US 2004O224012A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0224012 A1 Suvanprakorn et al. (43) Pub. Date: Nov. 11, 2004

(54) TOPICAL APPLICATION AND METHODS Related U.S. Application Data FOR ADMINISTRATION OF ACTIVE AGENTS USING LIPOSOME MACRO-BEADS (63) Continuation-in-part of application No. 10/264,205, filed on Oct. 3, 2002. (76) Inventors: Pichit Suvanprakorn, Bangkok (TH); (60) Provisional application No. 60/327,643, filed on Oct. Tanusin Ploysangam, Bangkok (TH); 5, 2001. Lerson Tanasugarn, Bangkok (TH); Suwalee Chandrkrachang, Bangkok Publication Classification (TH); Nardo Zaias, Miami Beach, FL (US) (51) Int. CI.7. . A61K 9/127; A61K 9/14 (52) U.S. Cl...... 424/450; 424/489 Correspondence Address: (57) ABSTRACT Eric G. Masamori 6520 Ridgewood Drive A topical application and methods for administration of Castro Valley, CA 94.552 (US) active agents encapsulated within non-permeable macro beads to enable a wider range of delivery vehicles, to provide longer product shelf-life, to allow multiple active (21) Appl. No.: 10/864,149 agents within the composition, to allow the controlled use of the active agents, to provide protected and designable release features and to provide visual inspection for damage (22) Filed: Jun. 9, 2004 and inconsistency. US 2004/0224012 A1 Nov. 11, 2004

TOPCAL APPLICATION AND METHODS FOR 0006 Various limitations on the shelf-life and use of ADMINISTRATION OF ACTIVE AGENTS USING liposome compounds exist due to the relatively fragile LPOSOME MACRO-BEADS nature of liposomes. Major problems encountered during liposome drug Storage in vesicular Suspension are the chemi CROSS REFERENCE TO OTHER cal alterations of the lipoSome compounds, Such as phos APPLICATIONS pholipids, cholesterols, ceramides, leading to potentially toxic degradation of the products, leakage of the drug from 0001) This application claims the benefit of U.S. Non the liposome and the modifications of the Size and morphol Provisional patent application Ser. No. 10/264,205, filed ogy of the phospholipid liposome vesicles through aggre Oct. 3, 2002, which further claims the benefit of U.S. gation and fusion. Liposome vesicles are known to be Provisional Patent Application No. 60/327,643 filed Oct. 5, thermodynamically relatively unstable at room temperature 2001. and can Spontaneously fuse into larger, leSS Stable altered FIELD OF INVENTION liposome forms. 0002 The present invention relates to a topical applica 0007 Also adding to the potential instability of lipo tion and methods for administration of active agents, includ Somes in conventional formulations is the pKa. The pKa of ing but not limited to cosmetic, cosmeceuticals and phar compounds may be defined by the pH at which concentra maceuticals, to biological organisms in need thereof. More tions of both the uncharged and charged forms of the Specifically, the present invention relates to encapsulation of molecules are found. active agents using conventionally prepared liposomes and 0008 Various schemes have been devised to avoid some aggregating or globulizing those liposomes into individual the Stability and limitations of liposome formulations, Such macro-beads. The macro-bead allows for isolation of differ as freeze drying of the composition. The freeze dried com ent active ingredients, thus allowing chemically incompat position is reconstituted as required for use. ible active ingredients to be placed into the same delivery vehicle. The macro-bead also increases the shelf-life, while 0009 What is needed is a liposome formulation that reducing environmental StreSS, of the liposome. avoids the disadvantages of pre-existing liposomes formu lations discussed above, that has a longer shelf-life, provides BACKGROUND OF THE INVENTION controlled and increased concentrations of active agents at or near the desired target administration site, allows Segre 0003) When phospholipids and many other amphipathic gation of different active agents and provides the ability to lipids are dispersed gently in an aqueous medium they Visually determine if the integrity of the lipoSome has been hydrate and Spontaneously form multilamellar concentric affected by undesired alterations. bilayer vesicles. The lipid bilayers are separated with layers of the aqueous media. These vesicles are commonly referred SUMMARY OF THE INVENTION to as multilamellar liposomes or multilamellar vesicles and usually have diameters of about 0.2 um to 5 Lim. Sonication 0010. The present invention contemplates the use of of the multilamellar vesicles results in the formation of liposome encapsulated materials made by any conventional Smaller unilamellar vesicles with diameters usually in the means and Subsequently, or in addition to the encapsulation range of 20 to 100 nm, containing an aqueous Solution in the process, provides a System to Suspend these liposomes into core. Multivesicular liposomes differ from multilamellar discrete multilamellar vesicles. The multilamellar vesicles liposomes in the random, non-concentric arrangement of the are designed with Surface tensions of different Strengths to chambers within the liposome. Amphipathic lipids can form provide an improved delivery System of a drug or other a variety of Structures other than liposomes when dispersed active agent. The present invention provides compositions in water, depending on the molar ratio of lipid to water, but and methods of administration of globules or beads of at low ratios the liposome is the preferred Structure. liposomal formulations and active agents in predetermined sizes with Similar or different active agents, thereby enhanc 0004. The physical characteristics of liposomes generally ing the use of the drug or active agents in a number of depend on pH and ionic strength. They characteristically different ways. show low permeability to ionic and polar Substances, but at certain temperatures can undergo a gel-liquid crystalline 0011. Accordingly, the present invention provides a com phase transition dependent upon the physical properties of position and method of administration of active agents the lipids used in their manufacture which markedly alters which, when used in combination with liposomes, enables a their permeability. The phase transition involves a change wider range of vehicles, provides longer life of the product, from a closely packed, ordered Structure, known as the gel provides controlled and increased concentrations of active State, to a loosely packed, less ordered Structure, known as agents at or near the desired target administration Site, the liquid crystalline phase. provides protected and designable release features, allows Segregation of different active agents and allows the con 0005 Various types of lipids differing in chain length, trolled use of the active agent and their visual inspection for Saturation, and head group have been used in liposomal drug damage and consistency. formulations for many years, including the unilamellar, multilamellar and multivesicular liposomes described 0012. In general, the invention comprises a composition above. The major goal of the field is to develop liposomal and method for the administration of beads or globules of formulations for Sustained release of drugs and other com liposomal formulations and active agents. The active agents pounds of interest and to develop liposome formulations include but are not limited to cosmetics, cosmeceuticals and from which the rate of release of the encapsulated material pharmaceuticals. A liposomal Suspension of multilamellar can be controlled. vesicles encapsulating the active agent is prepared by con US 2004/0224012 A1 Nov. 11, 2004

ventional methods. The liposomal Suspension is placed into desired; however the preferred concentration range is 1 to a physical or physiochemical bonding Solution resulting in a 1.5% by weight. Different beads require different concen liposomal first Solution. The resulting liposomal first Solu trations of the bonding Solution to provide the proper degree tion is then aliquoted into a Second Solution containing at of hardness of the shell. least one inorganic Salt. The at least one inorganic Salt of the Second Solution comprises 1-2% by weight of the Second 0018. The liposomal first solution is then introduced into Solution. Upon entry into the Second Solution, the liposomal a Second Solution comprising an anti-oxidant and one or first Solution develops a hardened Surface and forms a bead. more inorganic Salts. In the preferred embodiment, the The beads are then aggregated and washed with an inert anti-oxidant is Selected from the group consisting of BHA, Solution to remove any residual liposomal first Solution and BHT, Tocopherol and sodium edetate. However, any number Second Solution. The resulting liposomal beads are now of known anti-oxidants may be used. It is preferable that the ready for use. anti-oxidant comprise 0.01 to 0.5% by weight of the second Solution. In the preferred embodiment, the inorganic Salt is 0013 In the preferred embodiment, multiple portions of Selected from the group consisting of calcium chloride, an empty acqueous liposome formulation are lyophilized and calcium Sulfate, calcium carbonate, mangesium chloride, hydrated with a Solution of active agent or other material that magnesiun Sulfate, barium chloride, or barium Sulfate. In are to be encapsulated resulting in the formation of lipoSome alternate embodiments, other inorganic Salts may be used in multilamellar vesicles containing the active agent or mate the Second Solution. In the preferred embodiment, the inor rials. In the preferred embodiment, the active agent is ganic Salt comprises about 1 to 2% by weight of the Second Selected from the group consisting of cosmetics, cosmeceu Solution. ticals and pharmaceuticals. However, in alternate embodi ment, it may be possible for one skilled in the art to use other 0019. In the preferred embodiment, the liposomal first materials with different therapeutic characteristics. The por Solution is introduced into the Second Solution through a tions of liposome Solution are then Separated or pooled to predetermined orifice which allows for a specific size or form the final liposome preparation. Each batch may be amount of liposomal first Solution to be introduced. In washed prior to pooling to remove unencapsulated active prototype development testing, the types of delivery Systems agent. In the preferred liposome encapsulation process, 50 to used included needle injection and disc Spinning. However, 95% of the total active agent or other material is entrapped other types of delivery Systems, Such as spraying, hydraulic or encapsulated. Alternative methods of preparing the lipo preSSure pump, gravitational dipping, pneumatic pumping or Some preparation may be used, as will be readily apparent to liquidating methods may be used. The means of macro-bead one skilled in the art. formation can be achieved by a number of alternative embodiments, including but not limited to providing the 0.014. The liposome multilamellar vesicles are then liposome formulation through a spray, Spinning vessels, mixed into a vessel containing a pre-determined concentra injection, pumping, dripping or aliquoting method. tion of a physical reaction and/or potentially physiochemical bonding Solution. This mixture results in a liposomal first 0020. Upon a period of prolonged submersion of the Solution. In the preferred embodiment, the bonding Solution liposomal first Solution in the Second Solution, the liposomal contains at least one organic compound Selected from the first Solution develops a hardened outer Surface and forms a group consisting of agarose, cellulose, Sodium alginate, macro-bead. In the preferred embodiment, the macro-beads chitosans, or polymeric Substances. In the present invention, are generally spherical or irregular polygon in shape and natural polymers are preferable over Synthetic polymers to their appearance allows for identification and Verification of croSS-link the macro-beads. In alternate embodiments, other macro-bead formation. The shape, degree of hardening and compounds with the necessary characteristics of physical resulting force necessary to fracture the macro-bead is reaction or physiochemical bonding may be used. determined by the formulation of the inorganic Salt Solution, the pH of the inorganic Sal Solution, the time of Submersion 0.015. In another preferred embodiment, the liposomal or contact with the inorganic Salt Solution, and the relative first Solution is comprised of the multilamellar lipoSome temperature differentials between the liposome formulation containing cosmetic or pharmaceutical actives mixed with a and the inorganic Salt Solution. micro-emulsion Solution composed of organic oils in one phase and a group of organic compounds consisting of 0021. In the preferred embodiment, the pH of the inor agarose, cellulose, Sodium alginate, chitosans, or polymeric ganic Salt Solution was 6-7, the length of time of Submersion Substances at a pre-determined temperature. was 60 to 180 minutes, and the solution temperature was 25 to 30° C. 0016. The preferred bonding characteristics include the ability to form polymer network attraction, compatible with 0022. The hardness of the bead is measured in "yield liposomes, able to form beads in the presence of inorganic Strength', which is measured as the amount of weight Salts. The bonding may consist of polarity bonding, ionic required to rupture the macro-bead. The yield Strength is bonding, Van der Waals bonding and affinity bonding. expressed as grams per cubic millimeter (gm/mm). The preferred range of hardneSS or force necessary to fracture the 0.017. It is preferable that the bonding solution forms the bead is 1 to 4 gm/mm. However, the range of firmness may outer Shell of the macro-bead in the presence of inorganic vary, So long as the lipoSome formulation remains consti Salts and holds the liposomal actives inside at the same time tuted in macro-bead form. to maintain the Stability of the macro-bead and enhance the Stability of the liposomes. The bonding Solution can also 0023 The macro-beads of the present invention are non protect the inner microparticle lipoSomeS when exposed to permeable. Because the macro-beads are non-permeable, the inorganic Salts. The general concentration range of the diffusion or Slow-controlled release of the lipoSome Suspen bonding Solution depends upon the type of the macro-bead Sion and active agents through the hardened shell does not US 2004/0224012 A1 Nov. 11, 2004 occur. The liposome Suspension and active agents are only 0033. The therapeutic benefit of allowing the user to released when the hardened shell is fractured. Visually determine the location and amount of the active 0024. The macro-beads are physically separated by any agent applied to the treatment area thus enabling the user to means of Selection, Specific gravity or physical filtration and control the locus and levels of agent where the active rinsed with any conventional washing operation. In the ingredient is most needed. preferred embodiment, the beads are Separated by a Sieve 0034. The benefit of having active agents in bead form, and washed with deionized water for 15 minutes and then and thus not in direct contact with other active or inert rinsed again with deionized water. The outer portions of the Suspensions including other liposomes. This includes Second wet liposome embodiments, including liposome-micro and third levels of bead formation and levels of hardening emulsion Spheres, are then dehydrated to remove the remain encapsulation. ing water. Dehydration is accomplished by any chemical and/or physical means. The dried liposome micro-emulsion 0035. The benefit of being able to produce liposome Spheres are then Stored in a pre-determined concentration of beads of discrete and predetermined size for more accurate organic, inorganic, or aqueous aliquot of organic or inor administration of drugs or other active agents. ganic compound Solution, ready to be further processed into 0036) The benefit of having different types of delivery finished products. vehicles, containing the beads, to deliver the treatment, 0.025 The liposome macro-beads can be used in any whether inert or containing active agents, thereby effectively number of delivery vehicles. The variability and uses of the allowing for the vehicle to be an active agent. beaded liposome are extensive with the physical character istics and applications being determined and designed by the 0037. The benefit of having more than one active agent physical characteristics of the macro-bead wall and the encapsulated within the bead membrane itself, thereby pro contents of the macro-bead. Viding a multiple active agent liposomal mixture which only becomes interactive when the dynamics of the beads are 0026. Because the macro-bead has a hardened shell or affected to release their encapsulated agents. Surface, the Shell or Surface must be broken in order to release the lipsomal Suspension to contact the skin or 0038. The benefit of being able to define the physical mucous membrane. The preferred mechanism for rupturing characteristics of the Semi-rigid wall of the bead for Specific the macro-bead Surface is to have a dispensing means that protection and delivery of the liposomic compound or utilizing a mechanical means of Sufficient force to fracture compounds, including a slow and/or continuous delivery of the hardened Surface of the macro-beads to release the the active agent. liposomal Suspension. Once the liposomal Suspension is released into the skin or mucous membrane, the lipoSome 0039 The benefit of a bead protecting the liposomal will gradually absorb into the skin or mucous membrane. AS formulation from physically changing forces Such as ultra the liposome is absorbed, the multilamellar layers of the Sound, Vibration, light, microwaves and other energy pro lipoSome slowly rupture and release the active agents con Viding Sources, by both the Semi-rigid wall and the type of tained within to the Surrounding tissues. vehicles used. 0027. In one embodiment, carbopol gel will be used for 0040. The benefit of designing extended shelf life and oil-Soluble actives. The carbopol gels may be neutralized by protection of the lipoSome through various means including means of alkaline Substances or buffered by a predetermined the Suspension of the beads in vehicles, which would ordi pH buffer solution to yield clear gels. narily adversely react with a liposome. 0028. In another embodiment, silicone derivatives will be 0041. The ability to visually determine if any undesired used for water Soluble actives. The silicone derivatives alterations or lack of integrity bead wall has affected the vehicles are designed Such that an anhydrous environment is integrity of the liposome is also a benefit. A broken or achieved and the clarity and/or Viscosity are adjusted distended bead can indicate the potential instability of the through the quantities of the organic Silicones or Solvents liposomes. comprising the Silicone bases of intended use. 0042. The benefit of a hardened surface wall which can 0029. The now prepared final macro-bead formulation then be processed in various means for Special uses by can be used for any of the desired embodiments. The means and compounds that would otherwise have been variability and uses of the macro-beaded liposome are damaging or altering to the liposomal active agents. extensive with the physical characteristics and applications being determined and designed by the physical characteris 0043. The benefit of easily designing and producing a tics of the macro-bead wall and the contents of the macro variety of different bead walls and differently controlled bead. releases of active agents, released through a number of different mechanisms for maintaining or delivering a lipo 0030 The benefits of defined macro-beads include one or Some at the desired site of the delivery, which delivery can more of the following for each use: be released and controlled by the fracture of the bead wall 0031. The therapeutic benefit of treating all types of through various means of wall release. Thus, the entire Dermatocytosis. design becomes a tool for the effective delivery individually or as part of a System which requires the addition of outside 0.032 The therapeutic benefit from the user being able to energy or intervention. provide controlled and increased concentration of active agent released at or near the desired target Site of adminis 0044) The benefit of a designed indicator of any liposome tration on or in the Skin. degradation, infiltration or loss of bead wall integrity. US 2004/0224012 A1 Nov. 11, 2004

