| Transdermal norelgestromin delivery system -> Monitor Keywords |
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Transdermal norelgestromin delivery systemRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Preparations Characterized By Special Physical Form, Web, Sheet Or Filament Bases; Compositions Of Bandages; Or Dressings With Incorporated Medicaments, Bandages With Incorporated Medicaments, Transdermal Or PercutaneousTransdermal norelgestromin delivery system description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070098772, Transdermal norelgestromin delivery system. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS REFERENCE TO RELATED U.S. APPLICATION DATA [0001] The present application is derived from and claims priority to provisional application U.S. Ser. No. 60/720,200, filed Sep. 23, 2005, which is herein incorporated by reference in its entirety. TECHNICAL FIELD [0002] This invention relates to a medical patch for transdermal administration of norelgestromin (NGMN) and to a method of treating a subject by administering norelgestromin (NGMN) thereto with the medical patch. In particular, the invention relates to transdermal systems for administration of NGMN preferably in combination with an estrogen with adhesive system having high enhancer tolerance when used in transdermal drug delivery. BACKGROUND [0003] Transdermnal devices for the delivery of biologically active agents have been used for maintaining health and therapeutically treating a wide variety of ailments. For example, analgesics, steroids, etc., have been delivered with such devices. Such transdermal devices include patches in which a biologically active agent is delivered to the body tissue passively without use of an additional energy source. Many such devices have been described, for example, in U.S. Pat. Nos. 3,598,122, 3,598,123, 4,379,454, 4,286,592, 4,314,557, 4,568,343, and U.S. Application No. 2003002682, all of which are incorporated herein by reference in their entireties. [0004] A transdermal patch is typically a small adhesive bandage that contains the drug to be delivered. A simple type of such transdermal patches is an adhesive monolith including a drug-containing reservoir disposed on a backing. The reservoir is typically formed from a pharmaceutically acceptable pressure sensitive adhesive. In some cases, the reservoir can be formed from a non-adhesive material, the skin-contacting surface of which is provided with a thin layer of a suitable adhesive. The rate at which the drug is administered is dependent upon the rate at which drug partitions from the patch into the skin and then diffuses across the epidermis before being absorbed systemically. [0005] Although the transdermal delivery of therapeutic agents has been the subject of intense research and development for over 30 years, only a relatively small number of drug molecules are suitable for transdermal delivery due to the fact that human skin is an excellent barrier. Various techniques have been explored to enhance the permeation of drug molecules that are not otherwise suitable for transdermal delivery. Of these techniques, chemical enhancement is the most established and is currently employed commercially. Pressure sensitive adhesives, such as acrylic adhesives, are used in most transdermal drug delivery devices as a means of providing intimate contact between the drug delivery device and the skin. The use of drugs and permeation enhancers ("enhancers"), especially at high concentrations, usually has a significant impact on the properties of pressure sensitive adhesives, such as cohesive strength, adhesive flow, tackiness and adhesion strength. Therefore, pressure sensitive adhesives have to be designed in a way that they can provide the needed performance in the presence of enhancers. [0006] Combinations of norelgestromin (NGMN), formerly known as 17-deacetyl norgestimate, and ethinyl estradiol (EE) have been administered orally to women as a contraceptive. These two drugs have also been described as deliverable transdermally, as mentioned, for example, in U.S. Pat. No. 5,693,335; 5,876,746; and 5,972,377. Other patents related to transdermal delivery of sex hormones are, for example, U.S. Pat. No. 4,906,169 and 5,422,119. However, delivering the sex hormones through a body surface at an adequate flux rate is a challenge. [0007] Currently, transdermal patches for delivery of NGMN and EE (once a week ORTHO EVRA.RTM. patches from Ortho-McNeil Pharmaceutical) have three