PATENT ABSTRACT
The invention provides a composition useful for making oral dosage forms capable of dissolving in the mouth in less than 40 seconds without the need for a conventional super disintegrant and having a friability of less than 1%; wherein the composition includes liquiflash particles and an excipient mass. A preferred excipient mass according to the invention contains a directly compressible inorganic salt; a cellulose derivative or a combination of a directly compressible inorganic salt and a cellulose derivative. Preferably, the liquiflash particles and the excipient mass are combined in proportions such that the active ingredient remains substantially within the microspheres when the composition is compressed to obtain a dosage form having a hardness of 20 to 50 N. The compositions of the invention allow for the fabrication of oral dosages having improved hardness and friability.

PATENT DESCRIPTION
RELATED APPLICATIONS 
       [0001]    This application is a Continuation application of U.S. application Ser. No. 10/176,135, filed Jun. 21, 2002, now allowed, which is a Continuation-in-Part application of U.S. application Ser. No. 09/179,926 filed Oct. 27, 1998, the content of which are hereby incorporated by reference in their entirety. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The invention relates to compressible compositions and dosage forms based thereon, such as tablets and lozenges, which, when ingested, quickly dissolve in the mouth, but which effectively mask the taste of unpleasant active agent(s) therein. Also, the invention relates to readily processable compositions having enhanced friability and hardness properties which permit shaping, e.g., tableting, without the need for complex packaging equipment. 
       BACKGROUND 
       [0003]    The post-genomics phase in the life sciences arena has brought an increased yield of new small molecules that are pursued to target particular diseases based on the new understanding of the molecular basis of disease. The tremendous progress achieved in molecular structural biology has allowed the identification and de novo design of efficient molecules or so called “smart drugs.” The new technologies based on the unraveling of the human genome, the intensive progress in elucidating the structures of the enzymes encoded therein combined with the efficiencies of combinatorial chemistry will continue to generate small molecules that need to be administered to patients in efficient and organoleptically acceptable forms. One aspect associated with ameliorating the effects of ingesting molecules that are generally unpalatable is to provide the drug in dosage forms, such as tablets and lozenges, which, when ingested, quickly dissolve in the mouth. 
         [0004]    Tablets may be defined as solid dosage pharmaceutical forms containing drug substances with or without suitable fillers. They are produced by compression or compaction of a formulation containing the drug and certain excipients selected to aid in the processing and to improve the properties of the product. Tablets may be coated or uncoated and are made from powdered, crystalline materials. They may include various diluents, binders, disintegrants, lubricants, glidants and in many cases, colorants. Excipients used are classified according to the function they perform. For example, a glidant may be used to improve the flow of powder blend in the hopper and into the tablet die. 
         [0005]    There has been widespread use of tablets since the latter part of the 19th century and the majority of pharmaceutical dosage forms are marketed as tablets. Major reasons of tablet popularity as a dosage form among pharmaceutical manufacturers are simplicity, low cost, and the speed of production. Other reasons include stability of drug product, convenience in packaging, shipping, and dispensing. To the patient or consumer, tablets offer convenience of administration, ease of accurate dosage, compactness, portability, blandness of taste, ease of administration, and elegant distinctive appearance. 
         [0006]    Tablets may be plain, film or sugar coated, bisected, embossed, layered, or sustained release. They can be made in a variety of sizes, shapes and colors. Tablets may be swallowed, chewed, or dissolved in the buccal cavity or beneath the tongue. They may be dissolved in water for local or topical application. Sterile tablets are normally used for parenteral solutions and for implantation beneath the skin. 
         [0007]    In addition to the active or therapeutic ingredients, tablets may contain a number of inert materials known as excipients. They may be classified according to the role they play in the final tablet. The primary composition includes a filler, binder, lubricant, and glidant. Other excipients which give physical characteristics to the finished tablet are coloring agents, and flavors in the case of chewable tablets. Without excipients most drugs and pharmaceutical ingredients cannot be directly compressed into tablets. This is primarily due to the poor flow and cohesive properties of most drugs. Typically, excipients are added to a formulation to impart good flow and compression characteristics to the material being compressed. Such properties are imparted to these excipients through pretreatment steps such as wet granulation, slugging, spray drying spheronization, or crystallization. 
         [0008]    Lubricants are typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression, and allow for removal of the compressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts usually less than 1% by weight. 
         [0009]    In addition, tablets often contain diluents which are added to increase the bulk weight of the blend resulting in a practical size for compression. This is often necessary where the dose of the drug is relatively small. 
         [0010]    Another commonly used class of excipients in tablets is binders. Binders are agents, which impart cohesive qualities to the powdered material. Commonly used binders include starch, and sugars such as sucrose, glucose, dextrose, and lactose. 
         [0011]    Disintegrants are often included to ensure that the tablet has an acceptable rate of disintegration. Typical disintegrants include starch derivatives and salts of carboxymethylcellulose. 
         [0012]    Other desirable characteristics of excipients include the following:
       High compressibility to allow strong tablets to be made at low compression forces.   Good flow properties that can improve the flow of other excipients in the formula.   Cohesiveness (to prevent tablet from crumbling during processing, shipping and handling).       
 
