MXPA97004291A - System of release transdermica conrecubrimiento adhesivo and disco de selladodesprendi - Google Patents

Abstract

The present invention relates to a device (10) for administering an active agent to the skin or mucosa of an individual comprising a laminated composition of an adhesive coating (26), a support layer (14) below the central portion of the adhesive coating, a membrane permeable to the active agent (16), the support layer and the membrane define a reservoir (12) containing a formulation of the active agent, a removable sealing disc (20) under the membrane permeable to the active agent , a thermal seal (22) around the periphery of the peelable seal disc, the membrane permeable to the active agent and the support layer, and a removable, removable coating (24) under the exposed coating and the peelable seal disc. The adhesive layer is above and peripheral to the path of the active agent towards the skin or mucosa and is protected from degradation by the components of the reservoir by a multiplicity of thermal seals. The removable sealing disc that it contains protects against the release of the reservoir containing the active agent and the release liner protects the adhesive from exposure to the environment before its application.

Description

TRANSDERMAL RELEASE SYSTEM WITH ADHESIVE COATING AND DESPENDABLE SEALING DISC TECHNICAL FIELD 5 This invention is in the field of transdermal and transmucosal administration of active agents (drugs). More particularly, it relates to a device for achieving such administration having a reservoir containing active agent and an adhesive layer for securing the device to the skin or mucosa. The adhesive layer is above and peripheral to the path of the active agent to the skin or mucosa and is protected from degradation by the components of the reservoir by a multiplicity of thermal seals. A removable sealing disc protects against the release of the reservoir containing the active agent and the release liner protects the adhesive from the. Exposure to the environment before use. 2 »BACKGROUND OF THE INVENTION Devices for administering drugs through the skin or mucosa have been described in many patents.

These devices are usually of two types: systems of matrix and liquid reservoir systems. Both systems are REF: 24768 laminated compositions having, from bottom to top, a releasable, removable liner, a pressure-sensitive adhesive layer for adhering the device to the skin, a drug-containing layer, and a waterproof backing layer to the drug. In the matrix type system, the drug is dispersed within a solid or semi-solid carrier. In the reservoir type system, the drug, typically in liquid solution, is contained within the sandwich container, usually formed between the support layer and a drug permeable membrane layer. Numerous reservoir type systems have been described. U.S. Patent No. 4,710,191 to Kwiatek et al., Involves a reservoir-type device that includes a releasable, heat-sealed, release liner layer below the reservoir and a portion of the support layer extending beyond the reservoir . In a second embodiment, a microporous membrane is included between the support layer and the reservoir. U.S. Patent No. 4,829,224 to Chang et al., Discloses a device with a reservoir that is defined by a support layer and a drug permeable membrane layer. An annular layer made of an adhesive is peripheral to the reservoir. The removable coating layer is located under the membrane. A second removable layer, the releasable liner, is found underneath the entire assembly. A first thermal seal connects the support layer and the membrane and surrounds the reservoir. A second concentric thermal seal around the first thermal seal connects the support layer and the release liner. The second thermal seal is broken when the release liner is removed. The device may include an inner liner which is under the membrane and portions of the support layer. This internal coating is removed after removal of the releasable coating so that the membrane is exposed. U.S. Patent No. 4,983,395 to Chang et al. Relates to another device with a support layer and a membrane layer defining a reservoir. A removable inner reservoir is located below the reservoir and portions of the support and membrane layers outside the periphery of the reservoir. An adhesive layer is located under the inner lining and the remaining portions of the support and membrane layers. A releasable, removable liner is found beneath the adhesive layer. A first thermal seal connects the support and membrane layers on the periphery of the reservoir. A second thermal seal is located under the first thermal seal and connects the membrane and the inner lining. In use, the release liner and the inner liner are peeled off to expose the underlying surfaces of the membrane and adhesive layers before placing the device on the skin or mucosa. The present invention is an improved device for the transdermal or transmucosal release of a drug in which a removable sealing layer, occlusive, is located under the reservoir that contains the drug and serves to prevent the release of the drug before use. A release liner covers the removable sealing layer and the exposed portions of the adhesive coating. In this way, the releasable liner does not need to be occlusive and can thus be chosen from a wide variety of materials that may have the ability to breathe, and may have a stretchable, elastic quality. Such devices are cheap and easy to manufacture. Furthermore, in the devices of this invention only the central portion of the device in line with the reservoir is occlusive, leaving the portion of the peripheral device to the central portion non-occlusive or capable of breathing.