DETAILED DESCRIPTION OF THE material that is to be encapsulated, and may be washed to INVENTION remove unencapsulated material. 004.5 The present invention contemplates the use of 0051. In a fourth alternative procedure, a plurality of lipoSome encapsulated materials made by any conventional portions of an organic Solution of lipids is provided in a means and Subsequently, or in addition to the encapsulation plurality of containers, and the organic Solvents are evapo process, provides a composition to Suspend these liposomes rated from each portion, resulting in the formation of a thin into discrete macro-beads. The macro-beads are designed lipid film on the walls of each container. The evaporation with Surface tensions of different Strengths to provide an process may be any conventional evaporation process, Such improved delivery System of a drug or other active agent. as rotary evaporation. An acqueous Solution of the material to The present invention is a topical application and method of be encapsulated is then added to each portion and the administration of macro-beads of liposomal formulations container is agitated. The resulting Solution is the formation and active agents in predetermined sizes with Similar or of a plurality of portions of liposomes that have trapped the different active agents, thereby enhancing the use of the drug material. These portions are then pooled to form the final or active agents in a number of different ways. liposome preparation. 0046) The present invention provides a topical applica 0052. In an adaptation of the fourth alternative process tion and method of administration which, when added to any described above, an aqueous Solution of a material to be other active or inactive delivery of liposomes, enables a encapsulated is added to one the plurality of containers wider range of vehicles, provides longer life of the product, which have the thin lipid film on the walls, and this container protects active agents from environmental StreSS, allows is agitated to hydrate the lipid film and form a liposome additional active agents within the compound, allows chemi Suspension. This Suspension is then added to another con cally incompatible active agents to be placed into the same tainer having the thin lipid film on the walls thereof. This delivery vehicle, provides protected and designable release container is agitated to hydrate the lipid film. This proceSS is features, and allows the controlled use of the active agent repeated until all of the containers having the thin lipid film and their visual inspection for damage and consistency. The have been hydrated, resulting in the formation of the final active agents being Selected from the group consisting of liposome preparation. cosmetics, cosmeceuticals and pharmaceuticals. 0053 Other conventional approaches to making lipo 0047 The present invention is compatible with all known Some mixtures may be used, Such as rotating Systems to and anticipated liposomal structures and results in predeter encapsulate the active form in a Suspension or the use of an mined sizes of globulized macro-beads allowing for a Sec aqueous Solution, which is under pressure, and is injected ond and additional level of control, shelf life and application with the active agent into a lipid Solution to form liposomes, ease. Liposome compositions, which have this additional referred to as “reverse phasing method”. Step of placing the lipoSome into macro-beads, have been 0054. It is preferable that the selected liposome encap shown to be more effective in the delivery of the active agent sulation process traps or encapsulates 50 to 95% of the in Several means. They also enjoy Superior or increased shelf available total active agents. It is preferable that the active life of the active agent, and allow different active agents to agent comprise 0.01 to 5 weight percent of the liposome remain Segregated until release upon fracture of the bead composition. Surface. They also allow for the Storage of normally incom patible active agents in one composition to be delivered to 0055. The prepared liposome is then mixed into a vessel the biological organism. containing a predetermined concentration of a physical reaction and/or potentially physiochemical bonding Solu 0.048. In the preferred embodiment, the intended lipo tion. It is preferable that the bonding Solution contains at Some is made by any known means of formation. Typical least one organic compound Such as agarose, cellulose, lipoSome manufacturing processes comprise the following Sodium alginate, chitosans, polymeric Substances or other Steps: multiple portions of an "empty' aqueous lipoSome compounds with the necessary characteristic of physical formulation are provided, each portion is lyophilized and reaction or physiochemical bonding. In the present inven hydrated with a Solution of the active agents or materials that tion, natural polymers are preferable over Synthetic poly are to be encapsulated, resulting in the formation of lipo mers to cross-link the macro-beads. The resulting Solution is Somes which have trapped the active agent or material. hereinafter referred to as the “liposomal first solution”. These portions are then Separated or pooled to form a batch of material, which typically constitutes the final lipoSome 0056. In another preferred embodiment, the liposomal preparation. Each batch may be washed prior to pooling to first Solution comprises the multilamellar lipoSome contain remove unencapsulated material. ing cosmetic or pharmaceutical actives mixed with a micro emulsion Solution composed of organic oils in one phase and 0049. Alternatively, liposomes are prepared using an a group of organic compounds consisting of agarose, cellu organic Solution of lipids which are dried and hydrated with lose, Sodium alginate, chitosans, or polymeric Substances at water to form "empty' liposome formulations. Each portion a pre-determined temperature. is then lyophilized and hydrated with a solution of the 0057 The charge of the liposome can be altered to affect material to be encapsulated. the depth of penetration into the dermis. The charge of the 0050. In another alternative procedure, liposome formu liposome is altered by the typed of charged lipids composed lation compounds are made by lyophilizing an empty lipo in the liposomal preparation. The negatively charged lipids, Some formulation and aliquoting the lyophilized material Such as dicetyl phosphate, dipalmitiyl phosphatidyl gly into a plurality of portions prior to lyophilization. Each Verol, will Stay in the epidermis above the basement mem lyophilized portion is then hydrated with a solution of the brane Zone. The basement membrane Zone is negatively US 2004/0224012 A1 Nov. 11, 2004

charged, So the negatively charged liposome will be repelled Some-micro-emulsion Solution is then introduced into the by the basement membrane Zone causing the negatively inorganic Salt Solution through a predetermined orifice charged lipoSome to remain in the epidermis. On the other which allows for a Specific Size or amount of lipsome hand, a positively charged lipid, Such as Sterylamine, will be micro-emulsion Solution to be introduced. drawn by the opposite charged basement membrane Zone, 0063. Upon a period of prolonged submersion in the Subsequently penetrating deeper into the dermis. Second Solution, the liposomal first Solution develops a 0.058. The preferred physical reaction or physiochemical hardened Surface and forms a macro-bead, typically 1 to 4 bonding characteristics include the ability to form polymer mm in size. Differing appearances allow for identification network attraction, compatible with liposomes, able to form and Verification of the formation and size of the macro-bead. beads in the presence of inorganic Salts. The bonding may The shape, degree of hardening and resulting force neces consist of polarity bonding, ionic bonding, Van der Waals Sary to fracture the macro-bead in order to release its active bonding and affinity bonding. ingredient is determined by the formulation of the Second 0059. It is preferable that the bonding solution forms the solution, the pH of the second solution, the time of submer outer shell or hardened Surface of the macro-bead in the Sion or contact with the Second Solution, and the relative presence of inorganic Salts and holds the liposomal actives temperature differentials. In Summary, pH will have signifi inside the macro-bead at the same time maintaining the cant impact on the bead formation. Too low of a pH (pH stability of the macro-bead and enhancing the stability of the below 5) the bead cannot be formed. For high pH (pH above liposomes. The bonding Solution can also protect the inner 8), the matrix polymers, e.g., alginate, will precipitate. microparticle liposomes when exposed to the inorganic Regarding the time of Submersion, if the bead remains in the Salts. The general concentration range of the bonding Solu Second Solution for too long, the bead will contract resulting tion depends upon the type of the bead; however the in an undesired Smaller-Sized and hard bead. In regards to preferred concentration range is 1 to 1.5% by weight. temperature, at temperatures above 80 C., alginate will Different macro-beads require different concentrations of the degrade and cannot form the bead. In the preferred embodi bonding Solution to provide the proper degree of hardness of ment, the pH was 6-7, the typical period of Submersion was the shell. 60-180 minutes and the solution temperature was 25 to 30 C. 0060. The liposomal first solution is preferably intro duced into a Second Solution, comprising an anti-oxidant and 0064. The macro-beads of the present invention are non one or more inorganic salts, through a predetermined orifice permeable. Because the macro-beads are non-permeable, which allows for a specific Size or amount of liposomal first diffusion or Slow-controlled release of the lipoSome Suspen Solution one to be introduced into the second solution. The Sion and active agents through the hardened shell does not anti-oxidant comprises about 0.01 to 0.5% by weight of the occur. The lipoSome Suspension and active agents are only Second Solution. The inorganic Salt preferably comprises released when the hardened shell is fractured. about 1 to 2% by weight of the second solution. The effect 0065. The preferred general shape of the formed bead is of the interaction of the liposomal first solution with the generally spherical or irregular polygon. The hardness of the Second Solution is to harden the outer most exposed areas of macro-bead is measured in "yield Strength', which is mea the introduced liposomal first Solution over a period of Sured as the amount of weight required to rupture the prolonged Submersion. In prototype testing the anti-oxidant macro-bead. The yield strength is expressed as grams per of the second solution was comprised of BHA, BHT, Toco cubic millimeter (gm/mm). The preferred range of hardness pherol and Sodium edetate. However, many other known or force necessary to fracture the macro-bead is 1 to 4 anti-oxidants may be used. The inorganic Salts used com gm/mm. However, the range of firmness may vary, so long prised of calcium chloride or Sodium hydroxide, although as the liposome formulation remains constituted in bead other types of inorganic Salts can be used Such as calcium form. Sulfate, calcium carbonate, magnesium chloride, magnesium 0066. The yield strength is a measurement of the resis Sulfate, barium chloride, barium Sulfate or other Salts. tance force of the macro-bead. The equipment measures the 0061. In the preferred embodiment, the liposomal first resistance force by adding weight, either liquid or Solid, onto Solution is introduced into the Second Solution by dripping the plate that is located over the macro-bead until the the liposomal first Solution through a Small needle or pre macro-bead ruptures. The weight is recorded as yield determined orifice or by Spinning the liposomal first Solution Strength per cubic millimeter. with a centrifugal force via a rotating disc. The predeter mined orifice allows for a Specific size or amount of lipo 0067. The beads are physically separated by any means Some Solution to be introduced. In prototype development of Selection, Specific gravity or physical filtration and rinsed testing, other types of delivery System also used included with any conventional washing operation. In the preferred Spraying, hydraulic preSSure pump, gravitational dipping, embodiment, the beads are Separated by a Sieve and washed pneumatic pumping or liquidating methods. with deionized water for 15 minutes and then rinsed again with deionized water. The outer portions of the wetliposome 0.062. In another preferred embodiment, the liposomal embodiments, including liposome-micro emulsion Spheres, first Solution comprises the multilamellar lipoSome contain are then dehydrated to remove the remaining water. The ing cosmetic or pharmaceutical activce mixed with a micro dehydration process is accomplished by any chemical and/or emulsion Solution composed of organic oils in one phase and physical means. The dried liposome micro-emulsion spheres a group of organic compounds consisting of agarose, cellu are then Stored in a pre-determined concentration of organic, lose, Sodium alginate, chitosans or polymeric Substances. In inorganic, or aqueous aliquot of organic or inorganic com the present invention, natural polymers are preferable over pound Solution, ready to be further processed into finished Synthetic polymers to cross-link the macro-beads. The lipo products. US 2004/0224012 A1 Nov. 11, 2004

0068 Depending upon the designed use of the macro encapsulated within the same macro bead. Another preferred bead, various compositions are achieved by changes to the embodiment utilizes more than active agent encapsulated Surface thickness of the macro-bead, the size of the macro within different macro beads, but placed into the same bead, the shape of the macro-bead, and any additional delivery vehicle. This alternative allows for chemically compounds which are added to the delivery vehicle. incompatible active agents to be placed into the same 0069. The now prepared final macro-bead composition delivery vehicle for Simultaneous application. can be used in a multitude of applications. The variability 0073. In another embodiment, the invention relates to a and uses of the macro-beaded liposome are extensive with composition and method of administering one or more the physical characteristics and applications being deter active agents to a Subject comprising the Steps of mined and designed by the physical characteristics of the macro-bead wall and the contents of the macro-bead. 0074 (a) providing a liposome encapsulated macro bead composition containing at least one active 0070 Because the macro-bead has a hardened shell or agent, Surface, the Shell or Surface must be broken in order to release the lipsomal Suspension to contact the skin or 0075 (b) placing a selection of the macro-beads is mucous membrane. The preferred mechanism for rupturing into a delivery vehicle resulting in a final formula the macro-bead Surface is to have a dispensing means that tion, utilizing a mechanical means of Sufficient force to fracture the hardened Surface of the macro-beads to release the 0076 (c) applying the final formulation to an area of liposomal Suspension. Once the liposomal Suspension is skin or mucous membrane by a dispensing means, released into the skin or mucous membrane, the lipoSome the dispensing means utilizing a mechanical means will gradually absorb into the skin or mucous membrane. AS of Sufficient force to fracture the hardened Surface of the liposome is absorbed, the multilamellar layers of the the macro-beads to release the liposomal Suspension. lipoSome slowly rupture and release the active agents con 0.077 Stability Data tained within to the Surrounding tissues. 0071. In one preferred embodiment the liposome encap 0078. The macro-bead of the present invention provides Sulated macro-bead composition is used for topical applica greater Shelf-life of the liposomal Suspension and protects tion. The liposome encapsulated macro-bead composition the lipoSome from environmental Stresses. The macro-bead comprises a therapeutically effective amount of an active also allows for visual identification of a change in appear agent encapsulated in a liposome Suspension of multilamel ance after a prolonged Storage period. lar vesicles in an amount from about 0.01 to 5 weight percent 0079 1. Liposomal Suspension: Chemical Stability Data based on the weight of the whole composition, in admixture with a physical reaction bonding Solution wherein an aliquot 0080 A. The Percentage of Active Ingredient in Liposo of the admixture is Submersed for a period of time in a mal Suspension Solution containing an anti-oxidant and at least one inor 0081. The percentage of actives in liposomal suspension ganic Salt to form the hardened Surface of the macro-bead. assayed by HPLC decreased after 8 months at room tem 0.072 In another preferred embodiment, the invention perature but no changes could be detected at 4 C., as shown relates to a topical comprising more than one active agent by the below graph. US 2004/0224012 A1 Nov. 11, 2004

Percentage of Active in Liposomal suspension

2 ad C O e s C SS O 1 2 3 4 5 6 7 8 9 O 11 12 13 14 15

Months US 2004/0224012 A1 Nov. 11, 2004

0082 B. The Percentage of Actives Entrapped in Lipo Somal Suspension 0.083. The percentage of active entrapped in liposomal suspension assayed by HPLC didn't change after 1 year both at room temperature and at 4 C. as shown in the graph below. US 2004/0224012A1 Nov. 11, 2004

Percentage Capture of Active in Liposomal suspension

d E CL

s

SS US 2004/0224012 A1 Nov. 11, 2004 10

0084 2. Liposomal Suspension: Physical Stability Data -continued Identifications Specification Results Identifications Specification Results Acceptable perOX- <12 uM of TEP equivalent Changed after 8-10 idation (Thiobarbi- per umol of phospholipids months Appearance Yellowish milky Changed after 8-10 turic acid assay) suspension months Odor Characteristic Changed after 10-12 months (Rancidity) 0085 3. Liposomal Macro-Beads: Chemical Stability Viscoscity 100-200 cps. Changed after 8-10 Data months 0086 A. The Percentage of Active Ingredients in Lipo Colour Yellow Changed after 6-8 Somal Beads months 0087. The percentage of active agents in liposomal beads pH 5.5-6.5 Not change assayed by HPLC slightly decreased but still in the specified Acceptable aerobic <100 aerobic organism/g Not change range after 1 year when Stored at 4 C. The same result was microbial count detected at ambient temperature. The results are shown in the graph below. US 2004/0224012 A1 Nov. 11, 2004 11

Percentage of Acitve in Liposomal Bead US 2004/0224012 A1 Nov. 11, 2004 12

0088 B. The Percentage of Acitve Entrapped in Liposo mal Beads 0089. The percentage of active entrapped in liposomal beads assayed by HPLC didn’t change after 1 year both at room temperature and at 4 C. The results are shown in the graph below. US 2004/0224012 A1 Nov. 11, 2004 13