         [0016]    The three processes for making compressed tablets are wet granulation, direct compression, and dry granulation (slugging or roller compaction). The method of preparation and type of excipients are selected to give the tablet formulation the desired physical characteristics that allow for the rapid compression of the tablets. After compression, the tablets must have a number of additional attributes such as appearance, hardness, disintegrating ability, and an acceptable dissolution profile. Choice of fillers and other excipients will depend on the chemical and physical properties of the drug, behavior of the mixture during processing, and the properties of the final tablets. Preformulation studies are done to determine the chemical and physical compatibility of the active component with proposed excipients. 
         [0017]    The properties of the drug, its dosage forms, and the economics of the operation will determine selection of the best process for tableting. Generally, both wet granulation and direct compression are used in developing a tablet. 
         [0018]    The dry granulation method may be used where one of the constituents, either the drug or the diluent, has sufficient cohesive properties to be tableted. The method consists of blending, slugging the ingredients, dry screening, lubrication, and compression. 
         [0000]    The wet granulation method is used to convert a powder mixture into granules having suitable flow and cohesive properties for tableting. The procedure consists of mixing the powders in a suitable blender followed by adding the granulating solution under shear to the mixed powders to obtain a granulation. The damp mass is then screened through a suitable screen and dried by tray drying or fluidized bed drying. Alternately, the wet mass may be dried and passed through a mill. The overall process includes: weighing, dry powder blending, wet granulating, drying, milling, blending lubrication and compression. 
         [0019]    In general, powders do not have sufficient adhesive or cohesive properties to form hard, strong granules. A binder is usually required to bond the powder particles together due to the poor cohesive properties of most powders. Heat and moisture sensitive drugs cannot usually be manufactured using wet granulation. The large number of processing steps and processing time are problems due to high level manufacturing costs. Wet granulation has also been known to reduce the compressibility of some pharmaceutical excipients such as microcrystalline cellulose. 
         [0020]    Direct compression is regarded as a relatively quick process where the powdered materials are compressed directly without changing the physical and chemical properties of the drug. The active ingredient(s), direct compression excipients and other auxiliary substances, such as a glidant and lubricant are blended in a twin shell blender or similar low shear apparatus before being compressed into tablets. This type of mixing was believed to be essential in order to prepare “pharmaceutically acceptable” dosage forms. For example, Remington&#39;s Pharmaceutical Sciences (RPS), pp 1203 to 1932 17.sup.th edition (1985), cautions pharmaceutical scientists that the manner in which a lubricant is added to a formulation must be carefully controlled. 
         [0021]    Accordingly, lubricants are usually added to a granulation by gentle mixing. RPS warns that prolonged blending of a lubricant with a granulation can materially affect hardness and disintegration time for the resulting tablets. Furthermore, Ansel et al (1995) Pharmaceutical Dosage Forms and Drug Delivery Systems, 6.sup.th Ed. p. 199, indicates that excessive blending of lubricants with the granulate ingredients cause water proofing of the granule and reduces tablet hardness or strength of the compressed tablet. For these reasons, high shear mixing conditions have not been used to prepare direct compression dosage forms. 
         [0022]    The advantages of direct compression include uniformity of blend, few manufacturing steps involved, (i.e. the overall process involves weighing of powders, blending and compression, hence less cost), elimination of heat and moisture, prime particle dissociation, and physical stability. 
         [0023]    In addition to the assignee of the subject application, Biovail Laboratories, current manufacturers of rapidly disintegrating or dissolving solid dose oral formulations include Cima Labs, Prographarm/Ethypharm, R. P. Scherer, and Yamanouchi-Shaklee. All of these manufacturers market different types of rapidly dissolving solid oral dosage forms. 
