USOO544607OA United States Patent 19 11 Patent Number: 5,446,070 Mantelle (45) Date of Patent: "Aug. 29, 1995

54 COMPOST ONS AND METHODS FOR 4,659,714 4/1987 Watt-Smith ...... 514/260 TOPCAL ADMNSTRATION OF 4,675,009 6/1987 Hymes ...... 604/304 PHARMACEUTICALLY ACTIVE AGENTS 4,695,465 9/1987 Kigasawa ...... 424/19 4,748,022 5/1988 Busciglio. ... 424/195 75 Inventor: Juan A. Mantelle, Miami, Fla. 4,765,983 8/1988 Takayanagi. ... 424/434 4,789,667 12/1988 Makino ...... 514/16 73) Assignee: Nover Pharmaceuticals, Inc., Miami, 4,867,970 9/1989 Newsham et al. ... 424/435 Fla. 4,888,354 12/1989 Chang ...... 514/424 4,894,232 1/1990 Reul ...... 424/439 * Notice: The portion of the term of this patent 4,900,552 2/1990 Sanvordeker ...... 424/422 subsequent to Aug. 10, 2010 has been 4,900,554 2/1990 Yanagibashi. ... 424/448 disclaimed. 4,937,078 6/1990 Mezei...... 424/450 Appl. No.: 112,330 4,940,587 7/1990 Jenkins ...... 424/480 21 4,981,875 l/1991 Leusner ...... 514/774 22 Filed: Aug. 27, 1993 5,023,082 6/1991 Friedman . ... 424/426 5,234,957 8/1993 Mantelle ...... 514/772.6 Related U.S. Application Data FOREIGN PATENT DOCUMENTS 63 Continuation-in-part of PCT/US92/01730, Feb. 27, 0002425 6/1979 European Pat. Off. . 1992, which is a continuation-in-part of Ser. No. 0139127 5/1985 European Pat. Off. . 813,196, Dec. 23, 1991, Pat. No. 5,234,957, which is a 0159168 10/1985 European Pat. Off. . continuation-in-part of Ser. No. 661,827, Feb. 27, 1991, 250187 6/1987 European Pat. Off. . abandoned. 0331392 2/1989 European Pat. Off. . 51 Int. Cl...... - A - P - d - d ------A61K 47/32 363224 10/1989 European Pat. Off. . U.S. C...... 217989 3/1983 Germany . 52 a a is a 8 88.8 s 514/772.6; 424/485; 52460 11/1966 Luxembourg. 424/486; 424/487; 424/488; 514/781; 514/782 352.239 12/1972 Sweden . 58 Field of Search - A - a 424/435, 443, 447, 449, 1360820 7/1974 United Kingdom. 424/450, 484, 485, 486, 487, 488; 514/772.6, 89/10740 11/1989 WIPO . 818, 947, 781, 782 OTHER PUBLICATIONS 56 References Cited U.S. PATENT DOCUMENTS J. F. Butterworth, et al., “Molecular Mechanisms of Local Anesthesia: A Review', Anesthesiology 2,142,537 1/1939 Tisza ...... 167/52 72:711–754, 1990. Pertinent pp. 720-721. 2,277,038 3/1942 Curtis ...... 167/52 2,352,691 7/1944 Curtis ...... 260/472 Primary Examiner-Thurman K. Page 2,501,544 3/1950 Shrontz ...... 128/268 Assistant Examiner-Carlos Azpuru 3,249,109 5/1966 Maeth ...... 28/268 Attorney, Agent, or Firm-Foley & Lardner 3,632,740 1/1972 Robinson ...... 424/28 3,640,741 2/1972 Etes ...... 106/170 57 ABSTRACT 3,814,095 6/1974 Lubens ...... 128/260 3,972,995 8/1976 Tsuk ...... 424/28 Compositions for topical application comprising a ther 4,302.465 11/1981 Ekenstam .. ... 424/267 apeutically effective amount of a pharmaceutical 4,307,075 12/1981 Martin ...... 424/28 agent(s), a pharmaceutically acceptable carrier, and a 4,466,973 8/984 Rennie ...... 424/267 solvent for the pharmaceutical agent(s) in the carrier 4,529,601 7/1985 Broberg ... 514/626 4,572,832 2/986 Kigasawa ...... 424/19 and methods of administering the pharmaceutical 4,608,249 8/1986 Otsuka ...... 424/28 agents to a mammal are disclosed. 4,615,697 10/1986 Robinson ...... 604/890 4,652,060 12/1986 Broberg ...... 424/28 45 Claims, No Drawings 5,446,070 1. 2 able to have the anesthetic agent present in a high con COMPOSITIONS AND METHODS FOR TOPICAL centration to effect a rapid onset and, additionally or ADMNSTRATION OF PHARMACEUTICALLY alternatively, in excess of the amount that can be imme ACTIVE AGENTS diately absorbed through the dermis at the site of appli cation, so as to prolong anesthesia. On the other hand, CROSS-REFERENCE TO RELATED the presence of the anesthetic agent primarily in crystal APPLICATIONS line form may irritate sensitive tissues such as mucosal This application is a continuation-in-part of tissues. This is particularly true with regard to lido PCT/US92/01730, filed Feb. 27, 1992, which is a con caine. tinuation-in-part application of U.S. patent application 10 A number of references disclose local anesthetic com Ser. No. 07/813,196, filed Dec. 23, 1991, now issued as positions. For instance, Swedish Patent Publication No. U.S. Pat. No. 5,234,957, which is a continuation-in-part 352,239 published Dec. 27, 1972 in the name of S. G. of U.S. patent application Ser. No. 07/661,827 filed Feb. Davis et al., assigned to Astra Pharmaceutical Products, 27, 1991 and now abandoned, all of which applications Inc., and based on Swedish patent application No. are hereby incorporated by reference. 15 1774.4/70 filed Dec. 30, 1970, discloses a local anesthetic film containing up to 50% lidocaine in crystallized, BACKGROUND OF THE INVENTION microdispersed form. In its final form, this composition 1. Field of the Invention lacks a solvent for the anesthetic agent. The preparation The present invention relates to compositions and is prepared by adding a solution of lidocaine in an or methods for the topical administration of pharmaceuti 20 ganic solvent or an acid addition salt in water, under cally active agents to a mammal in need thereof. More heat and agitation, to a solution or suspension of a film particularly, the present invention relates to anesthesia forming material, namely carboxymethyl cellulose, pol and local anesthetic agents for topical administration. yvinyl alcohol, or a mixture of polyvinyl alcohol and Still more particularly, the invention relates to a method polyvinyl pyrrolidone in water, followed by heating to for the topical administration of an anesthetic agent or a 25 remove any solvent present. combination of anesthetic agents to prevent or amelio U.S. Pat. No. 4,937,078 to Mezei, et al. describes a rate pain. liposome encapsulated local anesthetic or analgesic There is no limitation on the type of pharmaceutical agent that can be used in the present invention, pro agent that is said to provide, when applied to the skin or vided that it can be absorbed topically, typically percu 30 mucous membrane, greater local anesthesia and analge taneously. Thus, the pharmaceutical agent includes sia than the same agents incorporated in conventional both drugs that are topically applied for local effects vehicles such as ointments, creams, or lotions. These and those which can be administered topically for sys liposomal films are preferably applied under occlusion. temic effects. U.S. Pat. Nos. 4,572,832 and 4,695,465 to Kigasawa 2. Description of Background Art 35 and 3,249,109 to Maeth all describe the use of water Anesthetic agents are pharmacologically active soluble protein based systems which incorporate anes agents that block nerve conduction when applied in thetics, and which also contain a tackifier and a poly therapeutically effective amounts. They can be used for hydric alcohol solvent. In the compositions of these local or systemic application. Anesthetic agents have references, the water soluble protein gives the base its been used extensively in the medical field to obtain consistency and bulk and serves as an essential vehicle topical anesthesia. The term "topical” or "topically” is for the incorporation of medicaments and therapeutic used here in its coventional sense as referring to a spot, agents. which can be in or on any part of the body, including U.S. Pat. No. 4,894,232 to Reil, et al. discloses a base but not limited to the epidermis, any other dermis, or for mucosal or denture adhesive pastes and a process for any other body tissue. Topical administration or appli 45 the preparation thereof. Lidocaine is one possible thera cation means the direct contact of the anesthetic with peutic agent suitable for this paste. tissue, such as skin or membrane, particularly the oral or U.S. Pat. No. 3,814,095 to Lubens describes an absor buccal mucosa. Topical administration also includes bent pad for topical application of an anesthetic agent application to hardened tissue such as teeth and append and having a peripheral adhesive. ages of the skin such as nails and hair. Previous methods 50 It is also known to combine two local anesthetic free of applying topical anesthetic agents to the skin or mu bases with different melting points. By mixing the two cosa have used "non-finite' or liquid or semi-liquid anesthetic bases, an eutectic mixture has been reported carriers such as gels, lotions, emulsions, creams, plas that is liquid at room temperature, making it possible to ters, or ointments, or "finite' carriers, non-spreading attain higher concentrations of the active bases. substances which retain their form, e.g. patches, dress 55 U.S. Pat. No. 4,888,354 by Chang relates to a combi ings and bandages. nation of the free base and an acid addition salt of a Local anesthetics generally are esters or amides of variety of drugs, typically in a liquid carrier, to increase benzoic acid derivatives, administered either as the free skin penetration rates. Anesthetics, along with a list of base or the acid-addition salt. Free bases tend to be other suitable drugs are mentioned. This reference spe irritating at high concentrations. Acid-addition salts cifically teaches that base and acid-addition forms of the have low skin permeability. same drug be used in carrier. To be effective, a topical, local anesthetic should U.S. Pat. No. 2,352,691 to Curtis teaches the use of contain sufficient concentration of the active agent to salicylate salts of alkamine esters of amino benzoic acid produce an anesthetic effect, it should penetrate the to enhance the water solubility of anesthetic agents. The tissue such as intact skin or mucosa sufficiently to de 65 salt form predominates over any base form. In one ex liver a therapeutic dose, and it should exhibit rapid ample, this reference discloses a solution of procaine onset of anesthetic action and have a prolonged anes acetyl salicylate containing insoluble anesthetics such as thetic effect. In achieving the foregoing, it is often desir benzocaine, butesin, orthoform, or their salts, in certain 5,446,070 3 glycols which are combined with a volatile solvent, and crodispersed in the carrier, it is more readily available then used to saturate gauze bandages or other suitable for permeation into the tissue, e.g. the skin or dermal fabrics. membrane. U.S. Pat. No. 2,142,537 to Tisza describes an oint It still further has surprisingly been found that the use ment containing isoamylhydrocupreine in combination 5 of two different local anesthetic agents, the first in base with a quick acting local anesthetic to overcome the form and the second in salt form, in a pharmaceutically undesirable irritation caused by the prolonged acting acceptable carrier in a finite or non-finite form, includ anesthetic isoamylhydrocupreine or its salts. The prepa ing a non-aqueous solvent for the anesthetic agents, ration of Tisza combines short and long acting anes permits the attainment of high anesthetic agent concen thetic agents. However, such preparation is not pro 10 trations in the final product, for example of up to 50% vided in a convenient form for topical administration, by weight in microdispersed form, without crystalliza nor does it appear to contain a high concentration of tion of the anesthetic agents which can cause irritation finely-dispersed drug. of the skin or other dermal membrane or other tissue. U.S. Pat. No. 4,900,552 by Sanvordeker et al. dis Thus, in one embodiment, the present invention is in closes a trilaminate film suitable for prolonged and sus 15 tained delivery of an active ingredient in a buccal cav convenient form for topical application of the anes ity. Specifically a hydratable mucoadhesive base layer, thetic agents, thereby enabling such anesthetics to pene a non-adhesive reservoir layer and a water-impermeable trate tissue such as intact skin, skin appendages or mu carrier film sandwiched between and bonded to the cous membranes and have a highly localized effect. base layer and the reservoir layer form the trilaminate Furthermore, the combination of the salt and base film. This reference generally describes and claims the forms, advantageously results in rapid onset of anes addition of an active ingredient to the non-adhesive thetic action with prolonged anesthetic effect. reservoir layer. SUMMARY OF THE INVENTION U.S. Pat. No. 2,277,038 to Curtis relates to prepara tions containing a mixture of two or more anesthetic 25 The invention relates to a flexible, finite, bioadhesive agent salts having different pH values in solution, composition for topical application comprising: whereby the pH value of the combined mixture in solu (a) a therapeutically effective amount of at least one tion may be adjusted to obtain a higher degree of stabil pharmaceutically active agent which is in solid ity of the solution, and at relatively higher pH, a more form at ambient temperatures and pressures; rapid onset of anesthetic action. The anesthetic agents (b) a pharmaceutically acceptable solvent for the in Curtis are not in highly dispersed form and are used pharmaceutically active agent, in an amount from in a liquid-soaked fabric. about 5 to about 70 weight percent based on the Procaine salts of different drugs, namely procaine weight of the whole composition, the solvent in penicillin G, given by intramuscular injection are also cluding about 5 to about 50 weight percent of a known to prolong the antimicrobial action of the antibi 35 plasticizer; Otc. (c) in admixture with the pharmaceutically active Commonly, prolongation of anesthesia with topical agent in the solvent, a pharmaceutically acceptable anesthetics has been achieved by the addition of vaso polysaccharide bioadhesive carrier in an amount constrictors, such as the catecholamine, epinephrine, from about 20 to about 50 weight percent based on which caused constriction of blood vessels. Since cate 40 the weight of the whole composition; cholamines are not particularly effective when applied wherein the composition is substantially free of wa topically, such a prolongation is of minimal usefulness ter, substantially water insoluble and is a bioadhesive; for topical anesthetics. The primary drawbacks of this and wherein the pharmaceutically active agent is pres approach are the potential adverse side effects of cate ent in non-crystallized form in the composition. cholamines, and the prolongation itself. 