Percentage Capture of Active in Liposomal bead

110

100

90

70

60

US 2004/0224012 A1 Nov. 11, 2004

0090. 4. Liposomal Macro-Beads: Physical Stability B6, Vitamin B12, Biotin, Folic Acid, Pantothenic Acid Data and Pantethine, Vitamin C, Vitamin D, Vitamin E, Vitamin K 0094 Minerals, such as: Boron, Calcium, Chromium, Identifications Specification Results Copper, Fluorine, Germanium, Iodine, Iron, Magne sium, Manganese, Molybdenum, Phosphorus, Potas Appearance White or Yellowish opaque Not changed bead after 1 year sium, Selenium, Silicon, Vanadium, Zinc Odor Characteristic Not changed 0095 Amino Acids, such as: L-Arginine, L-Aspartic after 1 year Viscoscity N/A N/A Acid, Branched-Chain Amino Acids, L-Cysteine (and Colour White or Yellow Not changed Glutathione), L-Glutamine/L-Glutamic Acid, Glycine, after 1 year L-Histidine, L-Lysine, L-Methionine and Taurine, pH 5.0-6.0 Not change L-Phenylalanine, D-Phenylalanine, DL-Phenylalanine, Acceptable aerobic microbial <100 aerobic organism/g Not change L-Tryptophan, L-Tyrosine count Acceptable peroxidation <12 uM of TEP equivalent Not changed 0096 Lipids, such as: AL, Fish Oils/EPA and DHA, (Thiobarbituric acid assay) per umol of phospholipids after 1 year Gamma-Linolenic Acid and Oil of Evening Primrose, Glycosphingolipids, Inositol (Myo-Inositol) and Phos phatidylinositol, Lecithin/Phosphatidylcholine/Cho 0.091 The term active agent as used in the specification line, Liposomes, Lipotropes/Activated Lipotropes, sections entitled “Summary of the Invention” and “Detailed Monolaurin and Caprylic Acid, Phosphatidylserine and Description of the Invention” and in the above examples is Phosphatidylethanolamine intended to include the following therapeutic categories: topically applied antifungals, Such as Terbinafine, Ketocona 0097 Herbs, such as: Aconite, Alfalfa, Aloe Vera and Zole, Climbazole, Tolnaftate; anti-inflammatories, Such as Derivatives, Angelica/Dong Quai, Astragalus, Bay chamomile, corticosteroids and nonsteroidal anti-inflamma berry Root Bark, Black Cohosh, Blessed Thistle, tory drugs (NSAIDS); antiarthritics; corticosteroids, such as Buchu, Burdock, Butcher's Broom, Capsicum/Hot ClobetaSone, Triancinolone acetonide, Betamethasone; Vita Peppers, Cascara Sagrada, Catnip, Chamomile, Chap mins, Such as Retinoic Acid and derivatives, Vitamin K1, arral, Chickweed, Comfrey/Allantoin, Cruciferous Vitamin C, Vitamin B, Vitomin II (Biotin), Vitamin B3, Vegetables, Damiana, Dandelion, Devil's Claw, Nicotinamide, Vitamin E, whitening agents, Such as, hyd Echinacea, Ephedra/Ma-Huang, Euphorbia, Eyebright, roquinone, Arbutin, licorice, Kojic acid, AZelaic acid, Fennel, Fenugreek, Feverfew, Forskolin, Fo-Ti, Garlic Sodium lactate, AHAS, antioxidants, Such as Tranexamic and Onions, Ginger, Ginkgo, Ginseng, Goldenseal, Acid, Polyphenols, nitrus oxide, moisturizers, Such as Aloe Gotu Kola, Hawthorn, Herbal Analbesic Ointments and Vera and Evening primrose oil, Silicone derivatives, Jojoba Oils, Herbal Fiber, Horsetail Grass, Juniper, Kava oil, anabolics, Such as Testoterone, Dihydroepiandrosterone Kava, Licorice, LiguStrum, Melaleuca, Marshmallow, (DHEA), Stanozolol, analgesics (dental, narcotic and non Mexican Wild Yam, Milk Thistle, Mistletoe/Iscador, narcotic), Such as Paracetamol, aspirin; anesthetics (local) Mullein, Myrrh, Nettle, Oats, Parsley, Pau d’arco, Such as Xylocain, Prilocain, Benzocain; antiasthmatics Quinine, Red Clover, Red Raspberry, Saint John's (nonbronchodilator, Steroidal, inhalant) Such as Theophyl Wort, Sarsaparilla, Schizandra, Senna, Skullcap, Slip line, Terbutaline Sulfate; antibacterial (antibiotics) such as pery Elm, Triphala, Uva Ursi, Valerian, Walnuts, Wheat Pennicillins, Cephalosporines, Sulfonamides, Erythromy Grass/Barley Grass, White Oak, Yellow Dock, Yohim cin; antihistaminics such as Psuedophedrine HCl, Chlophe bine namine maleate, Hydroxy Zine, antineoplastics, Such as 0098 Metabolite Supplements, such as: Acidophilus/ Methotrexate, Cisplatin, Boxorubicin HCl, Bleomycin HCl, Yogurt/Kefir, Bioflavonoids, Brewer’s Yeast/Skin Res 5-fluorouracil; antiparasitics Such as Mebedazole, Albenda piratory Factor/Glucan, Coenzyme Q, Dietary Fiber, Zole, Diethylcarbamazine citrate; vasodilators, vasoconstric Enzymes, L-Carnitine, Lipoic Acid, Mushrooms: Shii tors such as Etilefrine HCl, Ethyladrianol HCl, anti-tumor, take and Rei-Shi, PABA, Panagamic Acid/DMG i.e., Seborrheic keratosis to malignant tumors Such as basal (“Vitamin B-15”), Royal Jelly, Seaweeds and Deriva cell carcinoma, anti-viral (warts and molluscum contagio tives, Spirulina and Chlorella, Succinates and Cyto Sum) Such as Acylcovir, Ganciclovir Na, Famciclovir; anti chromes, Wheat Germ/Wheat-Germ. Oil/Octacosanol. Seborrheic Such as Selenium Sulfide; anti-vertigo Such as Meclizine HCl, Diphenidol HCl, compazine; anti insects 0099. The term “administering” is intended to mean any (anti lice); deliverance of toxins, Such as botox (nerve mode of application to a tissue, which results in the physical paralysis); deliverance of hormones Such as estrogen andro contact of the composition with an anatomical Site. The term gen, glucocorticoid; delivery of nicotine, prophylactic uses “Subject' is intended to include all biological organisms. of many of the above; for anti cold; for release of heat; prevention of contact dermatitis and irritants and immuno 0100. In accordance with one embodiment, the liposome SuppreSSants, Such as the crolimus group of drugs including beads are introduced into an inert delivery vehicle or Solu but not limited to primecrolimus and tacrolimus. tion, Such as lotions, ointments, creams or Sprays, for its use. 0101 Another embodiment provides for the liposome 0092. The term active agent is also intended to include beads to be contained in an inert delivery solution which is the following categories: translucent or opaque to the desired level of light reduction. 0093 Vitamins, such as: Vitamin A/Beta-Caroteine, 0102) Another embodiment provides for the liposome Vitamin B1 (Thiamin), Vitamin B3 (Niacin), Vitamin beads to be fractured by a mechanical means as the delivery US 2004/0224012 A1 Nov. 11, 2004

Solution is metered or dispensed from a device. The pre variations are intended to be included within the scope of the ferred fracturing means can be an orifice which is signifi invention as described in this specification. cantly Smaller than the Size of the particular bead, however any known fracturing means may be utilized. 0114 Indeed, the present invention is intended to encom pass and be Suitable for use by Substituting any of the 0103) Another embodiment provides for the liposome following drugs for the active agent in the composition and bead walls to be degraded by non-physical chemical means, methods for administration of the Same: including both pre-existing chemical conditions or the intro duction of a degrading chemical through other means Such 0115 alpha-ADRENERGIC AGONIST such as as within the delivery vehicle, or with other liposome beads. Adrafinil, Adrenolone, Amidephrine, Apraclonidine, Budralazine, Clonidine, Cyclopentamine, Detomidine, 0104. Another embodiment provides for the liposome Dimetofrine, Dipivefrin, Ephedrine, Epinephrine, beads to be coated with a particular color or pattern of Fenoxazoline, Guanabenz, Guanfacine, Hydroxyam recognition So as to allow the user to meter and judge the phetamine, Ibopamine, Indanazoline, Isometheptene, amount of active reagent without unnecessary dilution. Mephentermine, Metaraminol, Methoxamine, Methyl 0105. Another embodiment provides for the size of the hexaneamine, Metizolene, Midodrine, Modafinil, Mox lipoSome beads to change in response to any changes to the onidine, Naphazoline, Norepinephrine, Norfenefrine, lipoSome occurring within the bead wall, thereby indicating Octodrine, Octopamine, Oxymetazoline, Phenyleph a potentially compromised liposome bead. rine, Phenylpropanolamine, Phenylpropylmethy lamine, Pholedrine, Propylhexedrine, Pseudoephe 0106 Another embodiment provides for the liposome drine, Rilmenidine, Synephrine, Talipexole, beads to be Suspended in chronologically degrading walls, Tetrahydrozoline, Tiamenidine, TramaZoline, Tuami or bead walls that are altered by enzymatic or pH factors, noheptane, Tymazoline, Tyramine, Xylometazoline Such as the enzymes and pH changes found when adminis tered Systemically. The liposome bead can be designed to 0116 beta-ADRENERGIC AGONIST such as allow the active agents to remain protected until fracture or Albuterol, Bambuterol, Bitolterol, Carbuterol, Clen Surface tension release by the appropriate enzyme, chrono buterol, Clorprenaline, Denopamine, Ephedrine, Epi logical passage, or pH change. nephrine, Etafedrine, Ethylnorepinephrine, Fenoterol, Formoterol, HeXoprenaline, Ibopamine, Isoetharine, 0107 Another embodiment provides for various degrees Isoproterenol, Mabuterol, Metaproterenol, Methox of hardening of the liposome bead wall, the degree of yphenamine, Oxyfedrine, Pirbuterol, Prenalterol, Pro hardening being predetermined to provide for greater or caterol, Protokylol, Reproterol, Rimiterol, Ritodrine, lesser forces to cause the degradation of the bead wall and Salmerterol, Soterenol, Terbutaline, Tretoquinol, release of its contents at distinct intervals or levels. Tulobuterol, Xamoterol 0108) Another embodiment provides for coating the lipo 0117) alpha-ADRENERGICBLOCKER such as Amo Some beads with various compounds, which are reactive to Sulalol, Arotinilol, Dapiprazole, Doxazosin, Ergoloid the active agent. The incompatible agents are separated by Mesylates, Fenspiride, Indoramine, Labetalol, Nafto the hardened shell, and only become interactive upon the pidil, Nicergoline, PraZosin, Tamsulosin, Terazosin, fracture or softening of the bead wall. Tolazoline, Trimazosin, Yohimbine 0109 Anther embodiment provides for mechanical 0118 beta-ADRENERGIC BLOCKER such as Ace means of release on the using of apparel, for example shoes, butolol, Alprenolol, AmoSulalol, Arotinolol, Atenolol, to activate the fracture or destruction of the bead wall, So as Befunolol, Betaxolol, Bevantolol, Bisoprolol, Bopin to release the active agent. dolol, Bucumolol, Bufetolol, Bufuralol, Bunitrolol, 0110. Another embodiment provides for the use of a Bupranolol, Butidrine, Butofilolol, Carazolol, Car photoactive Suspension of the vehicle So as to release the teolol, Carvedilol, Celiprolol, Cetamolol, Cloranolol, lipoSome from the bead on the event of a predetermined Dilevalol, Epanolol, Esmolol, Indenolol, Labetalol, condition or level of light or other waveform, or any other Levobunolol, Mepindolol, Metipranolol, Metoprolol, energy transmission, Such as ultrasound, microwave, light or Moprolol, Nadolol, Nadoxolol, Nebivalol, Nifenalol, percussion forces. Nipradillol, Oxprenolol, Penbutolol, Pindolol, Prac tolol, Pronethalol, Propranolol, Sotalol, Sulfinalol, Tali 0111 Another embodiment provides for the use of a nolol, Tertatolol, Tilisolol, Timolol, Toliprolol, chemically reactive vehicle compound which, upon the Xibenolol event of the vehicle coming into contact with its reactive counterpart, the liposome bead wall is fractured and the 0119) ALCOHOL DETERRENT such as Calcium lipoSome released. Cyanamide Citrated, Disulfiram, Nitrefazole 0112 Another embodiment provides for the fracture 0120 ALDOSE REDUCTASE INHIBITOR such as through temperature Sensitive bead walls, with relative tem Epalrestat, Sorbinil, Tolrestat, Zopolrestat peratures providing relative release points. 0121 ANABOLIC Such as Androisoxazole, Andros 0113. The foregoing list of therapeutic categories and tenediol, Bolandiol, Bolasterone, Clostebol, Ethylestre various embodiments are illustrative of the invention and are nol, Formebolone, Methandriol, Methenolone, Meth merely exemplary. A person skilled in the art may make yltrienolone, Nandrolone, Norbolethone, Oxabolone, variations and modifications without departing from the Oxymesterone, Pizotyline, Quinbolone, Stenbolone, Spirit and Scope of the invention. All Such modifications and Trenbolone US 2004/0224012 A1 Nov. 11, 2004 16

0122 ANALGESIC (DENTAL) such as Chlorobu olone, Methandrostenolone, 17-Methyltestosterone, 17 tanol, Clove, Eugenol alpha-Methyl-testosterone 3-Cyclopentyl Enol Ether, 0123 ANALGESIC (NARCOTIC) such as Alfentanil, Norethandrolone, Normethandrone, Oxandrolone, Allylprodine, Alphaprodine, Anileridine, Benzylmor Oxymesterone, Oxymetholone, Prasterone, Stanlolone, phine, Bezitramide, Buprenorphine, Butorphanol, Stanozolol, Testosterone, Tiomesterone ClonitaZene, Codeines, DeSomorphine, Dextromora 0126 ANESTHETIC such as Acetamidoeugenol, mide, DeZocine, Diampromide, Dihydrocodeine, Dihy Alfadolone Acetate, Alfaxalone, Ambucaine, Amol drocodeinone Enol Acetate, Dihydromorphine, anone, Amylocalne, BenoXinate, Benzocaine, Betox Dimenoxadol, Dimepheptanol, Dimethylthiambutene, ycaine, Biphenamine, Bupivacaine, Butacaine, Butam Dioxaphetyl Butyrate, Dipipanone, Eptazocine, Etho ben, Butanilicaine, Butethamine, Buthalital, heptazine, Ethylmethlythiambutene, Ethylmorphine, Butoxycaine, Carticaine, Chloroprocaine, Cocaethyl EtonitaZene, Fentanyl, Hydrocodone, Hydromorphone, ene, Cocaine, Cyclomethycaine, Dibucaine, Dime Hydroxypethidine, Isomethadone, Ketobemidone, thisoquin, Dimethocaine, Diperadon, Dyclonine, Levorphanol, Lofentanil, Meperidine, Meptazinol, Ecgonidine, Ecgonine, Ethyl Chloride, Etidocaine, Metazocine, Methadone, Metopon, Morphine, Mor Etoxadrol, beta-Eucaine, Euprocin, Fenalcomine, phine Derivatives, Myrophine, Nalbuphine, Narceline, Fomocaine, Hexobarbital, Hexylcaine, Hydroxydione, Nicomorphine, Norlevorphanol, Normethadone, Nor Hydroxyprocaine, Hydroxytetracaine, Isobutyl p-Ami morphine, Norpipanone, Opium, Oxycodone, Oxymor nobenzoate, Ketamine, Leucinocaine MeSylate, phone, Papaveretum, Pentazocine, Phenadoxone, LeVOXadrol, Lidocaine, Mepivacaine, Meprylcaine, Phenazocine, Phenoperidine, Piminodine, Piritramide, Metabutoxycaine, Methohexital, Methyl Chloride, Proheptazine, Promedol, Propiram, Propoxyphene, Midazolam, Myrtecaine, Naepaine, Octacaine, Remefentanil, Sufentanil, Tilidine Orthocaine, Oxethazaine, Parethoxycaine, Phenacaine, 0124) ANALGESIC (NON-NARCOTIC) such as Ace Phencyclidine, Phenol, Piperocaine, Piridocaine, Poli clofenac, Acetaminophen, AcetaminoSalol, Acetanil docanol, Pramoxine, Prilocalne, Procaine, Propanidid, ide, Acetylsalicylsalicylic Acid, Alclofenac, Almino Propanocaine, Proparacaine, Propipocaine, Propofol, profen, Aloxiprin, Aluminum Bis(acetylsalicylate), Propoxycaine, Pseudococaine, Pyrrocaine, Ropiv Aminochlorthenoxazin, 2-Amino-4-picoline, Amino acaine, Salicyl Alcohol, Sodium Oxybate, Tetracaine, propylon, Aminopyrine, Ammonium Salicylate, Amtol Thialbarbital, Thiamylal, Thiobutabarbital, Thiopental, metin Guacil, Antipyrine, Antipyrine Salicylate, Tolycaine, Trimecaine, Zolamine Antrafenine, ApaZone, Aspirin, Benorylate, Benox 0127. ANOREXIC such as Aminorex, Amphecloral, aprofen, BenZpiperylon, BenZydamine, Bermoprofen, Amphetamine, BenZaphetamine, Chlorphentermine, Bromofenac, p-Bromoacetanilide, 5-Bromosalicylic Clobenzorex, Cloforex, Clortermine, Cyclexedrine, Acid Acetate, Bucetin, BufeXamac, Bumadizon, Buta Dextroamphetamine, Diethylpropion, Diphemethoxi cetin, Calcium Acetylsalicylate, Carbamazepine, Car dine, N-Ethylamphetamine Fenbutrazate, Fenflu biphene, CarSalam, Chloralantipyrine, Chlorthenox ramine, FenproporeX, Furfurylmethylamphetamine, azin(e), Choline Salicylate, Cinchophen, Ciramadol, Levophacetoperate, Mazindol, Mefenorex, Metam Clometacin, Clonixin, Cropropamide, Crotethamide, feproamone, Metamphetamine, Norpseudoephedrine, Dexoxadrol, Difenamizole, Diflunisal, Dihydroxyalu Pentorex, Phendimetrazine, Phenmetrazine, Phenpen minum Acetylsalicylate, Dipyrocetyl, Dipyrone, Emor termine, Phenylpropanolamine, Picilorex, Sibutramine faZone, Enfenamic Acid, Epirizole, EterSalate, Ethen Zamide, Ethoxazene, Etodolac, Felbinac, Fenoprofen, 0128 ANTHELMINTIC (CESTODES) such as Floctafenine, Flufenamic Acid, Fluoresone, Flupirtine, Arecoline, Aspidin, Aspidinol, Dichlorophen(e), FluproduaZone, Flurbiprofen, Fosfosal, Gentisic Acid, Embelin, Kosin, Napthalene, Niclosamide, Pellert Glafenine, Ibufenac, Imidazole Salicylate, Indometha ierine, Quinacrine cin, Indoprofen, IsofeZolac, Isoladol, Isonixin, Keto 0129. ANTHELMINTIC (NEMATODES) such as profen, Ketorolac, p-Lactophenetide, Lefetamine, Lor Alantolactone, Amocarzine, AmoScanate, AScaridole, noxicam, Loxoprofen, Lysine Acetylsalicylate, Bephenium, Bitoscanate, Carbon Tetrachloride, Car Magnesium Acetylsalicylate, Methotrimeprazine, Vacrol, Cyclobendazole, Diethylcarbamazine, Metofoline, Mofezolac, Morazone, Morpholine Salicy Diphenane, Dithiazanine Iodide, Dymanthine, Gentian late, Naproxen, Nefopam, Nifenazone, 5' Nitro-2' pro Violet, 4-Hexylresorcinol, Ivermectin, Kainic Acid, poxyacetanilide, Parsalmide, Perisoxal, Phenacetin, Levamisole, Mebendazole, 2-Napthol, Oxantel, Phenazopyridine, Phenocoll, Phenopyrazone, Phenyl Papain, piperazines, Pyrantel, Pyrvinium Pamoate, Acetylsalicylate, Phenyl Salicylate, Phenyramidol, alpha-Santonin, Stilbazium Iodide, Tetrachloroethyl Pipebuzone, Piperylone, Propacetamol, Propy ene, Thiabendazole, Thyrnol, Thymyl N-Isoamylcar phenaZone, RamifenaZone, Rimazolium Metilsulfate, Salacetamide, Salicin, Salicylamide, Salicylamide bamate, Triclofenol piperazine, Urea Stibamine O-Acetic Acid, Salicylsulfuric Acid, Salsalate, Salver 0130 ANTHELMINTIC (SCHISTOSOMA) such as ine, Simetride, Sodium Salicylate, Suprofen, Talniflu Amoscanate, Amphotalide, Antimony(s) and Deriva mate, Tenoxicam, Terofenamate, Tetradrine, Tinori tives, Becanthone, Hycanthone, Lucanthone, Nirida dine, Tolfenamic Acid, Tramadol, Tropesin, Viminol, Zole, Oxamniquine, Praziquantel, Stibocaptate, Sti Xenbucin, Zomepirac bophen, Urea Stibamine 0125 ANDROGEN such as Boldenone, Cloxotest 0131 ANTHELMINTIC (TREMATODES) such as osterone, Fluoxymesterone, Mestanolone, Mester Anthiolimine, Tetrachloroethylene US 2004/0224012 A1 Nov. 11, 2004 17

