MXPA01006199A - Transparent transdermal nicotine delivery devices - Google Patents

Abstract

A transparent transdermal delivery device for delivering nicotine which has an Opacity Index of less than 48.6%.

Description

TRANSPARENT DEVICES TRANSPARENT FOR. THE NICOTINE ADMINISTRATION Priority claim The inventor claims the benefit of the filing date of the Provisional Applications S.N. 60 / 112,730; 60 / 124,679 and 60 / 126,798. FIELD OF THE INVENTION The present invention relates to transdermal delivery devices for administering nicotine for use in smoking cessation treatments. In particular, the invention is directed to transdermal nicotine administration devices that are transparent. BACKGROUND OF THE INVENTION The transdermal route of parenteral drug administration provides many advantages over other routes of administration. Transdermal systems for administering a wide variety of drugs or other beneficial agents are described in U.S. Patent Nos. 3,598,122; 3,598,123; 3,731,683; 3,797,494; 4,031,894; 4,144,317; 4,201,211; 4,286,592; 4,314,557; 4,379,454; 4.435, 180; 4,559,222; 4,568,343; 4, 573,995; 4,588,580; 4, 645.502; 4, 698, 062; 4,704,282; 4,725,272; 4,781,924; 4,788, 062; 4,816,258; 4, 849.226; 44,, 990044,, 447755;; 44,, 990088, .002277;; 4,917,895; 4,938,759; 4,943,435; ,004,610; 5,071,656; 5,122,382; 5,141,750; 5,284,660; 5,314,694; 5,342,623; 5,411,740; and 5,635,203, which are hereby incorporated by reference in their entirety. The administration. of nicotine buccally, nasally and transdermally to help a patient who wishes to quit smoking has been shown to be clinically effective in reducing the rate of recurrence. Nicotine chewing gum and transdermal nicotine are two of the most widely used forms of nicotine replacement therapy currently available. Transdermal devices for administering nicotine are described in U.S. Patent Nos. 4,597,961; 4,758,434; 4,764,382; 4,839,174; 4,908,213; 4,915,950; 4,943,435; 4,946,853; 5,004,610; 5,016,652; 5,077,104; 5,230,896; 5,411,739; 5,462,745; 5,508,038; 5,599,554; 5,603,947 and 5,726,190, for example, which are hereby incorporated by reference in their entirety. Most transdermal drug delivery devices of the prior art utilize an impervious reinforcement on the surface of the device distal to the skin to protect the device from damage and to prevent loss of the active ingredient (s). In order to improve user satisfaction, these reinforcement layers are often dyed in a color similar to skin tones. However, as can be readily appreciated, it is not commercially practical to provide pigmented reinforcement layers for transdermal systems that approximate all skin colors. Another approach that has been taken is to provide transparent transdermal systems in which all the elements forming a device are sufficiently transparent to allow the natural color of the skin to be visible through the device. Marketed products that take this approach include the Alora® and Climara® estrogen replacement patches and the Duragesic® transdermal fentanyl delivery system. When these devices are applied to the skin, the natural color of the patient's skin is visible through the patch, making the patch presence extremely harmless. Government regulations require that these products carry an identification indication, but indications may be printed on these devices in white or light-colored ink which is not noticeable from a distance of several meters, but is still legible on close inspection. It has been found that these clear patches are useful with non-volatile drugs such as fentanyl and hormone replacement steroids, but none of these clear products has been developed for the administration of nicotine.