DETAILED DESCRIPTION OF THE INVENTION The invention is a device for administering an active agent to the skin or mucosa of an individual comprising a laminated composition of: (a) an adhesive coating having a central portion and a peripheral portion; (b) a support layer which is below the central portion of the adhesive coating; (c). a membrane permeable to the active agent that lies beneath the support layer, the support layer and the membrane define (d) a reservoir therebetween that contains an active agent; (e) a peelable seal disk beneath the membrane permeable to the active agent; (f) a thermal seal around the periphery of the releasable sealing disc, the membrane permeable to the active agent and the support layer; and (g) a removable, removable liner, below the peripheral portion of the adhesive coating and the peelable seal disk.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a sectional view, amplified of an embodiment of the device of the invention. Figures 2A and 2B are plan views, amplified of additional embodiments of the device of the invention. Figure 3 is a sectional view, amplified of another embodiment of the invention, Figure 4 is an amplified view of the embodiment of Figure 3 showing the disassembled embodiment. Figure 5 is a graph showing a comparison of calculated and experimental cumulative release kinetics of treometamine keterolact based on the tests described in Example 23.

MODES FOR CARRYING OUT THE INVENTION Figure 1 shows a device, generally designated as being designed to deliver a formulation of an active agent to the skin or mucosa. The device 10 is a laminated composition. A drug reservoir 12 is formed between an upper support layer 14 and a lower drug permeable membrane layer 16. A removable sealing disc 20 is located below the membrane layer 16. The three layers, the support layer 14 , the membrane layer 16 and the peelable sealing disc 20 are thermally sealed together at their periphery 22, the membrane layer 16 is thermally sealed to the support layer 14 and the peelable seal disc 20 is thermally sealed to the barrier layer. membrane 16. A releasable liner 24 is placed below the peelable seal disc 20 and extends beyond the periphery of the thermal seal 22. An adhesive layer 26 is placed on the support layer 14 and the portions of the releasable liner 24 that they extend beyond the periphery of the thermal seal 22. A more superior coating layer 30 is on the adhesive layer 26. In this embodiment the releasable coating is removed together with the removable sealing disc before placing the device on the skin. Figures 2A and 2B show additional embodiments of the device wherein a tongue 32 extends beyond the thermal seal 22 and allows for easy removal of the peelable seal disc 20. The tongue 32 may extend a short distance beyond the thermal seal 22 as is shown in Figure 2A or may extend towards the periphery 34 of the device 10 as shown in Figure 2B.