45 The invention further relates to a composition for Although many local anesthetic compositions have topical application comprising: been proposed, it has been discovered that the incorpo (a) a therapeutically effective amount of a first local ration of one or more anesthetic agents in a solvent for anesthetic agent in base form; the anesthetic agent into a flexible, finite, pharmaceuti (b) a therapeutically effective amount of a different, cally acceptable carrier, permits an exceptionally high 50 second local anesthetic agent in non-salicylate loading of anesthetic agent in the carrier, permitting acid-addition salt form; and more rapid delivery of the anesthetic agent to the tissue (c) in an admixture with the anesthetic agents, a phar such as the dermal membrane without substantive crys maceutically acceptable carrier tallization of the anesthetic agent which can limit ab wherein the anesthetic agents comprise about 1 to sorption by the skin and which can cause irritation of 55 about 50% by weight of the total composition. the skin or other dermal membrane or tissue. The invention further relates to a composition for It has surprisingly been found that concentrations of topical application comprising: substantially dissolved anesthetic agent as high as 50% (a) a therapeutically effective amount of a first local by weight can be achieved in a system in which the anesthetic agent in base form; adhesion of the adhesive carrier is not hindered. Prolon 60 (b) a therapeutically effective amount of a different, gation of anesthesia can thus be achieved by increasing second local anesthetic agent in acid-addition salt the amount of time the composition is applied, without form; and detrimental irritation. The compositions of the present (c) in an admixture with the anesthetic agents, a phar invention are in convenient form for topical application maceutically acceptable carrier which is substan of the anesthetic agents, thereby enabling such anesthet tially water free; ics to penetrate the dermis, for example, intact skin or a wherein the anesthetic agents comprise about 1 to mucous membrane. Moreover, the anesthetic action is about 50% by weight of the total composition and highly localized. Because the drug is substantially mi wherein the amount by weight of the base for an anes 5,446,070 5 6 thetic agent is equal to or greater than the amount by maceutical agent or a combination of agents to produce weight of the salt form. a local or systemic effect over a prolonged period of These compositions may further comprise a backing time. material which conforms to the size and shape of a In accordance with one embodiment of the present single dosage of the composition. invention, a pharmaceutically acive agent and a plasti This invention also relates to a method of administer cizer for the adhesive are in admixture with a pharma ing the foregoing compositions. ceutically acceptable adhesive, which is preferably a The invention relates to method of administering one bioadhesive, and more preferably a polysaccharide bi or more pharmaceutically active agents in a bioadhesive oadhesive, is provided in a finite, flexible form for topi to a subject comprising the steps of: 10 cal application to the skin or dermal membrane of a (a) providing a flexible, finite, bioadhesive composi mammal. Preferably, the pharmaceutically active agent tion for topical application comprising a therapeu is in solid form at ambient temperatures and pressures. tically effective amount of at least one pharmaceu In accordance with a further embodiment of the pres tically active agent which is in solid form at ambi ent invention, a combination of local anesthetic agents, ent temperatures and pressures; 15 a solvent for the anesthetic agents and a finite or non a pharmaceutically acceptable solvent for the phar finite, fluid or flexible, pharmaceutically acceptable maceutically active agent, in an amount from about carrier is provided for topical application to a tissue, for 5 to about 70 weight percent based on the weight of example the skin or mucosa of a mammal. the whole composition, the solvent including about The anesthetic agents of this invention are those 5 to about 50 weight percent of a plasticizer; 20 known, or of a type known, in the art. The local anes in admixture with the pharmaceutically active agent thetic bases encompassed by this invention are weak in the solvent, a pharmaceutically acceptable polysac organic bases which are lipophilic in nature and thus charide bioadhesive carrier in an amount from about 20 poorly soluble in water. However, these bases will react to about 50 weight percent based on the weight of the with organic or inorganic acids to form acidic, water whole composition; 25 soluble acid addition salts. Thus, the term "base' as wherein the composition is substantially free of wa used herein means the un-ionized form of the anesthetic ter, substantially water insolubie and is a bioadhesive; that can furnish an electron pair to form a covalent and wherein the pharmaceutically active agent is pres bond. The term "acid' as used herein is a substance that ent in non-crystallized form in the composition; and can take up an electron pair to form a covalent bond. (b) contacting an area of skin or mucous membrane 30 The term "salt” as used herein means the form pro with the composition to administer the pharmaceu duced by a base, for example an anesthetic base, upon its tically active agent. reaction with an organic or inorganic acid. The invention further relates to a method of adminis The base form and the salt form of the anesthetic tering a pharmaceutically acceptable composition to a agent incorporated in the present combination composi subject, comprising the steps of: 35 tion must be different anesthetic agents to achieve maxi (a) providing a composition comprising a therapeuti mum duration of the combined anesthetic effect. By the cally effective amount of a first local anesthetic term “different' is meant that the salt form in any com agent in base form; a therapeutically effective bination is not a salt of the base form used in the given amount of a different, second local anesthetic agent combination. in a non-salicylate acid-addition salt form; and in an Local anesthetic agents suitable for use in the practice admixture with the anesthetic agents, a pharmaceu of this invention include amides and esters. Examples of tically acceptable carrier; the amides are lidocaine, prilocaine, mepivacaine, wherein the anesthetic agents comprise about 1 to about bupivacaine, dibucaine and etidocaine. Esters include 50% by weight of the total composition; and procaine, tetracaine, propoxycaine, chloroprocaine, (b) contacting an area of tissue, such as skin or mu 45 benzocaine, butamben picrate, cocaine, hexylcaine, pi cous membrane, with the composition to adminis perocaine, oxyprocaine and proparacaine. Other suit ter the local anesthetics. able local anesthetics for use in the practice of this in The invention further relates to a method of adminis vention include cyclomethycaine, dimethisoquin, keto tering a pharmaceutically acceptable composition to a caine, diperodon, dyclonine and pramoxine, all typi subject, comprising the steps of: 50 cally administered in the form of the acid addition hy (a) providing a composition comprising a therapeuti drochloride or sulfate salts. cally effective amount of a first local anesthetic The acid-addition salts of the present invention are agent in base form; a therapeutically effective any non-toxic, pharmaceutically acceptable organic or amount of a different, second local anesthetic agent inorganic salts which in certain embodiments are non in an acid-addition salt form; and in an admixture 55 salicylate. Typical inorganic salts are the hydrogen with the anesthetic agents, a pharmaceutically ac halides, especially the hydrochlorides, carbonates, bo ceptable carrier which is substantially free of water rates, phosphates, sulfates, hydrogen sulfates, hydrobro wherein the anesthetic agents comprise about 1 to about mides, nitrates, sulfides, and arsenates. Typical organic 50% by weight of the total composition; and salts are salts of mono- and polycarboxylic acids such as (b) contacting an area of tissue, such as skin or mu the citrate, tartrate, malate, cinnamate, oxalate, formate, cous membrane, with the composition to adminis succinate and phthalates. The term "non-salicylate' ter the local anesthetics. used herein means that in certain embodiments, the acid addition salts do not include salts of esters of salicylic DETAILED DESCRIPTION OF THE acid and its analogs such as aspririn. INVENTION 65 The solvents for the finite and non-finite forms of the This invention provides a composition which when anesthetic agents are non-toxic, pharmaceutically ac administered topically, for example to an area of the ceptable substances, preferably liquids, which do not skin, skin appendage, teeth or mucosa, delivers a phar substantially negatively affect the adhesion properties 5,446,070 7 8 or solubility of the system. The solvent is preferably a Preferably the pharmaceutically active agent is sub polyhydric alcohol or combination of polyhydric alco stantially dissolved in the solvent so that when mixed hols. The term polyhydric alcohol means any organic with the finite adhesive or non-finite fluid carrier, the polyalcohol and includes dipropylene glycol, propylene agent is microdispersed in the composition. glycol, polyethylene glycol, glycerin, butylene glycol, Solvent selection for the combination of anesthetic hexylene glycol, polyoxyethylene, polypropylene gly agents depends on the form of the anesthetic agent, col, sorbitol, ethylene glycol, and the like. Other suit namely whether it is in free base form or acid-addition able solvents include fatty acids such as oleic acid, lin salt form. Solvents for the salt form of anesthetic agent oleic acid, capric acid and the like, as well as fatty esters are polar organic solvents. Polar organic solvents are or alcohols. Further suitable solvents include other 10 preferably polyhydric alcohols, as discussed above. non-toxic, non-volatile solvents commonly used in der Various other solvents suitable for either the base or mal or transdermal compositions for dissolving like acid-addition form of the anesthetic agent are those compounds. solvents known to dissolve either or both of these two The above mentioned polyhydric alcohols may in types of forms including cyclic ketones such as 2-pyr clude those having 2 to 6 alcoholic hydroxyl groups. 15 rolidone; N-(2-hydroxyethyl) pyrrolidone, N-methyl Such polyhydric alcohols include glycols, triols and pyrrollidone, 1-dodecylazacycloheptan2-one and other polyols having 4 to 6 alcoholic hydroxyl groups. Typi n-substituted alkyl-azacycloalkyl-2-ones (azones) dime cal of said glycols are glycols containing 2 to 6 carbon thylformadide, and dimethylsulfoxide. Other suitable atoms, e.g. ethylene glycol, propylene glycol, butylene solvents for the free base form of the anesthetic agent glycol, polyethylene glycol (average molecular weight are cell envelope disordering compounds known to be about 200–8,000, preferably about 200 to 6,000), etc. useful in topical pharmaceutical preparations, which Examples of said triols include glycerin, trimethylolpro compounds are thought to assist in skin penetration by pane, etc. Said polyols are exemplified by sorbitol (sor disordering the lipid structure of the stratum corneum bit), polyvinylpyrrolidone, etc. These polyhydric alco cell-envelopes. Some of these compounds are generally hols may be used either singly or in combination (pref 25 encompassed by the formula: erably, of two or three). Thus, for example, glycerin alone or a mixture of glycerin and butylene glycol is R-X employed. Among those polyhydric alcohols, those which sat wherein R is a straight-chain alkyl of about 7 to 16 isfy the requirements relevant to the adjustment and 30 carbon atoms, a non-terminal alkenyl of about 7 to 22 maintenance of softness of the external surface of the carbon atoms, or a branched-chain alkyl of from about invention, the compatibility or co-dispersibility with the 13 to 22 carbon atoms, and X is -OH, -COOCH3, other components, and provide a proper consistency of -COOC2H5, -OCOCH3, -SOCH3, -P(CH3)2O, the composition, may be freely used. Those which are -COOCH2H4OC2H4OH, -COOCH(CHOH)4C low in volatility are generally preferred and, in this 35 H2OH, -COOCH2CHOHCH3, -COOCH2C regard, dipropylene glycol, glycerin, propylene glycol, H(OR")CH2OR". -(OCH2CH2)OH, -COOR", or butylene glycol, and sorbitol are appropriate solvents, -CONR'2 where R is -H, -CH3, -C2H5, -C3H7 according to the invention. OR-C2H4OH; R' is -H, or a non-terminal alkenyl of Although the exact amount of the polyhydric alco about 7 to 22 carbon atoms; and m is a positive integer hols in the composition depends on the nature of other from 2 to 6; provided that when R" is an alkenyl and X components, and therefore cannot be stated in general is -OH or -COOH, at least one double bond is in the terms, the proportion may range from about 5 to about cis-configuration. 70 or even 90 weight percent based on the whole com It has been discovered that high concentrations of a position, and depending on the amount of other ingredi combination of microdispersed anesthetic agents, entS. 45 namely up to 50% by weight of the optionally finite, In one embodiment, the solvent is in an amount from flexible composition, require the use of a solvent as about 20 to 53 weight percent based on the weight of herein described. In one embodiment of the invention, the whole composition. The solvent includes from the anesthetic agent(s) is in an amount of from 10 to 40 about 5% to about 50%, and more preferably about weight percent based on the weight of the total compo 10% to 30% of a solvent known to plasticize the bi 50 sition. Omission of the solvent in the procedure of Ex oadhesive carrier. A particularly useful plasticizer is ample 1 below yields a product filled with crystals or a glycerine. crystalline mass. The high concentrations of microdispersed anesthetic In particularly preferred embodiments of this inven agent of this invention are achieved typically by mixing tion, the free base local anesthetic agent is selected from the anesthetic agents with the solvent, preferably at an 55 the group comprising lidocaine, procaine, propoxy elevated temperature, for example about 70 to 100 C., caine, mepivacaine, prilocaine, dyclonine, pramoxine, to obtain a mixture, preferably a solution, of the anes benzocaine and chloroprocaine. The salt form is prefer thetic agents which is then added to the pharmaceuti ably one selected from the group comprising priocaine, cally acceptable carrier. tetracaine, bupivacaine, dyclonine, dibucaine, etido The term "microdispersed' is intended to mean that caine and lidocaine salts. The aforementioned bases and in the solvent, and subsequently the carrier, there is an salts can be used alone or in combination with other intimate dispersion of the pharmaceutically active agent anesthetic bases and salts as needed to achieve therapeu at the molecular or ionic level, such that crystals of the tically effective levels when administered transder pharmaceutically active agent cannot be detected using mally, or through other topical route. a microscope having a magnification of 25X. As such, 65 The term “therapeutically effective amount' is in the pharmaceutically active agent is in "non-crystal tended to mean the amount of drug sufficient to pro lized' form when in the compositions of the present duce an anesthetic effect when applied topically. These invention. amounts are known in the art or may be determined by 5,446,070 10 methods known in the art, and typically range from The term 'onset of anesthesia' is intended to mean about 1 to 20,000 mg per human adult and preferably the time to peak effect on the individual nerves. Onset about 10 to 10,000 mg and most preferably range from of anesthesia principally depends upon the lipid solubil about 20 to 5,000 mg of the anesthetic agent per applica ity, molecular size, and quantity of available, un-ionized tion, depending upon the anesthetic agents chosen, and form of the local anesthetic. Thus, anesthetics with a whether the tissue, such as the skin or mucous mem high lipid solubility or a low pKa, or both, have a more brane is the site of action. The only upper limit on the rapid onset of anesthesia. amount of anesthetic in the composition is that the prep The term "duration of anesthesia' as used herein aration is substantially free of crystals of anesthetic means the period of time during which the local anes agent and the amount of solvent used is not sufficient to 10 thetic measurably blocks nerve conduction. The forego undesirably affect the adhesive properties of the finite ing depends upon all of the factors listed for onset of composition. Thus, the single ingredient anesthetic anesthesia, as well as on the extent of protein binding of agent contains a therapeutically effective amount of the anesthetic agent. anesthetic agent within the foregoing range. The anesthetic agent free base can penetrate intact 15 skin to a limited degree, and will more rapidly penetrate The concentration as well as the quantity of anes the skin if the keratin layers are abraded. In the case of thetic per unit area, namely per square or cubic centime the oral mucosa, the anesthetic base will penetrate much ter can be varied independently in order to achieve the more readily due to the different keratin composition desired effect. Higher concentrations of anesthetic base and the resulting difference in the hydrophilicity as contained in a dosage form of decreased thickness will 20 compared to the stratum corneum of intact skin. result in an anesthetic with fast onset and short duration. As a general rule, the salt forms of the aforemen High concentrations of the anesthetic base contained in tioned anesthetics do not appreciably penetrate intact a dosage form of increased thickness (higher mg of skin, but the un-ionized base form do penetrate to a anesthetic per square or cubic centimeter) will result in limited degree. Both forms, salt and base, will penetrate potent anesthesia with fast onset and long duration. 