WO1991003998A1 - Disposistif de liberation transdermique a commencement retarde - Google Patents

Disposistif de liberation transdermique a commencement retarde Download PDF

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Publication number
WO1991003998A1
WO1991003998A1 PCT/US1990/005198 US9005198W WO9103998A1 WO 1991003998 A1 WO1991003998 A1 WO 1991003998A1 US 9005198 W US9005198 W US 9005198W WO 9103998 A1 WO9103998 A1 WO 9103998A1
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WO
WIPO (PCT)
Prior art keywords
layer
active compound
skin
compound
subject
Prior art date
Application number
PCT/US1990/005198
Other languages
English (en)
Inventor
Gary W. Cleary
Kenneth J. Colley
Jesus Miranda
Chia-Ming Chiang
Original Assignee
Cygnus Research Corporation
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 Research Corporation filed Critical Cygnus Research Corporation
Priority to AU65153/90A priority Critical patent/AU650851B2/en
Publication of WO1991003998A1 publication Critical patent/WO1991003998A1/fr
Priority to NO92920970A priority patent/NO920970L/no
Priority to FI921121A priority patent/FI921121A0/fi

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/02—Adhesive plasters or dressings
    • A61F13/023—Adhesive plasters or dressings wound covering film layers without a fluid handling layer
    • A61F13/0243—Adhesive plasters or dressings wound covering film layers without a fluid handling layer characterised by the properties of the skin contacting layer, e.g. air-vapor permeability
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/02—Adhesive plasters or dressings
    • A61F13/0259—Adhesive plasters or dressings characterised by the release liner covering the skin adhering layer
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F2013/00361—Plasters
    • A61F2013/00902—Plasters containing means
    • A61F2013/00906—Plasters containing means for transcutaneous or transdermal drugs application