Figures 3 and 4 describe another embodiment, generally designated 40, of the laminated composition of the invention. The device of Figures 3 and 4 differs from that of Figure 1 by the presence of a second adhesive layer which is below the peelable sealing disc and the peripheral portion of the first adhesive layer. More specifically, the device 40 consists of (from the surface above the basal surface) a non-occlusive coating layer 42, a first adhesive layer 44, a support layer 46, a drug reservoir 48 that comprises a formulation in solution or gelled of a transdermally administrable drug; a membrane layer permeable to the drug 50; a releasable sealing disc 52, a second adhesive layer 54, and a releasable coating layer 56. As shown, the support film, reservoir, membrane, and peelable seal disc are "in line" and have additional areas. small that the coating, the two adhesive layers and the releasable coating. The latter extends peripherally beyond the entire periphery of the former. The support film, the membrane and the releasable sealing disc are thermally sealed around their peripheries. In use the releasable coating layer, the portion of the second adhesive layer which is under the removable sealing disc, and the sealing disc are separated from the rest of the assembly. The separate or disassembled configuration is shown in Figure 4. In this regard, the relative bonding forces between the releasable layer and the second adhesive layer, the second adhesive layer and the first adhesive layer and the removable sealing disc, and the disc The peelable seal and the membrane are such that when the releasable liner is removed, the central portion of the second adhesive layer and the peelable seal disc move with it. The assembly of the removed removable layer is discarded. The sub-assembly containing the drug reservoir is placed on the skin, with the peripheral ring of the second adhesive layer being the means by which that sub-assembly is fixed to the skin or mucosa. When this is placed on the skin, the drug reservoir is in communication by diffusion with the skin via the membrane. In other words, the drug is free to diffuse through the membrane to the skin. The support layer 14 or 46 of the device may be composed of a single film or a plurality of films. In any case, its internal surface must be capable of being thermally sealed to the membrane layer 16 or 50. One or more of the films constituting the support layer should be impermeable to the components of the drug formulation contained in the reservoir . Examples of materials used as support layers in the transdermal delivery devices that may be used in the present invention are polyethylene, polypropylene, polyvinyl chloride, polyethylene terephthalate, ethylene-vinyl acetate copolymers and combinations thereof. The layer may include one or more metallic layers and / or one or more fibrous layers. Preferably the support layer is occlusive. The term "active agent" or "drug" as used to describe the main active ingredient of the device which purports a biologically active compound or mixture of the compounds having a therapeutic, prophylactic or other pharmacological and / or physiological beneficial effect on the user of the device. Examples of types of drugs that can be used in the device of the invention are anti-inflammatory drugs, analgesics, antiarthritic drugs, antispasmodics, antidepressants, antipsychotic drugs, tranquilizers, anti-aging drugs, narcotic antagonist, antiparkinsonism agents, agonists cholinergic, anticancer drugs, immunosuppressive agents, antiviral agents, antibiotic agents, appetite suppressants, antiemetics, anticholinergics, antihistamines, antimigraine agents, coronary vasodilators, cerebral or peripheral, hormonal agents, contraceptive agents, antithrombotic agents, diuretics, antihypertensive agents, cardiovascular drugs and similar. Appropriate drugs of such types are capable of permeating through the skin either inherently or by virtue of the treatment of the skin with a percutaneous abscess enhancer. Due to the size of the device, the patient is limited to accepting the reasons, the preferred drugs that are effective at low concentration in the bloodstream. Examples of specific drugs are steroids such as estradiol, progesterone, norgestril, levonorgestril, norethindrone, medroxyprogesterone acetate, 3-ketodesogestril, testosterone and their esters, nitro compounds such as nitroglycerin and isosorbide nitrates, nicotine, chlorpheniramine, terfenadine, triprolidine, hydrocortisone, oxicam derivatives, such as piroxieam, ketoprofen, mucopolysaccharides such as tiomucase, buprenorphine, fentanyl, naloxone, codeine, dihydroergotamine, pizotiline, salbutamol, terbutaline, prostaglandins such as misoprostol and enprostil, omeprazole, imipramine, benzamides such as etoclopamine, scopolamine, peptides such as factor growth promoter and somatostatin, clonidine, dihydropyridines such as nifedipine, verapamil, ephedrine, pindolol, etoprolol, spironolactone, nicardipine hydrochloride, calcitriol, thiazides such as hydrochlorothiazide, flunarizine, sidononymines such as molsidomine, sulfated polysaccharides such as fractions of heparin and salts of such compounds with pharmaceutically acceptable acids or bases. In addition to the drugs described above, depending on the permeability of the skin to the drug or drugs, the reservoir may also contain a percutaneous absorption enhancer that increases the permeability of the skin to the drug or drugs and is coadministered to the skin. Examples of percutaneous absorption enhancers are those referred to in U.S. Patent Nos. 3,989,816, 4,863,970, 4,316,893, 4,405,616, 4,060,084 and 4,379,454 and J. Pharm Sci (1975) 64: 901-924. The formulation contained in the reservoir may further include solvents, gelling agents, stabilizers, anti-irritants and other additives. The membrane layer 16 or 50 is permeable to the drug. This should be a "dense" membrane made of material that is inherently permeable to reservoir components that are administered to the skin or mucosa or can be made of a microporous membrane whose pores are filled with a drug permeable material including the reservoir formulation of drug itself which may include enhancers if desired. In the case of dense membranes, the components dissolve in the material and diffuse through the material to the skin. In the case of microporous materials, the components diffuse through the pores into the skin. The membrane may or may not be of an element that controls the rate depending on the particular drug involved, the permeability of the skin to the drug, and the rate of release required to provide the therapy. Examples of materials for making dense membranes are given in U.S. Patent Nos. 3,598,122 and 4,650,484. Examples of materials for making microporous membranes are provided in U.S. Patent Nos. 3,797,494 and 4,031,894. Adhesive layers 26, -44 and 54 are composed of pressure-sensitive surgical adhesives such as those that are commonly used to attach transdermal drug delivery devices, bandages or other dressings to the skin. Examples of such adhesives are polyisobutene (PIB), natural rubber adhesives, acrylate and methacrylate adhesives and silicone adhesives. Non-occlusive breathable adhesives such as acrylate / methacrylate / silicone adhesives are preferred. The removable sealing disc 20 or 52 can be composed of a single layer or a multiplicity of layers. The disk should be (1) impermeable to the components of the drug reservoir formulation that diffuse through the membrane, (2) thermally sealable to the membrane layer, and (3) inherently peelable or rendered so by such techniques like the treatment with silicone or fluorocarburo or treatment on the surface with a layer incompatible with the seal. Suitable removable sealing discs include those made of Bertek 4418 Removable Seal, Total Healthcare Packaging TPC-0812 or TPC-0760 and UCB Medical Industries LR 4/25. The releasable coating 24 or 56 may also be composed of a single layer or a multiplicity of layers. Unlike the peelable seal disc, however, the release liner need not be impermeable to the components of the drug formulation since the peelable seal disc protects against release of the reservoir components. Therefore, suitable releasable coatings can be made of materials such as polyester, low density polyethylene (LDPE), high density polyethylene (HDPE), polypropylene, polystyrene, polyamide, nylon, polyvinyl chloride and especially papers, and include Akrosil Bioliberable coatings, Scotchpak 1022 release coatings, Adhesives Research AR5MS, Custom Coating and Laminating 7000 on HDPE or 6020 on polyethylene terephthalate (PET).

