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, 5,047,244.5,234.957 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. at least two active agents comprising The invention further relates to a bioadhesive composition (1) combinations of the same active agent in free in a flexible, finite form for topical application comprising: 1O acid, free base and Salt forms, or (a) a mixture of two or more bioadhesives wherein at least (2) combinations of different active agents, each one bioadhesive is a soluble PVP polymer; being delivered to a Subject at a different flux rate; (b) optionally a pharmaceutically acceptable Solvent Suit (iv) optionally, a pressure-sensitive adhesive; able for use with an active agent, the Solvent optionally wherein the composition is Substantially free of water and including a plasticizer for the bioadhesives, 15 Substantially water insoluble; (c) in an admixture with at least two active agents, the at (b) contacting an area of skin or mucous membrane, least two active agents comprising preferably the oral mucosa, with Said bioadhesive com position to administer the two or more active agents, (i) combinations of the same active agent in free acid, wherein the composition either includes at least one free base and Salt forms, or active agent or, alternately, is used together with an (ii) combinations of different active agents, each being active agent. delivered to a subject at a different flux rate; The present invention also includes a bioadhesive com (d) optionally, a pressure-sensitive adhesive; and position in a flexible, finite form for topical application of wherein the composition is Substantially free of water and one or more active agents resulting from an admixture which Substantially water insoluble. 25 comprises: (a) at least one Soluble polyvinylpyrrolidone The invention further relates to a composition in a polymer (PVP); (b) at least one bioadhesive; (c) a therapeu flexible, finite form for topical application comprising: tically effective amount of one or more active agents, and (d) (a) a mixture of two or more bioadhesives wherein at least optionally one or more Solvents. one bioadhesive is a soluble PVP polymer; The invention further includes a composition for admin (b) optionally a pharmaceutically acceptable Solvent Suit istration of one or more active agents comprising: (a) a able for use with an active agent, the Solvent optionally Source of one or more active agents, and (b) an adhesive including a plasticizer for the bioadhesives, layer adapted for adhering to dermal or mucosal tissue and wherein the composition is Substantially free of water, which results from an admixture which comprises: (i) at substantially water insoluble and is both a bioadhe least one soluble polyvinylpyrrolidone polymer (PVP); (ii) Sive and a pressure-Sensitive adhesive; and wherein 35 at least one bioadhesive; and (iii) optionally one or more the composition either includes at least one active Solvents, wherein the Source (a) is different than the adhesive agent or, alternately, is used together with an active layer (b). agent. Further objects, features and advantages of the present The bioadhesive compositions further comprise a backing invention will become apparent from consideration of the material and a release liner which conforms to the Size and 40 detailed description of preferred embodiments which fol shape of an individual dosage unit or delivery System. lows. The invention also relates to a method of prolonged topical administration of one or more active agents to a DETAILED DESCRIPTION OF THE Subject comprising the Steps of: INVENTION INCLUDING PREFERRED (a) providing a bioadhesive composition in a flexible, 45 EMBODIMENTS finite form comprising: This invention relates to bioadhesive compositions for the (i) a mixture of two or more bioadhesives wherein at delivery of an active agent having local or Systemic action, least one bioadhesive is a soluble PVP polymer; and methods of use thereof. The advantage of these bioad (ii) optionally a pharmaceutically acceptable Solvent 50 hesive compositions lies in their ability to maintain direct or Suitable for use with an active agent, the Solvent intimate contact with the Site of application for a prolonged optionally including a plasticizer for the bioadhe periods of time, Such as, for example, greater than 1 hour, Sives, preferably 2 hours, more preferably 4 hours, even more (iii) optionally, a pressure-Sensitive adhesive; preferably greater than 8 hours, up to even 24 hours. It is wherein the composition is Substantially free of water and 55 believed the use of a soluble PVP polymer in combination Substantially water insoluble; with another bioadhesive, especially an insoluble (b) contacting an area of skin or mucous membrane, bioadhesive, Such as a natural gum, in a Solvent that includes preferably the oral mucosa, with Said bioadhesive com a plasticizer for the bioadhesives, allows each to Swell (i.e., position to administer the one or more active agents, absorb moisture) independent of each other and consecu wherein the composition either includes at least one 60 tively rather than at the same time, Such as when applied to active agent or, alternately, is used together with an mucosa, thus providing enhanced and prolonged adherence active agent. to wet or moist Surfaces Such as mucous membranes and The invention additionally relates to a method of pro teeth, and thereby increasing the effective penetration or longed topical administration of two or more active agents absorption, and Sustained delivery, of the active agent. to a Subject comprising the Steps of: 65 While not wishing to be bound by any theory, the inven (a) providing a bioadhesive composition in a flexible, tors believe that the combination of PVP and another bio finite form comprising: adhesive provides for a Superior adhesion not attainable by US 6,562,363 B1 S 6 either the PVP or other bioadhesive alone. It is believed that acrylic and methacrylamide, and N-Vinyl-2-pyrrolidone, the presence of a bioadhesive, Such as karaya gum, has the alkyl acrylates and methacrylates, vinyl acetate, acrylonitrile effect of preferentially absorbing and Swelling with liquids, and Styrene; and generally, any physiologically acceptable Such as Solvents, plasticizers and Saliva which otherwise polymer showing bioadhesive properties. may interfere with the bioadhesive properties of the PVP. Particularly suitable bioadhesives include natural or syn Thus, the addition of the other bioadhesive provides a faster thetic polysaccharides. The term “polysaccharide' as used acting and longer duration of adhesion. herein means a carbohydrate decomposable by hydrolysis into two or more molecules of monosaccharides or their The compositions are further provided in a finite, flexible derivatives. Suitable polysaccharides include cellulose form for convenient topical application of the active agent. materials, as Specified above, pectin, a mixture of Sulfated The present compositions do not Substantially degrade Sucrose and aluminum hydroxide, N-Vinyl lactam polysac during use and do not cause undue irritation or side effects charides and most preferably natural gums Such as karaya, which have been experienced with other transmucosal com guar, okra, arabic, acacia, pectina, ghatti, tragacanth, positions of the prior art. Xanthan, locust bean, psyllium Seed, tamarind, destria, The term “bioadhesives” or “mucoadhesives” as used casein and the like. herein mean natural, Synthetic or Semi-Synthetic materials 15 Some Suitable polyacrylic acid polymers include poly that adhere and preferably Strongly adhere to a Surface Such mers of acrylic acid crosslinked with polyalkenenyl ethers as skin, teeth or mucous membrane upon wetting or hydra (generically known as carbomers) or divinyl glycol tion. In order for a material to qualify as a bioadhesive, it (generically known as polycarbophils) and commercially must be capable of maintaining close or intimate contact available from B. F. Goodrich, Cincinnati, Ohio, under the with a wet or moist Surface for a minimal amount of time. trademark Carbopole copolymers or resins, Pemulen poly The bioadhesive composition of the present invention is meric emulsifiers and Noveon polycarbophils. Particularly finite and “self adhesive” in that it is capable of attaching to preferred are Carbopol(R) 934 NF, 934P NF, 940 NF and the Site of application without the need to reinforce Such 971P NF. attachment by means of the use of another adhesive applied Exemprlary polyethylene glycol ethers of aliphatic alco over it or to a backing. 25 hols include polyoxyethylene (4) lauryl ether, polyoxyeth A bioadhesive is frequently characterized as one that ylene (2) oleyl ether and polyoxyethylene (10) oleyl ether absorbs a certain number of times its weight in water (i.e., which are sold under the trademark BRIJ(R) 30, 93 and 97 by is water Swellable). Depending on the bioadhesive, this can ICI Americas, Inc., and BRIJCR 35, 52, 56,58, 72, 76, 78,92, be as low as about 10 or as high as about 1000 times its 96, 700 and 721. weight it water. Exemplary bioadhesives are natural veg The term “polyvinylpyrrolidone” or “PVP" refers to a polymer, either a homopolymer or copolymer, containing etable gums which absorb from about 30 to about 50 times vinylpyrrolidone (also referred to as N-vinylpyrrolidone, their weight in water depending on the gum chosen. N-vinyl-2-pyrrolidone and N-vinyl-2-pyrrolidinone) as a Bioadhesion is often a difficult phenomenon to measure. monomeric unit. PVP polymers include soluble and The bioadhesive Strength for purposes of this invention can 35 insoluble homopolymeric PVPs, and copolymers such as be measured by Standard tests for measuring force, e.g. in Vinylpyrrollidone/vinyl acetate and Vinylpyrrollidone/ dynes per Square centimeter, as disclosed in Robinson, U.S. dimethylamino-ethylmethacrylate. The cross-linked Pat. No. 4,615,697, and is a minimum of 50 dynes per square homopolymer is insoluble and is generally known in the centimeter, and more preferably 100 to 500 dynes per square pharmaceutical industry under the designations centimeter or even 1,000 dynes per Square centimeter. 40 polyvinylpolypyrrollidone, crospovidone and PVP. The The bioadhesive materials of the present invention copolymer Vinylpyrrollidone-Vinyl acetate is generally include polymers, either water Soluble or water insoluble, known in the pharmaceutical industry under the designations with or without crosslinking agents, known in the literature Copolyvidon(e), Copolyvidonum or VP-VAc. as being bioadhesive. There can be used for this purpose The term “soluble' when used with reference to PVP various bioadhesives including, preferably natural materials 45 Such as gums, carmelose, chitosan, carrageenans, eucheuma, means that the polymer is Soluble in water and generally is fucoidan, hypnea, laminaran, furcellaran, agar, agarose, not Substantially croSS-linked, and has a molecular weight of algin, a my lose, Scleroglu can, arabino glactins, less than about 2,000,000. See, generally, Buhler, KOLLI galactomannan, Starches, alginates Such as potassium and DON (R): POLYVINYLPRYRROLIDONE FOR THE Sodium, pectins, polypeptides Such as gelatins, collagen and 50 PHARMACEUTICAL INDUSTRY, BASF Aktiengesell the like; cellulose materials including Substituted and unsub schaft (1992). Soluble PVP polymers have been identified Stituted celluloses Such as cellulose, ethy cellalose, under in the pharmaceutical industry under a variety of methylcellulose, nitro cellulose, propylcellulose, names, the most commonly used include PoVidone, hydroxypropylcellulose, hydroxyethylcellulose, carboxym Polyvidon(e), Polyvidonum, Polyvidonum, poly (N-vinyl ethylcellulose and hydroxypropylmethylcellulose, cellulose 55 2-pyrrolidinone, poly (N-vinylbutyrolactam), poly (1-vinyl derivates, alkylcellulose and hydroxyalkylcellulose deriva 2-pyrrolidone), poly 1-(2-oxo-1-pyrrolidinyl)ethylene). tives wherein the alkyl group is 1 to 7 carbons, cellulose The term "mucous membrane' or “mucosa” as used acetate butyrate and carboxyalkylcellulose, Synthetic and herein means oral, buccal, vaginal, rectal, nasal, intestinal Semi-Synthetic polymers including carboxyvinyl and opthalmic Surfaces. copolymers, polyethylene glycol, polyethylene glycol ethers 60 The term “buccal' or “oral” as used herein means the of aliphatic alcohols (such as cetyl, lauryl, oleyland Stearyl), mouth and the Surrounding esophegeal area including the polyhydroxyalkyl methacrylates, propylene glycol alginate, gums, teeth, palate, tongue, tonsils and periodontal tissue. polyethylene oxides, polyacrylamides and polyacrylic acids, The term “adhesive' as used herein means a natural or Vinyl polymerS Such as polyvinyl alcohol, polyvinyl ethers, Synthetic material that is capable of Sticking to the Site of polyvinyl acetate and polyvinylpyrrolidones, and copoly 65 topical application or administration. merization and/or crosslinking of both hydrophilic and The term “topical” or “topically” is used herein in its hydrophobic monomerS Such as hydroxyalkyl esters of conventional meaning as referring to direct contact with a US 6,562,363 B1 7 8 Spot on a mammal, which can be any anatomical Site or completely or Substantially delivered after a period of, for Surface area including skin, mucous membranes or hardened example, about 1 to about 90 minutes, in particular for a tissue Such as bone, teeth or nails. period ranging from about 5 to about 60 minutes. At the The term “administering” or “administration” is intended Same time, another active agent could be present in the to mean any mode of application to a tissue which results in composition Such that the Second agent is delivered over a the physical contact of the composition with an anatomical longer time period, for example, up to a period of about 24 Site or Surface area. hours, in particular for a period ranging from about 5 minutes to about 16 hours. That is, in one embodiment of the The term “subject' is intended to include all warm present invention, the first agent would have an overall blooded mammals, preferably humans. higher rate of flux than the Second agent resulting in an As used herein, the term “prolonged” or “extended” refers earlier depletion of the first agent from the bioadhesive to a time period of more than 30 minutes. The present composition. composition is capable of being maintained in contact with The period of time for delivering the active agents would mucosa, Such as buccal mucosa, for a period of time up to depend on many factors, i.e., the dosing conditions, the 24 hours, preferably for periods ranging from about 30 15 agents being delivered, etc. For example, in accordance with minutes to about 24 hours, more preferably from about 1 the present invention, it would be possible to include a hour to about 16 hours, and most preferably from about 1 topical anesthetic agent which is delivered quickly, Say hour to about 12 hours. within 20 minutes, and also include a Second anesthetic As used herein, the term “flux' is defined as the absorp agent which is the same or different from the first anesthetic tion of the active agent through the skin or mucosa, and is and could optionally be systemic, which would be delivered described by Fick's first law of diffusion: over an extended period, Say over a period of up to 8 hours or even 24 hours. Such an arrangement would be Suitable for multiple applications, Such as during dental procedures. where J is the flux in g/cm/sec, D is the diffusion coefficient Alternatively, two or more active agents can be topically of the drug through the skin or mucosa in cm2/sec and 25 administered to achieve either a prolonged therapeutic effect dCm/dx is the concentration gradient of the active agent or multiple therapeutic effects, or both. For example, a acroSS the skin or mucosa. non-Steroidal anti-inflammatory agent can be topically The phrase “flexible, finite form' is intended to mean a administered in conjunction with an anesthetic agent Such Solid form capable of conforming to a Surface with which it that the bioadhesive composition provides a reduction in comes into contact, and which is capable of maintaining the pain by means of both the analgesic effect and the anesthesia contact in Such Solid form So as to facilitate topical appli of the Such agents, respectively. The intended effects of Such cation without any adverse physiological response, and a combination of agents, or other multiple combinations of Without being appreciably decomposed by aqueous contact agents, can be for a period of time up to 24 hours for the during administration to a Subject. multiple agents, or for varying periods of time over a 24 hour An important characteristic of the embodiments of the 35 period. present invention relates to the Substantially water-free and The rate of delivery of the active agents may be controlled water-insoluble nature of the composition. By the term by either the concentration and/or Solubility of Such agents “substantially water-free” is meant that the composition in the bioadhesive composition, the pH of the composition, contains less than about 10% by weight water, and prefer the thickness of the composition or the size of the System as ably less than 5%, and most preferably less than 3% prior to 40 a finished dosage form, or the permeability or Solubility of its topical application. In general, it is desirable to avoid the the of the entire composition. addition of water entirely and to eliminate, as far as possible, AS used herein, the term “active agent” (and its the presence of water in the other ingredients of the com equivalents, "agent,” “bioactive agent,” “drug,” “medica position. By the term “substantially water-insoluble” is ment” and “pharmaceutical”) is intended to have the broad meant that the composition remains "finite” and does not 45 est meaning and includes at least one of any therapeutic, generally detach from the Site of application and under the prophylactic, pharmacological or physiological active conditions of regular, intended use for a period of at least 3 Substance, or mixture thereof, which is delivered to a hours. The advantages to be derived from the substantially mammal to produce a desired, usually beneficial, effect. water-free and water-insoluble nature of the compositions of More specifically, any active agent which is capable of the present invention include achievement of higher con 50 producing a pharmacological response, localized or centrations of active agent. Another advantage of these Systemic, irrespective of whether therapeutic, diagnostic or compositions is minimization of precipitation of the active prophylactic in nature, is within the contemplation of the agent, which precipitation affects processing of the invention. It should be noted that the active agents or drugs composition, affects rate of delivery of the active agents and may be used singularly or as a mixture of two or more agents in certain cases can affect Sensitivity of the Subject to the 55 or drugs, and in amounts Sufficient to prevent, cure, active agent. diagnose, mitigate or treat a disease or condition, as the case The present compositions may in one embodiment may be. include the use of two active agents which may be the same 1. C.-Adrenergic agonists Such as Adrafinil, Adrenolone, or different. For example, one agent may be in base form and Amidephrine, Apraclonidine, Budralazine, Clonidine, the other agent may be in acid or Salt form. In addition, one 60 Cyclopentamine, Detomidine, Dimetofrine, Dipivefrin, agent may be present which is delivered quickly having a Ephedrine, Epinephrine, Fenoxazoline, Guanabenz, relatively high flux rate, together with a Second agent which Guanfacine, Hydroxyamphetamine, Ib opamine, is delivered over a prolonged time period and has a lower Indiana Zoline, I Some the ptene, Mephen termine, flux rate. Meta raminol, Methoxamine Hydro chloride, Specifically, the present composition permits the dosing 65 Methylhexaneamine, Metizolene, Midodrine, Naphazoline, of two or more active agents Simultaneously. For example, Norepinephrine, Norfenefrine, Octodrine, Octopamine, a first agent could be present in the composition So as to be Oxymetazoline, Phenylephrine Hydrochloride, Phenylpro US 6,562,363 B1 9 10 panolamine Hydrochloride, Phenylpropylmethylamine, (acetylsalicylate), Aminochlorthenoxazin,2-Amino-4- Phole drine, Propylhexe drine, Pseudoephe drine, picoline, Aminopropylon, Aminopyrine, Ammonium Rilmenidine, Synephrine, Tetrahydrozoline, Tiamenidine, Salicylate, Antipyrine, Antipyrine Salicylate, Antrafenine, TramaZoline, Tuaminoheptane, Tymazoline, Tyramine and Apa Zone, Aspirin, Be nory late, Benoxaprofen, Xylometazoline. BenZpiperylon, BenZydamine, p-Bromoacetanilide, 2. B-Adrenergic agonists Such as Albuterol, Bambuterol, 5-Bromosalicylic Acid Acetate, Bucetin, BufeXamac, Bitolterol, Carbute rol, Clenbute rol, Clorprenaline, Bumadi Zon, Butacetin, Calcium Acetylsalicylate, Denopamine, Dioxethedrine, Dopexamine, Ephedrine, Carbamazepine, Carbetidine, Carbiphene, CarSalam, Epinephrine, Etafedrine, Ethylnorepinephrine, Fenoterol, Chloralantipyrine, Chlorthenoxazin(e), Choline Salicylate, Formoterol, HeXoprenaline, Ibopamine, Isoetharine, Cinchophen, Ciramadol, Clometacin, Cropropamide, Isoprote renal, Mabute rol, Meta prote renol, Crotethamide, Dexoxadrol, Difenamizole, Diflunisal, Dihy Methoxyphenamine, Oxyfedrine, Pirbuterol, Prenalterol, droxyaluminum Acetylsalicylate, Dipyrocetyl, Dipyrone, Procaterol, Protokylol, Reproterol, Rimiterol, Ritodrine, EmorfaZone, Enfenamic Acid, Epirizole, EterSalate, Soterenol, Terbuterol and Xamoterol. EthenZamide, Ethoxazene, Etodolac, Felbinac, Fenoprofen, 3. C.