Definitions

  • This invention relates to devices and methods for administering biologically active compounds through the skin, i.e., transdermally. More specifically, the invention relates to a device and method for transdermal delivery having a delayed onset of delivery.
  • transdermal deliv ⁇ ery provides a comfortable, convenient, and noninvasive means for delivering drugs.
  • com ⁇ pounds which would otherwise be degraded, metabolically deactivated, or poorly absorbed.
  • Transdermal delivery using a continuous-release type of device also allows one to terminate administra ⁇ tion immediately should the need arise, e.g., in the event of an adverse drug reaction, or over-elevation of drug plasma concentration.
  • Drug delivery devices may generally be classi ⁇ fied as either "matrix” or “reservoir” in construction.
  • a matrix or monolithic device generally comprises a drug-permeable solid polymer, having a drug dispersed throughout.
  • Matrix devices may be formed from erodible or non-erodible polymers (transdermal devices are typically non-erodible) .
  • Reservoir devices generally comprise a depot of essentially pure drug (or drug with excipient) surrounded by a rate-controlling membrane, where the rate of drug diffusion through the membrane controls the rate of release. Combinations of matrix reservoirs with rate-controlling membranes have also been proposed.
  • the typical design criteria are to provide a substantially constant and continuous release rate, and to provide a release rate capable of delivering a therapeutically effective amount of the compound. Additionally, the device must be non-irritating, and is preferably designed to be of a convenient size.
  • the conventional transdermal device is designed with the goal of delivering a therapeutic compound at a substantially constant rate ("zero-order" delivery) .
  • administration of some compounds at a constant, continuous rate may cause drug tolerance to develop.
  • a transdermal patch-type device must be removed periodically to interrupt continuous delivery. This in turn creates additional problems of patient compliance and design of the patch adhesive (which must adhere to the skin continuously) , and fails to accommodate the patient's circadian rhythms.
  • Nitroglycerin is a vasodilator currently administered for coronary disorders, especially angina pectoris and congestive heart failure. As nitroglycerin cannot be administered orally, it is typically adminis- tered sublingually, or via transdermal patch. Commer ⁇ cially available patches, such as Transder Nitro ® and Nitro-Dur ® , provide essentially constant plasma concen ⁇ trations of nitroglycerin over a 24 hour period, and are changed daily. However, recent studies suggest that continuous administration of nitroglycerin induces tol- erance, with concomitant loss of efficacy in the patient.
  • European Patent Application No. 0290262 (published 9 November 1988) describes a transdermal device which provides a delayed onset of administration of nitrate drugs to the skin. It consists of a backing layer, a rupturable pod sandwiched between the backing and a nonwoven fabric layer, an initially drug impermeable barrier membrane, an adhesive layer and a release liner.
  • the pod is constructed of two layers that have rupturable seals about their peripheries so as to define a lumen that contains the drug and an activator liquid that is capable of plasticizing the barrier membrane and making it increasingly permeable to drugs.
  • the delay is achieved through use of an activator liquid.
  • the use of an activator complicates the formulation, economics, and regulatory approval of the device.
  • the drug release kinetics of the device are complicated because they depend on the permeability of the barrier membrane which varies with the degree of membrane plasticization.
  • the purposes of another embodiment of the invention is to provide a delayed onset transdermal drug delivery device that does not involve a rupturable drug reservoir but instead is effected through assembly of components of the device just prior to device use. Disclosure of the Invention
  • the device of the invention provides a con ⁇ tinuous, constant transdermal release of an active sub ⁇ stance, wherein the onset of release is delayed from 1-24 hours, depending on the length of time that the drug is delivered.
  • This provides a "wash out” period, during which the plasma concentration of any compound remaining in the patient's system from application of the previous device is allowed to drop to near baseline levels. Accordingly, a patient may wear the patch for 24 hours, replacing the patch with a fresh patch prior to going to sleep. The wash out period thus occurs during the patient's sleep, and is followed by effective plasma concentrations of the active compound during the waking hours.
  • kits for preparing a device for administering an active compound transdermally to a subject's skin, having a delayed onset of delivery comprising: a first layer comprising a polymeric matrix impregnated with said active compound, said compound and matrix being selected to obtain a first compound diffu-
  • ____c 10 2 sion coefficient of about 10 to about 10 cm /sec in said matrix; a second layer not in contact with said first layer, comprising an adhesive capable of adhering to said first layer and to said subject's skin, said second layer having a second diffusion coeffi .ci.ent of about 10-5 to about 10 —10 cm2/sec in said matrix, wherein said second layer is substantially devoid of said active compound.
  • Another aspect of the invention is a method for administering an active compound to a subject by application of a controlled-release device, wherein the onset of administration is delayed from the device application time, which method comprises: laminating a first layer and a second layer together to form an adhesive laminate, where said first layer comprises a polymeric matrix impregnated with said active compound, said compound and matrix being selected to obtain a first compound diffusion coefficient of about 10 ⁇ to about lo " cm /sec in said matrix, and said second layer comprises an adhesive capable of adhering to said first layer and to said subject's skin, said second layer having a second diffusion coefficient of about 10 -5 to about 10 —10 cm2/sec in said matrix, said second layer initially being substantially devoid of said active compound; and applying said adhesive laminate to the skin of said subject before the active compound equilibrates in the adhesive laminate.