The coating layer 30 or 42 is on the adhesive layer 26 or 44 and can be made of materials such as polyolefin, polyurethane, nylon, polyester, vinyl, acetate taffeta or other woven or non-woven elastomeric fabrics or films. Preferably the coating material is non-occlusive (it has the ability to breathe). The respective components of the device can be formulated and assembled using methods that are known from the techniques of drug formulation, transdermal devices and lamination. The shape of the device is not critical, and the devices of preformed shapes can be directly mounted or purchased, cut or formed in other circumstances from large sheets of laminated compositions. The following examples illustrate the invention better. These examples are not intended to limit the invention in any way.

EXAMPLES Example 1 A medical grade pressure sensitive acrylic adhesive, MA-31 (Adhesives Research, Glen Rock, PA) was coated on a siliconized release liner with low peel strength using a casting blade with a 10 mil space . The adhesive solvent was evaporated at 80 ° C for 15 minutes to provide a final dry adhesive thickness of 0.002 inches. The coating material Volara Foa 15EO (Voltek, Division of Sekisui America Corp, Lawrence MA), was then laminated onto the dry adhesive film to form the coating adhesive sheet. This adhesive coating sheet was used in a last stage of the manufacturing process as described below. A gelled testosterone formulation was prepared by dissolving 15 mg / ml of testosterone in a solution containing 50.0 / 15.0 / 30.0 / 2.5 / 2.5% (volume / volume) of ethanol / water / glycerin / monooleate • glycerol / methyl laurate. The resulting solution was gelled with 3.0% (weight / volume) of Carbopol 1342. The pH of the resulting gel was adjusted to 4.5 to 5.0 by the addition of 2N sodium hydroxide. The total patch with the peelable seal disc was fabricated as follows: A CoTran 9711 microporous membrane (3M, St. Paul) was placed on a LR4 / 25 peelable seal disc film (UCB Medical Industries, Bloomfield, CT). 0.9 g of the testosterone formulation was distributed on the microporous membrane. The support film (Scotchpak 1012, 3M, St. Paul MN) was prewound to provide a flat, circular cup with a volume of about 1.0 ce. This pre-onset support film was placed on the gel so that the dent in the support film was filtered over the gel mound. The support film is then thermally sealed to the microporous membrane sheet / release film at 370 ° F with a pressure of 30 psi and a drying time of 0.4 seconds. A circular heat sealing die or die with an inner diameter of 1.22 inches and a thermal seal width of 0.3 inches was used. A reservoir containing gel with an active surface of 7.5 cm2 was formed. This thermal sealing step simultaneously creates a permanent reservoir seal between the microporous membrane and the supporting film and the removable seal between the microporous membrane and the releasable sealing disc film. This intermediate-containing drug reservoir system with a diameter of 3.5 cm_ and a total surface area of 9.6 cm2 was cut with die or matrix of the thermally sealed sheet. The anterior reservoir system was laminated to the previously prepared coating adhesive sheet by removing the protective release liner of the coating adhesive, placing the punch or die cut reservoir system on the adhesive with the backing film in contact with the adhesive by rewinding the adhesive. releasable coating on the exposed adhesive and finally cutting with die or matrix the transdermal delivery system with current coated adhesive of this sheet. The cutting die or die used for this operation has a diameter of 5.5 cm thus cutting a transdermal delivery system with a final surface area of 23.8 cm2, which includes the peripheral adhesive area. The activation of this system before application to the skin proceeds in a two-step process: the releasable lining that covers the adhesive is removed first, followed by the removal of the film from the detachable disc that protects the reservoir.