0132 ANTIACNE Such as Algestone Acetophenide, Thiosulfate, Hydroxychloroquine, KebuZone, Loben Azelaic Acid, Benzoyl Peroxide, Cioteronel, Cyproter Zarit, Melittin, Methotrexate, Myoral, Penicillamine one, Motretinide, Resorcinol, Retinoic Acid, Tazaro tene, Tetroquinone, Tioxolone 0140). ANTIBACTERIAL (ANTIBIOTIC) 0141 Aminoglycosides Such as Amikacin, Apramycin, 0133) ANTIALLERGIC such as Amlexanox, Astemi Arbekacin, Bambermycins, Butirosin, Dibekacin, Dih Zole, AZelastine, Cromolyn, Fenpiprane, Ibudilast, drostreptomycin, Fortimicin(s), Fradiomycin, Gen Lodoxamide, Nedocromil, Oxatomide, Pemirolast, tamicin, Ispamicin, Kanamycin, Micronomicin, Neo Pentigetide, Picumast, Repirinast, Suplast Tosylate, mycin, Neomycin Undecylenate, Netilmicin, Tranilast, TraxanoX Paromomycin, Ribostamycin, Sisomicin, Spectinomy 0134). ANTIAMEBIC such as Arsthinol, Bialamicol, cin, Streptomycin, Tobramycin, Trospectomycin Carbarsone, Cephaeline, Chlorbetamide, Chloro quinone, Chlorphenoxamide, Chlorotetracycline, 0.142 Amphenicols such as Azidamfenicol, Chloram Dehydroemetine, Dibromopropamidine, Diloxanide, phenicol, Florfenicol, Thiamphenicol DephetarSone, Emetine, Fumagillin, Glaucarubin, Gly 0.143 Ansamycins such as Rifamide, Rifampin, Rifa cobiarsol, 8-Hydroxy-7-iodo-5-quinolinesulfonic Acid, mycin, Rifapentine, Rifaximin Iodochlorhydroxyquin, Iodoquinol, Paromomycin, Phanquinone, Polybenzarsol, Propamidine, Quinfa 0144) beta-Lactams mide, Secnidazole, Sulfarside, Teclozan, Tetracycline, 0145 Carbapenems such as Biapenem, Imipenem, Thiocarbamizine, ThiocarbarSone, Tinidazole Meropenem, Panipenem 0135 ANTIANDROGEN such as Bicalutamide, 0146 Cephalosporins such as Cefaclor, Cefadroxil, Bifluranol, Cioteronel, Cyproterone, Delmadinone Cefamandole, Cefatrizine, Cefazedone, Cefazolin, Cef Acetate, Flutamide, Nilutamide, OSaterone, Oxen capene Pivoxil, Cefclidin, Cefdinir, Cefditoren, dolone Cefepime, Cefetamet, Cefixime, CefnmenoXime, Cefo 0136. ANTIANGINAL such as Acebutolol, Alpre dizime, Cefonicid, CefoperaZone, Ceforanide, Cefo nolol, Amiodarone, Amlodipine, Arotinolol, Atenolol, taxime, Cefotiam, CefoZopran, Cefpimizole, Cefpira Barnidipine, Bepridil, Bevantolol, Bucumolol, Bufe mide, Ce?pirome, Cefpodoxime Proxetil, Cefprozil, tolol, Bufuralol, Bunitrolol, Bupranolol, Carazolol, Cefroxadine, CefSulodin, Ceftazidime, Cefteram, Ceft Carteolol, Celiprolol, Cinepazet Maleate, Diltazem, eZole, Ceftibuten, Ceftizoxime, Ceftriaxone, Elgodipine, Epanolol, Felodipine, Gallopamil, Imola Cefuroxime, CefuZonam, Cephacetrile Sodium, Ceph mine, Indenolol, ISOSorbide Dinitrate, Isradipine, alexin, Cephaloglycin, Cephaloridine, Cephalosporin, Limaprost, Mepindolol, Metoprolol, Molsidomine, Cephalothin, Cephapirin Sodium, Cephradine, Pivee Nadolol, Nicardipine, Nicorandil, Nifedipine, Nife falexin malol, Nilvadipine, Nipradillol, Nitroglycerin, Oxpre 0147 Cephamycins such as Cefbuperazone, Cefineta nolol, Oxyfedrine, OZagrel, Penbutolol, Pentaerythritol Zole, Cefnminox, Cefetan, Cefoxitin Tetranitrate, Pindolol, Pronethalol, Propranolol, Rano lazine, Semotiadil, Sotalol, Terodiline, Timolol, Tolip 0.148 Monobactams such as Aztreonam, Carumonam, rolol, Tronitrate Phosphate, Verapamil, Zatebradine Tigemonam 0137 ANTIARRHYTHMIC such as Acebutolol, 014.9 Oxacephems such as Flomoxef, Moxolactam Acecainide, Adenosine, Ajmaline, Alprenolol, Amio 0150 Penicillins such as Amidinocillin, Amdinocillin darone, Amoproxan, Aprindine, Arotinolol, Atenolol, Pivoxil, Amoxicillin, Ampicillan, Apalcillin, Azimilide, Bevantolol, Bidisomide, Bretylium Tosy ASpoxicillin, AZidocillan, AZlocillan, Bacampicillin, late, Bucumolol, Bufetolol, Bunaftine, Bunitrolol, Benzylpenicillinic Acid, Benzylpenicillin, Carbenicil Bupranolol, Butidrine, Butobendine, Capobenic Acid, lin, Carindacillin, Clometocillin, Cloxacillin, Cyclacil Carazolol, Carteolol, Cifenline, Disopyramide, Dofetil lin, Dicloxacillin, Epicillin, Fenbenicillin, Floxicillin, ide, Encainide, Esmolol, Flecainide, Hydroquinidine, Hetacillin, Lenampicillin, Metampicillin, Methicillin, Ibutilide, Indecainide, Indenolol, Ipratropium, Mezlocillin, Nafcillin, Oxacillin, Penamecillin, Peneth Lidocaine, Lorajmine, Lorcainide, Meobentine, Mexi amate Hydriodide, Penicillin G Benethamine, Penicil letine, Moricizine, Nadoxolol, Nifenalol, Oxprenolol, lin G BenZathine, Penicillin G Benzhydrylamine, Peni Penbutolol, Pilsicainide, Pindolol, Pirmenol, Practolol, cillin G Calcium, Penicillin G Hydrabamine, Penicillin Prajmaline, Procainamide, Pronethalol, Propafenone, GPotassium, Penicillin G Procaine, Penicillin N, Peni Propranolol, Pyrinoline, Quinidine, Sematilide, cillin 0, Penicillin V, Penicillin V BenZathine, Penicillin Sotalol, Talinolol, Tlisolol, Timolol, Tocainide, Vera V Hydrabamine, Penimepicycline, Phenethicillin, Pip pamil, Vicquidil, Xibenolol eracillin, Pivapicillin, Propicillin, Quinacillin, Sulbeni 0138 ANTIARTERIOSCLEROTIC such as Pyridinol cillin, Sultamicillin, Talampicillin, Temocillin, Ticar Carbamate cillin 0139 ANTIARTHRITIC/ANTIRHEUMATIC such as 0151. Others such as Ritipenem Actarit, Allocupreide Sodium, Auranofin, Aurothioglu cose, Aurothioglycanide, AZathioprine, Bucillamine, 0152 Lincosamides such as Clindamycin, Lincomycin Calcium 3-Aurothio-2-propanol-1-Sulfonate, Cloro 0153. Macrollides such as Azithromycin, Carbomycin, quine, Clobu Zarit, CuproXoline, Diacerein, Glu Clarithromycin, Dirithromycin, Erythromycin(s) and cosamine, Gold Sodium Thiomalate, Gold Sodium Derivatives, Josamycin, Leucomycins, Midecamycins, US 2004/0224012 A1 Nov. 11, 2004 18

Miokamycin, Oleandomycin, Primycin, Rokitamycin, 0164. ANTICHOLINERGIC such as Adiphenine, Rosaramicin, Roxithromycin, Spiramycin, Troleando Alverine, Ambutonomium, Aminopentamide, Amix mycin etrine, Amprotropine Phosphate, Anisotropine Methyl bromide, Apoatropine, Atropine, Atropine N-Oxide, 0154 Polypeptides such as Amphomycin, Bacitracin, Benactyzine, Benapry Zine, BenZetimide, BenZilonium, Capreomycin, Colistin, Enduracidin, Enviomycin, Benztropine Mesylate, Bevonium Methyl Sulfate, Fusafungine, Gramicidin(S), Gramicidin S, Mikamy Biperiden, Butropium, N-Butylscopolammonium Bro cin, Polymyxin, Pristinamycin, Ristocetin, Teicoplanin, mide, BuZepide, Camylofine, Caramiphen, Chlorben Thiostrepton, Tuberactinomycin, Tyrocidine, Tyrothri Zoxamine, Chlorphenoxamine, Cimetropium, Clid cin, Vancomycin, Viomycin(s), Virginiamycin, Zinc inium, Cyclodrine, Cyclonium, Cycrimine, Deptropine, Bacitracin Dexetimide, Dibutoline Sulfate, Dicyclomine, Diethaz O155 Tetracyclines such as Apicycline, Chlortetracy ine, Difemerine, Dihexyverine, Diphemanil Methylsul cline, Clomocycline, Demeclocycline, Doxycycline, fate, N-(1,2-Diphenylethyl)nicotinamide, Dipiprover Guamecycline, Lymecycline, Meclocycline, Methacy ine, Diponium, Emepronium, Endobenzyline, cline, Minocycline, Oxytetracycline, Penimepicycline, Ethopropazine, Ethybenztropine, Ethylbenzhydramine, Pipacycline, Rolitetracycline, Sancycline, Tetracycline Etomidoline, Eucatropine, Fenpiverinium, Fentonium, Flutropium, Glycopyrrolate, Heteronium, Hexocyc 0156. Others such as Cycloserine, Mupirocin, Tuberin, lium Methyl Sulfate, Homatropine, Hyoscyamine, Ipratropium, Isopropamide, Levomepate, Mecloxam O157. ANTIBACTERIAL (SYNTHETIC) ine, MepenZolate, Metcaraphen, Methantheline, 0158 2,4-Diaminopyrimidines such as Brodimoprim, Methixene, Methscopolamine, Octamylamine, Oxybu Tetroxoprim, Trimethoprim tynin, Oxyphencyclimine, Oxyphenonium, Pentapip eride, Penthienate, Phencarbamide, Phenglutarimide, 0159. Nitrofurans such as Furaltadone, Furazolium, Pipenzolate, Piperidolate, Piperilate, Poldine Methys Nifuradene, Nifuratel, Nifurfoline, Nifurpirinol, Nifur ulfate, Pridinol, Prifinium, Procyclidine, Propantheline, prazine, Nifurtoinol, Nitrofurantoin Propenzolate, Propiverine, Propyromazine, Scopola mine, Scopolamine N-Oxide, Stramonium, Sultropo 0160 Quinolones and Analogs such as Cinoxacin, nium, Thiphenamil, Tiemonium, Timepidium, Tiqui Ciprofloxacin, Clinafloxacin, Difloxacin, Enoxacin, Zium, Tridihexethyl Iodide, Trihexyphenidyl Fleroxacin, Flumequine, Grepafloxacin, Lomefloxacin, Hydrochloride, Trimebutine, Tropacine, Tropenzile, Miloxacin, Nalidixic Acid, Norfloxacin, Ofloxacin, Tropicamide, TroSpium, Valethamate, Vamicamide, Oxolinic Acid, Pazufloxacin, Pefloxacin, Pipemidic Xeny tropium Acid, Piromidic Acid, RoSoxacin, Rufloxacin, Spar floxacin, Temafloxacin, ToSufloxacin, Travafloxacin 0165 ANTICONVULSANT such as Acetylphenetu ride, Albutoin, Aloxidone, Aminoglutethimide, 0.161 Sulfonamides such as Acetyl Sulfamethoxypyra 4-Amino-3-hydroxybutyric Acid, Atrolactamide, Bec zine, Benzylsulfamide, Chloramine-B, Chloramine-T, lamide, Buramate, Calcium Bromide, Carbamazepine, Dichloramine T, N'-Formyl-sulfisomidine, N'-beta-D- Cinromide, Clomethiazole, Clonazepam, Decimenide, Glucosylsulfanilamide, Mafenide, 4'-(Methyl-sulfa Diethadione, Dimethadione, Doxenitoin, Eterobarb, moyl)sulfanilanilide, Noprylsulfamide, Phthalylsulfac Ethadione, Ethosuximide, Ethotoin, Felbamate, Fluo etamide, Phthalylsulfathiazole, Salazosulfadimidine, resone, Gabapentin, 5-Hydroxytryptophan, Lamot Succinylsulfathiazole, Sulfabenzamide, Sulfacetamide, rigine, Magnesium Bromide, Magnesium Sulfate, Sulfachlorpyridazine, Sulfachrysoidine, Sulfacytine, Mephenyloin, Methobarbital, Metharbital, Methetoin, Sulfadiazine, Sulfadicramide, Sulfadimethoxine, Sul Methsuximide, 5-Methyl-5-(3-phenanthryl)-hydantoin, fadoxine, Sulfaethidole, Sulfaguanidine, Sulfaguanol, 3-Methyl-5-phenylhydantoin, Narcobarbital, Sulfalene, Sulfaloxic Acid, Sulfamerazine, Sulfameter, Nimetazepam, Nitrazepam, Oxcarbazepine, Sulfamethazine, Sulfamethizole, Sulfamethomidine, Paramethadione, Phenacemide, Phenetharbital, Phene Sulfamethoxazole, Sulfamethoxypyridazine, Sulfame turide, Phenobarbital, Phensuximide, Phenylmethyl trole, Sulfamidochrysoidine, Sulfamoxole, Sulfanil barbituric Acid, Phenyloin, Phethenylate Sodium, amide, 4-Sulfanilamidosalicylic Acid, N-Sulfanilyl Potassium Bromide, Primidone, Progabide, Sodium Sulfanilamide, Sulfanillylurea, N-Sulfanillyl-3,4- Bromide, Solanum, Strontium, Suclofenide, Sulthiame, Xylamide, Sulfanitran, Sulfaperine, Sulfaphenazole, Tetrantoin, Tiagabine, Topiramate, Trimethadione, Val Sulfaproxyline, Sulfapyrazine, Sulfapyridine, Sulfa proic Acid, Valpromide, Vigabatrin, Zonisamide Somizole, Sulfasymazine, Sulfathiazole, Sulfathiourea, Sulfatolamide, Sulfisomidine, Sulfisoxazole 0166 ANTIDEPRESSANT 0162 Sulfones such as Acedapsone, Acediasulfone, 0.167 Bicyclics such as Binedaline, Caroxazone, Cit AcetoSulfone, DapSone, DiathymoSulfone, Glucosul allopram, Dimethazan, Indalpine, Fencamine, Indelox fone, Solasulfone, Succisulfone, Sulfanilic Acid, p-Sul azine, Nefopam, Nomifensine, Oxitriptan, Oxypertine, fanilylbenzylamine, Sulfoxone, Thiazolsulfone Paroxetine, Sertraline, Thiazesim, Trazodone 0163 Others such as Clofoctol, Hexedine, Meth 0168 Hydrazides/Hydrazines such as Benmoxine, enamine, Methenamine Anhydromethylene-citrate, Iproclozide, Iproniazid, Isocarboxazid, Nialamide, Methenamine Hippurate, Methenamine Mandelate, Octamoxin, Phenelzine Methenamine Sulfosalicylate, Nitroxoline, Taurolidine, 0169 Pyrrolidones such as Cotinine, Rolicyprine, Xibomol Rolipram US 2004/0224012 A1 Nov. 11, 2004 19

