WO2020008370A1 - Timbre transdermique - Google Patents

Timbre transdermique Download PDF

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Publication number
WO2020008370A1
WO2020008370A1 PCT/IB2019/055650 IB2019055650W WO2020008370A1 WO 2020008370 A1 WO2020008370 A1 WO 2020008370A1 IB 2019055650 W IB2019055650 W IB 2019055650W WO 2020008370 A1 WO2020008370 A1 WO 2020008370A1
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WO
WIPO (PCT)
Prior art keywords
transdermal dosage
drug layer
antagonist
active agent
dosage system
Prior art date
Application number
PCT/IB2019/055650
Other languages
English (en)
Inventor
Luke WERRETT
Benjamin David DIEKER
James Marcus MOESSER
Original Assignee
Clexio Biosciences Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Clexio Biosciences Ltd. filed Critical Clexio Biosciences Ltd.
Publication of WO2020008370A1 publication Critical patent/WO2020008370A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7092—Transdermal patches having multiple drug layers or reservoirs, e.g. for obtaining a specific release pattern, or for combining different drugs

Definitions

  • the present disclosure relates to transdermal dosage forms containing large amounts/high loads of active agent(s) and processes of manufacture thereof.
  • 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.
  • 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.
  • transdermal dosage forms having improved adhesion and processes of manufacture thereof.
  • 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
  • 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.
  • 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.
  • 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.
  • transdermal dosage form is 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.
  • an active agent such as a pharmaceutical agent, e.g., an opioid
  • transmucosal refers to buccal, nasally, sublingual, topical, rectal, and/or vaginal.
  • uccal administration refers to a topical route of administration by which a composition is held or applied to the buccal area of the inner cheek.
  • 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.
  • the "patient” or “animal” or mammal is a human.
  • 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.
  • 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.
  • 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.
  • two forms of naltrexone are present in the transdermal dosage form.
  • the naltrexone is in the form of its free base.
  • the naltrexone is in the form of its HCI salt.
  • biological effect refers to a physical reaction in a patient.
  • the effect is analgesic, euphoria, respiratory, anti-depressive, or combinations thereof.
  • 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.
  • 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-)
  • 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-
  • 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.
  • the active agent may be utilized in any solid state form such as amorphic or polymorphic form of the active agent.
  • the active agent is amorphous.
  • the active agent is crystalline.
  • 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.
  • the active agent such as fentanyl is in the form of a base.
  • the active agent such as fentanyl base is in amorphous form when formulated with excipients in the final transdermal dosage form.
  • the antagonist such as Naltrexone is in salt form such as HCI.
  • the antagonist such as Naltrexone salt is in micronized form.
  • the micronized Naltrexone salt is maintained in crystalline form within the transdermal dosage form.
  • the transdermal dosage form comprises crystalline ionic antagonist such as Naltrexone salt, admixed with povidone and silicone.
  • the antagonist such as Naltrexone is in base form.
  • the antagonist such as Naltrexone base is in amorphous form when formulated with excipients in the final transdermal dosage form.
  • 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.
  • 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.
  • the prodrugs are esters.
  • 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.
  • 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.
  • the proximal surface of a component can be either continuous or discontinuous.
  • 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.
  • 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.
  • the distal surface of a component can be either continuous or discontinuous.
  • 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.
  • central 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.
  • 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.
  • final size of a component refers to the area of that component in the complete/final patch.
  • the “final size” is the area of the complete/final patch.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • treatment of pain includes reduction of pain intensity, amelioration of pain or the cessation of pain in an animal.
  • prevention of pain includes the avoidance of the onset of pain in an animal.
  • the phrase "dispersed” unless otherwise specified refers to dispersed, mixed, and/or dissolved either homogenously and/or heterogeneously.
  • 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.
  • porous medium and “porous material” are used interchangeably.
  • drug layer 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.
  • a drug layer is a layer or strip of the transdermal dosage system.
  • 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.
  • second drug layer refers to a compartment, layer or strip of a transdermal dosage system which contains one or more active or adverse agents.
  • said second drug layer is a layer or strip of the transdermal dosage system.
  • 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.
  • a drug e.g. the active agent and/or an antagonist
  • 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.”
  • 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.
  • substantially free of an active agent and/or antagonist 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.
  • 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.
  • 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.
  • normal storage conditions are storage/stability testing at 25°C ⁇ 2°C/60% RH (relative humidity) ⁇ 5% RH.
  • resistant to transdermal absorption 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.
  • the patch is flexible.
  • the transdermal dosage system moves as the skin of the patient moves.
