US 20030059471A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0059471 A1 Compton et al. (43) Pub. Date: Mar. 27, 2003

(54) ORAL DELIVERY FORMULATION Related U.S. Application Data (63) Continuation of application No. 09/055,560, filed on (76) Inventors: Bruce Jon Compton, Lexington, MA Apr. 6, 1998, now abandoned. (US); Nancy E. Solari, West Newton, (60) Provisional application No. 60/069,501, filed on Dec. MA (US); Margaret A. Flangan, Stow, 15, 1997. Provisional application No. 60/073,867, MA (US) filed on Feb. 4, 1998. Correspondence Address: Stephen J Gaudet Publication Classification 68H Stiles Road (51) Int. Cl." ...... A61K 9/14 Salem, NH 03079 (US) (52) U.S. Cl...... 424/489 (21) Appl. No.: 09/997.277 (57) ABSTRACT Flakes containing drugs and methods for forming and using (22) Filed: Nov. 29, 2001 Such flakes are provided. US 2003/0059471 A1 Mar. 27, 2003

ORAL IDELIVERY FORMULATION oncology patients, late-stage AID patients, post-Surgical patients and patients who other advanced disease States RELATED APPLICATIONS which are physically debilitating. 0001. This application claims the benefit of priority under 0007. There remains a need for dosage formats which are 35 U.S.C. Section 119 to U.S. patent application entitled compatible with Such populations and which addresses the “Oral Delivery Formulation”, filed Dec. 15, 1997 and U.S. physical and physiological limitations of these populations. patent application entitled “Oral Delivery Formulation”, There remains a need to provide dosage formats which can filed Feb. 4, 1998. Serial numbers presently not known. This be administered to patients which experience difficulty in application also claims the benefit of priority under 35 Swallowing Solids (tablet) and liquids. U.S.C. S120 to U.S. patent application entitled “Oral Deliv 0008. In attempts to solve some of the above issues, ery Formulation', filed Apr. 4, 1998, serial number presently different formulations of nano- or micro-granules have been not known. reported (see, U.S. Pat No. 5,618,527). These formulations consist of Spherically-shaped particles in either a liquid or a BACKGROUND OF THE INVENTION tablet form, in which the particles are not greater than 125 tum diameter to avoid the Sensation of grittiness. Also, the 0002 Current orally delivered drugs are formulated in particles need to have Smooth edgeS. These requirements either Solid (i.e., tablet, capsule or granules) or liquid (i.e., severely limit the flexibility of the drug manufacture and Solution, Suspension or emulsion) form. Solid dosage forms delivery. are conventionally the dosage of choice as they are typically more Stable, leSS expensive to manufacture and have 0009 Similar attempts to reduce the sensation of gritti achieved general acceptance by consumers. The manufac neSS was described by using a blend of a gritty drug with a ture of Solid dosage forms typically involves the processing seedy fibrous fruit (U.S. Pat. No. 5,102,664). In this com of the drug with Suitable excipients in order to produce a bination the Seedy fibrous fruit texture masks the grittineSS freely-flowing powder. The type of processing and excipi of the drug. The problem of grittineSS also is evidenced in ents chosen to manufacture the powder can be altered to certain topical formulations. Topical formulations which provide desired effects Such as controlled release of the drug. contain particles of drugs (or particles containing drugs) Once processed, the powder can be directly packaged into have an unpleasant gritty feel when applied to the skin. Sachets, compressed into tablets or filled into capsules. 0010. There exists the need for a drug delivery format Tablets can further be coated in order to improve palatability which is adaptable to patient populations that have trouble or provide controlled release of the drug. chewing and Swallowing. There also exists a need for a drug 0.003 Oral liquid dosage forms are primarily used by the delivery System which is adaptable to all formats, including pediatric population and those who experience difficulty in oral, topical, injectable, and other delivery formats. There Swallowing. Liquid dosage forms are available orally as also is a need for a drug delivery System that can permit Solutions, Suspensions or emulsions. These liquids often adjustment of the release profile of the drug. Various aspects contain colorants and flavorings in an attempt to increase of the present invention address the foregoing needs. palatability and patient acceptance. 0004. Many patients, however, are unable to adequately SUMMARY OF THE INVENTION ingest either Solid or liquid dosage forms. To address this 0011. The present invention provides novel methods and problem, health care providers often crush Solid dosage products for the manufacture and use of novel drug delivery forms and disperse them in a semi-solid medium (e.g., Systems. applesauce, pudding). However, when tablets or capsules are 0012. According to one aspect of the invention, a com tampered with, the drug release kinetics of the pharmaceu position is provided. The composition is a plurality of tics are altered. This can result in dose dumping and Serum discrete, Substantially flat flakes, each having an average concentrations which are non-optimal and can be dangerous. length, an average width and an average thickness, wherein 0005 There are a number of drug administration and each of the length and the width are at least three times the patient compliance issues peculiar to the geriatric market, thickness, wherein a longest dimension of each flake is which result from hard to Swallow tablets, unpleasant taste between 100 nanometers and 5 millimeters, and wherein the and texture, frequent dosing regimens or unfavorable side flakes comprise a drug or a nondrug nonnutritional active effect profiles of certain drugs. Current tablet and liquid agent. In one embodiment, each of the flakes has a Surface dosage forms do not address the needs of the elderly patient. area, and the ratio of the Surface area to the thickness is at Physical limitations prevalent amongst the elderly hinder least 25 units: 1 unit. In another embodiment, the longest their ability to Swallow traditional dosage forms and to dimension of each flake is between 10 microns and 1 Self-administer medication (e.g., arthritis, tremors associated millimeter. In still another embodiment, the ratio of the with neurological disorders, Visual impairment, and memory surface area to the thickness is at least 100 units: 1 unit. problems). Physical limitations present in this age group 0013 The drug can comprise a very small amount of the include difficulty in Swallowing due to dehydration, “mouth flakes or it can comprise a very large amount of the flakes breathing, and esophageal lesions. Chewing also is difficult by weight. Thus, the drug can comprise between 0.001% and due to reduced bulk and tone of oral musculature as well as 100% by weight of the flakes. In certain embodiments, the loSS of or degradation in the quality of their teeth. drug is at least 0.05% be weight of the flakes. In important 0006 Other patient populations present drug administra embodiments, the drug is at least 5% by weight of the flakes. tion and patient compliance issues. These include pediatric In other important embodiments, the drug is at least 10%, at patients (i.e. children about 5 years old or less), certain least 25%, or at least 50% by weight of the flakes. US 2003/0059471 A1 Mar. 27, 2003

0.014. The drug can be embedded within the flakes or the pharmaceutical preparation is formulated as an implant. In drug can be coated on the flakes. If the drug is embedded yet another embodiment, the pharmaceutically acceptable within the flakes, then the flakes can be made entirely of the carrier is a Semi-Solid. These forms can be controlled release drug or the drug can be dispersed throughout all or a portion forms, delayed-release forms or Sustained-release forms. of the flakes. If the drug is dispersed throughout the flake, The Semi-Solid can be a hydrogel or a food. The flakes can then the drug can be a component of the flake, can be be coated as described above. They also can be coated with contained in discrete microparticles dispersed throughout a taste-masking composition. the flake, can be in one or more layers comprising the flake or can be physically and/or chemically retained within a 0019. According to still another aspect of the invention, flake which comprises a porous matrix. The drug also can be a method is provided for treating a Subject having a condi coated on a Surface of the flakes. The coating can be an even tion. The method involves administering to a Subject in need continuous coating or can be a noncontinuous coating. The of Such treatment an amount of a drug effective to treat the drug can be contained in microSpheres which are coated on condition, wherein the drug comprises a plurality of flakes. the flakes. The drug also can be coated directed onto the In important embodiments, the flakes comprise any one of flakes or can be attached covalently or noncovalently to the the pharmaceutical preparations as described above. In another important embodiment, the drug is administered flakes by linkers. orally. In another important embodiment, the Subject has a 0.015. In one important embodiment, the flakes further condition making it difficult to Swallow. The subject can be comprise a coating on the flakes. This coating can in Some Selected from the group consisting of a geriatric Subject, a embodiments Separate the drug from the environment. The Subject with cancer, a Subject who is post-Surgically recov coating can be an enteric coating covering the flake. Other ering, an infant, a child five years old or less, or a late-stage coatings are described below. AIDS subject. 0016. The flakes can be made of any one of a variety of 0020. According to yet another aspect of the invention, a materials, polymers or non-polymers, discussed in greater method is provided for preparing a pharmaceutical prepa detail below. The flakes can comprise natural polymers. In ration. The method is all improvement to the known meth Some embodiments, the flakes are at least 25% by weight of ods for forming pharmaceutical preparations by incorporat the natural polymer. The flakes also can comprise a Synthetic ing a drug within or coating a drug onto a particle, the polymer. In many embodiments, the flake is at least 5% by improvement comprising incorporating the drug within or weight a nonfood. In most embodiments, the flake is at least onto a flake. In important embodiments, the flakes are as 25%, at least 50% and at least 75% by weight of a nonfood. described above. In other embodiments, the flake can comprise a drug uptake 0021 According to another aspect of the invention, a enhancer. A drug uptake enhancer is a material which, when method is provided for preparing a pharmaceutical prepa it is administered together with the drug, facilitates uptake of ration. The method involves incorporating a drug into or the drug in the environment in which the drug is delivered. upon a plurality of flakes. In one embodiment, the flakes are Drug uptake enhancers are well known for a variety of drugs formed first, and then the drug is coated onto, or allowed to and are approved by the FDA. penetrate into, the flakes. In another embodiment, the drug 0.017. According to another aspect of the invention, is incorporated into the flakes by forming the flakes in the another composition is provided. The composition is a environment of the drug. plurality of discrete, Substantially flat flakes, each having an average length, an average width and an average thickness, 0022. The drug-incorporated flakes (DIF) may be admin wherein each of the length and the width or at least three istered in a variety of media, including liquid, tablet and times the thickness, wherein the longest dimension of each food-feedable basis. The DIF provides all the benefits for fake is between 100 nanometers and 5 millimeters, and controlling the release kinetics of the drug available in wherein each flake comprises a porous matrix. The pores are conventional drug delivery methods. In addition, it may large enough to accommodate a drug or a nondrug, nonnu alleviate many of the shortcomings of nano- and macro tritional active agent. In this aspect of the invention, the granules in terms of Size and manufacturing constraints. composition can further comprise a drug or active agent. The 0023 The invention has been described in this summary flake in Some embodiments is at least 5%, at least 10%, at in connection with drugs. Drugs are defined specifically in least 25%, or at least 50% a nonfood. Important embodi the Specification as excluding nontherapeutic doses of nutri ments Such as dimensions, ratios, percent drug contained tional Supplements. The drugs typically are not nutritional within the flake, and So on are as described above. Supplements Such as Vitamins and minerals (i.e. nonnutri tional drugs). The agent carried by the flakes of the inven 0.018. According to another aspect of the invention, a tion, however, need not be a drug. The agent can be a pharmaceutical preparation is provided. The pharmaceutical nondrug active agent Such as an insect repellant, a SunScreen preparation contains any one of the compositions as agent, a pesticide, etc. Classes of nondrug agents are described above, and a pharmaceutically acceptable carrier. The pharmaceutical composition contains an amount of the described below. drug effective for treating a condition treatable by the drug. 0024. The invention also contemplates both food and In certain embodiments, the pharmaceutical preparation is nonfood flakes. In most embodiments of the invention the formulated as an oral dosage form. The oral dosage form can flake is a nonfood Such as a Synthetic polymer for carrying be a Semi-Solid food. In another embodiment, the pharma the drug or other active agent. It is an embodiment of the ceutical preparation is formulated as a topical preparation. invention, however, that the flake can be a food Such as an The topical preparation can contain an agent that is non oat flake or a grape nut flake. When the flake is a food, then Suitable for oral ingestion. In Still another embodiment, the the drug either is not a nutritional Supplement, or, if it is a US 2003/0059471 A1 Mar. 27, 2003

nutritional Supplement, it is present at therapeutic levels 0031. The invention involves in one aspect the delivery which are above nutritional Supplement levels of the prior of drugs in or on such flakes. A “plurality” of flakes is art. Thus, the invention intends to exclude the prior art referred to. A plurality means greater than 100. In important nutritionally Supplemented food flakes Such as fortified embodiments, the plurality is greater than a thousand, oatflakes and fortified cereal flakes. greater than ten thousand and even greater than one hundred 0.025. It is known that a variety of drugs have enhanced thousand. therapeutic effects due to improvements in drug delivery 0032. The flakes can be non-porous or porous. The flakes when delivered together with a drug uptake enhancer. Such can be made entirely of the drug or can be as low as 0.001% enhancers can be included with a drug in a Single flake or can drug-containing. Thus, the drug may be combined with any be provided Separate from the drug carried on its own flake. of the variety of normal excipients, binders, fillers and the Thus, the plurality of flakes can be mixtures of flakes, Some like and formed into a Solid flake. The excipients may be containing a drug and Some carrying nondrug component, non-polymers or polymers. In one important non-polymer that act as an adjunct to therapy. One important example of embodiment, which is merely exemplary, the flake is a this is flakes which have anti-constipation properties. Many “fused' flake. In a “fused' flake, a drug, a carrier, or both are drugs cause constipation and many patients Such as geriat melted and recrystallized to form a crystalline matrix of the rics are chronically constipated. Flakes which are a mixture drug and/or carrier. In a totally fused flake, both the drug and of drugs and anti-constipation agents arc useful for Such the carrier are melted and recrystallized. In a partially fused patient populations. flake, only the carrier is melted and recrystallized, thereby capturing the drug in the crystalline matrix of the carrier. 0026. The present invention also provides a spoon-feed Sterols are particularly Suited for melting and recrystaliza able drug delivery vehicle. The vehicle includes a viscose tion. For example, various cholesterol-type compounds, base having a consistency capable of being Spoon-feed. The including cholesterol acetate may be used. Compounds Such Viscose base may be food or non-food. Particles comprising as palmitic acid also can be used. Detailed parameters about a drug and, optionally, a Synthetic or natural carrier are forming “fused” drug delivery materials are disclosed in added to or mixed into the Viscose base. The particles may have any Suitable Size and shape, Such as by way of example, U.S. Pat. Nos. 4,748,024, 4,892,734 and 5,039,660, the Spherical, oblong, and flake-like particles as described entire disclosures of which are incorporated herein by ref above. The drug may be provided premixed with the base, erence. These patents illustrate that Virtually any amount of or it may be Supplied Separately from the base for mixing drug and carrier, including no carrier, can be used in the just prior to consumption. formation of Such materials. 0033. The excipient also may be a polymer. The types of 0027. The spoon-feedable drug delivery vehicle also can polymers that may be used are described in great detail be a nutritionally fortified delivery vehicle (NFDV). The below. The polymers are substantially coextensive with the NFDV has a semi-viscose or semi-solid consistency which materials which are used in connection with making nano may be readily Spoon-fed. This base may be Supplied in a and microparticles or spheres (hereinafter “microparticles”). unit dose package in a variety of flavors and compositions. Such polymers further include bioadhesives which are par The NFDV provides a spoon-fed base for administration of ticularly Suited for oral delivery methodologies, as is drugs which addresses the difficulties in Some patient popu described and known in the prior art. Using Such polymers, lations intolerant of orally delivered medication. In addition, nonporous flakes can be manufactured or porous flakes can it can provide necessary dietary nutrients and/or fiber. be manufactured. The drug can be loaded into the flake during the manufacture of the flake or may be added to the DETAILED DESCRIPTION OF THE flake after the manufacture of the flake, by causing the drug INVENTION to be absorbed into or adsorbed onto the flake or by coating 0028. It has been observed previously that spherical or the drug onto the outside Surface of the flake. In the various granular particulates leave a gritty Sensation in the mouth methodologies used for manufacturing microparticles, it is which can be unpleasant to the patient when administering shown that a drug can be physically entrapped within the micro-granules. The present invention has recognized that polymer, chemically bound within the polymer (covalently drugs which are incorporated into a flaked delivery vehicle or noncovalently) or physiochemically entrapped within or possess enhanced mouth feel by eliminating or reducing the bound to the polymer. The present invention does not gritty feel characteristic of the prior art particles. It is involve the use of new polymers and the like, but instead anticipated that the flakes of the present invention will be involves the use of known technology for drug delivery with better tolerated by the patient, leading to more complete the exception that the materials are manufactured and fash ioned in the form of a flake rather than in an amorphous or dosages and higher compliance when used for oral delivery. Spherical particle. 0029. A flake is a substantially flat, thin layer or unit and thus possesses a dimension which is Substantially less than 0034. Also as well known in the prior art, the flakes can be coated with materials. Such coatings can be enteric the other two dimensions. The flake may be substantially coatings for permitting the flakes to pass through the Stom planar or Similar to curvilinear. ach and into the intestine prior to releasing the drug. Such 0.030. In a preferred embodiment, the flake has a size of coatings also can be taste-masking coatings, Such as is between 10 and 500 microns along its longest dimension. described in U.S. Pat No. 5,084.278 and the patents cited The flakes preferably are free flowing. The flakes can be therein, the disclosure of which is incorporated herein by relatively uniform and consistent in size and morphology or reference. The present invention does not present new can be a mixture of flakes of different sizes and morpholo coating technology, but instead the flake particles of the gIeS. present invention can be coated in the same manner as the US 2003/0059471 A1 Mar. 27, 2003 prior art particle and microparticle delivery technologies. 0039 The flakes also can be made of ion exchange The coatings may be made from the same material as the materials to cause a Selective release of drugs in a particular flake or from different materials. The coatings, in general, tissue. One example is using a resin that will release a drug are adapted to protect the drugs contained in the flakes, to in the presence of high concentrations of Sodium ions, Such provide advantages to the flakes in their environment of use as are present in the Small intestine. The flakes also can be (Such as by permitting the flake to pass through the stom manufactured from a mixture of monomers and drug, ach), to cause the flakes to be less likely to aggregate with whereby the monomer is polymerized into a polymer about one another and the like. the drug to form a molecularly imprinted polymer, which 0035. The release dynamic of drugs from the flakes can acts as a cage for the drug molecule. Thus, the flakes may be be controlled in a conventional manner, just as the release made of biodegradable polymers and non-biodegradable profile of drugs is controlled in other similar technologies polymers and non-polymers as is conventional, all Selected Such as in a particle-based or polymer-based delivery Sys to influence the release profile of drug. tems. According to the invention, therefore, flakes can be 0040. One important class of polymers useful in the manufactured So as to control and/or vary parameterS Such invention are the bioadhesive polymers. Such polymers call as Size, morphology, materials and coatings to influence be fashioned as flakes containing drugs and will adhere to release of drugs from the flakes. Controlling Such param the intestine. This can accomplish a number of desirable eters can achieve drug release profiles as desired, including results. First, it can increase residence time of the flakes in delayed-release, timed-release, and Sustained-release. One the intestine, thereby affecting the amount of drug released advantage of the flakes according to the invention is that the in the intestine. In addition, the bioadhesive-containing drug release profile can be made more uniform, because, unlike will Stick to the intestine, and act as a Sustained-release for a particle or sphere, the Surface area of a flake is delivery form for Such time as it is present Sticking to the relatively constant as it erodes. In any event, Virtually any intestine. The drug will be released slowly by diffusion or release profile can be achieved using technologies which are through degradation of the polymer in the intestine, thereby well known to those of ordinary skill in this art. controlling the release profile of the drug. 0.036 The flakes can be manufactured in virtually any 0041. The flakes also can be coated, applying principals size, although preferred sizes are as described above. A conventional in the particle-based delivery art. Thus, the principal characteristic of Size which affects the length of flakes can be coated with enteric coatings to permit the time over which a drug is released is the thickness of the flakes to Survive the environment of the stomach. The flakes flake. The thicker the flake, of course, the longer the period can be coated with pH Sensitive materials to cause the of time over which drug will be released, all other param coating to dissolve only after the flake enters the intestine. eters being kept equal. This is particularly So if the flake is Coatings which would dissolve at neutral pH, generally, are bioerodable. The flakes also can be of different Surface areas, useful for this purpose. The flakes also can be coated with which will affect the release kinetics of drugs contained lipophilic coatings which tend to dissolve only after con therein or coated thereon. The plurality of flakes, therefore, tacting the bile in the large intestine. can be a mixture of sizes, uniformly distributed over a range or be two or more discrete sizes to achieve a pulsed-type 0042. The thickness of Such coatings, of course, also can release, etc. The flakes can be relatively large So as to lend be varied, whereby Some flakes are exposed for drug deliv themselves to topical and oral delivery formatS or can be ery prior to others, thereby effecting an extended drug extremely Small, permitting them to be injected. release profile. 0037. The morphology of the flakes also will affect the 0043. The coatings may be free of drug or may contain release profile of drugs from the flake. Smooth Surfaces the drug. If the coating contains a drug, then it can be the represent relatively Smaller Surface areas, whereas rough Same drug or a different drug than is in the flake. If it is the Surfaces represent relatively larger Surface areas, as is well Same drug, it can be of the same concentration or at a known. different concentration. Likewise, the coating can be made 0.038. The materials from which the flakes are made also of the same material as the flake or of a different material will affect the release profiles of drugs from the flakes. than the flake. Thus, the flake can be a particular polymer Again, this is well known to those of ordinary skill in this art. containing a drug, and the coating can be the same polymer For example, a flake formed of melted and recrystallized free of drug or the coating can be a different material drug and/or carrier will dissolve more slowly than a drug altogether. It should be mentioned, as well, that the flake can and/or carrier that Simply are pressed into a flake without contain a Single drug or a combination of drugs. melting, due to the energy of the crystal lattice of the melted 0044) The flakes also can be formed of a variety of layers, and recrystallized material. At one extreme, the flake can be Some of which can act as a coating. One layer can be a drug made of a polymer or fiber that is not bioerodable, whereby and another layer can be, inter alia, (1) a coating to influence the only drug released is that which diffuses from or is the drug-release profile, (2) the same drug but at a different released by the flake as it passes through the gastrointestinal concentration, (3) a different drug, (4) a barrier layer to tract. At another extreme, the flake can be made of a material Separate two layers, (5) a Substrate for another layer, (6) a that erodes completely before it passes through the gas food, (7) a nonfood and So on. Thus, the flakes according to trointestinal tract. Such flakes can be made of materials the invention may be 1, 2, 3, or more layers. Such layered which erode Selectively in the Stomach, materials which flakes can be manufactured easily, Such as, for example, by erode Selectively in the Small intestine, materials which pressing two or more layers together, by Spraying a plurality erode Selectively in the large intestine, or materials which of layerS Sequentially onto a belt or drum, by Vortexing will erode partially or completely in more than one of these preformed flakes to render them airborne in a mist that will Selected tissue regions. coat the flakes to create another layer, and So on. US 2003/0059471 A1 Mar. 27, 2003

