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EP0656771A1 - Dispositif d'apport medicamenteux percutane depose par empreinte - Google Patents

Dispositif d'apport medicamenteux percutane depose par empreinte

Info

Publication number
EP0656771A1
EP0656771A1 EP93901003A EP93901003A EP0656771A1 EP 0656771 A1 EP0656771 A1 EP 0656771A1 EP 93901003 A EP93901003 A EP 93901003A EP 93901003 A EP93901003 A EP 93901003A EP 0656771 A1 EP0656771 A1 EP 0656771A1
Authority
EP
European Patent Office
Prior art keywords
nicotine
drug
patient
layer
hours
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP93901003A
Other languages
German (de)
English (en)
Other versions
EP0656771A4 (fr
Inventor
Jesus Miranda
Gary W. Cleary
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cygnus Inc
Original Assignee
Cygnus Therapeutic Systems
Cygnus Inc
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, Cygnus Inc filed Critical Cygnus Therapeutic Systems
Publication of EP0656771A1 publication Critical patent/EP0656771A1/fr
Publication of EP0656771A4 publication Critical patent/EP0656771A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • 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
    • A61K31/465—Nicotine; Derivatives thereof
    • 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

Definitions

  • This invention relates generally to transdermal delivery devices and to methods of making and using such devices. More particularly the invention relates to transdermal nicotine delivery systems which include particular amounts of nicotine within a matrix allowing the device to be worn for 24 hours but be depleted of nicotine to the extent that nicotine is not further delivered to the patient after a period of about 16 hours.
  • transdermal nicotine delivery systems which include particular amounts of nicotine within a matrix allowing the device to be worn for 24 hours but be depleted of nicotine to the extent that nicotine is not further delivered to the patient after a period of about 16 hours.
  • a variety of devices have been proposed or used for administering drugs transdermally. These devices are generally in the form of a bandage or skin patch that includes a reservoir that contains the drug and a pressure-sensitive adhesive component by which the device is attached to the skin. Depending upon the inherent permeability of the skin to a particular drug, the device may also include means for coadministering a percutaneous absorption enhancer or an element, such as a membrane interposed between the reservoir and the skin, that regulates the rate at which the drug or the percutaneous absorption enhancer is administered to the skin.
  • a percutaneous absorption enhancer or an element such as a membrane interposed between the reservoir and the skin
  • the solvent selected is necessarily organic, rather than aqueous.
  • organic solvents are flammable and/or toxic, an element of risk is thus introduced into device fabrication and use.
  • Another shortcoming is that with volatile drugs or drugs that are sensitive to heat, evaporation of the solvent can either volatilize or degrade the drug.
  • the present invention is addressed to these shortcomings, and provides a device fabrication process which eliminates the necessity for both organic solvents and high-temperature evaporation. The process minimizes drug degradation and loss to the environment, while eliminating the possibility of contamination with organic residues which may be harmful to the skin, e.g., as irritants, sensitizers, carcinogens, or the like.
  • Most drug delivery devices are designed so that they can be worn for 24 hours.
  • the 24-hour wear period provides for good patient compliance in that the patient can replace the patch each day at approximately the same time.
  • most patches are designed so as to continually deliver a particular drug to the patient during the entire 24-hour period.
  • the continuous delivery of drug to a patient over a 24-hour period is often not desirable.
  • Problems related to the continuous delivery of the drug to the patient over a 24-hour period varied depending on the type of drug. With respect to certain drugs the problem becomes one of tolerance, i.e., the patient becomes less reactive to larger and larger amounts of drugs in that the drugs are continually being delivered.
  • Tolerance is a problem with drugs such as narcotics and nitroglycerin used as a vasodilator.
  • drugs such as narcotics and nitroglycerin used as a vasodilator.
  • nicotine the continuous delivery of the nicotine to the patient can result in problems such as sleep disorders, skin irritation and the like (see D.M. Daughton et al.. Arch. Intern. Med. 151:749-752 (1991) and K.O. Fagerstrom et al., J. Smoking Related Dis., in press).
  • the present invention addresses these problems by loading specific amounts of the drug into the device such that the drug will be substantially depleted from the patch after a given period of time, i.e., the drug is depleted from the patch to the extent that drug is no longer delivered to the patient even though it may remain in the patch.
