WO1993007842A1 - Amelioration par voie thermique de l'administration percutanee de medicaments - Google Patents

Amelioration par voie thermique de l'administration percutanee de medicaments Download PDF

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Publication number
WO1993007842A1
WO1993007842A1 PCT/US1992/008519 US9208519W WO9307842A1 WO 1993007842 A1 WO1993007842 A1 WO 1993007842A1 US 9208519 W US9208519 W US 9208519W WO 9307842 A1 WO9307842 A1 WO 9307842A1
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WO
WIPO (PCT)
Prior art keywords
skin
drug
area
flux
temperature
Prior art date
Application number
PCT/US1992/008519
Other languages
English (en)
Inventor
Donald R. Wilson
Renee A. Fallon
Original Assignee
Cygnus Therapeutic Systems
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 Cygnus Therapeutic Systems filed Critical Cygnus Therapeutic Systems
Publication of WO1993007842A1 publication Critical patent/WO1993007842A1/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
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates

Definitions

  • This invention is in the field of transdermal drug administration. More particularly it relates to methods and devices in which the flux of the drug through the skin is increased by heating the device and the area of skin underlying the device.
  • U.S. 4,685,911 describes a skin patch in which the drug formulation contains a "base" that is a solid at normal temperature. It is indicated that it is desirable that the base be in a melted form while the patch is being worn.
  • Col. 3 of the patent indicates that if the base is composed of compounds that do not melt at normal body temperature, then the device may include a heating element to heat the patch to temperatures at which such compounds melt. Accordingly, heat is used in this patent to melt a normally solid component of the device, not to enhance the flux of the drug through the skin.
  • U:S. 4,747,841 describes a moxibustion device. Moxibustion involves oxidizing (burning) moxa and transporting the combustion vapors through the skin.
  • Th patented device is a skin patch that includes an in situ pyrogen that is oxidized to heat the oxa and form the combustion products.
  • the basal surface of the device is defined by a gas-permeable fabric that acts as thermal insulation.
  • This patent thus uses in situ-qener ted hea to combust moxa to form vapors that are easily absorbed through the skin. Heat is not used to increase the flux of nonvaporous materials through the skin.
  • 4,830,855 describes a transdermal drug delivery device that employs a side-chain crystallizable polymer diffusion matrix.
  • the polymer undergoes a phase transition (melts) at a given temperature, below which it is impermeable to drug and above which it is substantially permeable to the drug.
  • the device is heated either by external or internal means to cause the matrix to melt and become permeable to the drug. Accordingly, heat in this device is used to melt a component of the device so that the component becomes permeable. Heat is not used to enhance the diffusion of the drug through the skin.
  • the present invention is particularly useful for administering drug types that are most efficacious when administered in an initial pulse or burst that affords a rapid onset of therapeutically effective blood levels.
  • drug types are analgesics, sedatives, anti-emetics, appetite suppressants, anti-anxiety drugs, and anti-depressants.
  • Applicants are aware of two prior transdermal device designs that have been proposed for providing an administration regime that is initiated by a pulse. Neither of them involves heating the device and/or the area of skin underlying the device.
  • SUBSTITUTI contained, an underlying rate-controlling membrane that controls the release rate of the drug from the reservoir, and a basal adhesive layer that is loaded with drug.
  • the drug in the adhesive migrates rapidly into the skin providing a "burst.” The burst is followed by the controlled delivery of drug from the reservoir via the rate- controlling membrane.