         [0024]    Cima Labs markets OraSolv™, which is an effervescent direct compression tablet purportedly having an oral dissolution time of five to thirty seconds, and DuraSolv™, which is a direct compression tablet having a taste-masked active agent and a purported oral dissolution time of 15 to 45 seconds. Cima&#39;s U.S. Pat. No. 5,607,697, for “Taste Masking Microparticles for Oral Dosage Forms,” describes a solid dosage form consisting of coated microparticles that disintegrate in the mouth. The microparticle core has a pharmaceutical agent and one or more sweet-tasting compounds having a negative heat of solution selected from mannitol, sorbitol, a mixture of an artificial sweetener and menthol, a mixture of sugar and menthol, and methyl salicylate. The microparticle core is coated, at least partially, with a material that retards dissolution in the mouth and masks the taste of the pharmaceutical agent. The microparticles are then compressed to form a tablet. Other excipients can also be added to the tablet formulation. 
         [0025]    WO 98/46215 for “Rapidly Dissolving Robust Dosage Form,” assigned to Cima Labs, is directed to a hard, compressed, fast melt formulation having an active ingredient and a matrix of at least a non-direct compression filler and lubricant. A non-direct compression filler is typically not free-flowing, in contrast to a direct compression (DC grade) filler, and usually requires additionally processing to form free-flowing granules. 
         [0026]    Cima also has U.S. patents and international patent applications directed to effervescent dosage forms (U.S. Pat. Nos. 5,503,846, 5,223,264, and 5,178,878) and tableting aids for rapidly dissolving dosage forms (U.S. Pat. Nos. 5,401,513 and 5,219,574), and rapidly dissolving dosage forms for water soluble drugs (WO 98/14179 for “Taste-Masked Microcapsule Composition and Methods of Manufacture”). 
         [0027]    Prographarm/Ethypharm markets Flashtab™, which is a fast melt tablet having a disintegrating agent such as carboxymethyl cellulose, a swelling agent such as a modified starch, and a taste-masked active agent. The tablets have a purported oral disintegration time of under one minute (U.S. Pat. No. 5,464,632). 
         [0028]    R. P. Scherer markets Zydis™, which is a freeze-dried tablet having an oral dissolution time of 2 to 5 seconds. Lyophilized tablets are costly to manufacture and difficult to package because of the tablets sensitivity to moisture and temperature. U.S. Pat. No. 4,642,903 (R. P. Scherer Corp.) refers to a fast melt dosage formulation prepared by dispersing a gas throughout a solution or suspension to be freeze-dried. U.S. Pat. No. 5,188,825 (R. P. Scherer Corp.) refers to freeze-dried dosage forms prepared by bonding or complexing a water-soluble active agent to or with an ion exchange resin to form a substantially water insoluble complex, which is then mixed with an appropriate carrier and freeze dried. U.S. Pat. No. 5,631,023 (R. P. Scherer Corp.) refers to freeze-dried drug dosage forms made by adding xanthan gum to a suspension of gelatin and active agent. U.S. Pat. No. 5,827,541 (R. P. Scherer Corp.) discloses a process for preparing solid pharmaceutical dosage forms of hydrophobic substances. The process involves freeze-drying a dispersion containing a hydrophobic active ingredient and a surfactant, in a non-aqueous phase; and a carrier material, in an aqueous phase. 
         [0029]    Yamanouchi-Shaklee markets Wowtab™, which is a tablet having a combination of a low moldability and a high moldability saccharide. U.S. patents covering this technology include U.S. Pat. No. 5,576,014 for “Intrabuccally Dissolving Compressed Moldings and Production Process Thereof,” and U.S. Pat. No. 5,446,464 for “Intrabuccally Disintegrating Preparation and Production Thereof.” 
         [0030]    Other companies owning rapidly dissolving technology include Janssen Pharmaceutica. U.S. patents assigned to Janssen describe rapidly dissolving tablets having two polypeptide (or gelatin) components and a bulking agent, wherein the two components have a net charge of the same sign, and the first component is more soluble in aqueous solution than the second component. See U.S. Pat. No. 5,807,576 for “Rapidly Dissolving Tablet;” U.S. Pat. No. 5,635,210 for “Method of Making a Rapidly Dissolving Tablet;” U.S. Pat. No. 5,595,761 for “Particulate Support Matrix for Making a Rapidly Dissolving Tablet;” U.S. Pat. No. 5,587,180 for “Process for Making a Particulate Support Matrix for Making a Rapidly Dissolving Tablet;” and U.S. Pat. No. 5,776,491 for “Rapidly Dissolving Dosage Form.” 