  • Yet another aspect of the invention is a device for administering an active compound transdermally following application to a subject's skin, having a delayed onset of delivery, said device comprising: (a) a rupturable reservoir containing the active compound in liquid form;
  • Figure 1 shows a schematic cross-section of a presently preferred embodiment of the invention, wherein the active compound is sequestered within a rupturable capsule.
  • Figure 2 is a schematic cross-section of a kit embodiment of the invention which is laminated by the user.
  • the layers depicted are thin solid films, prefer ⁇ ably flexible and/or elastomeric, and are laminated together immediately prior to application by the user.
  • the view depicted illustrates a cross-section of the device with the protective release liner and liner/carrier in place.
  • Figure 3 shows a perspective view of the kit embodiment after removal of the upper release liner, just prior to lamination.
  • Figure 4 depicts a schematic cross section of the kit embodiment immediately after lamination, follow ⁇ ing removal of the liner/carrier.
  • Figure 5 is a schematic cross section of another presently preferred embodiment, having a ruptur ⁇ able capsule formed as part of the drug reservoir of the device.
  • Figure 6 is a cross section of a dispensing device, suitable for dispensing devices of the invention as shown in Figure 1 or Figure 5.
  • Figure 7 depicts graphically the results of the experiment reported in Example 1.
  • Figure 8 depicts graphically the results of the experiment reported in Example 2.
  • FIG. 9 depicts graphically the results of the experiments reported in Example 3. Modes of Carrying Out The Invention
  • active compound refers to any substance which may be administered to an animal to obtain a beneficial effect.
  • Active compounds may be drugs, for example, vasodilators such as nitro ⁇ glycerin, amyl nitrate, isosorbide dinitrate or mono- nitrate and the like, L-DOPA, analgesics, antiinflam- matories, antihistamines, antibiotics, antihypertens- ives, hormones, and the like, which are useful for pre ⁇ venting or ameliorating a given disorder.
  • vasodilators such as nitro ⁇ glycerin, amyl nitrate, isosorbide dinitrate or mono- nitrate and the like
  • L-DOPA analgesics
  • antiinflam- matories antihistamines
  • antibiotics antihypertens- ives
  • hormones and the like
  • active compounds include contraceptives (e.g., estradiol, levo- norgestrel, 3-ketodesogestrel, gestodene, and the like) , vitamins, appetite suppressants, nicotine, caffeine and other stimulants, growth promoters (particularly when administered to livestock) , and the like.
  • Suitable active compounds within the scope of this invention are capable of diffusion or absorption through the skin.
  • mammals includes animals such as humans, livestock including cattle, sheep, goats, horses, small animals such as dogs, cats, and mice, wildlife and zoo animals such as elephants, lions, tigers, antelope, and the like.
  • animal refers to mammals and birds, including domestic fowl such as chickens, geese, ducks, turkeys, game hens, and the like.
  • liquid carrier refers to a solvent compatible with the reservoir matrix and adhesive lay ⁇ ers, as well as with skin, in which the active compound is soluble.
  • the active compound will preferably be mod ⁇ erately soluble in the carrier.
  • Suitable carriers gen ⁇ erally enhance the release rate of active compound from devices of the invention.
  • Exemplary carriers include lower alcohols such as methanol, ethanol, propanol, iso- propanol, and the like, glycols such as propylene glycol and the like, glycol ethers and esters, dimethylsulf- oxide, tetrahydrof ran, acetone, and the like.
  • delayed onset refers to the situation where no active compound is released from the device of the invention until some time after the device is applied to the skin. For a 24 hour patch, this delay period will typically be 1-18 hours, prefer ⁇ ably about 12 hours in duration. Patches designed for longer duration (e.g., a weekly patch) may have cor- respondingly longer delay periods.
  • Figure 1 depicts a presently preferred device of the invention, having a rupturable capsule containing the active compound prior to administration.
  • This embodiment 20 comprises an optional wick layer 23, which is capable of diffusing the active compound, but which does not act as a reservoir: the wick layer preferably does not absorb the active compound to a significant degree, and thus does not retain a substantial amount of the compound.
  • the wick layer is preferably formed from a non-woven fabric, and must be capable of adhering to the adjacent layers under conditions of use (e.g., when saturated with active compound and vehicle) .
  • a non-permeable backing layer 21 forms the outer surface of the device, and prevents loss of the active compound through the upper surface.
  • the backing layer is prefer ⁇ ably occlusive, waterproof, drug-proof (for at least the administration period of the device) , and suitable for lamination to the adjacent layer.
  • Backing layer 21 may be heat-sealed or crimped onto the adjacent layer, forming a perimeter region 22, which seals the reservoir area 27 formed by the void between backing layer 21 and the adjacent layer 23.
  • Backing layer 21 and the layer adjacent 23 are laminated together to form a reservoir volume 27.
  • the reservoir volume is a space that contains rupturable capsule 30, comprising the active compound 33, option- ally a vehicle, permeation enhancer, solubilizer, and the like, sealed within a non-permeable film wall material 31.
  • Capsule 30 is maintained in an intact state, so that no active compound 33 is within the reservoir volume, exposed to the wick layer (or other layer) prior to administration.
  • the capsule may be fabricated from any material which is impermeable to the active compound and its vehicle, and which may be ruptured when desired to release the active compound (and carrier if present) and activate the device.