  • the transdermal dosage system does not become displaced from the patient as the skin moves or shifts.
  • micronized refers to particles wherein the particles are about 10 pm or less in diameter.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • transdermal dosage form having reduced potential for abuse comprising fentanyl and more than one naltrexone layers.
  • a transdermal dosage form comprises fentanyl, a first naltrexone component, and a second naltrexone component.
  • the drug layer comprises naltrexone in the form of a pharmaceutically acceptable salt
  • the second drug layer comprises naltrexone in the form of a pharmaceutically acceptable base.
  • 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.
  • 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.
  • 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.
  • the proximal surface of the drug layer has an area of about 5 to about 150 cm 2 .
  • the surface area of the dosage form is about 5 to about 60 cm 2 .
  • the surface area of the dosage form is about 25 to about 35 cm 2 or about 100 to about 125 cm 2 .
  • the transdermal dosage form releases about 10 to about 100 pg of fentanyl per hour to skin.
  • 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.
  • the transdermal dosage form comprises fentanyl base or alkaloid in an amount of about 1 to about lOmg.
  • 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.
  • 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.
  • 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.
  • naltrexone from the system when used transdermally, is controlled so that antagonist levels are sufficiently low while maintaining fentanyl's effect.
  • 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.
  • 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.
  • a permeable backing layer 150 is adjacent to the second drug layer 140.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the dosage form is provided such that the naltrexone is not absorbed to any biologically significant degree into a blood stream when administered transdermally.
  • 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.
  • the dosage form is provided such that the ratio of naltrexone to fentanyl in the dosage form is more than 3:1.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the fentanyl or naltrexone is preferably dispersed substantially homogeneously throughout a polymeric material.
  • the fentanyl or naltrexone is dissolved in the polymeric material.
  • fentanyl is substantially in amorphous form.
  • the naltrexone includes a crystalline form substantially dispersed throughout the polymeric material.
  • the polymeric matrix is a pressure sensitive adhesive (PSA).
  • PSA pressure sensitive adhesive
  • 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • 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.
  • 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.
  • polystyrene resin examples include ally I acrylate, allyl methacrylate, diallyl maleate, and the like.
  • 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.
  • 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.
  • the fentanyl or naltrexone can be mixed with a carrier, such as a viscous liquid, semi-solid or gel material.
  • 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.
  • 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 glyco
  • the skin penetration enhancers, drug solubilizers, plasticizers, and other additives can be dispersed or mixed, optionally substantially uniformly, or optionally dissolved in the composition.
  • 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.
  • 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.
  • 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%.
  • polyvinylpyrrolidone (PVP) is used.
  • 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.
  • 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 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.
  • the barrier layer comprises polyester such as PET laminated to a polymer such as polyurethane, polyethylene, and ethylene copolymers.
  • the barrier layer comprises polyester such as PET laminated to ethylene copolymers such as ethylene-vinyl acetate copolymer (EVA).
  • EVA ethylene-vinyl acetate copolymer
  • 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.
  • 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.
  • the backing is non-sticking and hydrophobic.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the transdermal dosage form 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.
  • 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.
  • 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.
  • an abuser may attempt to extract the fentanyl from the transdermal dosage form with a solvent, such as a liquid or gas.
  • the dosage form when tampered with in such a manner, will release both naltrexone and fentanyl.
  • 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.
  • 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.
  • 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.
  • the transdermal dosage form is present in a container, e.g., a box.
  • the kit further comprises a set of instructions directing the use of the transdermal dosage form to treat a patient, e.g., for pain.
  • the instructions may be a printed label affixed to or printed on the container.
  • 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.
  • a drug e.g. an active agent and/or antagonist
  • 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).
  • 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 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.
  • 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).
  • the adhesive strips have about the same width as the drug-adhesive strip.
  • 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.
  • migration of the drug into the adhesive strips may compromise adhesion.
  • 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.
  • 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.
  • 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.
  • 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.
  • the layer is a barrier layer.
  • the layer is a backing layer, for example in a single drug layer patch.
  • the adhesive strip 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.
  • 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.
  • 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.
  • 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,
  • 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.