  • the second design is described in U.S. Patent No. 4,698,062. It uses a first reservoir • which contains a sufficient amount of the drug to provide a baseline flux over the entire administration period and a second reservoir which contains a permeation enhancer in an amount that is sufficient to provide enhancement only during the beginning of the administration period.
  • the magnitude and duration of the period of enhanced drug flux is apparently dependent only upon the amount of enhancer contained in the second reservoir and its effect on skin flux.
  • the patent indicates that this pattern of drug release may be achieved with various enhancers including ethanol, n- decylmethylsulfoxide, dimethyl lauramide, and polyethylene glycol monolaurate.
  • Another aspect of the invention is a device for administering a thermally stable drug transdermally through an area of unbroken human skin comprising in combination:
  • Figure 1 is an elevated cross-section (not to scale) of one embodiment of the invention.
  • Figure 2 is an elevated cross-section (not to scale) of a second embodiment of the invention.
  • Figure 3 is an elevated cross-section (not to scale) of a third embodiment of the invention.
  • Figure 4 is a graph of the results of the skin flux tests described in the example. Modes for Carrying Out the Invention
  • drug intends a biologically active compound or mixture of compounds that has a therapeutic, prophylactic, or other beneficial effect on the wearer of the device. It is particularly useful for administering drugs where a rapid onset of efficacy is desired.
  • drugs examples include: sedatives, hypnotics and antianxiety agents such as diazepa , midazolam, lorzipam and alprazolam; barbituates such as pentobarbital and secobarbital; antihistamines such as hydroxyzine, diphenhydramine, promethazine and propiomazine; buterophenones such as droperidol; opioids such as morphine, meperidine, fentanyl, sufentanyl, and alfentanyl; antiemetics such as droperidol, hydroxyzine, benzquinamine, scopolamine, and cyclizine; anticholinergic drugs such as atropine, scopolamine, and glycopyrrolate; and alpha 2 agonists such as clonidine and dexmedetomidine.
  • antihistamines such as hydroxyzine, diphenhydramine, promethazine and propiomazine
  • buterophenones such as drop
  • flux intends the rate of transfer of drug across skin as measured by the in vitro human cadaver skin tests described in Medical Device and Diagnostic Industry (1985) 8.:35-42, with the proviso that the temperature at which the test is carried out may be altered per the invention.
  • the units of flux are preferably expressed as ⁇ g/cm 2 /hr.
  • thermally stable intends a drug that has no substantial chemical reactivity with the other components of the device or the surrounding environment (e.g., air) and does not degrade or otherwise alter its chemical or physical nature at the temperatures to which the device is heated per the invention.
  • normal skin temperature intends that range of temperatures in which healthy living human skin exists under normal living conditions. This range is normally 35 to 37°C.
  • predetermined time period will usually denote a period of time in the range of 0.5 to 8 hrs, more us .-Ily 1 to 4 hrs. Relative to the entire period over which drug is administered transdermally to the patient, the "predetermined time period" during which the device and skin are heated may come at the beginning, at the end, or at an intermediate time of the entire period. Further, the heating may be repeated during the entire period, meaning that there can be a multiplicity of "predetermined time periods" during the entire administration period. The entire administration period will usually last 1 to 7 days, more usually 1 to 3 days.
  • the devices of this invention will normally be either the conventional "matrix” type or "reservoir or container” type.