         [0031]    Eurand America, Inc. has U.S. patents directed to a rapidly dissolving effervescent composition having a mixture of sodium bicarbonate, citric acid, and ethylcellulose (U.S. Pat. Nos. 5,639,475 and 5,709,886). 
         [0032]    L.A.B. Pharmaceutical Research owns U.S. patents directed to effervescent-based rapidly dissolving formulations having an effervescent couple of an effervescent acid and an effervescent base (U.S. Pat. Nos. 5,807,578 and 5,807,577). 
         [0033]    Schering Corporation has technology relating to buccal tablets having an active agent, an excipient (which can be a surfactant) or at least one of sucrose, lactose, or sorbitol, and either magnesium stearate or sodium dodecyl sulfate (U.S. Pat. Nos. 5,112,616 and 5,073,374). 
         [0034]    Laboratoire L. LaFon owns technology directed to conventional dosage forms made by lyophilization of an oil-in-water emulsion in which at least one of the two phases contains a surfactant (U.S. Pat. No. 4,616,047). For this type of formulation, the active ingredient is maintained in a frozen suspension state and is tableted without micronization or compression, as such processes could damage the active agent. 
         [0035]    Takeda Chemicals Inc., Ltd. owns technology directed to a method of making a fast dissolving tablet in which an active agent and a moistened, soluble carbohydrate are compression molded into a tablet, followed by drying of the tablets. 
         [0036]    Biovail Corporation (the parent of the assignee of the subject application) markets Flash Dose™, which is a direct compression tablet containing a processed excipient called Shearform™. Shearform™ is a floss type substance of mixed polysaccharides converted to amorphous fibers. U.S. patents describing this technology include U.S. Pat. No. 5,871,781 for “Apparatus for Making Rapidly Dissolving Dosage Units;” U.S. Pat. No. 5,869,098 for “Fast-Dissolving Comestible Units Formed Under High-Speed/High-Pressure Conditions;” U.S. Pat. Nos. 5,866,163, 5,851,553, and 5,622,719, all for “Process and Apparatus for Making Rapidly Dissolving Dosage Units and Product Therefrom;” U.S. Pat. No. 5,567,439 for “Delivery of Controlled-Release Systems;” and U.S. Pat. No. 5,587,172 for “Process for Forming Quickly Dispersing Comestible Unit and Product Therefrom.” 
         [0037]    One way to provide self-binding flowable formulations is to formulate using Shearform™ matrices or flosses. These matrices result when using certain processing techniques, such as the following: U.S. Pat. No. 5,587,172, incorporated herein by reference, discusses the use of flash heat techniques to produce sucrose-containing shearform flosses, which are then processed to yield quick-dissolving tablets. 
         [0038]    The use of shearform matrices for forming comestible units is described in WO95/34290 (published Dec. 21, 1995) from co-assigned PCT application No. PCT/US95/07144, filed Jun. 6, 1995. This case discloses a quick dissolving tablet which is formed by: (1) using flash-flow technology to provide a shearform matrix; (2) combining the partially recrystallized shearform matrix with an additive to form flowable, compactible particulate blends; and (3) compacting the blends at relatively low pressures to produce dosage forms, such as tablets. 
         [0039]    Additionally, PCT publication WO 95/34293 (published Dec. 21, 1995) from co-assigned PCT Application No. PCT/US95/07194, filed Jun. 6, 1995, discloses a process and apparatus for making rapidly dissolving dosage forms by flash-flow processing. In this PCT application, a shearform matrix is formed by the flash-flow process, the shearform matrix is combined with an additive, and the matrix is molded to make a unit dosage form. 
         [0040]    Co-owned U.S. patent application Ser. No. 08/915,068, filed Aug. 20, 1997, now U.S. Pat. No. 5,840,331; and Ser. No. 09/132,986, filed Aug. 12, 1998, now U.S. Pat. No. 6,048,541, describe tablet formulations derived from saccharide-based carriers in which the use of a unique combination of feedstock ingredients yields self-binding, flowable matrices and tablet compositions. This combination—which uses a blend of sugar alcohols, i.e., sorbitol and xylitol—is superior to glycerine in providing cohesive properties and flowability. 
         [0041]    Shapeable, preferably tabletable, compositions derived from partially hygroscopic matrices containing these sugar alcohols are useful—in the presence of tableting aids and crystallization promoters—in both high- and low-pressure tableting processes. Tablets and other dosage forms, e.g., lozenges, made therefrom rapidly dissolve when placed in the mouth, generally in less than 30 seconds. 