-Adrenergic blockerS Such as AmoSulalol, Arotinolol, 15 Floctafenine, Flufenamic Acid, Fluoresone, Flupirtine, Dapiprazole, Doxazosin, Ergoloid MeSylates, Fenspiride, FluproduaZone, Flurbiprofen, Fosfosal, Gentisic Acid, Indoramin, Labetalol, Nicergoline, PraZosin, Terazosin, Glafenine, Ibufenac, Imidazole Salicylate, Indomethacin, Tolazoline, Trimazosin and Yohimbine. Indoprofen, ISOfe Zolac, Isoladol, Isonixin, Ketoprofen, 4. B-Adrenergic blockerS Such as Acebutolol, Alprenolol, Ketorolac, p-Lactophenetide, Lefetamine, Loxoprofen, Amosulalol, Arotinolol, Atenolol, Befunolol, Betaxolol, Lysine Acetylsalicylate, Magnesium Acetylsalicylate, Bevantolol, Bisoprolol, Bopindolol, Bucumolol, Belfetolol, Methotrimeprazine, Metofoline, Miroprofen, Morazone, Bufuralol, Bunitrolol, Bupranolol, Butidrine Hydrochloride, Morpholine Salicylate, Naproxen, Nefopam, Nifenazone, 5' Butofilolol, Carazolol, Carteolol, Carvedilol, Celiprolol, Nitro-2' propoxyacetanilide, Parsalmide, Perisoxal, Cetamolol, Cloranolol, Dilevalol, Epanolol, Esmolol, Phenacetin, Phenazopyridine Hydrochloride, Phenocol, Inde nolol, Labe talol, Levobunolol, Mepindolol, 25 Phenopyrazone, PhenylAcetylsalicylate, Phenyl Salicylate, Metipranalol, Metoprolol, Moprolol, Nadoxolol, Nifenalol, Pheny ramidol, Pipebu Zone, Piperylone, Prodilidine, Nipradillol, Oxprenolol, Penbutolol, Pindolol, Practolol, Propacetamol, Propyphena Zone, Proxazole, Quinine Pronethalol, Propranolol, Sotalol, Sulfinalol, Talinolol, Salicylate, Ramifena Zone, Rimazolium Metilsulfate, Tertatolol, Timolol, Toliprolol and Xibenolol. Salacetamide, Salicin, Salicylamide, Salicylamide O-Acetic 5. Alcohol deterrents Such as Calcium Cyanamide Acid, Salicylsulfuric Acid, Salsalte, Salverine, Simetride, Citrated, Disulfiram, Nadide and Nitrefazole. Sodium Salicylate, Sulfamipyrine, Suprofen, Talniflumate, 6. Aldose reductase inhibitorS Such as Epalrestat, Tenoxicam, Terofenamate, Tetradrine, Tinoridine, Tolfe Ponalrestat, Sorbinil and Tolrestat. namic Acid, Tolpronine, Tramadol, Viminol, Xenbucin and 7. Anabolics Such as Androisoxazole, Androstenediol, Zomepirac. Bolandiol, Bolasterone, Clostebol, Ethylestrenol. 35 11. Androgens Such as Androsterone, Boldenone, Formyldie no lone, 4-Hydroxy-19-nortestosterone, Dehydroepiandrosterone, Fluoxymesterone, Mestanolone, Methandriol, Methenolone, Methyltrienolone, Nandrolone, Mesterolone, Methandrostenolone, 17-Methyltestosterone, Nandrolone De cano ate, Nandrolone 17C.-Methyltestosterone 3-Cyclopenty1 Enol Ether, p-HeXyloxyphenylpropionate, Nandrolone Phenpropionate, Nore thandrolone, Normethandrone, Oxandrolone, Norbolethone, Oxymesterone, Pizotyline, Quinbolone, 40 Oxymesterone, Oxymetholone, Prasterone, Stanlolone, Stenbolone and Trenbolone. Stanozolol, Testosterone, Testosterone 17-Chloral 8. Analgesics (dental) Such as Chlorobutanol, Clove and Hemiacetal, Testosterone 17B-Cypionate, Testosterone Eugenol. Enant hate, Testosterone Nicotinate, Testosterone 9. Analgesics (narcotic) Such as Alfentanil, Allylprodine, Pheynylacetate, Testosterone Propionate and Tiomesterone. Alphaprodine, Anileridine, Benzylmorphine, Bezitramide, 45 12. Anesthetics Such as Acetamidoeugenol, Alfadolone Bupre norphine, Butorphanol, ClonitaZene, Codeine, Acetate, Alfaxalone, Amucaine, Amolanone, Amylocaine Codeine Methyl Bromide, Codeine Phosphate, Codeine Hydrochloride, BenoXinate, Benzocaine, Betoxycaine, Sulfate, DeSomorphine, Dextromoramide, DeZocine, Biphenamine, Bupivacaine, Butacaine, Butaben, Diampromide, Dihydrocodeine, Dihydrocodeinone Enol Butanilicaine, Burethamine, Buthalital Sodium, Acetate, Dihydromorphine, Dimenoxadol, Dimepheptanol, 50 Butoxycaine, Carticaine, 2-Chloroprocaine Hydrochloride, Dimethylthiambutene, Dioxaphetyl Butyrate, Dipipanone, Cocaethylene, Cocaine, Cyclomethycaine, Dibucaine Eptazocine, Ethoheptazine, Ethylmethlythiambutene, Hydrochloride, Dimethisoquin, Dimethocaine, Diperadon Ethylmorphine, EtonitaZene, Fentanyl, Hydrocodone, Hydrochloride, Dyclonine, Ecgonidine, Ecgonine, Ethyl Hydro co do n e Bit art rate, Hydro morphone, Aminobenzoate, Ethyl Chloride, Etidocaine, Etoxadrol, Hydroxype thidine, Isomethadone, Keto be midone, 55 B-Eucaine, Euprocin, Fenalcomine, Fomocaine, Levorphanol, Lofentanil, Meperidine, MeptaZinol, Hexobarbital, Hexylcaine Hydrochloride, Hydroxydione Metazocine, Methadone Hydrochloride, Metopon, Sodium, Hydroxyprocaine, Hydroxytetracaine, Isobutyl Morphine, Morphine Derivatives, Myrophine, Nalbuphine, p-Aminobenzoate, Kentamine, Leucinocaine MeSylate, Narceline, Nicomorphine, Norlevorphanol, Normethadone, LeVoxadrol, Lidocaine, Mepivacaine, Meprylcaine Normorphine, Norpip anone, Opium, Oxycodone, 60 Hydrochloride, Metabutoxycaine Hydrochloride, Metho Oxymorphone, Papaveretum, Pentazocine, Phenadoxone, hexital Sodium, Methyl Chloride, Midazolam, Myrtecaine, Phenazocine, Pheoperidine, Piminodine, Piritramide, Nae paine, Octacaine, Orthocaine, OXetha Zaine, Proheptazine, Promedol, Prope ridine, Propiram, Parethoxycaine, Phenacaine Hydrochloride, Phencyclidine, Propoxyphene, Sufentanil and Tilidine. Phenol, Piperocaine, Piridocaine, Polidocanol, Pramoxine, 10. Analgesics (non-narcotic) Such as Acetaminophen, 65 Prilocaine, Procaine, Propanidid, Propanocaine, AcetaminoSalol, Acetanilide, Acetylsalicylsalicylic Acid, Proparacaine, Propipocaine, Propofol, Propoxycaine Alclofenac, Alminoprofen, Aloxiprin, Aluminum Bis Hydrochloride, Pseudococaine, Pyrrocaine, Quinine Urea US 6,562,363 B1 11 12 Hydochloride, Risocaine, Salicyl Alcohol, Tetracaine CinepaZet Maleate, Diltiazem, Epanolol, Felodipine, Hydrochloride, Thialbarbital, Thimylal, Thiobutabarbital, Gallopamil, Imolamine, Indenolol, ISOSorbide Dinitrate, Thiopental Sodium, Tolycaine, Trimecaine and Zolamine. Isradipine, Limaprost, Mepindolol, Metoprolol, 13. Anorexics Such as Aminorex, Amphecloral, Molsidomine, Nadolol, Nicardipine, Nifedipine, Nifenalol, Amphetamine, BenZaphetamine, Chlorphen termine, Nilvadipine, Nipradillol, Nisoldipine, Nitroglycerin, Clobenzorex, Cloforex, Clortermine, Cyclexedrine, Destro Oxprenolol, Oxyfedrine, OZagrel, Penbutolol, Pentaerythri amphetamine Sulfate, Diethylpropion, Diphemethoxidine, tol Tetranitrate, Pindolol, Pronethalol, Propranolol, Sotalol, N-Ethylamphetamine, Fenbut razate, Fenfluramine, Terodiline, Timolol, Toliprolol and Verapamil. Fen prop ore X, Fur furyl methyl ampheta mine, 24. Antiarrhythmics Such as Acebutol, Acecaine, Le Vo phace top e rate, Ma Zind ol, Mefe no re X, Adenosine, Ajmaline, Alprenolol, Amiodarone, Amoproxan, Metamfe pro a mone, Methampheta mine, Aprindine, Arotinolol, Atenolol, Bevantolol, Bretylium Norpseudoephedrine, Phendimetrazine, Phendimetrazine Tosylate, Bubumolol, Bufetolol, Bunaftine, Bunitrolol, Tartrate, Phenmetrazine, Phenpentermine, Phenylpropano Bupranolol, Butidrine Hydrochloride, Butobendine, lamine Hydrochloride and Picilorex. Capobenic Acid, Carazolol, Carteolol, Cifenline, 14. Anthelmintics (Cestodes) Such as Arecoline, Aspidin, 15 Cloranolol, Disopyramide, Encainide, Esmolol, Flecainide, Aspidinol, Dichlorophen(e), Embelin, Kosin, Napthalene, Gallopamil, Hydroquinidine, Indecainide, Indenolol, Iprat Niclosamide, Pellertierine, Pellertierine Tannate and Quina ropium Bromide, Lidocaine, Lorajmine, Lorcainide, crine. Meobentine, Metipranolol, Mexiletine, Moricizine, 15. Anthelmintics (Nematodes) Such as Alantolactone, Nadoxolol, Nifenalol, Oxprenolol, Penbutolol, Pindolol, AmoScanate, AScaridole, Bephenium, Bitoscanate, Carbon Pirmenol, Practolol, Prajma line, Procain amide Tetra chloride, Carva crol, Cyclobe n dazole, Hydrochloride, Pronethalol, Propafenone, Propranolol, Diethylcarbamazine, Diphenane, Dithiazanine Iodide, Pyrinoline, Quinidine Sulfate, Quinidine, Sotalol, Talinolol, Dymanthine, Gentian Violet, 4-Hexylresorcinol, Kainic Timolol, Tocainide, Verapamil, Vicquidil and Xibenolol. Acid, Mebendazole, 2-Napthol, Oxantel, Papain, Piperazine, 25. Antiarteriosclerotics such as Pyridinol Carbamate. Piperazine Adipate, Piperazine Citrate, Piperazine Edetate 25 26. Antiarthritic/Antirheumatics Such as Allocupreide Calcium, Piperazine Tartrate, Pyrantel, Pyrvinium Pamoate, Sodium, Auranofin, Aurothioglucose, Aurothioglycanide, C.-Santonin, Stilbazium Iodide, Tetrachloroethylene, Azathioprine, Calcium 3-Aurothio-2-propanol-1-Sulfonate, Tetramisole, thia bendazole, Thy mol, Thy myl Celecoxib, Chloroquine, Clobu Zarit, Cuproxoline, N-Isoamylcarbamate, Triclofenol Piperazine and Urea Diacerein, Glucosamine, Gold Sodium Thiomalate, Gold Stibamine. Sodium Thiosulfate, Hydroxychloroquine, Kebu Zone, 16. Anthelmintics (Onchocerca) Such as Ivermectin and Lobenzarit, Melittin, Methotrexate, Myoral and Penicil Suramin Sodium. lamine. 17. Anthelmintics (Schistosoma) Such as Amoscanate, 27. Antibacterial (antibiotic) drugs including: Amphotalide, Antimony Potassium Tartrate, Antimony Aminoglycosides Such as Amikacin, Apramycin, Sodium Gluconate, Antimony Sodium Tartrate, Antimony 35 Arbekacin, Bambermycins, Butirosin, Dibekacin, Sodium Thioglycollate, Antimony Thioglycollamide, Dihdrostreptomycin, Fortimicin(s), Gentamicin, Becanthone, Hycanthone, Lucanthone Hydrochloride, Ispamicin, Kanamycin, Micronomicin, Neomycin, Niridazole, Oxamniquine, Praziquantel, Stibocaptate, Sti Neomycin Undecylenate, Netilmicin, Paromomycin, bophen and Urea Stibamine. Ribo Stamycin, Sisomicin, Spectinomycin, 18. Anthelmintic (Trematodes) such as Anthiolimine and 40 Streptomycin, StreptonicOZid and Tobramycin; Tetrachloroethylene. Amphenicols Such as AZidamfenicol, Chloramphenicol, 19. Antiacne drugs. Such as Adapelene, AlgeStone Chloramphenicol Palmitate, Chloramphe nicol Acetophenide, AZelaic Acid, Benzoyl Peroxide, Cyoctol, Pantothenate, Florfenicol and Thiamphenicol; Cyproterone, Motretinide, Resorcinol, Retinoic Acid, Tetro Ansamycins Such as Rifamide, Rifampin, Rifamycin and quinone and Tretinonine. 45 Rifaximin; 20. AntiallergicS Such as Amlexanox, Astemizole, B-Lactams, including: AZelastine, Cromolyn, Fenpiprane, Histamine, Ibudilast, Carbapenems. Such as Imipenem; Nedocromil, Oxatomide, Pentigetide, Poison Ivy Extract, Cephalosporins Such as Cefactor, Cefadroxil, Poison Oak Extract, Poison Sumac Extract, Repirinast, Cefamandole, Cefatrizine, CefaZedone, Cefazolin, Tranilast, Traxanox and Urushiol. 50 Cefixime, Cefnmenoxime, Cefodizime, Cefonicid, 21. Antiamebics Such as Arsthinol, Bialamicol, CefoperaZone, Ceforanide, Cefotaxime, Cefotiam, CarbarSone, Cephaeline, Chlorbetamide, Chloroquine, Ce?pimizole, Ce?pirimide, Cefpodoxime Proxetil, Chlorphenoxamide, Chlortetracycline, Dehydroemetine, Cefroxadine, CefSulodin, Ceftazidime, Cefteram, Dibromopropamidine, Diloxanide, DephetarSone, Emetine, Ceftezole, Ceftibuten, Ceftizoxime, Ceftriaxone, Fumagillin, Glaucarubin, Glycobiarsol, 8-Hydroxy-7-iodo 55 Cefuroxime, CefuZonam, Cephacetrile Sodium, 5-quinoline Sulfonic Acid, Iodochlorhydroxyquin, Cephale Xin, Cephaloglycin, Cephaloridine, Iodoquinol, Paromomycin, Phanquinone, Phears one Cephalosporin, Cephalothin, Cephapirin Sodium, Sulfoxylate, Polybenzarsol, Propamidine, Quinfamide, Cephradine and Piveefalexin; Secnidazole, SulfarSide, Teclozan, Tetracycline, Cephamycins Such as CefbuperaZone, Cefnmetazole, Thiocarbamizine, ThiocarbarSone and Tinidazole. 60 Cefnminox, Cefetan and Cefoxitin; 22. Antiandrogens Such as Bifluranol, Cyoctol, Monobactams Such as Aztreonam, Carumonam and Cyproterone, Delmadinone Acetate, Flutimide, Nilutamide Tigemonam, and Oxendolone. Oxacephems. Such as Flomoxef and Moxolactam, 23. Antianginals. Such as Acebutolol, Alprenolol, Penicillins such as Amidinocillin, Amdinocillin Amiodarone, Amlodipine, Arotinolol, Atenolol, Bepridil, 65 Pivoxil, Amoxicillin, Ampicillan, Apalcillin, Bevantolol, Bucumolol, Bufetolol, Bufuralol, Bunitrolol, ASpoxicillin, AZidocillan, AZlocillan, Bacampicillin, Bupranolol, Carozolol, Carteolol, Carvedilol, Celiprolol, Benzylpenicillinic Acid, Benzylpenicillin Sodium, US 6,562,363 B1 13 14 Carbenicillin, Carfecillin Sodium, Carindacillin, Sulfaethidole, Sulfaguanidine, Sulfaguanol, Sulfalene, Clometocill in, Cloxacill in, Cyclacillin, Sulfaloxic Acid, Sulfamerazine, Sulfameter, Dicloxacillin, Diphenicillin Sodium, Epicillin, Sulfamethazine, Sulfamethizole, Sulfamethomidine, Fenbenicillin, Floxicillin, Hetacillin, Lenampicillin, Sulfame thoxazole, Sulfame thoxypyrida Zine, Metampicillin, Methicillin Sodium, Mezlocillin, Sulfametrole, Sulfamidochrysoidine. Sulfamoxole, Nafcillin Sodium, Oxacillin, Penamecillin, Peneth Sulfanilamide, Sulfanilamidomethanesulfonic Acid amate Hydriodide, Penicillin G Benethamine, Peni Triethanolamine Salt, 4-Sulfanilamidosalicylic Acid, cillin G Benzathine, Penicillin G Benzhydrylamine, N-Sulfanilylsulfanilamide, Sulfanily lure a, Penicillin G Calcium, Penicillin G Hydrabamine, N-Sulfanilyl-3,4-xylamide, Sulfanitran, Sulfaperine, Penicillin G Potassium, Penicillin G Procaine, Peni Sulfaphenazole. Sulfaproxyline, Sulfapyrazine, cillen N, Penicillin O, Penicillin V, Penicillin V Sulfapyridine, SulfaSomizole, Sulfasy mazine, Ben Zathine, Penicillin V Hydrab amine, Sulfathiazole, Sulfathiourea, Sulfatolamide, Sulfisomi Penimepicycline, Phenethicillin Potassium, dine and Sulfisoxazole; Piperacillin, Pivapicillin, Propicillin, Quinacillin, Sulfones Such as AcedapSone, AcediaSulfone, Acetosul Sulbenicillin, Talampicillin, Temocillin and Ticarcil 15 fone Sodium, DapSone, DiathymoSulfone, Glucosul lin; fone Sodium, Solasulfone, Succisulfone, Sulfanilic Lincosamides Such as Clindamycin and Lincomycin; Acid, p-Sulfanilylbenzylamine, p.p'-Sulfonyldianiline Macrollides Such as Azithroimycin, Carbomycin, N.N'digalactoside, Sulfoxone Sodium and Thiazolsul Clarithromycin, Erythromycin, Erythromycin fone, and Acistrate, Erythromycin Estolate, Erythromycin others. Such as Clofoctol, Hexedine, Methenamine, Meth Glucoheptonate, Erythromycin Lactobionate, Erythro enamine Anhydromethylene-citrate, Methenamine mycin Propionate, Erythromycin Stearate, Josamycin, Hippurate, Methenamine Mandelate, Methenamine Leucomycins, Mide camycins, Miokamycin, Sulfosalicylate, Nitroxoline and Xibornol. Oleandomycin, Primycin, Rokitamycin, Rosaramicin, 29. AnticholinergicS Such as Adiphenine Hydrochloride, ROXithromycin, Spiramycin and Troleandomycin; 25 Alverine, Ambutonomium Bromide, Aminopentamide, Polypeptides Such as Amphomycin, Bacitracin, Amixe trine, Amprotropine Phosphate, Anisotropine Capreomycin, Colistin, Enduracidin, Enviomycin, Methylbromide, Apoatropine, Atropine, Atropine N-Oxide, Fu Safungine, Gramicidin(s), Gramicidin S, Benactyzine, Benapry Zine, BenZetimide, BenZilonium Mika mycin, Polymyxin, Polymyxin Bromide, Benztropine Mesylate, Bevonium Methyl Sulfate, B-Methanesulfonic Acid, Pristinamycin, Ristocetin, Biperiden, Butropium Bromide, N-Butylscopolammonium Teicoplanin, Thio Strepton, Tuberactinomycin, Bromide, Bu Zepide, Camylo fine, Caramiphen Tyrocidine, Tyrothricin, Vancomycin, Viomycin, Vio Hydrochloride, Chlorbenzoxamine, Chlorphenoxamine, mycin Pantothenate, Virginiamycin and Zinc Bacitra Cimetropium Bromide, Clidinium Bromide, Cyclodrine, cin; Cyclonium Iodide, Cycrimine Hydrochloride, Deptropine, Tetracyclines Such as Apicycline, Chlortetracycline, 35 Dexe timide , Dibutoline Sulfate, Dicyclomine Clomocycline, De me clocycline, Doxycycline, Hydrochloride, Diethazine, Difemerine, Dihexyverine, Guame cycline, Lyme cycline, Me clocycline, Diphemanil Methylsulfate, N-(1,2-Diphenylethyl) Metha cycline, Minocycline, Oxytetracycline, nicotinamide, Dipiproverine, Diponium Bromide, Emepro Penimepicycline, Pipacycline, Rolitetracycline, nium Bromide, Endobenzyline Bromide, Ethopropazine, 40 Ethybenztropine, Ethylbenzhydramine, Etomidoline, Sancycline, Senociclin and Tetracycline; and Eucatropine, Fenpiverinium Bromide, Fentonium Bromide, other antibioticS Such as CycloSerine, Mupirocin and Flutropium Bromide, Glycopyrrolate, Heteronium Bromide, Tuberin. Hexocyclium Methyl Sulfate, Homatropine, Hyoscyamine, 28. Antibacterial drugs (Synthetic), including: I pratropium Bromide, Isopropamide, Levome pate, 2,4-Diaminopyrimidines Such as Brodimoprim, TetroX 45 Mecloxamine, Mepenzolate Bromide, Metcaraphen, Meth oprim and Trimethoprim; antheline Bromide, Methixene, Methscopolamine Bromide, Nitrofurans Such as Furaltadone, Furazolium Chloride, Octamylamine, Oxybutynin Chloride, Oxyphencyclimine, Nifuradene, Nifuratel, Nifurfoline, Nifurpirinol, Oxyphenonium Bromide, Pentapiperide, Penthienate Nifurprazine, Nifurtoinol and Nitrofurantoin; Bromide, Phencarbamide, Phenglutarimide, Pipenzolate Quinolones and Analogs Such as Amifloxacin, Cinoxacin, 50 Bromide, Piperidolate, Piperilate, Poldine Methysulfate, Ciprofloxacin, Difloxacin, Enoxacin, Fleroxacin, Pridinol, Prifinium Bromide, Procyclidine, Propantheline Flumequine, Lomefloxacin, Miloxacin, Nalidixic Acid, Bromide, Propenzolate, Propyromazine, Scopolamine, Sco Norfloxacin, Ofloxacin, Oxolinic Acid, Pefloxacin, polamine N-Oxide, Stilonium Iodide, Stramonium, Pipemidic Acid, Piromidic Acid, Rosoxacin, Tema Sultroponium, Thihexinol, Thiphenamil, Tiemonium Iodide, floxacin and ToSufloxacin; 55 Timepidium Bromide, Tiquizium Bromide, Tridihexethyl Sulfonamides Such as Acetyl Sulfamethoxypyrazine, Iodide, Trihexyphenidyl Hydrochloride, Tropacine, Acetyl SulfiSoxazole, AZOSulfamide, Benzylsulfamide, Tropenzile, Tropicamide, Trospium Chloride, Valethamate Chloramine-B, Chloramine-T, Dichloramine T. Bromide and Xeny tropium Bromide. Formosulfathiazole, N°Formylsulfisomidine, N°-?3-D- 30. Anticonvulsants Such as Acetylpheneturide, Albutoin, Glucosylsulfanila mide, Mafen ide, 4'- 60 Aloxidone, Aminoglutethimide, 4-Amino-3-hydroxybutyric (Methylsulfamoyl)sulfanila nilide, Acid, Atrolactamide, Beclamide, Buramate, Calcium p-Nitro sulfa thiazole, No prylsulfamide, Bromide, Carbamazepine, Cinromide, Clomethiazole, Phthalylsulfacetamide, Phthalylsulfathiazole, Clonazepam, Decimenide, Diethadione, Dimethadione, Sala Zo Sulfadimidine, Succinylsulfathiazole, Doxenitoin, Eterobarb, Ethadione, Ethosuximide, Ethotoin, Sulfabenzamide, Sulfacetamide, Sulfachlorpyridazine, 65 Fluores one, Garbapentin, 5-Hydroxy tryptophan, Sulfachrysoidine, Sulfacy tine, Sulfadiazine, Lamotrigine, Lomactil, Magnesium Bromide, Magnesium Sulfadicramide, Sulfadimethoxine, Sulfadoxine, Sulfate, Mephenytoin, Mephobarbital, Metharbital, US 6,562,363 B1 15 16 Methetoin, Methsuximide, 5-Methyl-5-(3-phenanthryl) 35. Antiestrogens Such as Delmadinone Acetate, hydantoin, 3-Methyl-5-phenylhydantoin, Narcobarbital, Ethamoxytriphetol, Tamoxifen and Toremifene. Nimetazepam, Nitrazepam, Paramethadione, Phenacemide, 36. Antifungal drugs (antibiotics), including: Phenetharbital, Pheneturide, Phenobarbital, Phenobarbital Polyenes Such as Amphotericin-B, Candicidin, Sodium, Phensuximide, Phenylmethylbarbituric Acid, Phenytoin, Phethenylate Sodium, Potassium Bromide, Dermostatin, Filipin, Fungichromin, Hachimycin, Pregabatin, Primidone, Progabide, Sodium Bromide, Hamycin, Lucensomycin, Mepartricin, Natamycin, Sodium Valproate, Solanum, Strontium Bromide, Nystatin, Pecilocin and Perimycin; and Suclofenide, Sulthiame, Tetrantoin, Tiagabine, otherS Such as AZaSerine, Griseofulvin, Oligomycins, Trimethadione, Valproic Acid, Valpromide, Vigabatrin and Neomycin Undecylenate, Pyrrolnitrin, Siccanin, Tuber Zonisamide. 1O cidin and Viridin. 