  • the drug is dispersed in a solid or semisolid matrix or carrier.
  • the devices of Figures 1 and 2 depict two such matrix-type devices, generally designated 10 and 11, respectively.
  • Device 10 is a three-layer laminated composite.
  • the top layer 12 is a conductive layer (e.g., metal foil) that serves as a backing and a means for conducting heat from an external source (not ..shown) to the underlying matrix layer 13.
  • Matrix layer 12 is composed of a dispersion of drug in an adhesive polymer carrier that is permeable to the drug. Permeation enhancers may also be dispersed in the carrier if desired.
  • the amount of drug in-the matrix will be sufficient to provide the drug at the desired fluxes over the intended administration period. This will vary from drug to. drug.
  • adhesive polymer carriers useful for formulating the matrix are polysiloxanes, polyacrylates, plasticized ethylene-vinyl acetate copolymers (PEBAX copolymers) , polyurethanes, and rubbery polymers such as polyisobutene.
  • the bottom layer is a conventional strippable release liner layer 14 which is removed prior to use to expose the basal surface of layer 13. In operation, the release liner is stripped from the bottom of the composite to expose the underside of the drug-containing adhesive layer 13. The bilayer device is then placed on the skin with the underside of layer 13 contacting and adhered to the skin.
  • the matrix is in direct contact with the skin so that the drug that is dissolved in the carrier will migrate from the carrier to the skin due to the drug concentration gradient between the carrier and the skin. It will be appreciated that the matrix need not be in direct contact with the skin and that other drug- permeable layers may be interposed between the matrix and the skin as long as a diffusional pathway between the matrix and the skin is maintained.
  • the area of unbroken skin that is in diffusional contact with the matrix is that area which is heated per the invention. This area will normally be 10 to 100 cm 2 , more usually 20 to 60 cm 2 in size.
  • a heat source (direct conduction, radiation, etc.) is placed in contact with conductive layer 12. Heat is conducted from layer 12 through the matrix 13 to the underlying skin. The extent of heat transfer is controlled (e.g., by the temperature of the source and/or the duration of contact ⁇ so as to avoid heating the underlying skin above 45°C. in this regard, prolonged heating of the skin at 45°C or above may cause pain or damage (scalding or burning) to the skin. It will be appreciated that conductive, inductive, or radiant external heat sources may be used to heat the device and underlying skin. The extent of the heating will be sufficient to raise the temperature of the underlying skin above the normal skin temperature, typically to between about 40°C and 45°C.
  • the temperature of the device may be approximately the same as the skin or greater than the heated skin temperature. Typically it will be the same as or within about 10°C hotter than the skin.
  • the increase in temperature results in an increase in flux (usually between about 10% and 1000% increase) --which is believed to correspond primarily to an increase in the solubility of the drug in the carrier and the underlying skin and an increase in molecular movement within the device and the underlying skin. It is noted in this regard that no normally solid component of device 10 (or of the devices of Figures 2 and 3) melts at the temperatures to which the device is heated per this invention.
  • FIG. 2 illustrates an alternative embodiment of a matrix-type device.
  • This device generally designated 11, includes an internal heat-generating means.
  • device 11 includes a heat- conducting layer 15, a drug-containing adhesive polymer matrix 16, and a removable release liner layer 17.
  • first and second chemical species 22 and 23 which, when combined, react exothermally (without explosion) .