         [0042]    The production of microspheres containing active agent(s) is described in co-owned U.S. Pat. No. 5,683,720, incorporated herein by reference. The patent deals with the use of Liquiflash™ processing to spheronize compositions containing one or more active agents. 
         [0043]    Co-owned U.S. Pat. No. 6,165,512 provides compositions and shaped oral dosage forms made therefrom having improved properties. Among those properties are improved processability before shaping and enhanced dissolution and taste-masking properties when the dosage forms are used. The compositions of the &#39;512 patent are based on matrices, or flosses, which comprise at least one sugar alcohol, which matrices are generally considered “single floss” or “unifloss” systems. These systems are exemplified by xylitol-containing shearform matrixes, or flosses, containing a carrier and two or more sugar alcohols. 
         [0044]    Various ingredients, such as coated microspheres containing active agent(s), are added, in suitable amounts, to the compositions of the present invention after the matrices are collected and chopped, but before they are shaped, e.g., by tabletting. 
         [0045]    Highly useful dosage forms result when microspheres made from compositions containing active agents, solubilizers and spheronization aids are coated with taste-masking agents, then combined with flosses and conventional pharmaceutical ingredients. The resultant tablets enjoy the processing ease associated with the use of glycerine-free flosses and the taste and release properties associated with coated microspheres. 
         [0046]    The above mentioned existing quick dissolve technologies present numerous limitations. The above mentioned Prographarm (Ethypharm) dosage forms require relatively high levels of super disintegrant which complicates their use and limits their friability and hardness thereby requiring specialized packaging. Similarly, the Cima dosage forms require effervescent excipients which also reduces their friability and hardness qualities. The RP Scherer, Yamanouchi and Takada technologies employ complicated processing techniques (i.e. lyophilization, solvents with heat treatment or drying). Those techniques increase the cost associated with the formation of the dosage forms on a large scale. 
         [0047]    While Shearform™ matrices are an advance in the art, they also involve an increased cost associated with the processing of the floss matrix which limits their use at a large scale. As well, these amorphous matrices require specialized robotic tableting equipment and generally do not provide friability and hardness properties required for bulk packaging such as in bottles. 
         [0048]    As indicated above, disintegrants are often included to ensure that the tablet has an acceptable rate of disintegration. Typical disintegrants include starch derivatives and salts of carboxymethylcellulose. Thus, there still exists a need for non-sticking tabletable compositions which, can be used to make fast-dissolving, pleasant tasting dosage forms at a low cost and without the need for excessive amounts of super disintegrant or complicated processing equipment. 
       SUMMARY OF THE INVENTION 
       [0049]    The present invention is based on the unexpected discovery that quick dissolve Flashdose™ tablets can be provided without the need for floss matrices. The inventors have unexpectedly discovered that under certain processing conditions, direct compression of Liquiflash™ microspheres, in particular microspheres prepared according to co-owned U.S. patent application Ser. No. 09/179,926 provides quick dissolve dosage without the need for a floss matrix or super disintegrant as defined below or with quantities of super disintegrant that are well below the levels employed with the dosage forms discussed in the background section. 
         [0050]    In addition to the fast dissolve properties provided by the compositions of the invention, other advantages of the invention include the use of appropriate excipient mass (e.g., directly compressible inorganic salt; cellulose derivatives, etc.), which in turn facilitates the processing of the composition and eliminates the need for complex processing equipment. The components of the composition of the invention and the processing methods associated therewith allow for substantially lowering the cost associated with the production of the quick dissolve dosage forms of the invention which in turn facilitates their use at a large scale. Also, the simplicity of the excipients and the techniques employed in forming the dosage forms of the invention reduces the number of steps in manufacturing the dosage forms, thereby drastically reducing the opportunities for contamination and other quality impacting deleterious effects. The dosage forms of the invention are also advantageous in that higher loads of active agent can be obtained. 