  • the ability to use a completely impermeable capsule allows one to employ compounds which are normally precluded from use in transdermal devices due to their volatility. Because the volatile compound will be completely contained within the internal cap ⁇ sule, one may employ vehicles and enhancers such as ethanol, acetone, methanol, ethyl acetate and the like, or use active compounds such as nicotine, without loss of compound from the device prior to administration.
  • Non- rupturable devices of the prior art must be permeable to the compounds contained therein, and thus tend to lose any volatile components during shipping and storage prior to administration. (Even if the volatile components are contained with the prior art device within a pouch, the components will not be distributed properly within the device at the time of administration.)
  • Rupturable cap- sules may have a rupturable seal at a seam (or other deliberately weakened portion of the wall) , or may be prepared from a fragile or frangible material (for example, glass, silica, crystalline or brittle polymers, etc.), either crushable or having a scored portion to allow rupture by flexing the patch.
  • the capsule is formed from an aluminum foil-laminated heat seal film having a ruptur ⁇ able heat seal 32.
  • This film is flexible, and comprises a layer of aluminum (about 0.3-1 mil) with a heat seal layer comprising EVA, polypropylene, or modified polyethylene (about 0.3-0.8 mil).
  • the capsule may be fashioned from any frangible or friable container or film.
  • a thin glass capsule or brittle (e.g., crystalline) polymer may alternatively be employed.
  • the capsule may be scored or necked to enhance breaking.
  • the capsule may be attached to the backing layer 21 or the layer adjacent the back ⁇ ing layer (23, 24, or 25), or may be simply encapsulated within the reservoir volume 27 in loose form.
  • Underlying the reservoir and wick layer are a microporous membrane layer 24 and a contact adhesive layer 25.
  • Layer 24 contributes structural integrity to the device, as well as a means to delay the permeation of drug through the device to the skin. Its pores are preferably empty prior to the rupture of the reservoir; in other words, the microporous membrane is substantially devoid of active compound and vehicle prior to rupture of the reservoir. Further, microporous membrane layer 24 is not plasticized by any component of the active compound formulation.
  • Suitable films for the layer 24 include, without limitation, microporous films of about 0.5-3.0 mil in thickness composed of, for example, polypropylene
  • Skin contact adhesive layer 25 is a pressure-sensitive adhesive suitable for application to human skin.
  • the adhesive selected must also be compatible with the active compound and its vehicle, and must be suitable for lamination to the upper layers.
  • Presently preferred contact layer adhesives include acrylic, silicone, polyisobutylene, polyurethane, SIS, and SBS pressure sensitive adhesives.
  • the layer may range in thickness from about 0.5 to about 5.0 mil.
  • the adhesive layer is preferably protected prior to administration by means of a release liner 26, which is generally a thin film or sheet which has been treated to allow easy removal from the adhesive layer.
  • the active compound is sequestered within a non-permeable capsule prior to activation: accordingly, the release liner need only protect the contact adhesive, without regard for the nature of the active compound since the release liner is not exposed to the active compound during storage. In other words, the release liner need not be impermeable to the active compound, thus making available a wider range of materials.
  • siliconized or fluorocarbon-treated paper or polystyrene may be used, in place of more expensive polymer films such as polyester or polycarbonate, which might otherwise be required.
  • the thickness of the release liner is not critical, and may be determined by aesthetic criteria. In general, the release liner must exhibit sufficient thickness and structural integrity that it may be peeled or stripped easily from the contact adhesive layer, preferably in one or two pieces. A thickness of about 3 mil is generally sufficient.
  • the release liner may be provided in the form of a long strip with multiple perforations spaced at appropriate intervals, such that the device of the invention may be provided on "tear-off" rolls or accordion-pleated stacks.
  • a sufficient number of devices to treat a patient for a month can be provided on one strip, or within one con ⁇ tainer.
  • each device can then be numbered or dated, to aid patients in compliance. For example, on the fourth day of the month, the patient can determine if he or she has already applied the device for the day by determining whether or not the device marked "4" has been removed yet. This is a significant advantage for devices which are applied on a daily or weekly basis over an extended period of time.
  • FIG. 5 Another embodiment of the invention is shown in Figure 5.
  • the rupturable capsule is provided as part of the backing layer 21, rather than as a separate layer 31.
  • an impermeable layer 34 is laminated to the wick layer 23, and a rupturable membrane or film 35 is provided to separate the reservoir volume 27 in contact with the wick layer from the sequestered portion.
  • the device may be packaged in a con ⁇ tainer which provides for capsule rupture and/or release liner removal automatically upon removal.
  • a con ⁇ tainer which provides for capsule rupture and/or release liner removal automatically upon removal.
  • the container may be a box 46 of any suitable shape, having pressure means 41 and 42 above and below an aperture 48 sized to admit the device 44 after capsule rupture.
  • a plurality of devices are provided on a long carrier strip 26, wound in a roll around a wide-diameter spool 45 (wide enough to avoid premature capsule rupture due to flexing) .
  • the carrier passes through pressure means 41 and 42, rupturing the capsule, and then passes through aperture 48.
  • the pressure means may be a pair of pres- sure rollers as depicted, a roller opposed to a flat surface, or simply two flat surfaces having a separation decreasing in the direction of travel as the device is dispensed.
  • the pressure means is preferably a cam-shaped roller.
  • the pressure means may optionally be tensioned by means of a spring or other device (not shown) .