  • a device may be fabricated using the present process so as to contain a volatile fragrance. Such a device is designed to exude fragrance over a protracted, predetermined period of time.
  • Transdermal delivery devices which include a backing layer which is substantially impermeable to the drug, and a drug matrix layer which may be in the form of a pressure-sensitive pharmaceutically acceptable contact adhesive having the drug dispersed therein.
  • the drug is loaded into the drug matrix layer in an amount such that the drug will, after about 14-18 hours (preferably 16 hours) of contact with the patient, be depleted of the drug to the extent that delivery of the drug to the patient is slowed to a rate such that the effect of the drug on the patient is negligible.
  • the loading amount of the drug into the drug matrix layer is closely controlled and varies somewhat depending on the particular drug in that different drugs have different rates of delivery.
  • the nicotine when the system is designed to deliver nicotine, the nicotine is loaded into the drug matrix layer in an amount in the range of about 0.70 to about 1.15, more preferably 0.75 to 0.95 mg/cm 2 .
  • a drug delivery system of the invention By placing a drug delivery system of the invention on a patient there is provided a method of drug delivery whereby the patch is placed on the patient for a period of 24 hours during which time the drug is delivered to the patient during only about 14-18 hours (preferably about 16 hours) after which the drug is depleted from the patch to the extent that any further delivery to the patient is so insignificant as to not have any detectable pharmacological effect on the patient.
  • the delivery devices of the invention are obtained by a method comprising: (a) laminating an adsorbent source layer to a pressure-sensitive, pharmaceutically acceptable contact adhesive layer, the contact adhesive layer comprised of a material that is permeable to the drug and which defines a basal surface for adhesion to skin;
  • a preferred embodiment of the invention is a transdermal drug delivery device for administering nicotine to a human patient transdermally and continuously for a period of approximately 16 hours.
  • the device is comprised of a backing layer which is substantially impermeable to nicotine, which backing layer defines the upper surface of the device.
  • the device is further comprised of an anchor adhesive layer which is adjacent to the backing layer and laminated thereto. Thereafter, a layer of pressure- sensitive, pharmaceutically acceptable, contact adhesive which is permeable to nicotine is provided. This pressure-sensitive adhesive layer defines the basal surface of the device which is adhered to the skin of the patient.
  • the device is also preferably comprised of an adsorbent source layer which is in contact with and contained between the anchor adhesive layer and layer of pressure-sensitive adhesive.
  • the nicotine is preferably dispersed uniformly throughout the layer of pressure-sensitive contact adhesive in an amount such that the nicotine in the device will, after 16 hours of contact with the patient, be depleted to the extent that the delivery of the nicotine to the patient is slowed to a rate such that the effect of the nicotine on the patient is negligible, i.e., no pharmacological detectable effect.
  • the amount of nicotine is preferably in the range of 0.75 to 0.95 mg/cm 2 but can vary outside that range in an amount of about 25% ⁇ .
  • a method and device similar to the aforementioned are provided for the incorporation and release of fragrance. In such a case, the fragrance is initially deposited onto the source layer and then released over time through the adhesive and backing layers which are selected so as to be permeable to the fragrance.
  • a key advantage of the present invention is in the "printing" of the selected drug, drug-vehicle combination, or other material, in liquid form, on the adsorbent source layer in a particular amount. That is, the material is loaded into the device by substantially uniform deposition on the surface of the source layer. For many materials, this one-step deposition eliminates the need for organic solvents as well as the need for heat treatment.
  • the drug migrates into the underlying contact adhesive layer and, depending on the material selected for the anchor adhesive layer, into that layer as well.
  • the release kinetics of the drug into the skin from the contact adhesive layer are determined by the degree of drug loading (which can be at, above, or below saturation in this system) and the diffusivity and solubility of the drug in the two adhesive layers.
  • the source layer thus serves to initially retain the deposited drug which then migrates from the source layer into one or both adhesive layers.
  • Figure 1 shows a partly schematic, sectional view of a transdermal drug delivery device according to the invention.