         [0051]    As well, the compositions and dosage forms of the invention are greatly advantageous in that packaging is simplified. In fact, the present invention provides a unique combination of materials and processing techniques that allows the packaging of quick dissolve dosage forms in recipients as commonly used and easy to access as prescription or over the counter bottles and blister packaging. The simpler packaging advantages of the composition of the invention are due at least in part to the improved friability and hardness obtained with the quick dissolve dosage forms of the invention. 
         [0052]    In one embodiment, the invention provides a composition useful for making oral dosage forms capable of dissolving in the mouth in less than 40 seconds without the need for a conventional super disintegrant and having a friability of less than 1%; wherein the composition comprises drug-containing liquiflash particles and an excipient mass. Preferred excipient mass comprises a directly compressible inorganic salt, a cellulose derivative or a mixture of a directly compressible salt and a cellulose derivative. Preferably, the liquiflash particles and the mass of excipient are combined in proportions such that the active ingredient remains substantially within the microspheres when the composition is compressed to obtain a dosage form having a hardness of about 20 N to 50 N. The improved hardness and friability are obtained due to the discovery that the combination of the microspheres and the excipient mass allows for higher compression force. 
         [0053]    The liquiflash particles are preferably coated with at least one taste-masking coating. The coating preferably contains at least one cellulosic polymer. To improve the dissolution properties of the dosage form of the invention the composition may further comprises microcrystalline cellulose which facilitates disintegration in the mouth without having super disintegrant properties. A preferred linear polyol comprises mannitol, alone or in combination with sorbitol. 
         [0054]    A preferred embodiment of the invention provides a composition useful for making oral dosage forms capable of dissolving in the mouth in less than 30 seconds and having a friability of less than 1%; wherein the composition comprises liquiflash particles containing at least one bioaffecting agent and a combination of at least one solubilizer and at least one spheronization aid, said liquiflash particles being coated after spheronization; a mass comprising an excipient mass and less than 2.5% by weight of a super disintegrant. 
         [0055]    As indicated below, the compositions of the invention can be successfully employed to prepare oral dosage forms of a variety of active agents. Particularly preferred active agents include fluoxetine; paroxetine and zolpidem. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0056]    The invention is concerned with bio-affecting microparticles produced from compositions containing a unique combination of ingredients. The composition, the microparticles, their production and comestible units containing them are disclosed. 
         [0057]    Unless stated otherwise, all percentages recited herein are weight percentages, based on total composition weight. 
       I. Disintegrants and Super Disintegrants: 
       [0058]    A disintegrant is an excipient which is added to a tablet or capsule blend to aid in the break up of the compacted mass when it is put into a fluid environment. This is especially important for immediate release products where rapid release of drug substance is required. A disintegrant can be added to a powder blend for direct compression or encapsulation. It can also be used with products that are wet granulated. In wet granulation formulations, the disintegrant is normally effective when incorporated into the granule (intragranularly). However, it may be more effective if added 50% intragranularly, and 50% extra-granularly (i.e., in the final dry mixture). While there are some tablet fillers (e.g., starch and microcrystalline cellulose) which aid in disintegration, there are more effective agents referred to as superdisintegrants. Some superdisintegrants and their properties are listed below. 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 Crosscarmelose 
                 High swelling capacity, effective at low 
               