layers. The backing layer is composed of a beige flexible film with a low-density pigmented polyethylene outer layer and a polyester inner layer. The backing layer provides structural support and protects the middle adhesive layer from the environment. The middle layer contains polyisobutylehe/polybutene adhesive, micronized crospovidone (an insoluble crosslinked polyvinyl pyrrolidone), non-woven polyester fabric and lauryl lactate. The micronized crospovidone serves as a hydrophilic filler material that helps seven day wear by absorbing moisture at the skin/adhesive interface. The other components in this layer are the hormones, norelgestromin and ethinyl estradiol. The third layer is the protective liner, which protects the adhesive layer during storage and is removed just prior to patch application. It is a transparent polyethylene terephthalate (PET) film with a polydimethylsiloxane coating on the side that is in contact with the middle adhesive layer. [0008] The total amount of NGMN released from a 20 cm.sup.2 ORTHO EVRA.RTM. patch over a seven-day wear period is 1.05 mg (corresponding to 17.5% of the total NGMN load and to an hourly average flux of about 0.3 .mu.g/cm.sup.2-h. The total amount of EE released over the seven-day wear period is 0.14 mg (corresponding to 18.7% of the total EE loading) and to an hourly average flux of about 0.04 .mu.g/cm.sup.2-h. In this current system, polyisobutylene (PIB) adhesive is highly plasticized and suffers cold-flow during storage and wear, resulting in a black-border that forms around the patch over the wear period. The inclusion of a high level (20% wt/wt) of micronized crospovidone in the current system also results in an adhesive formulation that becomes opaque white over the wear period. During the seven day wear, as moisture is absorbed, the adhesive drug layer changes from translucent to opaque and white in appearance requiring the use of an opaque backing layer to mask this phenomena during wear in the currently commercially available systems. There continues to be a need for improved delivery of sex hormones, especially sustained delivery over a period of time, and especially for NGMN, an estrogen, or NGMN in combination with an estrogen, for contraceptive effect or hormone replacement via a product with better rheology, more appealing appearance, and which is less obvious on most skin types and easier to remove. Such better products will lead to improved patient compliance. SUMMARY [0009] The present invention provides a method and a device for transdermal delivery of an effective amount of NGMN, an estrogen, or NGMN in combination with an estrogen (for contraceptive effect or for providing hormone replacement) to an individual in need thereof. In one aspect, a patch with polyacrylate reservoir suitable for multiple day delivery of NGMN is provided. In another aspect, a high loading of permeation enhancer enables high flux rate with a relatively small area, suitable for a transdermal patch that can be maintained adhesively on the body surface for an extensive period of time, such as 3, 7 days, and even longer, with acceptable rheological and adhesive properties and better appearance. [0010] The preparation of formulations with polyacrylate for adhesion rather than PIB results in improved cold-flow resistance. This feature in turn results in an improvement in both patch aesthetics, ease of removal and improved patient compliance. The use of polyacrylate also results in formulations that are and remain translucent (versus opaque in appearance due to undissolved PVP particles and moisture uptake during 7 day wear) which, when combined with a transparent or translucent backing, have an improved translucent appearance after application and during wear. Although PVP, either dissolved, dispersed (e.g., in micronized form), or combination thereof, can be used, it is not required for the formulation of the present invention to adhere to the body surface. Further, the increased drug flux per unit area also results in a smaller patch size, again improving aesthetics and patient acceptability, and reducing the likelihood of unintentional detachment. [0011] In the currently commercially available 7-day wear patches, the amount of NGMN and EE loaded into the adhesive drug layer resulting in adhesive layer about 0.006 inch (0.15 mm) to 0.008 inch (0.20 mm) thick. The thicker adhesive layer requires the addition of a non-woven backing for structural support during manufacturing, patch application and patch