  • Figure 2 shows an apparatus which may be used in fabricating a transdermal drug delivery device according to the method of the invention.
  • Figure 3 shows the .in vitro permeation of nicotine through human cadaver skin from a transdermal drug delivery device fabricated according to the presently disclosed method.
  • a drug in “liquid form” is meant either a drug that is itself a liquid or a drug which is suspended, dissolved or dispersed in a selected solvent.
  • Solvents may or may not be aqueous, depending on the particular drug used, and may include commonly used liquid vehicles and skin penetration enhancers. Preferred solvents are nonaqueous and selected so that they can be incorporated into the final system without adverse effect.
  • pharmaceutically acceptable material as used herein is meant a material which does not interfere with the biological effectiveness of the drug administered and which is not for any reason biologically or otherwise undesirable.
  • a “permeable” adhesive is meant a material in which the selected drug has at least moderate solubility and diffusivity, i.e., drug solubility ont he order of 5 to 50 wt.%, preferably 10 to 30 wt.%, and diffusivity in the range of about 1 x 10"* to about 1 x 10" 12 cm 2 /sec.
  • substantially impermeable as used herein to describe the backing layer is meant that an effective amount of the selected drug will be contained within the device without loss of any substantial amount through the backing layer. It should be noted that where the device is used for the release of fragrance, however, the backing layer is, by contrast, permeable to the fragrance. In such an embodiment, the device thus allows for release of fragrance into the atmosphere.
  • the transdermal drug delivery device provided by the present method is shown generally at 10.
  • the device is designed specifically for transdermal administration of a drug at controllable, therapeutically effective rates.
  • the device 10 is in the form of a laminated composite that is adapted to be adhered to a predetermined area of unbroken skin or mucosal tissue.
  • the individual layers of the device include an upper backing or "outer skin” layer 11, an anchor adhesive layer 12, a source layer 13 onto which the drug and/or vehicles are deposited initially, a contact adhesive 14 which is adapted to adhere to the skin or mucosa, and a release liner 15.
  • the backing layer 11 functions as the primary structural element of the device and provides the device with much of its flexibility, suitable drape, and, where necessary, depending upon the material incorporated into the device, occlusivity.
  • the backing layer also serves as a protective covering to prevent loss of the drug (and/or vehicle, solubilizer or permeation enhancer, if present) via transmission through the upper surface of the device.
  • the backing layer will by contrast allow release of fragrance into the atmosphere.
  • Backing layer 11 may also be used to impart the device with a desirable or necessary degree of occlusivity which in turn causes the area of skin on which the device is placed to become hydrated. In such a case, a layer is selected that has a level of water vapor transmissibility that makes the device occlusive to the degree required to cause the area of skin to be hydrated.
  • the device provide at least about 90% hydration, more preferably at least about 95% hydration of the skin, as measured by a dielectric hydration probe available from Dr. Howard Maibach, U.C.S.F., San Francisco, California.
  • a dielectric hydration probe available from Dr. Howard Maibach, U.C.S.F., San Francisco, California.
  • Such occlusivity is desirable when drugs such as estradiol or other steroids are being administered.
  • layers that provide a composite that is "breathable", i.e., transmits water vapor from the skin to the atmosphere. Such breathability contributes to the nonocclusive nature of the composite and lessens the likelihood that the area of skin on which the composite is worn will become highly hydrated and irritated.
  • Backing 11 is preferably made of a sheet or film of a preferably flexible elastomeric material that is substantially impermeable to the selected drug.
  • the layer is preferably on the order of 0.0005" to 0.003" in thickness, and may or may not contain pigment.
  • the layer is preferably of a material that permits the device to mimic the contours of the skin and be worn comfortably on areas of skin, such as at joints or other points of flexure, that are normally subjected to mechanical strain with little or no likelihood of the device disengaging from the skin due to differences in the flexibility or resiliency of the skin and the device.
  • elastomeric polymers that are useful for making layer 11 are polyether block amide copolymers (e.g., PEBAX copoly ers) , such as NUKRELL polymers, polyurethanes such as PELLATHANE or ESTANE polymers, silicone elastomers, polyester block copolymers that are composed of hard and soft segments (e.g., HYTREL polymers) , rubber-based polyisobutylene, styrene, and styrene-butadiene and styrene-isoprene copolymers.