31. Antidepressants, including: 37. Antifungal drugs (Synthetic), including: BicyclicS Such as Binedaline, CaroXaZone, Citalopram, Allylamines such as Naftifine and Terbinafine; Dimethazan, Indalpine, Fencamine, Fluvoxamine Maleate, Indeloxazine Hydrochcloride, Nefopam, Imidazole S. Such as Bifonazole, Butoconazole, Nomifensine, Oxitriptan, Oxypertine, Paroxetine, 15 Chlordantoin, Chlormidazole, Cloconazole, Sertraline, Thiazesim, Trazodone, Venlafaxine and Clotrimazole, Econazole, Enilconazole, Fenticonazole, Zometapine; ISO conazole, Ke to conazole, Miconazole, HydrazideS/Hydrazines Such as Benmoxine, Iproclozide, Omoconazole, Oxiconazole, Nitrate, Sulconazole and Iproniazid, Isocarboxazid, Nialamide, Octamoxin and Tioconazole; Phenelzine; Triazoles Such as Fluconazole, Itraconazole and Tercona Pyrrollidones Such as Cotinine, Rolicyprine and Rolipram; Zole; and Tetracyclics such as Maprotiline, Metralindole, Mianserin otherS Such as Acrisorcin, Amorolfine, Biphenamine, and Oxaprotiline. Bromosalicylchloranilide, Buclosamide, Calcium Tricyclics Such as Adina Zolam, Amitriptyline, Propionate, Chlophenesin, Ciclopirox, Cloxyquin, Amitriptylinoxide, Amoxapine, Butriptyline, 25 Coparaffinate, Diamthazole, Dihydrochloride, Clomipramine, Deme Xiptiline, De Sipramine, EXalamide, Flucytosine, Halethazole, Hexetidine, Dibenzepin, Dimetracrine, Dothiepin, Doxepin, Loflucarban, Nifuratel, Potassium Iodide, Propionic Fluacizine, Imipramine, Imipramine N-Oxide, Acid, Pyrithione, Salicylanilide, Sodium Propionate, Iprindole, Lofepramine, Melitracen, Metapramine, Sulbentine, Tenonitrozole, Tolciclate, Tolindate, Nortriptyline, Noxiptilin, Opipramol, Pizotyline, Tolnaftate, Tricetin, Ujothion, Undecylenic Acid and Propizepine, Protriptyline, Quinupramine, Tianeptine Zinc Propionate. and Trimipramine, and 38. Antiglaucoma drugs. Such as Acetazolamide, otherS Such as Adrafinil, Benacty Zine. Bupropion, Befunolol, Betaxolol, Bupranolol, Carteolol, Dapiprazoke, Butacetin, Deanol, Deanol Aceglumate, Deanol Dichlorphenamide, Dipivefrin, Epinephrine, Levobunolol, Acetamidobenzoate, Dioxadrol, Etope ridone, 35 Methazolamide, Metipranolol, Pilocarpine, Pindolol and Febarbamate, Femoxetine, Fenpentadiol, Fluoxetine, Timolol. Fluvoxamine, Hematoporphyrin, Hypercinin, 39. Antigonadotropins Such as DanaZol, Gestrinone and Levophacetoperane, Medifoxamine, Mina prine, Paroxypropione. Moclobemide, Oxaflozane, Piberaline, Prolintane, 40. Antigout drugs. Such as Allopurinol, Carprofen, Pyrisuccide anol, Rubidium Chloride, Sulpiride, 40 Colchicine, Probenecid and Sulfinpyrazone. Sultopride, Teniloxazine, ThoZalinone, Tofenacin, 41. Antihistamines, including: Toloxatone, Tranylcypromine, L-Tryptophan, Vilox Alkylamine derivatives Such as Acrivastine, Bamipine, azine and Zimeldine. Bromphe niramine, Chlorphe niramine, 32. Antidiabetics, including: Dimethindene, Metron S, Pheniramine, 45 Pyrrobutamine, Thenaldine, Tolpropamine and Biguanides such as Buformin, Metformin and Phen Triprolidine; formin; A mino alkyl ether S Such as Biet a nautine, Hormones Such as Glucagon, Insulin, Insulin Injection, Bromodiphenhydramine, Carbinoxamine, Clemastine, Insulin Zinc Suspension, Isophane Insulin Suspension, Diphenly pyraline, Doxylamine, Embrammine, Protamine Zinc Insulin Suspension and Zinc Insulin 50 Crystals, Me dry la mine, Mephen phy dra mine, Sulfonylure a derivatives Such as Acetohexamide, p-Methyldiphenhydramine, Orphen a drine, 1-Butyl-3-met a nily lure a, Carbutamide, Phenyltoloxamine, Piprinhydrinate and Setasine; Chlorpropamide, Glibornuride, Gliclazide, Glipizide, Ethylenediamine derivatives Such as Alloclamide, Gliquidone, Glisoxepid, Glyburide, Glybuthiazol(e), 55 p-Bromtripelennamine, Chloropyramine, Chlorothen, Glybuzole, Glyhexamide, Glymidine, Glypinamide, Histapyrrodine, Methafurylene, Methaphenilene, Phenbutamide, Tolazamide, Tolbutamide and Tolcycla Methapyrilene, Phenbenzamine, Pyrilamine, Talastine, mide; and Thenyldiamine, Thonzylamine Hydrochloride, Tripe otherS Such as Acarbose, Calcium Mesoxalate and Migli lennamine and Zolamine; tol. 60 Piperazines Such as Cetirizine, Chlorcyclizine, 33. Antidiarrheal drugs. Such as Acetyltannic Acid, Albu Cinnarizine, Clocinizine and Hydroxy Zine; min Tannate, Alkofanone, Aluminum Salicylates-Basic, Tricyclics, including: Catechin, Dife noxin, Diphenoxylate, Lidamidine, Phenothiazines Such as Ahistan, Etyme mazine, Loperamide, Mebiquine, Trillium and Uzarin. Fenethazine, N-Hydroxyethylprometha Zine 34. Antidiuretics Such as DeSmopressin, Fely pressin, 65 Chloride, Isoprometha Zine, Me quita Zine, Lypressin, Ornipressin, Oxycinchophen, Pituitary Promethazine, Pyrathiazine and Thiazinamium Posterior, Terlipressin and Vasopressin. Methyl Sulfate; and US 6,562,363 B1 17 18 otherS Such as AZatadine, Clobenzepam, Hydrazines and phthalazines Such as Budralazine, Cyproheptadine, Deptropine, Isothipendyl, Lorata Cadra la Zine, Dihydra la Zine, Endra la Zine, dine and Prothipendyl; and Hydracarbazine, Hydralazine, Pheniprazine, Pildrala other antihistamines Such as Antazoline, Astemizole, Zine and Todralazine, AZelastine, Cetoxime, Clemizole, Clobenztropine, Imidazole derivatives Such as Clonidine, Lofexidine, Diphenazoline, Diphenhydramine, FluticaSone Phentolamine, Phentolamine Mesylate, Tiamenidine Propionate, Mebhydroline, Phenindamine, Terfenadine and Tolonidine; and Tritoqualine. Quaternary ammonium compounds AZamethonium 42. Antihyperlipoproteinemics, including: Bromide, Chlorisondamine Chloride, Hexamethonium, 1O Pentacynium Bis(methyl sulfate), Pentamethonium Aryloxyalkanoic acid derivatives Such as Beclorbrate, Bromide, Pentolinium Tartate, Phenactopinium Chlo Bazafibrate, Binifibrate, Ciprofibrate, Clinofibrate, ride and Trimethidiunum Methosulfate; Clofibrate, Clofibric Acid, Etonfibrate, Fenofibrate, Quinazoline derivatives Such as AlfuZosin, BunaZosin, Gemfibrozil, Nicofibrate, Pirifibrate, Ronifibrate, Sim Doxazosin, Prasosin, Terazosin and TrimaZosin; fibrate and Theofibrate; Reserpine derivatives Such as Bietaserpine, DeSerpidine, Bile acid Sequesterants Such as Cholestyramine Resin, 15 Rescinnamine, Reserpine and Syrosingopine, Colestipol and Polidexide; Sulfonamide derivatives Such as AmbuSide, Clopamide, HMG CoA reductase inhibitors such as Fluvastatin, Furosemide, Indapamide, QuinethaZone, Tripamide Lovastatin, Pravastatin Sodium and Simvastatin; and Xipamide; and Nicotinic acid derivatives Aluminum Nicotinate, otherS Such as Ajmaline, Y-Aminobutyric Acid, Acipimox, Niceritrol, Nicoclonate, Nicomol and Bufeniode, Candesartan, Chlorthalidone, Cicletaine, Ciclosidomine, Cryptenamine Tannates, EproSartan, OXiniacic Acid; Fenoldopam, FloSequinan, Indoramin, Irbesartan, Thyroid hormones and analogS Such as EtiroXate, Thyro Ketanserin, LOSartan, Metbutamate, Mecamylamine, propic Acid and ThyroXine, and Methyldopa, Methyl 4-Pyridyl Ke tone otherS Such as Acifran, AZacosterol, Benfluorex, 25 Thiosemicarbarzone, Metola Zone, Minoxidil, B-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Muzolimine, Pargyline, Pempidine, Pinacidil, Clomestone, Detaxtran, Dextran Sulfate Sodium, 58, Piperoxan, Primaperone, Protoveratrines, Raubasine, 11, 14, 17-Eicosapentaenoic Acid, Eritade nine, Rescimetol, Rilmenidene, Saralasin, Sodium Furazbol, Meglutol, Melinamide, Mytatrienediol, NitroprusSide, Ticrynafen, Trimethaphan Camsylate, Ornithine, Y-Oryzanol, Pantethine, Penataerythritol Tyrosinase, Urapidil and Valsartan. Tetraacetate, C.-Phenylbutyramide, Pirozadil, Probucol, 44. Antihyperthyroids Such as 2-Amino-4-methylthiazole, C-Sitosterol, Sultosilic Acid, Piperazine Salt, Tiadenol, 2-Aminothiazole, Carbimazole, 3,5-Dibromo-L-tyrosine, Triparanol and Xenbucin. 3,5-Diiodotyrosine, Hinderin, Iodine, Iothiouracil, 43. Antihypertensive drugs, including: Methimazole, Methylthiouracil, Propylthiouracil, Sodium Arylethanolamine derivatives Such as Amosulalol, 35 Perchlorate, Thibenzazoline, Thiobarbital and 2-Thiouracil. Bufuralol, Dilevalol, Labetalol, Pronethalol, Sotalol 45. Antihypotensive drugs. Such as AmeZinium Methyl and Sulfinalol; Sulfate, Angiotensin Amide, Dimetofrine, Dopamine, Aryloxypropanolamine derivatives Such as Acebutolol, Etifelmin, Etilefrin, Gepefrine, Metaraminol, Midodrine, Alp renolol, Arotinolol, Atenolol, Beta Xolol, Norepinephrine, Pholedrinead and Synephrine. Bevantolol, Bisoprolol, Bopindolol, Bunitrolol, 40 46. Antihypothyroid drugs. Such as Levothyroxine Bupranolol, Butofilolol, Carazolol, Cartezolol, Sodium, Liothyronine, Thyroid, Thyroidin, Thyroxine, Carvedilol, Celiprolol, Cetamolol, Epanolol, Indenolol, Tiratricol and TSH. Mepindolol, Metipranolol, Metoprolol, Moprolol, 47. Anti-Inflammatory (non-steroidal) drugs, including: Nadolol, Nipradillol, Oxprenolol, Penbutolol, Pindolol, 45 Aminoarylcarboxylic acid derivatives Such as Enfenamic Propranolol, Talinolol, Tetraolol, Timolol and Tolip Acid, Etofenamate, Flufenamic Acid, IsoniXin, rolol, Meclofenamic Acid, Mefanamic Acid, Niflumic Acid, Benzothiadiazine derivatives Such as Althiazide, Talniflumate, Terofenamate and Tolfenamic Acid; Bendro flume thiazide, Ben Zthiazide, Arylacetic acid derivatives Such as Ace metacin, Ben Zylhydrochlorothiazide, Buthiazide, 50 Alclofenac, Amfenac, BufeXamac, Cinmetacin, Chlorothiazide, Chlorthalidone, Cyclopenthiazide, Clopirac, Diclofenac Sodium, Etodolac, Felbinac, Cyclothiazide, DiaZoxide, Epithiazide, Ethiazide, Fenclofenac, Fenclorac, Fenclozic Acid, Fentiazac, Fen qui Zone, Hydrochlor othiazide, Glucametacin, Ibufenac, Indomethacin, ISOfeZolac, Hydroflumethiazide, Methyclothiazide, Meticrane, ISOXepac, LonaZolac, Metiazinic Acid, Oxametacine, Metolazone, Paraflutizide, Polythiazide, Tetrachlorme Proglumetacin, Sulindac, Tiaramide, Tolimetin and thiazide and Trichlormethiazide, 55 Zomepirac, N-Carboxyalkyl (peptide/lactam) derivatives such as Arylbutyric acid derivatives Such as Bumadizon, Alacepril, Captopril, CilaZapril, Delapril, Enalapril, Butibufen, Fenbufen and Xenbucin; Enalaprilat, Fosinopril, Lisinopril, Moveltipril, Arylcarboxylic acids Such as Clidanac, Ketorolac and Perindopril, Quinapril and Ramipril; 60 Tinoridine; Dihydropyridine derivatives Such as Amlodipine, Arylpropionic acid derivatives Such as Alminoprofen, Felodipine, Isradipine, Nicardipine, Nifedipine, Benoxaprofen, Bucloxic Acid, Carprofen, Fenoprofen, Nilvadipine, Nisoldipine and Nitrendipirne; Fluinoxaprofen, Flurbiprofen, Ibuprofen, Ibuproxam, Guanidine derivatives Such as Bethanidine, Debrisoquin, Indoprofen, Ketoprofen, Loxoprofen, Miroprofen, Guanabenz, Guanacline, Guanadrel, GuanaZodine, 65 Naproxen, Oxaprozin, Piketoprofen, Pirprofen, Guanethidine, Guanfacine, Guanochlor, GuanoXabenz Pranoprofen, Protizinic Acid, Suprofen and Tiaprofenic and Guanoxan; Acid; US 6,562,363 B1 19 20 Pyrazoles such as Difenamizole and Epirizole; NitroSoureas Such as Carmustine, Chlorozotocin, Pyrazolones Such as ApaZone, BenZpiperylon, Feprazone, Fotemustine, Lomustine, Nimustine and Ranimus Mofebutazone, Morazone, Oxyphen but a Zone, tine, and Phenylbutazone, Pipebu Zone, Propyphena Zone, otherS Such as Camptothecin, Dacarbazine, RamifenaZone, SuxibuZone and ThiazolinobutaZone; Mannomustine, Mitobronitol, Mitolactol and Pipo Salicylic acid derivatives Such as AcetaminoSalol, broman; Aspirin, Benorylate, Bromosaligenin, Calcium Antibiotics Such as Aclacinomycins, Actinomycin F, Acetylsalicylate, Diflunisal, EterSalate, Fendosal, Gen Anthramycin, AZ, a Serine, Ble o my c in S, tisic Acid, Glycol Salicylate, Imidazole Salicylate, Cactinomycin, Carubicin, Car Zinophilin, Lysine Acetylsalicylate, MeSalamine, Morpholine Chromomycins, Dactinomycin, Daunorubicin, Salicylate, 1-Narhthyl Salicylate, Olsalazine, 1O 6-Diazol-5-oxo-L-nor leucine, Doxorubicin, Parsalmide, PhenylAcetylsalicylate, Phenyl Salicylate, Epirubicin, Mitomycins, Mycophenolic Acid, Nogalamycin, Olivomycins, Peplomycin, Salacetamide, Salicylamine O-Acetic Acid, Salicylsul Plicamycin, Porfiro my cin, Puromycin, furic Acid, Salsalate and SulfaSalazine; Streptonigrin, Streptozocin, Tubercidin, Ubenimex, Thiazinecarboxamides Such as Droxicam, ISOXicam, 15 Zinostatin and Zorubicin; PiroXicam and Tenoxicam, and Antimetabolites, including: otherS Such as e-Acetamido cap roic Acid, Folic acid analogs Such as Denopterin, Methotrexate, S-Adenosylmethionine, 3-Amino-4-hydroxybutyric Pteropterin and Trimetrexate; Acid, Amixetrine, BendaZac, BenZydamine, Bucolome, Purine analogS Such as Fludarabine, 6-Mercaptopurine, Difenpiramide, DitaZol, EmorfaZone, GuaiaZulene, Thiamiprine and Thioguanaine; and Nabumetone, NimeSulide, Orgotein, Oxaceprol, Pyrimidine analogs Such as Ancitabine, AZacitidine, Paranyline, Perisoxal, Pifoxime, ProquaZone, ProX 6-AZauridine, Carmofur, Cytarabine, Doxifluridine, azole and Tenidap. Enocitabine, Floxuridine Fluroouracil and Tegafur; 48. Antimalarial drugs. Such as AcedapSone, Amodiaquin, Enzymes Such as L-ASparaginase; and Arteether, Artemether, Artemisinin, ArteSunate, Bebeerine, 25 otherS Such as Aceglatone, AmSacrine, BeStrabucil, Berberine, Chirata, Chlorguanide, Chloroquine, Bisantrene, Bryostatin 1, Carboplatin, Cisplatin, Chlorproguanil, Cinchona, Cinchonidine, Cinchonine, Defo famide, De me colcine, Diaziquone, Cyclogu a nil, Gentiopic rin, Halo fantrine, Elfornithine, Elliptinium Acetate, Etoglucid, Hydroxychloroquine, Mefloquine Hydrochloride, Etoposide, Gallium Nitrate, Hydroxyurea, 3-Methylarsacetin, Pamaquine, Plasmocid, Primaquine, Interferon-C., Interferon-B, Interferon-Y, Interleukine-2, Lentinan, Letrozole, Lonidamine, Pyrimethamine, Quinacrine, Quinine, Quinine Bisulfate, Mito gua Zone, Mito Xantrone, Mopidamol, Quinine Carbonate, Quinine Dihydrobromide, Quinine Nitracrine, Pentostatin, Phenamet, Pirarubicin, Dihydrochloride, Quinine Ethylcarbonate, Quinine Formate, Podophyllinicc Acid, 2-Ethy thydrazide, Quinine Gluconate, Quinine Hydriodide, Quinine Polynitrocubanes, Procarbazine, PSK7, Razoxane, Hydrochloride, Quinine Salicylate, Quinine Sulfate, Qui 35 Sizofiran, Spirogermanium, Taxol, Teniposide, nine Tannate, Quinine Urea Hydrochloride, Quinocide, Tenua Zonic Acid, Tria Ziquone, 2.2.2"- Quinoline and Sodium Arsenate Diabasic. Trichlorotriethylamine, Urethan, Vinblastine, 49. Antimigraine drugs. Such as Alpiropride, Vincristine, Vindesline and Vinorelbine. Dihydroergotamine, Eletriptan, Ergocornine, Ergocorninine, 52. Antineoplastic (hormonal) drugs, including: Ergocryptine, Ergot, Ergotamine, FlumedroXone acetate, 40 Androgens Such as Calusterone, DromoStanolone Fonazine, Lisuride, Methysergid(e), Naratriptan, Oxetorone, Propionate, EpitioStanol, MepitioStane and Testolac Pizotyline, Rizatriptan and Sumatriptan. tone, 50. Antinauseant drugs. Such as Acetylleucine Antiadrenals. Such as Aminoglutethimide, Mitotane and Monoe thanolamine, Ali Zapride, BenZquinamide, TriloStane; Bietanautine, Bromopride, Buclizine, Chlorpromazine, 45 Antiandrogens Such as Flutamide and Nilutamide; and Clebopride, Cyclizine, Dimenhydrinate, Dipheniodol, Antiestrogens Such as Tamoxifen and Toremifene. Domperidone, Granisetron, Meclizine, Methalltal, 53. Antineoplastic adjuncts including folic acid replen Metoclopramide, Metopimazine, Nabilone, Ondansteron, isherS Such as Frolinic Acid. Oxypendyl, Pipamazine, Piprinhydrinate, Prochlorperazine, 54. Antiparkinsonian drugs. Such as Amantadine, Scopolamine, Tetrahydrocannabinols, Thiethylperazine, 50 Benserazide, Bietanautine, Biperiden, Bromocriptine, ThioproperZaine and Trimethobenzamide. Budipine, Cabergoline, Carbidopa, Deprenyl (a/k/a 51. Antineoplastic drugs, including: L-deprenyl, L-deprenil, L-deprenaline and Selegiline), Alkylating agents, including: DeXetimide, Diethazine, Diphenhydramine, Droxidopa, Alkyl Sulfonates Such as BuSulfan, ImproSulfan and Ethopropa Zine, Ethylben Zhydramine, Le Vodopa, Piposulfan; 55 Naxagolide, Pergolide, Piroheptine, Pramipexole, Pridinol, AZiridines Such as BenZOdepa, Carboquone, Meture Prodipine, Quinpirole, Remacemide, Ropinirole, Terguride, depa and Uredepa; Tigloidine and Trihexyphenidyl Hydrochloride. Ethylenimines and methylmelamines Such as 55. Antipheochromocytoma drugs. Such as Metyrosine, Alt reta mine, Trie thylene me la mine, Phenoxybenzamine and Phentolamine. Triethylenephosphoramide, Triethylenethiophos 60 56. Antipneumocystis drugS Such as Effornithine, Penta phoramide and Trimethylolomelamine; midine and Sulfamethoxazole. Nitrogen mustards Such as Chlorambucil, 57. Antiprostatic hypertrophy drugs. Such as Gestonorone Chlornaphazine, Chclophosphamide, Estramustine, Caproate, Mepartricin, Oxendolone and Proscar7. Ifosfamide, Mechlorethamine, Mechlorethamine 58. Antiprotozoal drugs (Leshmania) Such as Antimony Oxide Hydrochloride, Melphalan, Novembichin, 65 Sodium Gluconate, Ethylstibamine, HydroxyStilbamidine, Phenesterine, Prednimustine, Trofosfamide and N-Methylglucamine, Pentamidine, Stilbamidine and Urea Uracil Mustard; Stibamine. US 6,562,363 B1 21 22 59. Antiprotozoal drugs (Trichomonas) Such as Halogens and halogen compounds Such as Bismuth AcetarSone, Aminitrozole, Anisomycin, AZanidazole, Iodide Oxide, Bismuth Iodosubgallate, Bismuth Forminitrazole, Furazolidone, Hachimycin, Lauroguadine, Tribromophenate, Bornyl Chloride, Calcium Iodate, Mepartricin, Metronidazole, Nifuratel, Nifuroxime, Chlorinated Lime, Cloflucarban, Flurosalan, Iodic Nimorazole, Secnidazole, Silver Picrate, Tenonitrozole and 5 Acid, Iodine, Iodine Monochloride, Iodine Trichloride, Tinidazole. Iodoform, Methenamine Tetraiodine, Oxychlorosene, 60. Antiprotozoal drugs (Trypanosma) Such as Povidone-Iodine, Sodium Hypochlorite, Sodium Benznidazole, Eflornithine, Melarsoprol, Nifurtimox, Iodate, Symclosene, Thymol Iodide, Triclocarban, Tri Oxophenarsine, Hydrochloride, Pentamidine, Propamidine, closan and Troclosene Potassium; Puromycin, Quinapyramine, Stilbamidine, Suramin Mercurial compounds Such as Hydragaphen, Meralein Sodium, Trypan Red and Tryparasmide. Sodium, Merbromin, Mercuric Chloride, Mercuric 61. Antipuritics Such as Camphor, Cyproheptadine, Chloride, Ammoniated, Mercuric Sodium Dichlorisone, Glycine, HalometaSone, 3-Hydroxycamphor, p-Phenolsulfonate, Mercuric Succinimide, Mercuric Menthol, Mesulphen, Methdilazine, Phenol, Polidocanol, Sulfide, Red, Mercurophen, Mercurous Acetate, Mer Risocaine, Spirit of Camphor, Thenaldine, Tolpropamine and Trimeprazine. 15 curous Chloride, Mercurous Iodide, Nitromersol, 62. Antipsoriatic drugs. Such as Acitretin, Ammonium Potassium Tetraiodomercurate(II), Potassium Tri Salicylate, Anthralin, 6-AZauridine, Bergapten(e), iodomercurate (II) Solution, Thimerfonate Sodium and Chrysarobin, Etretinate and Pyrogallol. Thimerosal; 63. Antipsychotic drugs, including: Nitrofurans such as Furazolidone, 2-(Methoxymethyl)-5- Butyrophenones Such as Benperidol, Bromperidol, nitrofuran, Nidroxy Zone, Nifuroxime, Nifurzide and Droperidol, Fluanisone, Haloperidol, Melperone, Nitrofurazone; Moperone, Pipamperone, Sniperone, Timiperone and Phenols Such as Acetomeroctol, Bithionol, Cadmium Trifluperidol; Salicylate, Carvacrol, Chloroxylenol, Clorophene, Phenothiazines Such as Acetophenazine, Butaperazine, CreSote, Cresol(s), p - CreSol, Fentic lor, Carphenazine, Chlorproethazine, Chlorpromazine, 25 Hexachlorophene, 1-Napthyl Salicylate, 2-Napthyl Clo Spira Zine, Cy ame ma Zine, Dixy razine, Salicylate, 2,4,6-Tribromo-m-cresol, and 3',4',5'- Fluphenazine, Imiclopazine, Mepazine, MeSoridazine, Trichlorosalicylanilide; Methoxypromazine, Metofenazate, Oxaflumazine, Quinolines Such as Aminoquinuride, BenZOXiquine, Perazine, Pericyazine, Perimethazine, Perphenazine, Broxyquinoline, Chloro Xine, Chlorduinaldol, Pipe racetazine, Pipotiazine, Prochlorpe razine, Cloxyquin, Ethylhydrocupreine, Euprocin, Halquinol, Promazine, Sulforida Zine, Thiopropa Zate, Hydrastine, 8-Hydroxquinoline, 8-Hydroxquinoline Thioridazine, Trifluoperazine and Triflu promazine; Sulfate and Iodochlorhydroxyquin; and Thioxanthenes Such as Chlorprothixene, Clopenthixol, otherS Such as Aluminum Acetate Solution, Aluminum Flupentixol and Thiothixene; Subacetate Solution, Aluminum Sulfate, 3-Amino-4- other tricyclicS Such as BenZquinamide, Carpipramine, 35 hydroxybutyric Acid, Boric Acid, Chlorhexidine, Clocapramine, Clomacran, Clothiapine, Clozapine, ChloroaZodin, m-Cresyl Acetate, Cupric Sulfate, Opipramol, Prothipendyl, Tetrabenazine, and Dibromopropamidine, Ichthammol, Negatol 7, Zotepine, and Noxytiolin, Ornidazole, B-Propiolactone, C-Terpineol. otherS Such as Alizapride, Amisulpride, Buramate, 68. AntiSpasmodic drugs. Such as Alib endol, Fluspirilene, Molindone, Penfluridol, Pimozide, Spir 40 Ambucetamide, Aminopromazine, Apoatropine, Bevonium ilene and Sulpiride. Methyl Sulfate, Bietamiverine, Butaverine, Butropium 64. Antipyretics Such as Acetaminophen, AcetaminoSalol, Bromide, N-Butylscopolammonium Bromide, Caroverine, Acetanilide, Aconine, Aconite, Aconitine, Alclofenac, Alu Cimetropium Bromide, Cinnamedrine, Clebopride, Coniine minum Bis(acetylsalicylate), Aminochlorthenoxazin, Hydrobromide, Coniine Hydrochloride, Cyclonium Iodide, Aminopyrine, Aspirin, Benorylate, BenZydamine, 45 Difemerine, Diisopromine, Dioxaphetyl Butyrate, Dipo Berberine, p-Bromoacetanilide, BufeXamac, Bumadizon, nium Bromide, Drofenine, Emepronium Bromide, Calcium Acetysalicylate, Chlorthenoxazin(e), Choline Ethaverine, Fecle mine, Fenalamide, Fe noverine, Salicylate, Clidanac, Dihydroxyaluminum Acetylsalicylate, Fenpiprane, Fenpiverinium Brcmide, Fentonium Bromide, Dipyrocetyl, Dipyrone, Epirizole, EterSalate, Imidazole Flavoxate, Flopropione, Gluconic Acid, Guaiactamine, Salicylate, Indomethacin, IsofeZolac, p-Lactophenetide, 50 Hydramitrazine, Hymecromone, Leiopyrrole, Mebeverine, Lysine Acetylsalicylate, Magnesium Acetylsalicylate, Moxaverine, Nafiverine, Octamylamine, Octaverine, Meclofenamic Acid, Morazone, Morpholine Salicylate, Pentapiperide, Phenamacide Hydrochloride, Phloroglucinol, Naproxen, Nifenazone, 51-Nitro-2'-propoxyacetanilide, Pinaverium Bromide, Piperilate, Pipoxolan Hydrochloride, Phenacetin, Phenicarbazide, Phenocol, Phenopyrazone, Pramiverin, Prifinium Bromide, Properidine, Propivane, Phenyl Acetylsalicylate, Phenyl Salicylate, Pipebuzone, 55 Propyromazine, Prozapine, Race femine, Rociverine, Propacetamol, Propy phena Zone, Ramife naZone, Spasmolytol, Stilonium Iodide, Sultroponium, Tiemonium Salacetamide, Salicylamide O-Acetic Acid, Sodium Iodide, Tiquizium Bromide, Tiropramide, Trepibutone, Salicylate, Sulfamipyrine, Tetrandrine and Tinoridine. Tricromyl, Trifolium, Trimebutine, N,N-Trimethyl-3,3- 65. Antirickettsial drugs Such as p-Aminobenzoic Acid, diphenyl-propylamine, Tropenzile, TroSpium Chloride and Chloramphenicol, Chloramphenicol Palmitate, Chloram 60 Xeny tropium Bromide. phenicol Pantothenate and Tetracycline. 69. Antithrombotic drugs. Such as Anagrelide, Argatroban, 66. Antiseborrheic drugs such as Chloroxine, 3-O- Cilostazol, Chrysoptin, Daltroban, Defibrotide, Enoxaparin, Lauroylpyridoxol Diacetate, Piroctone, Pyrithione, Fraxiparine7, Indobufen, Lamoparan, OZagrel, Picotamide, Resorcinol, Selenium Sulfides and Tioxolone. Plafibride, Reviparin, Tedelparin, Ticlopidine, Triflusal and 67. Antiseptics, including: 65 Warfarin. Guanidines Such as Alexidine, AmbaZone, Chlorhexidine 70. AntituSSive drugs. Such as Allocamide, Amicibone, and Picloxydine; Ben properine, BenZonatate, Bibenzonium Bromide, US 6,562,363 B1 23 24 Bromoform, Butamirate, Butlethamate, Caramiphen Hexoprenaline, Isoetharine, Isoproterenol, Mabuterol, Ethane disulfonate, Carbetapentane, Chlophedianol, Metaprote renol, N-Methylephedrine, Pirbuterol, Clobutinol, Cloperastine, Codeine, Codeine Methyl Procate rol, Protokylol, Reproterol, Rimiterol, Bromide, Codeine N-Oxide, Codeine Phosphate, Codeine Salmeterol, Soterenol, Terbutaline and Tulobuterol; Sulfate, Cyclexanone, Dextromethorphan, Dibunate Quaternary ammonium compounds Such as Bevonium Sodium, Dihydrocodeine, Dihydrocodeinone Enol Acetate, Methyl Sulfate, Clutropium Bromide, Ipratropium Bro Dime morfan, Dime thoXanate, C., C.