0170 Tetracyclics such as Maprotiline, Metralindole, 0186 Triazoles such as Fluconazole, Itraconazole, Mianserin, Oxaprotiline Saperconazole, Terconazole 0171 Tricyclics such as Adinazolam, Amitriptyline, 0187. Others such as Acrisorcin, Amorolfine, Biphe Amitriptylinoxide, Amoxapine, Butriptyline, Clomi namine, BromoSalicylchloranilide, Buclosamide, Cal pramine, Demexiptiline, Desipramine, Dibenzepin, cium Propionate, Chlophenesin, CiclopiroX, Clox Dimetracrine, Dothiepin, DOXepin, Fluacizine, Imi yguin, Coparaffinate, Diamthazole, Dihydrochloride, pramine, Imipramine N-Oxide, Iprindole, Exalamide, Flucytosine, Halethazole, Hexetidine, Lof Lofepramine, Melitracen, Metapramine, Nortriptyline, lucarban, Nifuratel, Potassium Iodide, Propionates, Noxiptilin, Opipramol, Pizotyline, Propizepine, Prot Propionic Acid, Pyrithione, Salicylanilide, Sulbentine, riptyline, Quinupramine, Tianeptine, Trimipramine Tenonitrozole, Triacetin, Ujothion, Undecylenic Acid 0172 Others such as Adrafinil, Benactyzine, Bupro 0188 ANTIGLAUCOMA such as Acetazolamide, pion, Butacetin, Dioxadrol, Duloxetine, Etoperidone, Befinolol, Betaxolol, Brimonidine, Bupranolol, Car Febarbamate, Femoxetine, Fenpentadiol, Fluoxetine, teolol, Dapiprazoke, Dichlorphenamide, Dipivefrin, Fluvoxamine, Hematoporphyrin, Hypercinin, Dorzolamide, Epinephrine, Latanoprost, Levobunolol, Levophacetoperane, Medifoxamine, Milnacipran, Methazolamide, Metrpranolol, Pilocarpine, Pindolol, Minaprine, Moclobemide, Nefazodone, Oxaflozane, Timolol, Unoprostone Piberaline, Prolintane, Pyrisuccideanol, Ritaserin, RopXindole, Rubidium, Sulpiride, TandoSpirone, 0189 ANTIGONADOTROPIN such as DanaZol, Thozalinone, Tofenacin, Toloxatone, Tranylcypromine, Gestrinone, Paroxypropione L-Tryptophan, Venlafaxine, Viloxazine, Zimeldine 0190. ANTIGOUT such as Allopurinol, Carpofen, 0173 ANTIDIABETIC Colchicine, Probenecid, Sulfinpyrazone 0.174 Biguanides such as Buformin, Metformin, Phen 0191). ANTIHISTAMINIC formin 0.192 Alkylamine Derivatives such as Acrivastine, 0.175 Sulfonylurea Derivatives such as Acetohexam Bamipine, Brompheniramine, Chlorpheniramine, ide, 1-Butyl-3-metanily lurea, Carbutamide, Chlorpro Dimethindene, Metron S, Pheniramine, Pyrrobutamine, pamide, Glibomuride, Gliclazide, Glimepiride, Glipiz Thenaldine, Tolpropamine, Triprolidine ide, Gliquidone, Glisoxepid, Glyburide, 0193 Aminoalkyl Ethers such as Bietanautine, Bro Glybuthiazol(e), Glybuzole, Glyhexamide, Glymidine, modiphenhydramine, Carbinoxamine, Clemastine, Glypinamide, Phenbutamide, Tolazamide, Tolbuta Diphenylhydramine, Diphenlypyraline, Doxylamine, mide, Tolcyclamide Embramine, Medrylamine, Moxastine p-Methyl diphenhydramine, Orphenadrine, Phenyltoloxamine, 0176) Others such as Acarbose, Calcium Mesoxalate, Miglitol, Repaglinide Setasine 0194 Ethylenediamine Derivatives such as Allocla 0177. ANTIDIARRHEAL such as Acetorphan, mide, Chloropyramine, Chlorothen, Histapyrrodine, Acetyltannic Acid, Alkofanone, Aluminum Salicylates, Methafurylene, Methaphenilene, Methapyrilene, Pyril Catechin, DilfenoXin, Diphenoxylate, Lidamidine, Lop amine, Talastine, Thenyldiamine, Thonzylamine, eramide, Mebiquine, Trillium, Uzarin, Zaldaride Tripelennamine, Zolamine 0178 ANTIDIURETIC such as Desmopressin, Fely pressin, Lypressin, Omipressin, Oxycinchophen, Terli 0.195 Piperazines such as Cetirizine, Chlorcyclizine, pressin, Vasopressin Cinnarizine, Clocinizine, Hydroxy Zine 0179 ANTIESTROGEN such as Centchroman, Del 0196) Tricyclics madinone Acetate, Tamoxifen, Toremifene 0197) Phenothiazines such as Ahistan, Etymemazine, Fenethazine, N-Hydroxyethylpromethazine, Iso 0180 ANTIFUNGAL (ANTIBIOTICS) promethazine, Mequitazine, Promethazine, ThiaZina 0181 Polyenes such as Amphotericin-B, Candicidin, mium Methyl Sulfate Dermostatin, Filipin, Fungichromin, Hachimycin, 0.198. Other tricyclics such as AZatadine, Cloben Hamycin, Lucensomycin, Mepartricin, Natamycin, Zepam, Cyproheptadine, Deptropine, Isothipendyl, Nystatin, Pecilocin, Perimycin Loratadine 0182. Others such as AZaserine, Griseofulvin, Oligo 0199. Others such as Antazoline, Astemizole, Azelas mycins, Neomycin Undecylenate, Pyrrolnitrin, Sicca tine, Cetoxime, Clemizole, Clobenztropine, Ebastine, nin, Tubercidin, Viridin Emedastine, Epinastine, FeXofenadine, Levocabastine, 0183 ANTIFUNGAL (SYNTHETIC) Mebhydroline, Phenindamine, Terfenadine, Tritoqual 0.184 Allylamines such as Butenafine, Naftifine C 0185 Imidazoles such as Bifonazole, Butoconazole, 0200 ANTIHYPERLIPOPROTEINEMIC Chlordantoin, Chlormidazole, Cloconazole, Clotrima 0201 Aryloxyalkanoic Acid Derivatives such as Zole, Econazole, Enilconazole, Fenticonazole, Flutri Beclorbrate, Bazafibrate, Binifibrate, Ciprofibrate, Cli mazole, ISOconazole, Ketoconazole, Lanoconazole, nofibrate, Clofibrate, Clofibric Acid, Etonfibrate, Miconazole, Omoconazole, Oxiconazole Nitrate, Fenofibrate, Gemfibrozil, Nicofibrate, Pirifibrate, Ron Sertaconazole, Sulconazole, Tioconazole ifibrate, Simfibrate, Theofibrate US 2004/0224012 A1 Nov. 11, 2004

0202 Bile Acid Sequesterants such as Cholestyramine 0217. Others such as Aimaline, gamma-Aminobutyric Resin, Colestipol, Polidexide Acid, Bufeniode, Carmoxirole, Chlorthalidone, Cicle taine, Ciclosidomine, Clentiazem, Cryptenamine Tan 0203 HMG CoA Reductase Inhibitors such as Atorv nates, Fantofarone, Fenoldopam, FloSequinan, astatin, Fluvastatin, Lovastatin, Pravastatin, Simvasta Indoramin, Ketanserin, Levcromakalim, Metbutamate, tin Mecamylamine, Methyldopa, Methyl 4-Pyridyl Ketone 0204 Nicotinic Acid Derivatives Acipimox, Alumi Thiosemicarbarzone, Metolazone, Milberfradil, num Nicotinate, Niceritrol, Nicoclonate, Nicomol, Minoxidil, Muzolimine, Naftopidil, Pargyline, Pempi OXiniacic Acid dine, Pinacidil, Piperoxan, Protoveratrines, Raubasine, Rescimetol, Saralasin, Semotiadil, Sodium Nitroprus 0205 Thyroid Hormones/Analogs such as Etiroxate, Side, Ticrynafen, Trimethaphan Camsylate, Tyrosinase, Thyropropic Acid, Thyroxine Urapidil 0206. Others such as Acifran, AZacosterol, Benfluorex, beta-Benzalbutyramide, Carnitine, Chondroitin Sul 0218 ANTIHYPERTHYROID such as 2-Amino-4- fate, Clomestone, Detaxtran, Dextran Sulfate Sodium, methylthiazole, 2-Aminothiazole, Carbimazole, 3,5- 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Dibromo-L-tyrosine, 3,5-Diiodotyrosine, Iodine, Furazbol, Meglutol, Melinamide, Mytatrienediol, Methimazole, Methylthiouracil, Propylthiouracil, Omithine, gamma-Oryzanol, Pantethine, Penataeryth Sodium Perchlorate, Thibenzazoline, Thiobarbital, ritol Tetraacetate, alpha-Phenylbutyramide, Phylate 2-Thiouracil Acids and Salts, Pirozadil, Probucol, beta-Sitosterol, 0219 ANTIHYPOTENSIVE such as Amezinium Sultosilic Acid, Tiadenol, Triparanol, Xenbucin Methyl Sulfate, Angiotensin Amide, Dimetofrine, Dopamine, Etifelmin, Etilefrin, Gepefrine, Metarami 0207. ANTIHYPERTENSIVE nol, Methoxamine, Midodrine, Norepinephrine, 0208 Benzothiadiazine Derivatives such as Althiaz Pholedrine, Synephrine ide, Bendroflumethiazide, Benzthiazide, Benzylhydro chlorothiazide, Buthiazide, Chlorothiazide, Chlorthali 0220 ANTIHYPOTHYROID such as Levothyroxine, done, Cyclopenthiazide, Cyclothiazide, Diazoxide, Liothyronine, Thyroid, Thyroidin, Thyroxine, Tiratri Epithiazide, Ethiazide, Fenguizone, Hydrochlorothiaz col, TSH ide, Hydroflumethiazide, Indapamide, Methyclothiaz 0221) ANTI-INFLAMMATORY (NONSTEROIDAL) ide, Meticrane, Metolazone, Paraflutizide, Polythiaz 0222 Aminoarylcarboxylic Acid Derivatives such as ide, Quinethazone, Teclothiazide, Trichlormethiazide Enfenamic Acid, Etofenamate, Flufenamic Acid, 0209 N-Carboxyalkyl (peptide/lactam) Derivatives Isonixin, Meclofenamic Acid, Mefanamic Acid, Niflu Such as Alacepril, Benazepril, Captopril, Ceronapril, mic Acid, Talniflumate, Terofenamate, Tolfenamic CilaZapril, Delapril, Enalapril, Enalaprilat, Fosinopril, Acid SVR, RR's "ENER (0223) Aryacetic Acid privatives, such as Act ril s s s clofenac, Acemetacin, Alclofenac, Amfenac, Amtol p metin Guacil, Bromfenac, BufeXamac, Cinmetacin, 0210 Guanidine Derivatives Bethanidine, Debriso Clopirac, Diclofenac, Etodolac, Felbinac, Fenclozic quin, Guanabenz, Guanacline, Guanadrel, GuanaZod Acid, Fentiazac, Glucametacin, Ibufenac, Indometha ine, Guanethidine, Guanfacine, Guanochlor, Guanoxa cin, ISOfeZolac, ISOXepac, Lonazolac, Metiazinic Acid, benz, GuanoXan MofeZolac, Oxametacine, PiraZolac, Proglumetacin, 0211 Hydrazines/Phthalazines such as Budralazine, Sulindac, Tiaramide, Tolimetin, Tropesin, Zomepirac Cadralazine, Dihydralazine, Endralazine, Hydracarba 0224) Arylbutyric Acid Derivatives such as Bumadi zine, Hydralazine, Pheniprazine, Pildralazine, Todrala Zon, Butibufen, Fenbufen, Xenbucin Zine 0225. Arylcarboxylic Acids such as Clidanac, Ketoro 0212 Imidazole Derivatives such as Clonidine, lac, Tinoridine Lofexidine, Monoxidine, Phentolamine, Tiamenidine, 0226) Arylpropionic Acid Derivatives such as Almi Tolonidine noprofen, Benoxaprofen, Bermoprofen, Bucloxic Acid, 0213 Quaternary Ammonium Compounds Azametho Carprofen, Fenoprofen, Flunoxaprofen, Flurbiprofen, nium, Chlorisondamine, Hexamethonium, Penta Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen, LOXO cynium Bis(methyl sulfate), Pentamethonium, Pento profen, Naproxen, Oxaprozin, Piketoprofen, Pirprofen, linium Tartate, Phenactopinium, Trimethidiunum Pranoprofen, Protizinic Acid, Suprofen, Tiaprofenic MethoSulfate Acid, Ximoprofen, Zaltoprofen 0214) Quinazoline Derivatives such as Alfuzosin, 0227 Pyrazoles such as Difenamizole, Epirizole BunaZoSin Doxazosin, PraZOsin, Terazosin, TrimaZosin 0228 Pyrazolones such as Apazone, BenZpiperylon, 0215 Reserpine Derivatives such as Bietaserpine, Feprazone, Mofebutazone, Morazone, Oxyphenbuta DeSerpidine, Rescinnamine, Reserpine, Syrosingopine Zone, PhenylbutaZone, PipebuZone, PropyphenaZone, 0216 Sulfonamide Derivatives such as Ambuside, RamifenaZone, SuxibuZone, ThiazolinobutaZone Clopamide, Furosemide, QuinethaZone, Tripamide, 0229 Salicylic Acid Derivatives such as Acetaminos Xipamide alol, Aspirin, Benorylate, Bromosaligenin, Calcium US 2004/0224012 A1 Nov. 11, 2004 21

