(12) United States Patent (10) Patent No.: US 6,562,363 B1 Mantelle Et Al
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USOO6562363B1 (12) United States Patent (10) Patent No.: US 6,562,363 B1 Mantelle et al. (45) Date of Patent: May 13, 2003 (54) BIOADHESIVE COMPOSITIONS AND 4,764,378 A 8/1988 Keith et al. ................. 424/435 METHODS FOR TOPCAL RE33,093 E. 10/1989 Schiraldi et al. ............ 424/676 ADMINISTRATION OF ACTIVE AGENTS 4,889,720 A 12/1989 Konishi ...................... 424/448 5,032.207 A 7/1991 Sablotsky et al. .......... 156/250 (75) Inventors: Juan Montells SR-- . tyle, 5,234.9575,047,244. A * 8/19939/1991 SanvordekerMantelle .................. et al........ 514/772.6 424/435 s s s 5,346,701 A * 9/1994 Heiber et al. ............... 424/435 all of FL (US) 5,446,070 A 8/1995 Mantelle .................. 514/772.6 5,656.286 A 8/1997 Miranda et al. (73) ASSignee: Nye harmaceuticals Inc., Miami, 6,210,699 B1 4/2001 Acharya et al. ............ 424/435 FOREIGN PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this DE 244.1626 3/1975 patent is extended or adjusted under 35 DE 2951319 7/1981 U.S.C. 154(b) by 0 days. EP SO7160 10/1992 FR 2 532546 9/1982 (21) Appl. No.: 09/161,312 GB 1OSOO70 12/1966 GB 2 046 773. A 11/1980 (22) Filed: Sep. 28, 1998 JP 63-160661 7/1988 SE 352 239 12/1972 Related U.S. Application Data * cited bw examiner (60) Provisional application No. 60/061,155, filed on Sep. 26, y 1997. Primary Examiner Thurman K. Page (51) Int. Cl." A61F 13/00; A61F 13/02; ASSistant Examiner-Humera N. Sheikh - - - - - - - A61K 970; A61K 4733. A61 L 1516 (74) Attorney, Agent, or Firm-Foley & Lardner (52) U.S. Cl. ....................... 424/434; 424/443; 424/448; (57) ABSTRACT 514/772.5 (58) Field of Search ................................. 424/435, 434 Bioadhesive compositions in a flexible, finite form for 424/443, 448, 2, 514772 s topical application to Skin or mucous membranes compris s s as ing a composition which results from an admixture of at (56) References Cited least one PVP polymer, at least one bioadhesive, optionally a pharmaceutically acceptable Solvent Suitable for use with U.S. PATENT DOCUMENTS an active agent, and methods of administering active agents 4,503,034. A 3/1985 Maupetit et al. .............. 424/80 to a Subject, are disclosed. The bioadhesive composition can Jevne et al. ................ 523/111 either include an active agent incorporated directly in the 4,593,053 A 6/1986 4,740,365 A * 4/1988 Yukimatsu et al. ......... 424/435 composition, or a separate Source of an active agent. 4,751,087. A 6/1988 Wick .......................... 424/449 4,755,396 A 7/1988 Geisler et al. .............. 427/197 34 Claims, No Drawings US 6,562,363 B1 1 2 BOADHESIVE COMPOSITIONS AND be maintained at the Site of administration in order to METHODS FOR TOPCAL achieve maximum prolongation of therapeutic effects, both ADMINISTRATION OF ACTIVE AGENTS Systemically and locally. A Successful bioadhesive device for topical administra This application is based on provisional application tion of active agents for prolonged periods of time needs to 60/061,155 filed Sep. 26, 1997. Satisfy a number of physical characteristics. For instance, the release liner should be easily peelable from the bioadhesive BACKGROUND OF THE INVENTION portion, yet the latter must be both sufficiently adhesive and cohesive to maintain close or intimate contact with the Site 1. Background of the Invention of application for prolonged periods of time, typically This invention relates generally to bioadhesive composi between 1 to 2 hours, and up to even 24 hours with certain tions and methods for the topical administration of active active agents. The bioadhesive composition must further agents to a mammal. More particularly, this invention relates retain the active agent at an appropriate rate for Sustained or to compositions capable of being used in wet or moist controlled delivery under the conditions prevailing in wet environments, especially on mucous membranes, for a pro 15 and moist environments associated with mucosa. In longed period of time. There is no limitation on the type of addition, the bioadhesive composition must be non-toxic, drug that can be used in the present invention, provided that not cause chemical irritation and, must be easily removable it can be topically administered. Thus, the active agent with minimal mechanical irritation or damage to the appli includes both drugs that are topically applied for local effects cation Site. and those which can be administered topically for Systemic In this regard, compositions according to the present effects. invention are capable of adhering for prolonged periods of 2. Description of Related Art time, Such as, for example, greater than 1 hour, preferably 2 Mucous membranes Such as the mucosa of the buccal hours, more preferably 4 hours, even more preferably cavity have Several physical attributes, Such as a rich blood greater than 8 hours, up to even 24 hours, to moist tissue Supply, that makes it a desirable site for topical administra 25 Such as mucosa and thus the desired therapeutic effects are tion