  • the heat will typically be generated via heat cf combustion (oxidation) or heat of solution. Controlled oxidations such as those used in commercially available handwarmers (e.g., reaction between iron filings, salt and water) will normally be employed.
  • salts or other compounds which have a substantial positive (i.e., generate heat) heat of solution when dissolved in water may be used. See Handbook of Chemistry and
  • the conductive layer 15 is, of course, impermeable to chemical species 22 and the reaction products of species 22 and 23.
  • release liner 17 is removed and the device is placed on the skin with matrix 16 in diffusional communication therewith. Pressure is then applied to backing 21 and wall 20 to cause wall 20 to rupture and allow the two chemical species to mix and react.
  • the resulting heat generated by the reaction is transferred via conducting layer 15 to the matrix 16 and thence to the underlying skin. Accordingly, the matrix and underlying skin are heated and the flux of the drug through the skin is increased as in the operation of the device of Figure 1.
  • FIG. 3 illustrates a reservoir-type device, generally designated 25.
  • the device is composed of a conductive overlay 26, a backing layer 27, a drug- containing reservoir 28 wherein the drug is a liquid or is in solution, a drug-permeable membrane 29, a peripheral adhesive 30, and a release layer 31.
  • the heat-conducting overlay 26 serves the same function as layer 12 of the device of Figure 1, namely, to conduct heat from an external source to the underlying structure.
  • Overlay 26 will be made of materials such as metal foil or polymer containing metal powder.
  • Backing layer 27 serves as a partial means for defining and containing reservoir 28.
  • the underlying membrane 29 serves as the other member which defines the basal wall of the reservoir and serves as a basal confinement means.
  • Layer 27 will normally be made of drug-impermeable materials such as polyesters or pol propylenes.
  • the drug reservoir will comprise the drug and, if the drug is not itself liquid, a liquid carrier in which the drug is dissolved.
  • Membrane 29 is permeable to drug and defines a diffusional pathway for drug to migrate from the reservoir to the skin. It is heat sealed at 32 to the backing 27 about the periphery of the reservoir.
  • the peripheral adhesive layer 30 is the means by which the device is attached to the skin.
  • the release liner 31 is a conventional removable layer. Accordingly, except for the conductive overlay, device 25 is of conventional reservoir-type structure and design.
  • the release liner is removed from the underside of the device and the device is placed on the skin.
  • a heat source is then placed in contact with the conductive layer, and the device and underlying skin are heated as in the case of device 10 of Figure 1.
  • the devices of the invention may be equipped with a temperature sensor (e.g., a thermocouple or thermistor) located at the interface between the device and the skin, and means coupling the sensor to the heat source by which the heat source may be regulated as needed to maintain the temperature at said interface at a desired level or range.
  • a temperature sensor e.g., a thermocouple or thermistor
  • Example An aerylate adhesive mixture of 1 part Gelva 737 to 4 parts Gelva 788 by solid weight was prepared.
  • Modified Franz vertical cells were used for in vitro penetration studies which were carried out to determine the burst effect.
  • the release liner was peeled off the system prior to placing the system on heat- separated human epidermis.
  • the epidermis and patch were then mounted between the donor and receiver compartments and clamped in place.
  • the receiver compartments were filled with phosphate buffer, pH 5, and the temperature was maintained at 44°C for the first 2 hours and at 32°C thereafter. Samples were taken at preset intervals and assayed by HPLC. The results of these tests are shown in Figure 4.
  • the heating markedly enhanced the flux of the dexmedetomidine through the skin.