Example 2 Transdermal systems were made with an adhesive coating using the procedure described in Example 1, except that the adhesive used was a medical grade acrylic adhesive, Gelva 737 (Monsanto, St. Louis, MO).

Example 3 Transdermal systems were made with an adhesive coating using the procedure described in Example 1, except that the adhesive used was an adhesive of medical grade PIB MA-24 (Adhesives Research, Glen Rock, PA).

Example 4 Transdermal systems were made with an adhesive coating using the procedure described in Example 1, except that a silicone-based adhesive, BIO PSA X7-2920 (Dow Corning, Midland, MI) was used. The release liner used was the Akrosil Bioliberable coating (Menasha, WI) which is compatible with the above silicone adhesive.

Example 5 Transdermal systems were made with an adhesive coating using the procedure described in Example 1, except that the adhesive used was an adhesive (acrylic copolymer) TSR Adhesive (Sekisui Chemical Company, Osaka, Japan).

Example 6 Transdermal systems were made with an adhesive coating using the same procedures described in Example 1, except that the removable sealing disc film was a multi-layered flexible PET / LDPE / Sheet / Primacor 3440 / LLDPE / Film foil packaging material. Thermal Sealing, TPC-0812 (Tolas Healthcare Packaging, Feasterville, PA).

Example 7 Transdermal systems were made with an adhesive coating using the same procedure described in Example 1, except that the releasable sealing disc film was a thin release film material, a multi-layer film of PET / adhesive / Sheet / Adhesive / LLDPE / Thermal Seal (Technipaq, Crystal Lake, IL).

Example 8 Transdermal systems were made with an adhesive coating using the procedure described in Example 1, except that the coating material was a stamped polyurethane elastomeric film.

Example 9 Transdermal systems were made with an adhesive coating using the procedure described in Example 1, except that the coating material was a 100% non-woven polyester fabric.

Example 10 Transdermal systems were made with an adhesive coating using the procedure described in Example 1, except that the coating material was a nylon film bonded by centrifugation.

Example 11 Transdermal systems were made with an adhesive coating using the procedure described in Example 1, except that the coating material was a non-woven taffeta acetate film.