Acetylsalicylate, Diflunisal, EterSalate, Fendosal, Gen 0241 Nitrosoureas Carmustine, Chlorozotocin, Fote tisic Acid, Glycol Salicylate, Imidazole Salicylate, mustine, Lomustine, Nimustine, Ranimustine Lysine Acetylsalicylate, MeSalamine, Morpholine Sali cylate, 1-Naphthyl Salicylate, Olsalazine, Parsalmide, 0242 Others such as Dacarbazine, Mannomustine, Phenyl Acetylsalicylate, Phenyl Salicylate, Salaceta Mitobronitol, Mitolactol, Pipobroman, Temozolomide mide, Salacetamide O-Acetic Acid, Salicylsulfuric 0243 Antibiotics such as Aclacinomycins, Actinomy Acid, Salsalate, SulfaSalazine cin F, Anthramycin, AZaserine, Bleomycins, Cactino mycin, Carubicin, CarZinophilin, Chromomycins, Dac 0230. Thiazinecarboxamides such as Ampiroxicam, tinomycin, Daunorubicin, 6-Diazo-5-oxo-L- DroXicam, ISOXicam, Lornoxicam, PiroXicam, Tenoxi norleucine, Doxorubicin, Epirubicin, Idarubicin, Ca Menogaril, Mitomycins, Mycophenolic Acid, Nogala 0231. Others such as epsilon-Acetamidocaproic Acid, mycin, Olivomycins, Peplomycin, Pirarubicin, Plica S-Adenosylmethionine, 3-Amino-4-hydroxybutyric mycin, Porfiromycin, Puromycin, Streptonigrin, Strep Acid, Amixetrine, Bendazac, BenZydamine, alpha-Bis toZocin, Tubercidin, Zinostatin, Zorubicin abolol, Bucolome, Difenpiramide, Ditazol, Emorfa Zone, Fepradinol, GuaiaZulene, Nabumetone, Nime 0244 Antimetabolites Sulide, Oxaceprol, Paranyline, Perisoxal, ProquaZone, 0245. Folic Acid Analogs such as Denopterin, Edatr Superoxide Dismutase, Tenidap, Zileuton exate, Methotrexate, Piritrexim, Pteropterin, Tomu 0232 ANTIMALARIAL Such as Acedapsone, Amo dex(E), Trimetrexate diacquin, Arteether, Artemether, Artemisinin, Artesu 0246 Purine Analogs such as Cladribine, Fludarabine, nate, Atovaquone, Bebeerine, Berberine, Chirata, Chlo 6-Mercaptopurine, Thiamiprine, Thioguanaine rguanide, Chloroquine, Chlorproguanil, Cinchona, Cinchonidine, Cinchonine, Cycloguanil, Gentiopicrin, 0247 Pyrimidine Analogs such as Ancitabine, AZac Halofantrine, Hydroxychloroquine, Mefloquine Hydro itidine, 6-AZauridine, Carmofur, Cytarabine, Doxiflu chloride, 3-Methylarsacetin, Pamaquine, Plasmocid, ridine, Emitefur, Enocitabine, Floxuridine, Fluororacil, Primaquine, Pyrimethamine, Quinacrine, Quinidine, Gemcitabine, Tegafur Quinine, Quinocide, Quinoline, Sodium Arsenate, Dia 0248 Enzymes Such as L-Asparaginase basic 0249 Others such as Aceglatone, Amsacrine, Bisant 0233 ANTIMIGRAINE such as Alpiropride, Dihy rene, Defofamide, Demecolcine, Diaziquone, droergotamine, Dolasetron, Ergocornine, Ergocorni Elformithine, Elliptinium Acetate, Etoglucid, Fenretin nine, Ergocryptine, Ergot, Ergotamine, FlumedroXone ide, Gallium Nitrate, Hydroxyurea, Lonidamine, Milte Acetate, Fonazine, Lisuride, Methysergid(e), Oxetor fosine, MitoguaZone, Mitoxantrone, Mopidamol, one, Pizotyline, Sumatriptan Nitracrine, Pentostatin, Phenamet, Podophyllinicc Acid, 2-Ethylthydrazide, Procarbazine, Razoxane, 0234 ANTINAUSEANT such as Acetylleucine Sobu ZOxane, Spirogermanium, TenuaZonic Acid, Tri Monoethanolamine, Alizapride, AZasetron, BenZquina aziquone, 2,2,2"-Trichlorotriethylamine, Urethan mide, Bietanautine, Bromopride, Buclizine, Chlorpro mazine, Clebopride, Cyclizine, Dimenhydrinate, 0250) ANTINEOPLASTIC (HORMONAL) Dipheniodol, Dolasetron, Domperidone, Granisetron, Meclizine, Methalltal, Metoclopramide, Metopi 0251 Androgens such as Calusterone, Dromo mazine, Nabilone, Ondansteron, Oxypendyl, Pipam Stanolone, EpitioStanol, MepitioStane, Testolactone azine, Prochlorperazine, Scopolamine, Sulpiride, Tet 0252) Antiadrenals such as Aminoglutethimide, Mito rahydrocannabinols, Thiethylperazine, tane, TriloStane Thioproperazine, Trimethobenzamide, Tropisetron 0253 Antiandrogens such as Bicalutamide, Flutamide, 0235 ANTINEOPLASTIC Nilutamide 0236 Alkylating agents 0254 Antiestrogens such as Droloxifene, Tamoxifen, 0237 Alkyl Sulfonates such as Busulfan, Improsulfan, Toremifene Piposulfan 0255] ANTINEOPLASTIC ADJUNCT 0238 Aziridines such as Benzodepa, Carboquone, 0256 Folic Acid Replenisher such as Folinic Acid Meturedepa, Uredepa 0257 ANTIPARKINSONIAN such as Amantadine, 0239 Ethylenimines and Methylmelamines such as Benserazide, Bietanautine, Biperiden, Bromocriptine, Altretamine, Triethylenemelamine, TriethylenephoS Budipine, Carbidopa, Dexetimide, Diethazine, Droxi phoramide, Triethylenethiophosphoramide dopa, Ethopropazine, Ethylbenzhydramine, LaZabe mide, Levodopa, Mofegiline, Pergolide, Piroheptine, 0240 Nitrogen Mustards such as Chlorambucil, Chlo Pramipexole, Pridinol, Prodipine, Ropinirole, Sel maphazine, Cyclophosphamide, Estramustine, Ifosfa egiline, Talipexole, Terguride, Trihexyphenidyl Hydro mide, Mechlorethamine, Mechlorethamine Oxide chloride Hydrochloride, Melphalan, Novembichin, Perfosfa mide, Phenesterine, Prednimustine, Trofosfamide, 0258 ANTIPHEOCHROMOCYTOMA such as Uracil Mustard Metyrosine, Phenoxybenzamine, Phentolamine US 2004/0224012 A1 Nov. 11, 2004 22

0259 ANTIPNEUMOCYSTIS such as Atovaquone, Chlorthenoxazin(e), Choline Salicylate, Clidanac, Efformithine, Pentamidine, Sulfamethoxazole Dihydroxyaluminum Acetylsalicylate, Dipyrocetyl, Dipyrone, Epirizole, EterSalate, Imidazole Salicylate, 0260 ANTIPROSTATIC HYPERTROPHY such as Indomethacin, ISOfeZolac, para-Lactophenetide, Lysine Epristeride, Finasteride, Gestonorone Caproate, Acetylsalicylate, Magnesium Acetylsalicylate, Mepartricin, OSaterone, Oxendolone, Tamsulosin, Meclofenamic Acid, Morazone, Morpholine Salicylate, Terazosin Naproxen, Mifenazone, 5'-Nitro-2'-propoxyacetanilide, 0261) ANTIPROTOZOAL (LEISHMANIA) such as Phenacetin, Phenicarbazide, Phenocoll, Phenopyra Ethylstibamine, HydroxyStilbamidine, N-Methylglu Zone, PhenylAcetylsalicyliate, Phenyl Salicylate, Pipe camine, Pentamidine, Stilbamidine, Sodium Stiboglu buZone, Propacetamol, PropyphenaZone, Ramifena conate, Urea Stibamine Zone, Salacetamide, SSalicylamide-O-Acetic Acid, 0262 ANTIPROTOZOAL (TRICHOMONAS) such Sodium Salicylate, Tetrandrine, Tinoridine as AcetarSone, Aminitrozole, Anisomycin, AZanida 0273 ANTIRICKETTSLkL such as p-Aminobenzoic Zole, Furazolidone, Hachimycin, Lauroguadine, Acid, Chloramphenicol, Tetracycline Mepartricin, Metronidazole, Nifuratel, Nifuroxime, Nimorazole, Secnidazole, Silver Picrate, Tenonitro 0274) ANTISEBORRHEIC such as Chloroxine, 3-O- Zole, Tinidazole Lauroylpyridoxol Diacetate, Piroctone, Pyrithione, Resorcinol, Selenium Sulfides, Tioxolone 0263 ANTIPROTOZOAL (TRYPANOSOMA) such as Benznidazole, Eflomithine, Melarsoprol, Nifur 0275 ANTISEPTIC timox, Oxophenarsine, Pentamidine, Propamidine, 0276 Guanidines such as Alexidine, Ambazone, Chlo Puromycin, Quinapyramine, Stilbamidine, Suramin rhexidine, Picloxydine Sodium, Trypan Red, Tryparasmide 0277 Halogens/Halogen Compounds such as Bismuth 0264. ANTIPRURITIC such as Camphor, Cyprohep Iodide Oxide, Bismuth Iodosubgallate, Bismuth Tri tadine, Dichlorisone, Glycine, Halometasone, 3-Hy bromophenate, Bornyl Chloride, Calcium Iodate, Chlo droxycamphor, Menthol, Mesulphen, Methdilazine, rinated Lime, Cloflucarban, lodic Acid, Iodine, Iodine Phenol, Polidocanol, Spirit of Camphor, Thenaldine, Monochloride, Iodine Trichloride, Iodoform, Meth Tolpropamine, Trimeprazine enamine Tetraiodine, Oxychlorosene, PoVidone-Iodine, 0265 ANTIPSORIATIC such as Acitretin, Ammo Sodium Hypochlorite, Sodium Iodate, Symclosene, nium Salicylate, Anthralin, 6-AZauridine, Ber Triclocarban, Triclosan, Troclosene Potassium gapten(e), Calcipotriene, Chrysarobin, Etretinate, 0278 Nitrofurans such as Furazolidone, 2-(Meth Lonapalene, Pyrogallol, Tacalcitol, Tazaroteine oxymethyl)-5-Nitrofuran, Nidroxy Zone, Nifuroxime, 0266. ANTIPSYCHOTIC Nifurzide, Nitrofurazone 0267 Butyrophenones such as Benperidol, Bromperi 0279 Phenols such as Acetomeroctol, Bithionol, Cad dol, Droperidol, Fluanisone, Haloperidol, Melperone, mium Salicylate, Carvacrol, Chloroxylenol, Clo Moperone, Pipamperone, Sniperone, Timiperone, Tri rophene, Creosote, CreSol, Fenticlor, Hexachlo fluperidol rophene, 1-Napthyl Salicylate, 2-Napthyl Salicylate, 2,4,6-Tribromo-m-cresol, 3',4',5-Trichlorosalicylanil 0268 Phenothiazines such as Acetophenazine, Butaperazine, Carphenazine, Chlorproethazine, Chlor ide promazine, Clospirazine, Cyamemazine, Dixyrazine, 0280 Quinolines such as Aminoquinuride, Benzox Fluphenazine, Imiclopazine, Mepazine, MeSoridazine, iquine, Broxyquinoline, Chloroxine, Chlorquinaldol, Methoxypromazine, Metofenazate, Oxaflumazine, Cloxyquin, Ethylhydrocupreine, Euprocin, Halquinol, Perazine, Pericyazine, Perimethazine, Perphenazine, Hydrastine, 8-Hydroxquinoline Sulfate, Iodochlorhy Piperacetazine, Pipotiazine, Prochlorperazine, Pro droxyquin mazine, Sulforidazine, Thiopropazate, Thioridazine, Trifluoperazine, Triflupromazine 0281 Others such as Aluminum Acetate Solution, Alu minum Subacetate Solution, Aluminum Sulfate, 0269. Thioxanthenes such as Chlorprothixene, Clo 3-Amino-4-hydroxybutyric Acid, Boric Acid, Chlo penthixol, Flupentixol, Thiothixene rhexidine, ChloroaZodin, m-Cresyl Acetate, Cupric 0270. Other Tricyclics such as Benzquinamide, Sulfate, Dibromopropamidine, Ichthammol, Negatol, Carpipramine, Clocapramine, Clomacran, Clothiapine, Noxythiolin, Octenidine, Ornidazole, beta-Propriolac Clozapine, Mosapramine, Olanzapine, Opipramol, Pro tone, alpha-Terpineol thipendyl, Serocquel E), Tetrabenazine, Zotepine 0282 ANTISPASMODIC such as Alibendol, Ambuc etamide, Aminopromazine, Apoatropine, Bevonium 0271 Others such as Buramate, Fluspirilene, Molin Methyl Sulfate, Bietamiverine, Butaverine, Butropium, done, Penfluridol, Pimozide, Ziprasidone N-Butylscopolammonium Bromide, Caroverine, 0272 ANTIPYRETIC such as Acetominophen, Cimetropium, Cinnamedrine, Clebopride, Cyclonium AcetaminoSalol, Acetanilide, Alclofenac, Aluminum Iodide, Difemerine, Diisopromine, Dioxaphetyl Bis(ascetylsalicylate), Aminochlorhenoxazin, Ami Butyrate, Diponium Bromide, Drofenine, Emepronium nopyrine, Aspirin, Benorylate, BenZydamine, Ber Bromide, Ethaverine, Etomidoline, Feclemine, Fenala berine, Bermoprofen, para-Bromoacetanilide, BufeX mide, Fenoverine, Fenpiprane, Fenpiverinium Bro amac, Bumadizon, Calcium Acetylsalicylate, mide, Fentonium Bromide, Flavoxate, Flopropione, US 2004/0224012 A1 Nov. 11, 2004 23

Gluconic Acid, Hydramitrazine, Hymecromone, dine, Foscarnet Sodium, Indinavir, Interferon (alpha, Leiopyrrole, Mebeverine, Moxaverine, Nafiverine, beta, gamma), Kethoxal, Lysozyme, Methisazone, Octamylamine, Octaverine, Pentapiperide, Phenama Moroxydine, Nevirapine, Podophyllotoxin, Ribavirin, cide, Phloroglucinol, Pinaverium, Piperilate, Pipoxolan Rimantadine, Ritonavir, Saquinavir, Stallimycin, Sta Hydrochloride, Pramiverin, Prifinium Bromide, Propy tolon, Tromantadine, Xenazoic Acid romazine, Prozapine, Racefemine, Rociverine, Sin tropium Bromide, Spasmolytol, Sultroponium, Tiemo 0291 ANXIOLYTIC nium Iodide, Tigloidine, Tiquizium Bromide, 0292 Arylpiperazines Such as Buspirone, Enciprazine, Tiropramide, Trepibutone, Tricromyl, Trifolium, Tri Flesinoxan, Ipsapirone, Lesopitron, TandoSpirone mebutine, N,N-1Trimethyl-3,3-diphenylpropylamine, Tropenzile, Trospium Chloride, Xenotropium Bromide 0293 Benzodiazepine Derivatives Alprazolam, Bro mazepam, Camazepam, Chlordiazepoxide, Clobazam, 0283 ANTITHROMBOTIC such as Argatroban, Cil CloraZepate, Chotiazepam, Cloxazolam, Diazepam, OStaZol, Clopidrgrel, Cloricromen, Dalteparin, Dal Ethyl Loflazepate, Etizolam, Fluidazepam, Flutazolam, troban, Defibrotide, Enoxaparin, Indobufen, Iloprost, Flutoprazepam, Halazepam, Ketazolam, Lorazepam, Integrelin, Isbogrel, Lamifiban, Lamoparan, Nadro Loxapine, Medazepam, Metaclazepam, Mexazolam, parin, OZagrel, Picotamide, Plafibride, Reviparin Nordazepam, Oxazepam, Oxazolam, Pinazepam, Sodium, Ridogrel, Sulfinpyrazone, Taprostene, Ticlo Prazepam, Tofisopam pidine, Tinzaparin, Tirofiban, Triflusal 0294 Carbamates such as Cyclarbamate, Emylcamate, 0284 ANTITUSSIVE such as Allocamide, Amici Hydroxyphenamate, Meprobamate, Phenprobamate, bone, Benproperine, BenZonatate, Bibenzonium, Bro Tybamate moform, Butamirate, Butethamate, Caramiphen Ethanedisulfonate, Carbetapentane, Chlophedianol, 0295) Others Abecamil, Alpidem, Benzoctamine, Cap Clobutinol, Cloperastine, Codeine, Codeine Methyl todiamine, ChlormeZanone, EtifoXine, Fluoresone, Bromide, Codeine N-Oxide, Codeine Phosphate, Glutamic Acid, Hydroxyzine, Mecloralurea, Mephe Codeine Sulfate, Cyclexanone, Dextromethorphan, noxalone, Oxanamide, PaZinaclone, Suriclone Dihydrocodeine, Dihydrocodeinone Enol Acetate, Dimemorfan, Dimethoxanate, Dropropizine, Drote 0296 BENZODIAZEPINE ANTAGONIST such as banol, Eprazinone, Ethyl Dibunate, Ethylmorphine, Flumazenil Fominoben, Guiaiapate, Hydrocodone, Isoaminile, 0297 BRONCHODILATOR Levopropoxyphene, Morclofone, Narceline, Normetha done, NoScapine, Oxeladin, OXolamine, Pholcodine, 0298 Ephedrine Derivatives such as Albuterol, Bam Picoperine, Pipazethate, Piperidione, Prenoxdiazine, buterol, Bitolterol, Carbuterol, Clenbuterol, Clorprena Racemethorphan, Sodium Dibunate, Tipepidine, line, Dioxethedrine, Ephedrine, Epinephrine, Zipeprol EproZinol, Etafedrine, Ethylnorepinephrine, Fenoterol, Formoterol, HeXoprenaline, Isoetharine, Isoproterenol, 0285 ANTIULCERATIVE such as Aceglutamide Mabuterol, Metaproterenol, N-Methylephedrine, Pir Aluminum Complex, epsilon-Acetamidocaproic Acid buterol, Procaterol, Protokylol, Reproterol, Rimiterol, Zinc Salt, Acetoxolone, Aldioxa, Arbaprostil, Benexate Salmeterol, Soterenol, Terbutaline, Tulobuterol Hydrochloride, Carbenoxolone, Cetraxate, Cimetidine, Colloidal Bismuth Subcitrate, Ebrotidine, Ecabet, 0299 Quaternary Ammonium Compounds such as EnproStil, Esaprazole, Famotidine, Gefamate, Guaia Bevonium Methyl Sulfate, Flutropium Bromide, Ipra Zulene, IrSogladine, Lansoprazole, Misoprostol, Niza tropium Bromide, Oxitropium Bromide, Tiotropium tidine, Omeprazole, Ornoprostil, gamma-Oryzanol, Bromide Pantoprazole, Pifamine, Pirenzepine, Plaunotol, Pola 0300 Xanthine Derivatives such as Acefylline, Ace preZinc, Rabeprazole, Ranitidine, Rebamipide, Rio fylline piperazine, Ambuphylline, Aminophylline, prostil, Rosaprostol, Rotraxate, Roxatidine Acetate, Bamifylline, Choline Theophyllinate, Doxofylline, Sofalcone, Spizofurone, Sucralfate, Telenzepine, Dyphylline, Etamiphyllin, Etofylline, Guaithylline, Teprenone, Trimoprostil, Thrithiozine, Troxipide, Zoli Proxyphylline, Theobromine, 1-Theobromineacetic midine Acid, Theophylline 0286 ANTIUROLITHIC such as Acetohydroxamic 0301. Others such as Fenspiride, Medibazine, Meth Acid, Allopurinol, Potassium Citrate, Succinimide Oxyphenanime, Tretoquinol 0287. ANTIVENIN such as Lyovac Antivenin 0302) CALCIUM CHANNEL BLOCKER 0288 ANTIVIRAL 0303 Arylalkylamines such as Bepridil, Clentiazen, 0289 Purines/Pyrimidinones such as Acyclovir, Cido Diltiazem, Fendiline, Gallopamil, Mibefradil, Preny fovir, Cytarabine, Dideoxyadenosine, Didanosine, lamine, Semotiadil, Terodiline, Verapamil Edoxudine, Famciclovir, Floxuridine, Ganciclovir, 0304 Dihydropyridine Derivatives such as Amlo Idoxuridine, Inosine Pranobex, Lamivudine, MADU, dipine, Aranidipine, Barnidipine, Benidipine, Cilnid Penciclovir, Sorivudine, Stavudine, Trifluridine, Vala ipine, Efonidipine, Elgodipine, Felodipine, Isradipine, cyclovir, Vidrarbine, Zalcitabine, Zidovudine Lacidipine, Lercanidipine, Manidipine, Nicardipine, 0290. Others such as Acemannan Acetylleucine Mono Nifedipine, Nilvadipine, Nimodipine, Nisoldipine, ethanolamine, Amantadine, Amidinomycin, Delaviri Nitrendipine US 2004/0224012 A1 Nov. 11, 2004 24