  • the device may further comprise means for separating the carrier/liner 26 from the device, such as roller 43. In this embodiment, carrier 26 may be ejected through a separate aperture 49.
  • the spool 45 may optionally comprise an axle 47 affixed to the interior of the enclosure 46.
  • the axle 47 may be further connected to a handle or crank (not shown) , by which the carrier roll may be advanced and the devices of the invention dispensed.
  • the devices may be dispensed by simply pulling the carrier strip 26 until the device is ejected.
  • the carrier selected must be strong enough to pull the device through the pressure means.
  • the pressure means must be far enough from the carrier separation means 43 (if present) that the device has completely passed the pressure means and the capsule ruptured prior to separation from the carrier.
  • Other devices not pictured may easily be constructed.
  • the roll of patches may be replaced with an accordion-folded stack of patches on a pleated carrier.
  • the pressure means may be crank operated rather than the supply roll (particularly when the pressure means are rollers) .
  • the device may be designed to bend the capsule until ruptured.
  • Other variations will be apparent to those of ordinary skill in the art.
  • capsule 31 is ruptured by applying pressure so that the active com ⁇ pound is released from the capsule into the reservoir volume 27.
  • This may be accomplished by placing the device on a flat surface and pressing the capsule with a finger or thumb, or by some external pressure such as passing the device through a suitable mechanical pres ⁇ sure device, such as a pair of rollers (similar to a mangle as found on old cloths washing machines) , or by bending or flexing the patch to cause rupture of a weak ⁇ ened or scored area.
  • the release liner 26 is removed from contact layer 25, and the device applied to a suit ⁇ able area of intact skin, for example the upper arm, thigh, chest, lower abdomen, and the like.
  • the device may be applied to the skin prior to activation by rupturing the capsule.
  • the active compound and vehicle are released from the cap ⁇ sule, and diffuse through the adjacent layers.
  • the wick layer acts to spread the active compound over the entire available underlying layer, providing for an even flow across the area of the device.
  • the compound diffuses through the wick layer, the microporous membrane layer, and into the contact layer, where it accumulates until sufficient concentration has developed that diffusion into the patient's skin begins at a significant rate. Due to the fact that the intermediate layers are not equilibrated with the compound, a substantial delay occurs prior to significant diffusion into the skin.
  • Figure 2 shows another embodiment of the invention 1, having a polymeric matrix reservoir layer 12 containing an active compound 13 and optionally a liquid carrier 19.
  • This reservoir layer is laminated permanently to an impermeable backing layer 11, which prevents loss of active compound from the "non-contact" side of the device, and which may additionally provide some degree of structural support.
  • layers 11 and 12 are shown here as distinct layers, the backing layer may be formed from a portion of the matrix reser- voir layer by suitable treatment, such as heat, chemical crosslinking, radiation, and the like, so as to render the surface substantially impermeable to the active com ⁇ pound and carrier (if present) .
  • Layer 11 is preferably supported by a liner/carrier 17.
  • the reservoir layer 12 is preferably protected on its other side (opposite backing 11) by a releasable protective liner 16.
  • a con ⁇ tact adhesive layer 14 is provided which is not in con ⁇ tact with said reservoir layer 12, and may serve as the delay layer.
  • Adhesive layer 14 is substantially free of active compound 13, although it may contain a liquid carrier, permeation enhancer or the like if desired.
  • An additional release liner 15 may be laminated to adhesive layer 14 if desired.
  • the release liner 15 and adhesive layer 14 are supported by a liner/carrier, preferably the same liner/carrier 17 which supports reservoir 12 and backing 11.
  • the adhesive layer 14 is preferably protected on its upper surface (opposite optional release liner 15) by an additional releasable protective liner, preferably an extension of said protective liner 16.
  • An additional delay layer (not shown) may be laminated between contact adhesive layer 14 and protective liner 16, if desired.
  • the protective liner 16 is first removed from the upper surface of the device.
  • the exposed surface of adhesive layer 14 is then laminated to the exposed surface of reservoir layer 12.
  • this lamination is preferably assisted by means of a crease or fold line 18, as shown in Figure 3.
  • Lamination is accomplished by simply folding the device along the fold line, and pressing layer 14 onto layer 12. It is preferred that the reservoir-backing sublaminate and the adhesive-liner sublaminate be arranged on the liner/carrier so that folding the liner/carrier along the crease insures that the completed device layers will overlap completely. This results in the configuration shown in Figure 4.
  • liner/carrier 17 is removed from layer 14 (or release liner 15 if present) . If release liner 15 is present, it also is removed, and the exposed adhesive layer 14 applied to the subject's skin. Carrier 17 is then removed from backing layer 11, leaving the device comprising layers 11, 12, and 14 on the subject's skin. Active compound 13 (and optionally liquid carrier 19) then begins to diffuse into layer 14, and finally into the subject's epidermis. A substantial time delay occurs before the active compound begins to diffuse into the epidermis at a significant rate, due to the fact that layer 14 is not equilibrated with reservoir 12 at the time of application.
  • the devices of the invention are particularly suited for repeated administration.
  • a device of the invention When used to admin ⁇ ister nitroglycerine (e.g., for treatment of congestive heart failure) or nicotine (e.g., to reduce cigarette craving) , a device of the invention is preferably applied shortly before retiring for the evening. Due to the delayed onset of release, little or no compound is released while the subject is sleeping. Instead, com ⁇ pound is released at or just before time for the subject to wake up, when the compound is most needed. The device continues to release active compound over the next sixteen hours. Then, the device is removed, and is replaced with a fresh device. Thus, the plasma level of active compound may decline to baseline during the sub- ject's sleep, so that tolerance or undesirable side effects do not develop.