Nicotine is a colorless, volatile liquid alkaloid, strongly alkaline, easily oxidized, subject to degradation. when exposed to light and highly permeable through not only human skin, but also many of the polymers conventionally used in the manufacture of reinforcement layers and packaging materials for transdermal products (see for example the United States Patent from North America number 5,077,104). As a result, the reinforcement layers of currently available transdermal nicotine delivery devices use opaque skin color multi-laminated films that typically contain a metallized layer, such as aluminum. Not only commercially available transdermal nicotine patches use opaque reinforcements, but many of these devices, due to the complexities of nicotine handling and processing, have other components that are not transparent. For example, the original Prostep® transdermal nicotine product uses a drug container in the form of an opaque white gel, held in place by an opaque adhesive layer. The nicotine patches Habitrol® and Nicotrol® incorporate absorbent bearings in the drug container in which the nicotine is absorbed. It has also been proposed to co-administer nicotine with other substances that improve nicotine-quitting therapy. See, for example, U.S. Patent Nos. 4,908,213; 5,599,554; and 5,726,190 noted above, and International Publication WO 97/33581. SUMMARY OF THE INVENTION The present invention relates to transparent transdermal delivery devices for the transdermal administration of nicotine either alone or in combination with other agents. These devices should be sufficiently transparent so that the subject's skin is clearly visible through the device when placed on the skin. Identification indications may be printed on the device in white or light-colored ink in a manner that is not noticeable from a short distance, but that is legible on close inspection. DETAILED DESCRIPTION OF THE INVENTION The preferred devices of this invention use, as a reinforcing layer, a transparent polymeric film which has a nicotine permeability of less than 1 μg / cm2 'Hour, preferably less than 0.5 μg / cm2' hour, a Nicotine solubility which is less than 1 weight percent and preferably less than 0.1 weight percent. These films are preferably less than about 0.0524 millimeters thick and more preferably about 0.0508-0.1016 millimeters thick. These films are used in combination with one or more of the elements of a transdermal device (other than the removable release filler) such as the drug container, adhesive and membrane that control the regime, which must be sufficiently transparent to allow the The natural color of the skin is clearly visible through the assembled device after placement on the skin. The finished product should have an Opacity value of less than about 48.6 percent, preferably less than about 35.11 percent, and more preferably less than 20 percent. In addition to being transparent and sufficiently nicotine-impermeable, the reinforcement layer should also have sufficient mechanical strength and physical integrity to maintain the system intact throughout its intended administration period, which is typically 18 to 24 hours, and it must provide a stable interface with adjacent layers such as the drug container or the adhesive layers of the transdermal device. This combination of properties is not always found in a material, and thus the transparent reinforcement layers used on the devices of this invention can be multi-layered films. In addition to having a low nicotine permeability, a reinforcement layer should also have a low solubility for nicotine. This is because nicotine is toxic and it could be dangerous for a child, for example, to lick the backing layer if it had a substantial amount of nicotine dissolved. Suitable polymer materials possessing properties required by this invention include Scotchpak® 1220 which is a bilaminate film of polyethylene terephthalate / ethylene vinyl acetate (PET EVA), sold by the company 3M Company, Minneapolis, Minnesota, and Saranex® 2057 which is a high density polyethylene (HDPE) / ethylene acrylic acid (EAA) / nylon / EAA multilaminate available from the Dow Chemical Company, Midland, Michigan. Nitrile rubber graft copolymers can also be used with acrylonitrile and methyl acrylate sold as Barex® films described in U.S. Patent No. 5,077,104 noted above. These films, which comprise a graft copolymer formed from about 73-77 percent acrylonitrile and from about 23-27 percent c-copolymerized methyl acrylate in the presence of about 8-10 parts by weight of butadiene copolymers / Acrylonitrile containing about 70 weight percent of polymer units derived from butadiene are the preferred reinforcing materials. The transparent transdermal delivery devices of this invention can be of any of the forms described in the aforementioned patents. The preferred form, however, comprises a laminate of the reinforcing layer, a nicotine container layer containing nicotine dissolved in a vehicle at a concentration below the saturation concentration of the nicotine in the vehicle. If the component of the drug container is self-adhesive, a simple monolithic device could be employed. However, in many cases it is desirable to include additional components such as rate control membranes, and a separate adhesive layer to keep the devices on the skin as described in U.S. Patent Nos. 5,004,610 and 5,342,623 listed above. . It is further contemplated that addition to nicotine the device may also contain other drugs or other active substances that cooperate with or increase the effect of nicotine on smoking cessation, smoking replacement or smoking substitution therapy. For all these devices, a removable release filler would normally be applied to the adhesive surface of the patch that is used to keep the device on the skin, this release filler is removed before use. Various materials suitable for the manufacture of the various components are known in the art and are described in the aforementioned patents.