25 abraded keratin layers. The salt as well as the base will Low concentrations of the anesthetic base in a dosage penetrate, to a differing degree, the buccal mucosa due form of decreased thickness will result in mild anesthe to the buccal mucosa's hydrophilicity, as compared to sia with longer onset and short duration. Low concen the stratum corneum of intact skin. Generally, the trations of the anesthetic base contained in a dosage higher the lipid content of the mucosal membrane, the form of increased thickness will have mild anesthesia 30 more rapidly the base form of the anesthetic agent will with longer onset and longer duration. As shown in the be absorbed. Therefore, when the composition is used above explanation, the ability to vary the concentration for application to oral or buccal mucosa, the different of anesthetic from very low (about 1%) to high (40% or lipid contents of the gum (gingiva) and the alveolar higher) of the total composition, when combined with mucosa must be kept in mind in order to obtain the the ability to coat thin (about 0.001 inches) or thick 35 optimal penetration rate. (about 0.500 or more inches) enables the practitioner of Although applicants do not intend to be bound by the invention to vary the dosage of the system as needed any theory or proposed mechanism of operation, it is for particular anatomical sites of interest. believed that the base which is lipid soluble has a rapid As a general rule, in the case of a given tissue, e.g. the onset of anesthesia since it enters the lipo-protein nerve mucosal application, the anesthetic drug selected, the membrane preventing the depolarization and ion ex concentration and thickness and the duration of the change involved in stimulus conduction. On the other application is determined based upon the anesthetic's hand, the salt which is not lipid soluble, penetrates to ability to penetrate the tissue, for example mucosa, and the lipo-protein nerve membrane only after the buffer to be at peak effectiveness within about 2 to 30 minutes. ing capacity of the skin or mucosal tissue converts the The duration of the effect of the anesthetic on the tissue, 45 salt to the base, the final result being a delayed onset of for example the oral mucosa, should range between anesthesia. about 2 to 240 minutes, depending on the anesthetic The salts of this invention are selected on the basis of agent selected, the concentration of the anesthetic and onset of anesthesia and duration of anesthesia. Adjust the thickness of application. Longer or shorter dura ing the ratio of base to salt affects the relative onset as tions can also be selected dependent on need, as will be 50 well as the duration of anesthetic action. The greater apparent to one skilled in the art. the amount of anesthetic agent having a rapid onset of The ratio of the free base form to the salt form in the action, the shorter the onset of anesthesia. Similarly, the composition of this invention will depend on several greater the amount of the anesthetic agent having a factors, namely: (1) the identity of the salt and base prolonged duration of anesthesia, the more prolonged used; (2) the desired duration of action; and (3) the 55 the duration of anesthesia. More than two anesthetic desired rapidity of anesthetic effect. As a general rule in agents may be used to have abroader spectrum of activ the case of mucosal application, the ratios of base to salt ity. Moreover, the composition can include other drugs are such that the free base form preferably should pene used concomitantly. trate the mucosa and be at its peak effectiveness within Generally, the concentration of solubilized pharma about a 2 to 30 minute period, whereas, the salt form ceutically active agent can range, on a weight basis, should preferably penetrate the mucosa and be at its between about 1 and about 50%, preferably between 2.5 peak effectiveness within a period of about 10 to 75 and 40% and more preferably between 5 and 30% of the minutes. The duration of the effect of these on the oral total weight of the composition. In a preferred embodi mucosa will range between about 2 to 240 minutes de ment of the invention, the concentration of the dis pending on the base/salt combination selected and the 65 solved drug is between 5% and 20% by weight of the length of application time. In practice to achieve this total composition. The base used in the preferred em effect, the amount by weight base form will be in excess bodiment for a single ingredient preparation is lido of the amount by weight of the salt form. Cae. 5,446,070 11 12 Generally, for the combination of anesthetics, the composition. Such backing may be a three dimensional ratio by weight of base to salt is about 90:10 to about material such as paper, a non-woven fabric or a natural 60:40, preferably about 75:25 to about 60:40, and more or synthetic polymer substance. Methods of coating preferably about 70:30 to about 60:40. For other salts, backings are well-known in the art and include tech the ratios are comparable based on relative molar 5 niques involving Mayer rod, gravure, and knife-over amounts. Generally, the ratio by weight of base to salt is roll. Further processing of backings may involve the more than 1:1. In a preferred embodiment of the inven use of converting equipment for die cutting. tion, the ratio is about 2:1 base to salt, respectively. The The finished dosage form will be substantially occlu base used in the preferred embodiment is lidocaine and sive to water permeation in in-vivo. the preferred salt is a salt of prilocaine, bupivacaine, 10 dyclonine, mepivacaine, or tetracaine, preferably the For example, in one embodiment, the anesthetic hydrochloride salt. agents are dissolved in a solvent, preferably a polyhyd Table 1 below summarizes the peak and duration of ric alcohol, and then the resulting mixture is added to an action of selected local anesthetics based primarily on adhesive prior to being placed onto the flexible form or application to skin or mucous membranes: 15 backing. In another embodiment, the resulting mixture is an cream, gel, emulsion, lotion, salve, plaster, paste, TABLE 1. ointment, spray-solution or other "non-finite' composi Maximum Peak duration Local Minimun Adult Dose Effect of Effect tion. The final form in which the composition of the Anesthetic Adult Dose (mg) (minutes) (minutes) invention will be applied depends upon the anatomical Dibucaine 25 <15 120-240 - 20 site of application and ease of access. Lidocaine 750 2-5 30-60 The phrase "flexible, finite, pharmaceutically accept Benzocaine 5000 30-60 able carrier' is intended to mean a solid capable of Cocaine 50 2-5 30-120 Tetracaine 50 3-8 30-60 conforming to a surface with which it comes into Dyclonine 100 <10 <60 contact and which is capable of maintaining the contact Pranoxine 200 3-5 NA 25 So as to facilitate topical application without any ad NA: Not Available. verse physiological response, and which can be used to Source: drug Facts and Comparisons, 1990 edition, J.B. Lippincott Company, St. establish the compositions herein in their preferred solid Louis, MO. Page 601. form without being appreciably decomposed by aque In general, the relative speed of onset of anesthesia ous contact during administration to a patient. and duration of anesthesia for any given form of anes 30 An important characteristic of the embodiment of the thetic agent is available in the literature or can be calcu present invention wherein a bioadhesive carrier is en lated by standard tests. ployed, relates to the substantially water-free and wa Onset time, as well as duration of anesthesia, will ter-insoluble nature of the composition. By the term vary from individual to individual as well as on the basis "substantially water-free' is meant that the preparation of the site of application. When applying the composi 35 contains less than about 10% by weight water, and tion to highly keratinized dermal tissues, the onset of preferably less than 5%, and most preferably less than anesthesia may take as long as 2 to 4 hours. 3%. In general, it is desirable to avoid the addition of The composition of this invention can be manufac water entirely and to eliminate, as far as possible, the tured by numerous methods known in the art which presence of water in the other ingredients of the compo permit the achievement of a microdispersed anesthetic sition. By the term 'substantially water insoluble' is agent, including extruding, molding, solvent casting, meant that the composition remains "finite' and does coating, and all other methods which employ a solvent not generally detach from the skin, dermal membrane to disperse the drug in a finite or non-finite carrier. or other tissue at the site of application and under the In one embodiment of the invention, the composition conditions of regular, intended use for a period of at comprises a combination of a first anesthetic agent in 45 least 3 hours. The advantages to be derived from the the form of a base and a second anesthetic agent in the substantially water-free and water-insoluble nature of form of an acid-addition salt. In this embodiment, the the compositions of the present invention include term "pharmaceutically acceptable carrier' is intended achievement of higher concentrations of drug. Another to be any suitable finite or non-finite carrier including advantage of these compositions is minimization of liquids, semi-liquids or solid carriers, such as a bioadhe 50 precipitation of drug, which precipitation affects pro sive. Thus, the active agents may be admixed with a cessing of the composition, affects rate of delivery of non-adhesive tape or other finite carrier or a carrier such as a cream, gel, emulsion, lotion, salve, paste, plas the drugs and in certain cases can affect sensitivity of ter, ointment, spray-solution, or any other “non-finite' the subject to be treated to the drug. carrier known in the art of pharmaceutical delivery. 55 Suitable adhesive carriers include any of the non For example, the base of a non-finite carrier may be toxic polymers, particularly those of the type used to fatty oils, lanolin, vaseline, paraffins, glycols, higher carry drugs for transdermal delivery including natural fatty acids and higher alcohols. or synthetic elastomers, such as polyisobutylene, sty Contrary to the typical method for manufacturing a rene, butadiene, styrene isoprene block copolymers, drug in a solvent containing adhesive, the adhesive acrylics, urethanes, silicones, styrene butadiene copoly composition of this invention contains a non-volatile mers, methyl acrylate copolymers, acrylic acid, poly solvent. Thus the composition is either not dried to acrylates, and polysacchrides such as, karaya gun, trag prevent removal of the solvent from the adhesive or a acanth gum, pectin, guar gum, cellulose, and cellulose solvent is used at least part of which is not substantially derivatives such as methyl cellulose, propyl cellulose, evaporated during the conditions of manufacture. The cellulose acetate and the like, along with other sub composition in question can then be applied to a flexible stances known for use in transdermal preparations capa backing or a combination of backings which will serve ble of forming a solid colloid that can adhere to tissue, to define the size and shape of a single dosage of the used alone or in combination with other suitable carri 5,446,070 13 14 ers. A particularly preferred carrier is a bioadhesive for In general, the composition can have the following application to the dermis, preferably the mucosa. types and amounts of ingredients: The adhesive can be modified so as to adhere to the skin or mucosal tissue, depending on the intended appli Typical Preferred Optimum cation site. As stated above, preferred adhesives for Range Range Range application to the skin are bioadhesives. (% (% (% The term “adhesive' as used herein means a sub Ingredient by weight) by weight) by weight) stance, inorganic or organic, natural or synthetic, that is Finite Form capable of surface attachment to the intended applica Adhesive 15 to 60 20 to 50 20 to 35 tion site. 10 Solvent (with plast.) 2 to 75 5 to 70 20 to 40 The term "bioadhesive' as used herein means an Anesthetic agent 1 to 50 5 to 40 10 to 30 (single ingredient) adhesive which attaches and preferably strongly at Anesthetic agent 1 to 50 5 to 40 10 to 30 taches to a live or freshly killed biological surface such (multiple ingredient) as skin or mucosal tissue upon hydration. Indeed, to Anesthetic base .7 to 50 5 to 40 7 to 20 qualify as a bioadhesive, a substance must be capable of 15 Anesthetic salt .3 to 25 2 to 30 3 to 20 maintaining adhesion in moist or wet in in vivo or in Non-finite Form Solvent 2 to 90 5 to 70 20 to 40 vitro environments. The final finite composition of the Anesthetic agent to 50 5 to 40 10 to 30 present invention is "self-adhesive' in that it attaches to (single ingredient) the site of interest without the need to reinforce its Anesthetic agent to 50 5 to 40 10 to 30 attachment by way of another adhesive which is applied 20 (multiple ingredient) to a backing. Anesthetic base .7 to 50 5 to 40 7 to 20 The strength of adherence can be measured by stan Anesthetic salt 3 to 25 2 to 30 3 to 20 dard tests for measuring the force, e.g. in dynes per square centimeter, as disclosed in U.S. Pat. No. In one embodiment, the flexible, finite, bioadhesive 4,615,697. Suitable bioadhesives include those prepared 25 composition for topical application comprises: from optionally partially esterified polyacrylic acid a therapeutically effective amount of at least one polymers, including but not limited to, polyacrylic acid pharmaceutically active agent which is in solid polymers lightly crosslinked with a polyalkenyl poly form at ambient temperatures and pressures; ether such as those commercially available from B. F. a pharmaceutically acceptable solvent for the phar Goodrich, Cincinnati, Ohio, under the trademarks Car 30 maceutically active agent, in an amount from about bopol 934, 934P, 940 and 941. 5 to about 70 weight percent based on the weight of Other suitable bioadhesives include natural or syn the whole composition, said solvent including thetic polysaccharides. The term "polysaccharide' as about 5 to about 50 weight percent of a plasticizer used herein means a carbohydrate decomposable by for the bioadhesive; hydrolysis into two or more molecules of monosaccha 35 in admixture with the pharmaceutically active agent rides or their derivatives. Suitable polysaccharides in in the solvent, a pharmacetuically acceptable poly clude cellulose derivatives such as methylcellulose, saccharide bioadhesive in an amount from about 20 cellulose acetate, carboxymethylcellulose, hydroxyeth to about 50 weight percent based on the weight of ylcellulose and the like. Other suitable bioadhesives are the whole composition; wherein the composition is pectin, a mixture of sulfated sucrose and aluminum substantially water insoluble and self-adhesive; and hydroxide, hydrophilic polysaccharide gums such as wherein the pharmaceutically active agent is pres natural plant exudates, including karaya gum, ghatti ent in non-crystallized from in the composition. gum, tragacanth gum, xanthan gum,jarayagun and the In another embodiment, the invention relates to a like, as well as seed gums such as guar gum, locust bean composition and method of administering: gum, psillium seed gum and the like. The term non 45 (a) a therapeutically effective amount of a first local finite carrier refers to any liquid or semi liquid known anesthetic agent in base form; for or suitable for use in pharmaceutical preparations as (b) a therapeutically effective amount of a different, will be apparent to one skilled in the art. second local anesthetic agent in non-salicylate In addition to the above ingredients, there may also acid-addition salt form; and be incorporated other additives selected from among 50 (c) in an admixture with the anesthetic agents, a the various pharmaceutically acceptable additives avail pharmaceutically acceptable carrier; able to those skilled in the art. These additives include wherein the anesthetic agents comprise about 1 to about binders, stabilizers, preservatives, flavorings and pig 50% by weight of the total composition. ments. In a preferred finite form embodiment, the com The invention further relates to a composition and positions of the present invention also contain a binder 55 method of administering: such as lecithin which "binds' the other ingredients, (a) a therapeutically effective amount of a first local thereby enhancing the uniform consistency of the final anesthetic agent in base form; composition. (b) a therapeutically effective amount of a different, The composition is administered in appropriate sizes, second local anesthetic agent in acid-addition salt typically having a surface area of from about 0.1 to form; and about 200 cm2 or conveniently 0.2 to 100 cm2. The (c) in an admixture with the anesthetic agents, a phar anesthetic agent is loaded into the composition in as maceutically acceptable carrier which is substan high a concentration as necessary to effect therapy, e.g., tially free of water; in a range from about 0.1 mg/cm2 to about 50 or more wherein the anesthetic agents comprise about 1 to about mg/cm2 or 0.1 mg/ml to about 500 or more mg/ml 65 50% by weight of the total composition and wherein when a non-finite carrier such as an ointment, gel, lo said composition is substantially free of water. tion, cream, paste, plaster, emulsion, or spray-solution is The term "administering” is intended to mean any used. mode of application to a tissue which results in the 5,446,070 15 16 physical contact of the composition with an anatomical site in need of anesthesia. The term “subject' is in -continued tended to include all warm-blooded mammals, prefera Ingredient % (w/w) bly humans. Solvent (isocetyl alcohol) 7 In one method of the invention wherein a bioadhesvie Solvent (glycerin) 26 Anesthetic agent base (lidocaine base) 26 carrier is employed, the pharmaceutically acceptable Anesthetic agent salt (tetracaine hydrochloride) 13 solvent is in a preferred amount from about 20 to about 53 weight percent of which the plasticizer represents about 10 to 30 weight percent based on the weight of The procedure of Example 1 is used with appropriate the whole composition and the bioadhesive carrier is in O substitution of ingredients to prepare this formulation. an amount from about 20 to about 34 weight percent EXAMPLE 4 based on the weight of the whole composition. More preferably, the bioadhesive composition of this method is comprised of 20 to 34 weight percent of karaya gum, Ingredient % (w/w) about 20 to 53 weight percent of at least one glycol, and 15 Adhesive (karaya gum) 27 Solvent (propylene glycol) 29 about 10 to 25 weight percent of lidocaine base and is Solvent (glycerin) 4 further comprised of a binder in an amount sufficient to Anesthetic agent base (lidocaine base) 28 bind the other ingredients. Anesthetic agent salt (dyclonine hydrochloride) 2 The following examples will further describe the instant invention, and are used for the purposes of illus 20 tration only, and should not be considered as limiting in The procedure of Example 1 is used with appropriate any way the invention being disclosed herein. Percent substitution of ingredients to prepare this formulation. (%) as used in these examples refer to percentage of the EXAMPLE 5 liquid formulation on a weight to weight basis and tem peratures are given in degrees celsius (C.). 