  • PEBAX copoly ers such as NUKRELL polymers
  • polyurethanes such as PELLATHANE or ESTANE polymers
  • silicone elastomers silicone elastomers
  • polyester block copolymers that are composed of hard and soft segments (e.g., HYTREL polymers) , rubber-based polyisobutylene, styrene,
  • Polymers that are flexible include polyethylene, polypropylene, polyesters, e.g., polyester terephthalate (PET), which may be in the form of films or laminates.
  • PET polyester terephthalate
  • the preferred polymer used for the backing will depend on the material or drug incorporated into the device and on the nature of any vehicles, solubilizers, or the like that are used.
  • Anchor adhesive layer 12 adheres to backing layer 11 and to source layer 13.
  • the anchor adhesive is preferably but not necessarily of a material in which the selected drug or vehicle has moderate solubility and diffusivity. In such a case, after equilibration, the drug will have diffused not only into the contact adhesive layer 14, but also into the anchor adhesive. Diffusion into both adhesive layers is useful insofar as regulation of release kinetics is concerned. That is, by careful selection of the materials used for the anchor and contact adhesive layers, the distribution of drug throughout the entire system can be regulated. This is because the release kinetics of the drug from the device can be controlled by the diffusivity and solubility of the drug in both of the adhesive layers as well as in backing layer 11.
  • An important aspect of the invention is providing for a specific range of drug loading which will allow the drug to be delivered to the patient over a period of about 14-18 hours (preferably 16 hours) even though the device is worn by the patient for 24 hours. This is accomplished by including a particular concentration of the drug into a layer such as the pressure-sensitive contact adhesive layer. The concentration of the drug within this layer will vary somewhat depending upon the particular drug being delivered. In connection with the present invention it has been found that it is necessary to include nicotine in a concentration within the range of about 0.70 to about 1.15 mg/cm 2 , preferably 0.75 - 0.95 mg/cm 2 and most preferably about 0.83 mg/cm 2 .
  • the nicotine By including nicotine in the adhesive layer in this concentration and placing the patch on the patient the nicotine will be delivered to the patient for approximately 16 hours, after which the drug will be depleted from the delivery system to the extent that the rate of delivery of the drug to the patient is slowed to such an extent that the delivery of nicotine to the patient becomes negligible, i.e., no detectable pharmacological effect.
  • the nicotine may be in the form of a free base or a salt and a particularly useful salt is nicotine monoacetate.
  • the concentration of any particular drug in the adhesive layer will vary somewhat depending on the permeability of that drug to human skin and also somewhat based on the adhesive material.
  • anchor adhesive layer 12 examples include polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, plasticized ethylene-vinyl acetate copolymers, low molecular weight polyether block amide copolymers (PEBAX copolymers) , tacky rubbers such as polyisobutene, polystyrene-isoprene copolymers, polystyrene-butadiene copolymers, and mixtures thereof.
  • the particular polymer(s) used for the anchor adhesive layer will depend on the drug, vehicle, enhancer, etc., selected.
  • the thickness of the anchor adhesive layer may vary but is typically in the range of about 0.0005" to about 0.005".
  • Source layer 13 is a thin, flexible layer of an adsorbent material which provides the surface on which the drug is printed or otherwise deposited.
  • the source layer allows the liquid drug (together with vehicle, solubilizer or the like) to be printed on its surface as a result of having surface properties not found in either the contact or anchor adhesive layers.
  • the drug is deposited in liquid form onto one face of this layer in a substantially uniform pattern. The drug must wet the surface in such a way that squeezing of liquid to the periphery of the device during lamination is substantially prevented.
  • the material is selected so that the drug is adsorbed, rather than absorbed, by the layer, since the drug must be available to migrate into contact adhesive layer 14 and preferably into anchor adhesive layer 12 as well.
  • the source layer is preferably of a non-woven fabric, e.g., polyester, polyethylene, polypropylene, polyamides, rayon or cotton, and a particularly preferred material for the source layer is a 100% non-woven polyester. Woven fabrics, however, can also be used if desired.
  • the thickness of the source layer may vary, but is preferably in the range of about 0.001" to 0.010".
  • the source layer does not serve as a drug reservoir; the drug is only transiently adsorbed by the source layer pending equilibration, i.e., migration into one or both of the adjacent adhesive layers.