  • Backing layer 11 and 21 is preferably made of a sheet or film of a preferably flexible elastomeric material that is substantially impermeable to the active compound.
  • the layer is preferably on the order of 0.01 to 0.08 mm in thickness, and may optionally be pigmented (e.g., to resemble the subject's skin color).
  • the layer is fabricated from a material that permits the device to mimic the contours of the skin and to be worn comfortably on areas of skin such as joints or other points of flexure normally subjected to mechanical strain. This reduces the possibility of disengaging or losing the device due to differences in flexibility or resiliency of the skin and the device.
  • Exemplary elastomeric polymers useful for preparing backing layer 11 include polyether block amide copolymers (e.g., PEBAX copolymers) , polyethylene methylmethacrylate block copolymers (EMA) such as NUKRELL polymers, polyurethanes such as PELLATHANE or ESTANE polymers, silicone elastomers, polyester block copolymers such as HYTREL, rubber-based polyisobutylene, styrene, and styrene-buta- diene and styrene-isoprene copolymers.
  • Flexible polymers include polyethylene, polypropylene, and polyesters such as polyester terephthalate (PET) , which may be provided as films or laminates. One may also use laminates or combinations of any of the above materials.
  • the polymeric matrix reservoir 12 is composed of a polymeric material in which the active compound is poorly to moderately soluble, and capable of diffusing the active compound at a high rate.
  • the reservoir layer must also be capable of adhering to the adjacent layers, to prevent delamination.
  • selection of the par ⁇ ticular material will depend in part upon the active compound (and its vehicle, e.g., solubilizers, permeation enhancers, etc.) selected, and the adhesives employed.
  • Devices of the invention employing a rupturable capsule preferably contain the active compound in the form of a liquid or gel.
  • the vehicle must be capable of flowing following rupture of the sequestering capsule.
  • the vehicle will comprise silicone fluid, PGML, propylene glycol, other carriers such as lactose, and the like.
  • the contact adhesive layer 14 and 25 is gener ⁇ ally fabricated from an active compound-permeable poly ⁇ mer which adheres to both the reservoir matrix and to mammalian skin without irritation.
  • exemplary materials for forming layer 14 and 25 include without limitation polysiloxanes, polyisobutylenes, polyacrylates, poly ⁇ urethanes, plasticized ethylene-vinyl acetate copoly ⁇ mers, low molecular weight polyether block amide copolymers (PEBAX copolymers) , and mixtures thereof.
  • the particular material used will depend upon the diffusion coefficient of the active compound (and optionally the liquid carrier) in the adhesive layer, and the diffusion coefficient in the reservoir layer. Generally, both diffusion coefficients should be in the range of about 10 to about 10 ⁇ cm /sec.
  • the various carriers and release liners may be formed from any material having the desired degree of flexibility and impermeability. These liners are gener- ally rendered “strippable" from the contact adhesive layer using silicone or fluorocarbon surface treatments.
  • the devices of the invention are generally prepared by standard thin-film lamination techniques.
  • Example 1 In Vitro Delayed Flux Determination
  • Water based acrylic adhesive (Flexcryl 1625, 69% solids) was coated onto a 0.075 mm thick siliconized polyester film at a thickness of 0.25 mm.
  • the adhesive coating was cured at 75°C for 30 min in order to remove all of the water; cured thickness was 0.01 mm (10 mg/cm 2) .
  • a disc of the cured adhesive was die-cut and laminated to the stratum corneum side of a disc of human cadaver epidermis.
  • the skin/adhesive composite was mounted on a glass diffusion cell (effective flux area
  • a measured volume of receiver solution (0.9% NaCl and 0.01% NaN. in deionized water) was placed in the receptor compartment.
  • the donor was 1.5 g of a nitroglycerin suspension consisting of 2.5 wt% nitro ⁇ glycerine; 48.8 wt% Dow 360 silicone fluid, 350 cts; 23.8 wt% propylene glycol monolaurate (Gatteanke) ; and 24.7 wt% lactose.
  • the nitroglycerin suspension was placed in the donor compartment directly in contact with the adhesive. The donor compartment was then occluded, and the cell maintained at 32°C.
  • Figure 7 shows the results of this test. Solid circles indicate the amount per cm 2 per hour (in micrograms) for the above-described composite. Open circles indicate the results obtained using Nitro-Dur ® . As shown in the Figure, Nitro-Dur ® reached essentially peak flux rate by 2-4 hours after administration, whereas the composition of the invention delayed full onset to 4.5-5 hours after administration.
  • Water based acrylic adhesive (Flexcryl 1625, 69% solids) was coated onto a 0.075 mm thick siliconized polyester film at a thickness of 0.125 mm.
  • the adhesive coating was cured at 75°C for 30 min in order to remove all of the water; cured thickness was 0.05 mm (5 g/cm 2) .
  • a disc of the cured adhesive was die-cut and laminated to the stratum corneum side of a disc of human cadaver epidermis.
  • the skin/adhesive composite was mounted on a glass diffusion cell (effective flux area 0.713 cm 2) wi.th the ski.n side facing the receptor com ⁇ partment.
  • a measured volume of receiver solution (0.9% NaCl and 0.01% NaN in deionized water) was placed in the receptor compartment.
  • the donor was 1.5 g of a nitroglycerin suspension consisting of 2.3 wt% nitro- glycerine; 75.0 wt% Dow 360 silicone fluid, 350 cts; and 22.5 wt% lactose.
  • the nitroglycerin suspension was placed in the donor compartment directly in contact with the adhesive. The donor compartment was then occluded, and the cell maintained at 32°C. Samples of the receiv- ing solution were taken periodically and analyzed by HPLC to determine the amount of nitroglycerin permeated per unit time.