-Diphenyl-2- mide and OXitropium Bromide; piperidinepropanol, Dropropizine, Drotebanol, EpraZinone, Xanthine derivatives Such as Acefylline, Acefylline Ethyl Dibunate, Ethylmorphine, Fominoben, Guiaiapate, Pipera Zine, Ambu phylline, Aminophylline, Hydrocodone, Isoaminile, Levopropoxyphene, Morclofone, Bamifylline, choline Theophyllinate, Doxofylline, Narceline, Normethadone, NoScapine, Oxeladin, OXolamine, Dyphylline, Enprofylline, Etamiphyllin, Eto?ylline, Pholcodine, Picoperine, Pipazethate, Piperidione, Prenoxdi Guaithylline, Proxyphylline, Theobromine, azine Hydrochloride, Race methorphan, TaZiprinone 1-Theobromineacetic Acid and Theophylline; and Hydrochloride, Tipepidine and Zipeprol. others such as Fenspiride, Medibazine, Montekulast, 71. Antiulcerative drugS Such as Aceglutamide Aluminum 15 Methoxyphenanime, Tretoquinol and Zafirkulast. Complex, e-Acetamidocaproic Acid Zinc Salt, Acetoxolone, 78. Calcium channel blockers, including: Arbaprostil, Benexate Hydrochloride, Bismuth Subcitrate Arylalkylamines Such as Bepridil, Ditiazem, Fendiline, Sol (Dried), Carbenoxolone, Cetraxate, Cimetidine, Gallopanil, Prenylamine, Terodiline and Verapamil; Enprostil, Esaprazole, Famotidine, Ftaxilide, Gefarnate, Dihydropyridine derivatives such as Felodipine, GuaiaZulene, IrSogladine, Misoprostol, Nizatidine, Isradipine, Nicardipine, Nifedipine, Nilvadipine, Omeprazole, Ornoprostil, Y-Oryzanol, Pifar nine, Nimodipine, Nisoldipine and Nitrendipine; Pirenzepine, Plaunotol, Ranitidine, RioproStil, Rosaprostol, Piperazine derivatives Such as Cinnarizine, Flunarisine Rotraxate, Roxatidine Acetate, Sofalcone, Spizofurone, and Lidoflazine, and Sucralfate, Teprenone, Trimoprostil, Thrithiozine, Troxipide otherS Such as Bencyclane, Etafenone and Perhexiline. and Zolimidine. 25 79. Calcium regulatorS Such as Calcifediol, Calcitonin, 72. Antiurolithic drugs. Such as Acetohydroxamic Acid, Calcitriol, Clodronic Acid, Dihydrotachysterol, Elcatonin, Allopurinol, Potassium Citrate and Succinimide. Etidronic Acid, Ipriflavone, Pamidronic Acid, Parathyroid 73. Antivenin drugs. Such as Lyovac7 Antivenin. Hormone and Teriparatide Acetate. 74. Antiviral drugs, including: 80. Cardiotonics Such as Acefylline, Acetyldigititoxins, Purines and pyrimidinones Such as Acyclovir, Cytarabine, 2-Amino-4-picoline, Amrinone, Benfurodil Hemisuccinate, Dideoxyadenosine, Dideoxycytidine, Dideoxyinosine, Buclasdesine, Cerberoside, Camphotamide, Convallatoxin, Edoxudine, Floxuridine, Ganciclovir, Idoxuridine, Cymarin, Denopamine, Deslanoside, Ditalin, Digitalis, Inosine Pranobex, MADU, Penciclovir, Trifluridine, Digitoxin, Digoxin, Dobutamine, Dopamine, DopeXamine, Vidrarbine and Zidovudine; and Enoximone, Erythrophleine, Fenalcomine, Gitalin, Gitoxin, otherS Such as Acetylleucine Monoethanolamine, 35 Glycocyamine, Heptaminol, Hydrastinine, Ibopamine, Amantadine, Amidinomycin, CoSalane, Cuminalde Lanotodises, Metamivam, Milrinone, Neriifolin, Oleandrin, hyde Thiosemicarb Zone, Foscar net Sodium, Ouabain, Oxyfedrine, Prenalterol, Proscillaridin, Imiquimod, Interferon-C, Interferon-B, Interferon-Y, ReSibu fogenin, Scillaren, Scillarenin, Strophanthin, Kethoxal, Lysozyme, MethisaZone, MoroXydine, Sulmazole, Theobromine and Xamoterol. Podophyllotoxin, Ribavirin, Rimantadine, Stallimycin, 40 81. Chelating agents Such as DeferOZmine, Ditiocarb Statolon, Tromantadine and Xenazoic Acid. Sodium, Edetate Calcium Disodium, Edetate Disodium, 75. Anxiolytic drugs, including: Edeate Sodium, Edetate Trisodium, Penicillamine, Pentetate Arylpiperazines Such as BuSpirone, Gepirone, Ipsapirone Calcium Trisodium, Pentectic Acid, Succimer and Trientine; and TondoSpirone. 82. Cholecystokinin antagonists Such as Proglumide. 45 83. Cholelitholytic agents such as Chenodiol, Methyl Benzodiazepine derivatives Such as Alprazolam, tert-Butyl Ether, Monooctanoin and Ursodiol. Bromazepam, Camazepam, Chlordiazepoxide, 84. Choleretics such as Alibendol, Anethole Trithion, Clobazam, CloraZepate, Chotiazepam, Cloxazolam, AZintamide, Cholic Acid, Cicrotoic Acid, Clanobutin, Diazepam, Ethyl Loflazepate, Etizolam, Fluidazepam, Cyclobutyrol, Cyclovalone, Cynarin(e), Dehydrocholic Flutazolam, Flutoprazepam, Halazepam, Ketazolam, 50 Acid, Deoxycholic Acid, Dimecrotic Acid, O.-Ethylbenzyl Lorazepam, Loxapine, Medazepam, Metaclazepam, Alcohol, Exiproben, Feguprol, Fencibutirol, Fenipentol, MeXaZolam, Nordazepam, Oxazepam, Oxazolam, Florantyrone, Hyme cromone, Menbutone, 3-(o- Pinazepam, Prazepam and Tofisopam; Methoxyphenyl)-2-phenylacrylic Acid, Metochalcone, Carbamates Such as Cyclarbamate, Emylcamate, Moquizone, Osalmid, Ox Bile Extract, 4.4'-Oxydi-2- Hydroxyphenamate, Meprobamate, Phenprobamate 55 butanol, Piprozolin, Prozapine, 4-Salicyloylmorpholine, and Tybamate; and Sincalide, Taurocholic Acid, Timonacic, Tocamphyl, otherS Such as Alpidem, BenZOctamine, Captodiamine, Trepibutone and Vanitiolide. ChlormeZanone, EtifoXine, Flesinoxan, Fluoresone, 85. Cholinergic agents Such as Aceclidine, Acetylcholine Glutamic Acid, Hydroxy Zine, Le Sopitron, Bromide, Acetylcholide Chloride, Aclatonium Napadisilate, Mecloralu rea, Mephenoxalone, Mirta Zepine, 60 Benzpyrinium Bromide, Bethanechol chloride, Carbachol, Oxanamide, Phenaglycodol, Suriclone and Zatosetron. Carpronium chloride, Demecarium Bromide, Dexpanthenol, 76. BenZodiazepine antagonistS Such as Flumazenil. Diisopropyl Paraoxon, Echothiophate Iodide, Edrophomium 77. Bronchodilators, including: chloride, Eseridine, Furtrethonium, Isoflurophate, Metha Ephedrine derivatives such as Albuterol, Bambuterol, choline chloride, Muscarine, NeoStigmine, Oxapropanium Bitolterol, Carbuterol, Clenbuterol, Clorprenaline, 65 Iodide, Physostigmine and Pyridostigmine Bromide. Dioxethedrine, Ephedrine, Epiniphrine, EproZinol, 86. Cholinesterase inhibitors such as Ambenonium Etafe drine, Ethylnorepinephrine, Fenote rol, Chloride, Distigmine Bromide and Galanthamine. US 6,562,363 B1 25 26 87. Cholinesterase reactivators such as Obidoximine Mucolytic enzymes Such as Lysozyme; Chloride and Pralidoxime Chloride. Penicillin inactivating enzymes Such as Penicillinase; and 88. Central nervous System Stimulants and agents Such as Proteolytic enzymes Such as Collagenase, Chymopapain, Amineptine, Amphetimine, Amphetaminil, Bemegride, Chymotrypsins, Papain and Trypsin. BenZphetamine, Brucine, Caffeine, Chlorphentermine, 96. Enzyme inducers (hepatic) Such as Flumecinol. Clofenciclan, Clortermine, Coca, Demanyl Phosphate, 97. Estrogens, including: Dexoxadrol, Dextroamphetamine Sulfate, Diethlpropion, Nonsteroidal estrogens Such as BenZestrol, Broparoestrol, N-Ethylamphetamine, Ethamivan, Etifelmin, Etryptamine, Chlorotrianisene, Dienestrol, Diethylstilbestrol, Dieth Fencamfamine, Fenethylline, Fenosolone, Flurothyl, ylstilbestrol Diproprionate, Dimestrol, Fosfestrol, Galanthamine, Hexacyclonate Sodium, Homocamfin, 1O Hexestrol, Methallenestril and Methestrol; and Ma Zindol, Mege X amide, Methamphetamine, Steroidal estrogens Such as Colpormon, Conjugated Methyl phen idate, Nike th a mide, Pemoline, Estrogenic Hormones, Equilenin, Equilin, Estradiol, Pentylenetetrazole, Phenidimetrazine, Phenmetrazine, Estradiol Benzoate, Estradiol 17(B-Cypionate, Estriol, Phentermine, Picrotoxin, Pipradrol, Prolintane and Pyrov Estrone, Ethinyl Estradiol, Mestranol, Moxestrol, alerone. 15 Mytatrienediol, Quinestradiol and Quinestrol. 98. Gastric Secretion inhibitorS Such as Enterogastrone 89. Decongestants Such as Amidephrine, Cafaminol, and Octreotide. Cyclopentamine, Ephedrine, Epinephrine, Fenoxazoline, 99. Glucocorticoids Such as 21-Acetoxyprefnenolone, Indanazoline, Metizoline, Naphazoline, Norde frin Aalclometasone, AlgeStone, Amicinonide, Beclomethasone, Hydrochloride, Octodrine, oxymetazoline, Phenylephrine Betamethasone, BudeSonide, Chloroprednisone, Clobetasol, Hydrochloride, Phenylpropanolamine Hydrochloride, Blovetasone, Clocortolone, Cloprednol, Corticosterone, Phenylpropyl methylamine, Propylhexe drine, Cortisone, Cortiva Zol, Defla Zacort, DeSonide, Pseudoephedrine, Tetrahydrozoline, Tymazoline and De Soxime taSone, De Xame thaSone, DifloraSone, Xylometazoline. Diflucortolone, Diflupredinate, Enoxolone, FluaZacort, 90. Dental agents, including: Flucloronide, Flumehtasone, Flunisolide, Fluocinolone Bisphosphonates (anti-periodontal disease and bone 25 Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone, resorption) Such as Alendronate, Clodronate, Fluorometholone, Fluperolone Acetate, Fluprednidene Etidronate, Pamidronate and Tiluldronate; Carries Pro Acetate, Fluprednisolone, Flurandrenolide, Formocortal, phylactics Such as Arginine and Sodium Fluoride; Halcinonide, HalometaSone, Halopredone Acetate, DeSensitizing Agents Such as Potassium Nitrate and Hydrocortamate, Hydrocortisone, Hydrocortisone Acetate, Citrate Oxalate. ydrocortisone Phosphate, Hydrocortisone 21-Sodium 91. DepigmentorS Such as Hydroquinine, Hydroquinone Succinate, Hydrocortisone Tebutate, MaZipredone, and Monobenzone. Medrysone, Meprednisone, Methyolprednisolone, Mometa Sone Furoate, Paramethasone, Prednicarbate, Prednisolone, 92. Diuretics, including: Prednisolone 21-Diethylaminoacetate, Prednisone Sodium Organomercurials. Such as Chlormerodrin, Meralluride, 35 Phosphate, Prednisolone Sodium Succinate, Prednisolone Mercamphamide, Mercaptomerin Sodium, Mercumal Sodium 21-m-Sulfo be nzoate, Predniso lone lylic Acid, Mercumatilin Sodium, Mercurous Chloride 21-Stearoylglycolate, Prednisolone Tebutate, Prednisolone and Mersalyl; 21-Trimethylacetate, Prednisone, Prednival, Prednylidene, Pteridines Such as Furterene and Triamterene; Prednylidene 21-Diethylaminoacetate, Tixocortal, Purines Such S Acefylline, Triamcinolone, Triamcinolone Acetonide, Triamcinolone 7-Morpholinomethyltheophylline, Pamabrom, Pro 40 Benetonide and Triamcinolone Hexacetonide. theobromine and Theobromine; 100. Gonad-Stimulating principles Such as BuSerelin, Clomiphene, Cyclofenil, Epimestrol, FSH, HCG and Steroids Such as Canrenone, Oleandrin and Spironolac LH-RH. tone, 101. Gonadotropic hormones such as LH and PMSG. Sulfonamide derivatives Such as Acetazolmide, 45 102. Growth hormone inhibitors Such as Octreotide and AmbuSide, AZOSemide, Bumetanide, Butazolamide, Somatostatin. Chloraminophenamide, Clofenamide, Clopamide, 103. Growth hormone releasing factors such as Semore Clorexolene, Diphenylmethane-4,4'-disulfonamide, lin. Disulfamide, EthbXZolamide, Furose mide, 104. Growth stimulants such as Somatotropin. Indapamide, Mefruside, Methazolamide, Piretanide, 50 105. Hemolytic agents such as Phenylhydrazine and Phe QuinethaZone, Torasemide, Tripamide and Xipamide, nylhydrazine Hydrochloride. Uracils. Such as Aminometradine and Amisometradine, 106. Heparin antagonists such as Hexadimethrine Bro otherS Such as Amano Zine, Amiloride, Arbutin, mide and Protamines. Chlora Zanil, Ethacry nic Acid, Eto Zolin, 107. Hepatoprotectants Such as S-Adenosylmethionine, Hydracarbazine, Isosorbide, Mannitol, Metochalcone, 55 Betaine, Catechin, Citolone, Malotilate, OraZamide, Muzolimine, Perhexiline, Ticrynafen and Urea. Phosphorylcholine, Protoporphyrin IX, Silymarin-Group, 93. Dopamine receptor agonists Such as Bromocriptine, Thiotic Acid and Tiopronin. Dopexamine, Fenoldopam, Ibopamine, Lisuride, Nax 108. ImmunomodulatorS Such as Amiprilose, agolide and Pergolide. Bucillamine, Ditiocarb Sodium, Inosine PranobeX, 94. Ectoparasiticides Such as Amitraz, Benzyl Benzoate, 60 Interferon-y, Interleukin-2, Lentinan, Muroctasin, Platonin, Carbaryl, Crotamiton, DDT, Dixanthogen, Isobornyl Procodazole, Tetramisole, Thymomodulin, Thymopentin Thiocyanoacetate-Technical, Lime Sulfurated Solution, and Ubenimex. LIndane, Malathion, Mercuric Oleate, Mesulphen and 109. Immunosuppressants Such as Azathioprine, Sulphur-Pharmaceutical. Cyclosporins and Mizoribine. 95. Enzymes, including: 65 110. Ion eXchange resins Such as Carbacrylic Resins, Digestive enzymes Such as C.-Amylase (Swine Pancreas), Cholestyramine Resin, Colestipol, Polidexide, Resodec and Lipase, Pancrelipase, Pepsin and Rennin; Sodium Polystyrene Sulfonate. US 6,562,363 B1 27 28 111. Lactation Stimulating hormone Such as Prolactin. Norethindrone, Norethynodrel, Norgesterone, Norgestimate, 112. LH-RH agonists such as Buserelin, Goserelin, Norgestrel, Norgestrienone, Norvinisterone, Pentagestrone, Leuprolide, Nafarelin, and Triptorelin. Progesterone, Promegestone, Quingestrone and Trenge 113. Lipotropic agents Such as N-Acetylmethionine, Cho StOne. line Chloride, Choline Dehydrocholate, Choline Dihydrogen 129. Prolactin inhibitors such as Metergoline. Citrate, Inositol, Lecithin and Methionine. 130. Prostaglandins and prostaglandin analogS Such as 114. Lupus erythematoSuS Suppressants Such as Bismuth Arbaprostil, Carboprost, EnproStil, Bemeprost, Limaprost, Sodium Triglycollamate, Bismuth Subsalicylate, Chloro Misoprostol, Ornoprostil, ProStacyclin, Prostaglandin E, quine and Hydroxychloroquine. Prostaglandin E, Prostagland in F, Rioprostil, 115. Mineralcorticoids such as Aldosterone, Rosaprostol, Sulprostone and Trimoprostil. Deoxycorticosterone, Deoxycorticosterone Acetate and 131. Protease inhibitorS Such as Aprotinin, Camostat, Fludrocortisone. Gabexate and NafamoStat. 116. Miotic drugs. Such as Carbachol, PhySoStigmine, 132. Respiratory Stimulants Such as Almitrine, Pilocarpine and Pilocarpus. Bemegride, Carbon Dioxide, Cropropamide, Crotethamide, 117. Monoamine oxidase inhibitors such as Deprenyl, 15 Dimefline, Dimorpholamine, Doxapram, Ethamivan, Iproclozide, Iproniazid, Isocarboxazid, Moclobemide, Fominoben, Lobeline, Mepixanox, Metamivam, Octomoxin, Pargyline, PhenelZine, Phenoxypropazine, Nikethamide, Picrotoxin, Pimeclone, Pyridofylline, Sodium Pivalylbenzhydrazine, Prodipine, Toloxatone and Tranyl Succinate and Tacrine. cypromine. 133. Sclerosing agents Such as Ethanolamine, 118. Mucolytic agents Such as Acetylcysteine, Ethylamine, 2-Hexyldecanoic Acid, Polidocanol, Quinine Bromhe Xine, Carbocysteine, Domiodol, Letosteine, Bisulfate, Quinine Urea Hydrochloride, Sodium Lysozyme, Mecysteine Hydrochloride, Mesna, Sobrerol, Ricinoleate, Sodium Tetradecyl Sulfate and Tribenoside. Stepronin, Tiopronin and Tyloxapol. 134. Sedatives and hypnotics, including: 119. Muscle relaxants (skeletal) Such as Afloqualone, Acyclic ureides Such as Acecarbromal, Apronalide, Alcuronium, Atracurium BeSylate, Baclofen, BenZoctamine, 25 BomisoValum, Capuride, Carbromal and Ectylurea; Benzoquinonium Chloride, C-Calebassine, Carisoprodol, Alcohols such as Chlorhexadol, Ethchlorvynol, Chlor me Za none, Chlorp he ne Sin Carb amate, Meparfynol, 4-Methyl-5-thiazoleethanol, tert-Pentyl Chlorproethazine, ChloZOXaZone, Curare, Cyclarbamate, Cyclobenzaprine, Dantrolene, Decamethonium Bromide, Alcohol and 2.2.2-Trichloroethanol; Diazepam, Eperisone, Fazadinium Bromide, Flumetramide, Amides Such as Butoctamide, Diethylbromoacetamide, Gallamine Triethiodide, Hexacarbacholine Bromide, Ibrotamide, Isovaleryl Diethylamide, Niaprazine, Hexafluorenium Bromide, Idrocilamide, Lauexium Methyl Tricetamide, Trimetozine, Zolpidem and Zopiclone; Sulfate, Leptodactyline, Memantine, Mephenesin, Barbituric acid derivatives such as Allobarbital, Mephenoxalone, Metaxalone, Methocarbamol, Metocurine Amobarbital, Aprobarbital, Barbital, Brallabarbital, Iodide, Nimetazepam, Orphenadrine, Pancuronium 35 Butabarbital Sodium, Butalbital, Butallylonal, Bromide, Phenprobamate, Phenyramidol, Pipecurium Bute thal, Carbu barb, Cyclobarbital, Bromide, Promoxolane, Quinine Sulfate, Styramate, Succi Cyclopentobarbital, Enallylpropymal, 5-Ethyl-5-(1- nylcholine Bromide, Succinylcholine Chloride, Succinyl pipe ridyl) barbituric Acid, 5-Furfuryl-5- choline Iodine, Suxethonium Bromide, Tetrazepam, isopropylbarbituric Acid, Heptabarbital, Hexethal Thiocolchicoside, Tizanidine, Tolperisone, Tubocurarine 40 Sodium, Hexobarbital, Mephobarbital, Methitural, Chloride, Vecuronium Bromide and Zoxolamine. Narcobarbital, Nealbarbital, Pentobarbital Sodium, 120. Narcotic antagonists Such as Amiphenazole, Phenallymal, Phenobarbital, Phenobarbital Sodium, Cyclazocine, Levallorphan, Nadide, Nalmfene, Nalorphine, Phenylmethylbarbituric Acid, Probarbital, Nalorphine Dinicotinate, Naloxone and Naltrexone. Propallylonal, Proxibarbal, Reposal, Secobarbital 121. Neuroprotective agents Such as Dizocilpine. 45 Sodium, Talbutal, Tetrabarbital, Vinbarbital Sodium 122. Nootropic agents Such as Aceglutamide, and Vinylbital; Acetylcarnitine, Aniracetam, Bife matlane, Exifone, Benzodiazepine derivatives Such as Brotizolam, Fipexide, Idebenone, Indeloxazune Hydrochloride, Doxefazepam, Estazolam, Flunitrazepam, Flurazepam, Nizofenone, Oxiracetam, Piracetam, Propentofylline, Pyriti Haloxazolam, Lopra Zolam, Lor metazepam, nol and Tacrine. 50 Nitrazepam, Quazepam, Temazepam and Triazolam, 123. Ophthalmic agents Such as 15-ketoprostaglandins. Bromides such as Ammonium Bromide, Calcium 124. Ovarian hormone Such as Relaxin. Bromide, Calcium Bromolactobionate, Lithium 125. Oxytocic drugs. Such as Carboprost, Cargutocin, Bromide, Magnesium Bromide, Potassium Bromide De a mino oxytocin, Ergono Vine, Ge me prost, and Sodium Bromide; Methylergonovine, Oxytocin, Pituitary (Posterior), Prostag 55 Carbamates Such as Amyl Carbamate-Tertiary, landin E, Prostaglandin F and Sparteine. Ethinamate, Hexaprpymate, Meparfynol Carbamate, 126. Pepsin inhibitors such as Sodium Amylosulfate. 127. Peristaltic stimulants such as Cisapride. Novonal and Tricholorourethan; 128. Progestogens Such as Allylestrenol, Anagestone, Chloral derivatives Such as Carbocloral, Chloral Betaine, Chlorma dinone Acetate, Delma dinone Acetate, 60 Chloral Form amide, Chloral Hydrate, De mege Stone, De Soge Strel, Dime this terone, Chloralantipyrine, Dichloralphenazone, Pentaerythritol Dydrogesterone, Ethisterone, Ethynodiol, Flurogestone Chloral and Triclofos; Acetate, Ge S to de ne, Ge Sto nor one Capro ate, Piperidinediones such as Glutehimide, Methyprylon, Halo progesterone, 17-Hydroxy-16-methylene Piperidione, Pyrithyldione, Taglutimide and Thalido progesterone, 17 C.-Hydroxyproge Sterone, 17 C.- 65 mide; Hydroxygesterone Caproate, Lynestrenol, Medrogestone, Quinazolone derivatives Such as Etaqualone, Mecloqua Medroxyprogesterone, Megestrol Acetate, Melengestrol, lone and Methaqualone, and US 6,562,363 B1 29 30 otherS Such as Acetal, Acetophenone, Aldol, Ammonium components of molecular complexes, and pharmaceutically Valerate, Amphenidone, d-Bornyl C-Bromoisovalerate, acceptable Salts, free acids or bases, or quaternary Salts of d-Bornyl Iso vale rate, Bromoform, Calcium the Same, or as combinations of these. Simple derivatives of 2-Ethylbutanoate, Carfinate, C.-Chloro lose, the drugs. Such as pharmaceutically acceptable ethers, esters, Clomethiazole, Cypripe dium, Do Xylamine, amides and the like which have desirable retention and Etodroxizine, Etomidate, Fenadiazole, Homofenazine, release characteristics but which are easily metabolized at Hydrobromic Acid, Mecloxamine, Menthyl Valerate, body pH, enzymes, pro-active forms, pro-drugs and the like Opium, Paraldehyde, Perlapine, Propiomazine, can also be employed. Rilmazafone, Sodium Oxybate, Sulfonethylmethane The active agent may comprise local anesthetic bases and Sulfonmethane. including weak organic bases which are lipophilic in nature 135. Thrombolytic agents such as APSAC, Plasmin, Pro and thus poorly soluble in water. However, such bases will Urokinase, Streptokinase, TiSSue Plasminogen Activator and typically react with organic or inorganic acids to form acidic, Urokinase; water-soluble acid addition salts. Thus, the term “base' 136. Thyrotropic hormones such as TRH and TSH. when used with reference to an anesthetic agent means the 137. UricoSurics Such as Benzbromarone, Ethelbenecid, 15 un-ionized form of an anesthetic that can furnish an electron Orotic Acid, Oxycinchophen, Probenecid, Sulfinpyrazone, pair to form a covalent bond. The term “acid” when used Ticrynafen and Zoxazolamine. with reference to an anesthetic agent means a Substance that 138. Vasodilators (cerebral) such as Bencyclane, can take up an electron pair to form a covalent bond. The Cinnarizine, Citicoline, Cyclandelate, Ciclonicate, Diiso term "Salt when used with reference to an anesthetic agent propylamine Dichloractetate, Eburnamorine, Fenoxedil, means the form produced by an anesthetic base upon its Flunarizine, Ibudilast, Ifenprodil, Nafronyl, Nicametate, reaction with an organic or inorganic acid. Nicergoline, Nimodipine, Papaverine, Pentifylline, Local anesthetic agents Suitable for use in the practice of Tinofedrine, Vincamine, Vinpocetine and Vicquidil. this invention include amides and esters. Examples of the 139. Vasodilators (coronary) Such as Amotriphene, amides are lidocaine, prilocaine, mepivacaine, bupivacaine, Bendazol, Benfurodil Hemisuccinate, BenZiodarone, 25 dibucaine and etidocaine. Esters include procaine, Chloacizine, Chromonar, Clobenfurol, Clonitrate, Dilazep, tetracaine, propoxycaine, chloroprocaine, benzocaine, Dipyridamole, Droprenilamine, Efloxate, Erythritol, Eryth butamben picrate, cocaine, hexylcaine, piperocaine, oxyp rity1 Tetranitrate, Etafenone, Fendiline, Floredil, rocaine and proparacaine. Other Suitable local anesthetics Ganglefene, Hexestrol Bis(B-diethylaminoethyl ether), for use in the practice of this invention include Hexobendine, Itramin Tosylate, Khellin, Lidoflazine, Man cyclomethycaine, dimethisoquin, ketocaine, diperodon, nitol Hexanitrate, Medibazine, Nicorandil, Nitroglycerin, dyclonine and pramoxine, all typically administered in the Pentaerythritol Tetranitrate, Pentrinitrol, Perhexiline, form of the acid addition hydrochloride or sulfate salts. Pimefylline, Prenylamine, Propatyl Nitrate, Pyridofylline, The acid-addition Salts of anesthetic agents Suitable for Trapidil, Tricromyl, Trimetazidine, Trolnitrate Phosphate the present invention include any non-toxic, pharmaceuti and Visnadine. 