25 Ingredient % (w/w) EXAMPLE 1. Adhesive (karaya gun) 26 Binder (lecithin) O Solvent (propylene glycol) 7 Ingredient % (w/w) 30 Solvent (butylene glycol) 7 Adhesive (karaya gum) 21 Solvent (glycerin) O Binder (lecithin) 11 Anesthetic agent base (lidocaine base) 20 Solvent (propylene glycol) 7 Anesthetic agent salt (dyclonine hydrochloride) O Solvent (glycerin) 19 Anesthetic agent base (lidocaine base) 28 Anesthetic agent salt (prilocaine hydrochloride) 4. The procedure of Example 1 is used with appropriate 35 substitution of ingredients to prepare this formulation, The final product is manufactured by first blending EXAMPLE 6 the lidocaine base, prilocaine hydrochloride, propylene glycol, lecithin and glycerin at about 70 to 90° C. until all of the drug is dissolved. The solution is then cooled Ingredient % (w/w) to 20 to 35° C. prior to adding the karayagum. Once Adhesive (karaya gun) 27 Binder (lecithin) 12 the karaya gun is added, the final composition is ap Solvent (propylene glycol) 8 plied to a suitable backing material such as a non Solvent (glycerin) 13 woven, polyester film (for example, the film sold under Anesthetic agent base (lidocaine base) 27 the trademark Sontara 8100, manufactured by DuPont 45 Anesthetic agent salt (bupivacaine hydrochloride) 13 de Nemours, E. I. and Co., Wilmington, Del.) and warmed to about 100° C. to accelerate the formation of The procedure of Example 1 is used with appropriate the gel into its final, finite form. substitution of ingredients to prepare this formulation. EXAMPLE 2 SO EXAMPLE 7

Ingredient % (w/w) Ingredient % (w/w) Adhesive (karaya gum) 30 Adhesive (karaya gum) 27 Solvent (glycerin) 30 Binder (lecithin) 12 Solvent (propylene glycol) 39 55 Solvent (propylene glycol) 8 Anesthetic agent base (lidocaine base) O.7 Solvent (glycerin) 13 Anesthetic agent salt (prilocaine hydrochloride) 0.3 Anesthetic agent base (lidocaine base) 3 Anesthetic agent salt (bupivacaine hydrochloride) 27 The procedure set forth in Example 1 is used with appropriate substitutions of quantities to prepare this 60 The procedure of Example 1 is used with appropriate formulation. substitution of ingredients to prepare this formulation. EXAMPLE 3 EXAMPLE 8

Ingredient % (w/w) 65 Ingredient % (w/w) Adhesive (karaya gum) 2 Adhesive (karaya gun) 21 Binder (lecithin) 4. Binder (lecithin) Solvent (propylene glycol) 3 Solvent (propylene glycol) 7 5,446,070 17 18 -continued Once the karaya gun is added, the final composition is Ingredient - - applied to a suitable backing material such as a non Solvent (glycerin)- - - 19 - - woven polyester film (for example the film sold under Anesthetic agent base (lidocaine base) 28 the trademark Sontata 800 manufactured by DuPont Anesthetic agent salt (mepivacaine hydrochloride) 14 de Nemours, E. I. and Co., Wilmington, Dell) and warmed at about 708 to 130 C. to accelerate the for The procedure of Example 1 is used with appropriate mation of the gel into its final solid form. This gel can be substitution of ingredients to prepare this formulation, directly applied to the oral mucosa or overlaid with a 10 skin contact adhesive for skin adhesion. EXAMPLE 9 EXAMPLE 13 Ingredient % (w/w) Adhesive (Carbopol 934P, a polycarboxylic 20 Ingredient % (w/w) acid sold by B. F. Goodrich Chemical Company) 15 Solvent (propylene glycol) 15 Bicy gum) : Solvent (glycerin) 20 inder (lecithin) Anesthetic agent base (lidocaine base) 30 Solvent (propylene glycol) 7 Anesthetic agent salt (bupivacaine hydrochloride) 15 Solvent (dipropylene glycol) 2 ammum Solvent (glycerin) 33 The procedure of Example 1 is used with appropriate 20 Anesthetic agent base (lidocaine base) O substitutiontitution of ingredientsi ients tot prepare this formulationf lation. The procedure of Example 12 is used with appropri EXAMPLE 10 ate substitution of ingredients to prepare this formula tion. Ingredient 25 EXAMPLE 14 Adhesive (karaya gun) 24 Solvent (propylene glycol) 3 Adhesive (glycerin) 4. Ingredient % (w/w) Solvent (isocetyl alcohol) 7 Binder (lecithin) 4. 30 Bioadhesive (karaya gum) 35 Anesthetic agent base (lidocaine base) 32 Binder (lecithin) 5 Anesthetic agent salt (tetracaine hydrochloride) 16 Solvent (propylene glycol) 7 wom Solvent (dipropylene glycol) 12 Solvent (glycerin) 36 The above formulation is prepared by a procedure Anesthetic agent base (lidocaine base) 5 which is analogous to that set forth in Example 1. 35 The addition of up to 2% by weight water in this formulation did not result in precipitation of the anes- The procedure of Example 12 is used with appropri thetic agent(s) prior to addition of the karayagum. The ate substitution of ingredients to prepare this formula addition of 3% to 10% water results in increased precip- or itation, which at 10% water results in a crystalline mass. 4 EXAMPLE 15 EXAMPLE 11 Ingredient % (w/w) Ingredient % (w/w) Bioadhesive (karaya gum) 30 Adhesive (tragacanth gum) 24 45 Binder (lecithin) 9 Adhesive (pectin) 5 Solvent (propylene glycol) 6 Solvent (propylene glycol) 12 Solvent (dipropylene glycol) 15 Solvent (glycerin) 12 Solvent (glycerin) 15 Anesthetic agent base (mepivacaine base) 35 Anesthetic agent base (lidocaine base) 25 Anesthetic agent salt (lidocaine hydrochloride) 12 50 The procedure of Example 12 is used with appropri The above formation is prepared by a procedure ate substitution of ingredients to prepare this formula analogous to that of Example 1. tion. EXAMPLE 12 EXAMPLE 16 55 Ingredient % (w/w) Ingredient r % (w/w) Bioadhesive (karaya gum) 33 Binder (lecithin) 9 Bioadhesive (karaya gun) 20 Solvent (propylene glycol) 6 Binder (lecithin) 9 Solvent (dipropylene glycol) 15 60 Solvent (propylene glycol) 6 Solvent (glycerin) Solvent (dipropylene glycol) 10 Anesthetic agent base (lidocaine base) 20 Solvent (glycerin) 10 Solvent (benzyl alcohol) 5 The final product is manufactured by first blending Anesthetic agent base (lidocaine base) 40 the lidocaine base, lecithin, propylene glycol, dipropyl- 65 ene glycol and glycerine at about 70 to 90° C. until all The procedure of Example 12 is used with appropri of the drug is dissolved. The solution is then chilled to ate substitution of ingredients to prepare this formula about 20 to 40 C. prior to adding the karaya gum. tion. 5,446,070 19 2O EXAMPLE 7 -continued Ingredient % (w/w) Solvent (glycerin) 17 Ingredient % (w/w) Anesthetic agent base (lidocaine base) 20 Bioadhesive (karaya gun) 25 5 Binder (lecithin) 8 solvent (isocetyl alcohol) 5 The procedure of Example 12 is used with the sol Solvent (propylene glycol) 2 vents and anesthetic agent base added in the initial step Solvent (glycerin) O Anesthetic agent base (prilocaine base) 40 1O followed later by the adhesives addition. EXAMPLE 22 The procedure of Example 12 is used with appropri ate substitution of ingredients to prepare this formula Ingredient % (w/w) tion. 15 Bioadhesive (cellulose acetate) 27 EXAMPLE 18 Solvent (dipropylene glycol) 43 Anesthetic agent base (prilocaine base) 20 Ingredient % (w/w) This formulation is prepared according to the proce Bioadhesive (karaya gum) 25 20 dure which is analogous to the procedure set forth in Binder (lecithin) 4 Example 1. Solvent (propylene glycol) 6 Solvent (benzyl alcohol) 10 Solvent (dipropylene glycol) 10 EXAMPLE 23 Solvent (glycerin) 5 Anesthetic agent base (tetracaine base) 40 25 Ingredient % (w/w) Bioadhesive (xanthan gum) 27 The procedure of Example 12 is used with appropri Bioadhesive (pectin) 6 Binder (lecithin) 9 ate substitution of ingredients to prepare this formula Solvent (propylene glycol) 6 tion. Solvent (dipropylene glycol) 15 EXAMPLE 19 30 Solvent (glycerin) 17 Anesthetic agent base (lidocaine base) 20 Ingredient % (w/w) The procedure of Example 12 is followed with the Bioadhesive (karaya gum) 30 appropriate substitution of ingredients. Binder (lecithin) 8 35 Solvent (propylene glycol) 12 EXAMPLE 24 Solvent (dipropylene glycol) 25 Solvent (benzyl alcohol) 5 Solvent (glycerin) 10 Ingredient % (w/w) Anesthetic agent base (dibucaine base) O 40 Drug (miconazole nitrate) 2 Solvent (Propylene glycol) 67 The procedure of Example 12 is used with appropri Thickener (hydroxymethylcellulose) Adhesive (karaya gum) 30 ate substitution of ingredients to prepare this formula Anesthetic agent base (lidocaine base) 2O tion. EXAMPLE 2.0 45 This formulation is prepared by dispersing the hy droxymethylcellulose into propylene glycol. Once the hydroxymethylcellulose is dispersed, the drug is added Ingredient % (w/w) at a temperature between 50 and 80° C. and mixed until Bioadhesive (karaya gum) 28 Bioadhesive (Carbopol 934) 2 50 dissolved. The sample is then cooled to approximately Solvent (propylene glycol) 6 20 to 35 C. prior to adding the karayagum. Once the Solvent (dipropylene glycol) 15 karaya gum is added, the formulation is applied to a Solvent (glycerin) 5 sheet of backing material, then the individual dosage Binder (lecithin) 9 Anesthetic agent base (lidocaine base) 25 forms are cut to the desirable shape to contain the de 55 sired amount of drug. The procedure of Example 12 is used with appropri EXAMPLE 2.5 ate substitution of ingredients to prepare this formula tion. The only difference is that the Carbopol 934 is Ingredient % (w/w) added to the original blend prior to heating it. 60 Binder (lecithin) 4 EXAMPLE 21 Solvent (propylene glycol) 26 Solvent (isocetyl alcohol) 7 Solvent (glycerin) 14 Anesthetic agent base (lidocaine base) 32 Ingredient % (w/w) Anesthetic agent salt (tetracaine HCl) 6 Bioadhesive (tragacanth gum) 27 65 Thickener (hydroxypropyl cellulose Klucel, HF) 1 Bioadhesive (pectin) 6 Binder (lecithin) 9 Solvent (propylene glycol) 6 The Klucel, HF is dispersed in propylene glycol in Solvent (dipropylene glycol) 5 order to make a 3% dispersion. In a separate container, 5,446,070 21 22 the remaining propylene glycol, isocetyl alcohol, lido EXAMPLE 30 caine base, tetracaine HCl, and lecithin are blended at 70°-90° C. This mixture is then allowed to cool prior to Hydrocortisone blending with the 3% Klucel solution in propylene glycol. Upon mixing the two parts, an ointment results. Formulation % (w/w) EXAMPLE 26 Ingredient 2 3 4 5 Corticosteroid (hydrocortisone) 1 0.5 0.5 2.0 Solvent (dipropylene glycol) 15 15 15.5 5 5 Ingredient % (w/w) 10 Solvent (glycerin) 42 42 42 40 34 Binder (lecithin) 28 Bioadhesive (karaya gum) 42 26 26 48 34 Solvent (propylene glycol) 19 Bioadhesive (xantham gum) - 16 16 O- - Solvent (glycerin) 47 Binder (lecithin) - - - -- 10 Anesthetic agent base (lidocaine base) 4 Solvent (propylene glycol) - - m 5 Anesthetic agent salt (prilocaine HCl) 2 15 EXAMPLE 31 The lidocaine base, pridocaine HCl, glycerin, propy lene glycol and lecithin are blended at 70°-90° C. until Formulation the drug is dissolved. The mixture is then allowed to - WW cool down to room temperature under gentle mixing Ingredient 1 2 3 4 resulting in an ointment. Coricosteroid (fluocinonide) 0.05 0.05 0.05 0.1 EXAMPLE 27 Solvent (propylene glycol) 33.28. 18.28 20.00 32.3 Solvent (dipropylene glycol) 0.0 15.00 13.28 0.0 25 Solvent (glycerin) 33.33 33.33 33.33 33.3 Bioadhesive (karaya gun) 33.34 33.34. 28.34 33.4 Ingredient % (w/w) Bioadhesive (guar gum) 0.0 0.0 5.00 0.0 Binder (surfactin) 2 Thickener (Carbopol 934P) 2 Solvent (water) 85 EXAMPLE 32 Solvent (propylene glycol) 5 30 Anesthetic agent base (lidocaine base) . 4 Anesthetic agent salt (prilocaine HCl) 2 % (w/w) Adrenocorticosteroid 0.05 (betamethasone dipropionate) Preparation is similar to Example 25 with water and 35 Solvent (propylene glycol) 33.28 Carbopol 934P being used instead of propylene glycol Solvent (glycerin) 33.33 and Klucel, respectively. A dispersion of 2 grams Car Bioadhesive (karaya gum) 33.34 bopol 934 in 85 grams of water is prepared. A cream results form the above composition. 40 EXAMPLE 33 EXAMPLE 28 - % (W)- Ingredient % (w/w) 1. 2 3 4. Antifungal (clotrimazole) 1.0 1.0 2.0 1.0 Binder (lecithin) 7 45 Adrenocorticosteroid 0.05 0.05 0.05 0.05 Solvent (propylene glycol) 44 (betamethasone dipropionate) Solvent (glycerin) 7 Solvent (dipropylene glycol) 15.00 15.00 15.00 10.00 Thickener (Klucel, HF) 2 Solvent (propylene glycol) 15.00 15.00 15.00 15.00 Anesthetic agent base (lidocaine base) 27 Solvent (glycerin) 30.95 30.95 30.95 38.00 Anesthetic agent salt (dyclonine HCl) 13 Bioadhesive (karaya gum) 38.0 0.0 0.0 35.95 50 Bioadhesive (xanthan gum) 0.0 35.00 32.00 0.0 Bioadhesive (pectin) 0.0 3.00 6.00 0.0 This ointment is prepared as in Example 25 with the appropriate substitution of ingredients to prepare this formulation. EXAMPLE 34 EXAMPLE 29 55 Potassium Nitrate % (w/w) Corticosteroid (mometasome furoate) 0.1 Solvent (propylene glycol) 33.3 Solvent (glycerin) 33.3 Formulation 60 Bioadhesive 33.3 % (w/w) Ingredient 1. 