  • the inner surface of either the anchor or contact adhesive layers may be treated and thus itself serve as the source layer for purposes of drug deposition.
  • Still another alternative is to use a contact or adhesive layer that has a porous surface, enabling the drug to be printed "into" the surface pores.
  • Contact adhesive layer 14 which plays the principal role in determining the rate at which drug is released from the device, is a pressure- sensitive skin contact adhesive comprised of a pharmaceutically acceptable material. Like source layer 13, it must be chemically and physically compatible with the drug and with any enhancer used. Further, the drug selected must have at least moderate solubility and diffusivity in this layer, since the drug must be able to readily migrate from source layer 13 into and through contact adhesive layer 14 and to the skin.
  • the thickness of the contact adhesive layer is preferably in the range of about 0.0005" to about 0.005".
  • Suitable materials for contact adhesive layer 14 include those enumerated for anchor adhesive 12. It is possible (in some cases) to use materials for the contact adhesive layer that are relatively impermeable to the drug, e.g., where the diffusivity of the drug through skin is quite high. In the case of a fragrance patch, contact adhesive layer 14 may or may not be permeable to the fragrance. In any particular device fabricated according to the present process, the materials chosen for the contact and anchor adhesive layers may be the same or different.
  • device 10 Prior to use, device 10 includes a release liner 15. Just prior to use, this layer is removed from the device to expose contact adhesive layer 14. The release liner will normally be made from a drug/vehicle/enhancer impermeable material that is inherently "strippable" or rendered so by techniques such as silicone or fluorocarbon treatment.
  • Device 10 need not include a means for controlling the rate at which either the drug or the enhancer is administered to skin. Instead, the release kinetics of the drug from the bandage can be controlled by the materials selected for the anchor and contact adhesive layers and by the degree of drug loading. Either the contact adhesive layer or the source layer could be rate-controlling, depending on the drug and materials selected. Alternatively, the drug and/or vehicle icroencapsulated to provide controlled release could be deposited on the source layer prior to lamination, i.e., instead of deposition of the drug in "liquid form" as previously defined.
  • the drug is presented to the skin at a rate in excess of the rate that the treated area of skin is able to absorb.
  • an element in the device that will control the release rate of the drug and/or the enhancer.
  • Such elements are known in the art.
  • the most common is a polymer membrane having appropriate drug/enhancer permeability properties interposed between the source layer and the contact adhesive layer.
  • drug as used to describe the principal active ingredient of the device intends a biologically active compound or mixture of compounds that has a therapeutic, prophylactic or other beneficial pharmacological and/or physiological effect on the wearer of the device.
  • types of drugs that may be used in the inventive device are anti-inflammatory drugs, analgesics, antiarthritic drugs, tranquilizers, narcotic antagonistis, antiparkinsonism agents, anticancer drugs, immunosuppression agents, antiviral agents, antibiotic agents, appetite suppressants, antiemetics, anticholinergics, antihistaminics, antimigraine agents, coronary, cerebral or peripheral vasodilators, anti-anginals, e.g., calcium channel blockers, hormonal agents, contraceptive agents, antithrombotic agents, diuretics, antihypertensive agents, cardiovascular drugs, chemical dependency drugs, and the like.
  • the appropriate drugs of such types are capable of permeating through the skin either inherently or by virtue of treatment of the skin with a percutaneous absorption enhancer. Because the size of the device is limited for patient acceptance reasons, the preferred drugs are those which are effective at low concentration in the blood stream.
  • steroids such as estradiol, progesterone, norethindrone, norethindrone acetate, levonorgestrel, ethynodiol diacetate, norgestamate, gestadene, desogestrel, 3-keto desogestrel, demegestone, promegestrone, testosterone, hydrocortisone, and their esters; nitro compounds such as amyl nitrate, nitroglycerine and isosorbide nitrates; amine compounds such as nicotine, chlorpheniramine, terfenadine and triprolidine; oxicam derivatives such as piroxicam; mucopolysaccharidases such as thiomucase; opioids such as buprenorphine, fentanyl and fentanyl derivatives or analogs, naloxone, codeine, dihydroergotamine, pizotiline, slabutamol and terbutaline; pros
  • the present method and device are suitable for use with volatile drugs and excipients, as no heat treatment step is involved or necessary.