004.5 Flakes having any one or more of the foregoing apply an insecticide. The insecticide can be covalently characteristics can be manufactured by adapting existing attached to the flakes which are topically applied as a Smooth technologies to flake manufacturing processes. For example, layer on the skin. Because the insecticides are covalently drugs can be incorporated into flakes at different concentra attached to the flakes, they are present for exerting the tions by applying to two separate preparations of prefabri desired action, but they are not released generally in high cated porous flakes, drugs at different concentrations in dose into the skin, thereby avoiding potential unwanted Side Solutions for diffusing into the two separate preparations of effects. Such SunScreen agents and insecticides on flakes also flakes. The flakes also can be made as molecular imprinted are desirable as the flakes themselves act as a Smooth polymers, whereby the polymer of the flake is made from the lubricant when applying the agents to the skin. mixture of drug and monomer, with the drug being captured in the polymer formed from the monomer. Coatings of 0049. In topical preparations, the flakes, in general, are various thicknesses also can be applied as is conventional. lubricating and therefore can prevent chafing of skin against Single, double, triple, and other multi-layered flakes, coated skin or clothing against Skin, as an additional benefit. or not, thus can be formed. Mixtures of flakes with different 0050 Flakes according to the invention also may be characteristics also can be used, e.g. uncoated flakes with applied in preparations that are intended for body cavities, coated flakes, mixtures of flakes with different concentra Such as intravaginal preparations or Suppository prepara tions of drugs, mixtures of flakes with different thicknesses, tions. Agents Such as antibiotics, antifungals, and the like mixtures of flakes carrying drugs with flakes that carry drug can be attached to flakes and conveniently delivered. The uptake enhances, etc. feel of Such flakes is Superior to the feel of the microparticles 0.046 According to one important embodiment, the sus of the prior art. Such topical preparations can include agents tained or controlled release microparticles of the prior art are for treating genital warts, kaposi Sarcoma, actinic keratosis used conventionally in the flake technology of the present and skin cancers in general. invention. In this aspect of the invention, microparticles, 0051. The topical preparations of the invention also can Such as microSpheres and nanospheres, are incorporated into be used for applying wound healing agents to the skin. The the flakes of the invention. In other words, microparticles wound healing agents can be attached to, coated on, or first are formed having known and desired release-profiles contained within the flakes of the invention, which can be characteristic of the prior art. Those microparticles then are applied topically. formed as part of the flakes of the invention. The micropar 0052 The flakes according to the invention also can be ticles can be pressed into flakes, Sprayed onto rotating drums applied parenterally. The preparations of the invention are as described in greater detail below and formed into flakes, particularly Suitable for local delivery of drug agents. The covalently attached to flakes and the like. Thus, in order to flakes of the invention have less mobility than microspheres achieve the release profiles characteristic of the prior art, no when placed within the body, Such as by injection into a new technology is required. Instead, the flakes simply can Solid tumor. Systemic exposure to the drug thereby is act as a delivery vehicle for existing microparticles. Such a reduced and it is believed that a more consistent release delivery vehicle would be particularly useful for oral prepa profile is obtained. The flakes of the invention also can be rations, topical preparations, and in other circumstances as used in a manner as described in the prior art by intravenous will be apparent to those of ordinary skill in the art. injection, whereby the flakes are manufactured at a particu 0047. It has been mentioned that one important use of the lar size and become desirably lodged in capillaries. flakes of the invention is for delivering drugs orally. Any drug which can be delivered orally according to the prior art 0053 Flakes according to the invention also can be used can be delivered using the flake technology of the invention. to cover areas in the body to prevent tissue adhesion, Such Virtually any release profile obtained in the prior art using as post-Surgical tissue adhesion. The flakes can be made, for oral delivery formats also can be obtained using the flakes example, of hyaluronic acid, and applied to cover areas of according to the invention. The flakes Simply provide a tissue to prevent tissue adhesions. convenient format for orally delivering drugs to particular 0054 The flakes of the invention thus can be included in target patient populations. any of the prior art forms used for administering drugs, including implants, topical preparations, inhalable prepara 0.048. The flakes also can be used in topical formulations. The flakes will provide a Smooth, non-gritty coating on the tions, Suppositories, ocular formulations, oral formulations skin, which can be used for delivering topically drugs and the like, which are well known. In certain of the contained in or attached to the flakes. Such topical prepa preparations according to the invention, Such as topical rations include Virtually all of the known drugs presently preparations, there may be included agents which are not delivered topically, but never before delivered as part of a Suitable for oral ingestion. Such agents include creams, flake. In addition, the flakes are particularly Suited for the lubricants and the like which are well known. delivery of certain agents, Such as Sunscreen agents and 0055. The flakes according to the invention can be manu insecticides. For Sunscreen agents, the flakes themselves factured according to many well known methodologies. The could comprise a physical or chemical SunScreen agent, flakes may be cast, Such as by drum casting or bell casting. which could be used to form a protective barrier from the The flakes may be fractured, chipped or shaved from solid Sun. Moreover, if the Sunscreen agent is covalently attached materials. The flakes may be pressed, Stamped or embossed to the flake, then the Sunscreen agent can be prevented from by conventional equipment. Likewise, the flakes may be entering cells, thereby reducing or even eliminating any side milled Such as using a roller milling apparatus. The flakes effects for Such Sunscreen agents. The agent is held on the also may be extruded such as in the form of a ribbon which flake and is not released into the skin. The same benefit can is broken into Smaller pieces. The flakes also may be rolled be obtained when using flakes according to the invention to from wet particulates. Exemplary materials for making US 2003/0059471 A1 Mar. 27, 2003 flakes include polyvinyl alcohol, poly(Vinylpyrollidone), tosamine, and neuraminic acid, and naturally occurring methyl cellulose, hydroxypropyl cellulose, hydroxypropyl derivatives thereof, and including dextran and cellulose, methyl cellulose, agar, carrageenan, Xanthan, polyethylene collagen, chemical derivatives thereof (Substitutions, addi glycol, a copolymer of acrylic and methacrylic acid esters, tions of chemical groups, for example, alkyl, alkylene, ethylcellulose, cellulose acetate, cellulose acetate phthalate, hydroxylations, oxidations, and other modifications rou poly(methyl methacrylate), poly(methyl acrylate), polyeth tinely made by those skilled in the art), albumin and other ylene, polypropylene, polyethylene oxide, PET, poly(Vinyl hydrophilic proteins, Zein and other prolamines and hydro isobutyl ether), poly(Vinyl acetate), poly(Vinyl chloride), phobic proteins, copolymers and mixtures thereof. In gen polyurethane, pectin, furcellaran, Starch, Zein, gelatin, col eral, these materials degrade either by enzymatic hydrolysis lagen, polygeline, alginic acid, propylene glycol alginate or or exposure to water in Vivo, by Surface or bulk erosion. The Sodium alginate. foregoing materials may be used alone, as physical mixtures (blends), or as co-polymers. The most preferred polymers 0056. A more comprehensive list is materials including, are polyesters, polyanhydrides, polystyrenes and blends but not limited to, nonbioerodable and bioerodable poly merS. Such polymerS have been described in great detail in thereof. the prior art. They include, but are not limited to: polya 0059 Particularly preferred in some embodiments are mides, polycarbonates, polyalkylenes, polyalkylene glycols, bioadhesive polymers. A bioadhesive polymer is one that polyalkylene oxides, polyalkylene terepthalates, polyvinyl binds to mucosal epithelium under normal physiological alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl conditions. Bioadhesion in the gastrointestinal tract pro halides, polyvinylpyrrollidone, polyglycolides, polysilox ceeds in two stages: (1) Viscoelastic deformation at the point anes, polyurethanes and copolymers thereof, alkyl cellulose, of contact of the Synthetic material into the mucus Substrate, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, and (2) formation of bonds between the adhesive synthetic nitro celluloses, polymers of acrylic and methacrylic esters, material and the mucus or the epithelial cells. In general, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, adhesion of polymers to tissues may be achieved by (i) hydroxy-propyl methyl cellulose, hydroxybutyl methyl cel physical or mechanical bonds, (ii) primary or covalent lulose, cellulose acetate, cellulose propionate, cellulose chemical bonds, and/or (iii)Secondary chemical bonds (i.e., acetate butyrate, cellulose acetate phthalate, carboxylethyl ionic). Physical or mechanical bonds can result from depo cellulose, cellulose triacetate, cellulose Sulphate Sodium Salt, Sition and inclusion of the adhesive material in the crevices poly (methyl methacrylate), poly(ethylmethacrylate), poly of the mucus or the folds of the mucosa. Secondary chemical (butylmethacrylate), poly(isobutylmethacrylate), poly(hexl bonds, contributing to bioadhesive properties, consist of methacrylate), poly(isodecylmethacrylate), poly(lauryl dispersive interactions (i.e., Van der Waals interactions) and methacrylate), poly (phenyl methacrylate), poly(methyl Stronger Specific interactions, which include hydrogen acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), bonds. The hydrophilic functional groups primarily respon poly(octadecyl acrylate), polyethylene, polypropylene poly sible for forming hydrogen bonds are the hydroxyl and the (ethylene glycol), poly(ethylene oxide), poly(ethylene carboxylic groups. Numerous bioadhesive polymers are terephthalate), poly(Vinyl alcohols), poly(Vinyl acetate, poly discussed in that application. Representative bioadhesive Vinyl chloride polystyrene and polyvinylpryrrollidone. polymers of particular interest include biocrodible hydrogels described by H. S. Sawhney, C. P. Pathak and J. A. Hubell 0057 Examples of preferred non-biodegradable poly in Macromolecules 1993, 26:581-587, the teachings of mers include ethylene vinyl acetate, poly(meth) acrylic acid, which are incorporated herein, polyhyaluronic acids, cascin, polyamides, copolymers and mixtures thereof. gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, 0.058 Examples of preferred biodegradable polymers chitosan, poly(methyl methacrylates), poly(ethyl methacry include Synthetic polymerS Such as polymers of lactic acid lates), poly butylmethacrylate), poly(isobutylmethacrylate), and glycolic acid, polyanhydrides, poly(ortho)esters, poly poly(hexlmethacrylate), poly(isodecl methacrylate), poly urethanes, poly(butic acid), poly(Valeric acid), poly(capro (lauryl methacrylate), poly(phenyl methacrylate), poly lactone), poly(hydroxybutyrate), poly(lactide-co-glycolide) (methyl acrylate), poly(isopropyl acrylate), poly(isobutyl and poly(lactide-co-caprolactone), and natural polymers acrylate), and poly(octadecl acrylate). Most preferred is Such as alginate and other polysaccharides that include but poly(fumaric-co-Sebacic)acid. Other Suitable bioadhesives are not limited to arabinans, fructans, fucans, galactans, are pectin, a mixture of Sulfated Sucrose and aluminum galacturonans, glucans, mannans, Xylans (Such as, for hydroxide, hydrophilic polysaccharide gums Such as natural example, inulin), levan, fucoidan, carrageenan, galatocaro plant exudates, including karaya gum, ghatti gum, traga lose, pectic acid, pectin, amylose, pullulan, glycogen, amy canth gum, Xanthan gum, jarayagum and the like, as well as lopectin, cellulose, dextran, pustulan, chitin, agarose, kera Seed gums Such as guar gum, locust bean gum, psillium Seed tan, chondroitan, dermatan, hyaluronic acid, alginic acid, gum and the like. Xanthan gum, Starch and various other natural homopolymer 0060 Polymers with enhanced bioadhesive properties or heteropolymerS Such as those containing one or more of can be provided wherein anhydride monomers or oligomers the following aldoses, ketoses, acids or amines: erythrose, are incorporated into the polymer. The oligomer excipients thueose, ribose, arabinose, Xylose, lyxose, allose, altrose, can be blended or incorporated into a wide range of hydro glucose, mannose, gulose, idose, galactose, talose, erythru philic and hydrophobic polymers including proteins, lose, ribulose, Xylulose, psicose, fructose, Sorbose, tagatose, polysaccharides and Synthetic biocompatible polymers. mannitol, Sorbitol, lactose, Sucrose, trehalose, maltose, cel Anhydride oligomers may be combined with metal oxide lobiose, glycine, Serine, threonine, cysteine, tyrosine, aspar particles to improve bioadhesion even more than with the agine, glutamine, aspartic acid, glutamic acid, lysine, argi organic additives alone. Organic dyes because of their nine, histidine, glucuronic acid, gluconic acid, glucaric acid, electronic charge and hydrophobicity/hydrophilicity can galacturonic acid, mannuronic acid, glucosamine, galac either increase or decrease the bioadhesive properties of US 2003/0059471 A1 Mar. 27, 2003 polymers when incorporated into the polymers. The incor lipids and are composed of chains of alkyl groups containing poration of oligomer compounds into a wide range of from 4 to 22 carbon atoms and 0-3 double bonds and different polymers which are not normally bioadhesive characterized by a terminal carboxyl group, -COOH. Fatty dramatically increases their adherence to tissue Surfaces acids may be Saturated or unsaturated and may be Solid, Such as mucosal membranes. Semisolid, or liquid. The most common Saturated fatty acids 0061 AS used herein, the term “anhydride oligomer' are butyric acid (C4), lauric acid (C12), palmitic acid (C16), refers to a diacid or polydiacids linked by anhydride bonds, and Stearic acid (C18). Unsaturated fatty acids are usually and having carboxy end groups linked to a monoacid Such derived from vegetables and consist of alkyl chains contain as acetic acid by anhydride bonds. The anhydride oligomers ing from 16 to 22 carbon atoms and 0-3 double bonds with have a molecular weight less than about 5000, typically the characteristic terminal carboxyl group. The most com between about 100 and 5000 daltons, or are defined as mon unsaturated fatty acids are oleic acid, linoleic acid, and including between one to about 20 diacid units linked by linolenic acid (all C18 acids). anhydride bonds. In one embodiment, the diacids are those 0067 Simple lipids can be esters of fatty acids, triglyc normally found in the Krebs glycolysis cycle. The anhydride erides, cholesterol esters and Vitamin A and D esters. Com oligomer compounds have high chemical reactivity. pound lipids can be phospholipids, glycolipids (cerebro 0062) The oligomers can be formed in a reflux reaction of sides), Sulfolipids, lipoproteins and lipopolysaccharides. the diacid with excess acetic anhydride. The exceSS acetic Derived lipids can be Saturated and unsaturated fatty acids anhydride is evaporated under Vacuum, and the resulting and mono or diglycerides. Analogs of these lipids can also oligomer, which is a mixture of Species which include be used. between about one to twenty diacid units linked by anhy dride bonds, is purified by recrystallizing, for example from 0068 Examples of lipids are: triglycerides-triolein, fatty toluene or other organic Solvents. The oligomer is collected acids-linoleic, linolenic and arachidonic, Sterols-testoster by filtration, and washed, for example, in ethers. The reac one, progesterone, cholesterol; phospholipids-phosphatidic tion produces anhydride oligomers of mono and poly acids acid, lecithin, cephalin (phosphatidyl ethanolamine) Sphin with terminal carboxylic acid groups linked to each other by gomyleins, glycolipids-cerebOSides, gangliosides. anhydride linkages. 0069. The lipids used may be of either natural, synthetic 0.063. The anhydride oligomer is hydrolytically labile. As or Semi-Synthetic origin. analyzed by gel permeation chromatography, the molecular weight may be, for example, on the order of 200-400 for 0070 Lipids which may be used to prepare the flakes fumaric acid oligomer (FAPP) and 2000-4000 for sebacic used in the present invention include but are not limited to: acid oligomer (SAPP). The anhydride bonds can be detected lipids Such as fatty acids, lySolipids, phosphatidylcholine by Fourier transform infrared spectroscopy by the charac with both Saturated and unsaturated lipids including dio teristic double peak at 1750 cm and 1820 cm, with a leoylphosphatidylcholine, dimyristoylphosphatidylcholine; corresponding disappearance of the carboxylic acid peak dipentadecanoylphosphatidylcholine; dilauroylphosphati normally at 1700 cm. dylcholine; dipalmitoylphosphatidylcholine (DPPC); dis tearoylphosphatidylcholine (DSPC); phosphatidylethanola 0064. In one embodiment, the oligomers may be made mines Such as dioleoylphosphatidylethanolamine and from diacids described for example in U.S. Pat. No. 4,757, dipalmitoylphosphatidylethanolamine (DPPE); phosphati 128 to Domb et al., U.S. Pat. No. 4,997,904 to Domb, and dylserine, phosphatidylglycerol; phosphatidylinositol, Sph U.S. Pat. No. 5,175,235 to Domb et al., the disclosures of ingolipids Such as Sphingomyelin; glycolipids Such as gan which are incorporated herein by reference. For example, glioside GM1 and GM2; glucolipids; sulfatides; monomerS Such as Sebacic acid, bis(p-carboxy-phenox glycosphingolipids, phosphatidic acids Such as dipalymi y)propane, isophathalic acid, fumaric acid, maleic acid, toylphosphatidic acid (DPPA), palmitic acid; Stearic acid; adipic acid or dodecanedioic acid may be used. arachidonic acid, oleic acid, lipids bearing polymerS Such as 0065 Organic dyes, because of their electronic charge polyethyleneglycol, i.e., PEGylated lipids, chitin, hyaluronic and hydrophobicity/hydrophobicity, may alter the bioadhe acid or polyvinylpyrrollidone, lipids bearing Sulfonated Sive properties of a variety of polymers when incorporated mono-, di-, oligo- or polysaccharides, cholesterol, choles into the polymer matrix or bound to the surface of the terol Sulfate and cholesterol hemisuccinate, tocopherol polymer. A partial listing of dyes that affect bioadhesive hemisuccinate; lipids with ether and ester-linked fatty acids, properties include, but are not limited to: acid fuchsin, alcian polymerized lipids (a wide variety of which are well known blue, alizarin red S, auramine o, azure a and b, Bismarck in the art); diacetyl phosphate, dicetyl phosphate, Steary brown y, brilliant cresyl blue ald, brilliant green, carmine, lamine; cardiolipin; phospholipids with Short chain fatty cibacron blue 3GA, congo red, cresyl Violet acetate, crystal acids of 6-8 carbons in length, Synthetic phospholipids with Violet, eosin b, eosiny, erythrosin b, fast green fef, giemsa, asymmetric acyl chains (e.g., with one acyl chain of 6 hematoylin, indigo carmine, Janus green b, Jenner's Stain, carbons and another acyl chain of 12 carbons); ceramides; malachite green oxalate, methyl blue, methylene blue, non-ionic liposomes including nioSomes Such as polyoxy methyl green, methyl violet 2b, neutral red, Nile blue a, ethylene fatty acid esters, polyoxyethylene fatty alcohols, orange II, orange G., Orcein, paraosaniline chloride, phloxine polyoxyethylene fatty alcohol ethers, polyoxyethylated Sor b, pyronin bandy, reactive blue 4 and 72, reactive brown 10, bitan fatty acid esters, glycerol polyethylene glycol oxyS reactive green 5 and 19, reactive red 120, reactive yellow tearate, glycerol polyethylene glycol ricinoleate, ethoxylated 2.3, 13 and 86, rose bengal, safrainin o, Sudan III and IV, Soybean Sterols, ethoxylated castor oil, polyoxyethylene Sudan black B and toluidine blue. polyoxypropylene polymers, and polyoxyethylene fatty acid 0.066 Fatty acids are carboxylic acid compounds found in Stearates, Sterol aliphatic acid esters including cholesterol animal and vegetable fat and oil. Fatty acids are classified as Sulfate, cholesterol butyrate, cholesterol iso-butyrate, cho US 2003/0059471 A1 Mar. 27, 2003

lesterol palmitate, cholesterol Stearate, lanosterol acetate, are not limited to, isolauric, isomyristic, isopalmitic, and ergosterol palmitate, and phytosterol n-butyrate, Sterol esters isoStearic acids. In addition, to the Saturated and unsaturated of Sugar acids including cholesterol glucuroncide, lanosterol groups, gas and gaseous precursor filled mixed micelles can glucuronide, 7-dehydrocholesterol glucuronide, ergosterol also be composed of 5 carbon isoprenoid and prenyl groupS. glucuronide, cholesterol gluconate, lanosterol gluconate, and ergosterol gluconate, esters of Sugar acids and alcohols 0073 Waxes can also be used to form the flakes of the including lauryl glucuronide, Stearoyl glucuronide, myris invention. In general, waxes are long chain fatty alcohol toylglucuronide, lauryl gluconate, myristoyl gluconate, and esters of fatty acids. Many waxes have Suitable melting Stearoyl gluconate, esters of Sugars and aliphatic acids characteristics for use in the compositions of the invention, including Sucrose laurate, fructose laurate, Sucrose palmi since they are solids at 25 C. Examples include animal tate, Sucrose Stearate, glucuronic acid, gluconic acid, accha waxes, vegetable waxes, petroleum waxes, Synthetic waxes, ric acid, and polyuronic acid; Saponins including Sarsasapo and mixtures thereof and include without limitation bees genin, Smilagenin, hederagenin, oleanolic acid, and wax, lanolin, candelilla wax, carnauba wax, microcrystalline digitoxigenin, glycerol dilaurate, glycerol trilaurate, glyc wax, carbowax, and mixtures thereof. Preferred waxes are erol dipalmitate, glycerol and glycerol esters including glyc made from Saturated or monounsaturated fatty acids and erol tripalmitate, glycerol distearate, glycerol triStearate, Saturated or unsaturated fatty alcohols. An example of the glycerol dimyristate, glycerol trimyristate; longchain alco latter is provided by arachidyl oleate. hols including n-decyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, and n-octadecyl alcohol; 6-(5-choles 0074 Suitable enteric coatings for flakes include ethyl ten-3 beta -yloxy)-1-thio-beta-D-galactopyranoside; diga cellulose, polyvinylchloride, methylcellulose, polyurethane, lactosyldiglyceride; 6-(5-cholesten-3 beta-yloxy)hexyl-6- cellulose acetate, polycarbonate, polyethylene, polypropy amino-6-deoxy-1-thio-beta -D-galactopyranoside, 6-(5- lene, shellac and polymers of acrylic and methyl acrylic cholesten-3 beta-yloxy)hexyl-6-amino-6-deoxyl-1-thio acids and esters of it. alpha -D-mannopyranoside; 12-(((7'- 0075. In another embodiment of the invention, the drug diethylaminocoumarin-3-yl)carbonyl)methylamino)- incorporated flakes may be incorporated into a Semi-Solid octadecanoic acid; N-12-(((7-diethylaminocoumarin-3-yl) base to form a Spoon-able drug delivery System. The Semi carbonyl)methyl)-amino) octadecanoyl-2-aminopalmitic Solid base may be comprised of pectin, guar gum, Xanthan acid; cholesteryl)4'-trimethylammonio)butanoate, N-Succi gum, gum arabic, gum acacia, locust bean gum, carrageenan nyldioleoylphosphatidylethanolamine; 1 2-dioleoyl-sn gum, alginic acid, psyllium hydrocolloid, oat bran gum, rice glycerol, 1 2-dipalmitoyl-sn-3-Succinylglycerol, 1,3-di bran gum, glucomannan, traganth gum, karayagum, tapioca, palmitoyl-2-Succinylglycerol; 1-hexadecyl-2-palmitoyl corn Starch, cellulose gums, agar, gelatin, polyacrylates, glycerophosphoethanolamine and palmitoylhomocysteine, polysaccharides, polyvinylpyrolidones, pyrrolidones, poly and/or combinations thereof. ols, collagen, polyethylene glycols, polyvinylalcohols, poly 0.071) If desired, a variety of cationic lipids such as ethers, polyesters, natural or Synthetic oils, liquid paraffin, DOTMA, N-1-(2,3-dioleoyloxy)propyl-N,N,N-trimethy beeswax, Silicon waves, natural or modified fatty acids, or lammoium chloride; DOTAP, 1,2-dioleoyloxy-3-(trimethy combinations of thereof. Additionally Viscous fruit purees lammonio)propane; and DOTB, 1,2-dioleoyl-3-(4-trim Such as apple, prune, apricot, pear, pineapple, banana, grape, ethyl-ammonio)butanoyl-sn-glycerol may be used. In Strawberry, raspberry, blackberry, boysenberry, loganberry, general the molar ratio of cationic lipid to non-cationic lipid dewberry, gooseberry, cranberry, mulberry, elderberry, blue in the liposome may be, for example, 1:1000, 1:100, pref berry, fig, currant, kiwi may be used. erably, between 2:1 to 1:10, more preferably in the range between 1:1 to 1:2.5 and most preferably 1:1 (ratio of mole 0076. In a preferred embodiment, the drug-incorporated amount cationic lipid to mole amount non-cationic lipid, flakes may be incorporated into the nutritionally fortified e.g., DPPC). A wide variety of lipids may comprise the delivery vehicle (NFDV) of the invention to form a spoon non-cationic lipid when cationic lipid is used to construct the able drug delivery System with additional advantages of microSphere. Preferably, this non-cationic lipid is dipalmi providing needed dietary requirements. See below for a toylphosphatidylcholine, dipalmitoylphosphatidyletha more detailed discussion of the NFDV. nolamine or dioleoylphosphatidylethanolamine. In lieu of 0077. Nutritionally Fortified Delivery Vehicle (NFDV) cationic lipids as described above, lipids bearing cationic polymerS Such as polylysine or polyarginine, as well as alkyl 0078. A spoon-feedable base specially fortified to phosphonates, alkyl phosphinates, and alkyl phosphites, enhance therapeutic effect is developed. The base could be may also be used to construct the flakes. either modeled after a dietary Supplement currently formu 0.072 In addition, examples of saturated and unsaturated lated and administered in numerous extended health care fatty acids that may be used to prepare the flakes used in the facilities throughout the country or developed specifically to present invention, may include molecules that may contain enhance the drug uptake. preferably between 12 carbon atoms and 22 carbon atoms in 007.9 The NFDV could be administered as a freestanding either linear or branched form. Hydrocarbon groups con product as well as in combination with drugs. The NFDV Sisting of isoprenoid units and/or prenyl groups can be used will be formulated to consist of a viscosity that will facilitate as well. Examples of Saturated fatty acids that are Suitable Spoon administration to patients currently unable to Swallow include, but are not limited to, lauric, myristic, palmitic, and tables, capsules, or liquid dosage forms. Stearic acids; examples of unsaturated fatty acids that may be used are, but are not limited to, lauroleic, physeteric, 0080. The NFDV could complement the drug uptake. It myristoleic, palmitoleic, petroSelinic, and oleic acids, has been demonstrated by Dr. Wurtman certain carbohy examples of branched fatty acids that may be used are, but drate-to-protein ratioS enhance the effect of dopamine. Thus, US 2003/0059471 A1 Mar. 27, 2003