Abstract

L'invention se rapporte à des procédés pour administrer des médicaments par voie transdermique par diffusion à partir d'un dispositif d'apport transdermique de médicaments (10). Ces procédés consistent à appliquer le dispositif (10) sur la peau et à chauffer le dispositif (10) et la peau sous le dispositif (10) en appliquant une source de chaleur externe au dispositif ou en déclenchant une réaction exothermique dans le dispositif, pour produire une augmentation de la température de la peau jusqu'à un niveau inférieur à 45 °C, de façon à produire ainsi un accroisement par voie thermique du flux de médicament à travers la peau. On prévoit une couche supérieure (12) constituée par une couche conductrice comme support, pour conduire la chaleur à la couche (13). La couche (12) est en polymère adhésif perméable au médicament. La couche de libération (14) est retirée avant l'utilisation.
PCT/US1992/008519 1991-10-15 1992-10-07 Amelioration par voie thermique de l'administration percutanee de medicaments WO1993007842A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US77498991A 1991-10-15 1991-10-15
US774,989 1991-10-15

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WO1993007842A1 true WO1993007842A1 (fr) 1993-04-29

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PT (1) PT100967A (fr)
WO (1) WO1993007842A1 (fr)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994028854A1 (fr) * 1993-06-11 1994-12-22 Koeltringer Peter Procede et dispositif permettant de traiter des tissus du corps
WO1997026940A1 (fr) * 1996-01-25 1997-07-31 Vesture Corporation Applicateur medical et procede
EP1117356A1 (fr) * 1998-09-29 2001-07-25 Zars, Inc. Procede et appareil d'administration de fentanyl et de suffentanil
EP1117357A1 (fr) * 1998-09-29 2001-07-25 Zars, Inc. Procedes et dispositifs servant a ameliorer l'administration de composes actifs sur le plan pharmaceutique
EP1401408A1 (fr) * 2001-06-11 2004-03-31 Zars, Inc. Utilisation de chaleur controlee pour induire une penetration rapide des agents pharmaceutiques a partir d'un depot cutane
WO2006006799A1 (fr) * 2004-07-09 2006-01-19 Sk Chemicals Co., Ltd. Systeme d'apport transdermique de ketoprofene avec element auto chauffant
US8211462B2 (en) 2002-07-30 2012-07-03 Ucb Pharma Gmbh Hot-melt TTS for administering rotigotine
US8246980B2 (en) 2002-07-30 2012-08-21 Ucb Pharma Gmbh Transdermal delivery system
US8246979B2 (en) 2002-07-30 2012-08-21 Ucb Pharma Gmbh Transdermal delivery system for the administration of rotigotine
US8545872B2 (en) 2002-12-30 2013-10-01 Ucb Pharma Gmbh Device for the transdermal administration of a rotigotine base
US9186334B2 (en) 2009-05-04 2015-11-17 Nuvo Research Inc. Heat assisted lidocaine and tetracaine for transdermal analgesia
US9186273B2 (en) 2009-05-04 2015-11-17 Nuvo Research Inc. Methods of treating pains associated with neuroma, nerve entrapment, and other conditions
US9186335B2 (en) 2002-07-30 2015-11-17 Ucb Pharma Gmbh Hot melt TTS for administering rotigotine
EP3054930A1 (fr) * 2013-10-07 2016-08-17 Teikoku Pharma USA, Inc. Procédés et compositions pour l'administration transdermique d'une quantité non sédative de dexmédétomidine
EP3054932A1 (fr) * 2013-10-07 2016-08-17 Teikoku Pharma USA, Inc. Dispositifs d'administration transdermique de dexmédétomidine et leurs méthodes d'utilisation
CN106456561A (zh) * 2013-10-07 2017-02-22 帝国制药美国公司 使用右旋美托咪啶经皮组合物治疗注意力缺陷多动症、焦虑症和失眠症的方法和组合物
US10251844B2 (en) 1998-03-30 2019-04-09 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system and method of use thereof for treating parkinsonism

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4879119A (en) * 1984-02-21 1989-11-07 Yamanouchi Pharmaceutical Co., Ltd. Patch
US5124157A (en) * 1989-08-18 1992-06-23 Cygnus Therapeutic Systems Method and device for administering dexmedetomidine transdermally

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4879119A (en) * 1984-02-21 1989-11-07 Yamanouchi Pharmaceutical Co., Ltd. Patch
US5124157A (en) * 1989-08-18 1992-06-23 Cygnus Therapeutic Systems Method and device for administering dexmedetomidine transdermally