Example 12 A commercially available wound dressing ie 4 inches x 4 inches, Mitraflex® Plus, distributed by Calgon Vestal Laboratories, was used as the adhesive coating. A formulation of gelled ketorolac tromethamine was prepared by dissolving 60 mg / ml of ketorolac tromethamine in a solution containing 55.28 / 33.17 / 10.0 / 1.55% (volume / volume) of isopropyl alcohol / water / glycerin / isopropyl methyl ester. The resulting solution was gelled with 5.0% (weight / volume) of Natrosol® Plus 330 CS and the pH of the resulting gel was adjusted to 5.1 ± (0.2) by the addition of 2N HC1. The gel also contained 0.1% (weight / volume) of butylated hydroxy toluene as an antioxidant. The coating patch with the peelable sealing disc was made as follows: A CoTran 9710 microporous membrane was placed on a releasable sealing disc film LR4 / 25. 3.44 g of the cetotolac tromethamine formulation was dispersed on the microporous membrane. The support film was pre-blended to provide a flat, circular cup. This dented support film was placed on the gel so that the dented on the support film was concentrated on the gel mound. The support film was then thermally sealed to the microporous membrane sheet / release film at 370 ° F with a pressure of 30 psi and a drying time of 0.4 seconds. An oval heat seal die or die was used to form a reservoir containing gel with an active surface area of 30 cm 2. This thermal sealing step simultaneously creates a permanent reservoir seal between the microporous membrane and the supporting film and a releasable seal between the microporous membrane and the releasable sealing disc film. This reservoir system containing intermediate drug, with a total surface area of 42.55 cm2, was then cut with a die or matrix of the thermally sealed sheet. The above reservoir systems were laminated to the Mitraflex® Plus coating adhesive sheet by removing the protective release liner from the wound dressing, placing the reservoir system cut in die or die over the adhesive with the support film in contact with the adhesive and re-coating the releasable coating on the exposed adhesive to obtain the transdermal delivery system with current coating adhesive. Activation of this system prior to application to the skin proceeds in a two-step process: the release liner covering the adhesive is removed first, followed by the removal of the release film that protects the reservoir.

Example 13 Transdermal systems were made with an adhesive coating using the procedure described in Example 12, except that the adhesive coating sheet used was manufactured as in Example 1. The final surface area of the transdermal delivery system was 63 cm2.

Example 14 Transdermal systems were made with an adhesive coating using the procedure described in Example 13, except that the adhesive used was a medical grade PIB adhesive, MA-24 (Adhesives Research, Glen Rock, PA).

Example 15 Transdermal systems were made with an adhesive coating using the procedure described in Example 13, except that a silicone-based adhesive was used, BIO PSA X7-2920 (Dow Corning, Midland, MI). The release liner used was the BioLiberable Akrosil coating (Menasha, I) which is compatible with the previous silicone adhesive.

Example 16 Transdermal systems were made with an adhesive coating using the procedure described in Example 13, except that the adhesive used was an acrylic copolymer adhesive, TSR Adhesive (Sekisui Chemical Company, Osaka Japan).

Example 17 Transdermal systems were made with an adhesive coating using the procedure described in Example 13, except that the peelable sealing disc film was a multi-layered flexible PET / LDPE / Sheet / Primacor 3440 / LLDPE / Seal film Thermal, TPC-0812 (Tolas Healthcare Packaging, Feasterville, PA).

Example 18 Transdermal systems were made with an adhesive coating using the same procedure described in Example 13, except that the releasable sealing disc film was a thin release film, a multi-layer film of PET / adhesive / sheet / adhesive / LLDPE / Thermal Sealing film (Technipaq, Crystal Lake, IL).

Example 19 Transdermal systems were made with an adhesive coating using the procedure described in Example 13, except that the coating material was a stamped polyurethane elastomeric film.

Example 20 Transdermal systems were made with an adhesive coating using the procedure described in Example 13, except that the coating material was a 100% nonwoven polyester fabric.

Example 21 Transdermal systems were made with an intermediate drug-c adhesive coating using the procedure described in Example 13, except that the coating material was a nylon film bonded by centrifugation.

Example 22 Transdermal systems were made with an adhesive coating using the procedure described in Example 13, except that the coating material was a non-woven taffeta acetate film.