35 cally acceptable organic or inorganic Salts which in certain 140. Vasodilators (peripheral) such as Aluminum embodiments are non-Salicylate. Typical inorganic Salts are Nicotinate, Bamethan, Bencyclane, Betahistine, Bradykinin, the hydrogen halides, especially the hydrochlorides, Brovincamine, Bufoniode, Buflo medil, Butalamine, carbonates, borates, phosphates, Sulfates, hydrogen Sulfates, Cetie dil, Ciclonicate, Cinepa Zide, Cinnari Zine, hydrobromides, nitrates, Sulfides, and arsenates. Typical Cyclandelate, Diisopropylamine Dichloracetate, Eledoisin, 40 organic Salts are Salts of mono- and polycarboxylic acids Fenoxidil, Flunarisine, Heronicate, Ifenprodil, Inositol Such as the citrate, tartrate, malate, cinnamate, oxalate, Niacinate, ISOXSuprine, Kallidin, Kallikrein, Moxisylyte, formate, Succinate and phthalates. The base form and the Salt Nafronyl, Nicametate, Nicergoline, Nicofuranose, Nicotinyl form of a Suitable anesthetic agent incorporated in the Alcohol, Nylidrin, Pentifylline, Pentoxifylline, Piribedil, present composition should preferably be different anes Protaglandin E, Suloctidil and Xanthinal Niacinate. 45 thetic agents to achieve maximum duration of the combined 141. Vasoprotectants Such as BenZarone, Bioflavonoids, anesthetic effect. The term “different' when used with Chromocarb, Clobeoside, Diosmin, Dobesilate Calcium, reference to an anesthetic agent means that the Salt form in Escin, Rolescu tol, Leucocyanidin, Metescufylline, any combination is not a Salt of the base form used in the Quercetin, Rutin and Troxerutin. given combination. 142. Vitamins, Vitamin Sources, and Vitamin extracts Such 50 In certain embodiments of this invention, the active as Vitamins A, B, C, D, E, and K and derivatives thereof, agents comprise a free base local anesthetic agent that is Calciferols, Glycyrrhiza and Mecobalamin. Selected from the group comprising lidocaine, procaine, 143. Vulnerary agents Such as Acetylcysteine, Allantoin, propoxycaine, mepivacaine, prilocaine, dy clonine, Asiaticoside, CadeXomer Iodine, Chitin, Dextranomer and pramoxine, benzocaine and chloroprocaine, in combination Oxaceprol. 55 with the salt form of a different anesthetic agent. The salt 144. Anticoagulants Such as heparin. form is preferably one Selected from the group comprising 145. Miscellaneous such as Erythropoietin (Hematinic), prilocaine, tetracaine, bupivacaine, dyclonine, dibucaine, Filgrastim, Finasterlde (Benign Prostate Hypertrophy) and etidocaine and lidocaine Salts. Interferon Beta 1-Alpha (Multiple Sclerosis). In embodiments of this invention comprising a combina The above list of active agents is based upon those 60 tion of both a free base form and a salt form of an anesthetic categories and Species of drugs set forth on pageS THER-1 agent, the ratio of the free base form to the salt form in the to THER-28 of The Merck Index, 12th Edition, Merck & Co. composition will depend on Several factors, namely: (1) the Rahway, N.J. (1996). This reference is incorporated by identity of the salt and base used; (2) the desired duration of reference in its entirety. action; and (3) the desired rapidity of anesthetic effect. As a The active agents contained in the bioadhesive composi 65 general rule in the case of mucosal application, the ratios of tion can be in different forms depending on the Solubility and base to Salt are such that the free base form preferably should release characteristics desired, Such as neutral molecules, penetrate the mucosa and be at its peak effectiveness within US 6,562,363 B1 31 32 about a 2 to 30 minute period, whereas, the salt form should preferably penetrate the mucosa and be at its peak effec TABLE 1. tiveness within a period of about 10 to 75 minutes. The Maximum Peak Duration duration of anesthesia will range from about 2 minutes to Local Minimum Adult Dose Effect of Effect Several hours, even up to 24 hours, depending on the Anesthetic Adult Dose (mg) (minutes) (minutes) base/Salt combination Selected and the length of application Dibucaine 25 <15 120-240 time. In practice to achieve this effect, the amount by weight Lidocaine 750 2-5 30-60 of the base form will normally be in excess of the amount by Benzocaine 5OOO 1. 30-60 weight of the salt form. Cocaine 50 2-5 30-120 1O Tetracaine 50 3-8 30-60 The term “onset of anesthesia' is intended to mean the Dyclonine 1OO &10 &60 time to obtain effect on the individual nerves. Onset of Pramoxine 2OO 3-5 NA anesthesia principally depends upon the lipid Solubility, NA: Not Available. molecular size, and quantity of available, un-ionized form of Source: Drug Facts and Comparisons, 1990 edition, J.B. Lippincott the local anesthetic. Thus, anesthetics with a high lipid 15 Company, St. Louis, MO. Page 601. Solubility or a low pKa, or both, have a more rapid onset of In general, the relative Speed of the onset of anesthesia anesthesia. and duration of anesthesia for any given form of an anes The term “duration of anesthesia” as used herein means thetic agent is available in the literature or can be calculated the period of time during which the local anesthetic mea by Standard tests for transmucosal dosage. Surably blocks nerve conduction. The foregoing depends Onset time, as well as duration of anesthesia, will vary upon all of the factors listed for onset of anesthesia, as well from individual to individual as well as on the basis of the as on the extent of protein binding of the anesthetic agent. Site of application. When applying the composition to highly An anesthetic agent free base can penetrate intact skin to keratinized dermal tissues, the onset of anesthesia may take a limited degree, and will more rapidly penetrate the skin if as long as 2 to 4 hours. the keratin layers are abraded. In the case of mucosa, the 25 The term “therapeutically effective amount” as used anesthetic free base will penetrate much more readily due to herein with reference to the active agent is intended to mean the different keratin composition and the resulting difference the amount of active agent Sufficient to produce the desired in the hydrophilicity as compared to the Stratum corneum of effect, local or Systemic, when applied topically over the intact skin. duration of intended use. The amounts necessary are known As a general rule, the Salt forms of anesthetic agents do in the literature or may be determined by methods known in the art, but typically range from about 0.1 to about 20,000 not appreciably penetrate intact skin, but the un-ionized base mg, and preferably about 0.1 to about 1,000 mg, and most forms do penetrate to a limited degree. Both forms, Salt and preferably range from about 0.1 to about 500 mg per human base, will penetrate abraded keratin layers. The Salt form as adult of about 75 kilograms body weight, depending on the well as the base form will penetrate, to a differing degree, 35 active agents chosen and the Site of application. The only mucosa due to the mucosa's hydrophilicity, as compared to upper limit on the amount of the active agent is that the the Stratum corneum of intact skin. Generally, the higher the composition should preferably be substantially free of crys lipid content of the mucosal membrane, the more rapidly the tals of the active agent and the amount of Solvent used is not base form of the anesthetic agent will be absorbed. sufficient to undesirably affect the bioadhesive properties of Therefore, when the bioadhesive composition is used for 40 the composition. application to buccal mucosa, the different lipid contents of Therapeutic dosage and dosage unit amounts can be the gum (gingiva) and the alveolar mucosa must be kept in estimated by in vitro flux data using human cadaver skin or, mind in order to obtain the optimal penetration rate. alternatively, using animal skin as described in U.S. Pat. No. Although applicants do not intend to be bound by any 4,751,087. theory or proposed mechanism of operation, it is believed 45 The concentration as well as the quantity of the active that the base form of an anesthetic agent which is lipid agent per unit area, namely per Square or cubic centimeter, Soluble has a rapid onset of anesthesia Since it enters the can be varied independently in order to achieve the desired lipo-protein nerve membrane preventing the depolarization therapeutic effect. For example, higher concentrations of and ion eXchange involved in Stimulus conduction. On the anesthetic base contained in a dosage form of decreased other hand, the Salt form of an anesthetic agent which is not 50 thickness will result in an anesthetic with fast onset and short lipid Soluble, penetrates to the lipo-protein nerve membrane duration. High concentrations of the anesthetic base con only after the buffering capacity of the skin or mucosal tissue tained in a dosage form of increased thickness (higher mg of converts the Salt to the base, the final result being a delayed anesthetic per Square or cubic centimeter) will result in onset of anesthesia. potent anesthesia with fast onset and long duration. Low The Salt forms of the anesthetic agents are Selected on the 55 concentrations of the anesthetic base in a dosage form of basis of onset of anesthesia and duration of anesthesia. decreased thickneSS will result in mild anesthesia with Adjusting the ratio of base to Salt affects the relative onset longer onset and short duration. Low concentrations of the as well as the duration of anesthesia. The greater the amount anesthetic base contained in a dosage form of increased of anesthetic agent having a rapid onset of action, the shorter thickness will have mild anesthesia with longer onset and time to the onset of anesthesia. Similarly, the greater the 60 longer duration. AS shown in the above explanation, the amount of the anesthetic agent having a prolonged duration ability to vary the concentration of active agents from very of anesthesia, the more prolonged the duration of anesthesia. low (about 1%) to high (40% or higher) of the total Moreover, the composition can include other drugs used composition, when combined with the ability to coat thin concomitantly. (about 0.001 inches) or thick (about 0.500 or more inches) Table 1 below Summarizes the peak and duration of action 65 enables the practitioner of the invention to vary the dosage of Selected local anesthetics based primarily on application as needed for the particular Site of topical application and to skin or mucous membranes: therapeutic effects. US 6,562,363 B1 33 34 The bioadhesive compositions of the present invention patibility or co-dispersibility with the other components, and may also contain one or more Solvents or coSolvents. Such provide a proper consistency of the composition, may be Solvents and coSolvents are those known in the art, and are freely used. Those which are low in volatility are generally non-toxic, pharmaceutically acceptable Substances, prefer preferred and, in this regard, dipropylene glycol, glycerin, ably liquids, which do not Substantially negatively affect the propylene glycol, butylene glycol, and Sorbitol are appro bioadhesive properties or Solubility of the active agents at priate Solvents, according to the invention. the concentrations used. The Solvent and coSolvent can be Although the exact amount of the polyhydric alcohols, or for the active agent or for the bioadhesive materials, or both. fatty acids, esters, ethers or alcohols, that may be used in the The solvent is preferably a polyhydric alcohol or combina composition depends on the nature and amount of other tion of polyhydric alcohols. The solvent should include from components, and therefore cannot be Stated in general terms, about 5% to about 50%, and more preferably from about the proportion may range up to about 30% by weight, and 10% to about 30% by weight of the dry weight of the total preferably from about 5% to about 20% by weight, and more bioadhesive composition of a Solvent known to plasticize the preferably from about 5% to about 10% by weight based on bioadhesive composition. Particularly useful plasticizers are the dry weight of the total bioadhesive composition. glycols Such as dipropylene glycol and propylene, fatty 15 The term “lsolubilized” is intended to mean that in the acids Such as oleic acid and linoleic acid, fatty acid esters Solvent, and Subsequently the bioadhesive composition, Such as isopropyl myristate, vegetable, animal and fish oils there is an intimate dispersion of the active agent at the Such as hydrogenated castor oil, canola, cod liver, and crystalline, molecular or ionic level, Such that crystals of the lanolin, mineral oil, glycerine, lecithin, tocopherol and toco active agent cannot be detected using a microscope having pheryl acetate. Alternatively, drugs which are liquid at room a magnification of 25x. AS Such, the active agent is termed temperature, Such as nitroglycerin, nicotine, Selegiline and herein to be in “non-crystallized” form when in the compo the like, may be used as plasticizers. Sitions of the present invention. The use of a Solvent (encompassing both Solvents and Generally, the concentration of Solubilized pharmaceuti plasticizers) has also been found to improve the appearance cally active agent can range from about 1% to about 50%, and texture of the finished composition, particularly for PVP 25 more preferably from about 2.5% to 40%, and optimally and karayagum embodiments. Specifically, the inclusion of from about 5% to about 30% by weight of the dry weight of a Solvent in the bioadhesive composition is believed to cause the total bioadhesive composition. In a preferred embodi the powdered karaya gum particles to Swell or gel when ment of the invention for topical administration of a Single added to a mixture or blend containing PVP, solvents and active agent, ketoprofen in the free acid form is used in a active agent (if the bioadhesive composition is not being concentration between 2% and 30% by weight of dry weight used as a separate adhesive layer). When finished, the of the total bioadhesive composition. bioadhesive composition will have a softer, smoother finish Generally, for topical administration of a combination of than a bioadhesive composition which does not contain anesthetic agents, the ratio by weight of free base to the Salt Solvents. A bioadhesive composition which does not contain forms is about 90:10 to about 40:60, preferably about 75:25 any Solvents will generally have adequate wear properties 35 to about 50:50, and more preferably about 70:30 to about and thus are not outside the Scope of the present invention. 60:40. For other salts, the ratios are comparable based on However, the use of solvents is preferred for the reasons relative molar amounts. Generally, the ratio by weight of noted above. base to salt is between about 1:2 to about 4:1. In a preferred The term “polyhydric alcohol” means any organic poly embodiment of the invention for a combination of anesthetic alcohol and includes dipropylene glycol, propylene glycol, 40 agents, the ratio is about 2:1 base to Salt, respectively, the polyethylene glycol, glycerin, butylene glycol, hexylene base used is lidocaine and the Salt used is a Salt ofprilocaine, glycol, polyoxyethylene, polypropylene glycol, Sorbitol, bupivacaine, dyclonine, mepivacaine, or tetracaine, prefer ethylene glycol, and the like. Other Suitable Solvents include ably the hydrochloride salt. fatty acids Such as oleic acid, linoleic acid, capric acid and Higher concentrations of active agents, namely up to 50% the like, polyethylene, polypropylene and ethers of fatty 45 by weight, can be achieved typically by mixing Such agent acids, as well as fatty esters or alcohols. Further Suitable (s) with an appropriate Solvent, preferably at an elevated Solvents include other non-toxic, non-volatile Solvents com temperature, for example about 70 to 100° C., to obtain a monly used in transdermal or transmucosal compositions for mixture, preferably a Solution, of the active agents which is Solubilizing active agents. then added to the bioadhesive materials. Omission of the The above-mentioned polyhydric alcohols may include 50 solvent will typically yield a final composition filled with those having 2 to 6 alcoholic hydroxyl groupS. Such poly crystals or a crystalline mass. hydric alcohols include glycols, triols and polyols having 4 Solvent Selection for a combination of active agents to 6 alcoholic hydroxyl groups. Typical of Said glycols are depends on the form of the agent, inter alia, whether it is in glycols containing 2 to 6 carbon atoms, e.g. ethylene glycol, free base, free acid, or acid-addition Salt form. propylene glycol, butylene glycol, polyethylene glycol 55 Suitable Solvents for the Salt form of anesthetic agents are (average molecular weight about 200-8,000, preferably typically polar organic Solvents. Polar organic Solvents are about 200 to 6,000), etc. Examples of said triols include preferably polyhydric alcohols, as discussed above. Suitable glycerin, trimethylolpropane, etc. Said polyols are exempli other Solvents for either the free base or acid-addition form fied by sorbitol (sorbit), polyvinylpyrrolidone, etc. These of anesthetic agents are those Solvents known to dissolve polyhydric alcohols may be used either Singularly or in 60 either or both of these two types of forms including cyclic combination (preferably, of two or three). Thus, for example, ketones such as 2-pyrrollidone; N-(2-hydroxyethyl) glycerin or dipropylene glycol alone, or a mixture of either pyrrolid one, N-methylpyrrollidone, glycerin or dipropylene glycol with butylene glycol, can be 1-dodecylazacycloheptan2-one and other n-Substituted employed. alkyl-azacycloalkyl-2-ones (aZones) dimethylformadide, Among those polyhydric alcohols, those which Satisfy the 65 and dimethylsulfoxide. Other suitable solvents for the free requirements relevant to the adjustment and maintenance of base form of an anesthetic agent include cell envelope Softness of the external Surface of the invention, the com disordering compounds known to be useful in topical phar US 6,562,363 B1 35 36 maceutical preparations, which compounds are thought to able Solvent comprising a Solvent known to plasticize the assist in mucosal penetration by disordering the lipid struc total bioadhesive composition. ture of the Stratum corneum cell-envelopes. Some of these In a preferred embodiment, the pharmaceutically accept compounds are generally encompassed by the formula: able solvent is in a preferred amount from about 20% to about 53% by weight based on the dry weight of the total R-X composition, the plasticizer portion of which represents about 10% to 30% by weight based on the dry weight of the wherein R is a straight-chain alkyl of about 7 to 16 carbon total composition, and the bioadhesive materials range in an atoms, a non-terminal alkenyl of about 7 to 22 carbon amount from about 20% to about 55% by weight based on atoms, or a branched-chain alkyl of from about 13 to 22 the dry weight of the total bioadhesive composition. More carbon atoms, and X is -OH, -COOCH, preferably, the bioadhesive composition of the present -COOCH5, -OCOCH, -SOCH, -P(CH)O, invention comprises about 10% to about 40% by weight of -COOCHHOCHOH, -COOCH (CHOH) a polysaccharide bioadhesive, about 10% to about 40% by CHOH, -COOCHCHOHCH3, -COOCHCH weight of a water soluble bioadhesive, about 10% to about (OR")CHOR". —(OCH2CH), OH, -COOR', or 60% by weight of a solvent, and about 5% to about 40% by -CONR' where R; is -H, -CH, -CH, -CH7 15 weight of an active agent, based on the dry weight of the OR -CHOH; R" is -H, or a non-terminal alkenyl total bioadhesive composition, and may further be com of about 7 to 22 carbon atoms, and m is a positive prised of a binder in an amount sufficient to bind the other integer from 2 to 6; provided that when R" is an alkenyl ingredients. Preferred embodiments comprise a mixture of and X is -OH or -COOH, at least one double bond soluble PVP and another bioadhesive, preferably a natural is in the cis-configuration. gum. The bioadhesive composition can also contain agents In particular, it has unexpectedly been found that when known to accelerate the delivery of the active agents through karayagum is employed as the polysaccharide bioadhesive the skin or mucosa. These agents have been referred to as and soluble PVP is employed as the water soluble penetration or permeation enhancers, accelerants, adjuvants, bioadhesive, with a pharmaceutically acceptable Solvent and absorption promoters, and are collectively referred to as 25 comprising a Solvent known to plasticize the total bioadhe "enhancers.” Sive composition, a bioadhesive composition that is also a Some examples of enhancers are monohydric alcohols preSSure-Sensitive adhesive is formed. This result is com Such as ethanol and isopropyl, butyl and benzyl alcohols, or pletely unexpected because neither karayagum nor Soluble dihydric alcohols Such as ethylene glycol, diethylene glycol, PVP alone is a pressure-sensitive adhesive. The formation of or propylene glycol dipropylene glycol and trimethylene a bioadhesive/pressure-Sensitive adhesive composition is glycol, or polyhydric alcohols Such as glycerin, Sorbitol and formed when karaya gum and PVP are employed at a ratio polyethylene glycol, which enhance drug Solubility; poly of between 1:10 and 10:1. ethylene glycol ethers of aliphatic alcohols (such as cetyl, In general, the bioadhesive composition can have the lauryl, oleyl and Stearyl) including polyoxyethylene (4) following types and amounts of ingredients: lauryl ether, polyoxyethylene (2) oleyl ether and polyoxy 35 ethylene (10) oleyl ether commercially available under the trademark BRIJGR) 30, 93 and 97 from ICI Americas, Inc., Typical Preferred Optimum and BRIJ(R) 35, 52, 56,58, 72, 76, 78, 92, 96,700 and 721; Range Range Range vegetable, animal and fish fats and oils Such as olive and Ingredient (% by weight) (% by weight) (% by weight) castor oils, Squalene, and lanolin; fatty acid esterS Such as 40 Bioadhesive 5 to SO 10 to 40 20 to 30 propyl oleate, decyl oleate, isopropyl palmitate, glycol PVP 5 to SO 10 to 40 15 to 30 palmitate, glycol laurate, dodecyl myristate, isopropyl Solvent 5 to 70 10 to 60 2O to 53 myristate and glycol Stearate which enhance drug diffusibil Active Agent 1 to 50 2.5 to 40 5 to 30 ity; fatty acid alcohols Such as oleyl alcohol and its deriva tives, fatty acid amides Such as oleamide and its derivatives, 45 The amount and type of PVP required in the preferred urea and urea derivatives Such as allantoin which affect the embodiments will depend on the quantity and type of drug ability of keratin to retain moisture; polar Solvents Such as present in the bioadhesive composition, as well as the type dimethyldecylphosphoxide, methyloctylsulfoxide, of bioadhesive, but can be readily determined through dimethyllaurylamide, dodecylpyrrollidone, isosorbitol, routine experimentation. dimethylacetonide, dimethylsulfoxide, decylmethylsulfox 50 Typically, the PVP is present in an amount from about 5% ide and dimethylformamide which affect keratin permeabil to about 50% by weight, preferably from about 10% to about ity; Salicylic acid which Softens the keratin; amino acids 40% by weight of the dry weight of the total bioadhesive which are penetration assistants, benzyl nicotinate which is composition. However, the amount of PVP can be higher a hair follicle opener; and higher molecular weight aliphatic than 20% for example, up to 40%, depending on the par Surfactants Such as lauryl Sulfate Salts which change the 55 ticular drug used and on the desired properties of the blend. Surface State of the skin and drugs administered and esters of Said PVP preferably has a molecular weight of about Sorbitol and Sorbitol anhydride such as polysorbate 20 2,000 to 1,200,000, more preferably 5,000 to 100,000, and commercially available under the trademark Tween(E) 20 most preferably 7,000 to 54,000. PVP having a molecular from ICI Americas, Inc., as well as other polySorbates Such weight of about 1,000,000 to about 1,500,000 is also pre as 21, 40, 60, 61, 65, 80, 81, and 85. 