  • the present invention is useful with drugs such as nicotine, nitroglycerin, amyl nitrate, and scopolamine.
  • the present device is also useful with drugs such as fentanyl, which will typically be incorporated into the patch using nonaqueous, volatile vehicles and/or enhancers which, because they volatilize during heat treatment, have proven difficult to incorporate into a transdermal delivery device by conventional means.
  • a percutaneous absorption enhancer will be present in the device along with the drug, i.e., will be initially deposited on source layer 13 together with the drug.
  • the enhancer may also increase the diffusivity of the drug in the source layer and in the adhesive layers, thus increasing the permeability of the device as a whole to the drug.
  • Any number of the many percutaneous absorption enhancers known in the art may be used in conjunction with the present invention. For examples of suitable enhancers, see U.S. Patents Nos.
  • enhancers will be included in the device, "printed" onto the source layer along with the drug or incorporated into one or both of the adhesive layers.
  • enhancers when the device is used to administer a drug to which the permeability of the skin is inherently sufficient to pass therapeutic amounts, it is not necessary to coad inister an enhancer.
  • the inclusion of an enhancer in the device is optional, depending on the particular drug that is being administered.
  • anchor adhesive 12 may be roll-coated onto a backing layer 11 of a commercially available film at a coating weight in the range of about 0.2 mg/cm 2 to 15 mg/cm 2 , more preferably in the range of about 1 mg/cm 2 to 10 mg/cm 2 .
  • the pressure-sensitive skin contact adhesive 14 may be coated onto release liner
  • the source layer 13 is then deposited onto either contact adhesive layer 14 or onto anchor adhesive 12, preferably onto the contact adhesive.
  • the selected drug in liquid form (optionally admixed with enhancer) , is then printed onto the exposed surface of source layer 13 using conventional printing techniques.
  • the drug is initially contained in one or both of the anchor and contact adhesive layers (e.g., by incorporation of the drug into the layers prior to lamination) , and enhancer and/or vehicle is printed onto the source layer.
  • Example 1 A bandage for delivering nicotine transdermally for approximately 16 hours was prepared as follows.
  • the anchor adhesive was coated onto a facestock of about 0.0015" flexible polyester laminate at a coating weight of 6.5 mg/cm 2 .
  • the composition of the anchor adhesive was approximately 1:5:2 polyisobutylene, m.w. 1.2 x 10 6 / polyisobutylene, m.w. 35,000/ polybutene blend, m.w. 2300.
  • the pressure- sensitive contact adhesive having the same composition as the anchor adhesive layer was coated, also at 6.5 mg/cm 2 , onto a 0.003" siliconized polyester release liner.
  • the source layer a 100% non-woven polyester fabric at 4.2 mg/cm 2 , was then laminated to the anchor adhesive.
  • Nicotine free base was deposited, neat, onto the source layer using a fine mist airbrush in a uniform pattern, at about 0.9 mg/cm 2 .
  • the contact adhesive/release liner composite was then laminated onto the exposed surface of the drug reservoir, forming a laminate of the final device as shown in Figure 1.
  • Individual devices were die cut from the laminated product. The resulting in vitro skin permeation over 13 hours is shown in Figure 3.
  • Example 2 Example 1 was repeated, except that prior to deposition the nicotine was diluted with freon to a concentration of 10 wt.% to facilitate dispersal in the source layer. After deposition, the freon is removed by blowing warm air (about 30°C) over the laminate for about 2 minutes.
  • Example 3 A bandage for delivering nitroglycerine was made in a manner similar to that described in Example 1 for the nicotine bandage.
  • the nitroglycerine was deposited onto the source layer as a 10% solution in ethanol using polyethylene glycol monolaurate (PGML) as carrier.
  • PGML polyethylene glycol monolaurate
  • the ethanol was allowed to evaporate and the final laminate was prepared as described in Example 1.
  • Example 4 A transdermal device for delivering nicotine monoacetate transdermally for approximately 16 hours was prepared as follows.
  • a first subassembly PIB adhesive was coated onto a facestock of a 12.5 micron flexible polyester film at a coating weight of 4.0 mg/cm 2 .
  • the PIB adhesive was coated, also at 4.0 mg/cm 2 , onto a 0.003" siliconized polyester release liner to provide a second subassembly.
  • a 100% polyester non-woven fabric at 35 g/yd 2 was then laminated to the PIB adhesive of the first assembly. Nicotine monoacetate was deposited, neat, onto the fabric in a uniform pattern, at about 1.1 mg/cm 2 .
  • the second subassembly composite was then laminated onto the exposed surface of the drug-containing fabric forming a five-layer laminate. Individual devices were die cut from the laminated composite.