Abstract

Un dispositif de libération transdermique comporte un réservoir contenant un composé actif, lequel est maintenu séparé des couches de libération du dispositif jusqu'à administration. Au moment de l'administration, le réservoir est stratifié sur les couches de libération, ou est rompu afin de placer le composé actif, le véhicule, et/ou les stimulateurs de pénétration en contact avec les couches de libération, ce qui a pour résultat l'administration du composé actif sur la peau après une période de retardement.
PCT/US1990/005198 1989-09-14 1990-09-13 Disposistif de liberation transdermique a commencement retarde WO1991003998A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU65153/90A AU650851B2 (en) 1989-09-14 1990-09-13 Transdermal delivery device having delayed onset
NO92920970A NO920970L (no) 1989-09-14 1992-03-12 Transdermal avleveringsinnretning med forsinket begynnelse
FI921121A FI921121A0 (fi) 1989-09-14 1992-03-16 Transdermal doseringsanordning med foerdroejd start.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US40747689A 1989-09-14 1989-09-14
US407,476 1989-09-14

Publications (1)

Publication Number Publication Date
WO1991003998A1 true WO1991003998A1 (fr) 1991-04-04

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ID=23612266

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Application Number Title Priority Date Filing Date
PCT/US1990/005198 WO1991003998A1 (fr) 1989-09-14 1990-09-13 Disposistif de liberation transdermique a commencement retarde

Country Status (6)

Country Link
EP (1) EP0491853A4 (fr)
JP (1) JP2605183B2 (fr)
AU (1) AU650851B2 (fr)
CA (1) CA2065403C (fr)
FI (1) FI921121A0 (fr)
WO (1) WO1991003998A1 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996000072A1 (fr) * 1994-06-23 1996-01-04 The Procter & Gamble Company Traitement du besoin de nicotine et/ou des symptomes de manque du fumeur au moyen d'une composition contenant de la nicotine et de la cafeine ou de la xanthine, pouvant etre administree par voie transdermique ou a travers les muqueuses
US5591767A (en) * 1993-01-25 1997-01-07 Pharmetrix Corporation Liquid reservoir transdermal patch for the administration of ketorolac
US5603947A (en) * 1993-07-09 1997-02-18 Cygnus Terapeutic Systems Method and device for providing nicotine replacement therapy transdermally/transbuccally
US5613958A (en) * 1993-05-12 1997-03-25 Pp Holdings Inc. Transdermal delivery systems for the modulated administration of drugs
US5817044A (en) * 1992-11-05 1998-10-06 Becton Dickenson And Company User activated iontophoertic device
WO1999009961A3 (fr) * 1997-08-21 1999-05-27 Lohmann Therapie Syst Lts Systemes de drain contenant des additifs
WO2005025549A2 (fr) * 2003-09-10 2005-03-24 Noven Pharmaceuticals, Inc. Dispositif multicouche d'administration transdermique de medicaments
WO2006109325A1 (fr) * 2005-04-11 2006-10-19 Roberto Vannucci Pansement adhesif a emballage de desinfectant
GB2438926A (en) * 2006-06-07 2007-12-12 Paul Marshall Transdermal patch
GB2443928A (en) * 2006-11-08 2008-05-21 Regen Therapeutics Plc Transdermal pharmaceutical composition comprising Zolpidem
GB2448855A (en) * 2007-05-04 2008-11-05 Mark Stephen Couchman Pressure activated transdermal medicament delivery system
US7858114B2 (en) 2006-05-08 2010-12-28 Teikoku Seiyaku Co., Ltd. Percutaneous absorption preparations of antidementia drugs
WO2012069820A1 (fr) 2010-11-22 2012-05-31 Dewan Fazlul Hoque Chowdhury Timbre transdermique multicouche
US8343538B2 (en) 2004-10-08 2013-01-01 Noven Pharmaceuticals, Inc. Compositions and methods for controlling the flux of a drug from a transdermal drug delivery systems
US9539318B2 (en) 2007-12-03 2017-01-10 Dbv Technologies Allergen desensitization method
EP3395337A1 (fr) * 2017-04-28 2018-10-31 Nitto Denko Corporation Précurseur de préparation d'absorption transdermique

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Publication number Priority date Publication date Assignee Title
CN109646806A (zh) * 2018-12-17 2019-04-19 南京日光生物科技有限公司 一种带远红外发热层的脊柱贴及其制备方法

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ES2028074T3 (es) * 1986-06-13 1992-07-01 Alza Corporation Activacion por humedad de un sistema de suministro transdermico de farmacos.
EP0290262A3 (fr) * 1987-05-08 1990-12-12 EASTMAN KODAK COMPANY (a New Jersey corporation) Thérapie de l'angine de poitrine par le nitrate