the NFDV may be formulated to enhance certain desired Cancer patients who undergo radiation therapy of the head effects of the administered drugs. and neck area or take chemotheraputic drugs experience the 0081. The NFDV could also complement other dietary lack of formation of Saliva and/or eSaphogatis which results issues, for example, addressing complications associated in inability to take solid food such as tablets. with the administration of narcotics. The uptake of narcotics, 0088. Examples of drugs that might be utilized in a Such as morphine, causes the inability to produce bowel delivery application of the invention include literally any movement. Also, many patients under morphine treatment hydrophilic or hydrophobic drug at a concentration for cannot Swallow Solid food. Incorporation the morphine into having a therapeutic benefit. Preferably, though not neces fortified high fiber base will allow an easy spoon-fed admin Sarily, the drug is one that has already been deemed Safe and istration of the drug and the ability to enhance bowel effective for use by the appropriate governmental agency or movement with dietary fiber. body. For example, drugs for human use listed by the FDA 0082 The high occurrence of constiption in the elderly under 21 C.F.R. 330.5, 331 through 361; 440-460; drugs for population has necessitated the addition of high fiber as a veterinary use listed by the FDA under 21 C.F.R. 550-582, dietary Supplement. Such a base is also Suited for elderly incorporated herein by reference, are all considered accept patients who need the Supplement fiber for regular bowel able for use in the present novel polymer networkS. movement (10 g a day). The NFDV may also contain 0089. The term “drug” includes pharmacologically active Simethicone to reduce flatulation. Substances that produce a local or Systemic therapeutic effect 0083) Table 1 describes some modifications for NFDV in animals, plants, or viruses. The term thus means any compositions designed to compliment treatment of a par Substance intended for use in the diagnosis, or therapeutic treatment or prevention of disease. The term “animal’ used ticular disease State. herein is taken to mean mammals, Such as primates, includ ing humans, sheep, horses, cattle, pigs, dogs, cats, rats, mice, TABLE 1. birds, reptiles, fish, insects, arachnids, protists (e.g. proto Benefits of particular NFDV composition as a complimentary Zoa), and prokaryotic bacteria. The term “plant’ means to a drug to treat a particular disease state (Adapted from higher plants (angiosperms, gymnosperms), fungi, and Windhover Information, Inc. pp. 14, 1997 prokaryotic blue-green "algae' (i.e. cyanobacteria). Disease State NFDV Composition 0090 The drug can be any type of compound including Renal failure different proteins proteins, polypeptides, polynucleotides, nucleoproteins, Liver disease different proteins polysacchariedes, glycoproteins, lipoproteins, and Synthetic Hypermetabolic States different proteins, amino acids and vitamins and biologically engineered analogs thereof. The term “pro Lung discasc High fat, low carbohydrate HIV enriched with specific amino acids and vitamins tein' is art-recognized and for purposes of this invention Diabetes mellitus carbohydrates, high fiber also encompasses peptides. The proteins or peptides may be Mal-absorption specific fats any biologically active protein or peptide, naturally occur ring or Synthetic. 0084. The NFDV could be fortified with vitamins (C, D, 0091 Examples of proteins include antibodies, enzymes, E), flavorings (citric acid, ascorbic acid, menthol, Sorbitol, Steroids, growth hormone and growth hormone-releasing xylitol). hormone, gonadotropin-releasing hormone, and its agonist and antagonist analogues, Somatostatin and its analogues, 0085 Container gonadotropins Such as luteinizing hormone and follicle Stimulating hormone, peptide-T, thyrocalcitonin, parathy 0.086 An oral medication delivery system, wherein said roid hormone, glucagon, Vasopressin, Oxytocin, angiotenisin container means comprises a dual or multiple chamber I and II, bradykinin, kallidin, adrenocorticotropic hormone, container. The container could be a rigid Substantially cylin thyroid Stimulating hormone, insulin, glucagon and the drical tube and Said container means includes rupturable numerous analogues and congeners of the foregoing mol membrane means for Separating the container into first and ecules. Second chambers, wherein Said pharmaceutically active agent in powder form is disposed within Said first chamber 0092. In general, the agents which can be delivered in the and the NFDV is disposed within said second chamber, flakes of the invention, include, but are not limited to, removable Seal means for Sealing Said delivery liquid in Said adhesives, gases, pesticides, herbicides, fragrances, antifoul Second chamber, and plunger means for Sealing Said phar lants, dies, Salts, oils, inks, catalysts, detergents, curing maceutically active agent in Said first chamber and for agents, flavors, foods, fuels, metals, paints, photographic rupturing Said rupturable membrane to mix Said pharmaceu agents, biocides, pigments, plasticizers, propellants and the tically active agent and Said delivery liquid. like. 0087 While the above examples have addressed the 0093. The agent also may be a drug. A drug is to be needs of the geriatric population, it will be readily apparent distinguished from a food neutraceutical. Drug, as used that the invention may be applied to other populations which herein, is meant to exclude nontherapeutic amounts of experience difficulty in taking conventional Solid and liquid Vitamins and minerals. Drugs, as used herein, also specifi dosage formats. For example, pediatric, oncology or other cally excludes foods. Flakes are known in the prior art as patients who cannot swallow will benefit from a spoon-able food, Such as oatmeal flakes and grape-nut flakes. Often drug delivery dosage form (SADD). Similarly to the elderly, these foods are fortified with non-therapeutic amounts of young children cannot handle the Swallowing of a tablet and Vitamins, minerals and the like. The present definition of prefer a dosage form that could be spoon-fed to them. drug is specifically intended to exclude Such prior art foods US 2003/0059471 A1 Mar. 27, 2003

and fortified foods. The present invention, instead, involves 0097 Adrenocortical suppressant: Aminoglutethim the delivery of drugs for therapeutic treatment of disease ide; TriloStane. States. The drug can be, but is not limited to:adrenergic agent, adrenocortical Steroid; adrenocortical SuppreSSant; 0.098 Alcohol deterrent: Disulfiram. aldosterone antagonist, amino acid; anabolic; analeptic, 0099 Aldosterone antagonist: Canrenoate Potassium; analgesic, anesthetic; anorectic, anti-acne agent, anti-adren Canrenone; Dicirenone; Mexrenoate Potassium; Pro ergic, anti-allergic, anti-amebic, anti-anemic; anti-anginal; renoate Potassium, Spironolactone. anti-arthritic, anti-asthmatic, anti-atherOSclerotic, antibacte rial; anticholinergic, anticoagulant; anticonvulsant, antide 0100 Amino acid: Alanine; Aspartic Acid; Cysteine preSSant; antidiabetic, antidiarrheal; antidiuretic, anti Hydrochloride; Cystine; Histidine; Isoleucine; Leu emetic, anti-epileptic, antifibrinolytic, antifungal; cine, Lysine, Lysine Acetate; Lysine Hydrochloride; antihemorrhagic, antihistamine; antihyperlipidemia; antihy Methionine; Phenylalanine; Proline; Serine; Threonine; pertensive; antihypotensive, anti-infective, anti-inflamma Tryptophan; Tyrosine; Valine. tory; antimicrobial; antimigraine; antimitotic, antimycotic, 0101 Ammonia detoxicant: Arginine: Arginine antinauseant, antineoplastic, antineutropenic, antiparasitic; Glutamate, Arginine Hydrochloride. antiproliferative, antipsychotic, antirheumatic, antisebor rheic, antisecretory; antispasmodic, antithrombotic, anti 0102 Anabolic: Bolandiol Dipropionate; Bolasterone; ulcerative; antiviral; appetite SuppreSSant; blood glucose Boldenone Undecylenate; Bolenol; Bolmantalate; Eth regulator, bone resorption inhibitor, bronchodilator; cardio ylestrenol; Methenolone Acetate; Methenolone Enan Vascular agent, cholinergic, depressant, diagnostic aid; thate; Mibolerone; Nandrolone Cyclotate; Norbole diuretic, dopaminergic agent; estrogen receptor agonist; thone; Pizotyline; Quinbolone; Stenbolone Acetate; fibrinolytic, fluorescent agent, free oxygen radical Scaven Tibolone; Zeranol. ger; gastric acid SupreSSant; gastrointestinal motility effec 0103) Analeptic: Modafinil. tor; glucocorticoid; hair growth Stimulant; hemostatic; his tamine H2 receptor antagonists, hormone; 0104 Analgesic: Acetaminophen; Alfentanil Hydro hypocholesterolemic, hypoglycemic, hypolipidemic, chloride, Aminobenzoate Potassium; Aminobenzoate hypotensive; imaging agent, immunizing agent; immuno Sodium; Anidoxime; Anileridine; Anileridine Hydro modulator; immunoregulator; immunostimulant; immuno chloride, Anilopam Hydrochloride; Anirolac, Antipy SuppreSSant; keratolytic, LHRH agonist, mood regulator; rine, Aspirin; Benoxaprofen; BenZydamine Hydrochlo mucolytic, mydriatic, nasal decongestant; neuromuscular ride; Biciifadine Hydrochloride; Brifentanil blocking agent; neuroprotective; NMDA antagonist; non Hydrochloride; Bromadoline Maleate; Bromfenac hormonal Sterol derivative, plasminogen activator, platelet Sodium; Buprenorphine Hydrochloride; Butacetin; activating factor antagonist, platelet aggregation inhibitor; Butixirate; Butorphanol; Butorphanol Tartrate; Car psychotropic, radioactive agent; Scabicide, Sclerosing agent; bamazepine, Carbaspirin Calcium, Carbiphene Hydro Sedative, Sedative-hypnotic, Selective adenosine Al antago chloride; Carfentanil Citrate; Ciprefadol Succinate; Ciramadol; Ciramadol Hydrochloride; Clonixeril; nist; Serotonin antagonist; Serotonin inhibitor, Serotonin Clonixin; Codeine; Codeine Phosphate; Codeine Sul receptor antagonist; Steroid; thyroid hormone; thyroid fate; Conorphone Hydrochloride; Cyclazocine; Dex inhibitor; thyromimetic, tranquilizer; amyotrophic lateral oxadrol Hydrochloride; Dexpemedolac, Dezocine; Sclerosis agent; cerebral ischemia agent, Paget's disease Diflunisal; Dihydrocodeine Bitartrate; Dimefadane; agent; unstable angina agent; vasoconstrictor; vasodilator; Dipyrone; Doxpicomine Hydrochloride; Drinidene; wound healing agent; Xanthine oxidase inhibitor. Enadoline Hydrochloride; Epirizole; Ergotamine Tar 0094) Examples include: trate; Ethoxazene Hydrochloride; Etofenamate; 0.095 Adrenergic: Adrenalone; Amidephrine Mesylate; Eugenol; Fenoprofen, Fenoprofen Calcium, Fentanyl Apraclonidine Hydrochloride; Brimonidine Tartrate; Citrate; Floctafenine; Flufenisal; Flumixin; Flunixin Dapiprazole Hydrochloride; Deterenol Hydrochloride; Meglumine; Flupirtine Maleate; FluproduaZone; Flu Dipivefrin; Dopamine Hydrochloride; Ephedrine Sulfate; radoline Hydrochloride; Flurbiprofen; Hydromorphone Epinephrine; Epinephrine Bitartrate; Epinephryl Borate; Hydrochloride; Ibufenac; Indoprofen; Ketazocine; Esprocquin Hydrochloride; Etafedrine Hydrochloride; Ketorfanol; Ketorolac Tromethamine; Letimide Hydro Hydroxyamphetamine Hydrobromide; Levonordefrin; chloride; Levomethadyl Acetate; Levomethadyl Mephentermine Sulfate; Metaraminol Bitartrate; Metizoline Acetate Hydrochloride; Levonantradol Hydrochloride; Hydrochloride; Naphazoline Hydrochloride; Norepineph Levorphanol Tartrate; Lofemizole Hydrochloride; rine Bitartrate; Oxidopamine; Oxymetazoline Hydrochlo Lofentanil Oxalate; Loreinadol, Lornoxicam, Magne ride; Phenylephrine Hydrochloride; Phenylpropanolamine sium Salicylate; Mefenamic Acid; Menabitan Hydro Hydrochloride; Phenylpropanolamine Polistirex, Prenalterol chloride; Meperidine Hydrochloride; Meptazinol Hydrochloride; Propylhexedrine; Pseudoephedrine Hydro Hydrochloride; Methadone Hydrochloride; Methadyl chloride; Tetrahydrozoline Hydrochloride; Tramazoline Acetate; Methopholine; Methotrimeprazine; Met Hydrochloride; Xylometazoline Hydrochloride. kephamid Acetate; Mimbane Hydrochloride; Mirfenta nil Hydrochloride; Molinazone; Morphine Sulfate; 0096. Adrenocortical steroid: Ciprocinonide; Desoxy Moxazocine; Nabitan Hydrochloride; Nalbuphine corticosterone Acetate; DeSoxycorticosterone Pivalate; Hydrochloride; Nalmexone Hydrochloride; Namox Dexamethasone Acetate, Fludrocortisone Acetate, Flu yrate; Nantradol Hydrochloride; Naproxen; Naproxen moxonide; Hydrocortisone Hemisuccinate; Methyl Sodium; Naproxol; Nefopam Hydrochloride; Nexeri prednisolone Hemisuccinate; Naflocort; Procinonide; dine Hydrochloride; Noracymethadol Hydrochloride; Timobesone Acetate, Tipredane. Ocfentanil Hydrochloride; Octazamide; Olvanil; US 2003/0059471 A1 Mar. 27, 2003 11

Oxetorone Fumarate; Oxycodone; Oxycodone Hydro rex Hydrochloride; Phenmetrazine Hydrochloride; chloride; Oxycodone Terephthalate; Oxymorphone Phentermine; Sibutramine Hydrochloride. Hydrochloride; Pemedolac, Pentamorphone; Pentazo 0110 Antagonist: Atipamezole; Atosiban; Bosentan; cine, Pentazocine Hydrochloride, Pentazocine Lactate; Cimetidine, Cimetidine Hydrochloride; Clentiazem Phenazopyridine Hydrochloride; Phenyramidol Hydro Maleate; Detirelix Acetate; Devazepide; Donetidine; chloride; Picenadol Hydrochloride; Pinadoline; Pir Etintidine Hydrochloride; Famotidine, Fenmetozole fenidone; Piroxicam Olamine; Pravadoline Maleate; Hydrochloride; Flumazenil; Icatibant Acetate; Icoti Prodilidine Hydrochloride; Profadol Hydrochloride; dine; Isradipine; Metiamide; Nadide; Nalmefene; Propiram Fumarate; Propoxyphene Hydrochloride; Nalmexone Hydrochloride; Naloxone Hydrochloride; Propoxyphene Napsylate; Proxazole; Proxazole Cit Naltrexone; Nilvadipine; Oxilorphan; Oxmetidine rate; Proxorphan Tartrate; Pyrroliphene Hydrochloride; Hydrochloride; Oxmetidine Mesylate; Quadazocine Remifentanil Hydrochloride; Salcolex; Salethamide Mesylate; Ranitidine; Ranitidine Bismuth Citrate; Ran Maleate; Salicylamide; Salicylate Meglumine; Sal itidine Hydrochloride; Sufotidine; Teludipine Hydro Salate; Sodium Salicylate; Spiradoline Mesylate; chloride; Tiapamil Hydrochloride; Tiotidine; Vapi.prost Sufentanil; Sufentanil Citrate; Talmetacin; Talniflu Hydrochloride; Zaltidine Hydrochloride. mate, Talosalate, Tazadolene Succinate, Tebufelone; Tetrydamine; Tifurac Sodium; Tilidine Hydrochloride; 0111 Anterior pituitary activator: Epimestrol. Tiopinac; Tonazocine Mesylate; Tramadol Hydrochlo 0112 Anterior pituitary suppressant: Danazol. ride; Trefentanil Hydrochloride; Trolamine; Veradoline Hydrochloride; Verilopam Hydrochloride; Volazocine; 0113 Anthelmintic: Albendazole; Anthelmycin; Bro Xorphanol Mesylate; Xylazine Hydrochloride; Zena moxanide; Bunamidine Hydrochloride; Butonate; Zocine MeSylate, Zomepirac Sodium, Zucapsaicin. Cambendazole; Carbantel Lauryl Sulfate; Clioxanide; Closantel; Cyclobendazole; Dichliorvos, Diethylcar 0105 Androgen: Fluoxymesterone; Mesterolone; bamazine Citrate; Dribendazole; Dymanthine Hydro Methyltestosterone; Nandrolone Decanoate; Nan chloride; Etibendazole, Fenbendazole; Furodazole; drolone Phenpropionate; Nisterime Acetate; Oxan Hexylresorcinol; Mebendazole; Morantel Tartrate; drolone; Oxymetholone; Silandrone; Stanozolol; Test Niclosamide; Nitramisole Hydrochloride; Nitrodan; osterone; Testosterone Cypionate, Testosterone Oxantel Pamoate; Oxfendazole; Oxibendazole; Par Enanthate; Testosterone Ketolaurate; Testosterone Phe bendazole; Piperamide Maleate; Piperazine; Piperazine nylacetate; Testosterone Propionate, Trestolone Citrate; Piperazine Edetate Calcium; Proclonol; Pyran Acetate. tel Pamoate; Pyrantel Tartrate; Pyrvinium Pamoate; 0106 Anesthesia, adjunct to: Sodium Oxybate. Rafoxanide; Stilbazium Iodide; Tetramisole Hydro chloride; Thiabendazole, Ticarbodine; Tioxidazole; 0107 Anesthetic: Aliflurane; Benoximate Hydrochlo Triclofenol Piperazine; Vincofos; Zilantel. ride; Benzocaine; Biphenamine Hydrochloride; Bupi vacaine Hydrochloride; Butamben; Butamben Picrate; 0114 Anti-acne: Adapalene; Erythromycin Salnace Chloroprocaine Hydrochloride, Cocaine; Cocaine din; Inocoterone Acetate. Hydrochloride; Cyclopropane; Desflurane; Dexi 0115) Anti-adrenergic: Acebutolol; Alprenolol Hydro Vacaine; Diamocaine Cyclamate; Dibucaine; chloride; Atenolol; Bretylium Tosylate; Bunolol Dibucaine Hydrochloride; Dyclonine Hydrochloride; Hydrochloride; Carteolol Hydrochloride; Celiprolol Enflurane; Ether; Ethyl Chloride; Etidocaine; Etoxa Hydrochloride; Cetamolol Hydrochloride; Cicloprolol drol Hydrochloride; Euprocin Hydrochloride; Flurox Hydrochloride; Dexpropranolol Hydrochloride; Diac ene, Halothane; Isobutamben; Isoflurane; Ketamine etolol Hydrochloride; Dihydroergotamine Mesylate; Hydrochloride; Levoxadrol Hydrochloride; Lidocaine; Dilevalol Hydrochloride; Esmolol Hydrochloride; Lidocaine Hydrochloride; Mepivacaine Hydrochloride; Exaprolol Hydrochloride; Fenspiride Hydrochloride; Methohexital Sodium; Methoxyflurane; Midazolam Flestolol Sulfate; Labetalol Hydrochloride; Levobetax Hydrochloride; Midazolam Maleate; Minaxolone; olol Hydrochloride; Levobunolol Hydrochloride; Met Nitrous Oxide, Norflurane; Octodrine; Oxethazaine; alol Hydrochloride; Metoprolol; Metoprolol Tartrate; Phencyclidine Hydrochloride; Pramoxine Hydrochlo Nadolol; Pamatolol Sulfate; Penbutolol Sulfate; Phen ride; Prilocaine Hydrochloride; Procaine Hydrochlo tolamine Mesylate; Practolol; Propranolol Hydrochlo ride; Propanidid; Proparacaine Hydrochloride; Propo ride; Proroxan Hydrochloride; Solypertine Tartrate; fol; Propoxycaine Hydrochloride; Pyrrocaine; Sotalol Hydrochloride; Timolol; Timolol Maleate; Risocaine; Rodocaine; Roflurane; Salicyl Alcohol; Tiprenolol Hydrochloride; Tolamolol; Zolertine Hydro Sevoflurane; Teflurane; Tetracaine; Tetracaine Hydro chloride. chloride; Thiamylal; Thiamylal Sodium; Thiopental Sodium ; Tiletamine Hydrochloride; Zolamine Hydro 011.6 Anti-allergic: Amlexanox; Astemizole, AZelas chloride. tine Hydrochloride; Eclazolast; Minocromil; Nedocro mil; Nedocromil Calcium; Nedocromil Sodium; 0108) Anorectic compounds including dexfenflu Nivinedone Sodium; Pemirolast Potassium; Pentiget ramine. ide; Pirquinozol; Poisonoak Extract; Probicromil Cal 0109) Anorexic: Aminorex; Amphecloral; Chlorphen cium; ProXicromil; Repiriniast; Tetrazolast Meglu termine Hydrochloride; Clominorex; Clortermine mine; Thiazinamium Chloride; Tiacrilast; Tiacrilast Hydrochloride; Diethylpropion Hydrochloride; Fenflu Sodium; Tiprinast Meglumine; Tixanox. ramine Hydrochloride; Fenisorex, Fludorex; Flumi 0117 Anti-amebic: Berythromycin; Bialamicol norex, Levamfetamine Succinate; Mazindol; Mefeno Hydrochloride; Chloroquine; Chloroquine Hydrochlo US 2003/0059471 A1 Mar. 27, 2003 12