2 3 4. Tooth Sensitivity Treatment Agent 5 10 5 5 EXAMPLE 35 (potassium nitrate) Solvent (glycerin) 42 37 38 40 65 Solvent (dipropylene glycol) 11 11 15 15 % (w/w) Bioadhesive (karaya gum) 42 42 42 40 2 3 Keratolytic Agent (salicylic acid) 15 20 30 5,446,070 23 24 -continued Sulfinalol, Talinolol, Tertatolol, Timolol, Toliprolol, Xibenolol % (w/w) ALCOHOL DETERRENT such as Calcium Cyana 1 2 3 mide Citrated, Disulfiram, Nitrefazole Solvent (glycerin) 20 20 15 5 ALDOSE REDUCTASE INHIBITOR such as Epal Solvent (propylene glycol) 15 15 15 Solvent (dipropylene glycol) 10 15 15 restat, Ponal restat, Sorbinil, Tolrestat Bioadhesive (karaya gum) 40 30 25 ANABOLIC such as Androisoxazole, Androstenediol, Bolandiol, Bolasterone, Clostebol, Ethylestrenol, Formyldienolone, 4-Hydroxy-19-nortestosterone, EXAMPLE 36 10 Methandriol, Methenolone, Methyltrienolone, Nan drolone, Nandrolone Decanoate, Nandrolone p-Hex yloxyphenyl-propionate, Nandrolone Phenpropion ate, Norbolethone, Oxymesterone, Quinbolone, Sten bolone, Trenbolone ANALGESIC (DENTAL) such Antineoplastic Agent 2 5 10 15 20 as Chlorobutanol, Clove, Eugenol, Potassium Ni (5-Aminolevulinic Acid) trate, Potassium Oxalate Solvent (dipropylene glycol) 10 10 15 15 15 ANALGESIC (NARCOTIC) such as Alfentanil, Al Solvent (oceic acid) 10 10 10 10 10 Solvent (glycerin) 30 30 20 20 30 lylprodine, Alphaprodine, Anileridine, Benzylmor Solvent (isocetyl alcohol) m 10 10 --- phine, Bezitramide, Buprenorphine, Butorphanol, Bioadhesive (karaya gum) 30 30 20 20 30 20 Clonitazene, Codeines, Desomorphine, Dextromora Bioadhesive (xantham gum) m - 10 10 - mide, Dezocine, Diampromide, Dihydrocodeine, Binder (lecithin) 18 5 10 10 - Dihydrocodeinone Enol Acetate, Dihydromorphine, Dimenoxadol, Dimepheptanol, Dimethylthiambu The foregoing examples are illustrative embodiments tene, Dioxaphetyl Butyrate, Dipipanone, Eptazocine, of the invention and are merely exemplary. A person 25 Ethoheptazine, Ethylmethiythiambutene, Ethylmor skilled in the art may make variations and modification phine, Etonitazene, Fentanyl, Hydrocodone, Hydro without departing from the spirit and scope of the in morphone, Hydroxypethidine, Isomethadone, vention. All such modifications and variations are in Ketobemidone, Levorphanol, Lofentanil, Meperi tended to be included within the scope of the invention dine, Meptazinol, Metazocine, Methadone, Metopon, as described in this specification and the appended 30 Morphine, Morphine Derivatives, Myrophine, Nal claims. buphine, Narceline, Nicomorphine, Norlevorphanol, Indeed, the present invention is intended to encom Normethadone, Normorphine, Norpipanone, Opium, pass and be suitable for use by substituting any of the Oxycodone, Oxymorphone, Papaveretum, Pentazo following drugs for the anesthetic agent as the pharma cine, Phenadoxone, Phenazocine, Pheoperidine, Pi cologically active agent in the composition and meth 35 minodine, Piritramide, Proheptazine, Promedol, ods for use of the same: Properidine, Propiram, Propoxyphene, Sufentanil, Tilidine a-ADRENERGIC AGONIST such as Adrafinil, ANALGESIC (NON-NARCOTIC) such as Acetami Adrenolone, Amidephrine, Apraclonidine, Budrala nophen, Acetaminosalol, Acetanilide, Acetylsalicy zine, Clonidine, Cyclopentamine, Detonidine, lates, Acetylsalicylsalicylic Acid, Alclofenac, Al Dimetofrine, Dipivefrin, Ephedrine, Epinephrine, minoprofen, Aloxiprin, Aluminum Bis(acetyl Fenoxazoline, Guanabenz, Guanfacine, Hydroxyam salicylate), Aminochlorthenoxazin, 2-Amino-4-pico phetamine, Ibopamine, Indanazoline, Isometheptene, line, Aminopropylon, Aminopyrine, Antipyrine, An Mephentermine, Metaraminol, Methoxamine, Meth tipyrine Salicylate, Antrafenine, Apazone, Aspirin, ylhexaneamine, Metizolene, Midodrine, Naphazoline, 45 Benorylate, Benoxaprofen, Benzpiperylon, Benzyda Norepinephrine, Norfenefrine, Octodrine, Octopa mine, p-Bromoacetanilide, 5-Bromosalicylic Acid mine, Oxymetazoline, Phenylephrine, Phenylpropa Acetate, Bufexamac, Bucetin, Bumadizon, Butacetin, nolamine, Phenylpropylmethylamine, Pholedrine, Carbamazepine, Carbetidine, Carbiphene, Carsalam, Propylhexedrine, Pseudoephedrine, Rilmenidine, Chloralantipyrine, Chlorthenoxazin (e), Choline Sali Synephrine, Tetrahydrozoline, Tiamenidine, 50 cylate, Cinchophen, Ciramadol, Clometacin, Cro Tramazoline, Tuaminoheptane, Tymazoline, Tyra propamide, Crotethamide, Dexoxadrol, Difenami mine, Xylometazoline zole, Diflunisal, Dipyrocetyl, Dipyrone, Emorfa A-ADRENERGIC AGONIST such as Formoterol, zone, Enfenamic Acid, Epirizole, Etersalate, Ethen Methoxyphenamine, Ritodrine, Terbuterol zamide, Ethoxazene, Etodolac, Felbinac, Feno a-ADRENERGIC BLOCKER such as Dapiprazole, 55 profen, Floctafenine, Flufenamic Acid, Fluoresone, Doxazosin, Ergoloid Mesylates, Fenspiride, Flupirtine, Fluproguazone, Flurbiprofen, Fosfosal, Prazosin, Terazosin, Tolazoline, Trimazosin, Yohim Gentisic Acid, Glafenine, Ibufenac, Imidazole Sali bine cylate, Indomethacin, Indoprofen, Isofezolac, Isola Ag-ADRENERGIC BLOCKER such as Acebutolol, dol, Isonixin, Ketoprofen, Ketorolac, p-Lactophene Amosulalol, Arotinolol, Atenolol, Befunolol, Betax tide, Lefetamine, Loxoprofen, Lysine Acetylsalicy olol, Bevantolol, Bisoprolol, Bopindolol, Bucumolol, late, Methotrimepraz ine, Metofoline, Miroprofen, Bufetolol, Bufuralol, Bunitrolol, Bupranolol, Morazone, Morpholine Salicylate, Naproxen, Nefo Butofilolol, Carazolol, Carteolol, Carvedilol, Celi pam, Nifenazone, 5' Nitro-2' propoxyacetanilide, prolol, Cetamolol, Cloranolol, Dilevalol, Epanolol, Parsalmide, Perisoxal, Phenacetin, Phenazopyridine, Esmolol, Indenolol, Labetalol, Levobunolol, Mepin 65 Phenocoll, Phenopyrazone, Phenyl Acetylsalicylate, dolol, Metipranolol, Metoprolol, Moprolol, Nadolol, Phenyl Salicylate, Phenyramidol, Pipebuzone, Pi Nadoxolol, Nifemalol, Nipradillol, Oxprenolol, pen perylone, Prodilidine, Propacetamol, Propyphena butolol, Pindolol, Practolol, Propranolol, Sotalol, zone, Proxazole, Quinine Salicylate, Ramifenazone, 5,446,070 25 26 Rimazolium Metilsulfate, Salacetamide, Salicin, Sali Hycanthone, Lucanthone, Niridazole, Oxamniquine, cylamide, Salicylamide Praziquantel, Stibocaptate, Stibophen O-Acetic Acid, Salicylic Acid, Salicylates and Deriva ANTHELMINTIC (TREMATODES) such as Anthi tives, Salicylsulfuric Acid, Salsalte, Salverine, Sime olimine tride, Sulfamipyrine, Suprofen, Talniflumate, Tenox 5 ANTIACNE such as Algestone Acetophenide, Azelaic icam, Terofenamate, Tetradrine, Tinoridine, Tolfe Acid, Benzoyl Peroxide, Dichloroacetic Acid, Mo namic Acid, Tolpronine, Tramadol, Viminol, Xenbu tretinide, Retinoic Acid, Tetroquinone cin, Zomepirac ANTIALLERGIC such as Amlexanox, Astemizole, ANDROGEN such as Boldenone, Fluoxymesterone, Azelastine, Cromolyn, Fenpiprane, Histamines, Mestanolone, Mesterolone, Methandrostenolone, 10 Ketotifen, Nedocronil, Oxatomide, Pentigetide, Poi 17-Methyltestosterone, 17a-Methyl-testosterone 3- son Ivy Extract, Poison Oak Extract, Poison Sumac Cyclopentyl Enol Ether, Norethandrolone, Norme- Extract, Repirinast, Tiaramide, Tranilast, Traxanox, thandrone, Oxandrolone, Oxymetholone, Prasterone, Urushiol Stanlolone, Stanozolol, Testosterone, Testosterone ANTIAMEBIC such 2S Arshinol, Bialamicol, Carbar 17-Chloral Hemiacetal, Testosterone 176-Cypionate, son, Cephaeline, Chlorbetamide, Chlorphenoxa Testosterone Enanthate, Testosterone Nicotinate, mide, Dehydroemetine, Dibromopropamidine, Testosterone Pheynylacetate, Testosterone Propio- Piloxanide, Dephetarsone, Emeline, Fumagillin, nate, Tiomesterone Glaucarubin, Glycobiarsol, 8-Hydroxy-7-iodo-5- ANESTHETIC such as Acetamidoeugenol, Alfado- Sign Acid, pREE lone Acetate, Alfaxalone, Amucaine, Amolanone, 20 SE El FEN E. Amylocaine, Benoximate, Betoxycaine, Biphenamine, mide S.a.i. GEde E.clozan 9 Thiocar Bupivacaine, Burethamine, Butacaine, Butaben, bami,ine Thiocarbarisone Tinidazole s -Chloroprocaine,E. Buthalital, Cocaethylene, Butoxycaine, Cocaine, Cyclo1Calne, ANTIANDROGEN such as Bifluranol, Cyoctol, Cy thvcaine, Dibucai Dimethisoquin, Dime- 25 proterone, Oxendolone E. yc 5. d lonine, E oqu dine, E ANTIANGINAL such as Amlodipine, Amyl Nitrite, nine,EE, thyl Amino enzoate,EE y unioriae,E. E. E.Etiao- CinepazetLimaprost, Maleate, Molsidomine, Imolamine, Nitroxyalklamide Isosorbide Dinitrate, Deriva caine, Etoxadrol, 3-Eucaine, Euprocin, Fenalcomine, tives Fomocaine, Hexobarbital, Hexylcaine, Hydroxydi 30 ANTIARRHYTHMIC such as Acecaine, Adenosine, one, Hydroxyprocaine, Hydroxytetracaine, Isobutyl Ajmaline, Alprenolol, s-Aminoalkyl-s-Arylsulfoxi p-Aminobenzoate, Kentamine, Leucinocaine Mesyl- mines, Amoproxan, Aprindine, Bretylium Tosylate, ate, Levoxadrol, Lidocaine, Mepivacaine, Mepryl- Bubumolol, Bunaftine, Butidrine, Butobendine, caine, Metabutoxycaine, Methohexital, Methyl Chlo- Capobenic Acid, Cifenline, Disopyramide, Encai ride, Midazolam, Myrtecaine, Naepaine, Octacaine, 35 nide, Flecanide, Hydroquinidine, Indecainide, Ipra Orthocaine, Oxethazaine, Parethoxycaine, Phena- tropium, Lorajmine, Lorcainide, Meobentine, Mex caine, Phencyclidine, Phenol, Piperocaine, Pirido- illetine, Moricizine, Pirmenol, Prajmaline, Procaina caine, Polidocanol, Pramoxine, Prilocaine, Procaine, mide, Pronethalol, Propafenone, Pyrinoline, Quini Propanidid, Propanocaine, Proparacaine, Propipo- dine, Quinidine Sulfate, Quinidine, Tocainide, Viqui caine, Propofol, Propoxycaine, Pseudococaine, Pyr- 40 dil rocaine, Risocaine, Salicy Alcohol, Tetracaine, ANTIARTERIOSCLEROTIC such as Pyridinol car Thialbarbital, Thimylal, Thiobutabarbital, Thiopen- bamate tal, Tolycaine, Trimecaine, Zolamine ANTIARTHRITIC/ANTIRHEUMATIC such as ANOREXIC such as Aminorex, Amphecloral, Benza- Allocupreide Sodium, Auranofin, Aurothioglucose, phetamine, Chlorphentermine, Clobenzorex, Clofo. 45 Aurothioglycanide, Azathioprine, Di-tert-Butyl TeX, Cyclexedrine, Diphemethoxidine, Fenbutrazate, phenols, Calcium3-Aurothio-2-propanol-1-sulfonate, Fenfluramine, Fenproporex, Furfurylmethylam- Clobuzarit, Cuproxoline, Diacerein, Glucosamine, phetamine, Levophacetoperate, Mefenorex, Metam- Gold Sodium. Thiomalate, Gold Sodium. Thiosulfate, feproamone, Norpseudoephedrine, Phenpentermine, Hydroxychloroquine, Kebuzone, Lobenzarit, Melit Picilorex ANTHELMINTIC (CESTODES) such as so tin, Myoral, Penicillamine Arecoline, Aspidin, Aspidinol, Dichlorophen(e), Em ANTIBACTERIAL (ANTIBIOTIC) belin, Kosin, Napthalene, Niclosamide, Pellertierine, Aminoglycosides such as Amikacin, Apramycin, Ar Pellertierine Tannate, Quinacrine bekacin, Bambermycins, Butirosin, Dibekacin, Dihdros ANTHELMINTIC (NEMATODES) such as Alan treptomycin, Fortimicin(s), Fradiomycin, Gentamicin, tolactone, Amoscanate, Ascaridole, Bephenium, 55 Ispamicin, Kanamycin, Micronomicin, Neomycin, Neo Bitoscanate, Carbon Tetrachloride, Carvacrol, Cy mycin Undecylienate, Netilmicin, Paromomycin, Ribos clobendazole, Diethylcarbamazine, Diphenane, Di tamycin, Sisomicin, Spectinomycin, Streptomycin, thiazanine Iodide, Dymanthine, Gentian Violet, 4 Streptonicozid, Tobramycin Hexylresorcinol, Kainic Acid, Mebendazole, 2-Nap Amphenicols such as Azidamfenicol, Chlorampheni thol, Oxantel, Piperazines, Pyrantel, Pyrvinium 60 col, Chloramphenicol Palmirate, Chloramphenicol Pan Pamoate, a-Santonin, Stilbazium Iodide, Tetrachlo tothenate, Florfenicol, Thiamphenicol roethylene, Thiabendazole, Thymol, Thymyl N Ansamycins such as Rifamide, Rifampin, Rifamycin, soamylcarbamate, Triclofenol Piperazine, Urea Stib- Rifaximin amine R-Lactams ANTHELMINTIC (ONCHOCERCA) such as Iver- 65 Carbapenems such as Imipenem mectin Cephalosporins such as 1-Carba (dethia) Cephalospo ANTHELMINTIC (SCHISTOSOMA) such as Am rin, Cefactor, Cefadroxil, Cefamandole, Cefatri photalide, Antimony(s) and Derivatives, Becanthone, zine, Cefazedone, Cefazolin, Cefixime, Cefnmenox 5,446,070 27 28 ime, Cefodizime, Cefonicid, Cefoperazone, Cefora famoyl)sulfanilanilide, p-Nitrosulfathiazole, Noprylsul nide, Cefotaxine, Cefotiam, Cefpimizole, Cefpiri famide, Phthalylsulfacetamide, Phthalysulfathiazole, mide, Cefpodoxime Proxetil, Cefroxadine, Cefsulo Salazosulfadimidine, Succinylsulfathiazole, Sulfabenza din, Ceftazidime, Cefteram, Ceftezole, Ceftibuten, mide, Sulfacetamide, Sulfachlorpyridazine, Sulfa Ceftizoxime, Ceftriaxone, Cefuroxime, Cefuzo chrysoidine, Sulfacytine, Sulfadiazine, Sulfadicramide, nam, Cephacetrile Sodium, Cephalexin, Cephalo Sulfadimethoxine, Sulfadoxine, Sulfaethidole, Sulfa glycin, Cephaloridine, Cephalosporin, Cephalo guanidine, Sulfaguanol, Sulfalene, Sulfaloxic Acid, Sul thin, Cephapirin Sodium, Cephradine, Pivoefalexin famerazine, Sulfameter, Sulfamethazine, Sulfamethi Cephamycins such as Cefbuperazone, Cefnetazole, zole, Sulfamethomidine, Sulfamethoxazole, Sulfameth Cefninox, Cefetan, Cefoxitin 10 oxypyridazine, Sulfametrole, Sulfamidochrysoidine, Monobactams such as Aztreonan, Carumonam, Sulfamoxole, Sulfanilanide, Sulfanilamidomethanesul Tigenonam fonic Acid Triethanolamine Salt, Oxacephems such as Flomoxef, Moxolactam 4-Sulfanilamidosalicylic Acid, N-Sulfanilylsulfanila Penicillins such as Amidinocillin, Amdinocillin mide, Sulfanillylurea, N-Sulfanillyl-3,4-xylamide, Sul Pivoxil, Amoxicillin, Ampicillan, Apalcillin, As 15 fanitran, Sulfaperine, Sulfaphenazole, Sulfaproxyline, poxicillin, Azidocillan, Azlocillan, Bacampicillin, Sulfapyrazine, Sulfapyridine, Sulfasomizole, Sul Benzylpenicillinic Acid, Benzylpenicillin, Car fasymazine, Sulfathiazole, Sulfathiourea, Sulfatolamide, benicillin, Carfecilin, Carindacillin, Clometocillin, Sulfisomidine, Sullfisoxazole Cloxacillin, Cyclacillin, Dicloxacillin, Diphenicil Sulfones such as Acedapsone, Acediasulfone, Aceto lin, Epicillin, Fenbenicillin, Floxicillin, Hetacillin, 20 sulfone, Dapsone, Diathymosulfone, Glucosulfone, Lenampicillin, Metampicillin, Methicillin, Me Solasulfone, Succisulfone, Sulfanilic Acid, p-Sulfanillyl zlocillin, Nafcillin, Oxacillin, Penamecillin, Pene benzylamine, p,p'-Sulfonyldianiline-N,N' digalactoside, thamate Hydriodide, Penicillin G Benethamine, Sulfoxone, Thiazolsulfone Penicillin G Benzathine, Penicillin G Benzhydryla Others such as Clofoctol, Hexedine, Magainins, Me mine, Penicillin G Calcium, Penicillin G. Hydraba 25 thenamine, Methenamine Anhydromethylene-citrate, mine, Penicillin G Potassium, Penicillin G Pro Methenamine Hippurate, Methenamine Mandelate, Me caine, Peniciliin N, Penicillin O, Penicillin V, Peni thenamine Sulfosalicylate, Nitroxoline, Squalamine, cillin V Benzathine, Penicillin V Hydrabamine, Xibornol Penimepicycline, Phenethicillin, Piperacillin, ANTICHOLINERGIC such as Adiphenine, Alverine, Pivapicillin, Propicillin, Quinacillin, Sulbenicillin, 30 Ambutonomium, Aminopentamide, Amixetrine, Am Talampicillin, Tenocillin, Ticarcillin protropine Phosphate, Anisotropine Methylbromide, Lincosamides such as Clindamycin, Lincomycin Apoatropine, Atropine, Atropine N-Oxide, Benacty Macrollides such as Azithromycin, Carbomycin, zine, Benapryzine, Benzetimide, Benzilonium, Benz Clarithromycin, Erythromycin(s) and Derivatives, tropine Mesylate, Bevonium Methyl Sulfate, Biperi Josamycin, Leucomycins, Midecanycins, Miokamycin, 35 den, Butropium, Oleandomycin, Primycin, Rokitamycin, Rosaramicin, N-Butylscopolammonium Bromide, Buzepide, Roxithromycin, Spiramycin, Troleandomycin Camylofine, Caramiphen, Chlorbenzoxamine, Chlor Polypeptides such as Amphomycin, Bacitracin, Cap phenoxamine, Cimetropium, Clidinium, Cyclodrine, reomycin, Colistin, Enduracidin, Enviomycin, Fusafun Cyclonium, Cyclopentolate, Cycrimine, Deptropine, gine, Gramicidin(s), Gramicidin S, Mikamycin, Poly Dexetimide, Dibutoline Sulfate, Dicyclomine, Dietha myxin, Polymyxin B-Methanesulfonic Acid, Pristina zine, Difemerine, Dihexyverine, Diphemanil Methyl mycin, Ristocetin, Teicoplanin, Thiostrepton, Tuberac sulfate, N-(1,2-Diphenylethyl)nicotinamide, Dipiprove tinomycin, Tyrocidine, Tyrothricin, Vancomycin, Vi rine, Diponium, Emepronium, Endobenzyline, Etho omycin(s), Virginiamycin, Zinc Bacitracin propazine, Ethybenztropine, Ethylbenzhydramine, Tetracyclines such as Apicycline, Chlortetracycline, 45 Etomidoline, Eucatropine, Fenpiverinium, Fentonium, Clomocycline, Deneciocycline, Doxycycline, Guame Flutropium, Glycopyrrolate, Heteronium, Hexocy cycline, Lymecycline, Meclocycline, Methacycline, clium Methyl Sulfate, Homatropine, Homatropine Minocycline, Oxytetracycline, Penimepicycline, Pipa Methyl Bromide, Hyoscyamine, Ipratropium, Isopropa cycline, Rolitetracycline, Sancycline, Senociclin, Tetra mide, Levomepate, Mecloxamine, Mepenzolate, Met cycline SO caraphen, Methantheline, Methixene, Methscopola Others such as Cycloserine, Mupirocin, Tuberin, mine, Octamylamine, Oxybutynin, Oxyphencyclimine, ANTIBACTERIAL (SYNTHETIC) Oxyphenonium, Pentapiperide, Penthienate, Phencar 2,4-Diaminopyrimidines such as Brodimoprim, Tet bamide, Phenglutarimide, Pipenzolate, Piperidolate, roxoprim, Trimethoprim Piperilate, Poldine Methysulfate, Pridinol, Prifinium, Nitrofurans such as Furaltadone, Furazolium, Nifura 55 Procyclidine, Propantheline, Propenzolate, dene, Nifuratel, Nifurfoline, Nifurpirinol, Nifurprazine, Propyromazine, Scopolamine N-Oxide, Stilonium, Stra Nifurtoinol, Nitrofurantoin monium, Sultroponium, Thihexinol, Thiphenamil, Quinolones and Analogs such as Amifloxacin, Cinox Tiemonium, Timepidium, Tiquizium, Tridihexethyl acin, Ciprofloxacin, Difloxacin, Enoxacin, Fleroxacin, Iodide, Trihexyphenidyl Hydrochloride, Tropacine, Flunequine, Lomefloxacin, Miloxacin, Nalidixic Acid, Tropenzile, Tropicamide, Trospium, Valethamate, Norfloxacin, Ofloxacin, Oxolinic Acid, Pefloxacin, Xeny tropium Pipemidic Acid, Piromidic Acid, Rosoxacin, Temaflox ANTICONVULSANT such as Acetylpheneturide, acin, Tosufloxacin Albutoin, Aloxidone, Aminoglutethimide, 4-Amino Sulfonamides such as Acetyl Sulfamethoxypyrazine, 3-hydroxybutyric Acid, Atrolactamide, Beclamide, Acetyl Sulfisoxazole, Azosulfamide, Benzylsulfamide, Buramate, Carbamazepine, Cinromide, Clonazepam, Chloramine-B, Chloramine-T, Dichloramine T, For Decimenide, Diethadione, Dimethadione, DOX mosulfathiazole, N2-Formyl-sulfisomidine, N-g-D- enitoin, Eterobarb, Ethadione, Ethosuximide, Ethio Glucosylsulfanilamide, Mafenide, 4'-(Methyl-sul toin, Fluoresone, 5,446,070 29 30 5-Hydroxytryptophan, Lamotrigine, Magnesium Sul ANTIFUNGAL (SYNTHETIC) fate, Mephenytoin, Metharbital, Methetoin, Methsuxi Allylamines such as Naftifine, Terbinafine mide, 5-Methyl-5-(3-phenanthryl)-hydantoin, 3-Meth Imidazoles such as Bifonazole, Butoconazole, Chlor yl-5-phenylhydantoin, Narcobarbital, Nimetazepam, dantoin, Chlormidazole, Cloconazole, Clotrimazole, Nitrazepam, Paramethadione, Phenacemide, Phenetu