               
                   
                 sodium 
                 concentrations (0.5-2.0% but can be used up 
               
               
                   
                   
                 to 5.0%). 
               
               
                   
                 Crospovidone 
                 Completely insoluble in water. Rapidly 
               
               
                   
                   
                 disperses and swells in water, but does not 
               
               
                   
                   
                 gel even after prolonged exposure. Greatest 
               
               
                   
                   
                 rate of swelling compared to other 
               
               
                   
                   
                 disintegrants. Greater surface area to volume 
               
               
                   
                   
                 ratio than other disintegrants. Recommended 
               
               
                   
                   
                 concentration: 1 to 3% 
               
               
                   
                   
                 Available in micronized grades if needed to 
               
               
                   
                   
                 improve uniform dispersion in the powder 
               
               
                   
                   
                 blend. 
               
               
                   
                 Sodium Starch 
                 Absorbs water rapidly, resulting in swelling 
               
               
                   
                 Glycolate 
                 which leads to rapid disintegration of 
               
               
                   
                   
                 tablets and granules. Recommended 
               
               
                   
                   
                 concentration: 1.0-4.0% but may need to use 
               
               
                   
                   
                 up to 6.0%. Gels on prolonged exposure to 
               
               
                   
                   
                 water. High concentrations may cause gelling 
               
               
                   
                   
                 and loss of disintegration. 
               
               
                   
                   
               
             
          
         
       
     
         [0059]    A super disintegrant according to the invention is a disintegrant that has a Eq. Moisture content at 25 C/90% RH of over 50%. A list of exemplary disintegrants, super disintegrants and other formulations with some disintegrant qualities are provided below: 
       Superdisintegrants and Disintegrants 
       [0060]      
         [0000]    
       
         
               
               
               
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                   
                   
                 Eq. Moisture 
                   
               
               
                 Brand 
                 Common 
                   
                 Functional 
                   
                 content at 
                   
               
               
                 name 
                 name 
                 Classification 
                 Category 
                 Properties 
                 25 C./90% RH 
                 Typical uses 
               
               
                   
               
             
             
               
                 CL- 
                 Crospovidone 
                 Polyvinylpoly- 
                 Tablet 
                 Hygroscopic 
                 62% 
                 Disintegrant 
               
               
                 Kollidon 
                   
                 pyrrolidone 
                 super- 
                 Swelling- 
                   
                 in dry  
               
               
                   
                   
                   
                 disintegrant 
                 18% in 10 s, 
                   
                 and wet 
               
               
                   
                   
                   
                   
                 45% in 20 s 
                   
                 granulation 
               
               
                 Ac- 
                 Croscarmellose 
                 Cellulose, 
                 Tablet 
                 Hygroscopic 
                 88% 
                 Disintegrant 
               
               
                 Disol 
                 sodium 
                 carboxymethyl 
                 and 
                 Wicking 
                   
                 for capsules, 
               
               
                 Primellose 
                   
                 ether, 
                 capsule 
                 and 
                   
                 tablets and 
               
               
                   