60 ferred. Other enhancers include oleic and linoleic acids, ascorbic PVPs are sold to the pharmaceutical industry under the acid, panthenol, butylated hydroxytoluene, tocopherol, toco trademarks KOLLIDON by BASF AG, Ludwigshafen, Ger pherol acetate, tocopheryl linoleate. many; PLASDONE, POLYPLASDONE and COPOLY In one embodiment of the present invention, the bioad MER 958 by ISP Technologies, Wayne, N.J. Preferred PVPs hesive composition comprises a mixture of at least one 65 are KOLLIDON 12PF, 17PF, 25, 30, 90 and VA-64. water-insoluble bioadhesive and at least one water Soluble In another preferred embodiment of the invention, the bioadhesive, an active agent, and a pharmaceutically accept bioadhesive composition includes a preSSure-Sensitive adhe US 6,562,363 B1 37 38 sive. The term “pressure-sensitive adhesive” as used herein DURO-TAK by National Starch Company, Bridgewater, refers to a Viscoelastic material which adheres instanta N.J.; GELVA by Monsanto, St. Louis, Mo.; HRJ by neously to most Surfaces with the application of very slight Schenectady International, Inc., Schenectady, N.Y.; MOR preSSure and remains permanently tacky. A polymer is a STIK by Morton International, Inc., Chicago, Ill., and preSSure-Sensitive adhesive within the meaning of the term EUDRAGIT RL and RS by Roehm Pharma GmbH, as used herein if it has the properties of a pressure-Sensitive Darmstadt, Federal Republic of Germany. adhesive per Se or functions as a preSSure-Sensitive adhesive The amount of the pressure-Sensitive adhesive used by admixture with tackifiers, plasticizers or other additives. depends upon the concentration of active agent used to Suitable pressure-sensitive adhesives include all of the achieve a therapeutic affect. Typically, the pressure-Sensitive non-toxic natural and Synthetic polymers known for or adhesive is in an amount of about 10% to about 60% by Suitable for use in transdermal devices as hydrophobic weight of the dry weight of the total bioadhesive adhesives including natural or Synthetic elastomers, Such as composition, and preferably about 15% to about 50%, and polyisobutylene, Styrene, polybutadiene, Styrene isoprene most preferably about 20% to about 40% by weight based on block copolymers, polyurethanes, polyacrylates, polysilox the dry weight of the total bioadhesive composition. anes and Styrene/butadiene copolymers. In yet a further embodiment of the present invention, the Particularly preferred pressure-Sensitive adhesives are 15 bioadhesive composition comprises from about 10% to acrylic polymers, and more particularly Solvent-based about 60% by weight of a solvent-based acrylic polymer, acrylic polymers. The term “acrylic polymer is intended to from about 20% to about 50% by weight of a PVP polymer, be used interchangeably with the terms acrylate polymer, from about 20% to about 53% by weight percent of at least polyacrylate and polyacrylic adhesive polymers as used one solvent, and from about 10% to about 25% by weight of herein and as known in the art. The term "solvent-based” is an active agent, based on the dry weight of the total used herein to mean Substantially free of Surfactants. bioadhesive composition, and may further be comprised of The acrylic polymers useful in practicing the invention a binder in an amount Sufficient to bind the other ingredients. are polymers of one or more monomers of acrylic acids and Again, the active agent desired for topical administration other copolymerizable monomers. The acrylic polymerS also may be solubilized within the bioadhesive composition or include copolymers of alkyl acrylates and/or methacrylates 25 may be administered Separately. and/or copolymerizable Secondary monomers or monomers In addition to the above ingredients, there may also be with functional groups. By varying the amount of each type incorporated various pharmaceutically acceptable additives of monomer added, the cohesive properties of the resulting and excipients available to those skilled in the art. These acrylic polymer can be changed as is known in the art. In additives include tackifying agents, which are particularly general, the acrylic polymer is composed of at least 50% by useful in those embodiments in which the active agent does weight of an acrylate or alkyl acrylate monomer, from 0 to not plasticize the bioadhesive composition, Such as aliphatic 20% of a functional monomer copolymerizable with the hydrocarbons, mixed aliphatic and aromatic hydrocarbons, acrylate, and from 0 to 40% of other monomers. aromatic hydrocarbons, Substituted aromatic hydrocarbons, Acrylate monomers which can be used include acrylic hydrogenated esters, polyterpenes and hydrogenated wood acid, methacrylic acid, butyl acrylate, butyl methacrylate, 35 rosins. Additional additives include binderS Such as lecithin hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, which "binds' the other ingredients, or Theological agents 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl (thickeners) containing silicone Such as fumed silica, methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl reagent grade Sand, precipitated Silica, amorphous Silica, methacrylate, decyl acrylate, decyl methacrylate, dodecyl colloidal Silicon dioxide, fused Silica, Silica gel, quartz and acrylate, dodecyl methacrylate, tridecyl acrylate, and tride 40 particulate Siliceous materials commercially available as cyl methacrylate. Syloid(R), Cabosil(R), Aerosil(R) and Whitelite(R), for purposes Functional monomers, copolymerizable with the above of enhancing the uniform consistency or continuous phase of alkyl acrylates or methacrylates, which can be used include the final composition. Other additives and excipients include acrylic acid, methacrylic acid, maleic acid, maleic diluents, Stabilizers, fillers, clayS, buffering agents, biocides, anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, 45 humectants, anti-irritants, antioxidants, preservatives, fla acrylamide, dimethylacrylamide, acrylonitrile, dimethy Voring agents, colorants, pigments and the like. Such addi laminoethyl acrylate, dimethylaminoethyl methacrylate, tives or excipients are typically used in amounts up to 25% tert-butylaminoethyl acrylate, tert-butylaminoethyl by weight of the bioadhesive composition, and preferably methacrylate, methoxyethyl acrylate and methoxyethyl from about 0.1% to about 10% by weight. methacrylate and other monomers having at least one unsat 50 The compositions according to the present invention can urated double bond which participates in copolymerization be prepared by mixing the one or more bioadhesives, in reaction in one molecule and a functional group on its side powder or liquid form, with the PVP and active agent, with chain Such as a carboxyl group, a hydroxyl group, a Sulfoxyl or without a pressure-Sensitive adhesive, preferably in an group, an amino group, an amido group and an alkoxyl, as appropriate Volatile, lower molecular weight Solvent. When well as a variety of other monomeric units including 55 a pressure-Sensitive adhesive is used, preferably the Volatile, alkylene, hydroxy-Substituted alkylene, carboxylic acid lower molecular weight Solvent is an organic Solvent Sup Substituted alkylene, Vinylalkanoate, Vinylpyrrollidone, plied with the pressure-Sensitive adhesive, for example, the Vinylpyridine, Vinylpirazine, Vinylpyrrole, Vinylimidazole, acrylic adhesive. Typical liquids for use as Such volatile Vinylcaprolactam, Vinyloxazole, Vinylacatate, Vinylpropi Solvents, as distinct from emulsion (typically aqueous) onate and Vinylmorpholine. 60 polymerization, Singularly or in combination with other Further details and examples of acrylic adhesives which Volatile and non-volatile Solvents, are volatile polar and are Suitable in the practice of the invention are described in non-polar organic liquids Such as lower molecular weight Satas, “Acrylic Adhesives,” Handbook of Pressure-Sensitive alkanols (e.g., isopropanol and ethanol), aromatics Such as Adhesive Technology, 2nd ed., pp. 396-456 (D. Satas, ed.), benzene derivatives (e.g., Xylene and toluene), lower Van Nostrand Reinhold, New York (1989). 65 molecular weight alkanes and cycloalkanes (e.g., hexane, Suitable acrylic adhesives are commercially available and heptane and cyclohexane) and alkanoic acid ester Such as include the polyacrylate adhesives Sold under the trademarks ethyl or butyl acetate. US 6,562,363 B1 39 40 Preferably, the mixture is cast at ambient temperature and BAREXCR, ethylene/vinyl acetate copolymers, ethylene/ pressure followed by evaporation of the volatile solvents, for ethylacrylate copolymers, metal-Vapor deposited films or example, by evaporation at Slightly elevated temperatures, to sheets thereof, rubber sheets or films, expanded Synthetic form the bioadhesive blend. The non-volatile or higher resin Sheets or films, non-woven fabrics, fabrics, knitted boiling point Solvents Such as the polyols used in the fabrics, clothes, foils and papers. composition remain therein. The backing layer generally has a thickness in the range An individual unit or device (often referred to as a of 2 to 1000 micrometers and the bioadhesive composition “delivery system') comprising the present invention can be is generally disposed on the backing layer in a thickness prepared in any manner known to those of skill in the art. An ranging from about 12 to 250 micrometers. The backing exemplary general method of preparation is as follows: layer may be pigmented, for example colored to either match 1. Appropriate amounts of the PVP polymer, pressure with or conversely easily distinguish from the Site of Sensitive adhesive(s), Solvent(s) and/or co-solvent(s), application, and/or contain printing, labeling and other enhancer(s), additive(s) and excipient(s) are combined and means of identification and/or tracability of the unit or thoroughly mixed together in a vessel. System itself. The backing layer may further be made opaque 2. The one or more active agents are then added to the 15 or Substantially opaque (i.e., preventing light or certain mixture and agitation is carried out until the agent(s) are energy wavelengths from penetrating or passing through), uniformly mixed therein, if the bioadhesive composition is Such as by metallization, fillers, inks, dyes and the like, for being used as both the adhesive and the active agent Source. purposes of protecting photosensitive active agents, Such as Otherwise, no active agent is added. ketoprofen, from degradation and/or preventing photoaller 3. Appropriate amounts of other bioadhesive material(s), gic reactions or irritations on the Subject. Such as kayara gum, may be then added to the active agent The release liner or peel Strip is also intended to prevent containing mixture, and thoroughly mixed. loSS of the active agent and/or enhancers to the environment, 4. The composition is then transferred to a coating opera and render the individual unit or delivery System (in con tion where it is coated onto a release liner at a controlled junction with the backing layer) transportable, as well as Specified thickness. The coated composition is then passed 25 generally protect the bioadhesive composition from con through an oven in order to drive off all volatile processing tamination and the like until its application to a Subject. The Solvents. release liner is typically also impermeable and occlusive, 5. The composition coated on the release liner is then and must be compatible with the particular bioadhesives brought into contact with a backing (layer) and wound into and/or active agents So as not to interfere with their ultimate rolls. topical application and therapeutic effect. 6. Appropriate Size and shape delivery Systems are die-cut Suitable materials that can be used, Singularly, in from the roll material and then pouched. combination, as laminates or as coextrusions, to form the The order of steps, the amount of the ingredients, and the release liner are also well known in the art and include any amount and time of agitation or mixing may be important material suitable for the backing layer. When the release process variables which will depend on the Specific 35 liner is composed of a material which typically does not polymers, active agents, Solvents and/or coSolvents, enhanc readily release (i.e., is not easily removed or separated from erS and additives and excipients used in the composition. the bioadhesive composition), for example paper, a coating These factors can be adjusted by those skilled in the art, material Such as a Silicone may be applied to the release liner while keeping in mind the objects of achieving a Solubilized by any conventional means. Preferred release liners are films active agent and providing a uniform product. It is believed 40 commercially available from DuPont, Wilmington, Del., that a number of other methods, for example, other methods under the trademark Mylare, and fluropolymer (silicone) of coating backings that are well-known in the art Such as coated films commercially available from Rexam Release, Mayer rod, gravure, knife-over roll, extrusion, casting, cal Oak Brook, Ill. under the trademark FL2000(E) and endaring and molding, or changing the order of certain Steps, MRL2000, and from 3M Corporation, St. Paul, Minn. under for example, in one embodiment, anesthetic agents are 45 the trademark ScotchPak(E) 1022. dissolved in a Solvent, preferably a polyhydric alcohol, and The configuration of an individual unit or delivery System then the resulting mixture is added to the other bioadhesive of the present invention can be in any shape, preferably a components prior to coating, can be carried out and will also defined geometric shape, and size (i.e., Surface area of give desirable results. application) as is necessary or desirable. The shape is The present inventors have found, however, that by add 50 achieved by conventional techniques, for example, cutting ing the non-PVP bioadhesive, Such as kayara gum, to a or punching, and Such techniques are described, for mixture containing the PVP and solvents, the finished bio example, in U.S. Pat. Nos. 5,032,207, 5,405,486 and 5,656, adhesive composition will have a Smoother, Softer finish. 285. The intended site of application is an important factor The backing layer, typically occlusive to water in determining the size and shape of an individual unit or permeation, Serves to retain and maintain the bioadhesive 55 delivery System of the present invention, and can be adjusted composition disposed thereon in a defined size and shape, by those skilled in the art as is necessary to effect therapy. prevent loSS of the active agent and/or enhancers to the Typically the size should not exceed 100 cm. Preferred environment, render the individual unit or delivery System sizes range from about 0.1 cm to about 60cm, and more (in conjunction with the release liner) transportable, and preferred range from about 1.5 cm to about 30cm’, and generally provide protection both prior to and after appli 60 optimally from about 2.0 cm to about 10cm. cation of the unit or System to a Subject. The bioadhesive compositions of the present invention Suitable materials that can be used, Singularly, in preferably comprise the active agents Solubilized therein, combination, as laminates or as coextrusions, to form the and attach directly to the Skin or mucosa after removal of the backing layer are well known in the art and include films or release liner. Sheets of polyethylene, polyester, polypropylene, 65 Alternatively, the bioadhesive composition may be polyurethane, polyolefin, polyvinyl alcohol, polyvinyl utilized, without an active agent, in a multi-layer delivery chloride, polyvinylidene, polyamide, Vinyl acetate resins, System as an “underlay' adhesive layer (i.e., attaches US 6,562,363 B1 41 42 directly to the skin or mucosa after removal of the release Such an extent that the composition adheres to the mucosal liner) in which the active agent is Solubilized or contained in tissue Substantially at the moment of contact with no addi one or more other Separate layers, and which other layers tional pressure. may or may not comprise embodiments of the bioadhesive compositions of the present invention. The following examples will further describe the instant In yet another aspect, the bioadhesive composition of the invention, and are used for the purposes of illustration only, present invention may be utilized, without an active agent, and should not be considered as limiting in any way the in a reservoir-type delivery System as an underlay adhesive invention being disclosed herein. or a peripheral adhesive layer or ring, in which the active agent is Solubilized or contained in a separate reservoir or Percent (%) as used in Example 1 refers to percentage of depot, and which reservoir or depot may or may not com the liquid formulation on a weight to weight basis and prise embodiments of the bioadhesive compositions of the temperatures are given in degrees celsius ( C.) present invention. If the bioadhesive composition is used as an adhesive ring around the active agent reservoir or drug depot, the bioad hesive layer is peripheral to the active agent reservoir. If the 15 bioadhesive composition is used as a separate underlying adhesive layer to the layer containing the active agent, the Example 1 adhesive layer is adjacent to and in contact with a first major Surface of the active agent layer. The composition may then include a backing layer which is in contact with a Second major Surface of the active agent layer which is opposite the Ingredient % (w.fw) first major Surface of the active agent layer; and a removable release liner which is in contact with a Second major Surface Bioadhesive (karaya gum) 21 of the adhesive layer which is opposite to the first major Polyvinylpyrrollidone 11 Surface of the active agent layer. 25 Solvent (propylene glycol) 7 If the bioadhesive layer is used without an active agent as Solvent (glycerin) 19 a separate underlying layer, the thickness of the underlying Anesthetic agent base (lidocaine base) 28 layer is generally in the range of 1 to 10 mils thick, more Anesthetic agent salt (prilocaine hydrochloride) 14 preferably 2 to 8 mils, and most preferably 4 to 6 mils thick. One especially preferred embodiment for the bioadhesive composition includes: Soluble PVP; a polysaccharide, pref erably a natural gum, more preferably kayara gum, a sepa rate plasticizer, which is preferably glycerin; a separate Solvent, which is preferably a polyhydric alcohol, more The final product is manufactured by first blending the preferably propylene glycol, and one or more active agents 35 lidocaine base, prilocaine hydrochloride, propylene glycol, if the active agent Source is not separate from the bioadhe PVP and glycerin at about 70 to 90° C. until all of the drug Sive composition. is dissolved. The solution is then cooled to 20 to 35° C. prior The amounts of each component (active agent is not to adding the karayagum. Once the karayagum is added, the included) in weight % based on the combined dry weight of 40 final composition is applied to a Suitable backing material the at least one Soluble polyvinylpyrrollidone polymer, the Such as a non-woven, polyester film (for example, the film kayara gum, the polyhydric alcohol and the glycerin is sold under the trademark Sontara 8100, manufactured by shown below: DuPont de Nemours, E. I. and Co., Wilmington, Del.) and warmed to about 100° C. to accelerate the formation into its 45 final, finite form. Typical Preferred Optimum Range Range Range Ingredient (% by weight) (% by weight) (% by weight) Kayara gum 10 to SO 2O to 40 25 to 35 EXAMPLE 1 a PVP 5 to 30 7 to 15 9 to 13 50 Propylene Glycol 7 to 40 15 to 35 25 to 30 Glycerin 10 to SO 2O to 40 25 to 35