Econazole, Emilconazole, Fenticonazole, Isoconazole, ride, Phensuximide, Phenytoin, Phethenylate Sodium, Ketoconazole, Miconazole, Omoconazole, Oxiconazole Primidone, Progabide, Solanum, Strontium, Suclofe Nitrate, Sulconazole, Tioconazole nide, Sulthiame, Tetrantoin, Trimethadione, Valproic Triazoles such as Fluconazole, Itraconazole, Ter Acid, Valpromide, Vigabatrin, Zonisamide conazole ANTDEPRESSANT 1O Others such as Acrisorcin, Amorolfine, Biphenamine, Bicyclics such as Binedaline, Caroxazone, Citalo Bromosalicylchloranilide, Buclosamide, Chlophenesin, pram, Dimethazan, Indalpine, Fencamine, Indeloxa Ciclopirox, Cloxyquin, Coparaffinate, Diamthazole, zine, Nefopam, Nomifensine, Oxitriptan, Oxypertine, Dihydrochloride, Exalamide, Flucytosine, Halethazole, Paroxetine, Sertraine, Thiazesin, Trazodone, Zometa Hexetidine, Loflucarban, Nifuratel, Potassium iodide, pine 15 Propionates, Propionic Acid, Pyrithione, Salicylanilide, Hydrazides/Hydrazines such as Benmoxine, proclo Sulbentine, Tenonitrozole, Tolciclate, Tolindate, Tol zide, proniazid, Isocarboxazid, Nialamide, Octamoxin, naftate, Tricetin, Ujothion, Undecylenic Acid Phenelzine ANTIGLAUCOMA such as Dapiprazoke, Dichlor Pyrrollidones such as Cotinine, Rolicyprine, Roli phenamide, Dipivefrin, Pilocarpine pran ANTIGONADOTROPIN such as Danazol, Gestri Tetracyclics such as Maprotiline, Metralindole, Mi none, Paroxypropione anserin, Oxaprotiline ANTIGOUT such as Colchicine, Probenecid, Sulfinpy Tricyclics such as Adinazolam, Amitriptyline, Ani 2ZOe triptylinoxide, Amoxapine, Butriptyline, Clomipramine, ANTHESTAMINIC Demexiptiline, Desipramine, Dibenzepin, Dimetra 25 crine, Dothiepin, Doxepin, Fluacizine, Imipramine, Alkylamine Derivatives such as Acrivastine, Bami Imipramine N-Oxide, Iprindole, Lofepramine, Meli pine, Brompheniramine, Chlorpheniramine, Dimethin tracen, Metapramine, Nortriptyline, Noxiptilin, Opi dene, Metron S, Pheniramine, Pyrrobutamine, Thenal pramol, Propizepine, Protriptyline, Quinupramine, Tia dine, Tolpropamine, Triprolidine neptine, Trimipramine 30 Aminoalkyl Ethers such as Bietanautine, Bromodi Others such as Benactyzine, Bupropion, Butacetin, phenhydramine, Carbinoxamine, Clemastine, Diphen Deanol, Deanol Aceglumate, Deanol Acetamidobenzo lypyraline, Doxylamine, Embrammine, Medrylamine, ate, Dioxadrol, Etoperidone, Febarbamate, Femoxe Mephenphydramine, p-Methyldiphenhydramine, Or tine, Fenpentadiol, Fluoxetine, Fluvoxamine, Hemato phenadr ine, Phenyltoloxamine, Piprinhydrinate, Seta porphyrin, Hypercinin, Levophacetoperane, Lithium, 35 She Medifoxamine, Minaprine, Moclobemide, Oxaflozane, Ethylenediamine Derivatives such as Alloclamide, Piberaline, Polycyclic Imides, Prolintane, Pyrisuc p-Bromtripelennamine, Chloropyramine, Chlorothen, cideanol, Rubidium, Sulpiride, Sultopride, Teniloxa Histapyrrodine, Methafurylene, Methaphenilene, Meth zine, Thozalinone, Tofenacin, Toloxatone, Tranylcy apyrilene, Phenbenzamine, Pyrilamine, Talastine, promine, L-Tryptophan, Viloxazine, Zimeldine Thenyldiamine, Thonzylamine, Tripelennamine, Zola ANTIDIABETIC mine Biguanides such as Buformin, Metformin, Phenfor Piperazines such as Cetirizine, Chlorcyclizine, Clocinizine, Hydroxyzine Sulfonylurea Derivatives such as Acetohexamide, Tricyclics 1-Butyl-3-metanillylurea, Carbutamide, Chlorpropa 45 Phenothiazines such as Ahistan, Etymemazine, Fene mide, Glibornuride, Gliclazide, Glimepiride, Glipizide, thazine, N-Hydroxyethylpromethazine, Isoprometha Gliquidone, Glisoxepid, Glyburide, Glybuthiazol(e), zine, Mequitaz inc, Promethazine, Pyrathiazine, Glybuzole, Glyhexamide, Glymidine, Glypinamide, Thiazinamium Methyl Sulfate Phenbutamide, Tolazamide, Tolbutamide, Tolicycla Others such as Azatadine, Clobenzepam, Cyprohep mide 50 tadine, Deptropine, Isothipendyl, Loratadine, Prothi Others such as Acarbose, Benzylthiazolidene-2,4- pendy dione, Calcium Mesoxalate, Miglitol Others such as Antazoline, Cetoxime, Clemizole, ANTIDIARRHEAL such as Acetyltannic Acid, Albu Clobenztropine, Diphenazoline, Diphenhydramine, min Tannate, Alkofanone, Aluminum Salicylates, Mebhydroline, Phenindamine, Terfenadine, Tritoqua Catechin, Difenoxin, Diphenoxylate, Lidamidine, 55 line Loperamide, Mebiquine, Trillium, Uzarin ANTIHYPERLIPOPROTEINEMIC ANTIDIURETIC such as Desmopressin, Felypressin, Aryloxyalkanoic Acid Derivatives such as Beclor Lypressin, Ornipressin, Oxycinchophen, Terlipressin, brate, Bazafibrate, Binifibrate, Ciprofibrate, Clinofi Vasopressin brate, Clofibrate, Clofibric Acid, Etonfibrate, Fenofi ANTIESTROGEN such as Delmadinone Acetate, brate, Gemfibrozil, Nicofibrate, Pirifibrate, Ronifibrate, Ethamoxytriphetol, Tamoxifen, Torenifene Simfibrate, Theofibrate ANTIFUNGAL (ANTIBIOTICS) Bile Acid Sequesterants such as Cholestyramine Polyenes such as Amphotericin-B, Candicidin, Der Resin, Colestipol, Polidexide mostatin, Filipin, Fungichromin, Hachimycin, Hamy HMG CoA Reductase Inhibitors such as Lovastatin, cin, Lucensomycin, Mepartricin, Natamycin, Nystatin, 65 Pravastatin, Simvastatin Pecilocin, Perimycin Nicotinic Acid Derivatives Aluminum Nicotinate, Others such as Azaserine, Griseofulvin, Oligomycins, Acipimox, Niceritrol, Nicoclonate, Nicomol, Oxiniacic Pyrrolnitrin, Siccanin, Tubercidin, Viridin Acid 5,446,070 31 32 Thyroid Hormones/Analogs such as Etiroxate, Aminoarylcarboxylic Acid Derivatives such as Thyropropic Acid Etofenamate, Meclofenamic Acid, Mefanamic Acid, Others such as Acifran, Azacosterol, Benfluorex, Niflumic Acid A-Benzalbutyramide, Benzodioxole, Carnitine, Chon Aryacetic Acid Derivatives such as Acemetacin, droitin Sulfate, Clomestone, Detaxtran, Dextran Sulfate 5 Amfenac, Cinmetacin, Clopirac, Diclofenac, Fen Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Eritade clofenac, Fenclorac, Fenclozic Acid, Fentiazac, nine, Farnesylated tetrahydro-naphthalenols, Furazbol, Glucametacin, Isoxepac, Lonazolac, Metiazinic Acid, Meglutol, Melinamide, Mytatrienediol, Naphtyl-tet Oxametacine, Proglumetacin, Sulindac, Tiaramide, rahydronaphtyl-diphosPhonates, Ornithine, y Tolimetin Oryzanol, Pantethine, Penataerythritol Tetraacetate, 10 Arylbutyric Acid Derivatives such as Butibufen, a-Phenylbutyramide, Phylate Acids and Salts, Piroza Fenbufen dil, Probucol, al-Sitosterol, Sultosilic Acid, Tiadenol, Arylcarboxylic Acids such as Clidanac, Ketorolac, Triparanol Tinoridine ANTHYPERTENSIVE Arylpropionic Acid Derivatives such as Bucloxic Benzothiadiazine Derivatives such as Althiazide, 15 Acid, Carprofen, Fenoprofen, Flunoxaprofen, Ibu Bendroflumethiazide, Benzthiazide, Benzylhydro profen, Ibuproxam, Oxaprozin, Piketoprofen, Pir chlorothiazide, Buthiazide, Chlorothiazide, Chlorthali profen, Pranoprofen, Protizinic Acid, Tiaprofenic Acid done, Cyclopenthiazide, Cyclothiazide, Diazoxide, Epi Pyrazoles such as Mepirizole thiazide, Ethiazide, Fenquizone, Hydrochlorothiazide, Pyrazolones such as Clofezone, Feprazone, Hydroflumethiazide, Methyclothiazide, Meticrane, 20 Mofebutazone, Oxyphenbutazone, Phenylbutazone, Metolazone, paraflutizide, polythiazide, Tetrachlorme Phenyl Pyrazolidininones, Suxibuzone, Thiazolinobuta thiazide, Trichlorimethiazide ZOe N-Carboxyalkyl (peptide/lactam) Derivatives such Salicylic Acid Derivatives such as Bromosaligenin, as Alacepril, Captopril, Cilazapril, Delapril, Enalapril, Fendosal, Glycol Salicylate, Mesalamine, 1-Naphthyl Enalaprilat, Fosinopril, Lisinopril, Moveltipril, perin 25 Salicylate, Olsalazine, Sulfasalazine dopril, Quinapril, Ramipril Thiazinecarboxanides such as Droxican, Isoxican, Guanidine Derivatives Bethanidine, Debrisoquin, Piroxicam Guanacline, Guanadrei, Guanazodine, Guanethidine, Others such as e-Acetamidocaproic Acid, S Guanochlor, Guanoxabenz, Guanoxan Adenosylmethionine, 3-Amino-4-hydroxybutyric Acid, Hydrazines/Phthalazines such as Cadralazine, Dihy 30 Amixetrine, Bendazac, Bucolome, Carbazones, Difen dralazine, Endralazine, Hydracarbazine, Hydralazine, piramide, Ditazol, Guaiazulene, Heterocylic Aminoal Pheniprazine, Pildralazine, Todralazine kyl Esters of Mycophenolic Acid and Derivatives, Imidazole Derivatives such as Lofexidine, Phentol Nabumetone, Nimesulide, Orgotein, Oxaceprol, Oxa amine, Tolonidine zole Derivatives, Paranyline, Pifoxime, 2-substituted-4, Quaternary Ammonium Compounds Azamethonium, 35 6-di-tertiary-butyl-s-hydroxy-1,3-pyrimidines, Proqua Chlorisondamine, Hexamethonium, Pentacynium Bis(- zone, Sialyl Lewis Dimers, Tenidap methyl sulfate), Pentamethonium, Pentolinium Tartate, ANTIMALARIAL such as Acedapsone, Al Phenactopinium, Trimethidiunum Methosulfate phaaminoquinolines, 4-Aminoquinolines, Amodia Quinazoline Derivatives such as Alfuzosin, quin, Arteether, Artemether, Artemisinin, Artesu Bunazosin nate, Bebeerine, Berberine, Chirata, Chlorguanide, Reserpine Derivatives such as Bietaserpine, Deserpi Chloroquine, Chlorproguani, Cinchona, Cinchoni dine, Rescinnamine, Reserpine, Syrosingopine dine, Cinchonine, Cycloguanil, Euguinine, Gentiopi Sulfonamide Derivatives such as Ambuside, Clopa crin, Halofantrine, Mefloquine Hydrochloride, 3 mide, Furosemide, Indapamide, Quinethazone, Tripa Methylarsacetin, Pamaquine, Plasmocid, Primaquine, mide, Xipamide 45 Pyrimethanine, Quinacrine, Quinine (Acids, Salts Others such as Aimaline, y-Aminobutyric Acid, and Derivatives), Quinine Formate, Quinine Gluco Bufeniode, Chlorthalidone, Cicletaine, Ciclosidomine, nate, Quinine Tannate, Quinine Urea Hydrochloride, Cryptenamine Tannates, Flosequinan, Indoramin, Ke Quinocide, Quinoform, Quinoline, Sodium Arsenate, tanserin, Metbutamate, Mecamylamine, Methyldopa, Diabasic Methyl 4-Pyridyl Ketone Thiosemicarbarzone, Metola SO ANTIMIGRAINE such as Alpiropride, Dihydroergot zone, Minoxidil, Muzolimine, Pargyline, Pempidine, amine, Ergocornine, Ergocorninine, Ergocryptine, Pinacidil, Piperoxan, Primaperone, Propargyl Glycine Ergot, Ergotamine, Flumedroxone Acetate, Fona Aminopropargyl Diols, Protoveratrines, Raubasine, zine, Methysergid(e), Oxetorone, Pizotyline, Suma Rescimetol, Saralasin, Sodium Nitroprusside, Ti triptan crynafen, Trimethaphan Camsylate, Tyrosinase, Urapi 55 ANTINAUSEANT such as Acetylleucine Monoetha dil nolamine, Bietanautine, Bromopride, Buclizine, ANTIHYPERTHY ROID such as 2-Amino-4-methyl Clebopride, Cyclizine, Dimenhydrinate, Dipheni thiazole, 2-Aminothiazole, Carbimazole, 3,5- odol, Domperidone, Granisetron, Meclizine, Me Dibromo-L-tyrosine, 3,5-Diiodotyrosine, Hinderin, thalltal, Metoclopramide, Metopimazine, Nabilone, Iodine, Iothiouracil, Methimazole, Methylthiouracil, Ondansteron, Oxypendyl, Pipamazine, Piprinhydri Propylthiouracil, Sodium Perchlorate, Thibenzazo nate, Scopolamine, Tetrahydrocannabinols, Thie line, Thiobarbital, 2-Thiouracil thylperazine, Trimethobenzamide ANTIHYPOTENSIVE such as Amezinium Methyl ANTINEOPLASTIC Sulfate, Angiotensin Amide, Etifelmin, Etilefrin, Alkylating agents Gepefrine 65 Alkyl Sulfonates such as Busulfan, Improsulfan, ANTIHYPOTHYROID such as Levothyroxine, Lio Piposulfan thyronine, Thyroid, Thyroidin, Thyroxine, Tiratricol Aziridines such as Benzodepa, Carboquone, ANTI-INFLAMMATORY (NONSTEROIDAL) Meturedepa, Uredepa 5,446,070 33 34 Ethylenimines and Methylmelamines such as Altreta ANTIPROTOZOAL (TRICHOMONAS) such as Ac mine, Triethylenemelamine, Triethylenephosphora etarsone, Aminitrozole, Anisomycin, Azanidazole, mide, Triethylenethiophosphoramide, Trime Forminitrazole, Furazolidone, Hachimycin, thylolomelamine Lauroguadine, Metronidazole, Nifuratel, Nimora Nitrogen Mustards such as Chlorambucil, Chlorna 5 zole, Silver Picrate, Tenonitrozole phazine, Chclophosphamide, Estramustine, Ifosfamide, ANTIPROTOZOAL (TRYPANOSOMA) such as Mechlorethamine, Mechlorethamine Oxide Hydrochlo Benzinidazole, Eflornithine, Melarsoprol, Nifurtinox, ride, Melphalan, Novembichin, Phenesterine, pred Oxophenarsine, Puromycin, Quinapyramine, Suramin nimustine, Trofosfamide, Uracil Mustard Sodium, Trypan Red, Tryparasmide Nitrosoureas Carmustine, Chlorozotocin, Fotemus O ANTIPRURITIC such as Camphor, Cyproheptadine, tine, Lomustine, Nimustine, Ranimustine Dichlorisone, Glycine, Halometasone, 3-Hydrox Others such as Dacarbazine, Mannomustine, Mito ycamphor, Menthol, Mesulphen, Methdilazine, Phe bronitol, Mitolactol, Pipobroman nol, Spirit of Camphor, Trimeprazine Antibiotics such as Aclacinomycins, Actinomycin ANTIPSORIATIC such as Acitretin, Anthralin, 6 F1, Anthramycin, Azaserine, Bleomycins, Cactinomy 15 Azauridine, Bergapten(e), Chrysarobin, Etretinate, cin, Carubicin, Carzinophilin, Chromomycins, Dactino Pyrogallol mycin, Daunorubicin, 6-Diazo-5-oxo-L-norleucine, ANTIPSYCHOTIC Doxorubicin, Epirubicin, Mitomycins, Mycophenolic Butyrophenones such as Benperidol, Bromperidol, Acid, Nogalamycin, Olivomycins, Peplomycin, Plica Droperidol, Fluanisone, Haloperidol, Melperone, Mop mycin, porfiromycin, Puromycin, Streptonigrin, Strep 20 erone, Pipamperone, Sniperone, Timiperone, Tri tozocin, Tubercidin, Ubenimex, Zinostatin, Zorubicin fluperidol Antimetabolites Phenothiazines such as Acetophenazine, Butapera Folic Acid Analogs such as Denopterin, Methotrex zine, Carphenazine, Chlorproethazine, Chlorproma ate, Pteropterin, Trimetrexate zine, Clospirazine, Cyanemazine, Dixyrazine, Fluphen Purine Analogs such as Fludarabine, 6-Mercaptopu 25 azine, Imiclopazine, Mepazine, Mesoridazine, Methoxy rine, Thiamiprine, Thioguanaine promazine, Metofenazate, Oxaflumazine, Perazine, Pyrimidine Analogs such as Ancitabine, Azacitidine, Pericyazine, Perimethazine, Perphenazine, Piperaceta 6-Azauridine, Carmofur, Cytarabine, Dideoxyuridines, zine, Pipotiazine, Prochlorperazine, Promazine, Sul Doxifluridine, Enocitabine, Floxuridine, Fluororacil, foridazine, Thiopropazate, Thioridazine, Trifluopera Tegafur 30 zine, Triflupromazine Enzymes such as L-Asparaginase, Pulmozyme Thioxanthenes such as Chlorprothixene, Clopen Others such as Aceglatone, Aldophophanide Glyco thixol, Flupentixol, Thiothixene side, Aminolevulinic Acid, Amsacrine, Bestrabucil, Other Tricyclics such as Benzquinamide, Carpipra Bisantrene, Carboplatin, Cisplatin, Defofamide, Deme mine, Clocapramine, Clomacran, Clothiapine, Cloza colicine, Diaziquone, Elfornithine, Elliptinium Acetate, 35 pine, Opipramol, Prothipendyl, Tetrabenazine, Zote Etoglucid, Etoposide, Gallium Nitrate, Hydroxyurea, pine Interferon-o, Interferon-g, Interferon-y, Interleukine-2, Others such as Alizapride, Amisulpride, 4-Arylpiper Lentinan, Lonidamine, MitoguaZone, Mitoxantrone, azines, 4-Arylpiperdines, Buramate, Fluspirilene, Mo Mopidamol, Nitracrine, Pentostatin, Phenamet, lindone, Penfluridol, Pimozide, Spirilene, Sulpiride Pirarubicin, podophyllinicc Acid, 2-Ethythydrazide, ANTIPYRETIC such as Aconine, Aconite, Aconitine, Procarbazine, PSK (R), Razoxane, Sizofiran, Spiroger Phenicarbazide manium, Taxol, Teniposide, Tenuazonic Acid, Triaziq ANTIRICKETTSIAL such as p-Aminobenzoic Acid uone, 2,2,2'-Trichlorotriethylamine, Urethan, Vinblas ANTISEBORRHEIC such as 3-O-Lauroylpyridoxol tine, Vincristine, Vindesine Diacetate, Piroctone, Resorcinol, Selenium Sulfides, ANTINEOPLASTIC (HORMONAL) 45 Tioxolone Androgens such as Calusterone, Dromostanolone ANTISEPTIC Propionate, Epitiostanol, Mepitiostane, Testolactone Guanidines such as Alexidine, Ambazone, Chlorhexi Antiadrenals such as Aminoglutethinide, Mitotane, dine, Picloxydine Trilostane Halogens/Halogen Compounds such as Bornyl Chlo Antiandrogens such as Flutamide, Nilutamide 50 ride, Calcium Iodate, Iodine, Iodine Monochloride, Antiestrogens such as Aromatase Inhibiting 4(5)- Iodine Trichloride, Iodoform, Povidione-Iodine, So Inidazoles dium Hypochlorite, Sodium Iodate, Symclosene, Thy ANTINEOPLASTIC ADJUNCT mol Iodide, Triclocarban, Triclosan, Troclosene Potas Folic Acid Replenisher such as Frolinic Acid S. ANTIPARKINSONIAN such as Amantadine, Benser 55 Nitrofurans such as Furazolidone, 2-(Methoxyme azide, Bietanautine, Biperiden, Budipine, Carbidopa, thyl)-5-Nitrofuran, Nidroxyzone, Nifuroxime, Nifur Deprenyl, Dexetimide, Diethazine, Droxidopa, Etho zide, Nitrofurazone. propazine, Ethylbenzhydramine, Levodopa, Piro Phenols such as Acetomeroctol, Chloroxylenol, heptine, Pridinol, Prodipine, Terguride, Tiapride, Hexachlorophene, 1-Napthyl Salicylate, 2,4,6-Tri Tigloidine bromo-m-cresol, 3,4,5-Trichlorosalicylanilide ANTIPHEOCHROMOCYTOMA such as Metyro Quinolines such as Aminoquinuride, Chloroxine, sine, Phenoxybenzamine Chlorquinaldol, Cloxyquin, Ethylhydrocupreine, Hal ANTIPNEUMOCYSTIS such as Effornithine quinol, Hydrastine, 8-Hydroxquinoline Sulfate ANTIPROSTATIC HYPERTROPHY Such as Pros Others such as Boric Acid, Chloroazodin, m-Cresyl car (E) 65 Acetate, Cupric Sulfate, Ichthammol ANTIPROTOZOAL (LEISHMANIA) such as Ethyl ANTISPASMODIC such as Alibendol, Ambuceta stibamine, Hydroxystilbamidine, N-Methylgluca