  • 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 .
  • 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.
  • the transdermal dosage system comprises a second drug layer comprising a second antagonist.
  • 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.
  • the drug layer comprises an active agent and a first antagonist
  • the transdermal dosage system comprises a second drug layer including a second antagonist
  • 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.
  • the active agent is at least one opioid agonist, e.g. fentanyl or a pharmaceutically acceptable salt thereof.
  • 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.
  • the drug layer comprises at least one adhesive, which may be a pressure sensitive adhesive.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the two adhesive laminates and the drug layer laminate are die-cut to their final size after lamination to the barrier.
  • the second drug layer laminate is die-cut to its final size after lamination to the barrier.
  • 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.
  • the at least two adhesive laminate is two adhesive laminates.
  • the two adhesive laminates are laminated to the barrier externally to the drug layer laminate at two opposing sides.
  • 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.
  • 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.
  • the two adhesive laminates and the drug layer laminate are die-cut to their final size after lamination to the barrier.
  • the second drug layer laminate is die-cut to its final size after lamination to the barrier.
  • the two adhesive laminates, the drug layer laminate and the second drug layer laminate are die-cut to their final size concurrently.
  • the drug layer further comprises at least one adhesive, for example a PSA, which may be silicone based PSA.
  • the drug layer comprises a first antagonist.
  • the second drug layer comprises a second antagonist.
  • the active agent is at least one opioid agonist.
  • the active agent is fentanyl or a pharmaceutically acceptable salt thereof.
  • the active agent is other than an opioid agonist.
  • the first antagonist is in salt form.
  • the second antagonist is in free base form and the free base may be in amorphous form.
  • first antagonist and the second antagonist are the same antagonist and the second antagonist is in free base form.
  • 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.
  • the transdermal dosage form further comprises a permeable backing layer distal to the second drug layer.
  • the proximal surface of the drug layer comprises a release liner.
  • the drug layer comprises one or more skin penetration enhancer, which may be polyvinylpyrrolidone.
  • 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.
  • the drug layer includes a silicone or an acrylic adhesive.
  • 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.
  • the first antagonist and the active agent are in a homogenous mixture.
  • 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.
  • the first antagonist and the second antagonist are both naltrexone or a pharmaceutically acceptable salt thereof.
  • 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,
  • 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.
  • the drug layer further comprises at least one adhesive, which may be a pressure sensitive adhesive.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the final wet blend was coated to a fluoropolymer coated polyester in-process release liner (ScotchpakTM 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 (ScotchpakTM 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.
  • 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 (ScotchpakTM 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).
  • 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.
  • Second Drug Layer Adhesive Laminates of 105 GSM coat weight
  • the wet blend was coated onto release liner ScotchpakTM 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 ScotchpakTM 9735 to form the Second Drug Intermediate Laminate.
  • zone 1 ⁇ 65°C
  • zone 2 ⁇ 85°C and zone 3: ⁇ 109°C
  • Barrier film ScotchpakTM 9735 to form the Second Drug Intermediate Laminate.
  • wide laminate was slit from the coater to a narrower laminate.
  • the release liner (ScotchpakTM 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 (ScotchpakTM 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 (ScotchpakTM 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.
  • a spacer was provided between the central active strip and each of the skin contact adhesive strips.
  • 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.
  • 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.
  • 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.
  • the final wet blend was coated to a fluoropolymer coated polyester in-process release liner (ScotchpakTM 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 (ScotchpakTM 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.
  • 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.
  • Second Drug Layer Adhesive Laminates of 110 GSM coat weight
  • the wet blend was coated onto release liner ScotchpakTM 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 ScotchpakTM 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 ScotchpakTM 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.
  • release liners ScotchpakTM 1022, ScotchpakTM 9755
  • the in- process release liner ScotchpakTM 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.
  • 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.
  • 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
  • the Second Drug Adhesive Laminate is formed by casting or coating the wet blend directly onto the barrier film (ScotchpakTM 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.
  • 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 (ScotchpakTM 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.
  • 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 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.
  • a spacer e.g. void
  • 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
  • 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.
  • 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.
  • 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.
  • results example 3a 3b and 3c show that there is no migration, or negligible migration of the active agent and/or the antagonist from the reservoir to the adhesive strips.
  • 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.