If the bioadhesive composition contains the one or more In example 1a, a composition is prepared as followed active agents, the amounts of the foregoing components may 55 without a drug. The composition can be then be used alone be adjusted by those skilled in the art depending on the as an underlay adhesive layer, or an active agent can be amount and type of the one or more active agents. added, prior to removal of Volatile processing Solvents. A preferred weight ratio of kayara gum to glycerin is of from 10:1 to 1:2, more preferably about 1:1. A preferred weight ratio of kayara gum to propylene glycol is of from 60 10:1 to 1:1, more preferably about 1:0.8. A preferred weight Ingredient wfw % (dry) ratio of the PVP to kayara gum is of from 1:1 to 1:7, Bioadhesive (karaya gum) 31.4 preferably 1:3 to 1:4. Polyvinylpyrrollidone (Kollidon K90) 10.4 It has been found that if the especially preferred compo Solvent (propylene glycol) 26.8 Plasticizer (glycerin) 31.4 Sition in the table above is used as a separate adhesive layer, 65 then the composition is capable of decreasing the time required for adhesion of a composition to mucosal tissue to US 6,562,363 B1 43 44 EXAMPLE 2 -continued A bioadhesive composition is prepared by combining 20.59% w/w wet of karayagum, 10.59% w/w wet of soluble EXAMPLES PVP (PLASDONE K90), 7.94% w/w wet of oleic acid, 45.0% w/w of ethanol and 15.88% w/w wet of ketoprofen in an appropriate container, and mixing thoroughly until the COMPONENT 1O 11 mixture is complately homogeneous. The resulting compo Sition has the ingredient concentrations on a dry weight Bupivicaine (salt) 1O O 2O basis, that is, after removal of the Volatile proceSS Solvent Ethanol (100) (100) (100) (ethanol).