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US4117841A (en) * 1977-02-07 1978-10-03 Anthony Perrotta Medicated bandage pocket
US4286592A (en) * 1980-02-04 1981-09-01 Alza Corporation Therapeutic system for administering drugs to the skin
US4839174A (en) * 1987-10-05 1989-06-13 Pharmetrix Corporation Novel transdermal nicotine patch
US4812305A (en) * 1987-11-09 1989-03-14 Vocal Rodolfo S Well medicine strip

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Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5817044A (en) * 1992-11-05 1998-10-06 Becton Dickenson And Company User activated iontophoertic device
US5591767A (en) * 1993-01-25 1997-01-07 Pharmetrix Corporation Liquid reservoir transdermal patch for the administration of ketorolac
US5613958A (en) * 1993-05-12 1997-03-25 Pp Holdings Inc. Transdermal delivery systems for the modulated administration of drugs
US5603947A (en) * 1993-07-09 1997-02-18 Cygnus Terapeutic Systems Method and device for providing nicotine replacement therapy transdermally/transbuccally
US5599554A (en) * 1994-06-23 1997-02-04 The Procter & Gamble Company Treatment of nicotine craving and/or smoking withdrawal symptoms
WO1996000072A1 (fr) * 1994-06-23 1996-01-04 The Procter & Gamble Company Traitement du besoin de nicotine et/ou des symptomes de manque du fumeur au moyen d'une composition contenant de la nicotine et de la cafeine ou de la xanthine, pouvant etre administree par voie transdermique ou a travers les muqueuses
WO1999009961A3 (fr) * 1997-08-21 1999-05-27 Lohmann Therapie Syst Lts Systemes de drain contenant des additifs
US8784874B2 (en) 2003-09-10 2014-07-22 Noven Pharmaceuticals, Inc. Multi-layer transdermal drug delivery device
WO2005025549A2 (fr) * 2003-09-10 2005-03-24 Noven Pharmaceuticals, Inc. Dispositif multicouche d'administration transdermique de medicaments
WO2005025549A3 (fr) * 2003-09-10 2005-05-26 Noven Pharma Dispositif multicouche d'administration transdermique de medicaments
US8865207B2 (en) 2004-10-08 2014-10-21 Noven Pharmaceuticals, Inc. Compositions and methods for delivering active agents in transdermal drug delivery systems
US8343538B2 (en) 2004-10-08 2013-01-01 Noven Pharmaceuticals, Inc. Compositions and methods for controlling the flux of a drug from a transdermal drug delivery systems
WO2006109325A1 (fr) * 2005-04-11 2006-10-19 Roberto Vannucci Pansement adhesif a emballage de desinfectant
US7858114B2 (en) 2006-05-08 2010-12-28 Teikoku Seiyaku Co., Ltd. Percutaneous absorption preparations of antidementia drugs
GB2438926A (en) * 2006-06-07 2007-12-12 Paul Marshall Transdermal patch
GB2443928A (en) * 2006-11-08 2008-05-21 Regen Therapeutics Plc Transdermal pharmaceutical composition comprising Zolpidem
GB2448855A (en) * 2007-05-04 2008-11-05 Mark Stephen Couchman Pressure activated transdermal medicament delivery system
GB2448855B (en) * 2007-05-04 2010-10-20 Mark Stephen Couchman Pressure activated transdermal medicament delivery system
US10758610B2 (en) 2007-12-03 2020-09-01 Dbv Technologies Allergen desensitization method
US9539318B2 (en) 2007-12-03 2017-01-10 Dbv Technologies Allergen desensitization method
US10022439B2 (en) 2007-12-03 2018-07-17 Dbv Technologies Allergen desensitization method
US10272151B2 (en) 2007-12-03 2019-04-30 Dbv Technologies Allergen desensitization method
US11202826B2 (en) 2007-12-03 2021-12-21 Dbv Technologies Allergen desensitization method
US11931411B2 (en) 2007-12-03 2024-03-19 Dbv Technologies Allergen desensitization method
WO2012069820A1 (fr) 2010-11-22 2012-05-31 Dewan Fazlul Hoque Chowdhury Timbre transdermique multicouche
EP3395337A1 (fr) * 2017-04-28 2018-10-31 Nitto Denko Corporation Précurseur de préparation d'absorption transdermique
US10953096B2 (en) 2017-04-28 2021-03-23 Nitto Denko Corporation Transdermal absorption preparation precursor

Also Published As

Publication number Publication date
JPH05500511A (ja) 1993-02-04
EP0491853A4 (en) 1992-11-04
CA2065403C (fr) 1996-06-18
FI921121A (fi) 1992-03-16
FI921121A0 (fi) 1992-03-16
JP2605183B2 (ja) 1997-04-30
CA2065403A1 (fr) 1991-03-15
EP0491853A1 (fr) 1992-07-01
AU6515390A (en) 1991-04-18
AU650851B2 (en) 1994-07-07

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