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Abstract

L'invention concerne un système galénique transdermique comprenant une couche de contact avec la peau comprenant une couche de médicament et une bande adhésive située à l'extérieur de la couche de médicament.
PCT/IB2019/055650 2018-07-02 2019-07-02 Timbre transdermique WO2020008370A1 (fr)

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Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4539256A (en) 1982-09-09 1985-09-03 Minnesota Mining And Manufacturing Co. Microporous sheet material, method of making and articles made therewith
US4693776A (en) 1985-05-16 1987-09-15 Minnesota Mining And Manufacturing Company Macromer reinforced pressure sensitive skin adhesive
US5149538A (en) 1991-06-14 1992-09-22 Warner-Lambert Company Misuse-resistive transdermal opioid dosage form
US5236714A (en) 1988-11-01 1993-08-17 Alza Corporation Abusable substance dosage form having reduced abuse potential
US5474783A (en) 1988-03-04 1995-12-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US5585111A (en) 1993-12-08 1996-12-17 Minnesota Mining And Manufacturing Company Transdermal delivery device
US5985317A (en) 1996-09-06 1999-11-16 Theratech, Inc. Pressure sensitive adhesive matrix patches for transdermal delivery of salts of pharmaceutical agents
WO2002041878A2 (fr) * 2000-11-16 2002-05-30 Euro-Celtique, S.A. Systeme d'administration transdermique de doses titrables
US20030026829A1 (en) 2001-03-16 2003-02-06 Venkatraman Subramanian S. Transdermal administration of fentanyl and analogs thereof
US20040126323A1 (en) 2002-08-20 2004-07-01 Ihor Shevchuk Transdermal dosage form comprising an active agent and a salt and free-base form of an adverse agent
US20040176402A1 (en) * 2000-02-08 2004-09-09 Benjamin Oshlack Controlled-release compositions containing opioid agonist and antagonist
US20040219195A1 (en) * 2003-04-30 2004-11-04 3M Innovative Properties Company Abuse-resistant transdermal dosage form
US20050095279A1 (en) * 2003-10-30 2005-05-05 Gale Robert M. Transdermal analgesic systems having reduced abuse potential
US20060198881A1 (en) * 2003-04-30 2006-09-07 Purdue Pharma L.P. Tamper resistant transdermal dosage form
US20060257460A1 (en) * 2005-05-13 2006-11-16 Jansen Rolf R Multilayer drug delivery system with barrier against antagonist exposure
US7182955B2 (en) 2003-04-30 2007-02-27 3M Innovative Properties Company Abuse-resistant transdermal dosage form
US20100076198A1 (en) 2008-09-19 2010-03-25 Mallinckrodt Inc. Crystalline forms of Fentanyl Alkaloid
US8747889B2 (en) 2002-04-23 2014-06-10 Durect Corporation Transdermal analgesic systems with reduced abuse potential
US20170209429A1 (en) * 2014-07-18 2017-07-27 Buzzz Pharmaceuticals Limited Abuse deterrent opiod/opiod-antagonist transdermal patch

Patent Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4539256A (en) 1982-09-09 1985-09-03 Minnesota Mining And Manufacturing Co. Microporous sheet material, method of making and articles made therewith
US4693776A (en) 1985-05-16 1987-09-15 Minnesota Mining And Manufacturing Company Macromer reinforced pressure sensitive skin adhesive
US5474783A (en) 1988-03-04 1995-12-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US5236714A (en) 1988-11-01 1993-08-17 Alza Corporation Abusable substance dosage form having reduced abuse potential
US5149538A (en) 1991-06-14 1992-09-22 Warner-Lambert Company Misuse-resistive transdermal opioid dosage form
US5585111A (en) 1993-12-08 1996-12-17 Minnesota Mining And Manufacturing Company Transdermal delivery device
US5985317A (en) 1996-09-06 1999-11-16 Theratech, Inc. Pressure sensitive adhesive matrix patches for transdermal delivery of salts of pharmaceutical agents
US20040176402A1 (en) * 2000-02-08 2004-09-09 Benjamin Oshlack Controlled-release compositions containing opioid agonist and antagonist
WO2002041878A2 (fr) * 2000-11-16 2002-05-30 Euro-Celtique, S.A. Systeme d'administration transdermique de doses titrables
US20030026829A1 (en) 2001-03-16 2003-02-06 Venkatraman Subramanian S. Transdermal administration of fentanyl and analogs thereof
US8747889B2 (en) 2002-04-23 2014-06-10 Durect Corporation Transdermal analgesic systems with reduced abuse potential
US20040126323A1 (en) 2002-08-20 2004-07-01 Ihor Shevchuk Transdermal dosage form comprising an active agent and a salt and free-base form of an adverse agent
US20040219195A1 (en) * 2003-04-30 2004-11-04 3M Innovative Properties Company Abuse-resistant transdermal dosage form
US20060198881A1 (en) * 2003-04-30 2006-09-07 Purdue Pharma L.P. Tamper resistant transdermal dosage form
US7182955B2 (en) 2003-04-30 2007-02-27 3M Innovative Properties Company Abuse-resistant transdermal dosage form
US8790689B2 (en) 2003-04-30 2014-07-29 Purdue Pharma L.P. Tamper resistant transdermal dosage form
US20050095279A1 (en) * 2003-10-30 2005-05-05 Gale Robert M. Transdermal analgesic systems having reduced abuse potential
US20060257460A1 (en) * 2005-05-13 2006-11-16 Jansen Rolf R Multilayer drug delivery system with barrier against antagonist exposure
US20100076198A1 (en) 2008-09-19 2010-03-25 Mallinckrodt Inc. Crystalline forms of Fentanyl Alkaloid
US20170209429A1 (en) * 2014-07-18 2017-07-27 Buzzz Pharmaceuticals Limited Abuse deterrent opiod/opiod-antagonist transdermal patch

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