EXAMPLE 2 15

EXAMPLES COMPONENT PERCENT BY WEIGHT Bioadhesive (Karaya Gum) 35.36 COMPONENT 12 13 14 Polyvinylpyrrolidone (PLASDONE K90) 19.19 Oleic Acid 15.15 Ketoprofen 3O.30 Bioadhesive (Karaya Gum) 32 O O Soy Polysaccharide (Emcosoy (R) 50) O O 50 Vinylpyrrolidone/Vinyl Acetate (Kollidon (R) VA64 28 40 O 25 Polyvinylpyrrolidone (Plasdone (R) K90) O O 25 In the following examples, the method of Example 2 is Alginic Acid NF (Satialgine TM H8) O 32 O used with the appropriate amounts of Starting materials to Dipropylene glycol 2O 18 O yield compositions having the following ingredient Oleic Acid O O 15 concentrations, on a weight percent by dry weight of the Sodium Diclofenac 2O 10 O total bioadhesive composition. Volatile solvents, where indi Diclofenac (acid) O O 10 cated by (), are not present in the final composition. Ethanol O O (60) Moreover, the drugs in examples 21-29 are dispersed in Ethyl Acetate (45) (75) O the final composition rather than Solubilized. 35

EXAMPLES EXAMPLES COMPONENT 3 4 5 6 7 8 40 COMPONENT 15 16 17 Bioadhesive 40 40 35 45 40 40 (Karaya Gum) Bioadhesive (Karaya Gum) 3O 35 O Polyvinylpyrrolidone 3O O O O O O Polyvinyl Acetate (Sentry (R) Plus PVAc 12) 35 O O (Kollidon (R) 12PF) Polyvinyl Acetate (Sentry (R) Plus PVAc 40) O 35 40 Polyvinylpyrrolidone O 25 O O O O Alginic Acid NF (Satialgine TM H8) O O 3O (Kollidon (R) 17) 45 Propylene Glycol O 2O 2O Polyvinylpyrrolidone O O 3O O O O Oleic Acid 15 O O (Kollidon (R 30) Ketoprofen 2O O O Polyvinylpyrrolidone O O O 2O O 2O Sodium Diclofenac O 1O O (Kollidon (R 90) Sodium Naproxen O O 1O Vinypyrrolidone/Vinyl O O O O 25 O Ethyl Acetate (50) (60) (60) Acetate (Kollidon (R) VA64) 50 Oleic Acid 1O 15 15 15 15 15 Ketoprofen 2O 2O 2O 2O 2O 2O Lidocaine (base) O O O O O 5 Volatile Solvent (75) (75) (85) (100) (85) (100) (Ethanol) EXAMPLES 55 COMPONENT 18 19 20 Bioadhesive (Karaya Gum) 6 10 12 Vinylpyrrolidone/Vinyl Acetate 7O 71 O EXAMPLES (ISP COPOYMER 958) Vinyl pyrrolidone/Dimethylaminoethylmethacrylate O O 64 60 COMPONENT 9 1O 11 (ISP COPOLYMER 5630) Oleyl Alcohol 6 6 6 Bioadhesive (Karaya Gum) 25 35 35 Depropylene Glycol 8 8 8 Polyvinylpyrrolidone (Plasdone (R) K90) 25 2O 2O Testosterone 1O O O Linoleic Acid 1O O 25 Methyl Testosterone O 5 O 1.3 Butylene Glycol 1O 25 O Testosterone Acetate O O 1O Lidocaine (base) 2O O O 65 Ethanol O O (100) Bupivicaine (base) O 2O O US 6,562,363 B1 45 46

EXAMPLES

COMPONENT 21 22 23 24 25 26 27 28

Bioadhesive O O O O O O O 29.9 (Kayara Gum) Soy Polysaccharide O O O O O O 4.9 O (Emcosoy (R) 50) Ethyl Cellulose O 24 O 9.9 37.9 O O O (Ethocel(R) 4) Polyvinylpyrrolidone O O 25 60 60 3O O 45 (Kollidon (R 90) Vinylpyrrolidone? Vinyl Acetate 40 50 O O O O O O (Kollidon (R) VA64) Polyvinyl Acetate O O O O O O 40 O (Sentry (R) Plus PVAc12) Ethyl Cellulose 19 O O O O O 25 O (Ethocel(R) 10) Ethyl Cellulose O O 14 O O 19.9 O O (Ethocel(R) 100) Oleic Acid 40 25 60 O O O 3O 25 Polyoxyethylene (2) Oleyl Ether O O O 2 2 O O O (BRIJ (R) 93) 1.3 Butylene Glycol O O O 28 O 50 O O Insulin 1. 1. 1. O1 O O O O Arg Vassopressin O O O O O.1 O O1 O Calatonin O O O O O O.1 O O.1 Ethyl Acetate (100) (100) (150) (200) (100) (100) (75) Acetone O O O O (200) O O O

EXAMPLES

Component 29 3O 31 32 33 34 35 36 Ethylcellulose (Ethocel(R) 7) 36.5 36.5 32.9 33.O 29.4 29.4 O O Ethylcellulose (Ethocel (R) 4) O O O O O O 33.O 36.7 Bioadhesive (Karaya Gum) 13.1 9.8 13.2 16.5 19.9 19.9 13.2 13.1 Polyvinylpyrrolidone (Kollidon (R) 30) 3.4 3.4 6.9 3.4 3.4 3.5 6.9 O Polyvinylpyrrolidone (Kollidon (R 90) 10.5 13.9 10.4 10.5 10.5 10.5 10.4 10.4 Dipropylene Glycol 7.3 7.3 7.3 7.3 7.4 7.4 7.3 7.2 Propylene Glycol 11.O. 11.O. 11.O. 11.O. 11.O. 110 1.O. 11.0 Ketoprofen 18.2 18.1 18.3 18.3 18.4 18.3 18.2 18.1 Polyethylene Oxide (WSRN 750) O O O O O O O 3.5

45 -continued

EXAMPLE EXAMPLE Component 37 38 39 40 41 42 43 50 Ketoprofen 1O 1O 1O 1O 1O 1O 1O Component 37 38 39 40 41 42 43 Dipropylene Glycol 4.5 4.5 4.5 4.5 4.5 4.5 4.5 Propylene Glycol 4.5 4.5 4.5 4.5 4.5 4.5 4.5 Phosphatidylcholine 29 29 29 29 29 29 29 Acrylic Adhesive O O O O O 4.5 O (Lecithin PG) 55 (Eudragit (R) L100) Eary's 4.5 O O O O O O Lactose Povidone O O O O O O 4.5 Polyvinylpyrrolidone O 4.5 O O O O O (Crospovidone Blend) (Kollidon (R) 17PF) Polyvinylpyrrolidone O O 4.5 O O O O (Ludipress (R) (Kollidon (R 30) Glycerin 18.5 18.5 18.5 18.5 18.5 18.5 18.5 Eto 0 0 0 4.5 0 0 0 90 Biadhesive 29 29 29 29 29 29 29 Vinylpyrrolidone? O O O O 4.5 O O (Karaya Gum) Vinyl Acetate (Kollidon (R) VA64) US 6,562,363 B1

EXAMPLES

Component 44 45 46 47 48 49 50 51 52 Cellulose Acetate 25.6 15.5 11.O. 10.9 15.5 9.4 O O O Bioadhesive (Karaya Gum) 16.1 18.6 19.8 19.6 18.6 17.O 220 17.0 18.8 Polyvinylpyrrolidone O O 9.9 21.7 20.6 17.9 23.2 17.2 19.8 (Kollidon (R 30) Ethylcellulose (Ethocel(R) 7) O O O O O 142 O 18.9 20.8 Dipropylene Glycol 224 25.8 27.5 27.2 25.8 23.6 30.5 18.9 20.8 Ketoprofen 18.0 21.5 21.9 20.6 19.5 17.9 24.3 28.O. 19.8 Polyvinylpyrrolidone 17.9 18.6 9.9 O O O O O O (Kollidon (R 90)

15

EXAMPLES 2O EXAMPLES

Component 53 54 55 Component 63 64 65 66

Ketoprofen 19 2O 19 Lidocaine (Base) 2O 20 20 Polyvinylpyrrolidone (Kollidon (R 90) 6 6 O 25 Bupivacaine HCL 1O 10 10 Polyvinylpyrrolidone (Kollidon (R) 30) O O 4 Phosphatidylcholine (Lecithin PG) 21 21 20 Polyvinylpyrrolidone (Kollidon (R) CL-M) O O 6 Dipropylene Glycol 5 O 5 Ethyl Cellulose (Ethocel(R) 7) 4 O O Propylene Glycol O 5 O Propylene Glycol 8 8 1O 3O Glycerin 16 12 17 15 Phosphatidylcholine (Lecithin PG) 21 22 19 Bioadhesive (Karaya Gum) 23, 27 23 25 Glycerin 14 15 14 Acrylic Adhesive (Eudragit L100) 5 5 O Bioadhesive (Karaya Gum) 28 29 28 Polyvinylpyrrolidone (Kollidon (R) CL-M) O O 5 35 Vinylpyrrolidone/Vinyl Acetate (Kollidon (R) VA64) O O O

EXAMPLE 40 Component 56 57 58 59 6O 61 62 EXAMPLES

Ketoprofen 11 11 11 11 11 11 11 Component 67 68 69 7O 71 72 Phosphatidylcholine (Lecithin PG) 25 24 24 24 34 33 25 Propylene Glycol 9 9 12 9 O O 9 Ketoprofen 29 29 29 29 29 29 Acrylic Adhesive (Eudragit (R) L100) 3 3 O 3 3 O Bioadhesive (Karaya Gum) 37 32 27 27 27 27 Polyvinylpyrrolidone O 3 3 6 O O O 45 Polyvinylpyrrolidone (Plasdone (R 90) 19 19 19 19 19 19 (Kollidon (R) CL-M) Oleic Acid 15 20 14 14 14 14 Vinylpyrrolidone? Vinyl Acetate O O O O O 3 3 Acrylic Adhesive (Duro-Tak (R) 87-2353) O O 11 O O (Kollidon (R) VA64) Polyisobutylene (Vistannex LMMS) O O O 11 O Bioadhesive (Karaya Gum) 32 32 32 32 33 32 33 Polyisobutylene (Vistannex LMMH) O O O O 11 Glycerin 19 18 18, 18 19 18 19 Rubber-Based Adhesive (Morstik (R) 103) O O O O O 11 50

EXAMPLES

Component 73 74 75 76 77 78 79 80 81 82 83 84 85

Lidocaine (Base) 2O 20 20 20 O O O O O 20 19 20 Ketoprofen O O O O 20 O O O O O O O Diclofenac (Acid) O O O O O O O 8 8 O O O Diclofenac (Sodium) O O O O O. O. O. 12 12 O O O Dipropyleneglycol 13 8 8 8 8 10 F 8 8 O O O Bioadhesive (Karaya Gum) 29 29 29 29 29 37 35 29 28 29 28 29 29 Polyvinylpyrrolidone (Kollidon (R) 30) O O O O O O O O O O O O Polyvinylpyrrolidone (Kollidon (R 90) O 5 O O 5 6 6 5 5 O 5 O Polyvinylpyrrolidone (Kollidon (R) CM) O O S O O O O O O O O O Acrylic Adhesive (Eudragit (R) RS100) O O O O O O 7 O 5 O 5 O US 6,562,363 B1 49

-continued

EXAMPLES

Component 73 74 75 78 79 80 81 82 83 84 85 Lactose Povidone (Crespovidone Blend) (Lupipress (R) 0 O O 5 O O O O O O O O Phosphatidylchaline (Lecithin PG) 22 22 22 22 28 26 22 20 22 21 22 22 Glycerin 16 16 16 16 19 19 16 14 16 14 16 16 Ethylcellulose (Ethocel(R) 7) O O O O O O O O O O O O Propylene Glycol O O O O O O O O 13 8 13 8

What is claimed is: 14. A composition according to claim 7, wherein the 1. A bioadhesive composition in a flexible, finite form for polyhydric alcohol comprises propylene glycol. topical application on mucous membranes of one or more 15 15. A composition as claimed in claim 1, wherein the one active agents resulting from an admixture which comprises: or more active agents is Selected from the group consisting (a) at least one Soluble polyvinylpyrrolidone polymer of: anesthetics, anti-inflammatories, analgesics, (PVP); antimigranes, antimicrobials, dental agents, antibiotics, (b) at least one bioadhesive; anorexics, polypeptide drugs, protein drugs, opioid agonists, (c) a therapeutically effective amount of one or more opioid antagonists, antie metics, antineoplastics, active agents, antiparkinsonians, antidiuretics, hormones, bronchodilators, (d) a backing layer which is occlusive to the active agents; central nervous System Stimulants and agents, oxyotics, and and vasodilators. (e) optionally one or more Solvents, wherein the compo 16. A composition for administration on mucous mem sition is substantially free of water. 25 branes of one or more active agents comprising: 2. A composition as claimed in claim 1, wherein the bioadhesive comprises a polysaccharide. (a) a Source of one or more active agents; 3. A composition as claimed in claim 1, wherein the (b) an adhesive layer adapted for adhering to mucosal bioadhesive comprises a natural gum. tissue and which results from an admixture which 4. A composition as claimed in claim 1, wherein the comprises: bioadhesive comprises karaya gum. (i) at least one Soluble polyvinylpyrrolidone polymer 5. A composition as claimed in claim 1, wherein the one (PVP); composition includes one or more Solvents. (ii) at least one bioadhesive; and 6. A composition as claimed in claim 5, wherein the one (iii) optionally one or more Solvents, wherein the or more Solvents includes a separate Solvent and a separate Source (a), containing the one or more active agents, plasticizer. 35 includes a separate layer than the adhesive layer (b); 7. A composition as claimed in claim 6, wherein the at and least one bioadhesive comprises karaya gum, and wherein (c) a backing layer which is occlusive to the active agents the Separate Solvent comprises a polyhydric alcohol and the and which is in contact with the Separate layer. Separate plasticizer comprises glycerin. 17. A composition according to claim 16, wherein a first 8. A composition as claimed in claim 7, wherein the at 40 major Surface of the adhesive layer is adjacent to and in least one soluble PVP is present in an amount of from 5-30 contact with a first major Surface of the Separate layer. wt %, the karayagum is present in an amount of from 10-50 18. A composition according to claim 17, wherein: wt %, the polyhydric alcohol is present in an amount of from 7-40 wit%, and the glycerin is present in an amount of from (c) said backing layer which is in contact with a second 10-50 wit%, all based on the combined weight of the at least 45 major Surface of the Separate layer which is opposite one soluble PVP, the karayagum, the polyhydric alcohol and the first major Surface of the Separate layer; and further the glycerin. comprising 9. A composition as claimed in claim 7, wherein the at (d) a removable release liner which is in contact with a least one soluble PVP is present in an amount of from 7-15 Second major Surface of the adhesive layer which is wt %, the karayagum is present in an amount of from 20–40 50 opposite to the first major Surface of the Separate layer. wt %, the polyhydric alcohol is present in an amount of from 19. A composition according to claim 16, wherein the 15-35 wt.%, and the glycerin is present in an amount of from Source (a) includes an active agent reservoir and the adhe 20-40 wit%, all based on the combined weight of the at least Sive layer is peripheral to the active agent reservoir. one soluble PVP, the karayagum, the polyhydric alcohol and 20. A composition according to claim 16, wherein the the glycerin. 55 adhesive layer includes one or more Solvents, wherein Said 10. A composition as claimed in claim 7, wherein the one or more Solvents comprises a separate Solvent and a weight ratio of the at least one PVP to karayagum is of from Separate plasticizer, and wherein Said at least one bioadhe 1:1 to 1:7. Sive comprises karaya gum. 11. A composition as claimed in claim 7, wherein the 21. A composition according to claim 20, wherein the weight ratio of the at least one PVP to karayagum is of from 60 Separate Solvent comprises a polyhydric alcohol, and 1:3 to 1:4. wherein the Separate plasticizer comprises glycerin. 12. A composition as claimed in claim 7, wherein the 22. A method for prolonged topical administration of one weight ratio of the karayagum to glycerin is of from 10:1 to or more active agents to a Subject comprising the Steps of: 1:2. (a) providing the composition of claim 1, and 13. A composition as claimed in claim 7, wherein the 65 (b) contacting an area of mucous membrane with said weight ratio of karaya gum to propylene glycol is of from composition to administer the one or more active 10:1 to 1:1. agents. US 6,562,363 B1 S1 52 23. A method for prolonged topical administration of one 27. A composition as claimed in claim 1, wherein the or more active agents to a Subject comprising the Steps of: Soluble polyvinylpyrrolidone polymer has a molecular (a) providing the composition of claim 16, and weight of about 1,000,000 to about 1,500,000. (b) contacting an area of mucous membrane with said 28. A composition as claimed in claim 1, wherein the composition to administer the one or more active composition contains less than 3% by weight of water. agents. 29. A device for the transmucosal delivery of one or more 24. A method for producing the composition according to active agents comprising: claim 1, comprising mixing (a) a mucoadhesive layer which adheres to mucosal (a) at least one Soluble polyvinylpyrrolidone polymer; 1O tissue, wherein Said mucoadhesive layer includes at (b) at least one bioadhesive; least one soluble polyvinylpyrrolidone polymer (PVP); (c) a therapeutically effective amount of one or more (b) an active agent layer; and active agents, (c) a backing layer which is occlusive to the active agents. (d) optionally one or more Solvents, to form a composi 30. The transmucosal delivery device according to claim tion; and 15 29, wherein said mucoadhesive layer further includes at least contacting Said composition with a backing layer which is one bioadhesive. occlusive to Said active agents. 31. The transmucosal delivery device according to claim 25. A method for producing the composition according to 30, wherein said bioadhesive is at least one compound claim 16, comprising: Selected from the group consisting of water-Soluble or water-insoluble polymers, natural gums, Starches, alginates, (a) forming an active agent Source which comprises one cellulose materials, and natural or Synthetic polysaccharides. or more active agents, 32. The transmucosal delivery device according to claim (b) forming a separate adhesive layer adapted for adhering 30, wherein Said bioadhesive includes karaya gum. to mucosal tissue, which comprises mixing: 33. The transmucosal delivery device according to claim (i) at least one Soluble polyvinylpyrrolidone polymer; 25 29, wherein Said active layer includes anesthetics, anti (ii) at least one bioadhesive; and inflammatories, analgesics, antimigranes, antimicrobials, (iii) optionally one or more Solvents, and dental agents, antibiotics, anorexics, polypeptide drugs, pro (c) contacting said adhesive layer with a backing layer tein drugs, opioid agonists, opioid antagonists, antiemetics, which is occlusive to the active agents. antineoplastics, antiparkinsonians, antidiuretics, hormones, 26. A method for decreasing the time required for adhe bronchodilators, central nervous System Stimulants and Sion of a composition to mucosal tissue, comprising: agents, oxyotics, vasodilators and mixtures thereof. applying the composition according to claim 16 to 34. The transmucosal delivery device according to claim mucosal tissue, whereby the composition adheres to the 29, wherein Said device is in a flexible, finite form. mucosal tissue Substantially at the moment of contact without any additional pressure.