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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Un dispositif d'apport médicamenteux percutané (10), lequel peut être porté par un patient humain pendant 24 heures tout en assurant à celui-ci l'apport continu d'un médicament pendant environ 16 heures, est produit par un procédé particulier de fabrication. Ce dispositif (10) est notamment utile pour l'apport de médicaments qui, s'ils sont administrés pendant 24 heures, entraînent des problèmes tels que l'effet d'épuisement du médicament (par ex. la nitroglycérine) ou bien des troubles du sommeil (par ex. la nicotine). Le médicament est chargé dans le dispositif (10) en une concentration telle qu'il se réduit dans le dispositif après environ 16 heures au point que la vitesse d'apport du médicament au patient est ralentie à tel point que l'effet pharmacologique du médicament sur le patient devient pratiquement non existant. Le dispositif (10) se présente sous la forme d'un composite stratifié qui est adapté pour être collé sur une région prédéterminée du tissu dermique ou muqueux intact. Les différentes couches du dispositif sont constituées d'une couche supérieure de support ou 'de peau extérieure' (11), d'une couche adhésive d'ancrage (12), d'une couche-source (13) sur laquelle le médicament et/ou les excipients sont déposés initialement, d'un adhésif de contact (14) conçu pour adhérer à la peau ou aux muqueuses, et d'un revêtement de libération (15).
EP93901003A 1992-08-25 1992-12-10 Dispositif d'apport medicamenteux percutane depose par empreinte. Withdrawn EP0656771A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US93504492A 1992-08-25 1992-08-25
PCT/US1992/010672 WO1994004109A1 (fr) 1992-08-25 1992-12-10 Dispositif d'apport medicamenteux percutane depose par empreinte
US935044 1997-09-22