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994028854A1 (fr) * 1993-06-11 1994-12-22 Koeltringer Peter Procede et dispositif permettant de traiter des tissus du corps
WO1997026940A1 (fr) * 1996-01-25 1997-07-31 Vesture Corporation Applicateur medical et procede
US10251844B2 (en) 1998-03-30 2019-04-09 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system and method of use thereof for treating parkinsonism
US10322093B2 (en) 1998-03-30 2019-06-18 Ucb Biopharma Sprl Method for producing a transdermal therapeutic system which contains a D2 agonist
EP1117356A1 (fr) * 1998-09-29 2001-07-25 Zars, Inc. Procede et appareil d'administration de fentanyl et de suffentanil
EP1117357A1 (fr) * 1998-09-29 2001-07-25 Zars, Inc. Procedes et dispositifs servant a ameliorer l'administration de composes actifs sur le plan pharmaceutique
EP1117356B1 (fr) * 1998-09-29 2006-03-15 Zars, Inc. Appareil d'administration de fentanyl et de suffentanil
EP1117357A4 (fr) * 1998-09-29 2006-05-03 Zars Inc Procedes et dispositifs servant a ameliorer l'administration de composes actifs sur le plan pharmaceutique
EP1401408A4 (fr) * 2001-06-11 2007-11-07 Zars Inc Utilisation de chaleur controlee pour induire une penetration rapide des agents pharmaceutiques a partir d'un depot cutane
EP1401408A1 (fr) * 2001-06-11 2004-03-31 Zars, Inc. Utilisation de chaleur controlee pour induire une penetration rapide des agents pharmaceutiques a partir d'un depot cutane
US8211462B2 (en) 2002-07-30 2012-07-03 Ucb Pharma Gmbh Hot-melt TTS for administering rotigotine
US8246980B2 (en) 2002-07-30 2012-08-21 Ucb Pharma Gmbh Transdermal delivery system
US8246979B2 (en) 2002-07-30 2012-08-21 Ucb Pharma Gmbh Transdermal delivery system for the administration of rotigotine
US9186335B2 (en) 2002-07-30 2015-11-17 Ucb Pharma Gmbh Hot melt TTS for administering rotigotine
US8545872B2 (en) 2002-12-30 2013-10-01 Ucb Pharma Gmbh Device for the transdermal administration of a rotigotine base
WO2006006799A1 (fr) * 2004-07-09 2006-01-19 Sk Chemicals Co., Ltd. Systeme d'apport transdermique de ketoprofene avec element auto chauffant
US9186273B2 (en) 2009-05-04 2015-11-17 Nuvo Research Inc. Methods of treating pains associated with neuroma, nerve entrapment, and other conditions
US9186334B2 (en) 2009-05-04 2015-11-17 Nuvo Research Inc. Heat assisted lidocaine and tetracaine for transdermal analgesia
EP3054932A1 (fr) * 2013-10-07 2016-08-17 Teikoku Pharma USA, Inc. Dispositifs d'administration transdermique de dexmédétomidine et leurs méthodes d'utilisation
CN106456561A (zh) * 2013-10-07 2017-02-22 帝国制药美国公司 使用右旋美托咪啶经皮组合物治疗注意力缺陷多动症、焦虑症和失眠症的方法和组合物
EP3054932A4 (fr) * 2013-10-07 2017-04-05 Teikoku Pharma USA, Inc. Dispositifs d'administration transdermique de dexmédétomidine et leurs méthodes d'utilisation
EP3054935A4 (fr) * 2013-10-07 2017-04-05 Teikoku Pharma USA, Inc. Méthodes et compositions permettant de traiter le trouble d'hyperactivité avec déficit de l'attention, l'anxiété et l'insomnie à l'aide de compositions transdermiques de dexmédétomidine
EP3054930A4 (fr) * 2013-10-07 2017-04-05 Teikoku Pharma USA, Inc. Procédés et compositions pour l'administration transdermique d'une quantité non sédative de dexmédétomidine
RU2658463C2 (ru) * 2013-10-07 2018-06-21 ТЕЙКОКУ ФАРМА ЮЭсЭй, ИНК. Способы и композиции для лечения синдрома дефицита внимания и гиперактивности, тревожности и бессонницы с применением трансдермальных композиций на основе дексмедетомидина
EP3054930A1 (fr) * 2013-10-07 2016-08-17 Teikoku Pharma USA, Inc. Procédés et compositions pour l'administration transdermique d'une quantité non sédative de dexmédétomidine
CN106456561B (zh) * 2013-10-07 2020-02-28 帝国制药美国公司 使用右旋美托咪啶经皮组合物治疗注意力缺陷多动症、焦虑症和失眠症的方法和组合物
US10772871B2 (en) 2013-10-07 2020-09-15 Teikoku Pharma Usa, Inc. Dexmedetomidine transdermal delivery devices and methods for using the same
US10874642B2 (en) 2013-10-07 2020-12-29 Teikoku Pharma Usa, Inc. Methods and compositions for treating attention deficit hyperactivity disorder, anxiety and insomnia using dexmedetomidine transdermal compositions
US10987342B2 (en) 2013-10-07 2021-04-27 Teikoku Pharma Usa, Inc. Methods and compositions for transdermal delivery of a non-sedative amount of dexmedetomidine

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PT100967A (pt) 1994-06-30
AU2782592A (en) 1993-05-21

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