhesive layer was adhered to the left side of the second drug layer. In other embodiments, a spacer was provided between the central active strip and each of the skin contact adhesive strips. All 3 release liners (Scotchpak™ 1022, Scotchpak™ 9744 and Scotchpak 1022) were removed from the three strips already adhered on the barrier film (Scotchpak™ 9735). One oversized release liner (Scotchpak™ 9755) was laminated to the left side. A second piece of release liner (Scotchpak™ 9755) was laminated to the right side of the patch overlapping the first piece of the same release liner. One patch was inserted into an open pouch and the pouch was sealed.

Example 2: Manufacture of a Transdermal Dosage System Comprising Fentanyl and Naltrexone

The transdermal dosage system as depicted in Figures 1 and 2 was manufactured using a process having four steps. For each of the first three steps, a wet blend was coated onto an in-process release liner, dried and laminated to another release liner or backing layer, resulting in intermediate elongated skin contact active strips and elongated skin contact adhesive strips which are laminated to temporary/in-process release liners on both sides, and a second drug naltrexone base strip that is laminated to a temporary/in- process release liner on one side and laminated to the woven backing layer on the other side. During the last two steps of the manufacturing process, each of the elongated intermediate skin contact laminate strips were laminated to a barrier film, leaving a spacer of about 1.0mm between the skin contact adhesive strips and the skin contact central active strip. The in-process release liners were replaced with a final release liner. The intermediate release liner was removed from the second drug laminate and laminated to barrier film. The combined laminate is then die-cut to the appropriate patch size.

All materials and system layout are the same as provided in Table 1.

Example 2a : Manufacture of the skin contact active laminate (Laver B)

Naltrexone hydrochloride suspension was prepared in three silicone adhesives, Bio-PSA ^® 7-4301 Bio- PSA ^® 7-4302 and Bio-PSA ^® 7-4202. Bio-PSA ^® 7-4301 and Bio-PSA ^® 7-4202 were mixed in a mixer bowl. The mixture was cooled to approximately 20°C and naltrexone hydrochloride and Bio-PSA ^® 7-4302 were added. The mixture was homogenized to form a uniform suspension. In a separate mixer bowl, fentanyl and povidone solution were prepared in a mixed solvent of ethanol and ethyl acetate, heated to approximately 50°C and mixed to form a clear, viscous solution. The final wet blend was prepared by adding the naltrexone hydrochloride suspension to the mixer bowl containing fentanyl and povidone K90 solution and mixing at a low speed for a minimum of 4 hours.

The final wet blend was transferred to four glass containers. The containers were placed in jar rollers and rotated at a slow speed to remove air bubbles and to keep the naltrexone hydrochloride crystals uniformly suspended.

To form Skin Contact Layer Active Laminate Strips of 105 GSM coat weight, the final wet blend was coated to a fluoropolymer coated polyester in-process release liner (Scotchpak™ 1022) in a continuous coater with slot-die coating knife and three-zone drying ovens at 0.3 meter/min web speed and zone temperatures (zone 1: ~85°C, zone 2: ~115°C and zone 3: 115°C) and laminated to a fluoropolymer coated polyester in-process release liner (Scotchpak™ 9755). The product was slit into elongated strips having the appropriate central active strip width during the laminate fabrication process. Note that the product may be also separately using a slitting machine.

Example 2b : Manufacture of the skin contact adhesive laminate (Layer B)

Duro-Tak ^® 87-4287 and ethyl acetate were loaded into a mixer bowl and mixed for approximately 30 min. Titanium dioxide was added to the mixer bowl and homogenized to form a uniform suspension.

To form Skin Contact Layer Adhesive Laminates of 105 GSM coat weight, wet blend was coated onto an in-process polyester release liner with a silicone coating (SG4130) in the continuous coater with slot-die coating knife and three-zone drying ovens at 0.3 meter/min web speed and zone temperature (zone 1: ~65°C, zone 2: ~85°C and zone 3: ~109°C) and laminated to an in-process fluoropolymer coated polyester release liner (Scotchpak 1022). Using a slitting machine, the product was slit into elongated strips having the appropriate strip width.

Example 2c : Manufacture of the second drug active laminate (Laver D) A 3 kg wet blend was prepared by charging naltrexone base, Povidone K90, ethyl acetate and ethyl alcohol to a 3 kg glass container. Heat and mix at 55°C for about 1 hour until a clear solution is formed. Duro- Tak ^® 387-2510, Brij ^® CS20-SO-MH and Bio-PSA ^® 7-4302 were added and mixed. The procedure was repeated to prepare six 3 kg wet blends. The six 3 kg wet blends were transferred to a 10 gallon mixer bowl and mixed until uniform. The wet blend was transferred from the 10 gallon mixer to six 3 kg containers. The 3 kg containers were placed onto a roller and rolled to remove air bubbles. In-process testing was performed: Description, Blend CU and Viscosity.