of active agents for Systemic delivery. Transmucosal ensured by the high degree of adhesion provided by the delivery of active agents further avoids first-pass metabo compositions of this invention. lism by the liver as well as poor uptake or inactivation via the gastrointestinal pathway. Examples of Such agents SUMMARY OF THE INVENTION include Steroids Such as estrogens, progestins and related This invention provides a bioadhesive composition com compounds, androgens and anabolic Steroids, non-Steroidal prising a mixture of at least two bioadhesive materials, anti-inflammatory agents Such as ketoprofen; diclofenac, especially comprising at least one Soluble polyvinylpyrroli propranolol; thyroid hormones; pH sensitive peptides and done (“PVP) polymer, optionally in an admixture with a Small proteins Such as insulin and ACTH, phySoStigmine; pharmaceutically acceptable Solvent Suitable for use with an Scopolamine, Verapamil, and gallopamil. 35 active agent, the Solvent optionally including a plasticizer Moreover, it is often desirable or necessary to deliver for the bioadhesives. The bioadhesive compositions of this pharmaceutical agents locally, Such as to alleviate pain in the invention either include at least one active agent Solubilized buccal cavity. within the composition or, alternately, are used together with Buccal and/or mucosal delivery compositions, devices the topical administration of at least one active agent at the and methods re disclosed, for example, in U.S. Pat. No. 40 Site of application, Such as the means to adhere a drug 3,972,995 to Tsuk, et al., U.S. Pat. No. 4,755,396 to Hsiao reservoir to the application Site. et al., U.S. Pat. No. 4,764,378 to Keith et al., U.S. Pat. No. In accordance with one aspect of the invention, an 4,740,365 to Yukimatsu et al., U.S. Pat. No. 4,889,720 to improved bioadhesive composition of a type which is Suit able for prolonged adherence to wet or moist Surfaces for Konishi et al U.S. Pat. No. 5,047,244 to Sanvordeker et al., 45 and RE 33,093 to Schiraldi et al. controlled release of an active agent therefrom comprises a The use of bioadhesives in the administration of active mixture of a polysaccharide, preferably a natural gum Such agents to mucous membranes has been known for Some as karaya gum, and a soluble PVP. time. The most commonly used bioadhesive compositions Optionally, the bioadhesive composition may further comprise a pressure-Sensitive adhesive, preferably a Solvent have “non-finite', (i.e., spreading Substances which do not 50 retain their form) and liquid or Semi-liquid carrierS Such as based acrylic polymer. pastes, gels, lotions, emulsions, creams, Sprays, drops or In accordance with another aspect of the invention, the ointments. Increasing use has been recently made of “finite” bioadhesive compositions provide for topical administration carriers (i.e., non-spreading Substances which retain their of two or more active agents of differing flux rates, in order form) Such as films, dressings and bandages, or which start 55 to achieve prolonged and/or multiple therapeutic effects. as finite then dissolve Such as lozenges and tablets. Such In accordance with yet another aspect of the invention, the compositions and devices have been less than Satisfactory in bioadhesive composition also serves as a pressure-Sensitive achieving controlled release of Such agents, and in main adhesive Suitable for prolonged adherence to either wet/ taining adhesion (i.e., simply staying in place) or efficacy for moist Surfaces or dry Surfaces, Such as Skin, for controlled prolonged periods of time. Moreover, they often leave 60 release of an active agent therefrom. unacceptable tacky residues upon removal. This invention also relates to methods of administering It is disclosed in U.S. Pat. No. 5,446,070 to Mantelle, that the foregoing compositions. concentrations of Substantially dissolved anesthetic agents In particular, the invention is directed to a bioadhesive and other drugs as high as 50% by weight can be achieved composition in a flexible, finite form for topical application in a System containing a bioadhesive carrier in which the 65 comprising: adhesion of the carrier is not hindered. However, a need (a) a mixture of two or more bioadhesives wherein at least exists to increase the amount of time Such compositions can one bioadhesive is a soluble PVP polymer; US 6,562,363 B1 3 4 (b) optionally a pharmaceutically acceptable Solvent Suit (i) a mixture of two or more bioadhesives wherein at able for use with an active agent, the Solvent optionally least one bioadhesive is a soluble PVP polymer; including a plasticizer for the bioadhesives, (ii) optionally a pharmaceutically acceptable Solvent (c) optionally, a pressure-sensitive adhesive; Suitable for use with an active agent, the Solvent wherein the composition is Substantially free of water and optionally including a plasticizer for the bioadhe Substantially water insoluble; and wherein the compo Sives, Sition either includes at least one active agent or, (iii) in an admixture with at least two active agents, the alternately, is used together with an active agent.