Publications (2)

Publication Number Publication Date
EP0656771A1 true EP0656771A1 (fr) 1995-06-14
EP0656771A4 EP0656771A4 (fr) 1996-07-31

Family

ID=25466511

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93901003A Withdrawn EP0656771A4 (fr) 1992-08-25 1992-12-10 Dispositif d'apport medicamenteux percutane depose par empreinte.

Country Status (8)

Country Link
EP (1) EP0656771A4 (fr)
JP (1) JPH08502727A (fr)
KR (1) KR950702811A (fr)
AU (1) AU3247193A (fr)
CA (1) CA2142871A1 (fr)
FI (1) FI950766A (fr)
NO (1) NO950725L (fr)
WO (1) WO1994004109A1 (fr)

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DE19814084B4 (de) 1998-03-30 2005-12-22 Lts Lohmann Therapie-Systeme Ag D2-Agonist enthaltendes transdermales therapeutisches System zur Behandlung des Parkinson-Syndroms und Verfahren zu seiner Herstellung
HU225734B1 (en) * 1999-07-28 2007-07-30 Zoltan Dardai Multilayer plaster for introducing peptidaceous pharmacons in living organisms and process for producing thereof
DE10110391A1 (de) 2001-03-03 2002-09-26 Lohmann Therapie Syst Lts Hochflexibles Nikotin transdermales therapeutisches System mit Nikotin als Wirkstoff
US8246980B2 (en) 2002-07-30 2012-08-21 Ucb Pharma Gmbh Transdermal delivery system
DE10234673B4 (de) 2002-07-30 2007-08-16 Schwarz Pharma Ag Heißschmelz-TTS zur Verabreichung von Rotigotin und Verfahren zu seiner Herstellung sowie Verwendung von Rotigotin bei der Herstellung eines TTS im Heißschmelzverfahren
DE10261696A1 (de) 2002-12-30 2004-07-15 Schwarz Pharma Ag Vorrichtung zur transdermalen Verabreichung von Rotigotin-Base
ATE448828T1 (de) 2003-10-27 2009-12-15 Univ Basel Transdermales arzneimittelabgabesystem
JP4745747B2 (ja) * 2004-08-12 2011-08-10 日東電工株式会社 フェンタニル含有貼付製剤
JP4824963B2 (ja) 2004-08-12 2011-11-30 日東電工株式会社 貼付材及び貼付製剤
AU2005284908B2 (en) 2004-09-13 2011-12-08 Morningside Venture Investments Limited Biosynchronous transdermal drug delivery
US8252321B2 (en) 2004-09-13 2012-08-28 Chrono Therapeutics, Inc. Biosynchronous transdermal drug delivery for longevity, anti-aging, fatigue management, obesity, weight loss, weight management, delivery of nutraceuticals, and the treatment of hyperglycemia, alzheimer's disease, sleep disorders, parkinson's disease, aids, epilepsy, attention deficit disorder, nicotine addiction, cancer, headache and pain control, asthma, angina, hypertension, depression, cold, flu and the like
US8372040B2 (en) 2005-05-24 2013-02-12 Chrono Therapeutics, Inc. Portable drug delivery device including a detachable and replaceable administration or dosing element
IL177071A0 (en) * 2005-08-01 2006-12-10 Nitto Denko Corp Method of preparing a nicotine transdermal preparation
EP1774964B1 (fr) 2005-10-13 2014-08-06 Nitto Denko Corporation Système therapeutique transdermique comprenant de nicotine et sa méthode de production
JP5535497B2 (ja) * 2008-03-06 2014-07-02 リンテック株式会社 経皮吸収貼付剤
JP5460971B2 (ja) * 2008-03-28 2014-04-02 リンテック株式会社 経皮吸収貼付剤
PL2468274T3 (pl) * 2010-12-14 2015-11-30 Luye Pharma Ag Przezskórny układ terapeutyczny do podawania substancji czynnej
CA2841785A1 (fr) 2011-07-06 2013-01-10 The Parkinson's Institute Compositions et methodes de traitement de symptomes chez des patients atteints de la maladie de parkinson
US10028858B2 (en) 2011-07-11 2018-07-24 Medicines360 Intrauterine systems, IUD insertion devices, and related methods and kits therefor
US10105487B2 (en) 2013-01-24 2018-10-23 Chrono Therapeutics Inc. Optimized bio-synchronous bioactive agent delivery system
JP2018511355A (ja) 2015-01-28 2018-04-26 クロノ セラピューティクス インコーポレイテッドＣｈｒｏｎｏ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｉｎｃ． 薬剤送達方法及びシステム
EP3267875A4 (fr) 2015-03-12 2018-12-05 Chrono Therapeutics Inc. Système d'entrée d'état de manque et de support
AU2018205529B2 (en) 2017-01-06 2023-08-10 Morningside Venture Investments Limited Transdermal drug delivery devices and methods
CA3101966A1 (fr) 2018-05-29 2019-12-05 Morningside Venture Investments Limited Procedes et systemes d'administration de medicament

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Also Published As

Publication number Publication date
FI950766A0 (fi) 1995-02-20
FI950766A (fi) 1995-03-22
KR950702811A (ko) 1995-08-23
JPH08502727A (ja) 1996-03-26
NO950725L (no) 1995-04-10
NO950725D0 (no) 1995-02-24
WO1994004109A1 (fr) 1994-03-03
EP0656771A4 (fr) 1996-07-31
AU3247193A (en) 1994-03-15
CA2142871A1 (fr) 1994-03-03

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