ride; Chloroquine Phosphate; Clamoxyquin Hydro Sodium; Ce?pimizole; Ce?pimizole Sodium; Ce?piramide; chloride; Clioquinol; Emetine Hydrochloride; Ce?piramide Sodium; Ce?pirome Sulfate; Cefpodoxime Iodoquinol; Paromomycin Sulfate; Quinfamide; Proxetil, Cefprozil; Cefroxadine; Cefsulodin Sodium; Symetine Hydrochloride; Teclozan; Tetracycline ; Tet Ceftazidime; Ceftibuten; Ceftizoxime Sodium; Ceftriaxone racycline Hydrochloride. Sodium; Cefuroxime; Cefuroxime Axetil, Cefuroxime Piv 0118 Anti-androgen: Benorterone; Cioteronel; Cypro oxetil, Cefuroxime Sodium; Cephacetrile Sodium; Cephal terone Acetate; Delmadinone Acetate, Oxendolone; exin; Cephalexin Hydrochloride; Cephaloglycin; Cephalo Topterone; Zanoterone. ridine; Cephalothin Sodium; Cephapirin Sodium; Cephradine; Cetocycline Hydrochloride; Cetophenicol; 0119) Anti-anemic: Epoetin Alfa; Epoetin Beta; Fer Chloramphenicol; Chloramphenicol Palmitate; Chloram rous Sulfate, Dried; Leucovorin Calcium. phenicol Pantothenate Complex; Chloramphenicol Sodium 0120 Anti-anginal: Amlodipine Besylate; Amlodipine Succinate; Chlorhexidine Phosphanilate; Chloroxylenol; Maleate; Betaxolol Hydrochloride; Bevantolol Hydro Chlortetracycline Bisulfate; Chlortetracycline Hydrochlo chloride; Butoprozine Hydrochloride; Carvedilol; ride; Cinoxacin; Ciprofloxacin; Ciprofloxacin Hydrochlo Cinepazet Maleate; Metoprolol Succinate ; Molsidom ride; Cirolemycin; Clarithromycin; Clinafloxacin Hydro ine; Monatepil Maleate; Primidolol; Ranolazine chloride; Clindamycin; Clindamycin Hydrochloride; Hydrochloride; Tosifen; Verapamil Hydrochloride. Clindamycin Palmitate Hydrochloride; Clindamycin Phos phate; Clofazimine; Cloxacillin Benzathine; Cloxacillin 0121 Anti-anxiety agent: Adatanserin Hydrochloride; Sodium; Cloxyquin; Colistimethate Sodium; Colistin Sul Alpidem; Binospirone Mesylate; Bretazenil; Gle fate; Coumermycin, Coumermycin Sodium; Cyclacillin; manserin; Ipsapirone Hydrochloride; Mirisetron Male CycloSerine; Dalfopristin; DapSone; Daptomycin; Demeclo ate; Ocinaplon; Ondansetron Hydrochloride; Panad cycline; Demeclocycline Hydrochloride; Demecycline; iplon; Pancopride, PaZinaclone; Scrazaipine Denofungin; Diaveridine; Dicloxacillin; Dicloxacillin Hydrochloride; Tandospirone Citrate; Zalospirone Sodium; Dihydrostreptomycin Sulfate; Dipyrithione; Hydrochloride. Dirithromycin; Doxycycline; Doxyeycline Calcium; Doxy cycline Fosfatex; Doxycycline Hyclate; Droxacin Sodium; 0.122 Anti-arthritic: Lodelaben. Enoxacin; Epicillin; Epitetracycline Hydrochloride; Eryth 0123 Anti-asthmatic: Ablukast; Ablukast Sodium; romycin; Erythromycin Acistrate; Erythromycin Estolate; AZelastine Hydrochloride, Bunaprolast; Cinalukast, Erythromycin EthylSuccinate; Erythromycin Gluceptate; Cromitrile Sodium; Cromolyn Sodium; Enofelast; Erythromycin Lactobionate; Erythromycin Propionate; IsamoXole; Ketotifen Fumarate; Leveromakalim, Erythromycin Stearate; Ethambutol Hydrochloride; Lodoxamide Ethyl; Lodoxamide Tromethamine; Mon Ethionamide; Fleroxacin; Floxacillin; Fludalanine; Flume telukast Sodium, Ontazolast, Oxarbazole; Oxatomide; quine; Fosfomycin; Fosfomycin Tromethamine; Fumoxicil Piriprost; Piriprost Potassium; Pirolate; Pobilukast lin; Furazolium Chloride; Furazolium Tartrate; Fusidate Edamine; QuaZolast, Repirinast; Ritolukast, Sulukast, Sodium; Fusidic Acid, Gentamicin Sulfate; Gloximonam; Tetrazolast Meglumine; Tiaramide Hydrochloride; Gramicidin; Haloprogin; Hetacillin; Hetacillin Potassium; Tibenelast Sodium; Tomelukast, Tranilast; Verlukast; Hexedine, Ibafloxacin; Imipenem; ISOconazole, Isepamicin; Verofylline; Zarirlukast. Isoniazid; Josamycin; Kanamycin Sulfate; Kitasamycin; Levofuraltadone; Levopropylcillin Potassium; Lexithromy 0.124. Anti-atherosclerotic: Mifobate; Timefurone. cin; Lincomycin; Lincomycin Hydrochloride, Lomefloxa 0.125 Antibacterial: Acedapsone; Acetosulfone Sodium; cin; Lomefloxacin Hydrochloride; Lomefloxacin Mesylate; Alamecin; Alexidine, Amdinocillin; Amdinocillin Pivoxil, Loracarbef, Mafenide; Meclocycline; Meclocycline Sul Amicycline; Amifloxacin; Amifloxacin MeSylate; Amika fosalicylate; Megalomicin Potassium Phosphate; Mequidox; cin; Amikacin Sulfate; AminoSalicylic acid; Aminosalicylate Meropenem; Methacycline; Methacycline Hydrochloride; Sodium; Amoxicillin; Amphomycin; Ampicillin; Ampicillin Methenamine; Methenamine Hippurate; Methenamine Sodium; Apalcillin Sodium; Apramycin; ASpartocin, Astro Mandelate; Methicillin Sodium; Metioprim; Metronidazole micin Sulfate; AVillamycin; AVoparcin, Azithromycin; Hydrochloride; Metronidazole Phosphate; Mezlocillin; Azlocillin; Azlocillin Sodium; Bacampicillin Hydrochlo Mezlocillin Sodium; Minocycline; Minocycline Hydrochlo ride; Bacitracin; Bacitracin Methylene Disalicylate; Baci ride; Mirincamycin Hydrochloride; Monensin; Monensin tracin Zinc, Bambermycins, Benzoylpas Calcium, Beryth Sodium; Nafcillin Sodium; Nalidixate Sodium; Nalidixic romycin; Betamicin Sulfate; Biapenem; Biniramycin; Acid; Natamycin; Nebramycin; Neomycin Palmitate; Neo Biphenamine Hydrochloride; Bispyrithione Magsulfex; mycin Sulfate; Neomycin Undecylenate ; Netilmicin Sul Butikacin; Butirosin Sulfate; Capreomycin Sulfate; Carba fate; Neutramycin; Nifuradene; Nifuraldezone; Nifuratel; dox; Carbenicillin Disodium; Carbenicillin Indanyl Sodium; Nifuratrone; Nifurdazil; Nifurimide; Nifurpirinol; Carbenicillin Phenyl Sodium; Carbenicillin Potassium; Nifurcquinazol; Nifurthiazole; Nitrocycline; Nitrofurantoin; Carumonam Sodium; Cefaclor, Cefadroxil, Cefamandole; Nitromide; Norfloxacin; Novobiocin Sodium; Ofloxacin; Cefamandole Nafate; Cefamandole Sodium; Cefaparole; Ormetoprim; Oxacillin Sodium; Oximonam; Oximonam Cefatrizine; Cefazaflur Sodium; Cefazolin; Cefazolin Sodium; Oxolinic Acid; Oxytetracycline; Oxytetracycline Sodium; Cefbuperazone; Cefdinir; Cefepime; Cefepime Calcium; Oxytetracycline Hydrochloride; Paldimycin; Hydrochloride; Cefetecol; Cefixime; Cefnmenoxime Hydro Parachlorophenol; Paulomycin; Pefloxacin; Pefloxacin chloride; Cefnmetazole; Cefnmetazole Sodium; Cefonicid Mesylate; Penamecillin; Penicillin G BenZathine; Penicillin Monosodium; Cefonicid Sodium; Cefoperazone Sodium; G Potassium; Penicillin G Procaine; Penicillin G Sodium; Ceforanide; Cefotaxime Sodium; Cefotetan; Cefotetan Penicillin V; Penicillin V BenZathine; Penicillin V Hydrab Disodium; Cefotiam Hydrochloride; Cefoxitin; Cefoxitin amine; Penicillin V Potassium; Pentizidone Sodium; Phenyl US 2003/0059471 A1 Mar. 27, 2003

Aminosalicylate; Piperacillin Sodium; Pirbenicillin Sodium; Solution; Anticoagulant Sodium Citrate Solution; Piridicillin Sodium; Pirlimycin Hydrochloride; Pivampicil Ardeparin Sodium; Bivalirudin; Brominidione; Dalte lin Hydrochloride; Pivampicillin Pamoate; Pivampicillin parin Sodium; Desirudin; Dicumarol; Heparin Cal Probenate; Polymyxin B Sulfate; Porfiromycin; Propikacin; cium; Heparin Sodium; Lyapolate Sodium; NafamoStat PyraZinamide, Pyrithione Zinc, Quindecamine Acetate; Mesylate; Phenprocoumon; Tinzaparin Sodium; War Quinupristin, Racephenicol; Ramoplanin; Ranimycin; Relo farin Sodium. mycin; Repromicin; Rifabutin; Rifametane; Rifamexil; Rifamide; Rifampin; Rifapentine; Rifaximin; Rolitetracy 0.130 Anticoccidal: Maduramicin. cline, Rolitetracycline Nitrate; Rosaramicin; Rosaramicin 0131) Anticonvulsant: Albutoin; Ameltolide; Atolide; Butyrate; Rosaramicin Propionate; Rosaramicin Sodium Buramate; Carbamazepine, Cinromide, Citenamide; Phosphate, Rosaramicin Stearate; ROSoxacin; RoxarSone; Clonazepam, Cyheptamide, DeZinamide, Dimethadi Roxithromycin; Sancycline; Sanfeltrinem Sodium; Sarmox one; Divalproex Sodium; Eterobarb; Ethosuximide; icillin, Sarpicillin; Scopafungin, Sisomicin; Sisomicin Sul Ethotoin; Flurazepam Hydrochloride; Fluzinamide; fate, Sparfloxacin; Spectinomycin Hydrochloride; Spiramy FoSphenytoin Sodium; Gabapentin, Ilepeimide, Lam cin; Stallimycin Hydrochloride; Steffimycin; Streptomycin otrigine, Magnesium Sulfate; Mephenytoin, Sulfate; Streptonicozid; Sulfabenz, Sulfabenzamide; Sulfac Mephobarbital; Methetoin; Methsuximide; Milacemide etamide; Sulfacetamide Sodium; Sulfacytine; Sulfadiazine; Hydrochloride; Nabazenil; Nafimidone Hydrochloride; Sulfadiazine Sodium; Sulfadoxine, Sulfalene; Sulfamera Nitrazepam; Phenacemide; Phenobarbital; Phenobar Zine, Sulfameter, Sulfamethazine, Sulfamethizole; Sul bital Sodium; Phensuximide; Phenytoin; Phenytoin famethoxazole; Sulfamonomethoxine, Sulfamoxole; Sulfa Sodium; Primidone; Progabide; Ralitoline; Remace nilate Zinc, Sulfanitran; SulfaSalazine, SulfaSomizole; mide Hydrochloride; Ropizine; Sabeluzole; Stiripentol; Sulfathiazole; Sulfazamet, Sulfisoxazole; Sulfisoxazole Sulthiame; Thiopental Sodium; Tiletamine Hydrochlo Acetyl; Sulfisoxazole Diolamine; Sulfomyxin; Sulopenem; ride; Topiramate; Trimethadione; Valproate Sodium; Sultamicillin; Suncillin Sodium; Talampicillin Hydrochlo Valproic Acid; Vigabatrin; Zoniclezole Hydrochloride; ride; Teicoplanin; Temafloxacin Hydrochloride; Temocillin; Zonisamide. Tetracycline; Tetracycline Hydrochloride ; Tetracycline Phosphate Complex; Tetroxoprim; Thiamphenicol; 0132) Antidepressant: Adatanserin Hydrochloride; Thiphencillin Potassium; Ticarcillin Cresyl Sodium; Ticar Adinazolam, Adinazolam MeSylate; Alaproclate; Ale cillin Disodium; Ticarcillin Monosodium; Ticlatone; Tiodo tamine Hydrochloride; Amedalin Hydrochloride; Ami nium Chloride; Tobramycin; Tobramycin Sulfate; Tosu triptyline Hydrochloride; Amoxapine, Aptazapine floxacin; Trimethoprim; Trimethoprim Sulfate; Maleate; Azaloxan Fumarate; Azepindole; Azipramine TriSulfapyrimidines, Troleandomycin; Trospectomycin Sul Hydrochloride; Bipenamol Hydrochloride; Bupropion fate; Tyrothricin; Vancomycin; Vancomycin Hydrochloride; Hydrochloride; Butacetin; Butriptyline Hydrochloride; Virginiamycin; Zorbamycin. CaroXaZone, Cartazolate, Ciclazindol; Cidoxepin Hydrochloride; Cilobamine Mesylate; Clodazon 0.126 Anticholelithic: Monoctanoin. Hydrochloride; Clomipramine Hydrochloride; Coti nine Fumarate; Cyclindole; Cypenamine Hydrochlo 0127. Anticholelithogenic: Chenodiol; Ursodiol. ride; Cyprolidol Hydrochloride; Cyproximide; Daleda 0128 Anticholinergic: Alverinc Citrate; Anisotropine lin Tosylate; Dapoxetine Hydrochloride; Dazadrol Methylbromide; Atropine; Atropine Oxide Hydrochlo Maleate; Dazepinil Hydrochloride; Desipramine ride; Atropine Sulfate, Belladonna, Benapry Zine Hydrochloride; Dexamisole; Deximafen; Dibenzepin Hydrochloride; Benzetimide Hydrochloride; Benzilo Hydrochloride; Dioxadrol Hydrochloride; Dothiepin nium Bromide; Biperiden; Biperiden Hydrochloride; Hydrochloride; Doxepin Hydrochloride; Duloxetine Biperiden Lactate; Clidinium Bromide; Cyclopentolate Hydrochloride; Eclanamine Maleate; Encyprate; Eto Hydrochloride; Dexetimide; Dicyclomine Hydrochlo peridone Hydrochloride; Fantridone Hydrochloride; ride; Dihexyverine Hydrochloride; Domazoline Fuma Fenmetozole Hydrochloride; Fenmetramide; Fezola rate; Elantrine; Elucaine; Ethybenztropine, Eucatro mine Fumarate; Fluotracen Hydrochloride; Fluoxetine; pine Hydrochloride; Glycopyrrolate; Heteronium Fluoxetine Hydrochloride; Fluparoxan Hydrochloride; Bromide; Homatropine Hydrobromide; Homatropine Gamfexine; Guanoxyfen Sulfate; Imafen Hydrochlo Methylbromide; Hyoscyamine; Hyoscyamine Hydro ride; Imiloxan Hydrochloride; Imipramine Hydrochlo bromide, Hyoscyamine Sulfate; Isopropamide Iodide, ride; Indeloxazine Hydrochloride; Intriptyline Hydro Mepenzolate Bromide; Methylatropine Nitrate; Meto chloride; prindole, ISOcarboxazid; Ketipramine quizine; Oxybutynin Chloride; Parapenzolate Bromide; Fumarate, Lofepramine Hydrochloride; Lortalamine; Pentapiperium Methylsulfate; Phencarbamide; Poldine Maprotiline; Maprotiline Hydrochloride; Melitracen Methylsulfate; Proglumide; Propantheline Bromide; Hydrochloride; Milacemide Hydrochloride; Minaprine Propenzolate Hydrochloride; Scopolamine Hydrobro Hydrochloride; Mirtazapine; Moclobemide; Modaline mide; Tematropium Methyl sulfate; Tiquinamide Sulfate; Napacitadine Hydrochloride; Napamezole Hydrochloride; Tofenacin Hydrochloride; Toquizine; Hydrochloride; Nefazodone Hydrochloride; Nisoxet Triampyzine Sulfate; Trihexyphenidyl Hydrochloride; ine; Nitrafudam Hydrochloride; Nomifensine Maleate; Tropicamide. Nortriptyline Hydrochloride; Octriptyline Phosphate; Opipramol Hydrochloride; Oxaprotiline Hydrochlo 0129. Anticoagulant: Ancrod; Anticoagulant Citrate ride; Oxypertine; Paroxetine; Phenelzine Sulfate; Dextrose Solution; Anticoagulant Citrate Phosphate Pirandamine Hydrochloride; Pizotyline; Pridefine Dextrose Adenine Solution; Anticoagulant Citrate Hydrochloride; Prolintane Hydrochloride; Protriptyline Phosphate Dextrose Solution; Anticoagulant Heparin Hydrochloride; Quipazine Maleate; Rolicyprine; US 2003/0059471 A1 Mar. 27, 2003 14

Seproxetine Hydrochloride; Sertraline Hydrochloride; Sulfex; Butoconazole Nitrate; Calcium Undecylenate; Sibutramine Hydrochloride; Sulpiride; Suritozole; Candicidin; Carbol-Fuchsin; Chlordantoin; Ciclopirox; Tametraline Hydrochloride; Tampramine Fumarate; CiclopiroX Olamine, Cillofungin; Cisconazole; Clotri Tandamine Hydrochloride; Thiazesim Hydrochloride; mazole; Cuprimyxin, Denofungin; Dipyrithione; Thozalinone; Tomoxetine Hydrochloride; Trazodone Doconazole; Econazole; Econazole Nitrate; Enilcona Hydrochloride; Trebenzomine Hydrochloride; Trimi zole; Ethonam Nitrate; Fenticonazole Nitrate; Filipin; pramine; Trimipramine Maleate; Venlafaxine Hydro Fluconazole, Flucytosine; Fungimycin, Griseofulvin; chloride; Viloxazine Hydrochloride; Zimeldine Hydro Hamycin; ISOconazole, Itraconazole, Kalafungin; chloride; Zometapine. Ketoconazole, Lomofungin; Lydimycin; Mepartricin; Miconazole; Miconazole Nitrate; Monensin; Monensin 0.133 Antidiabetic: Acetohexamide; Buformin; Butox Sodium; Naftifine Hydrochloride; Neomycin Unde amine Hydrochloride, Caniglibose, Chlorpropamide; cylenate; Nifuratel; Nifirmerone; Nitralamine Hydro Ciglitazone; Englitazone Sodium; Etoformin Hydro chloride; Nystatin; Octanoic Acid; Orconazole Nitrate; chloride; Gliamilide; Glibornuride; Glicetanile Oxiconazole Nitrate; Oxifungin Hydrochloride; Par Sodium; Gliflumide; Glipizide, Glucagon; Glyburide; conazole Hydrochloride; Partricin; Potassium Iodide; Glyhexamide; Glymidine Sodium; Glyoctamide; Gly Proclonol; Pyrithione Zinc, Pyrrolnitrin; Rutamycin; paramide; Insulin; Insulin, Dalanated; Insulin Human; Sanguinarium Chloride, Saperconazole, Scopafungin; Insulin Human, Isophane; Insulin Human Zinc, Insulin Human Zinc, Extended; Insulin, Isophane; Insulin Selenium Sulfide; Sinefungin; Sulconazole Nitrate; Lispro, Insulin, Neutral; Insulin Zinc, Insulin Zinc, Terbinafine; Terconazole; Thiram; Ticlatone; Tiocona Extended; Insulin Zinc, Prompt; Linogliride, Linog Zole; Tolciclate; Tolindate; Tolnaftate; Triacetin; Tri liride Fumarate; Metformin; Methyl Palmoxirate; Pal afungin; Undecylenic Acid; Viridofulvin; Zinc Unde moxirate Sodium; Pioglitazone Hydrochloride; Pirog cylenate, Zinoconazole Hydrochloride. liride Tartrate; Proinsulin Human; Seglitide Acetate; 0.143 Antiglaucoma agent: Alprenoxime Hydrochlo Tolazamide; Tolbutamide; Tolpyrramide; Troglitazone; ride; Colforsin; Dapiprazole Hydrochloride; Dipivefin Zopolrestat. Hydrochloride; Naboctate Hydrochloride; Pilocarlpine; 0134) Antidiarrheal: Rolgamidine, Diphenoxylate Pirnabine. hydrochloride (Lomotil), Metronidazole (Flagyl), 0144 Antihemophilic: Antihemophilic Factor. Methylprednisolone (Medrol), Sulfasalazine (AZulfi 0145 Antihemorrhagic: Poliglusam. dine). 0146 Antihemorrheologic:Phentoxifylline 0.135 Antidiuretic: Argipressin Tannate; Desmo pressin Acetate, Lypressin. 0147 Antihistaminic: Acrivastine; Antazoline Phos phate, Astemizole, AZatadine Maleate; Barmastine; 0.136 Antidote: Dimercaprol; Edrophonium Chloride; Bromodiphenhydramine Hydrochloride; Bromphe Fomepizole; Leucovorin Calcium; Levoleucovorin niramine Maleate; Carbinoxamine Maleate; Cetirizine Calcium; Methylene Blue; Protamine Sulfate. Hydrochloride; Chlorpheniramine Maleate; Chlorphe niramine PolistireX; Cinnarizine; Clemastine; Clemas 0.137 Antidyskinetic: Selegiline Hydrochloride. tine Fumarate; Closiramine Aceturate; Cycliramine 0138 Anti-emetic: Alosetron Hydrochloride; Batano Maleate; Cyclizine; Cyproheptadine Hydrochloride; pride Hydrochloride; Bemesetron; Benzquinamide; Chlor Dexbrompheniramine Maleate; Dexchlorpheniramine promazine; Chlorpromazine Hydrochloride; Clebopride; Maleate; Dimethindene Maleate; Diphenhydramine Cyclizine Hydrochloride; Dimenhydrinate; Diphenidol; Citrate; Diphenhydramine Hydrochloride; Dorastine Diphenidol Hydrochloride; Diphenidol Pamoate; Dolas Hydrochloride; Doxylamine Succinate; Ebastine; etron Mesylate ; Domperidone; Dronabinol; Fludorex, Flu Levocabastine Hydrochloride; Loratadine; Mianserin meridone, Galdansetron Hydrochloride; Granisetron; Gran Hydrochloride; Noberastine; Orphenadrine Citrate; isetron Hydrochloride; Lurosetron Mesylate; Meelizine Pyrabrom; Pyrilamine Maleate; Pyroxamine Maleate; Hydrochloride; Metoclopramide Hydrochloride; Metopi Rocastine Hydrochloride; Rotoxamine; Tazifylline mazine; Ondansetron Hydrochloride; Pancopride; Prochlo Hydrochloride; Temelastine; Terfenadine; Tripelen rperazine, Prochlorperazine Edisylate; Prochlorperazine namine Citrate; Tripelennamine Hydrochloride; Tripro Maleate; Promethazine Hydrochloride; Thiethylperazine; lidine Hydrochloride; Zolamine Hydrochloride. Thiethylperazine Malate; Thiethylperazine Maleate; Tri 0.148 Antihyperlipidemic: Cholestyramine Resin; methobenzamide Hydrochloride; Zacopride Hydrochloride. Clofibrate; Colestipol Hydrochloride; Crilvastatin; 0139 Anti-epileptic: Felbamate; Loreclezole; Tolgabide, Dalvastatin; Dextrothyroxine Sodium; Fluvastatin lamotrigine. Sodium; Gemfibrozil; Lecimibide; Lovastatin; Niacin; Pravastatin Sodium; Probucol; Simvastatin; Tiqueside; 0140 Anti-estrogen: Clometherone; Delmadinone Xenbucin. Acetate; Nafoxidine Hydrochloride; Nitromifene Citrate; Raloxifene Hydrochloride; Tamoxifen Citrate; Toremifene 0149 Antihyperlipoproteinemic: Acifran; Beloxam Citrate; Trioxifene Mesylate. ide; Bezafibrate; Boxidine; Butoxamine Hydrochlo ride; Cetaben Sodium; Ciprofibrate; Gemcadiol; 0141 Antifibrinolytic: Nafamostat Mesylate. Halofenate; Lifibrate; Meglutol; Nafenopin; Pimetine 0.142 Antifungal: Acrisorcin; Ambruticin; Amphoteri Hydrochloride; Theofibrate; Tibric Acid; Treloxinate. cin B; AZaconazole, AZaSerine; Basifungin; Bifona 0150 Antihypertensive: Alfuzosin Hydrochloride; Ali zole; Biphenamine Hydrochloride; Bispyrithione Mag pamide, Althiazide, Amiquinsin Hydrochloride, Amlo US 2003/0059471 A1 Mar. 27, 2003