0305 piperazine Derivatives such as Cinnarizine, Flu Etryptamine, Fencamfamine, Fenethylline, FenoZo narizine, Lidoflazine, Lomerizine lone, Flurothyl, Hexacyclonate Sodium, Homocamfin, Mazindol, Mefexamide, Methamphetamine, Meth 0306 Others such as Bencyclane, Etafenone, Fanto ylphenidate, Modafinil, Nikethamide, Pemoline, Pen farone, Perhexiline tylenetetrazole, Phenidimetrazine, Phenmetrazine, 0307 CALCIUM REGULATOR such as Calcifediol, Phentermine, Picrotoxin, Pipradrol, Prolintane, Pyrov Calcitonin, Calcitriol, Dihydrotachysterol, Elcatonin, alerone, Tetrahydrobenzothienopyridines Ipriflavone, Parathyroid Hormone, Teriparatide Acetate 0317 DECONGESTANT such as Amidephrine, Caf 0308 CARDIOTONIC such as Acetfylline, Acetyldig aminol, Cyclopentamine, Ephedrine, Epinephrine, ititoxins, 2-Amino-4-picoline, Amrinone, Benfurodil Fenoxazoline, Indanazoline, Metizoline, Naphazoline, Hemisuccinate, Buclasdesine, Camphotamide, Conva Nordefrin, Octodrine, Oxymetazoline, Phenylephrine, latoxin, Cymarin, Denopamine, Deslanoside, Digi Phenylpropanolamine, Phenylpropylmethylamine, talin, Digitalis, Digitoxin, Digoxin, Dobutamine, Propyhexedrine, Pseudoephredrine, Tetrahydrolzoline, Docarpamine, Dopamine, Dopexamine, Enoximone, TramaZoline, Tuaminoheptane, TymaZoline, Xylometa Erythrophleine, Fenalcomine, Gitalin, Gitoxin, Glyco Zoline cyamine, Heptaminol, Hydrastinine, Ibopamine, Lano todises, Loprinone, Milrinone, Neriifolin, Oleandrin, 0318 DENTAL CARRIES PROPHYLACTIC such as Ouabain, Oxyfedrine, Pimobendan, Prenalterol, Sodium Fluoride Proscillaridin, Resibufogenin, Scillaren, Scillarenin, 0319) DEPIGMENTOR such as Hydroquinine, Hyd Strophanthin, Sulmazole, Theobromine, Vesnarinone, roquinone, Monobenzone Xamoterol 0309 CHELATING AGENT such as Deferoxazmine, 0320 DIURETIC Ditiocarb Sodium, Edetate Calcium Disodium, Edetate 0321) Organomercurials such as Chlormerodrin, Mer Disodium, Edeate Sodium, Edetate Trisodium, Penicil alluride, Mercamphamide, Mercaptomerin Sodium, lamine, Pentetate Calcium Trisodium, Pentectic Acid, Mercumallylic Acid, Mercumatilin Sodium, Mercurous Succimer, Trientine Chloride, Mersalyl 0310 CHOLECYSTOKININ ANTAGONIST (CCK 0322 Purines such as Acefylline, 7-Morpholinometh Antagonist) yltheophylline, Pamabrom, Protheobromine, Theobro 0311 CHOLELITHOLYTIC AGENT such as Cheno mine diol, Methyl tert-Butyl Ether, Monooctanoin, Ursodiol 0323 Steroids such as Canrenone, Oleandrin, Spirono 0312 CHOLERETIC such as Alibendol, Anethole lactone Trithion, AZintamide, Cholic Acid, Cicrotoic Acid, Clanobutin, Cyclobutyrol, Cyclovalone, Cynarin(e), 0324 Sulfonamide Derivatives such as Acetazolmide, Dehydrocholic Acid, Deoxycholic Acid, Dimecrotic AmbuSide, AZOSemide, Bumetanide, Butazolamide, Acid, alpha-Ethylbenzyl Alcohol, Exiproben, Febu Chloraminophenamide, Clofenamide, Clopamide, Clo prol, Fencibutirol, Fenipentol, Florantyrone, Hymec reXolene, Disulfamide, EthoXZolamide, Furosemide, romone, Menbutone, 3-(o-Methoxyphenyl)-2-pheny Mefruside, Methazolamide, Piretanide, Torasemide lacrylic Acid, Metochalcone, Moquizone, OSalmid, OX Tripamide, Xipamide Bile Extract, 4,4'-Oxydi-2-butanol, Piprozolin, 4-Sali 0325 Uracils such as Aminometradine, Amisometra cyloylmorpholine, Sincalide, Taurocholic Acid, dine Tocamphyl, Trepibutone, Vanitiolide 0326. Others such as Amanozine, Amiloride, Arbutin, 0313 CHOLINERGIC such as Aceclidine, Acetylcho Chlorazanil, Ethacrynic Acid, EtoZolin, Hydracarba line, Acetylcholide, Aclatonium Napadisilate, BenZpy Zine, Isosorbide, Mannitol, Metochalcone, rinium Bromide, Bethanechol, Carbachol, Carpronium, Demecarium, Dexpanthenol, Diisopropyl Paraoxon, Muzolimine, Perhexiline, Triamterene, Urea Echothiophate, Edrophomium, Eptastigmine, Eseri 0327 DOPAMINE RECEPTOR AGONIST such as dine, Furtrethonium, Isoflurophate, Methacholine Bromocriptine, Cabergoline, Carmoxirole, DopeXam Chloride, Muscarine, NeoStigmine, Oxapropanium, ine, Fenoldopam, Ibopamine, Lisuride, Pergolide, PhySoStigmine, Pyridostigmine, Xanomeline Pramipexole, Quinagolide, Ropinirole, ROXindole, Tal ipexole 0314 CHOLINESTERASE INHIBITOR Such as Ambenonium, Distigmine, Eptastigmine, Galan 0328 ECTOPARASITICIDE such as Amitraz, Benzyl thamine Benzoate, Carbaryl, Crotamiton, DDT, Dixanthogen, Lime Sulfurated Solution, Lindane, Malathion, Mercu 0315 CHOLINESTERASE REACTIVATOR such as ric Oleate, Mesulfen, Sulfiram, Sulphur (Pharmaceuti ASOXime, Obidoximine, Pralidoxime cal) 0316 CNS STIMULANT/AGENT such as Aminept ine, Amphetimine, Amphetaminil, Bemegride, Benz 0329 ENZYME phetamine, Brucine, Caffeine, Chlorphentermine, Clo 0330 Digestive such as Amylase, Lipase, Pancreli rtermine, Coca, Deanol, Demanyl Phosphate, pase, Pepsin, Rennin Dexoxadrol, Dextroamphetamine Sulfate, Diethylpro pion, N-Ethylamphetamine, Ethamivan, Etifelmin, 0331 Penicillin Inactivating such as Penicillinase US 2004/0224012 A1 Nov. 11, 2004 25

0332 Proteolytic such as Collagenase, Chymopapain, mod, Inosine Pranobex, Interferon (alpha, beta, Chymotrypsins, Papain, Trypsin gamma), Lentinan, Levamisole, Macrophage Colony Stimulating Factor, Pidotimod, Platonin, Procodazole, 0333) ENZYME INDUCER (HEPATIC) such as Flu Propagermanium, Romurtide, Thymomodulin, Thymo mecinol pentin, Ubenimex 0334 ESTROGEN 0348 IMMUNOSUPPRESSANT such as Azathio 0335 Nonsteroidal such as Benzestrol, Broparoestrol, prine, Brequinar, CycloSporins, Gusperimus, 6-Mer Chlorotrianisene, Dienestrol, Diethylstilbestrol, captopurine, Mizoribine, Rapamycin Dimestrol, Fosfestrol, Hexestrol, Methallenestril, 0349) ION EXCHANGE RESIN such as Carbacrylic Methestrol Resins, Cholestyramine Resin, Colestipol, Polidexide, 0336 Steroidal such as Colpormon, Conjugated Estro Resodec, Sodium Polystyrene Sulfonate genic Hormones, Equilenin, Equilin, Estradiol, Estriol, Estrone, Ethinyl Estradiol, Mestranol, Moxestrol, 0350) LACTATION STIMULATING HORMONE Mytatrienediol, Quinestradiol, Quinestrol Such as Prolactin 0351) LH-RH AGONIST such as Buserelin, Deslore 0337 GASTRIC SECRETION INHIBITOR such as lin, Goserelin, Histrelin, Leuprolide, Nafarelin, Trip Enterogastrone, Octreotide, Telenzepine torelin 0338 GLUCOCORTICOID such as 21-Acetox yprefnenolone, AlclometaSone, AlgeStone, Amcinon 0352) LIPOTROPIC such as N-Acetylmethionine, ide, Beclomethasone, Betamethasone, BudeSonide, Choline Chloride, Choline Dehydrocholate, Choline Chloroprednisone, Clobetasol, ClobetaSone, Clocor Dihydrogen Citrate, Inositol, Lecithin, Methionine tolone, Cloprednol, Corticosterone, Cortisone, Cortiva 0353). LUPUS ERYTHEMATOSUS SUPPRESSANT Zol, Deflazacort, DeSonide, DeSoximetasone, Dexam Such as Bismuth Sodium Triglycollamate, Bismuth ethasone, Diflorasone, Diflucortolone, Difluprednate, Subsalicylate, Chloroquine, Hydroxychloroquine Enoxolone, FluaZacort, Flucloronide, Flumethasone, Flunisolide, Fluocinolone Acetonide, Fluocinonide, 0354) MINERALOCORTICOID such as Aldosterone, Fluocortin Butyl, Fluocortolone, Fluorometholone, Deoxycorticosterone, Fludrocortisone Fluperolone Acetate, Fluprednidene Acetate, Flupred 0355 MIOTIC such as Carbachol, Neostigmine, Phy nisolone, Flurandrenolide, Fluticasone Propionate, For SoStigmine, Pilocarpine mocortal, Halcinonide, Halobetasol Propionate, 0356) MONOAMINE OXIDASE INHIBITOR such as Halometasone, Halopredone Acetate, Hydrocortamate, Iproclozide, Iproniazid, ISOcarboxazid, LaZabemide, Hydrocortisone, Loteprednol Etabonate, MaZipredone, Mefegiline, Meclobemide, Octamoxin, Pargyline, Medrysone, Meprednisone, Methyolprednisolone, Phenelzine, Phenoxypropazine, Pivalylbenzhydrazine, MometaSone Furcate, Paramethasone, Prednicarbate, Prednisolone, Prednisolone 25-Diethylaminoacetate, Prodipine, Selegiline, Toloxatone, Tranylcypromine Prednisone Sodium Phosphate, Prednisone, Prednival, 0357 MUCOLYTIC such as Acetylcysteine, Brom Prednylidene, Rimexolone, Tixocortol, Triamcinolone, heXine, Carbocysteine, Domiodol, Erdosteine, Leto Triamcinolone Acetonide, Triamcinolone Benetonide, Steine, Lysozyme, Mecysteine, Mesna, Sobrerol, Triamcinolone Hexacetonide Stepronin, Tiopronin, Tyloxapol 0339) GONAD-STIMULATING PRINCIPLE such as 0358 MUSCLE RELAXANT (SKELETAL) such as Buserelin, Chorionic Gonadotropin, Clomiphene, Afloqualone, Alcuronium, Atracurium BeSylate, Cyclofenil, Epimestrol, FSH, LH, LH-RH Baclofen, BenZoctamine, Benzoquinonium, C-Cale bassine, Carisoprodol, ChlormeZanone, Chlorphenesin 0340 GONADOTROPIC HORMONE such as LH, Carbamate, Chlorphenesin, Chlorproethazine, ChloZ PMSG Oxazone, Curare, Cyclobamate, Cyclobenzaprine, Dan 0341 GROWTH HORMONE INHIBITOR such as trolene, Decamethonium, Diazepam, Doxacurium Octreotide, Somatostatin Chloride, Eperisone, Fazadinium, Flumetramide, Gal lamine Triethiodide, Hexacarbacholine, Hexafluore 0342 GROWTH HORMONE RELEASING FAC nium, Idrocilamide, Inaperisone, Lauexium Methyl TOR Such as Semorelin Sulfate, Leptodactyline, Memantine, Mephenesin, 0343 GROWTH STIMILANT such as Somatotropin Mephenoxalone, Metaxalone, Methocarbamol, Meto curine Iodide, Mivacurium Chloride, Nimetazepam, 0344) HEMOLYTIC such as Phenylhydrazine Orphenadrine, Pancuronium, Phenprobamate, 0345 HEPARIN ANTAGONIST such as Hexa Phenyramidol, Pipecurium, Promoxolane, Quinine, dimethrine Rocuronium, Styramate, Succinylcholine, Suxetho 0346) HEPATOPROTECTANT such as S-Adenosul nium Bromide, Tetrazepam, Thiocolchicoside, Tizani methionine, Betaine, Catechin, Citolone, Malotilate, dine, Tolperisone, Tubocurarine, Vecuronium, Zoxola Methionine, Orazamide, Phosphorylcholine, Protopor C phyrin IX, Silymarin-Group, Thiotic Acid, Timonacic, 0359 NARCOTIC ANTAGONIST such as Ami Tiopronin phenazole, Cyclazocine, Levallorphan, Nalmafene, 0347 IMMUNOMODULATOR such as Acemannan, Nalorphine, Naloxone, Naltrexone Amiprilose, Bucillamine, Ditiocarb Sodium, Imiqui 0360 NEUROPROTECTIVE such as Riluzole US 2004/0224012 A1 Nov. 11, 2004 26