mide, Aminopromazine, Bietamiverine, Butaverine, mine, Pentamidine, Stilbanidine Butropium, Caroverine, Cimetropium, Cinname 5,446,070 35 36 drine, Clebopride, Coniine Hydrobromide, Coniine, razepate, Chotiazepam, Cloxazolam, Diazepam, Ethyl Difemerine, Diisopromine, Dioxaphetyl Butyrate, Loflazepate, Etizolam, Fluidazepam, Flutazolam, Drofenine, Ethaverine, Feclemine, Fenalamide, Flutoprazepam, Halazepam, Ketazolam, Lorazepam, Fenoverine, Fenpiprane, Flavoxate, Flopropione, Loxapine, Medazepam, Metaclazepam, Mexazolam, Gluconic Acid, Guaiactamine, Hydramitrazine, Nordazepam, Oxazepam, Oxazolam, Pinazepam, Praze Hymecromone, Leiopyrrole, Mebeverine, Moxave pam, Tofisopam rine, Nafiverine, Octaverine, Phenamacide, Phloro Carbamates such as Cyclarbamate, Emylcamate, Hy glucinol, Pinaverium, Piperilate, Pipoxolan Hydro droxyphenamate, Meprobamate, Phenprobamate, chloride, Pramiverin, Properidine, Propivane, Tybamate Propyromazine, Prozapine, Racefemine, Rociverine, 10 Others Alpidem, Benzoctamine, Captodiamine, Spasmolytol, Stilonium, Tiropramide, Trepibutone, Chlormezanone, Etifoxine, Fluoresone, Glutamic Acid, Tricromyl, Trifolium, Trimebutine, N,N-1Trimethyl Hydroxyzine, Mecloralurea, Mephenoxalone, Oxana 3,3-diphenylpropylamine mide, Phenaglycodol, Suriclone ANTITHROMBOTIC such as Anagrelide, Argatro BENZODIAZEPINE ANTAGONST such as ban, Cilostazol, Daltroban, Defibrotide, Enoxaparin, 15 Flumazenil Fraxiparine (R), Indobufen, Lamoparan, Ozagrel, BRONCHODILATOR Picotamide, Plafibride, Tedelparin, Ticlopidine, Tri Ephedrine Derivatives such as Albuterol, Bam flusal buterol, Bitolterol, Carbuterol, Clenbuterol, Clorprena ANTITUSSIVE such as Allocamide, Amicibone, Ben line, Dioxethedrine, Eprozinol, Etafedrine, Ethylnorep properine, Benzonatate, Bibenzonium, Bromoform, inephrine, Fenoterol, Hexoprenaline, Isoetharine, Iso Butamirate, Butethamate, Caramiphen Ethanedisul proterenol, Mabuterol, Metaproterenol, N-Methylephe fonate, Carbetapentane, Chlophedianol, Clobutinol, drine, Pirbuterol, Procaterol, Protokylol, Reproterol, Cloperastine, Codeine Methyl Bromide, Codeine Rimiterol, Soterenol, Terbutaline, Tulobuterol N-Oxide, Codeine Phosphate, Codeine Sulfate, Cy Quaternary Ammonium Compounds such as Clu clexanone, Dextromethorphan, Dibunate Sodium, 25 tropium Bromide, Oxitropium Bromide Dihydrocodeine, Dihydrocodeinone Enol Acetate, Xanthine Derivatives such as Acefylline, Acefylline Dimemorfan, Dimethoxanate, ad-Diphenyl-2- Ambuphylline, Aminophylline, Bamifylline, Choline piperidinepropanol, Dropropizine, Drotebanol, Theophyllinate, Doxofylline, Dyphylline, Enprofylline, Eprazinone, Ethyl Dibunate, Ethylmorphine, Fomi Etamiphyllin, Etofylline, Guaithylline, Proxyphylline, noben, Guiaiapate, Hydrocodone, Isoaminile, Levo 30 Theobromine, 1-Theobromineacetic Acid, Theophyl propoxyphene, Morclofone, Narceline, Normetha line done, Noscapine, Oxeladin, Oxolamine, Pholcodine, Others such as Methoxyphenanime, Tretoquinol Picoperine, Pipazethate, Piperidione, Prenoxdiazine, CALCIUM CHANNEL BLOCKER Racemethorphan, Taziprinone Hydrochloride, Arylalkylamines such as Bepridil, Ditiazem, Fendi Tipepidine, Zipeprol 35 line, Gallopamil, Terodiline, Verapamil ANTIULCERATIVE such as Aceglutamide Alumi Dihydropyridine Derivatives such as Felodipine, nun Complex, e-Acetamidocaproic Acid Zinc Salt, Isradipine, Nicardipine, Nifedipine, Nilvadipine, Acetoxolone, Arbaprostil, Benexate Hydrochloride, Nimodipine, Nisoldipine, Nitrendipine Bismuth Subcitrate Sol (Dried), Carbenoxolone, Ce Piperazine Derivatives such as Flunarisine traxate, Cimetidine, Enprostil, Esaprazole, Famoti Others such as Perhexiline dine, Ftaxilide, Gefarnate, Guaiazulene, Irsogladine, CALCIUM REGULATOR such as Calcifediol, Calci Nizatidine, Omeprazole, Ornoprostil, y-Oryzanol, tonin, Calcitriol, Clodronic Acid, Dihydrotachyste - Pifarnine, Pirenzepine, Plaunotol, Ranitidine, Rio rol, Elcatonin, Etidronic Acid, priflavone, Pami prostil, Rosaprostol, Rotraxate, Roxatidine Acetate, dronic Acid, Parathyroid Hormone, Teriparatide Sofalicone, Spizofurone, Sucralfate, Teprenone, 45 Acetate Trimoprostil, Thrithiozine, Troxipide, Zolimidine CARDIOTONIC such as Acetyldigititoxins, 2-Amino ANTIUROLITHIC such as Acetohydroxamic Acid, 4-picoline, Amrinone, Buclasdesine, Cerberoside, Allopurinol, Potassium Citrate, Succinimide Camphotamide, Convallatoxin, Cymarin, Denopa ANTIVENIN such as Lyovac (R) Antivenin mine, Deslanoside, Ditalin, Digitalis, Digitoxin, , ANTIVIRAL SO Digoxin, Dobutamine, Dopamine, Dopexamine, Purines/Pyrimidinones such as 2-Acetyl-pyridine Enoximone, Erythrophleine, Fenalcomine, Gitalin, 5-((2-pyridylamino)thiocarbonyl) Thiocarbonohydra Gitoxin, Glycocyamine, Heptaminol, Hydrastinine, Zone, Acyclovir, Dideoxyadenosine, Dideoxycytidine, Lanotodises, Metamivam, substituted Methoxyphe Dideoxyinosine, Edoxudine, Floxuridine, Ganciclovir, nyl-4,5-dihydro-3(2H)-pridazinones, Millrinone, Idoxuridine, MADU, Pyridinone, Trifluridine, Vidrar 55 Neriifolin, Oleandrin, Ouabain, Oxyfedrine, Prenal bine, Zidovudine terol, Proscillaridin, Resibufogenin, Scillaren, Scil Others such as Acetylleucine Monoethanolamine, larenin, Strophanthin, Sulmazole, Theobromine, Acridinamine, Alkylisooxazoles, Amantadine, Xamoterol Amidinomycin, Cuminaldehyde Thiosemicarbzone, CHELATING AGENT such as Deferozmine, Edetate Foscarnet Sodium, Kethoxal, Lysozyme, Methisazone, Calcium Disodium, Edetate Disodium, Edeate So Moroxydine, Podophyllotoxin, Ribavirin, Rimantadine, dium, Edetate Trisodium, Pentetate Calcium Triso Stallimycin, Statolon, Thymosins, Tromantadine, dium, Pentectic Acid, Succimer, Trientine Xenazoic Acid CHOLECYSTOKININ ANTAGONIST (CCK An ANXOLYTIC tagonist) Arylpiperazines such as Buspirone, Gepirone, Ipsapi 65 CHOLELITHOLYTIC AGENT such as Chenodiol, Oe Methyl tert-Butyl Ether, Monooctanoin, Ursodiol Benzodiazepine Derivatives Alprazolam, Bromaze CHOLERETIC such as Alibendol, Anethole Trithion, pam, Camazepam, Chlordiazepoxide, Clobazan, Clo Azintamide, Cholic Acid, Cicrotoic Acid, Clanobu 5,446,070 37 38 tin, Cyclobutyrol, Cyclovalone, Cynarin(e), De Digestive such as ot-Amylase (Swine Pancreas), Lip hydrocholic Acid, Deoxycholic Acid, Dimecrotic ase, Pancrelipase, Pepsin, Rennin Acid, a-Ethylbenzyl Alcohol, Exiproben, Feguprol, Penicillin Inactivating such as Penicillinase Fencibutirol, Fenipentol, Florantyrone, Hymecro Proteolytic such as Collagenase, Chymopapain, Chy mone, Menbutone, 3-(o-Methoxyphenyl)-2-phenyla motrypsins, Papain, Trypsin crylic Acid, Metochalcone, Moquizone, Osalmid, Ox ENZYME INDUCER (HEPATIC) such as Flumeci Bile Extract, 4,4'-Oxydi-2-butanol, Piprozolin, Proza nol pine, 4-Salicyloylmorpholine, Sincalide, Taurocholic ESTROGEN Acid, Timonacic, Tocamphyl, Trepibutone, Vanitio Nonsteroidal such as Benzestrol, Broparoestrol, lide CHOLINERGIC such as Aceclidine, Acetyl O Chlorotrianisene, Dienestrol, Diethylstilbestrol, Dieth choline, Acetylcholide, Aclatonium Napadisilate, yistilbestrol Diproprionate, Dimestrol, Fosfestrol, Hex Benzpyrinium Bromide, Bethanechol, Carbachol, estrol, Methallenestril, Methestrol Carpronium, Demecarium, Dexpanthenol, Diisopro Steroidal such as Colpormon, Conjugated Estrogenic pyl Paraoxon, Echothiophate, Edrophomium, Eseri Hormones, Equilenin, Equilin, Esterified Estrogens, dine, Furtrethonium, Isoflurophate, Methacholine 15 Esteropipate, 17(3-Estradiol, Estradiol, Estradiol Ben Chloride, Muscarine, Neostigmine, Oxapropanium, zoate, Estradiol 17(3-Cypionate, Estriol, Estrone, Ethi Physostigmine, Pyridostigmine nyl Estradiol, Mestranol, Moxestrol, Mytatrienediol, CHOLINESTERASE INHIBITOR such as Ambeno Polyestradiol Phosphate, Quinestradiol, Quinestrol nium, Distigmine, Galanthamine GASTRIC SECRETION INHIBITOR Such as En CHOLINESTERASE REACTIVATOR such as Obi 20 terogastrone, Octreotide doximine, Pralidoxime CNS STIMULANT/A- GLUCOCORTICOID such as 21-Acetoxyprefneno GENT such as Amineptine, Amphetimine, Am lone, Aalclometasone, Algestone, Amicinonide, Be phetaminil, Bemegride, Benzphetamine, Brucine, clomethasone, Betamethasone, Betamethasone Di Caffeine, Chlorphentermine, Clofenciclan, Clorter propionate, Budesonide, Chloroprednisone, Clobeta mine, Coca, Demanyl Phosphate, Dexoxadrol, Dex 25 troamphetamine Sulfate, Diethlpropion, N-Ethylam Sol, Blovetasone, Clocortolone, Cloprednol, Cortico phetamine, Ethamivan, Etifelmin, Etryptamine, Fen sterone, Cortisone, Cortivazol, Deflazacort, Deso camfamine, Fenethylline, Fenosolone, Flurothyl, nide, Desoximetasone, Dexamethasone, Diflorasone, Hexacyclonate Sodium, Homocamfin, Mazindol, Diflucortolone, Difluprednate, Enoxolone, Fluaza Megexamide, Methamphetamine, Methylphenidate, 30 cort, Flucloronide, Flumehtasone, Flunisolide, Fluo Nicotine, Nicotinic Agonist, Nikethamide, Pemoline, cinolone Acetonide, Fluocinonide, Fuocortin Butyl, Pentylenetetrazole, Phenidimetrazine, Phennetra Fluocortolone, Fluorometholone, Fluperolone Ace zine, Phentermine, Picrotoxin, Pipradrol, Prolintane, tate, Fluprednidene Acetate, Fluprednisolone, Flur Pyrovalerone, Tetrahydrobenzothienopyridines andrenolide, Formocortal, Halcinonide, Halometa DECONGESTANT such as Cafaminol, Nordefrin 35 sone, Halopredone Acetate, Hydrocortamate, Hy DENTAL CARRIES PROPHYLACTIC Such as So drocortisone, Hydrocortisone Acetate, Hydrocorti diurn Fluoride sone Phosphate, Hydrocortisone 21-Sodium Succi DEPIGMENTOR such as Hydroquinine, Hydroqui nate, Hydrocortisone Tebutate, Mazipredone, Med none, Monobenzone rysone, Meprednisone, Methyolprednisolone, DURETC Mometasone Furcate, Paramethasone, Prednicarbate, Organomercurials such as Chlormerodrin, Merallu Prednisolone, Prednisolone 21-Diethylaminoacetate, ride, Mercamphamide, Mercaptomerin Sodium, Mercu Prednisone Sodium Phosphate, Prednisolone Sodium mallylic Acid, Mercumatilin Sodium, Mercurous Chlo Succinate, Prednisolone Sodium 21-m-Sulfobenzoate, ride, Mersalyl Prednisolone 21-Stearoylglycolate, Prednisolone Pteridines such as Furterene, Triamterene 45 Tebutate, Prednisolone 21-Trimethylacetate, Predni Purines such as 7-Morpholinomethyltheophylline, sone, Prednival, Prednylidene, Prednylidene 21-Die Panabrom, Protheobromine, Theobromine thylaminoacetate, Tixocortal, Triamcinolone, Triam Steroids such as Canremone, Oleandrin, Spironolac cinolone Acetonide, Triancinolone Benetonide, Tri tole amcinolone Hexacetonide GONAD-STIMULAT Sulfonamide Derivatives such as Acetazolmide, 50 ING PRINCIPLE such as Clomiphene, Cyclofenil, Azosemide, Bumetanide, Butazolamide, Chloramino Epimestrol, FSH, HCG, LH-RH phenamide, Clofenamide, Clorexolene, Diphenylme GONADOTROPIC HORMONE such as LH, PMSG thane-4,4'-disulfonamide, Disulfamide, Ethoxzolamide, GROWTH HORMONE INHIBITOR Such as Somato Flumethiazide, Mefruside, Methazolamide, Piretanide, statin Torasemide 55 GROWTH HORMONE RELEASING FACTOR Uracils such as Aminometradine, Amisometradine such as Semorelin Others such as Amanozine, Amiloride, Arbutin, GROWTH STIMULANT such as Somatotropin Chlorazanil, Ethacrynic Acid, Etozolin, Isosorbide, HEMOLYTIC such as Phenylhydrazine Mannitol, Metochalcone, Perhexiline, Urea HEPARIN ANTAGONIST such as Hexadimethrine, DOPAMINE RECEPTOR AGONIST Such as Protamines Bromocriptine, Fenoldopam, Lisuride, Naxagolide, HEPATOPROTECTANT such as Betaine, Citolone, Pergolide Malotilate, Orazamide, Phosphorylcholine, Proto ECTOPARASITICIDE such as Amitraz, Benzyl Ben porphyrin IX, Silymarin-Group, Thiotic Acid zoate, Carbaryl, Crotamiton, DDT, Dixanthogen, IMMUNOMODULATOR such as Amiprilose, Bucil Isobornyl Thiocyanoacetate (Technical), Lime Sul 65 lamine, Ditiocarb Sodium, Inosine Pranobex, Muroc furated Solution, Lindane, Malathion, Mercuric Ole tasin, Platonin, Procodazole, Tetramisole, 6-aryl-5,6- ate, Sulphur (Pharmaceutical) dihydroimidazol-(2,1-B) Thiazole Derivatives, ENZYME Thymomodulin, Thymopentin 5,446,070 39 40 IMMUNOSUPPRESSANT such as Cyclophilin, Cy none, 19-Norprogesterone, Norvinisterone, Pent closporins, FK-506, Mizoribine, Rapamycin, Rapa agestrone, Progesterone, Promegestone, Quinges mycin Sulfamates trone, Trengestone ION EXCHANGERESIN such as Carbacrylic Resins, PROLACTIN INHIBITOR such as Metergoline Resodec, Sodium Polystyrene Sulfonate PROSTAGLANDINAPROSTAGLANDIN ANA. LACTATION STIMULATING. HORMONE Such as LOG such as Bemeprost, Prostacyclin, Prostaglandin Prolactin E1, Sulprostone LH-RH AGONIST such as Buserelin, Goserelin, Leu PROTEASE INHIBITOR such as Aprotinin, Camo prolide, Nafarelin, Triptorelin stat, Gabexate, Nafamostat LIPOTROPIC such as N-Acetylmethionine, Choline O RESPIRATORY STIMULANT such as Almitrine, Chloride, Choline Dehydrocholate, Choline Dihy Dimefline, Dimorpholamine, Doxapram, Lobeline, drogen Citrate, Inositol, Lecithin, Methionine Mepixanox, Pimeclone, Sodium Succinate, Tacrine LUPUS ERYTHEMATOSUS SUPPRESSANT such SCLEROSINGAGENT such as Ethanolamine, Ethyl as Bismuth Sodium Triglycollamate, Bismuth Subsa amine, 2-Hexyldecanoic Acid, Sodium Ricinoleate, licylate 15 Sodium Tetradecyl Sulfate, Tribenoside MINERALOCORTICOID such as Aldosterone, De SEDATIVE/HYPNOTIC oxycorticosterone, Fludrocortisone Acyclic Ureides such as Acecarbromal, Apronalide, MIOTIC such as Pilocarpus Bonnisovalum, Capuride, Carbromal, Ectylurea MONOAMINE OXIDASE INHIBITOR Such as Phe Alcohols such as Chlorhexadol, Ethchlorvynol, 4 noxypropazine, Pivalylbenzhydrazine 20 Methyl-5-thiazoleethanol, tert-Pentyl Alcohol, 2,2,2- MUCOLYTIC such as Acetylcysteine, Bromhexine, Trichloroethanol Carbocysteine, Domiodol, Letosteine, Mecysteine, Amides such as Butoctamide, Diethylbronoaceta Mesna, Sobrerol, Stepronin, Tiopronin, Tyloxapol mide, Ibrotamide, Isovaleryl Diethylamide, Niaprazine, MUSCLE RELAXANT (SKELETAL) such as Tricetamide, Trimetozine, Zolpidem, Zopiclone Afloqualone, Alcuronium, Atracurium Besylate, Ba 25 Barbituric Acid Derivatives such as Allobarbital, clofen, Benzoquinonium, C-Calebassine, Carisopro Amobarbital, Aprobarbital, Barbital, Brallabarbital, dol, Chlorphenesin Carbamate, Chlozoxazone, Cu Butabarbital Sodium, Butabital, Butallylonal, Butethal, rare, Cyclobenzaprine, Dantrolene, Decamethonium, Carbubarb, Cyclobarbital, Cyclopenitobarbital, Enallyl Eperisone, Fazadinium, Flumetramide, Gallamine propymal, 5-Ethyl-5-(1-piperidyl) barbituric Acid, 5 Triethiodide, Hexacarbacholine, Hexafluorenium, 30 Furfuryl-5-isopropylbarbituric Acid, Heptabarbital, Idrocilamide, Lauexium Methyl Sulfate, Leptodactyl Hexethal Sodium, Hexobarbital, Mephobarbital, Me ine, Memantine, Mephenesin, Metaxalone, Methocar thitural, Narcobarbital, Nealbarbital, Pentobarbital So bamol, Metocurine Iodide, Pancuronium, dium, Phenallymal, Phenobarbital, Phenobarbital So Pipecurium, Promoxolane, Quinine Sulfate, Styra dium, Phenylmethylbarbituric Acid, Probarbital, Pro mate, Succinylcholine, Succinylcholine Suxethonium 35 pallylonal, Proxibarbal, Reposal, Secobarbital Sodium, Bromide, Tetrazepam, Thiocolchicoside, Tizanidine, Talbutal, Tetrabarbital, Vinbarbital Sodium, Vinylbital Tolperisone, Tubocurarine, Vecuronium, Zoxola Benzodiazepine Derivatives such as Brotizolam, e Doxefazepam, Estazolam, Flumitrazepam, Flurazepam, NARCOTIC ANTAGONIST such as Amiphenazole, Haloxazolam, Loprazolan, Lorimetazepam, Ni Cyclazocine, Levallorphan, Nadide, Nalmafene, Na trazepam, Quazepam, Temasepam, Triazolan lorphine, Nalorphine Dinicotinate, Naloxone, Nal Bromides such as Amnonium Bromide, Calcium trexone Bromide, Calcium Bromolactobionate, Lithium Bro NEUROPROTECTIVE such as Dizocilpine mide, Magnesium Bromide, Potassium Bromide, So NOOTROPIC such as Aceglutamide, Acetylcarnitine, dium Bromide Aniracetam, Bifematlane, Exifone, Fipexide, Idebe 45 Carbamates such as Amy Carbamate (Tertiary), Eth none, Indeloxazune, Nizofenone, Oxiracetam, Pirace inamate, Hexaprpymate, Meparfynol Carbamate, No tam, Propentofylline, Pyritinol vonal, Tricholorourethan OPHTHALMIC AGENT such as 15-ketoprostaglan Chloral Derivatives such as Carbocloral, Chloral dins Betaine, Chloral Formamide, Chloral Hydrate, Chlora OVARAN HORMONE Such as Relaxin 50 lantipyrine, Dichloralphenazone, Pentaerythritol Chlo OXYTOCIC such as Carboprost, Cargutocin, Deami ral, Triclofos nooxytocin, Ergonovine, Gemeprost, Methylergono Piperidinediones such as Glutehimide, Methyprylon, vine, Oxytocin, Pituitary (Posterior), Prostaglandin Piperidione, Pyrithyldione, Taglutimide, Thalidomide E2, Prostaglandin F2, Sparteine Quinazolone Derivatives such as Etaqualone, Me PEPSIN INIBITOR such as Sodium Amylosulfate 55 cloqualone, Methaqualone PERISTALTICSTIMULANT such as Cisapride Others such as Acetal, Acetophenone, Aldol, Ammo PROGESTOGEN such as Allylestrenol, Anagestone, nium Valerate, Amphenidone, d-Bornyl a-Bromoiso Chlormadinone Acetate, Delmadinone Acetate, valerate, d-Bornyl