To form Second Drug Layer Adhesive Laminates of 110 GSM coat weight, the wet blend was coated onto release liner Scotchpak™ 1022 in the continuous coater with slot-die coating knife and three zone drying ovens at 0.3 meter/min web speed and zone temperature (zone 1: ~65°C, zone 2: ~85°C and zone 3: ~109°C) and laminated to the non-coated elastic polyester fabric KOB051 backing film to form the Second Drug Intermediate Laminate.

Example 2d: Integration of the second drug active laminate, skin contact active laminate and skin contact adhesive laminate

A release liner was removed from one side of an elongated skin contact active strip, and the strip was laminated to the center of a Barrier film Scotchpak™ 9735 as described in Figure 3. Concurrently, release liner was removed from one side of the two elongated skin contact adhesive strips, and laminated to the Barrier film Scotchpak™ 9735 on both sides of the previously laminated center active strip, as described in Figure 3. A spacer of about 1.0mm was provided between the skin contact adhesive strips and the skin contact central active strip. The remaining release liners (Scotchpak™ 1022, Scotchpak™ 9755) were removed from the three strips already adhered on the barrier film (Scotchpak™ 9735) and replaced with a single Scotchpak™ 9755 release liner to complete skin contact laminate, as described in Figure 4. The in- process release liner Scotchpak™ 1022 was removed from the second drug naltrexone laminate and the laminate was laminated to the barrier film on the distal side from the skin contact laminate, as described in Figure 4. Using a rotary dies, the product was die-cut into individual patches, V shaped notch was formed in the final release liner, and then pouched.

Example 3: Manufacture of a Transdermal Dosage System Comprising of Fentanyl and Naltrexone

The transdermal dosage system as depicted in Figures 1 and 2 was manufactured using a three step process. For the first step, a wet blend was coated onto a barrier film, dried and laminated to a backing film. After lamination the material is collected as an in-process roll material for further processing. The second step includes two wet blends coated such that there is a 1mm spacer between each of the two wet blends simultaneously onto a liner which is dried and laminated to the material produced in the first step. The third step is cutting the combined laminate into the appropriate patch size followed by pouching.

Example 3a: Manufacture of the second drug active laminate

An 80kg wet blend was prepared by adding naltrexone base, Povidone K90, Brij ^® CS20-SO-MH, ethyl acetate and ethyl alcohol to a mixer bowl. Heat and mix at 55°C for about 2 hours until a clear solution is observed. Duro-Tak ^® 387-2510, and Bio-PSA ^® 7-4302 were added and mixed.

The Second Drug Adhesive Laminate is formed by casting or coating the wet blend directly onto the barrier film (Scotchpak™ 9754) in a continuous coating process using a target coating weight of 110 GSM. The wet blend is applied to the barrier layer using a slot die and conveyed into a two zone drying oven at approximately 3.0 feet /min web speed and zone temperature (zone 1 ~120°C and zone 2 ~140°C). The dried material exits the oven and is then laminated to the polyester fabric KOB 051 backing film to form the second drug intermediate laminate.

Example 3b: Manufacture of the skin contact adhesive laminate integrated with the second drug active laminate

A 50kg naltrexone hydrochloride wet blend was prepared using three silicone adhesives, Bio-PSA ^® 7-4301 Bio-PSA ^® 7-4302 and Bio-PSA ^® 7-4202. Bio-PSA ^® 7-4301 and Bio-PSA ^® 7-4202 were mixed in a mixer bowl. The mixture was cooled to approximately 20°C and naltrexone hydrochloride, titanium dioxide and Bio-PSA ^® 7-4302 were added. The mixture was homogenized to form a uniform suspension. In a separate mixer bowl, a fentanyl and povidone solution was prepared in a solvent mixture mixed of ethanol and ethyl acetate, heated to approximately 50°C and mixed to form a clear, viscous solution. The final wet blend was prepared by adding the naltrexone hydrochloride suspension to the mixer bowl containing fentanyl and povidone K90 solution and mixing at a low speed for a minimum of 4 hours.

A 40kg adhesive side strip wet blend was prepared by combining Duro-Tak ^® 87-4287 and ethyl acetate in a mixer bowl and mixed for approximately 30 min. Titanium dioxide was added to the mixer bowl and homogenized for approximately 60 minutes to form a uniform suspension.