dipine BeSylate, Amlodipine Maleate; Anaritide 0153 Anti-infective, topical: Alcohol; Aminacrine Acetate; Atiprosin Maleate; Belfosdil; Bemitradine; Hydrochloride; Benzethonium Chloride : Bithionolate Bendacalol Mesylate; Bendroflumethiazide; Benzthi Sodium; Bromchlorenone; Carbamide Peroxide; azide; Betaxolol Hydrochloride ; Bethanidine Sulfate; Cetalkonium Chloride; Cetylpyridinium Chloride Bevantolol Hydrochloride; Biclodil Hydrochloride; :Chlorhexidine Hydrochloride; Clioquinol; Domiphen Bisoprolol; Bisoprolol Fumarate; Bucindolol Hydro Bromide; Fenticlor, Fludazonium Chloride; Fuchsin, chloride; Bupicomide; Buthiazide: Candoxatril; Can Basic; Furazolidone; Gentian Violet; Halquinols; doxatrilat; Captopril; Carvedilol; Ceronapril; Chlo Hexachlorophene:Hydrogen Peroxide; Ichthammol; rothiazide Sodium; Cicletanine; Cilazapril; Clonidine; Clonidine Hydrochloride; Clopamide; Cyclopenthiaz Imidecyl Iodine; Iodine; Isopropyl Alcohol; Mafenide ide; Cyclothiazide; Darodipine; Debrisoquin Sulfate; Acetate; Meralein Sodium; Mercufenol Chloride; Mer Delapril Hydrochloride; Diapamide; Diazoxide; Dil cury, Ammoniated; Methylbenzethonium Chloride; evalol Hydrochloride; Diltiazem Hydrochloride; Dilt Nitrofurazone; Nitromersol; Octenidine Hydrochlo iazem Malate; Ditekiren; Doxazosin Mesylate; Ecadot ride; Oxychlorosene; Oxychlorosene Sodium; ril, Enalapril Maleate; Enalaprilat, Enalkiren; Parachlorophenol, Camphorated; Potassium Perman Endralazine MeSylate, Epithiazide, EproSartan; Epro ganate; Povidone-Iodine; Sepazonium Chloride; Silver Sartan Mesylate; Fenoldopam Mesylate; Flavodilol Nitrate; Sulfadiazine, Silver; Symclosene; Thimer Maleate; Flordipine; Flosequinan; Fosinopril Sodium; fonate Sodium; Thimerosal:Troclosene Potassium. Fosinoprilat, Guanabenz, Guanabenz. Acetate; Guana cline Sulfate; Guanadrel Sulfate; Guancydine; 0154 Anti-inflammatory: Alclofenae; AlclometaSone Guanethidine MonoSulfate; Guanethidine Sulfate; Dipropionate, AlgeStone Acetonide; Alpha Amylase; Guanfacine Hydrochloride; Guanisoquin Sulfate; Gua Amcinafal, Amcinafide, Amfenac Sodium; Amiprilose noclor Sulfate; Guanoctine Hydrochloride; Guanoxa Hydrochloride; Anakinra, Anirolac, AnitraZafen; Apa benz, Guanoxan Sulfate; Guanoxyfen Sulfate; Hydrala Zone, Balsalazide Disodium; Bendazac, Benoxaprofen; zine Hydrochloride; Hydralazine Polistirex; Benzydamine Hydrochloride; Bromelains; Broper Hydroflumethiazide, Indacrinone; Indapamide, Indola amole; BudeSonide; Carprofen, Cicloprofen; Cinta pril Hydrochloride; Indoramin; Indoramin Hydrochlo Zone; Cliprofen; Clobetasol Propionate; Clobetasone ride; Indorenate Hydrochloride; Lacidipine, Leniquin Butyrate; Clopirac, CloticasOne Propionate; Cormetha Sin; Leveromakalim, Lisinopril; Lofexidine Sone Acetate; Cortodoxone, Deflazacort, DeSonide; Hydrochloride; Losartan Potassium; Losulazine DeSoximetasone; Dexamethasone Dipropionate; Hydrochloride; Mebutamate; Mecamylamine Hydro Diclofenac Potassium; Diclofenac Sodium; Diflo chloride; Medroxalol; Medroxalol Hydrochloride; rasone Diacetate; Diflumidone Sodium; Diflunisal; Dif Methalthiazide; Methyclothiazide; Methyldopa; Meth luprednate; Diftalone; Dimethyl Sulfoxide; Drocinon yldopate Hydrochloride; Metipranolol; Metolazone; ide; Endrysone; Enlimomab, Enolicam Sodium; Metoprolol Fumarate; Metoprolol Succinate; Mety Epirizole; Etodolac, Etofenamate, Felbinac, Fenamole; rosine; Minoxidil; Monatepil Maleate; Muzolimine; Nebivolol; Nifidipine; Nitrendipine; Ofornine; Par Fenbufen, Fenclofenac; Fenclorac, Fendosal; Fenpipa gyline Hydrochloride; Pazoxide; Pelanserin Hydro lone, Fentiazac, Flazalone, Fluazacort, Flufenamic chloride; Perindopril Erbumine; Phenoxybenzamine Acid, Flumizole; Flunisolide Acetate; Flumixin; Hydrochloride; Pinacidil; Pivopril; Polythiazide, Pra Flunixin Meglumine; Fluocortin Butyl; Fluo Zosin Hydrochloride; Primidolol; Prizidilol Hydrochlo rometholone Acetate; FluguaZone; Flurbiprofen; Flure ride, Quinapril Hydrochloride, Quinaprilat, QuinaZosin tofen; Fluticasone Propionate; Furaprofen; Furobufen; Hydrochloride; Quinelorane Hydrochloride; Quin Halcinonide; Halobetasol Propionate; Halopredone pirole Hydrochloride; Quinuclium Bromide; Ramipril; Acetate, Ibufenac, Ibuprofen; Ibuprofen Aluminum; Rauwolfia Serpentina; Reserpine, Saprisartan Potas Ibuprofen Piconol; Ilonidap, Indomethacin; sium; Saralasin Acetate; Sodium Nitroprusside; Sulfi Indomethacin Sodium; Indoprofen; Indoxole; Intra malol Hydrochloride; Tasosartan; Teludipine Hydro Zole, Isoflupredone Acetate; ISOXepac, ISOXicam, Keto chloride; Temocapril Hydrochloride; Terazosin profen, Lofemizole Hydrochloride; Lomoxicam, Hydrochloride; Terlakiren; Tiamenidine; Tiamenidine Loteprednol Etabonate; Meclofenamate Sodium; Hydrochloride; Ticrynafen; Tinabinol; Tiodazosin; Meclofenamic Acid; Meclorisone Dibutyrate; Mefe Tipentosin Hydrochloride; Trichlormethiazide ; Trima namic Acid; Mesalamine; Meseclazone; Methylpred Zosin Hydrochloride; Trimethaphan Camsylate; Tri nisolone Suleptanate; Morniflumate; Nabumetone; moxamine Hydrochloride; Tripamide; Xipamide; Naproxen; Naproxen Sodium; Naproxol; Nimazone; Olsalazine Sodium; Orgotein; Orpanoxin; Oxaprozin, Zankiren Hydrochloride; Zolfenoprilat Arginine. Oxyphenbutazone; Paranyline Hydrochloride; Pen 0151. Antihypotensive: Ciclafrine Hydrochloride; tosan Polysulfate Sodium; Phenbutazone Sodium Glyc Midodrine Hydrochloride. erate; Pirfenidone; Piroxicam, PiroXicam Cinnamate; 0152 Anti-infective: Difloxacin Hydrochloride; Lau Piroxicam Olamine; Pirprofen; Prednazate; Prifelone; ryl Isoquinolinium Bromide; Moxalactam Disodium; Prednisolone Sodium Phosphate; Prodolic Acid; Pro Ornidazole; Pentisomicin; Sarafloxacin Hydrochloride; quaZone, Proxazole, Proxazole Citrate; RimeXolone; Protease inhibitors of HIV and other retroviruses; Inte Romazarit; Salcolex, Salnacedin, Salsalate, Sangui grase Inhibitors of HIV and other retroviruses; Cefaclor narium Chloride; Seelzone, Sermetacin; Sudoxicam, (Ceclor); Acyclovir (Zovirax); Norfloxacin (Noroxin); Sulinldac; Suprofen; Talmetacin; Talniflumate; Talos Cefoxitin (Mefoxin); Cefuroxime axetil (Ceftin); alate; Tebufelone; Tenidap; Tenidap Sodium; Tenoxi Ciprofloxacin (Cipro). cam; TeSicam, Tesimide; Tetrydamine; Tiopinac, Tixo US 2003/0059471 A1 Mar. 27, 2003 16

cortol Pivalate; Tolimetin; Tolimetin Sodium; Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Triclonide; Triflumidate; Zidometacin; Zomepirac Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocoda Sodium. Zole; Nogalamycin; Ormaplatin; OXisuran; Paclitaxel, Pegaspargase, Peliomycin; Pentamustine, Peplomycin Sul O155 Antikeratinizing agent: Doretinel; Linaroteine; fate; Perfosfamide; Pipobroman; Piposulfan; Piroxantrone Pelretin. Hydrochloride; Plicamycin; Plomestane; Porfimer Sodium; 0156 Antimalarial: Acedapsone; Amodiaquine Hydro Porfiromycin; Prednimustine; Procarbazine Hydrochloride; chloride; Amquinate; Arteflene; Chloroquine; Chloro Puromycin; Puromycin Hydrochloride; Pyrazofurin; Ribo quine Hydrochloride; Chloroquine Phosphate; prine, Rogletimide, Safingol, Safingol Hydrochloride; Cycloguanil Pamoate; Enpiroline Phosphate; Halofan Semustine; SimtraZene, Sparfosate Sodium, SparSomycin; trine Hydrochloride; Hydroxychloroquine Sulfate; Spirogermanium Hydrochloride, Spiromustine, Spiroplatin; Mefloquine Hydrochloride; Menoctone; Mirincamycin Streptonigrin; Streptozocin; Strontium Chloride Sr 89; Hydrochloride; Primaquine Phosphate; Sulofenur; Talisomycin; Taxane, Taxoid; Tecogalan Pyrimethamine; Quinine Sulfate; Tebuduine. Sodium; Tegafur, Teloxantrone Hydrochloride; Temoporfin; TenipoSide; Teroxirone; Testolactone; Thiamiprine; O157 Antimicrobial: Aztreonam; Chlorhexidine Glu Thioguanine; Thiotepa; Tiazofurin; Tirapazamine; Topote conate, Imidurea; Lycetamine, Nibroxane, Piraz can Hydrochloride; Toremifene Citrate; Trestolone Acetate; monam Sodium; Propionic Acid; Pyrithione Sodium; Triciribine Phosphate; Trimetrexate; Trimetrexate Glucur Sanguinarium Chloride; Tigemonam Dicholine. onate; Triptorelin; Tubulozole Hydrochloride; Uracil Mus 0158 Antimigraine: Dolasetron Mesylate; Naratriptan tard; Uredepa; Vapreotide; Verteporfin; Vinblastine Sulfate; Hydrochloride; Sergolexole Maleate; Sumatriptan Suc Vincristine Sulfate; Vindesine; Vindesine Sulfate; Vinepi cinate, Zatosetron Maleate. dine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; Vinrosidine Sulfate; Vinzolidine Sul 0159) Antimitotic: Podofilox. fate; Vorozole; Zeniplatin; Zinostatin; Zorubicin Hydrochlo 0160 Antimycotic: Amorolfine. ride. 0163 Other anti-neoplastic compounds include: 0.161 Antinauseant: Buclizine Hydrochloride; Cycliz 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; ine Lactate; Naboctate Hydrochloride. abiraterone, aclarubicin; acylfulvene, adecypenol; ado 0162 Antineoplastic: Acivicin; Aclarubicin; Acodazole Zelesin; aldesleukin; ALL-TKantagonists, altretamine; Hydrochloride; Acronine; Adozelesin; Aldesleukin; Altre ambamustine, amidox, amifostine, aminolevulinic tamine; Ambomycin; Ametantrone Acetate; Aminoglute acid; amrubicin; amsacrine; anagrelide, anastrozole; thimide, AmSacrine; Anastrozole, Anthramycin; Asparagi andrographolide, angiogenesis inhibitors, antagonist nase; ASprelin, AZacitidinie, AZetepa, AZotomycin; D; antagonist G.; antarelix; anti-dorsalizing morphoge Batimastat; Benzodepa; Bicalutamide; Bisantrene Hydro netic protein-1, antiandrogen, prostatic carcinoma, chloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sul antiestrogen; antineoplaston; antisense oligonucle fate, Brequinar Sodium; Bropirimine; BuSulfan; Cactinomy otides, aphidicolin glycinate, apoptosis gene modula cin, Calusterone; Caracemide, Carbetimer; Carboplatin; tors, apoptosis regulators, apurinic acid, ara-CDP-DL Carmustine; Carubicin Hydrochloride; Carzelesin; Cedefin PTBA, arginine deaminase, asulacrine, atameStane; gol; Chlorambucil; Cirolemycin; Cisplatin; Cladribine; Cri atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; Snatol MeSylate; Cyclophosphamide, Cytarabine; Dacarba aZasetron; azatoxin; azatyrosine, baccatin III deriva zine; Dactinomycin; Daunorubicin Hydrochloride; tives; balanol; batimastat; BCR/ABL antagonists; ben Decitabine, Dexormaplatin, DeZaguanine, DeZaguanine Zochlorins; benzoylstaurosporine; beta lactam deriva Mesylate; Diaziquone; Docetaxel; Doxorubicin; Doxorubi tives, beta-alethine, betaclamycin B; betulinic acid; cin Hydrochloride; Droloxifene; Droloxifene Citrate; Dro bFGF inhibitor, bicalutamide; bisantrene; bisaziridi moStanolone Propionate, DuaZomycin; Edatrexate, Eflorni nylspermine; bisnafide; bistratene A, bizelesin; thine Hydrochloride; Elsamitrucin; Enloplatin, Enpromate; breflate; bropirimine; budotitane; buthionine sulfox Epipropidine; Epirubicin Hydrochloride; Erbulozole; Eso imine, calcipotriol, calphostin C; camptothecin deriva rubicin Hydrochloride; Estramustine; Estramustine Phos tives, canarypox IL-2, capecitabine, carboxamide phate Sodium; Etanidazole; Ethiodized Oil 131; Etoposide; amino-triazole; carboxyamidotriazole; CaRest M3; Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride; CARN 700; cartilage derived inhibitor; carzelesin; Fazarabine, Fenretinide; Floxuridine, Fludarabine Phos casein kinase inhibitors (ICOS); castanospermine; phate, Fluorouracil; Flurocitabine; FoSquidone; Fostriecin cecropin B; cetrorelix; chlorins, chloroquinoxaline Sul Sodium; Gemcitabine; Gemcitabine Hydrochloride; Gold fonamide, cicaprost, cis-porphyrin, cladribine; clo Au 198; Hydroxyurca; Idarubicin Hydrochloride; Ifosfa mifene analogues, clotrimazole; collismycin A, collis mide; Ilmofosine; Isotretinoin; Interferon Alfa-2a, Inter mycin B; combretastatin A4, combretastatin analogue; feron Alfa-2b; Interferon Alfa-n1; Interferon Alfa-n3; Inter conagenin, crambescidin 816; crisinatol; cryptophycin feron Beta-1a; Interferon Gamma-1b, Iproplatin; Irinotecan 8, cryptophycin A derivatives, curacin A, cyclopentan Hydrochloride; Lanreotide Acetate; Letrozole; Leuprolide thraquinones, cycloplatam, cypemycin; cytarabine Acetate; Liarozole Hydrochloride; Lometrexol Sodium; ocfoSfate; cytolytic factor; cytostatin, dacliximab, Lomustine; LOSOXantrone Hydrochloride, Masoprocol; decitabine; dehydrodidemnin B; deslorelin; dexifosfa Maytansine; Mechlorethamine Hydrochloride; Megestrol mide; deXraZOxane, deXVerapamil, diaziquone; didem Acetate; Melengestrol Acetate; Melphalan; Menogaril; Mer nin B; didox; diethylnorspermine, dihydro-5-azacyti captopurine; Methotrexate; Methotrexate Sodium; Meto dine, dihydrotaXol, 9-, dioxamycin; diphenyl prine; Meturedepa; Mitindomide; Mitocarcin; Mitocromin; Spiromustine, docOSanol; dolasetron, doxifluridine, US 2003/0059471 A1 Mar. 27, 2003 17

droloxifene, dronabinol; duocarmycin SA, ebSelen; tein tyrosine phosphatase inhibitors, purine nucleoside ecomustine, edelfosine, edrecolomab, eflornithine; phosphorylase inhibitors, purpurins, pyrazoloacridine, elemene; emitefur; epirubicin, epristeride; estramustine pyridoxylated hemoglobin polyoxyethylene conjugate; analogue; estrogen agonists, estrogen antagonists; raf antagonists, raltitrexed; ramosetron; ras farnesyl etanidazole, etoposide phosphate, exemestane, fadro protein transferase inhibitors; ras inhibitors; ras-GAP Zole; faZarabine; fenretinide; filgrastim; finasteride; fla inhibitor; retelliptine demethylated; rhenium Re 186 Vopiridol; fleZelastine; fluiasterone; fludarabine; fluo etidronate, rhizoxin; ribozymes, RII retinamide; rodaunorunicin hydrochloride; forfenimex; rogletimide, rohitukine; romurtide, roquinimex, rubigi formeStane; fostriecin, fotemustine, gadolinium teXa none B1, ruboxyl, Safingol; Saintopin; SarCNU; Sarco phyrin, gallium nitrate, galocitabine; ganirelix; gelati phytol A, SargramoStim; Sdi 1 mimetics, Semustine; Senescence derived inhibitor 1; Sense oligonucleotides, nase inhibitors, gemcitabine; glutathione inhibitors, Signal transduction inhibitors, Signal transduction hepsulfam; heregulin; hexamethylene bisacetamide; modulators, Single chain antigen binding protein; Sizo hypericin; ibandronic acid, idarubicin; idoxifene, idra firan; Sobu ZOxane, Sodium borocaptate, Sodium pheny mantone, ilmofoSine, illomastat; imidazoacridones, lacetate, Solverol, Somatomedin binding protein; Son imiquimod, immunostimulant peptides; insulin-like ermin; Sparfosic acid; Spicamycin D; Spiromustine; growth factor-1 receptor inhibitor; interferon agonists, Splenopentin; Spongistatin 1; squalamine; Stem cell interferons, interleukins, iobenguane; iododoxorubicin; inhibitor; stem-cell division inhibitors; stipiamide; ipomeanol, 4-, irinotecan; iroplact, irSogladine, isoben Stromelysin inhibitors, Sulfinosine, Superactive vasoac gazole; isohomohalicondrin B; itasetron, jasplakino tive intestinal peptide antagonist; Suradista, Suramin; lide; kahalalide F, lamellarin-N triacetate; lanreotide; Swainsonine, Synthetic glycosaminoglycans, tallimus leinamycin; lenograstim; lentinan Sulfate, leptolstatin; tine; tamoxifen methiodide, tauromustine, tazarotene; letrozole; leukemia inhibiting factor; leukocyte alpha tecogalan Sodium, tegafur, tellurapyrylium, telomerase interferon; leuprolide-estrogen-progesterone; leupro inhibitors, temoporfin, temozolomide; teniposide, tet relin; levamisole, liarozole, linear polyamine analogue; rachlorodecaoxide, tetraZomine; thaliblastine; thalido lipophilic disaccharide peptide, lipophilic platinum mide; thiocoraline, thrombopoietin; thrombopoietin compounds, lisSoclinamide 7; lobaplatin, lombricine; mimetic, thymalfasin; thymopoietin receptor agonist; lometrexol; lonidamine; loSOXantrone; lovastatin; lox thymotrinan; thyroid Stimulating hormone, tin ethyl oribine; lurtotecan; lutetium texaphyrin, lySofylline; etiopurpurin; tirapaZamine, titanocene dichloride; lytic peptides, maitansine; mannostatin A, marimastat; topotecan; topSentin; toremifene; totipotent Stem cell masoprocol; maspin; matrilysin inhibitors, matrix met factor; translation inhibitors; tretinoin, triacetyluridine; alloproteinase inhibitors, menogaril; merbarone, meter triciribine, trimetrexate, triptorelin; tropisetron; turOS elin; methioninase; metoclopramide; MIF inhibitor; teride; tyrosine kinase inhibitors; tyrphostins; UBC mifepristone; miltefosine, mirimoStim; mismatched inhibitors, ubenimex, urogenital sinus-derived growth double Stranded RNA, mitoguaZone, mitolactol, mito inhibitory factor; urokinase receptor antagonists; vap mycin analogues, mitonafide; mitotoxin fibroblast growth factor-Saporin, mitoxantrone; mofaroteine, mol reotide; variolin B; Vector System, erythrocyte gene gramoStim; monoclonal antibody, human chorionic therapy; VelareSol, Veramine, Verdins, Verteporfin; gonadotrophin, monophosphoryl lipid A+myobacte Vinorelbine, VinXaltine, Vitaxin; Vorozole; Zanoterone; rium cell wall Sk, mopidamol, multiple drug resistance Zeniplatin, Zilascorb, Zinostatin stimalamer. gene inhibitor, multiple tumor Suppressor 1-based 0.164 Anti-cancer Supplementary Potentiating Agents: therapy; mustard anticancer agent, mycaperoxide B; Tricyclic anti-depressant drugs (e.g., imipramine, mycobacterial cell wall extract; myriaporone, N-acetyl desipramine, amitryptyline, clomipramine, trimipramine, dinaline, N-Substituted benzaimides, nafarelin; doxepin, nortriptyline, protriptyline, amoxapine and mapro nagreStip; naloxone-pentazocine, napavin; naphter tiline); non-tricyclic anti-depressant drugs (e.g., Sertraline, pin, nartograstim; nedaplatin; memorubicin; neridronic trazodone and citalopram); Ca" antagonists (e.g., Vera acid; neutral endopeptidase, nilutamide, nisamycin; pamil, nifedipine, nitrendipine and caroverine); Calmodulin nitric oxide modulators, nitroxide antioxidant, nitrul inhibitors (e.g., prenylamine, trifluoroperazine and clomi lyn, O6-benzylguanine; Octreotide, okicenone, oligo pramine); Amphotericin B; Triparanol analogues (e.g., nucleotides; Onapristone, ondansetron; ondansetron; tamoxifen); antiarrhythmic drugs (e.g., quinidine); antihy oracin, oral cytokine inducer; Ormaplatin, OSaterone; pertensive drugs (e.g., reserpine); Thiol depleters (e.g., Oxaliplatin, oxaunomycin; paclitaxel analogues, pacli buthionine and sulfoximine) and Multiple Drug Resistance taxel derivatives, palauamine, palmitoylrhizoxin; pam reducing agents Such as Cremaphor EL. The compounds of idronic acid; panaxytriol; panomifene, parabactin; the invention also can be administered with cytokines Such paZelliptine, pegaspargase; peldesine; pentosan as granulocyte colony Stimulating factor. polysulfate Sodium; pentostatin; pentroZole; perflu 0.165 Antineutropenic: Filgrastim; Lenograstim; Mol bron; perfosfamide, perillyl alcohol; phenazinomycin; gramoStim; RegramoStim; SargramoStim. phenylacetate; phosphatase inhibitors, picibanil; pilo carpine hydrochloride, pirarubicin; piritrexim; placetin 0166 Antiobsessional agent: Fluvoxamine Maleate. A, placetin B; plasminogen activator inhibitor, plati num complex, platinum compounds, platinum-triamine 0.167 Antiparasitic:p Abamectin; ClorSulon; Ivermec complex, porfimer Sodium; porfiromycin; propyl bis tin. acridone; prostaglandin J2, proteasome inhibitors, pro 0168 Antiparkinsonian: Benztropine Mesylate; tein A-based immune modulator; protein kinase C Biperiden; Biperiden Hydrochloride; Biperiden Lac inhibitor; protein kinase C inhibitors, microalgal; pro tate; Carbidopa-Levodopa; Carmantadine, Ciladopa US 2003/0059471 A1 Mar. 27, 2003 18

Hydrochloride; Dopamantine; Ethopropazine Hydro ride; Tioperidone Hydrochloride; Tiospirone Hydro chloride; LaZabemide, Levodopa, Lometraline Hydro chloride; Trifluoperazine Hydrochloride; Trifluperidol; chloride; Mofegiline Hydrochloride; Naxagolide Triflupromazine; Triflupromazine Hydrochloride; Hydrochloride; Pareptide Sulfate; Procyclidine Hydro Ziprasidone Hydrochloride. chloride; Quiniellorane Hydrochloride; Ropinirole Hydrochloride; Selegiline Hydrochloride; Tolcapone; 0177 Antirheumatic: Auranofin; Aurothioglucose; Trihexyphenidyl Hydrochloride. Bindarit; Lobenzarit Sodium; Phenylbutazone; Pira Zolac, Prinomide Tromethamine; Seprilose. 0169. Antiperistaltic: Difenoximide Hydrochloride; 0.178 Antischistosomal: Becanthone Hydrochloride; Difenoxin; Diphenoxylate Hydrochloride; Fluperam Hycanthone; Lucanthone Hydrochloride; Niridazole; ide; Lidamidine Hydrochloride; Loperamide Hydro Oxamniquine; Pararosaniline Pamoate, Teroxalene chloride; Malethamer; Nufenoxole; Paregoric. Hydrochloride. 0170 Antipneumocystic: Atovaquone. 0179 Antiseborrheic: Chloroxine; Piroctone; Piroc 0171 Antiproliferative agent: Piritrexim Isethionate. tone Olamine; Resorcinol Monoacetate. 0172 Antiprostatic hypertrophy: Sitogluside. 0180 Antisecretory: Arbaprostil; Deprostil; Fenoctim ine Sulfate; Octreotide; Octreotide Acetate; Omepra 0173 Antiprotozoal: Amodiaquine; Azanidazole; Zole Sodium; Rioprostil; Trimoprostil. Bamnidazole; Carnidazole; Chlortetracycline Bisulfate ; Chlortetracycline Hydrochloride; Flubendazole; 0181 Antispasmodic: Stilonium Iodide; Tizanidine Flunidazole; Halofuginone Hydrobromide; Imidocarb Hydrochloride. Hydrochloride; Ipronidazole; Metronidazole; Mis 0182 Antithrombotic: Anagrelide Hydrochloride; onidazole; Moxinidazole; NitarSone; Partricin; Puromy Bivalirudin; Dalteparin Sodium; Danaparoid Sodium; cin; Puromycin Hydrochloride; Ronidazole; Sulnida Dazoxiben Hydrochloride; Efegatran Sulfate; Enox Zole, Tinidazole. aparin Sodium; Ifetroban; Ifetroban Sodium; Tinza 0.174 Antipruritic: Cyproheptadine Hydrochloride; parin Sodium; Trifenagrel. Methdilazine; Methdilazine Hydrochloride; Trimepra 0183 Antitussive: Benzonatate; Butamirate Citrate; Zine Tartrate. Chlophedianol Hydrochloride; Codeine Polistirex; 0.175 Antipsoriatic: Acitretin; Anthralin; Azaribine; Codoxime; Dextromethorphan; Dextromethorphan Calcipotriene; Cycloheximide; Enazadrem Phosphate; Hydrobromide; Dextromethorphan Polistirex; Ethyl Etretinate, Liarozole Fumarate, Lonapalene, Tepoxa Dibunate; Guaiapate; Hydrocodone Bitartrate; Hydro lin. codone PolistireX; Levopropoxyphene NapSylate, NoS capine; Pemerid Nitrate; Pipazethate; Suxemerid Sul 0176 Antipsychotic: Acetophenazine Maleate; Alen fate. temol Hydrobromide; Alpertine, AZaperone; Batelap ine Maleate; Benperidol; Benzindopyrine Hydrochlo 0.184 Anti-ulcerative: Aceglutamide Aluminum; ride; Brofoxine; Bromperidol; Bromperidol Decanoate; Cadexomer Iodine; Cetraxate Hydrochloride; Eniso Butaclamol Hydrochloride; Butaperazine; Butapera prost, Isotiquimide, Lansoprazole, LaVoltidine Succi zine Maleate; Carphenazine Maleate; Carvotroline nate; Misoprostol; Nizatidine; Nolinium Bromide; Pan Hydrochloride; Chlorpromazine; Chlorpromazine toprazole; Pifarnine; Pirenzepine Hydrochloride; Hydrochloride; Chlorprothixene; Cinperene; Cintria Rabeprazole Sodium; Remiprostol; Roxatidine Acetate mide; Clomacran Phosphate; Clopenthixol; Clopi Hydrochloride; Sucralfate; Sucrosofate Potassium; mozide, Clopipazan MeSylate; Cloroperone Hydro Tolimidone. chloride; Clothiapine; Clothixamide Maleate; Clozapine; Cyclophenazine Hydrochloride; Droperi 0185 Anti-urolithic: Cysteamine; Cysteamine Hydro dol; Etazolate Hydrochloride; Fenimide; Flucindole; chloride; Tricitrates. FlumeZapine, Fluphenazine Decanoate, Fluphenazine 0186 Antiviral: Acemannan; Acyclovir; Acyclovir Enanthate; Fluphenazine Hydrochloride; Fluspiperone; Sodium; Adefovir; Alovudine; Alvircept Sudotox; Fluspirilene; Flutroline; Gevotroline Hydrochloride; Amantadine Hydrochloride; Aranotin; Arildone; Halopemide; Haloperidol; Haloperidol Decanoate; Ilo Atevirdine Mesylate; Avridine, Cidofovir, Cipamfyl peridone, Imidoline Hydrochloride; Lenperone, Maza line; Cytarabine Hydrochloride; Delavirdine Mesylate; pertine Succiniate; MeSoridazine; MeSoridazine Besy Desciclovir, Didanosine; Disoxaril; Edoxudine; Envi late; Metiapine; Milenperone; Milipertine; Molindone radene; Enviroxime; Famciclovir; Famotine Hydro Hydrochloride; Naranol Hydrochloride; Neflumozide chloride; Fiacitabine; Fialuridine; Fosarilate; Foscarnet Hydrochloride, Ocaperidone; Olanzapine; OXipero Sodium; Fosfonet Sodium; Ganciclovir, Ganciclovir mide; Penfluridol; Pentiapine Maleate; Perphenazine; Sodium; Idoxuridine; Kethoxal; Lamivudine; Lobu Pimozide; Pinoxepin Hydrochloride; Pipamperone; cavir; Memotine Hydrochloride; Methisazone; Nevi Piperacetazine; Pipotiazine Palmitate; Piquindone rapine; Penciclovir; Pirodavir; Ribavirin; Rimantadine Hydrochloride; Prochlorperazine Edisylate; Prochlor Hydrochloride; Saquinavir Mesylate; Somantadine perazine Maleate; Promazine Hydrochloride; Remox Hydrochloride; Sorivudine; Statolon; Stavudine; Tilor ipride; Remoxipride Hydrochloride; Rimcazole Hydro one Hydrochloride; Trifluridine; Valacyclovir Hydro chloride; Seperidol Hydrochloride; Sertindole; chloride; Vidarabine; Vidarabine Phosphate; Vidara Setoperone, Spiperone; Thioridazine; Thioridazine bine Sodium Phosphate; Viroxime; Zalcitabine; Hydrochloride; Thiothixene; Thiothixene Hydrochlo Zidovudine; ZinviroXime. US 2003/0059471 A1 Mar. 27, 2003 19