removal. The thicker adhesive layer also results in severe cold flow during storage in the pouch, and higher affinity for lint and dirt to adhere to the edge of the patch during wear. The currently available ORTHO EVRA.RTM. patches utilizes less than 20% of the NGMN and EE loaded into the patch during 7 days of wear. The effective dose of NGMN and EE in an ORTHO EVRA.RTM. contraceptive patch is 150 .mu.g/day of NGMN and 20 .mu.g/day of EE having a basal surface area (i.e. the area in diffusional contact with the skin) of 20 cm.sup.2. ORTHO EVRA.RTM. patches deliver the NGMN at a flux of 0.3 .mu.g/cm.sup.2-h, and EE at a flux of 0.04 .mu.g/cm.sup.2-h. [0012] The use of polyacrylates results in a simpler, less complex manufacturing process as the drug/adhesive layer is thinner removing the need for a non-woven. Thus, a transdermal NGMN or NGMN and EE delivery patch can be made to have NGMN or NGMN/EE loading of higher than 5 wt %, preferably from 5 to 20 wt %, more preferably from 5 to 10 wt % of NGMN in the reservoir to deliver NGMN about 125 to about 350 .mu.g/day, preferably from about 150 to about 300 .mu.g/day, and more preferably from about 150 to about 250 .mu.g/day for 7 days. With the appropriate size, patches can be made with NGMN/EE in the reservoir to deliver NGMN about 50 to about 250 .mu.g/day and EE about 5 to 35 .mu.g/day, preferably from about 75 to about 225 .mu.g/day NGMN and 10 to 30 .mu.g/day of EE, and more preferably from about 125 to about 175 .mu.g/day of NGMN and 15 to 25 .mu.g/day of EE for 7 days with acceptable rheology such as cold flow property. [0013] In one aspect of the invention, a novel technique is provided for increasing adhesive enhancer tolerance. It has been discovered that by increasing the glass transition temperature of the acrylate polymer using the ratio of soft monomer and hard monomer, it is possible to load enhancer concentrations into the polymer at a high weight percent to obtain a formulation and still achieve desirable adhesive characteristics. The loading of drug and/or enhancer into the polymer composition can be, e.g., greater than 20 dry weight %, greater than 30 dry weight % (or solids wt %), even up to 40-50 wt %, and still provide adequate adhesion and rheological characteristics for pressure sensitive adhesive (PSA) application. With sufficient loadings of permeation enhancers in such formulations, sustained high rates of drug delivery can be achieved. With adequate adhesive properties, the resulting reservoir with sufficient drug loading and permeation enhancers can be used to achieve effective therapeutic results. [0014] In one aspect of the invention, a clear multiple day patch with 3 to 7-day dermal adhesion is provided. It has been discovered that the use of a polyacrylate adhesive or proadhesive, having been plasticized with permeation enhancers to have an elastic modulus (storage modulus) of 1.times.10.sup.5 to 2.times.10.sup.5 dyn/cm.sup.2, i.e., 10,000 to 20,000 Pa (measured at 1 rad/s, 25.degree. C.), or more preferably 10,000 to 15,000 Pa (i.e., 1.0.times.10.sup.5 to 1.5.times.10.sup.5 dyn/cm.sup.2), either with or without PVP (e.g., up to about 6% PVP), when used with an occlusive nonporous backing, such as 0.5 mil PET/1.5 mil EVA results in superior skin adhesion for 7 days. The resultant polyacrylate formulations further result in a reduction in measured residue upon patch removal relative to existing commercial PIB-based products while providing comparable wearing performance. With the use of transparent backing such as the PET/EVA laminate, a clear patch that would not turn cloudy after multiple day use (e.g., 3 days, 7 days) can be achieved. BRIEF DESCRIPTION OF THE DRAWINGS [0015] FIG. 1 illustrates a cross-section through a schematic, perspective view of one embodiment of a transdermal therapeutic system according to the present invention. [0016] FIG. 2 illustrates a cross-section view through another embodiment of a transdermal therapeutic system of this invention. [0017] FIG. 3 illustrates the flux profile of a NGMN formulation with permeation enhancers GMO and NLS according to the present invention compared to NGMN in other formulations. [0018] FIG. 4 illustrates the flux profile of another NGMN formulation with EE and permeation enhancers GMO and NLS according to the present invention compared to NGMN in other formulations. [0019] FIG. 5 illustrates the flux profile of EE with the NGMN formulation of FIG. 4. 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