The adhesive component is preferably a pressure sensitive adhesive including, but not limited to, polysiloxanes, polyacrylates, polyurethanes, acrylic adhesives including crosslinked or non-crosslinked acrylic copolymers, vinyl acetate adhesives, ethylene-acetate copolymers, vinyl, and synthetic or natural rubbers including polybutadienes, polyisoprenes, and polyisobutylene adhesives, and mixtures and copolymers grafts thereof. The devices may also be provided with hydrophilic water absorbent polymers known in the art such as polyvinyl alcohol and polyvinyl pyrrolidone individually or in combination. The adhesive can be used to form a monolithic delivery device in which the nicotine is dissolved in the adhesive to form a self-adhesive drug container. Alternatively, the adhesive can be applied to the surface of a non-adhesive container in which the nicotine is dissolved, to form a multi-laminated device. A controlled rate membrane can also be connected between the nicotine container and the adhesive, as is known in the art. Nicotine can be administered in combination with another agent that could include anti-anxiolytics, antihypertensives, antidepressants, and appetite suppressants, such as fluoxetine, caffeine, buspirone, phenylpropanolamine, clonidine, paroxetine, citalopram, and sertraline. The nicotine in the device is present in the container in a sub-saturated condition (ie less than the unit activity) so that there is no undissolved nicotine present in the container. If other agents are present in the device, they are preferably present completely dissolved, but may be present in undissolved form as long as the final product shows the proper degree of transparency. In the present invention, nicotine and optionally other agents to be co-administered are administered through the skin or other body surface at a therapeutically effective rate for a predetermined period of time which for nicotine is preferably 16-24. hours. The transdermal therapeutic devices of the present invention are prepared in a manner known in the art, such as by the methods described in the transdermal device patents previously listed herein. The following example is offered to illustrate the practice of the present invention and is not intended to limit the invention in any way.

EXAMPLE 1 Several commercially available transdermal patches were tested for transparency and compared with transparent nicotine patches according to this invention. Nicotine patches were prepared as presented in Example IV of U.S. Patent No. 5,004,610 with a PET / EVA reinforcement (Scotchpak® 1220, 3M, Minneapolis, MN) or Saranex® (Dow Chemical Company, Midland, MI) replaced by the Scotchpak 1006 reinforcement. The light transmitted through the different systems was measured by a Macbeth 1500 / Plus color measuring system (Kollmorgem Instruments Corp., Newburgh, NY). Table 1 shows the Opacity index, which is the percentage of incidental light that is absorbed by the passage through the device, for the different systems tested. Table 1: Opacity of the Patch The Minitran® nitroglycerin system is clearly visible from a distance of approximately one and a half meters, while the FemPatch® is significantly less noticeable. However, the Alora®, Climara® and Nicoderm® patches are extremely non-eye-catching. Accordingly, the transdermal devices according to this invention should have an Opacity rating of less than 48.6 percent, preferably less than 35.11 percent, more preferably less than 20 percent. Having thus generally described the invention and preferred embodiments thereof, it is apparent that various modifications and substitutions will be apparent to those skilled in the art. These modifications and substitutions can be made without departing from the scope of the invention which is limited only by the following claims.

Claims (9)

1. A device for the transdermal administration of nicotine comprising a reinforcing layer, a nicotine containing drug container layer carried by the reinforcing layer, and means for maintaining the device in nicotine transmission relationship with the skin, wherein the The device is sufficiently transparent to allow the skin of the subject to which it is applied to be visible through said device.

The device of claim 1 wherein the reinforcement has a nicotine permeability of less than about 1.0 μg / cm2"hour

3. A device according to claim 1 wherein the reinforcement has a lower nicotine permeability 0.5 μg / cm2"hour.

4. A device according to the claim 2 wherein the reinforcement has a solubility for nicotine of less than about 1 weight percent.

5. A device according to the claim 3 wherein the reinforcement has a solubility for nicotine of less than about 0.1 weight percent.

6. A device according to the claim 4 wherein the device has an Opacity index of less than about 48.6 percent.

7. A device according to claim 6 wherein the device has an Opacity rating less than 35.11 percent.

8. A device according to claim 6 wherein the device has an Opacity index of less than 20 percent. The device of claim 1 wherein the reinforcement is formed of a material selected from the group consisting of PET / EVA, HDPE / EAA / nylon / EAA laminates and a film comprising a graft copolymer formed of approximately 73- 77 percent acrylonitrile and about 23-27 percent copolymerized methyl acrylate in the presence of about 8-10 parts by weight of butadiene / acrylonitrile copolymers containing about 70 percent by weight polymer units derived from butadiene .