0187. Appetite Suppressant: Dexfenfluramine Hydro anoSide; Digitalis, Digitoxin; Digoxin; Dobutamine; chloride; Phendimetrazine Tartrate; Phentermine Dobutamine Hydrochloride; Dobutamine Lactobion Hydrochloride. ate, Dobutamine Tartrate, Enoximone, ImaZodan 0188 Benign prostatic hyperplasia therapy agent: Hydrochloride; Indolidan; Isomazole Hydrochloride; Levdobutamine Lactobionate, Lixazinone Sulfate; Tamsulosin Hydrochloride. Medorinone; Milrinone; Pelrinone Hydrochloride; 0189 Blood glucose regulators: Human insulin; Glu Pimobendan; PiroXimone; Prinoxodan; Proscillaridin; cagon; TolaZamide, Tolbutamide, Chloropropamide; Quazinone; Tazolol Hydrochloride; Vesnarinone. Acetohexamide and Glipizide. 0196) Cardiovascular agent: Dopexamine; Dopexam 0.190 Bone resorption inhibitor: Alendronate Sodium; ine Hydrochloride. Etidronate Disodium; Pamidronate Disodium. 0197) Choleretic: Dehydrocholic Acid; Fencibutirol; 0191 Bronchodilator: Albuterol; Albuterol Sulfate; Hymecromone; Piprozolin; Sincalide; Tocamphyl. AZanator Maleate; Bamifylline Hydrochloride; Bitolterol Mesylate; Butaprost; Carbuterol Hydrochlo 0198 Cholinergic: Aceclidine; Bethanechol Chloride; ride; Clorprenaline Hydrochloride; Colterol Mesylate; Carbachol; Demecarium Bromide; Dexpanthenol; Doxaprost; Doxofylline; Dyphylline; Enprofylline; Echothiophate Iodide; Isoflurophate; Methacholine Ephedrine; Ephedrine Hydrochloride; Fenoterol; Fen Chloride; Neostigmine Bromide; Neostigmine Methyl prinast Hydrochloride; Guaithylline; Hexoprenaline Sulfate; Physostigmine; Physostigmine Salicylate; Phy Sulfate; Hoquizil Hydrochloride; Ipratropium Bro Sostigmine Sulfate; Pilocarpine; Pilocarpine Hydro mide; Isoetharine; Isoetharine Hydrochloride; Isoet chloride; Pilocarpine Nitrate; Pyridostigmine Bromide. harine Mesylate; Isoproterenol Hydrochloride; Isopro terenol Sulfate; Metaproterenol Polistirex, 0199 Cholinergic agonist: Xanomeline; Xanomeline Metaproterenol Sulfate; Nisbuterol Mesylate; Oxtriph Tartrate. yline; Picumeterol Fumarate; Piquizil Hydrochloride; 0200 Cholinesterase Deactivator: Obidoxime Chlo Pirbuterol Acetate; Pirbuterol Hydrochloride; Pro ride; Pralidoxime Chloride; Pralidoxime Iodide; Prali caterol Hydrochloride; Pseudoephedrine Sulfate; Qua doxime Mesylate. Zodine, Quinterenol Sulfate; Racepinephrine, Racepi nephrine Hydrochloride; Reproterol Hydrochloride; 0201 Coccidiostat: Arpinocid; Narasin; Semdurami Rimiterol Hydrobromide; Salmeterol; Salmeterol Xin cin; Semduramicin Sodium. afoate; Soterenol Hydrochloride; Sulfonterol Hydro 0202 Cognition adjuvant: Ergoloid Mesylates; Pirac chloride; Suloxifen Oxalate; Terbutaline Sulfate; Theo etam; Pramiracetam Hydrochloride; Pramiracetam Sul phylline; Xanoxate Sodium; Zindotrine; Zinterol fate; Tacrine Hydrochloride. Hydrochloride. 0203 Cognition enhancer: Besipirdine Hydrochloride; 0.192 Carbonic anhydrase inhibitor: Acetazolamide; Linopirdine; Sibopirdine. Acetazolamide Sodium; Dichlorphenamide; Dorzola mide Hydrochloride; Methazolamide; Sezolamide 0204 Gastric Acid Suppressasnt: Omeprazole. Hydrochloride. 0205 Diagnostic aid: Aminohippurate Sodium; Ana 0193 Cardiac depressant: Acecainide Hydrochloride; Zolene Sodium; Arclofenin, Arginine; Bentiromide; Acetylcholine Chloride; Actisomide, Adenosine; Benzylpenicilloyl Polylysine; Butedronate Tetraso Amiodarone; Aprindine, Aprindine Hydrochloride; dium; Butilfenin; Coccidioidin; Corticorelin Ovine Tri Artilide Fumarate; Azimilide Dihydrochloride; Bidiso flutate; Corticotropin, Repository; Corticotropin Zinc mide; Bucainide Maleate; Bucromarone; Butoprozine Hydroxide; Diatrizoate Meglumine; Diatrizoate Hydrochloride; Capobenate Sodium; Capobenic Acid; Sodium; Diatrizoic Acid; Diphtheria Toxin for Schick Cifenline; Cifenline Succinate; Clofilium Phosphate; Test; Disofenin; Edrophonium Chloride; Ethiodized Disobutamide; Disopyramide; Disopyramide Phos Oil, Etifenin; Exametazime, Ferristenc; Ferumoxides; phate; Dofetilide; Drobuline; Edifolone Acetate; Emi Ferumoxsil; Fluorescein; Fluorescein Sodium; Gado lium Tosylate; Encainide Hydrochloride; Flecainide benate Dimeglumine, Gadoteridol, Gadodiamide; Acetate; Ibutilide Fumarate; Indecainide Hydrochlo Gadopentetate Dimeglumine, Gadoversetamide; Histo ride; Ipazilide Fumarate; Lorajmine Hydrochloride; plasmin, Impromidine Hydrochloride; Indigotindisul Lorcainide Hydrochloride; Meobentine Sulfate; Mexi fonate Sodium; Indocyanine Green, Iobenguane Sul letine Hydrochloride; Modecainide; Moricizine; Oxira fate I 123; Iobenzamic Acid; Iocarmate Meglumine; mide; Pirmenol Hydrochloride; Pirolazamide; Prano Iocarmic Acid, Iocetamic Acid, Iodamide, Iodamide lium Chloride; Procainamide Hydrochloride; Megilumine, Iodipamide Meglumine, Iodixanol, Iodox Propafenone Hydrochloride; Pyrinoline; Quindonium amate Meglumine, Iodoxamie Acid, Ioglicic Acid; Bromide; Quinidine Gluconate; Quinidine Sulfate; Ioglucol, Ioglucomide, Ioglycamic Acid, Iogulamide; Recainam Hydrochloride; Recainam Tosylate; Risotil Iohexol, Iomeprol, Iopamidol, Iopanoic Acid, Iopentol; ide Hydrochloride; Ropitoin Hydrochloride; Sematil Iophendylate, Iprofenin, Iopronic Acid, Ioprocemic ide Hydrochloride; Suricainide Maleate; Tocainide; Acid, Iopydol, Iopy done, Iosefamic Acid, IoSeric Acid; Tocainide Hydrochloride; Transcainide. IoSulamide Meglumine, IoSumetic Acid; Iotasul; Iotet ric Acid; Iothalamate Meglumine; Iothalamate Sodium; 0194 Cardioprotectant: Dexrazoxane; Draflazine. Iothalamic Acid; Iotrolan; IotroXic Acid, IoverSol, Iox 0.195 Cardiotonic: Actodigin; Amrinone; Bemoradan; aglate Meglumine, Ioxagiate Sodium; Ioxaglic Acid; Butopamine; CarbaZeran; CarSatrin Succinate; Desl Ioxilan, Ioxotrizoic Acid, Ipodate Calcium, Ipodate US 2003/0059471 A1 Mar. 27, 2003 20

Sodium; Isosulfan Blue; Leukocyte Typing Serum; mocortal, Hydrocortisone; Hydrocortisone Acetate; Lidofenin; Mebrofenin; Meglumine; Metrizamide; Hydrocortisone Buteprate; Hydrocortisone Butyrate; Metrizoate Sodium; Metyrapone; Metyrapone Tartrate; Hydrocortisone Sodium Phosplhate; Hydrocortisone Mumps Skin Test Antigen; Pentetic Acid; Propyli Sodium Succinate; Hydrocortisone Valerate; odone; Quinaldine Blue, Schick Test Control; Sermo Medrysone; Methylprednisolone; Methylprednisolone relin Acetate; Sodium Iodide I 123; Sprodiamide; Stan Acetate; Methylprednisolone Sodium Phosphate; nous Pyrophosphate; Stannous Sulfur Colloid; Methylprednisolone Sodium Succinate; Nivazol; Succimer; Teriparatide Acetate; Tetrofosmin; Tolbuta Paramethasone Acetate; Prednicarbate; Prednisolone; mide Sodium; Tuberculin; Tyropanoate Sodium; Prednisolone Acetate; Prednisolone Hemisuccinate; Xylose. Prednisolone Sodium Phosphate; Prednisolone Sodium 0206 Diuretic: Ambuphylline; Ambuside; Amiloride Succinate; Prednisolone Tebutate; Prednisone; Predni Hydrochloride; Azolimine; Azosemide; Brocrinat; val; Ticabesone Propionate; Tralonide; Triamcinolone; Bumetanide; Chlorothiazide; Chlorthalidone; Cla Triamcinolone Acetonide; Triamcinolone Acetonide Zolimine; Clorexolone; Ethacrynate Sodium; Sodium; Triamcinolone Diacetate; Triamcinolone Ethacrynic Acid; EtoZolin, Fenguizone; Furosemide; Hexacetonide. Hydrochlorothiazide; Isosorbide; Mannitol; Mefruside; 0216 Gonad-stimulating principle: Buserelin Acetate; Ozolinone; Piretanide; Spiroxasone; Torsemide; Triam Clomiphene Citrate; Ganirelix Acetate; Gonadorelin terene; Triflocin, Urea. Acetate; Gonadorelin Hydrochloride; Gonadotropin, 0207 Dopaminergic agent: Ibopamine. Chorionic; Menotropins. 0208 Ectoparasiticide: Nifluridide; Permethrin. 0217 Hair growth stimulant: Minoxidil. 0218. Hemostatic: Aminocaproic Acid; Oxamarin 0209 Emetic: Apomorphine Hydrochloride. Hydrochloride; Sulmarin; Thrombin; Tranexamic Acid. 0210 Enzyme inhibitor: Acetohydroxamic Acid; Alr 0219. Histamine 112 receptor antagonists: Ranitidine estatin Sodium; Aprotinin; Benazepril Hydrochloride; (Zantac); Famotidine (Pepcid), Cimetidine (Tagamet); Benazeprilat, Benurestat; Bromocriptine; Bromocrip Nizatidine (Axid). tine Mesylate; Cilastatin Sodium; Flurofamide; Lergot rile; Lergotrile MeSylate; Levey closerine; Libenzapril; 0220 Hormone: Diethylstilbestrol; Progesterone; 17 Pentopril; Pepstatin; Perindopril; Polignate Sodium; hydroxy progesterone; Medroxyprogesterone, Norg Sodium Amylosulfate, Sorbinil; Spirapril Hydrochlo estrel; Norethynodrel; Estradiol; Megestrol (Megace); ride; Spiraprilat; Taleranol; Teprotide; Tolfamide; Norethindrone; Levonorgestrel; Ethyndiol; Ethinyl Zofenopril Calcium. estradiol; Mestranol; Estrone; Equilin, 17 alpha dihy droequilin; equilenin; 17 alpha dihydroequilenin; 17 0211 Estrogen: Chlorotrianisene; Dienestrol; Diethyl alpha estradiol; 17 beta estradiol; Leuprolide (lupron); stilbestrol; Diethylstilbestrol Diphosphate; Equilin; Glucagon; Testolactone, Clomiphene, Han memo Estradiol; Estradiol Cypionate; Estradiol Enanthate; pausal gonadotropins, Human chorionic gonadotropin; Estradiol Undecylate; Estradiol Valerate; Estrazinol Urofollitropin; Bromocriptine; Gonadorelin; Luteiniz Hydrobromide; Estriol; Estrofurate; Estrogens, Conju ing hormone releasing hormone and analogs, Gonadot gated; Estrogens, Esterified; Estrone; Estropipate; Ethi ropins; Danazol; Testosterone, Dehydroepiandroster nyl Estradiol; Fenestrel; Mestranol; Nylestriol; one; Androstenedione, Dihydroestosterone, Relaxin, Quinestrol. Oxytocin, Vasopressin; FolliculoStatin; Follicle regula 0212 Fibrinolytic: Anistreplase; Bisobrin Lactate; tory protein; Gonadoctrinins, Oocyte maturation Brinolase. inhibitor; Insulin growth factor; Follicle Stimulating Hormone, Luteinizing hormone, Tamoxifen., Corti 0213 Free oxygen radical Scavenger: Pegorgotein. corelin Ovine Triflutate; Cosyntropin; Metogest; Pitu 0214) Gastrointestinal Motility agents: Cisapride (Pro itary, Posterior, Seractide Acetate, Somalapor; pulsid); Metoclopramide (Reglan), Hyoscyamine Somatrem; Somatropin; Somenopor; Somidobove. (Levsin). 0221) Hypocholesterolemic: Lifibrol. 0215) Glucocorticoid: Amcinonide; Beclomethasone 0222 Hypoglycemic: Darglitazone Sodium: Glime Dipropionate, Betamethasone; Betamethasone Acetate; piride. Betamethasone Benzoate, Betamethasone Dipropi 0223 Hypolipidemic: Azalanstat Dihydrochloride; onate; Betamethasone Sodium Phosphate; Betametha Colestolone; Surfomer; Xenalipin. Sone Valerate; Carbenoxolone Sodium; Clocortolone Acetate; Clocortolone Pivalate; Cloprednol; Corti 0224 Hypotensive: Viprostol. cotropin; Corticotropin, Repository; Corticotropin Zinc Hydroxide; Cortisone Acetate; Cortivazol; Descino 0225 HMGCoA reductase inhibitors: Lovastatin lone Acetonide; Dexamethasone; Dexamethasone (Mevacor); Simvastatin (Zocor); Pravastatin (Prava Sodium Phosphate; Diflucortolone; Diflucortolone Piv chol); Fluvasatin (Lescol). alate; Flucloronide; Flumethasone; Flumethasone Piv 0226. Immunizing agent: Antirabies Serum; Antivenin alate; Flunisolide; Fluocinolone Acetonide; Fluocino (Latrodectus mactans); Antivenin (Micrurus Fulvius); nide, Fluocortolone, Fluocortolone Caproate; Antivenin (Crotalidae) Polyvalent; BCG Vaccine; Fluorometholone; Fluperolone Acetate; Flupredniso Botulism Antitoxin; Cholera Vaccine; Diphtheria Anti lone; Fluprednisolone Valerate; Flurandrenolide; For toxin; Diphtheria Toxoid; Diphtheria Toxoid Adsorbed; US 2003/0059471 A1 Mar. 27, 2003 21

Globulin, Immune; Hepatitis B Immune Globulin; 0243 Nasal decongestant: Nemazoline Hydrochloride; Hepatitis B Virus Vaccine Inactivated; Influenza Virus Pseudoephedrine Polistirex. Vaccine; Measles Virus Vaccine Live; Meningococcal Polysaccharide Vaccine Group A; Meningococcal 0244 Neuroleptic: Duoperone Fumarate; Risperidone. Polysaccharide Vaccine Group C; Mumps Virus Vac 0245 Neuromuscular blocking agent: Atracurium cine Live; Pertussis Immune Globulin; Pertussis Vac Besylate; Cisatracurium Besylate; Doxacurium Chlo cine; Pertussis Vaccine Adsorbed; Plague Vaccine; ride; Gallamine Triethiodide; Metocurine Iodide; Poliovirus Vaccine Inactivated; Poliovirus Vaccine Mivacurium Chloride; Pancuronium Bromide; Pipecu Live Oral; Rabies Immune Globulin; Rabies Vaccine; ronium Bromide; Rocuronium Bromide; Succinylcho Rh(D) Immune Globulin; Rubella Virus Vaccine Live; line Chloride; Tubocurarine Chloride; Vecuronium Smallpox Vaccine, Tetanus Antitoxin; Tetanus Immune Bromide. Globulin; Tetanus Toxoid; Tetanus Toxoid Adsorbed; Typhoid Vaccine; Yellow Fever vaccine; Vaccinia 0246 Neuroprotective: Dizocilpine Maleate. Immune Globulin; Varicella-Zoster Immune Globulin. 0247 NMDA antagonist: Selfotel. 0227 Immunomodulator: Dimepranol Acedoben; Imi 0248. Non-hormonal sterol derivative: Pregnenolone quimod; Interferon Beta-1b; Lisofylline; Mycopheno Succiniate. late Mofetil, Prezatide Copper Acetate. 0249. Oxytocic: Carboprost; Carboprost Methyl; Car 0228 Immunoregulator: Azarole; Fanetizole Mesy boprost Tromethamine; Dinoprost; Dinoprost late; Frentizole; Oxamisole Hydrochloride; Ristianol Tromethamine, Dinoprostone; Ergonovine Maleate; Phosphate; Thymopentin; Tilomisole. Meteneprost; Methylergonovine Maleate; Oxytocin; 0229 Immunostimulant: Loxoribine; Teecleukin. Sparteine Sulfate. 0230 Immunosuppressant: Azathioprine; Azathio 0250 Plasminogen activator: Alteplase; Urokinase. prine Sodium; CycloSporine; Daltroban; Gusperimus 0251 Platelet activating factor antagonist: Lexipafant. Trihydrochloride; Prednisolone Sodium Phosphate, 0252 Platelet aggregation99C9 inhibitor: Acadesine; Bera Prednisolone; Sirolimus; Tacrolimus. prost; Beraprost Sodium, Ciprostene Calcium; Itazi 0231. Impotence therapy adjunct: Delequamine grel, Lifarizine, OXagrelate. Hydrochloride. 0253 Post-stroke and post-head trauma treatment: 0232. Inihibitor: Acarbose; Atorvastatin Calcium; Citicoline Sodium. Beinserazide, Brocresine; Carbidopa; Clavulanate Potassium; DaZmegrel, Docebenone; EpoproStenol; 0254 Potentiator: Pentostatin; Talopram Hydrochlo Epoprostenol Sodium; Epristeride; Finasteride; Flurbi ride. profen Sodium; Furegrelate Sodium; Lufironil; Migli 0255 Progestin: Algestone Acetophenide; Amadinone tol; Orlislat; Pimagedine Hydrochloride; Pirmagrel; Acetate; Anagestone Acetate; Chlormadinone Acetate; Ponalrestat; Ridogrel; Sulbactam BenZathine; Sulbac CingeStol; Clogestone Acetate; Clomegestone Acetate; tam Pivoxil, Sulbactam Sodium; Suronacrine Maleate; DeSogeStrel; Dimethisterone; Dydrogesterone; Tazobactam; Tazobactam Sodium; Ticlopidine Hydro Ethynerone; Ethynodiol Diacetate; EtonogeStrel; chloride; Tirilazad Mesylate; Tolrestat; Velnacrine Flurogestone Acetate; Gestaclone, Gestodene, Gesto Maleate; Zifrosilone; Zileuton. norone Caproate; Gestrinone, Haloprogesterone; 0233 Keratolytic: Alcloxa; Aldioxa; Benzoyl Perox Hydroxyprogesterone Caproate; Levonorgestrel; ide; Dibenzothiophene; Etarotene; Isotretinoin; Motre LyneStrenol; Medrogestone; Medroxyprogesteone tinide; Picotrin Diolamine; Resorcinol; Resorcinol Acetate; Methynodiol Diacelate; Norethindrone; Nore Monoacetate, Salicylic Acid, Sumaroteine, Tazaroteine; thindrone Acetate, Norethynodrel; Norgestimate; Tetroquinone; Tretinoin. Norgestomet, Norgestrel, Oxogestone Phenpropionate; Progesterone, Quingestanol Acetate; Quingestrone; 0234. LHRH agonist: Deslorelin; Goserelin; Histrelin; Tigestol. Lutrelin Acetate, Nafarelin Acetate. 0256 Prostaglandin: Cloprostenol Sodium; Flupros 0235 Liver disorder treatment: Malotilate. tenol Sodium; Gemeprost; Prostalene; Sulprostone. 0236 Luteolysin: Fenprostalene. 0257 Prostate growth inhibitor: Pentomone. 0237 Memory adjuvant: Dimoxamine Hydrochloride; 0258 Prothyrotropin: Protirelin. Ribaminol. 0259 Psychotropic: Minaprine. 0238 Mental performance enhancer: Aniracetam. 0260 Pulmonary Surface: Beractant; Colfosceril 0239 Mood regulator: Fengabine. Palmitate. 0240 Mucolytic: Acetylcysteine; Carbocysteine; 0261 Radioactive agent: Fibrinogen 1125; Fludeoxy Domiodol. glucose F 18; Fluorodopa F 18; Insulin I 125; Insulin I 131; Iobenguane I 123; Iodipamide Sodium I 131; 0241 Mucosal Protective agents: Misoprostol (Cyto Iodoantipyrine I 131; Iodocholesterol I 131; Iodohip tec). purate Sodium I 123; Iodohippurate Sodium I 125; 0242) Mydriatic: Berefrine. Iodohippurate Sodium I 131; Iodopyracet I 125; US 2003/0059471 A1 Mar. 27, 2003 22