isovalerate, Bromoform, Calcium Demegestone, Desogestrel, Dimethisterone, Dy 2-Ethylbutanoate, Carfinate, a-Chlorolose, Clome drogesterone, Ethinylestrenol, Ethisterone, thiazole, Cypripedium, Doxylamine, Etodroxizine, Ethynodiol, Ethynodiol Diacetate, Flurogestone Ac Etomidate, Fenadiazole, Homofenazine, Hydrobromic etate, Gestodene, Gestonorone Caproate, Haloprog Acid, Mecloxamine, Menthyl Valerate, Opium, Paral esterone, 17-Hydroxy-16-methylene-progesterone, dehyde, Perlapine, Propiomazine, Rilmazafone, Sodium 17a-Hydroxyprogesterone, 17a-Hydroxygesterone Oxybate, Sulfonethylmethane, Sulfonmethane Caproate, Lynestrenol, Medrogestone, Medroxypro 65 THROMBOLYTIC such as APSAC, Plasmin, Pro gesterone, Megestrol Acetate, Melengestrol, Noreth Urokinase, Streptokinase, Tissue Plasminogen Acti indrone, Norethindrone Acetate, Norethynodrel, vator, Urokinase Norgesterone, Norgestimate, Norgestrel, Norgestrie THYROTROPIC HORMONE such as TRH, TSH 5,446,070 41 42 URICOSURIC such as Benzbromarone, Ethebenecid, 2. The composition of claim 1, wherein the pharma Orotic Acid, Zoxazolamine ceutically acceptable solventis in an amount from about VASODILATOR (CEREBRAL) such as Bencyclane, 20 to about 53 weight percent based on the weight of Ciclonicate, Cinnarizine, Citicoline, Diisopropyl the whole composition, of which the plasticizer repre amine Dichloractetate, Eburnamonine, Fenoxedil, sents about 10 to about 30 weight percent based on the Ibudilast, Ifenprodil, Nafronyl, Nicametate, Nicergo weight of the whole composition, and the bioadhesive line, Nimodipine, Papaverine, Pentifylline, Tinofe carrier is in an amount from about 20 to about 34 weight drine, Vincamine, Vinpocetine percent based on the weight of the whole composition. VASODILATOR (CORONARY) such as Amotri 3. The composition of claim 1, wherein the pharma phene, Bendazol, Benfurodil Hemisuccinate, Benzi O ceutically active agent is at least one local anesthetic in odcarone, Chloacizine, Chromonar, Clobenfurol, an amount of about 10 to 40 weight percent based on the Clonitrate, Dilazep, Dipyridamole, Droprenilamine, weight of the total composition. Efloxate, Erythritol, Erythrity Tetranitrate, Etafe 4. The composition of claim 1, wherein the pharma none, Floredil, Ganglefene, Hexestrol Bis(3-die ceutically active agent is from a class of drugs selected thylaminoethyl ether), Hexobendine, Isosorbitol Di 15 from the group consisting of analgesic anti-inflamma nitrate, tramin Tosylate, Khellin, Lidoflazine, Man tory drugs, central nervous system drugs, antihistaminic nitol Hexanitrate, Medibazine, Nicorandil, Nitroglyc or antiallergic drugs, acitonide anti-inflammatory erin, Pentaerythritol Tetranitrate, Pentrinitrol, Pime drugs, androgenic and estrogenic steroids, -respiratory fylline, Potassium Nitrite, Prenylamine, Propatyl drugs, sympathomimetic drugs, antimicrobial drugs, Nitrate, Pyridofylline, Trapidil, Tricromyl, 20 antihypertensive drugs, cardiotonic drugs, coronary Trimetazidine, Trolnitrate Phosphate, Visnadine vasodilators, vasoconstrictors, beta blocking and an VASODILATOR (PERIPHERAL) such as Bame tiarrhythemic drugs, calcium antagonistic and other than, Betahistine, Bradykinin, Brovincamine, Bufoni circulatory anticonvulsants, anti-vertigo-tranquilizing ode, Buflomedil, Butalamine, Cetiedil, Ciclonicate, 25 drugs, antipsychotic drugs, muscle-reactants drugs, Cinepazide, Cyclandelate, Eledoisin, Heronicate, anti-Parkinson drugs, non-steroidal hormones, anti-hor Inositol Niacinate, Isoxsuprine, Kallidin, Kallikrein, mones, vitamins, antitumor, enzymes, herb medicines or Moxisylyte, Nicofuranose, Nicotinyl Alcohol, Nyli crude extracts, miotics, cholinergic agonists, antimusca drin, pentoxifylline, Piribedil, Suloctidil, Xanthinal rinic or muscarinic cholinergic blocking drugs, mydri Niacinate 30 atics, psychic energizers, humoral agents, antispas VASOPROTECTANT such as Benzarone, Bioflavo modic drugs, antidepressants, antidiabetics, anorexic noids, Chromocarb, Clobeoside, Diosmin, Dobesilate drugs, anti-allergic drugs, decongestants, antipyretics, Calcium, Escin, Rolescutol, Leucocyanidin, Metes antimigraine drugs, antimalarial, antiulcer drugs, pep cufylline, Quercetin, Rutin, Troxerutin tides, and anti-estrogens. VITAMIN/VITAMIN SOURCE/EXTRACTS such 35 5. The composition of claim 4, in which the pharma as Vitamins A, B, C, D, E, and K and derivatives ceutically active agent is one or more steroids selected thereof, Calciferols, Glycyrrhiza, Mecobalamin from the group consisting of androgenic steroids, in VULNERARY such as Allantoin, Asiaticoside, Cadex cluding testosterone; methyltestosterone; fluoxymester omer Iodine, Chitin, Dextranomer one; estrogenic steroids, including conjugated estro The above list of pharmaceutical agents is based upon gens, esterified estrogens, estropipate, 17-6 estradiol, the list provided in The Merk Index, 11th Edition, 17-g estradiol esters such as 17-g-estradiol valerate, Merck & Co. Rahway, N.J. (1989). Moreover, the equilin, mestranol, estrone, estriol; 17-6 estradiol deriv above drugs may be used either in the free form or, if atives such as 17-g ethinyl estradiol; diethylstilbestrol, capable of forming salts, in the form of a saly with a progestational agents, including progesterone and pro suitable acid or base; if the drug has a carboxyl group, 45 gesterone analogs such as 19norprogesterone, hydroxy its esters may also be employed. progesterone caproate, 17-dihydroxyprogesterone, dy What is claimed is: drogesterone, medroxyprogesterone acetate; and nor 1. A flexible, finite, bioadhesive composition for topi ethindrone, norethindrone acetate, melengestrol, chlor cal application comprising: madinone; ethynodiol diacetate, norethynodrel, dy (a) a therapeutically effective amount of at least one 50 pharmaceutically active agent which is in solid drogesterone, dimethisterone, ethinylestrenol, norges form at ambient temperatures and pressures; trel, demegestone, promegestone, megestrol acetate, (b) a pharmaceutically acceptable solvent for the and anti-estrogen or anti-androgenic steroids. pharmaceutically active agent, in an amount from 6. The composition of claim3, wherein the anesthetic about 5 to about 70 weight percent based on the 55 agent is selected from the group consisting of procaine, weight of the whole composition, said solvent in lidocaine, prilocaine, mepivacaine, dyclonine, dibu cluding about 5 to about 50 weight percent of a caine, benzocaine, chloroprocaine, tetracaine, bupiva plasticizer; caine, and etidocaine and is in the form of the base or an (c) in admixture with the pharmaceutically active acid-addition salt or both forms. agent in the solvent, a pharmaceutically acceptable 7. The composition of claim 6, wherein the acid-addi polysaccharide bioadhesive carrier in an amount tion salt is hydrochloride. from about 20 to about 50 weight percent based on 8. The composition of claim 1, wherein the bioadhe the weight of the whole composition; sive is selected from the group consisting of guns and wherein the composition is substantially free of wa celluloses. ter, substantially water insoluble and is a bioadhe 65 9. The composition of claim 8, wherein the gum is sive; and wherein the pharmaceutically active selected from the group consisting of karayagum, trag agent is present in non-crystallized form in the acanth gum, pectingum, xanthan gum, guar gum, cellu composition. lose, and cellulose derivatives. 5,446,070 43 44 10. The composition of claim 3, wherein the solvent thetic agents comprise about 1 to about 50% by for the anesthetic agent is at least one polyhydric alco weight of the total composition. hol. 27. The composition of claim 26, wherein the first 11. The composition of claim 10, wherein the poly local anesthetic agent in base form is selected from the hydric alcohol is a polyalkylene glycol. group consisting of procaine, dyclonine, lidocaine, 12. The composition of claim 11, wherein the glycol prilocaine, mepivacaine, benzocaine, propoxycaine and is selected from the group consisting of dipropylene chloroprocaine. glycol, propylene glycol, ethylene glycol, polyethylene 28. The composition of claim 26, wherein the second glycol, glycerin, butylene glycol, hexylene glycol, poly local anesthetic agent in non-salicylate acid-addition propylene glycol, and sorbitol. O salt form is selected from the group consisting of a 13. The composition of claim 1 further comprising a dyclonine salt, a prilocaine salt, a tetracaine salt, a backing material conforming to the size and shape of a bupivacaine salt, a mepivacaine salt, a lidocaine salt, a single dosage of the composition. procaine Salt, an etidocaine salt, and a dibucaine salt. 14. The composition of claim 1 comprising about 20 29. The composition of claim 26, wherein the first to 34 weight percent of karaya gum, about 20 to 53 15 local anesthetic agent in base form is selected from the weight percent of at least one glycol, and about 10 to 25 group consisting of procaine, dyclonine, lidocaine, weight percent of lidocaine base prilocaine, nepivacaine, benzocaine, propoxycaine and and further comprising a binder in an amount suffi chloroprocaine and the -second local anesthetic in acid cient to bind the other ingredients. addition salt form is selected from the group consisting 15. The composition of claim 14 comprising about 30 of a dyclonine salt, a priocaine salt, a tetracaine salt, a weight percent of karaya gun, about 6 weight percent bupivacaine salt, a mepivacaine salt, a lidocaine salt, a propylene glycol, about 15 weight percent of dipropyl procaine salt, an etidocaine salt, and a dibucaine salt. ene glycol, about 15 weight percent of glycerine, about 30. The composition of claim 29, wherein the acid 25 weight percent of lidocaine base and about 9 weight addition salt is the hydrochloride. percent of lecithin. 25 31. A composition for topical application comprising: 16. The composition of claim 14, comprising about 33 (a) a therapeutically effective amount of a first local weight percent of karaya gum, about 7 weight percent anesthetic agent in base form; of propylene glycol, about 12 weight percent of dipro (b) a therapeutically effective amount of a different, pylene glycol, weight percent of glycerin, about 10 30 second local anesthetic agent in acid-addition salt weight percent lidocaine base and about 5 weight per form; and cent lecithin. (c) in an admixture with the anesthetic agents, a phar 17. The composition of claim 1, wherein the pharma maceutically acceptable carrier which is substan ceutically active agent is an anti-microbial agent. tially free of water 18. The composition of claim 17, wherein the anti 35 wherein the anesthetic agents comprise about 1 to microbial agent in an antifungal agent. about 50% by weight of the total composition and 19. The composition of claim 18, wherein the anti wherein said composition is substantially free of microbial agent is clotrimazole. Water. 20. The composition of claim 18, wherein the antimi 32. The composition of claim 31, wherein the first crobial agent is miconazole. local anesthetic agent in base form is selected from the 21. A method of administering one or more pharma group consisting of procaine, dyclonine, lidocaine, ceutically active agent to a subject comprising the steps priocaine, mepivacaine, benzocaine, propoxycaine and of: chloroprocaine. providing the composition set forth in claim 1; and 33. The composition of claim 31, wherein the second contacting an area of skin or mucous membrane with 45 local anesthetic agent in acid-addition salt form is se the composition to administer the pharmaceuti lected from the group consisting of a dyclonine salt, a cally active agent. prilocaine salt, a tetracaine salt, a bupivacaine salt, a 22. The method of claim 21, wherein the pharmaceu mepivacaine salt, a lidocaine salt, a procaine salt, an tically active agent is an anesthetic agent selected from etidocaine salt, and a dibucaine salt. the group consisting of procaine, dyclonine, lidocaine, 50 34. The composition of claim 33, wherein the first prilocaine, mepivacaine, benzocaine, propoxycaine, local anesthetic agent in base form is selected from the chloroprocaine, tetracaine, bupivacaine, etidocaine, and group consisting of procaine, dyclonin, lidocaine, prilo dibucaine. caine, mepivacaine, benzocaine, propoxycaine and 23. The method of claim 22, wherein the anesthetic chloroprocaine and the second local anesthetic in acid agent is administered in the form of a free base. 55 addition salt form is selected from the group consisting 24. The method of claim 22, wherein the anesthetic of a dyclonine salt, a prilocaine salt, a tetracaine salt, a agent is administered in the form of an acid-addition bupivacaine salt, a mepivacaine salt, a lidocaine salt, a salt. procaine salt, an etidocaine salt, and a dibucaine salt. 25. The method of claim 22, wherein the solvent is at 35. The composition of claim 34, wherein the acid least one polyhydric alcohol. addition salt is the hydrochloride. 26. A composition for topical application comprising: 36. The composition of claim 26 or 31, wherein the (a) a therapeutically effective amount of a first local solvent for the anesthetic agent is at least one polyhyd anesthetic agent in base form; ric alcohol. (b) a therapeutically effective amount of a different, 37. The composition of claim 36, wherein the poly second local anesthetic agent in non-salicylate 65 hydric alcohol is a polyalkylene glycol. acid-addition salt form; and 38. The composition of claim 37, wherein the glycol (c) in an admixture with the anesthetic agents, a phar is selected from the group consisting of dipropylene maceutically acceptable carrier wherein the anes glycol, propylene glycol, ethylene glycol, polyethylene 5,446,070 45 46 glycol, glycerin, butylene glycol, hexylene glycol, poly 42. The method of claim 41, wherein the acid-addi propylene glycol, and sorbitol. tion salt is hydrochloride. 39. The composition of claim 26 or 31, further com 43. The method of administering the composition of prising a backing material which conforms to the size claim 31 to a subject, comprising the steps of: and shape of a single dosage of the composition. 5 (a) providing a composition set forth in claim 31; and 40. The method of administering the composition of (b) contacting an area of tissue with the composition claim 26 to a subject, comprising the steps of: to administer the local anesthetics. (a) providing a composition set forth in claim 26; and 44. The method of claim 43, wherein the first local (b) contacting an area of tissue with the composition anesthetic agent in base form is selected from the group to administer the local anesthetics. 10 consisting of procaine, dyclonine, lidocaine, prilocaine, 41. The method of claim 40, wherein the first local mepivacaine, benzocaine, propoxycaine and chloropro anesthetic agent in base form is selected from the group caine and the second local anesthetic agent in acid-addi consisting of procaine, dyclonine, lidocaine, prilocaine, tion salt form is selected from the group consisting of a mepivacaine, benzocaine, propoxycaine and chloropro dyclonine salt, a prilocaine salt, a tetracaine salt, a caine and the second local anesthetic agent in acid-addi 15 bupivacaine salt, a mepivacaine salt, a lidocaine salt, a tion salt form is selected from the group consisting of a procaine salt, an etidocaine salt, and a dibucaine salt. dyclonine salt, a prilocaine salt, a tetracaine salt, a 45. The method of claim 43, wherein the acid-addi bupivacaine salt, a mepivacaine salt, a lidocaine salt, a tion salt is hydrochloride. procaine salt, an etidocaine salt, and a dibucaine salt. sk : k 20

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65 UNITED STATES PATENT ANDTRADEMARK OFFICE CERTFCATE OF CORRECTION

PATENT NO. : 5,446,070 DATED August 29, 1995 INVENTOR(S) : Juan A. MANTELLE It is certified that error appears in the above-indentified patent and that said Letters Patent is hereby Corrected as shown below:

On the Cover page, section (73), "Nover" should read spNOVera

Signed and Sealed this Nineteenth Day of March, 1996 (a teen BRUCE LEHMAN Attesting Officer Commissioner of Patents and Trademarks

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. : 5,446,070 DATED : August 29, 1995 INVENTOR(S) : Juan A. MANTELLE it is certified that error appears in the above-indentified patent and that said Letters Patent is hereby Corrected as shown below: column 41, line 41, "Merk" should read --Merck--; and line 44, "saly" should read --salt--.

Signed and Sealed this Twenty-eighth Day of May, 1996 Attest 8. (eam

BRUCELEMAN Attesting Officer Commissioner of Patents and Trademarks