Example 23 A ketorolac tromethamine gel composition was prepared as described in Example 12. The gel was evaluated for its in vitro cutaneous flow performance. Skin flux studies on human cadavers were conducted in vitro using modified Franz diffusion cells, placed in a calibrated water bath to maintain the surface of the skin at a temperature of 32 ° C. The epidermal membrane was separated from the skin of the full-thickness human corpse by the method of Kligman and Chr? Stopher (Arch. Dermatol.88, 702-705, 1963). The full-thickness skin was exposed to a heat of 60 ° C for 60 seconds. The stratum corneum and epidermis were gently detached from the dermis. The epidermal membrane was mounted on a diffusion cell with a surface area of 0.65 cm 2 with the epidermal side facing the receiving compartment and secured in place. The receptor compartment was then filled with an aqueous solution containing 0.02% sodium azide as a bacteriostatic. The cell was placed in a circulating water bath calibrated to maintain the surface of the skin at a temperature of 32 ± 1 ° C and the skin was allowed to hydrate overnight. The next morning, 75μl of gelled ketorolac formulation was pipetted into a cavity created by placing a Teflon washing device on the surface of the stratum corneum. The cavity was then occluded by holding an occlusive support film on the mounting of the Teflon washing device. A, through the experiment, the receiving compartment, which contained a magnetic bar, was continuously stirred by means of a magnetic stirrer placed under the water bath. At predetermined intervals, all the contents of the receptor compartment were collected to quantify the drug using the CLAP method in Table I. The receptor compartment was again filled with fresh re-receptor medium, taking care to eliminate any air bubbles at the interface of the receptor. skin / solution From the concentration curve against time, the average steady state flow, the interval flow and the cumulative release per unit area at 24 hours were calculated. In vivo release was projected by multiplying the in vitro cumulative release (μg / cm2 / 24h) by the active area of the patch (30 cm2) Table I In Viral Cutaneous Flow by the CLAP Method Column: Partisphere C-18 (100 mm) Flow Rate: 1.0 mi / min Wavelength: 314 nm Injection Volume: 10 μl Retention Time: 2.0 ± 0.3 min.

Mobile Phase: 60/40 / 0.5 (% volume / volume) Acetonitrile / H20 / Glacial Acetic Acid pH ~ 3.0 The coating patches, prepared as described in Example 12, were applied to the chest of 24 healthy adults (12 men and 12 women) in clinical trials with humans. Plasma samples were collected for quantitation of ketorolac at predetermined times. After the removal of the patches in each study, the patches used were extracted on 100 ml of methanol and analyzed for drug content using the CLAP method described in Table II. The difference between the drug content of the initial and final patch gave the amount of ketorolac 'released, based on the patch depletion analysis. > Table II Testing the Content of the Patch by the CLAP Method Column: Zorbax RX-C8 5 μm, 15 cm x 4.6 mm Flow Rate: 1.0 mi / min Wavelength: 314 nm - * Injection Volume: 10 μl Retention Time: 5.2 ± 0.2 min. Mobile Phase: 60/40/1 (volume / volume%) Acetonitrile / H20 / Glacial Acetic Acid pH ~ 3.0 Table III compares the in vivo cumulative release, based on patch depletion analysis, with the release of drug projected for the coating patch of 30 cm2, based on the results of cutaneous flow in vitro. The projected drug release was based on the average in vitro cumulative release (μg / cm2 / 24h) multiplied by the active area (30 cm2) of the coating patch. The average in vivo dose was calculated from the difference between the initial drug content of the patches and the residual drug content of the patches after their removal. In vivo, the 30 cm2 coating patch released (46.4 ± 17.5) mg / day of ketorolac tromethamine, with very good concordance with the estimated value of 53.7 mg / day. Figure 5 shows that the average in cumulative absorption kinetics in vivo, calculated according to the method of Wagner and Nelson (J. Pham, Sci. 52, 610, 611, 1963) agrees very well with the cumulative absorption kinetics in vitro.

Table III Projected and In Vivo Observed Operation of the Coating Patch System Example 24 Transdermal systems were made with an adhesive coating using the procedure described in Example 1, except that the die or die used to cut the liquid reservoir portion of the transdermal delivery system allowed the tongue of the peelable sealing disc to reach the edge. of the releasable coating, as shown in Figure 2B. This extended tab allows the final system to be activated in a one-step process, instead of the two-step process described in Example 1. In the one-step process, the release liner and the extended tongue of the sealing disc Detachable are held between the thumb and forefinger of the hand and the supporting film on the other. The removable sealing disc and the releasable liner are pulled from the support film to activate the system.