Iodopyracet I 131; Iofetamine Hydrochloride I 123; Secobarbital Sodium; Suproclone; Thalidomide; Tra Iomethin I 125; Iomethin I 131; Iothalamate Sodium I caZolate; Trepipam Maleate; Triazolam; Tricetamide; 125; Iothalamate Sodium I 131; Iotyrosine 1 131; Triclofos Sodium; Trimetozine; Uldazepam; Zaleplon; Liothyronine I 125; Liothyronine I 131; Merisoprol Zolazepam Hydrochloride; Zolpidem Tartrate. Acetate Hg 197; Merisoprol Acetate Hg 203; Meriso prol Hg 197; Selenomethionine Se 75; Technetium Tc 0269. Selective adenosine Al antagonist: Apixifylline. 99 m Antimony Trisulfide Colloid; Technetium Tc 99 m 0270 Serotonin antagonist: Altanserin Tartrate; Bicisate; Technetium Tc 99 m Disofenin; Technetium AmeSergide, Ketanserin; Ritanserin. Tc 99 m Etidronate; Technetium Tc 99 m. Exametazime; Technetium Tc 99 m Furifosmin, Technetium Tc 99 m 0271 Serotonin inhibitor: Cinanserin Hydrochloride; Gluceptate; Technetium Tc 99 m Lidofenin; Techne Fenclonine; Fonazine Mesylate; Xylamidine Tosylate. tium Tc 99 m Mebrofenin; Technetium Tc 99 m Medr 0272 Serotonin receptor antagonist: Tropanserin onate; Technetium Tc 99 m Medronate Disodium; Hydrochloride. Technetium Tc 99 m Mertiatide; Technetium Tc 99 m Oxidronate; Technetium Tc 99 m Pentetate; Techne 0273 Steroid: Dexamethasone Acefurate; Mometa tium Tc 99 m Pentetate Calcium Trisodium; Techne Sone Furoate. tium Tc 99 m Sestamibi; Technetium Tc 99 m 0274 Stimulant: Amfonelic Acid; Amphetamine Sul Siboroxime; Technetium Tc 99 m Succimer; Techne fate; Ampyzine Sulfate; Arbutamine Hydrochloride; tium Tc 99 m Sulfur Colloid; Technetium Tc 99 m Azabon; Caffeine; Ceruletide; Ceruletide Diethy Teboroxime; Technetium Tc 99 m Tetrofosmin, Tech lamine; Cisapride; DaZopride Fumarate; Dextroam netium Tc 99 m. Tiatide; Thyroxine 1125; Thyroxine 1 phetamine; Dextroamphetamine Sulfate; Difluanine 131; Tolpovidone 1131; Triolein 1125; Triolein 1131. Hydrochloride; Dimefline Hydrochloride; Doxapram 0262 Regulator: Calcifediol; Calcitonin; Calcitriol; Hydrochloride; Etryptamine Acetate; Ethamivan; Fen Clodronic Acid; Dihydrotachysterol, Etidronic Acid; ethylline Hydrochloride; Flubanilate Hydrochloride; Oxidronic Acid, Piridironate Sodium; Risedronate Flurothyl; Histamine Phosphate; Indriline Hydrochlo Sodium; Secalciferol. ride; Mefexamide; Methamphetamine Hydrochloride; Methylphenidate Hydrochloride; Pemoline; Pyrovale 0263. Relaxant: Adipheinine Hydrochloride; Aleuro nium Chloride; Aminophylline, AZumolene Sodium; rone Hydrochloride; Xamoterol; Xamoterol Fumarate. Baclofen; Benzoctamine Hydrochloride; Carisoprodol; 0275 Suppressant: Amflutizole; Colchicine; Chlorphenesin Carbamate; ChlorZoxazone; Cinflu Tazofelone. mide, Cinnamedrine; Clodanolene, Cyclobenzaprine Hydrochloride; Dantrolene; Dantrolene Sodium; 0276 Symptomatic multiple Sclerosis: Fampridine. Fenalamide; Fenyripol Hydrochloride; Fetoxylate 0277 Synergist: Proadifen Hydrochloride. Hydrochloride; Flavoxate Hydrochloride; Fletazepam; Flumetramide; Flurazepam Hydrochloride; Hexafluo 0278 Thyroid hormone: Levothyroxine Sodium; Lio renium Bromide; Isomylamine Hydrochloride; Lor thyronine Sodium; Liotrix. bamate; Mebeverine Hydrochloride; Mesuprine 0279) Thyroid inhibitor: Methimazole; Propylthiou Hydrochloride; Metaxalone; Methocarbamol; Methix ene Hydrochloride; Nafomine Malate; NeleZaprine racil. Maleate; Papaverine Hydrochloride; Pipoxolan Hydro 0280 Thyromimetic: Thyromedan Hydrochloride. chloride; Quinctolate; Ritodrine; Ritodrine Hydrochlo ride; Rolodine; Theophylline Sodium Glycinate; 0281 Tranquilizer: Bromazepam; Buspirone Hydro chloride; Chlordiazepoxide; Clazolam; Clobazam; Clo Thiphenamil Hydrochloride; Xilobam. razepate Dipotassium; CloraZepate Monopotassium; 0264 Repartitioning agent: Cimaterol. Demoxepam, DeXmedetomidine, Enciprazine Hydro chloride; Gepirone Hydrochloride; Hydroxyphe 0265 Scabicide: Amitraz, Crotamiton. namate; Hydroxyzine Hydrochloride; Hydroxyzine 0266 Sclerosing agent: Ethanolamine Oleate; Mor Pamoate; Ketazolam; Lorazepam, LorZafone, Loxap rhuate Sodium; Tribenoside. ine, Loxapine Succinate; Medazepam Hydrochloride; Nabilone; Nisobamate; Oxazepam; Pentabamate; 0267 Sedative: Propiomazine. Pirenperone, Ripazepam, Rolipram; Sulazepam, 0268 Sedative-hypnotic: Allobarbital; Alonimid; Taciamine Hydrochloride; Temazepam; Triflubazam; Alprazolam; Amobarbital Sodium; Bentazepam; Bro Tybamate; Valnoctamide. tizolam; Butabarbital; Butabarbital Sodium; Butalbital; Capuride; Carbocloral; Chloral Betaine; Chloral 0282 Amyotrophic lateral sclerosis agents: Riluzole. Hydrate; Chlordiazepoxide Hydrochloride; Cloperi 0283 Cerebral ischemia agents: Dextrorphan Hydro done Hydrochloride; Clorethate; Cyprazepam; Dex chloride. clamol Hydrochloride; Diazepam; Dichloral phenaZone; Estazolam; EthehlorVynol, Etomidate; 0284 Paget’s disease agents: Tiluldronate Disodium. Fenobam, Flunitrazepam, FoSazepam, Glutethimide; Halazepam, Lorimetazepam, Mecloqualone; Mep 0285 Unstable angina agents: Tirofiban Hydrochlo robamate; Methaqualone; Midaflur; Paraldehyde; Pen ride. tobarbital; Pentobarbital Sodium; Perlapine; Prazepam; 0286 Uricosuric: Benzbromarone; Irtemazole; Quazepam, Reclazepam, Roletamicide; Secobarbital; Probenecid; Sulfinpyrazone. US 2003/0059471 A1 Mar. 27, 2003 23

0287 Vasoconstrictor: Angiotensin Amide; Fely floxacin, balsalazide, bambuterol, baohuoside 1, barni pressin; MethySergide, MethySergide Maleate. dipine, basifungin; batebulast, batimastat; beauvericin; 0288 Vasodilator: Alprostadil; AZaclorzine Hydro becaplermin; becliconazole, befloxatone; belfoSdil; chloride; Bamethan Sulfate; Bepridil Hydrochloride; bellenamine; benflumetol; benidipine; benzisoxazole; Buterizine; Cetiedil Citrate; Chromonar Hydrochlo benzochlorins; benzoidaZOXan; benzoylstaurosporine; ride; Clonitrate; Diltiazem Hydrochloride; Dipy benztropine, bepridil, beractant, beraprost, ber ridamole; Droprenilamine; Erythrityl Tetranitrate; lafenone; bertosamil, besipirdine, beta-alethine; Felodipine; Flunarizine Hydrochloride; Fostedil; Hex betaclamycin B; betamipron; betaxolol, betulinic acid; obendine; Inositol Niacinate; Iproxamine Hydrochlo bevantolol, bicalutamide; bifemelane; bimakalim; ride; Isosorbide Dinitrate; Isosorbide Mononitrate; bimithil, binoSpirone, bioxalomycin alpha2, biriper IsoxSuprine Hydrochloride; Lidoflazine; Mefenidil; one; bis-benzimidazole A, bis-benzimidazole B; bisant Mefenidil Fumarate; Mibefradil Dihydrochloridc; rene, bisaramil, bisaziridinylspermine; bisnafide; biso Mioflazine Hydrochloride; Mixidine; Nafronyl prolol; bistramide D; bistramide K; bistratene A; Oxalate; Nicardipine Hydrochloride; Nicergoline; Nic boldine; bopindolol; brefeldin; breflate; brimonidine; orandil; Nicotinyl Alcohol; Nifedipine; Nimodipine; bromfenac, bromperidol; bropirimine; bucindolol, Nisoldipine; Oxfenicine; Oxprenolol Hydrochloride; budeSonide; budipine; budotitane; bunaprolast; Pentaerythritol Tetranitrate; Pentoxifylline; Pentrini bunaZosin; butenafine, buthionine Sulfoximine, butiXo trol; Perhexiline Maleate; Pindolol, Pirsidomine, Pre cort propionate; cadeXomer iodine, calanolide A, cal nylamine; Propatyl Nitrate; Suloctidil; Terodiline cipotriol, callphostin C, camonagrel, candesartan; can Hydrochloride; Tipropidil Hydrochloride; Tolazoline desartan cileXetil, candoxatril; candoxatrilat, Hydrochloride; Xanthinol Niacinate. capecitabine; capromab, capsaicin; captopril; carbazo mycin C; carbetocin, carbovir, carboxamide-amino 0289 Vulnerary: Allantoin. triazole; carboxyamidotriazole; carboxymethylated 0290 Wound healing agent: Ersofermin. beta-1,3-glucan, carperitide; carteolol, caurumonam, carvedilol, carvotroline, carZelesin; castanospermine; 0291 Xanthine oxidase inhibitor: Allopurinol; Oxypu cebaracetam; cecropin B; cefcapene pivoxil, cefdal rinol Oxime penteXil tosilate, cefdinir, cefditoren pivoxil, 0292. Other pharmaceutical agents include: 1-decpyr cefepime, cefetamet, cefetamet pivoxil, cefixime, cef rolidinone, 1-dodecpyrrolidinone; 16-alpha fluoroc luprenam, cefimetazole, cefminlox, cefodizime, cefoS Stradiol; 16-epieStriol; 16alpha-gitoxin; 17alpha estra elis, cefotetan, cefotiam, cefotiam heXetil, cefoZopran; diol; 17beta estradiol; 1alpha-hydroxyvitamin D2; cefpimizole, cefpiramide, cefpirome, cefpodoxime 2'-nor-cGMP; 20-epi-1.25 dihydroxyvitamin D3; proxetil, cefprozil, cefSulodin, cefteram, ceftibuten; 22-oxacalcitriol; 2CVV;3-isobutyl GABA; 6-FUDCA; ceftriaxone, cefuroxime axetil, celastrol, celikalim, 7-methoxytacrine; abamectin; abanoquil, abecarnil; celiprolol, cepacidine A, cericlamine; cerivastatin; abiraterone, acadesine; acamproSate; acarbose, ace ceronapril; certoparin Sodium, cetiedil, cetirizine, chlo clofenae; acemannan; acetomepregenol; acetyl-L-car roorienticin A, chloroorienticin B; chloroquinoxaline nitine, acetylcysteine, N-, acetylmethadol; acifran; Sulfonamide, cibenzoline, cicaprost, ciclesonide; acipimoX, acitemate; acitretin, aclarubicin, aclatonium; cicletanine, cicloprolol, cidofovir, cilansetron; cilaza napadisilate; aconiazide, acrivastinet; adafenoxate, pril; cilnidipine; cilobradine, ciloStaZol, cimetropium adapalene; adatanserin; adecypenol; adefovir dipivoxil, bromide, cinitapride, cinolazepam, cioteronel, ciprofi adelmidrol; ademetionine, adinazolam, adiposin; ado brate; ciprofloxacin; ciprostene, cis-porphyrin, Zelesin; adrafinil; alacepril; aladapcin; alaptide; cisapride, cisatracurium besilate, cistinexine, citalo albendazole, albolabrin; aldecalmycin; aldesleukin; pram; citicoline, citreamicin alpha, cladribine; alendronic acid; alentemol; alfacalcidol, alfuZosin; clarithromycin, clausenamide; clebopride; clinafloxa alglucerase, alinastine, aloSetron; alpha idoSone; cin; clobaZam; clobetaSone butyrate; clodronic acid; alproStadil; altretamine; altromycin B, ambamustine; clomethiazole; clopidogrel, clotrimazole; colestimide; amelometasone; ameSergide, ameZinium metilsulfate; colfoSceril palmitate, collismycin A, collismycin B; amfebutamone, amidox, amifloxacin; amifostine; combretastatin A4, complestatin; conagenin, contign amiodarone; amisulpride; amlexanoX, amlodipine; asterol, contortrostatin; coSalane, costatolide, cotinine; amlodipine, ampiroXicam, amrinone; amrubicin; amsa coumermycin A1, cucumariosid; curacin A; curdlan crine; amylin; amythiamicin; anagrelide, anakinra, Sulfate; curiosin; cyclazosin; cyclic HPMPC; cycloben ananain; anaritide; anastrozole; andrograpliolide; anor Zaprine, cyclobut A, cyclobut G., cyclocapron; cyclo drin; apadoline; apafant; apaxifylline, aphidicolin gly platam, cyclosin; cyclothialidine, cyclothiazomycin; cinate, apraclonidine, aproSulate Sodium; aptiganel; cypemycin; cyproterone, cytarabine ocfosfate; apurinic acid, aranidipine, arbekicin; arbidol; airb cytochalasin B, dacliximab, dactimicin; daidZein; daid utamine, ardeparin, Sodium, arecatannin B1; arga Zin; dalfopristin; dalteparin Sodium; danaparoid; daphl troban; aripiprazol; arotinolol, asimadoline; aspala nodorin A; dapiprazole, dapitant; darifenacin; darlucin tone; asperfuran, aspoxicillin; astemizole, asulacrine; A; darsidomine; did UTP, decitabine; deferiprone; atameStane, atenolol, S-; ate Virdine, atosiban; atova deflazacort, dehydrodidemnin B, dehydroepiandroster quone; atpenin B; atrimustine; atrinositol; aureobasidin one; delapril, deleguamine, delfaprazine; delmopinol, A. azadirachtine, azasetron; azatyrosine; azelaic acid; delphinidin; deoxypyridinoline, deprodone; depSido aZelastine; azelnidipine, azimilide, azithromycin; mycin; deramciclane, dermatan Sulfate; desflurane; aZOSemide, aztreonam, baccatin III; bacoside A, baco desirudin; deslorelin; desmopressin, desogeStrel; des Side B; bactobolamine, balaZipone; balhimycin;... balo OXoamiodarone; detajmium bitartrate; dexifosfamide; US 2003/0059471 A1 Mar. 27, 2003 24

deXketoprofen; dexloxiglumide; dexmedetomidine, interferon omega; interferon, consensus, interleukin-1, deXpemedolac, deXraZOxane, deXSotalol, dextrin 2-sul interleukin-1 alpha; interleukin-1beta; interleukin-10; phate, deXVerapamil, dezinamide, dezocine, diazi interleukin-11; interleukin-12, interleukin-12, interleu quone, diclofenac digolil; diclofenac potassium, dicra kin- 15; interleukin-2, interleukin-3, interleukin-4, nin; didemnin B; didox; dienogest; interleukin-5; interleukin-7; interleukin-8; iobenguane; diethylhomospermine; diethylnorspermine, dihydrexi iobitridol; iodoamiloride; iododoxorubicin; iofratol; dine, dihydro-5-azacytidine, dimethyl prostaglandin iomeprol; iopentol; iopromide; iopyrol; iotriside; iover A1; dimethylhomospermine; dimiracetam; dioxamy Sol; ioxilan; ipazilide, IpdR; ipenoxazone, ipidacrine; cin; dipliency prone; diphenyl Spiromustine; ipomeanol, 4-, ipriflavone, ipsapirone, irbesartan; diprafenone; dipropylnorspermine, dirithromycin; dis irinotecan, irloxacin; irSogladine, irtemazole; isal codermolide; disulfiram; ditekiren, docarpamine; Steine, isbogrel, isepamicin; isobengaZole; isoflox docosanol, 1-, dolfetilide; dolasetron; domitroban; ythepin; isohomohalicondrin B; isopropyl unopros dopexamine; dorZolamide; doSmalfate; dotarizine; tone, isradipine; itameline; itasetron; itopride; doxacurium chloride, doxazosin, doxifluridine, dox itraconazole, ketoprofen, R-, ketoprofen, S-, ketorolac, ofylline, draculin; draflazine, droloxifene, dronabinol, lacidipine, lactitol; lactivicin; laennec, lafutidine, drosperidone, drotaverine acephyllinate; droxicam, lamellarin-N triacetate, lamifiban, lamivudine, lamot ebiratide; ebrotidine, ebSelen, ecabapide, ecabet, eca rigine; lanoconazole, lanperisone; lanreotide; lanSopra dotril, ecdisteron; echicetin; echistatin, ecomustine; Zole; latanoprost; lateritin; laurocapram; lazabemide; ecteinascidin 722, ecteinascidin 729; ecteinascidin 743; Iemefloxacin; lemildipine; leminoprazole; lenercept; edaravone, edelfosine, edobacomab, edrecolomab, efe lenograstim; lentinian Sulfate, leptin, leptolstatin; ler gatran; eflornithine; efonidipine, egualcen; eleatonin; canidipine; lerisetron, IeSopitron; letraZuril; letrozole; eletriptan; elgodipine, eliprodil, eltenae, emalkalim, leucomyzin; leuprorelin; leveromakalim, levetirac emedastine, emiglitate, emitefur; emoctakin; enadoline etam; leVobetaxolol, levobunolol, levobupivacaine; hydrochloride; enalapril; enazadrem, englitaZone, enli levocabastine; levocarnitine, leVodropropizine, leVof momab, enoxacin; enoxaparin Sodium; enoXimone; loxacin; levomoprolol, levonorgestrel; levormelox entacapone, enterostatin; epoprostenol; ifene; levosimendan; levOSulpiride; linotroban; linsi epoxymeXrenone, epristeride, eprosartan; eptastig domine; lintitript; lintopride; liothyronine Sodium; mine; erdosteine, erSentilide, erSofermin; erythritol; lirexapride; lisinopril; lobaplatin; lobucavir, lodoxam eSuprone; etanidazole; etanterol, ethacizin; ethi ide, lombricine, lomefloxacin, lomerizine, lometrexol; nyleStradiol, etizolam, etodolac, etoposide phosphate; lonazolac, lonidamine; loracarbef, loratadine, lorglu etrabamine; eveninomicin; examorelin; exemestane; mide, lornoxicam, loSartan; losigamone, loSOXantrone; fadrozole, faerieflungin; famciclovir, fampridine, fanto loteprednol; loviride; loxoribine; lubeluzole; lurtote farone, faropenem; fasidotril; fasudil; fazarabine; can; luteinizing hormone; lutetium, luZindole, lydica fedotozine; felbamate; fenofibrate; fenoldopam; fenre mycin; lySofylline; lysostaphin, magainin 2 amide; tinide, fenspiride; fenticonazole; fepradinol, ferpifoSate magnolol; mallotochromene; mallotojaponin; maloti Sodium; ferristene; ferriXan; ferumoxSil; feXofenadine, late; mangafodipir; manidipine, maniwamycin A, man flavopiridol; flecainide; flerobuterol; fleroxacin; flesi nostatin A, manumycin E, manumycin F; mapinastine; noxan; flezelastine; flobufen, flomoxef; florfenicol; flo marimastat; Martek 8708; Martek 92211; masoprocol; rifenine; floSatidil; fluiasterone; fluconazole; fludara maspin; massetolide, meterelin; methoxatone; methyl bine; flumazenil; flumecinol; flumequine; flunarizine; histamine, R-alpha; methylinosine monophosphate, fluocalcitriol; fluorodaunorunicin hydrochloride; fluox methylprednisolone aceponate; methylprednisolone etine, R-; fluoxetine, S-; fluparoxan, flupirtine, flurbi Suleptanate, metipamide, metoclopramide; metoprolol, profen axetil, flurithromycin; fluticasone propionate; S-; metrifonate; mibefradil; michellamine B; micro flutrimazole; fluvastatin; fluvoxamine; forasartan; for colin A, midodrine, mifepristone, miglitol; millace fenirmex, formeStane; formoterol; formoterol, R,R-; mide; milameline; mildronate; milnacipran; milrinone; fosfomycin; trometamol; fosinopril; fosphenytoin; fos miltefosine, minaprine, miokamycin, mipragoside; triecin, fotemustine, gabapentin; gadobenic acid; mirfentanil; mirimoStim, mirtazapine, misoprostol; gadobutrol; gadodiamide; gadodiamide-EOB-DTPA; mitoguaZone, mitolactol, mitonafide, mitoxantrone; gadolinium teXaphyrin, gadoteric acid, gadoteridol; mivacurium chloride; mivaZerol, mixanpril, mizolas gadoverSetamide; galantamine; galdansetron; gallo tine, mizoribine; moclobemide; modafinil; moexipril; pamil, galocitabine, gamolenic acid, ganirelix; mofaroteine; mofeZolac, molgramoStim; mometasone; gepirone; gestrinone; girisopam, glaspimod; glaucoca montirelin; mopidamol, moracizine; mosapramine; lyxin A, glutapyrone; glycopine, glycopril; granisetron; moSapride; motilide; moxiraprine; moXonidine; nadi grepafloxacin; halichondrin B; halofantrine; halomon; floxacin; nadroparin calcium, nafadotride, nafamoStat; halopredone; hatomamicin; hatomarubigin A, nafarelin; naftopidil, naglivan, nagreStip; nalmefene, hatomarubigin B; hatomarubigin C; hatomarubigin D; naphterpin, napSagatran; naratriptan; nartograstim; ibogaine, ibopamine, ibudilast, illimaquinone, ilmofoS nasaruplase, nateplase, niperotidine, niravoline, nisa ine, illomastat, illoperidone, iloprost, imidapril, imida mycin; nisin; nisoldipine, nitaZOXanide, nitecapone; Zenil; indinavir; indolidan; indometacin farnesil; nitrendipine, nitrendipine, S-, nitrofurantoin monohy indometacin; tropine ester; indoramin; inocoterone; drate, nitrullyn; nizatidine, ofloxacin; Okicenone, olan inogatran; inolimomab, interferon alfa, interferon alfa Zapine, olopatadine, olprinone; Olsalazine, omeprazole; 2a; interferon alfa-2b; interferon alfa-N1; interferon onapristone, Ondansetron, Ondansetron, R-, Ontazolast; alfa-n3; interferon beta; interferon beta-1a1; interferon oracin; otenZepad; Oxaliplatin, oxamisole, OXan beta-1b, interferon gamma-1a; interferon gamma-1b; drolone, Oxaprozin, oxaunomycin; oXcarbazepine; oxi US 2003/0059471 A1 Mar. 27, 2003 25