The Skin Contact Layer Adhesive Laminate is produced by simultaneously coating or applying the fentanyl/naltrexone hydrochloride wet blend and adhesive side strip wet blend onto release liner (Scotchpak™ 9755) in a continuous coating process using a multi-cavity slot die whereby the two separate wet blends are zone coated at 105 GSM. The multi-cavity slot die determines the 1mm gap between each adhesive wet blend. The zone coated material is conveyed into a two zone drying oven at approximately 1.5 feet /min web speed and zone temperature (zone 1 ~85°C and zone 2 ~135°C). The dried material exits the oven and is laminated to the second drug active laminate positioned so the barrier film material is laminated to the skin contact adhesive material forming the combined laminate material.

Example 3c: Manufacture of a Transdermal Dosage System Comprising of Fentanyl and Naltrexone

The combined laminate material is unwound and passes through a kiss-cut die station where the backing film/adhesive layers are cut in a rectangular pattern. The release liner containing kiss-cut drug layer is then passed through a thru-cut die station where the system card with V-shaped notches are formed in the final release liner. Systems are then transferred onto an incoming lower pouching material. A top pouching material is then brought above the transdermal dosage system and heat sealed (Upper sealing temperature ~350°F and lower sealing temperature ~300°F, heat seal pressure ~70psi, dwell ~0.7 sec) forming individual pouched transdermal systems.

Example 4: Stability tests of transdermal Dosage System Comprising Fentanyl and Naltrexone

The present experimental example provides stability tests of the transdermal Dosage Systems manufactured as described in example 1 and example 2, which include a 1mm spacer between the central active strip and each of the two skin contact adhesive strips.

Example 4a : In vitro Stability test: cold flow tested by the percent increase in patch size area

Patches of various strengths (12.5 mcg/h, 25 mcg/h and 100 mcg/h) made by the process as described in example 1 including a spacer which is a void between the active agent-containing strip and the adhesive strips were stored at normal storage conditions (25°C ± 2°C/60% RH ± 5% RH) for six months. At six months, patch area was measured and compared to area after manufacture.

The results for the 12.5 mcg/h strength are presented in Table 2, for the 25 mcg/h in Table 3 and for the 100 mcg/h strength in Table 4.

Table 2

*AM=area exceeding the intended patch area

**AT=intended patch area Table 3

*AM=area exceeding the intended patch area

**AT=intended patch area

Table 4

*AM=area exceeding the intended patch area

**AT=intended patch area

Example 4b : In vitro Stability test: migration of Fentanyl and Naltrexone from the active agent drug layer to the adhesive strip during storage The transdermal Dosage System manufactured as described in examples 1 and 2 including a spacer which is a void between the active agent-containing strip and the adhesive strips is tested for the presence of the active agent (fentanyl) and the antagonist (naltrexone) in the adhesive strips at shelf life.

Patches made by the process as described in example 1 and 2 including a spacer (e.g. void) are stored at normal storage conditions (25°C ± 2°C/60% RH ± 5% RH). After each indicated time (At 1, 2, 3, 30, 90, 180 and 365 days; 10 patches per time point), the patches are collected, adhesive strips are separated from patch and tested for the presence of fentanyl and naltrexone.

Example 4c : In vivo Stability test: migration of Fentanyl and Naltrexone from the active agent drug layer to the adhesive strip after transdermal usage in health subjects

The transdermal Dosage System manufactured as described in examples 1 and 2 including a spacer which is a void is tested for the presence of the active agent (fentanyl) and the antagonist (naltrexone) in the adhesive strips after transdermal administration.

Healthy subjects are transdermally administered patches made by the process as described in example 1 and 2 including a spacer which is a void At each time point (3, 6, 12, 24, 36, 48 and 73 hours; 30 subjects per each time point), the patches are collected from the subjects, adhesive strips are separated from the patch and tested for the presence of fentanyl and naltrexone.

Results

The results of Example 3b show that the adhesive strip remains substantially free of the active agent and the antagonist, specifically fentanyl and naltrexone, for at least about 24 hours, at least about 48 hours, at least 72 hours, at least about one month, at least about three months, at least about six months or at least about 1 year of storage/shelf life.

The results of Example 3c show that the adhesive strip remains substantially free of the active agent and the antagonist, specifically fentanyl and naltrexone, for at least 3 hours, at least 24 hours, at least 36 hours, at least 48 hours or at least 72 hours after transdermal administration.

Therefore, the results example 3a 3b and 3c, as a whole, show that there is no migration, or negligible migration of the active agent and/or the antagonist from the reservoir to the adhesive strips.

The results of Example 3a show that patches in the strengths 12.5 mcg/h, 25 mcg/h and 100 mcg/h presented not more than 0.42%, not more than 0.12% and not more than 0.09% increase, respectively, in patch area, after about 6 months of shelf life in normal storage conditions. As a whole, the patches presented not more than 0.50% increase in patch area after about six months in normal storage conditions.

Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the disclosure and that such changes and modifications can be made without departing from the spirit of the disclosure. It is, therefore, intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the disclosure.