Example 25 A medical grade pressure sensitive adhesive, MA-31 (Adhesives Research, Glen Rock, PA) was coated on a siliconized releasable liner, high peel strength, using a casting blade with a space of 10 mils. The adhesive solvent was evaporated at 80 ° C for 15 minutes to provide a final dry adhesive thickness of 0.0015 inches. TO K) was then laminated to a siliconized high density polyethylene liner of 2 mils, in the process, of low strength, on the dry adhesive film forming the primary adhesive sheet. This primary adhesive sheet, and the coating adhesive sheet manufactured as described in Example 1, were used in a final stage of the manufacturing process as described below. The reservoir containing intermediate drug was manufactured as in Example 1, except that the weight of the gel 2 () testosterone was 1.8 g, the active surface was 15 cirr, and the total surface area was 18.4 cm2. This reservoir system was laminated to the primary adhesive sheet by removing the coating in the process, placing the cut-off reservoir in the center over the adhesive with the removable sealing disc film in contact with the adhesive. The protective coating of the coating adhesive sheet was then removed and the coating adhesive was laminated onto the primary adhesive / reservoir system, so that the coating adhesive was in contact with the supporting film of the intermediate drug containing reservoir and also the adhesive area of the primary adhesive sheet extending beyond the reservoir containing intermediate drug. The transdermal release system with final coating adhesive was cut from this sheet structure to give a system with a total surface area of 33 cm2. The activation of this system was carried out in a single step by pulling the coating resistant to the release of the coating adhesive. The peelable seal disc remains attached to the liner, thereby exposing the reservoir area.

Example 26 Transdermal systems were made with an adhesive coating using the same procedure described in Example 25, except that the adhesive used in the primary adhesive sheet and the coating adhesive sheet was a medical grade polyisobutene (PIB) adhesive MA-24 (Adhesives Research , Glen Rock, PA).

Example 27 Transdermal systems were made with an adhesive coating using the same procedure described in Example 25, except that the adhesive used in the primary adhesive sheet and the coating adhesive sheet was a silicone-based adhesive, BIO PSA X7-2920 (Dow Corning , Midland, MI). Modifications of the modes described above for carrying out the invention are obvious to those skilled in the field of chemistry, transdermal drug delivery, pharmacology and related fields are intended to be within the scope of the following claims. It is noted that with reference to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it refers. Having described the invention as above, property is claimed as contained in the following:

Claims (12)

1. A device for administering an active agent to the skin or mucosa of an individual, characterized in that it comprises a laminated composition of: (a) an adhesive coating having a central portion and a peripheral portion; (b) a support layer below the central portion of the adhesive coating; (c) a membrane permeable to the active agent below the support layer, the support layer and the membrane define (d) a reservoir therebetween containing an active agent formulation; (e) a peelable seal disk beneath the membrane permeable to the active agent; (f) a thermal seal around the periphery of the releasable sealing disc, the membrane permeable to the active agent and the support layer; and (g) a removable, removable liner, below the peripheral portion of the adhesive coating and the peelable seal disk.

2. The device according to claim 1, characterized in that the adhesive is made of a material selected from the group consisting of polyisobutenes, natural rubbers, acrylates, methacrylates and silicone.

3. The device according to claim 1, characterized in that the support layer comprises at least one impermeable film layer.

4. The device according to claim 1, characterized in that the membrane is selected from the group consisting of microporous membranes and dense membranes.

5. The device according to claim 1, characterized in that the peelable sealing disc is composed of at least one layer.

6. The device according to claim 1, characterized in that it also comprises a percutaneous absorption enhancer.

7. The device according to claim 1, characterized in that the formulation further comprises a material selected from the group consisting of a solvent, a gelling agent, stabilizer and an anti-irritant.

8. The device according to claim 1, characterized in that it includes an adhesive layer which is below the peripheral portion of the adhesive coating and releasable sealing disc and on top of the release liner.

9. The device according to claim 1, characterized in that the adhesive coating is non-occlusive and the support layer is occlusive.

10. A device for administering an active agent to the skin or mucosa of an individual, characterized in that it comprises a laminated composition of: (a) an adhesive coating having a central portion and. a peripheral portion; (b) a support layer below the central portion of the adhesive coating; (c) a membrane permeable to the active agent, the support layer and the membrane define (d) a reservoir therebetween containing an active agent formulation; (e) a peelable seal disk beneath the membrane permeable to the active agent; (f) a thermal seal around the periphery of the releasable sealing disc, the membrane permeable to the active agent and the support layer; and (g) a removable, removable liner, below the peripheral portion of the adhesive coating and the peelable seal disc; and (h) a tongue on the peelable seal disc to aid in disc removal.

11. The device according to claim 10, characterized in that it includes an adhesive layer which is located below the peripheral portion of the adhesive coating and the peelable sealing disc and is on the release liner.

12. The device according to claim 10, characterized in that the adhesive coating is non-occlusive and the support layer is occlusive.