0361). NOOTROPIC such as Aceglutamide, Acetyl 0376 Amides such as Butoctamide, Diethylbromoac camitine, Aniracetam, Besipridine, Bifemalane, Cho etamide, Isovaleryl Diethylamide, Niaprazine, Trime line AlfoScerate, Exifone, Fipexide, Idebenone, Indel toZine, Zolpidem, Zopiclone Oxazune, Nebracetam, Nefiracetam, Nizofenone, 0377 Barbituric Acid Derivatives such as Allobarbital, Oxiracetam, Piracetam, Pramiracetam, Propento?yl Amobarbital, Aprobarbital, Barbital, Brallabarbital, line, Pyritinol Sabeluzole, Tacrine, Velnacrine, Vincon Butabarbital Sodium, Butalbital, Butallylonal, ate, Xanomeline Butethal, Carbubarb, Cyclobarbital, Cyclopentobar 0362. OPHTHALMIC AGENT such as 15-ketopros bital, Enallylpropymal, 5-Furfuryl-5-isopropylbarbitu taglandins ric Acid, Heptabarbital, Hexethal Sodium, Hexobar bital, Mephobarbital, Methitural, Narcobarbital, 0363 OVARIAN HORMONE such as Relaxin Nealbarbital, Pentobarbital Sodium, Phenallymal, Phe 0364 OXYTOCIC such as Carboprost, Cargutocin, nobarbital, Phenylmethylbarbituric Acid, Propally Deaminooxytocin, Ergonovine, Gemeprost, Methyler lonal, Proxibarbal, Reposal, Secobarbital Sodium, gonovine, Oxytocin, Pituitary (Posterior), Prostaglan Talbutal, Tetrabarbital, Vinbarbital Sodium, Vinylbital din E, ProStaglandin F, Sparteine 0378 Benzodiazepine Derivatives such as Brotizolam, 0365 PEPSIN INIBITOR such as Sodium Amylosul Cinolazepam, Doxefazepam, Estazolam, Fluni fate trazepam, Flurazepam, Haloxazolam, Loprazolam, Lormetazepam, Nitrazepam, Quazepam, Temazepam, 0366 PERISTALTIC STIMULANT such as Cinitap Triazolam ride, Cisapride, Fedotozine, Loxiglumide 0379 Bromides such as Ammonium Bromide, Cal 0367 PROGESTOGEN such as Allylestrenol, Anage cium Bromide, Calcium Bromolactobionate, Lithium Stone, Chlormadinone Acetate, Delmadinone Acetate, Bromide, Magnesium Bromide, Potassium Bromide, Demegestone, DeSogeStrel, Dimethisterone, Dro Sodium Bromide spirenone, Dydrogesterone, Ethisterone, Ethynodiol, Flurogestone Acetate, Gestodene, Gestonorone 0380 Carbamates such as Carfimate, Ethinamate, Caproate, 17-Hydroxy-16-methylene-progesterone, 17 Hexapropymate, Novonal, Tricholorourethan alpha-Hydroxyprogesterone, LyneStrenol, Medroge 0381 Chloral Derivatives such as Carbocloral, Chloral Stone, Medroxyprogesterone, Megestrol Acetate, Betaine, Chloral Formamide, Chloral Hydrate, Dichlo Melengestrol, Norethindrone, Norethynodrel, Norges ralphenazone, Pentaerythritol Chloral, Triclofos terone, Norgestimate, Norgestrel, Norgestrienone, Nor Vinisterone, Pentagestrone, Progesterone, Promege 0382 Piperidinediones such as Glutethimide, Meth Stone, Trengestone yprylon, Piperidione, Pyrithyldione, Thalidomide 0368 PROLACTIN INHIBITOR such as Bromocrip 0383 Quinazolone Derivatives such as Etaqualone, tine, Cabergoline, LiSuride, Metergoline, Quinagolide, Mecloqualone, Methaqualone Terguride 0384 Others such as Acetal, Acetophenone, Aldol, 0369 PROSTAGLANDIN/PROSTAGLANDIN Ammonium Valerate, Amphenidone, d-Bomyl alpha ANALOG such as Arbaprostil, Bemeprost, Carboprost, Bromoisovalerate, d-Bornyl Isovalerate, Bromoform, EnproStil, Gemeprost, Latanoprost, Limaprost, Miso Calcium 2-Ethylbutanoate, alpha-Chlorolose, Clom prostol, Ornoprostil, ProStacyclin, ProStaglandin E, ethiazole, Cypripedium, Doxylamine, Etodroxizine, Prostaglandin E, PrSotaglandin F, Rioprostil, Etomidate, Fenadiazole, Homofenazine, Hydrobromic Rosaprostol, Sulprostone, Trimoprostil, Unoprostone Acid, Mecloxamine, Menthyl Valerate, Opium, Paral dehyde, Perlapine, Propiomazine, Rilmazafone, 0370 PROTEASE INHIBITOR such as Aprotinin, Sodium Oxybate, Sulfonethylmethane, Sulfonmethane CamoStat, Gabexate, NafamoStat, Urinastatin 0385) THROMBOLYTIC such as Anistreplase, Plas 0371) RESPIRATORY STIMULANT such as Almi min, Pro-Urokinase, Streptokinase, Tissue Plasmino trine, Bemegride, Cropropamide, Crotethamide, Dime gen Activator, Urokinase fline, Dimorpholamine, Doxapram, Ethamivan, Formi noben, Lobeline, Mepixanox, Nikethamide, Picotoxin, 0386 THYROTROPIC HORMONE such as TRH, Pimeclone, Pyridofylline, Sodium Succinate, Tacrine TSH 0372 SCLEROSING AGENT such as Ethanolamine, 0387 URICOSURIC such as Benzbromarone, Ethe Ethylamine, 2-Hexyldecanoic Acid, Polidocanol, benecid, Orotic Acid, Oxycinchophen, Probenecid, Sodium Ricinoleate, Sodium Tetradecyl Sulfate, Sulfinpyrazone, Zoxazolamine Tribenoside 0388 VASODILATOR (CEREBRAL) such as Bency clane, Cinnarizine, Citicoline, Cyclandelate, Cicloni 0373) SEDATIVE/HYPNOTIC cate, Diisopropylamine Dichloractetate, Ebumamo 0374. Acyclic Ureides such as Acecarbromal, nine, Fasudil, Fenoxedil, Flunarizine, Ibudilast, Apronalide, BomisoValum, Capuride, Carbromal, Ifenprodil, Lomerizine, Nafronyl, Nicametate, Nicer Ectylurea goline, Nimodipine, Papaverine, Pentifylline, 0375 Alcohols such as Chlorhexadol, Ethchlorvynol, Tinofedrine, Vincamine, Vinpocetine, Vicquidil Meparfynol, 4-Methyl-5-thiazoleethanol, tert-Pentyl 0389 VASODILATOR(CORONARY) such as Amot Alcohol, 2.2.2-Trichloroethanol riphene, Bendazol, Benftrodil Hemisuccinate, Benzi US 2004/0224012 A1 Nov. 11, 2004 27

odcarone, Chloacizine, Chromonar, Clobenfurol, Second Solution, each aliquot of the plurality of aliquots Clonitrate, DilaZep, Dipyridamole, Droprenilamine, of liposomal first Solution having a uniform size; Efloxate, Erythrityl Tetranitrate, Etafenone, Fendiline, wherein each aliquot of the plurality of aliquots of the Floredil, Ganglefene, Heart Muscle Extract, Hexestrol liposomal first Solution develops a hardened Surface Bis(..beta-diethylaminoethyl ether), Hexobendine, Itra upon a period of prolonged Submersion in the Second min Tosylate, Khellin, Lidoflazine, Mannitol Hexani Solution to form a plurality of macro-beads, the hard trate, Medibazine, Nitroglycerin, Pentaerythritol Tet ened Surface having a yield Strength of 1 to 4 grams per ranitrate, Pentrinitrol, Perhexiline, Pimethylline, cubic millimeter, the hardened Surface protecting and Prenylamine, Propatyl Nitrate, Pyridofylline, Trapidil, chemically isolating Said at least one liposomal Sus Tricromyl, Trimetazidine, TroInitrate Phosphate, Vis pension of multilamellar vesicles encapsulating at least nadine one active agent to increase shelf-life of Said at least 0390 VASODILATOR (PERIPHERAL) such as Alu one liposomal Suspension of multilamellar vesicles and minum Nicotinate, Bamethan, Bencyclane, Betahis to reduce environmental StreSS on Said at least one tine, Bradykinin, Brovincamine, Bufeniode, Buflom liposomal Suspension of multilamellar vesicles, physi edil, Butalamine, Cetiedil, Ciclonicate, Cinepazide, cally Separating the plurality of macro-beads from the Cinnarizine, Cyclandelate, Diisopropylamine Dichlo Second Solution, Washing the plurality of macro-beads roacetate, Eledoisin, Fenoxedil, Hepronicate, Iloprost, with a chemically inert Solution to remove any exceSS Inositol Niacinate, ISOXSuprine, Kallidin, Kallikrein, Second Solution; placing the plurality of macro-beads in Moxisylyte, Nafronyl, Nicergoline, Nicofuranose, Nic a storage medium, otinyl Alcohol, Nylidrin, Pentifylline, Pentoxifylline, wherein a Selection from the plurality of macro-beads in Prostaglandin E, Piribedil, Suloctidil, Tolazoline, Said Storage medium is placed into an inert delivery Xanthinal Niacinate Vehicle resulting in a final formulation, Said final for mulation being applied to an area of skin or mucous 0391 VASOPROTECTANT such as Benzarone, membrane by a dispensing means, Said dispensing Bioflavonoids, Chromocarb, Clobeoside, Diosmin, means utilizing a mechanical means of Sufficient force Dobesilate Calcium, Escin, Folescutol, Leucocyanidin, to fracture the hardened Surface to release the at least Metescufylline, Quercetin, Rutin, Troxerutin one liposomal Suspension of multilamellar vesicles 0392) VITAMIN/VITAMIN SOURCE/EXTRACTS encapsulating at least one active agent. Such as Vitamins A, B, C, D, E, and K and derivatives 2. The topical application of claim 1, wherein said at least thereof one liposomal Suspension of multilamellar vesicles com prises at least two liposomal Suspensions of multilamellar 0393 VULNERARY such as Acetylcysteine, Allan vesicles. toin, Asiaticoside, CadeXomer Iodine, Chitin, Dextra 3. The topical application of claim 2, wherein each nomer, Oxaceprol, Tocoretinate liposomal Suspension of multilamellar vesicles encapsulates 0394. The above list of pharmaceutical agents is based a different active agent. upon the list provided in The Merk Index, 21th Edition, 4. The topical application of claim 3, wherein each Merck & Co. Rahway, N.J. (1996). Moreover, the above liposomal Suspension of multilamellar vesicles is placed into drugs may be used either in the free form or, if capable of Separate physical reaction bonding Solutions resulting in at forming Salts, in the form of a Salt with a Suitable acid or least two liposomal first Solutions, each said liposomal first base; if the drug has a carboxyl group, its esters may also be Solution Separately introduced through the predetermined employed. orifice into the Second Solution. 5. The topical application of claim 3, wherein the different 0395. The preferred embodiments described herein are active agents are chemically incompatible. illustrative only, and although the examples given include 6. The topical application of claim 1, wherein the lipo much specificity, they are intended as illustrative of only a Somal Suspension of multilamellar vesicles is derived from few possible embodiments of the invention. Other embodi a phospholipids. ments and modifications will, no doubt, occur to those 7. The topical application of claim 1, wherein the at least skilled in the art. The examples given should only be one active agent is from a class of compounds Selected from interpreted as illustrations of Some of the preferred embodi the group consisting of antifungal drugs, anti-inflammatory ments of the invention. drugs, anti-arthritic drugs, corticosteroids, Vitamins, whit What is claimed is: ening agents, nitrous oxide, moisturizers, anabolic drugs, 1. A topical application comprising: analgesic drugs, anesthetic drugs, anti-asthmatic drugs, anti bacterial drugs, antihistaminic drugs, anti-neoplastic drugs, at least one liposomal Suspension of multilamellar anti-parasitic drugs, vasodilator drugs, vasoconstrictor vesicles encapsulating at least one active agent, Said at drugs, anti-tumor drugs, anti-Viral drugs, anti-Seborrheic least one liposomal Suspension of multilamellar drugs, anti-vertigo drugs, toxins, hormones, nicotine con vesicles being mixed with a physical reaction bonding taining compounds, immunosuppreSSants, compounds for Solution resulting in at least one liposomal first Solu prevention of contact dermatitis, compounds for prevention tion, of irritants, minerals, amino acids, lipids, herbs and metabo Said at least one liposomal first Solution being introduced lite Supplements. through a predetermined orifice into a Second Solution 8. The topical application of claim 1, wherein the at least containing an anti-oxidant and at least one inorganic one active agent is an amount from about 0.01 to about 5 Salt, Said predetermined orifice allowing a plurality of weight percent based on a total weight of the liposomal aliquots of liposomal first Solution to enter into the Suspension of multilamellar vesicles. US 2004/0224012 A1 Nov. 11, 2004 28

9. The topical application of claim 1, wherein the physical Solution having a uniform size of about 1 to 6 millimeters, reaction bonding Solution is Selected from the group con wherein each aliquot of the plurality of aliquots of the Sisting of agarose, cellulose, Sodium alginate, and chitosans. liposomal first Solution develops a hardened Surface upon a 10. The topical application of claim 1, wherein the anti period of prolonged Submersion in the Second Solution. oxidant is selected from the group consisting of BHA, BHT, 19. The topical application of claim 17, wherein said at Tocopherol and Sodium edetate. least one liposomal Suspension of multilamellar vesicles 11. The topical application of claim 1, where in the comprises at least two liposomal Suspensions of multilamel anti-oxidant is in an amount from 0.01 to 0.5 weight percent lar vesicles. of the Second Solution. 20. The topical application of claim 19, wherein each 12. The topical application of claim 1, wherein the at least liposomal Suspension of multilamellar vesicles encapsulates one inorganic Salt is Selected from the group consisting of a different active agent. calcium chloride, calcium Sulfate, calcium carbonate, mag 21. The topical application of claim 20, wherein each nesium chloride, magnesium Sulfate, barium chloride, liposomal Suspension of multilamellar vesicles is placed into barium Sulfate and Sodium hydroxide. Separate physical reaction bonding Solutions resulting in at 13. The topical application of claim 1, wherein the at least least two liposomal first Solutions, each said liposomal first one inorganic Salt is in an amount from 1 to 2 weight percent Solution Separately introduced through the predetermined of the Second Solution. orifice into the Second Solution. 14. The topical application of claim 1, wherein the period 22. The topical application of claim 20 wherein the of prolonged submersion is about 60 to 180 minutes. different active agents are chemically incompatible. 15. The topical application of claim 1, wherein the uni 23. The topical application of claim 17, wherein the form size is about 1 to 6 millimeters. liposomal Suspension of multilamellar vesicles is derived 16. The topical application of claim 1, wherein the plu from a phospholipid. rality of macro-beads are non-permeable. 24. The topical application of claim 17, wherein the at 17. A topical application comprising: least one active agent is from a class of compounds Selected a therapeutically effective amount of at least one active from the group consisting of antifungal drugs, anti-inflam agent encapsulated in at least one lipoSome Suspension matory drugs, anti-arthritic drugs, corticosteroids, Vitamins, of multilamellar vesicles in amount from about 0.01 to whitening agents, nitrous oxide, moisturizers, anabolic about 5 weight percent based on a total weight of the drugs, analgesic drugs, anesthetic drugs, anti-asthmatic drugs, antibacterial drugs, antihistaminic drugs, anti-neo liposome Suspension of multilamellar vesicles, plastic drugs, anti-parasitic drugs, vasodilator drugs, vaso the liposomal Suspension of multilamellar vesicles being constrictor drugs, anti-tumor drugs, anti-Viral drugs, anti encapsulated within a plurality of macro-beads, the Seborrheic drugs, anti-vertigo drugs, toxins, hormones, plurality of macro-beads having a hardened Surface nicotine containing compounds, immunosuppressants, com with a yield Strength of 1 to 4 grams per cubic milli pounds for prevention of contact dermatitis, compounds for meter, the hardened Surface being non-permeable thus prevention of irritants, minerals, amino acids, lipids, herbs protecting and chemically isolating Said at least one and metabolite Supplements. liposomal Suspension of multilamellar vesicles to 25. The topical application of claim 18, wherein the increase shelf-life of Said at least one liposomal Sus physical reaction bonding Solution is Selected from the pension of multilamellar vesicles and to reduce envi group consisting of agarose, cellulose, Sodium alginate, and ronmental StreSS on Said at least one liposomal Suspen chitosans. Sion of multilamellar vesicles, 26. The topical application of claim 18, wherein the a Selection of the plurality of macro-beads being placed anti-oxidant is Selected from the group consisting of BHA, into an inert delivery vehicle to create a final formu BHT, Tocopherol and sodium edetate. lation, the final formulation being applied to an area of 27. The topical application of claim 18, where in the skin or mucous membrane by a dispensing means, Said anti-oxidant is in an amount from 0.01 to 0.5 weight percent dispensing means utilizing a mechanical means of of the Second Solution. Sufficient force to fracture the hardened Surface to 28. The topical application of claim 18, wherein the at release the at least one liposomal Suspension of multi least one inorganic Salt is Selected from the group consisting lamellar vesicles. of calcium chloride, calcium Sulfate, calcium carbonate, 18. The topical application of claim 17, wherein the magnesium chloride, magnesium Sulfate, barium chloride, plurality of macro-beads is formed by mixing the at least one barium Sulfate and Sodium hydroxide. liposomal Suspension of multilamellar vesicles with a physi 29. The topical application of claim 18, wherein the at cal reaction bonding Solution and introducing the admixture least one inorganic Salt is in an amount from 1 to 2 weight through a predetermined orifice into a Second Solution percent of the Second Solution. containing an anti-oxidant and at least one inorganic Salt, the 30. The topical application of claim 18, wherein the predetermined orifice allowing a plurality of aliquots of period of prolonged submersion is about 60 to 180 minutes. liposomal first Solution to enter into the Second Solution, each aliquot of the plurality of aliquots of liposomal first