conazole, OXiracetam; OXOdipine; OZagrel, palauamine; acid; tinzaparin Sodium, tiotropium bromide; tipredane; palinavir, palmitoylrhizoxin; pamaqueside, pam tiqueside; tirandalydigin; tirapazamine; tirilaZad; icogrel, pamidronic acid, panamesine; panaxytriol, tirofiban; tiropramide, topSentin; toraSemide; panipenem, panipenum; pannorin, panomifene, pan toremifene, toSufloxacin; trafermin; trandolapril; traX tethine; pantoprazole; parabactin; parnaparin Sodium; anox, tretinoin, tretinoin tocoferil, triacetyluridine, tri paroxetine; parthenolide, paZelliptine; paZufloxacin; caprilin; trichohyalin; trichosanthin, alpha; triciribine; pefloxacin, pegaspargase; peldesine, pemedolac, trientine, triflavin; trimegestone; triptorelin; troglita pemirolast, penciclovir; pentafuside, pentamidine, pen Zone; trombodipine, tropisetron; trospectomycin; tro tamorphone; pentigetide; pentosan, pentostatin; pentro vafloxacin; troVirdine; tucarcSol; tulobuterol; tyloge Zole, perflubron; perfofamide; pergolide, perindoprilat, nin; urapidil, uridine triphosphate, Valaciclovir, peroSpirone; phenaridine, phenazinomycin; Valproate magnesium, Valproate Semisodium; Valsar tan; vamicamide, Vanadeine; Vaninolol, Vapreotide; phenserine; phensuccinal; phentolamine mesilate; phe Variolin B; VelareSol, Venlafaxine, Veramine; Vera nylacetate; phenylalanyl ketoconazole, picenadol; pamil, (S); Verdins, Veroxan; verteporfin, Vesnarinone; picibanil; picroliv, picumeterol, pidotimod, pilocarpine Vexibinol; vigabatrin; Vinburnine citrate; Vinburnine hydrochloride; pilsicainide; pimagedine, pimilprost, resinate; Vinconate; Vinorelbine; Vinpocetine, Vinpocet pimobendan; pinacidil; pinocebrin; pioglitaZone; pipe ine citrate; Vintoperol, VinXaltine, Voriconazole; Voro curonium bromide, pirarubicin; piretanide, pirfeni Zole, VOXergolide; Xemilofiban, Ximoprofen; yan done, piritrexim; pirlindole, pirmagrel, pinnenol; piro gamblin, Zabicipril; Zacopride; Zacopride, R-, davir, pirodomast; piroXicam cinnamate; Zafirlukast; Zalcitabine; Zaleplon; ZaloSpirone; Zalto propagermanium; propentofylline; propionylcarnitine, profen, Zanamivir, Zankiren, Zanoterone; Zatebradine, L-, propiram; propiram-paracetamol, propiverine, pro Zatosetron; Zenarestat; Zeniplatin, Zifrosilone; Zilas pyl bis-acridone; prostaglandin J2, prostratin; prote corb, Zileuton; Zinostatin stimalamer, Ziprasidone; grin, protoSufloxacin; prulifloxacin; pyrazoloacridine, Zoledronie acid; Zolmitriptan; Zolpidem; Zonisamide; quaZepam, quetiapine, quiflapon; quinagolide; Zopiclone; Zopiclone, S-, Zopolrestat; Zotepine. quinapril; quinfamide, quinupristin, raloxifene, raltitr exed; ramatroban; ramipril; ramosetron; ranelic acid; 0293 Also included are commonly used geriatric drugs, ranitidine bismuth citrate, ranolazine, recainam, Such as FuroSemide, Lanoxin, Potassium Chloride, Depa regaVirumab, relaxin, repirinast; resinferatoxin; reticu kote, Trazodone-HCL, Zantac, Dilantin, Zobolt, Risperdal, lon; reviparin Sodium; revizinone, ricasetron; ridogrel, PriloSec, Folic Acid, Halperidol, AXid, Carbamazepine, rifabutin; rifapentine; rifaximin, rilopirox, riluzole; Metoprolol Tartrate, Prinivil, Coumadin, Tegretol, Propul rimantadine, rimeXolone, rimoprogin, riodipine, rip sid, Hydrochlorothiazide, Digoxin, Nitroglycerin, Methyl isartan; risedronic acid; rispenzepine, risperidone; dopa, PraZosin, Oral Hypoglycemics. ritainserin; ritipenem; ritipenem acoxil, ritolukast, 0294 Particularly important agents are: amantadine ritonavir, rizatriptan benzoate; rohitukine, rokitamycin; hydrochloride, hyoscyamine Sulfate, fluoxetine and traZ ropinirole; ropivacaine, roquinimex, roXaitidine, roX odone hydrochloride for neurological disorders, nifidipine, indole, roXithromycin, rubiginone B1; ruboxyl, diltiazem, phenotoxifyline for cardiovascular disease, keto rufloxacin, rupatidine, ruzadolane, Safingol, Safironil; profen, aspirin, piroXicam, indomethacin, ibuprofen for artl Saintopin; Salbutamol, R-; Salmeterol, Salmeterol, ritis, omeprazole for ulcers, and isotretinoin for cancer. R-Salnacedin, Sameridine, Sampatrilat, Sanfetrinem; Saprisartan; Sapropterin; Saquinavir, SarCNU, Sarco 0295) The agent may be a sunscreen agent. Examples of phytol A SargramoStim; Sarpogrelate, Saruplase; Sunscreen agents include: p-aminobenzoate analogS Such as Saterinone; Satigrel, Satumomab pendetide; Selegiline; 2-ethylhexyl-4-dimethylaminobenzoate (Padimate O); Selenium thiosemicarbazone, Sematilide, Semdurami p-methoxy-2-ethyl-hexyl-cinnamate (Parsol 1789); oxyben cin; Semotiadil; Semustine, Sermorelin; Sertaconazole; Zone (benzophenone-3); ethylhexylsalicylate; diphenylacry Sertindole, Sertraline, Setiptiline, Sevirumab, Sevoflu late polyisobutylene, alkyl-B, B-diphenylacrylate and C-cy rane, SeZolamide, Silipide; Silteplase; Simendan; Simv ano-B, B-diphenylacrylate; 1-(4-aminophenyl)-2- astatin; Sinitrodil, Sinnabidol, Sipatrigine, Sirolimus, morpholinylethanone; (1-(4-methoxylphenyl)-3-(4-tert sizofiran; Somatomedin B, Somatomedin C; Somatrem; butyl-phenyl)-propan-1-3-dione; methyl anthranilate; Somatropin; Sonermin; Sotalol, StauroSporine, Stavu octocrylene; Tretinoin C-hydroxyacid; diphenylacrylate dine, Stepronin; Stipiamide, Stiripentol; Stobadine, Suc polyisobutylene, 1-(4-aminophenyl)-2-morpholinyletha cibun; Sucralfate, SulfaSalazine, Sulfinosine, Sulfoxam none; diphenylacrylate polyisobutylene, digalloyl trioleate; ine, Sulopenem; Sultamicillin; Sultopride, Sulukast, glyceryl p-aminobenzoate, 4-(omega-dialkylaminoalkox Sumatriptan; Symakalim, tandoSpirone; tapgen; tapros y)phenylmethylene)-1,3,3 -trimethyl-2- tene; tasOSartan; taZanolast, tazaroteine, teicoplanin; oXabicyclo(2.2.2)octan-6-ones, 5-(arylmethylene)-1,3,3-tri telenzepine, tellurapyrylium; telmesteine, telmisartan; methyl-2-oxabicyclo(2.2.2)Octan-6-ones; melanin. temocapril; temoporfin, temozolomide, tenidap; teni 0296. The agent also can be insect repellants. A widely poside; tenoSal; tenoxicam, tepirindole; tepoxalin; tera used insect repellant is N-N-diethyl-3-methylbenzamide. ZoSin; terbinafine; terfenadine, terflavoxate, terguride; terlakiren, terlipressin, terodiline, tertatolol, testoster 0297. The agent also may be cultured cells, lyophillized one buciclate, tetrachlorodecaoxide, tetraZomine; thali and captured within the matrix of the flake. Such cells can blastine; thalidomide; thiocoraline; thiofedrine; thiom be recombinant cells engineered to produce desirable thera arinol; thioperamide; thyroid stimulating hormone; peutic products. tiagabine; tianeptine, tiapafant; tibolone, ticlopidine, 0298 Imaging agents are agents capable of imaging a tienoXolol, tilisolol, tilnoprofen arbamel; tiludronic desired Site, e.g. tumor, in Vivo. Examples of imaging agents US 2003/0059471 A1 Mar. 27, 2003 26 include Substances having a label which is detectable in Stabilizers, preservatives, flavorings and pigments. In Some Vivo, e.g. antibodies attached to fluorescent labels. The term embodiments, the compositions of the present invention also antibody includes whole antibodies or fragments thereof. contain a binder Such as lecithin which “binds” the other 0299 Specific targeting agents include agents capable of ingredients, thereby enhancing the uniform consistency of delivering a therapeutic agent to a desired Site, e.g. tumor, the final composition. and providing a therapeutic effect. Examples of targeting 0305 When administered as flakes containing drugs, the agents include agents which can carry toxins or other agents formulations of the invention are applied in pharmaceuti which provide beneficial effects. The targeting agents can be cally acceptable amounts and in pharmaceutically accept an antibody linked to a toxin, e.g. ricin A or an antibody able compositions. Such preparations may routinely contain linked to a drug. Salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic ingredients. When used in 0300 Neurotransmitters are substances which are medicine the Salts should be pharmaceutically acceptable, released from a neuron on excitation and travel to either but non-pharmaceutically acceptable Salts may conveniently inhibit or excite a target cell. Examples of neurotransmitters be used to prepare pharmaceutically acceptable Salts thereof include dopamine, Serotonin, q-aminobutyric acid, norepi and are not excluded from the Scope of the invention. Such nephrine, histamine, acetylcholine, and epinephrine. pharmacologically and pharmaceutically acceptable Salts 0301 Cell response modifiers are chemotactic factors include, but are not limited to, those prepared from the such as platelet-derived growth factor (PDGF). Other following acids: hydrochloric, hydrobromic, Sulphuric, chemotactic factors include neutrophil-activating protein, nitric, phosphoric, maleic, acetic, Salicylic, p-toluene Sul monocyte chemoattractant protein, macrophage-inflamma fonic, tartaric, citric, methane Sulfonic, formic, malonic, tory protein, platelet factor, platelet basic protein, and mela Succinic, naphthalene-2-Sulfonic, and benzene Sulfonic. noma growth Stimulating activity; epidermal growth factor, Also, pharmaceutically acceptable Salts can be prepared as transforming growth factor (alpha), fibroblast growth factor, alkaline metal or alkaline earth Salts, Such as Sodium, platelet-derived endothelial cell growth factor, insulin-like potassium or calcium Salts. growth factor, nerve growth factor, and bone growth/carti 0306 Suitable buffering agents include: acetic acid and a lage-inducing factor (alpha and beta), or other bone mor salt (1-2% W/V); citric acid and a salt (1-3% W/V); and phogenetic protein. phosphoric acid and a salt (0.8-2% W/V). 0302). Other cell response modifiers are the interleukins, 0307 Suitable preservatives include benzalkonium chlo interleukin inhibitors or interleukin receptors, including ride (0.003-0.03% W/V); chlorobutanol (0.3-0.9% W/V); interleukin 1 through interleukin 10; interferons, including parabens (0.01-0.25% W/V) and thimerosal (0.004-0.02% alpha, beta and gamma; hematopoietic factors, including W/V). erythropoietin, granulocyte colony Stimulating factor, mac 0308 The active compounds of the present invention rophage colony Stimulating factor and granulocyte-mac may be a pharmaceutical composition having a therapeuti rophage colony Stimulating factor; tumor necrosis factors, cally effective amount optionally included in a pharmaceu including alpha and beta; transforming growth factors tically-acceptable carrier. The term "pharmaceutically-ac (beta), including beta-1, beta-2, beta-3, inhibin, and activin; ceptable carrier as used herein means one or more and bone morphogenetic proteins. compatible Solid or liquid-filler, dilutants or encapsulating 0303 Antioxidants are substances which inhibit oxida Substances which are Suitable for administration to a human tion or SuppreSS reactions promoted by oxygen or peroxides. or other animal. The term “carrier denotes an organic or Antioxidants, especially lipid-Soluble antioxidants, can be inorganic ingredient, natural or Synthetic, with which the absorbed into the cellular membrane to neutralize oxygen active ingredient is combined to facilitate the application. radicals and thereby protect the membrane. The antioxidants The components of the pharmaceutical compositions are useful in the present invention may be Selected from the capable of being commingled with the flakes of the present group consisting of all forms of Vitamin A including retinal invention, and with each other, in a manner Such that there and 3,4-didehydroretinal, all forms of caroteine Such as is no interaction which would Substantially impair the Alpha-caroteine, beta-caroteine (beta, beta-carotene), desired pharmaceutical efficacy. gamma-carotene, delta-caroteine, all forms of Vitamin C 0309 Compositions suitable for parenteral administra (D-ascorbic acid, L-aseorbic acid), all forms of tocopherol tion conveniently comprise a Sterile preparation. This prepa such as Vitamin E (Alpha-tocopherol, 3,4-dihydro-2,5,7,8- ration may be formulated according to known methods. The tetramethyl-2-(4,8,12-trimethyltri-decyl)-2H-1-benzopyran Sterile preparation thus may be a Sterile Solution or Suspen 6-ol), beta-tocopherol, gamma-tocopherol, delta-tocopherol, Sion in a non-toxic parenterally-acceptable diluent or Sol tocoquinone, tocotrienol, and Vitamin E esters which readily vent. In addition, Sterile, fixed oils are conventionally undergo hydrolysis to Vitamin E Such as Vitamin E acetate employed as a Solvent or Suspending medium. For this and Vitamin E Succinate, and pharmaceutically acceptable purpose any bland fixed oil may be employed including Vitamin E Salts Such as Vitamin E phosphate, prodrugs of Synthetic mono or di-glycerides. In addition, fatty acids Such Vitamin A, carotene, Vitamin C, and Vitamin E, pharma as oleic acid find use in the preparation of injectables. ceutically acceptable Salts of Vitamin A, carotene, Vitamin Carrier formulations Suitable for oral, Subcutaneous, intra C, and Vitamin E, and the like, and mixtures thereof. venous, intramuscular, etc. can be found in Remington's 0304. In addition to the above ingredients, there may also Pharmaceutical Sciences, Mack Publishing Company, Eas be incorporated other additives Selected from among the ton, Pa. various pharmaceutically acceptable additives available to 0310. A subject as used herein means humans, primates, those skilled in the art. These additives include binders, horses, cows, pigs, sheep, goats, dogs, cats and rodents. US 2003/0059471 A1 Mar. 27, 2003 27

0311. The conjugates of the invention are administered in 0319. The drug flakes are reduced to the desired size (1 effective amounts. An effective amount means that amount um to 5 mm) by a mechanical mill. The preferred range is necessary to delay the onset of, inhibit the progression of, 10-500 um. halt altogether the onset or progression of or diagnose the particular condition being treated. When administered to a 0320 The flakes are fractionated to the desired size Subject, effective amounts will depend, of course, on the distribution using mechanical Screens or used as is. particular condition being treated; the Severity of the con 0321) The desired fractions are coated with a single or dition; individual patient parameters including age, physical more coatings comprised of natural or Synthetic polymers condition, Size and weight, concurrent treatment, frequency using a spray coater. The first coat can be comprised of of treatment; and the mode of administration. These factors methyl cellulose while the Second can be a Synthetic ionic are well known to those of ordinary skill in the art and can polymer to impart Selective Solubility to the coating. be addressed with no more than routine experimentation. It is preferred generally that a maximum dose be used, that is, 0322 B. Roll Milling the highest Safe dose according to Sound medical judgment. 0323. Using acceptable pharmaceutical processing meth 0312 Dosage may be adjusted appropriately to achieve ods a drug Substance is formulated and granulated. desired drug levels, locally or Systemically. Generally, daily 0324. The granules are compressed between a rolling oral doses of active compounds will be from about 0.01 mechanism including at least one deflection-compensating mg/kg per day to 1000 mg/kg per day. In the event that the roller. Flakes are formed of a thickness of less than 0.1 mm. response in a Subject is insufficient at Such doses, even higher doses (or effective higher doses by a different, more 0325 The flakes are dried and processed as above. localized delivery route) may be employed to the extent that 0326 C. Thin-film Manufacturing patient tolerance permits. 0327 Onto a moving belt is sprayed a thin film of coating 0313 A variety of administration routes are available. agent Such as ethyl cellulose. After drying a drug Solution The particular mode Selected will depend of course, upon the contained in a non-miscible Solvent for the coating layer is particular drug Selected, the Severity of the disease State Sprayed. After drying a Second layer of coating Solution is being treated and the dosage required for therapeutic effi Sprayed to for a 3-laminated product. cacy. The methods of this invention, generally speaking, 0328. The product is removed with a fixed knife blade may be practiced using any mode of administration that is and milled to form uniform flakes by mechanical milling. medically acceptable, meaning any mode that produces The preferred size range is 100-500 um. effective levels of the active compounds without causing clinically unacceptable adverse effects. Such modes of 0329. The flakes are coated again to cover the edges administration include oral, rectal, Sublingual, topical, nasal, and/or to add additional desired properties Such as to provide transdermal, intradermal or parenteral routes. The term a slip, taste masking or a moisture barrier or Sustained or "parenteral' includes Subcutaneous, intravenous, intramus controlled release characteristic. cular, or infusion. Intravenous routes are preferred. 0330) D. Spray, Inkjet or Drip Method 0314. The compositions may conveniently be presented 0331 1. Inkjet, spray, or drip drug slurry onto belt in unit dosage form and may be prepared by any of the dryer or barrel or flat surface drying device. This methods well known in the art of pharmacy. All methods may be a continuous manufacturing process. include the Step of bringing the conjugates of the invention 0332 2. Drying can be effectuated by heat or into association with a carrier which constitutes one or more vacuum or both. accessory ingredients. In general, the compositions are pre 0333 3. In cases where drying is not necessaryk the pared by uniformly and intimately bringing the compounds Slurry flakes may be polymerized, for instance, by into association with a liquid carrier, a finely divided Solid infrared or ultraViolet radiation that does not degrade carrier, or both, and then, if necessary, Shaping the product. the drug product or other additives contained in the 0315 Compositions suitable for oral administration may Slurry. be presented as discrete units Such as capsules, cachets, 0334 4. In some cases both steps 2 and 3 may be tablets, or lozenges, each containing a predetermined used to manufacture the flakes. amount of the active compound. Other compositions include 0335 5. In Some cases, inert materials (e.g. gels, Suspensions in aqueous liquors or non-aqueous liquids Such absorbents, etc.) may be used to create a flake and as a Syrup, an elixir, or an emulsion. processed as described above. The flake may then be placed in contact with a drug So that it is absorbed. Examples A Subsequent drying or other step (e.g. polymeriza 0316 Drug-Incorporated Flakes (DIF) tion) may be necessary to complete the formation of the flake. 0317 A. Spray Drying Method 0336 6. Once produced the flakes may be coated 0318) A drug Solution containing acceptable pharmaceu with a variety of agents for taste masking, controlled tical excipient is sprayed onto a rotating drum (roll drum drug release, enteric release or for other purposes drier). The System can be warm and under reduced pressure, known by those skilled in the art of drug dosage depending on the drug and Solution characteristics. The coatings. Multiple coating Coatings may incorporate thickness of the flake is determined by the rate of drum compounds Such as antistatic agents. PowderS or roation rate, temperature, partial preSSure, humidity, and other additives may be added to the flakes to promote composition of the drug Solution. the pouring of flow of the flakes from containers. US 2003/0059471 A1 Mar. 27, 2003 28

0337 E. Press, Stamp or Embossing Method 11. The composition of any one of claims 1-3 further comprising a coating on the flakes which Separates the drug 0338 1. Flakes may be produce by injecting or from the environment. flowing a slurry into or onto a mold, cavity, a 12. The composition of any one of claims 1-3 further plurality of cavities or embossing a thin film of slurry comprising an enteric coating covering the flake. in Such a way as to form flake-like particles. This 13. The composition of any on of claims 1-3, wherein the may be a continuous process. flake comprises at least two layers, each of Said layers being 0339 2. Drying and/or polymerizing the flakes may of a different composition. be accomplished in a similar fashion as described 14. The composition of claims 1-3, wherein at least two above in Method 1. layerS is at least three layers. 15. The composition any one of claims 1-3, wherein the 0340 F. Hybrid Methods flake comprises at least 25% by weight of a natural polymer. 0341 1. Flakes may be formed by plating or printing 16. The composition of any one of claims 1-3, wherein the a nucleating agent onto a Surface over which you flake comprises a Synthetic polymer. flow or expose a Saturated or SuperSaturated liquid. 17. The composition of any one of claims 1-3, wherein the When the liquid comes into contact with the nucle flake comprises a drug uptake enhancer. ating agent, Small crystal-like flakes are formed. The 18. The composition of any one of claims 1-3, wherein the proceSS may be stopped by removal of the liquid, for flake is at least 5% by weight a nonfood. instance. The flakes may then be coated or a Subse 19. The composition of any one of claim 1-3, wherein the quent crystal layer may be added of the Same, or flake is at least 10% by weight a nonfood. different agent. 20. A composition comprising: 0342. 2. Flakes may be formed by preparing a slurry a plurality of discrete, Substantially flat flakes, each hav which is photopolymerizable or contains a photopo ing an average length, an average width and an average lymerizable agent in it. As a thin film of slurry passes thickness, wherein each of the length and width are at by, it may be exposed to a polymerizing radiation least three times the thickness, wherein a longest Source of controlled size So that flakes are formed in dimension of each flake is between 100 nanometers and situ. 5 millimeters, and wherein each flake comprises a 0343 3. Flakes may be made out of a continuous porous matrix. sheet of woven or nonwoven material which 30 is 21. The composition of claim 20 further comprising a Saturated with a drug and cut (e.g. laser, die cut, etc.) drug contained in the porous matrix. into Small flat particles. 22. The composition of claim 20, wherein the flakes are at least 5% by weight nonfood. What is claimed is: 23. A pharmaceutical preparation comprising the compo 1. A composition comprising: Sition of any one of claims 1-19, and a pharmaceutically acceptable carrier, wherein the drug is present in an amount a plurality of discrete, Substantially flat flakes, each hav effective for treating a condition. ing an average length, an average width and an average 24. The pharmaceutical preparation of claim 13 formu thickness, wherein each of the length and width are at lated as a dosage form, Selected from the group consisting least three times the thickness, wherein a longest of an oral dosage form, a topical dosage form and an dimension of each flake is between 100 nanometers and implantable dosage form. 5 millimeters, and wherein the flakes comprise a drug 25. The pharmaceutical preparation of claim 23, wherein of a nondrug active agent. the preparation contains an agent nonSuitable for oral inges 2. The composition of claim 1, wherein each of the flakes tion. has a Surface area, and wherein the ratio of the Surface area 26. The pharmaceutical preparation of claim 23, wherein to the thickness is at least 25 units: 1 unit. the pharmaceutically acceptable carrier is a Semi-Solid. 3. The composition of claim 2, wherein the longest 27. The pharmaceutical preparation of claim 23, wherein dimension of each flake is between 10 microns and 1 tie pharmaceutically acceptable carrier is a hydrogel. millimeter and wherein the ratio is at least 100 units: 1 unit. 28. The pharmaceutical preparation of claim 23, wherein 4. The composition of any one of claims 1-3, wherein the the pharmaceutically acceptable carrier is a Semi-Solid food. drug comprises at least 5% by weight of the flakes. 29. A method of treating a Subject having a condition, with 5. The composition of any one of claims 1-3, wherein the a drug, comprising: drug comprises at least 10% by weight of the flakes. 6. The composition of any one of claims 1-3, wherein the administering to a Subject in need of Such treatment an drug comprises at least 25% by weight of the flakes. amount of the drug effective to treat the condition, 7. The composition of any one of claims 1-3, wherein the wherein the drug comprises a plurality of flakes. drug comprises at least 50% by weight of the flakes. 30. The method of claim 29, wherein the flakes comprise 8. The composition of anyone of claims 1-3, wherein the the pharmaceutical preparation of claim 23. drug is embedded in the flakes. 31. The method of claim 29, wherein the flakes comprise 9. The composition of any one of claims 1-3, wherein the the pharmaceutical preparation of claim 24. drug is coated on the flakes. 32. The method of claim 29, wherein the flakes comprise 10. The composition of any one of claims 1-3, wherein the the pharmaceutical preparation of claim 25. drug is contained in microSpheres embedded within or 33. The method of claim 29, wherein the flakes comprise coated on the flakes. the pharmaceutical preparation of claim 26. US 2003/0059471 A1 Mar. 27, 2003 29

34. The method of claim 29, wherein the flakes comprise least three times the thickness, wherein a longest the pharmaceutical preparation of claim 27. dimension of each flake is between 100 nanometers and 35. The method of claim 29, wherein the flakes comprise 5 millimeters. the pharmaceutical preparation of claim 28. 40. A method for preparing a pharmaceutical preparation 36. The method of claim 29, wherein the flakes are comprising incorporating a drug into or upon a plurality of administered orally. flakes. 37. The method of claim 29, wherein the subject is Selected from the group consisting of a geriatric Subject, a 41. The method of claim 37, wherein the flake comprises: Subject with cancer, a Subject who is post-Surgically recov a plurality of discrete, Substantially flat flakes, each hav ering, a child 5 years or younger and a pregnant mother. ing an average length, an average width and an average 38. In a method for preparing a pharmaceutical prepara thickness, wherein each of the length and width are at tion by incorporating a drug within or coating a drug onto a least three times the thickness, wherein a longest particle, the improvement comprising incorporating the drug dimension of each flake is between 100 nanometers and within or onto a flake. 5 millimeters. 39. The improvement of claim 35, wherein the flake 42. The method of claim 37, wherein the flakes are formed comprises: first, and then the drug is coated onto, or allowed to penetrate a plurality of discrete, Substantially flat flakes, each hav into, the flakes. ing an average length, an average width and an average thickness, wherein each of the length and width are at