                   
                 sodium salt, 
                 superdis- 
                 swelling- 
                   
                 granules 
               
               
                   
                   
                 crosslink 
                 integrant 
                 12% in 10 s, 
                   
                   
               
               
                   
                   
                   
                   
                 23% in 20 s 
                   
                   
               
               
                 Explotab 
                 Sodium 
                 Sodium 
                 Tablet 
                 Swelling 
                   
                 Disintegrant 
               
               
                 Primojel 
                 starch 
                 carboxy- 
                 and 
                 capacity: in 
                   
                 in dry  
               
               
                   
                 glycolate 
                 methyl starch 
                 capsule 
                 water swells 
                   
                 and wet 
               
               
                   
                   
                   
                 superdis- 
                 up to 300 
                   
                 granulation 
               
               
                   
                   
                   
                 integrant 
                 times its 
                   
                   
               
               
                 Explotab 
                 Sodium 
                 (Cross linked  
                 Super- 
                 volume 
                   
                   
               
               
                 V17 
                 starch 
                 low 
                 disintegrant 
                 Swells to 
                   
                 Disintegrant 
               
               
                   
                 glycolate 
                 substituted 
                   
                 greater 
                   
                 and 
               
               
                   
                   
                 carboxymethyl 
                   
                 extent than 
                   
                 dissolution 
               
               
                   
                   
                 ether) Sodium 
                   
                 explortab 
                   
                 aid. Not for 
               
               
                   
                   
                 carboxymethyl 
                   
                   
                   
                 use in wet 
               
               
                   
                   
                 starch 
                   
                   
                   
                 granulation 
               
               
                 Explotab 
                 Sodium 
                 (Cross linked  
                 Super- 
                   
                   
                 Designed for 
               
               
                 CLV 
                 starch 
                 low 
                 disintegrant 
                   
                   
                 wet  
               
               
                   
                 glycolate 
                 substituted 
                   
                   
                   
                 granulation 
               
               
                   
                   
                 carboxymethyl 
                   
                   
                   
                 that utilize 
               
               
                   
                   
                 ether) Sodium 
                   
                   
                   
                 high shear 
               
               
                   
                   
                 carboxymethyl 
                   
                   
                   
                 equipment 
               
               
                   
                   
                 starch, highly 
                   
                   
                   
                   
               
               
                   
                   
                 cross linked 
               
               
                   
               
             
          
         
       
     
       II. Compositions 
       [0061]    The compositions of the invention employ optional excipients with (a) a bioaffecting agent and (b) one or more processing aids. 
         [0062]    A. Bio-Affecting Agents 
         [0063]    The active ingredients useful herein can be selected from a large group of therapeutic agents. Respective classes include those in the following therapeutic categories: ace-inhibitors; alkaloids; antacids; analgesics; anabolic agents; anti-anginal drugs; anti-allergy agents; anti-arrhythmia agents; antiasthmatics; antibiotics; anticholesterolemics; anticonvulsants; anticoagulants; antidepressants; antidiarrheal preparations; anti-emetics; antihistamines; antihypertensives; anti-infectives; anti-inflammatories; antilipid agents; antimanics; anti-migraine agents; antinauseants; antipsychotics; antistroke agents; antithyroid preparations; anabolic drugs; antiobesity agents; antiparasitics; antipsychotics; antipyretics; antispasmodics; antithrombotics; antitumor agents; antitussives; antiulcer agents; anti-uricemic agents; anxiolytic agents; appetite stimulants; appetite suppressants; beta-blocking agents; bronchodilators; cardiovascular agents; cerebral dilators; chelating agents; cholecystokinin antagonists; chemotherapeutic agents; cognition activators; contraceptives; coronary dilators; cough suppressants; decongestants; deodorants; dermatological agents; diabetes agents; diuretics; emollients; enzymes; erythropoietic drugs; expectorants; fertility agents; fungicides; gastrointestinal agents; growth regulators; hormone replacement agents; hyperglycemic agents; hypoglycemic agents; ion-exchange resins; laxatives; migraine treatments; mineral supplements; mucolytics, narcotics; neuroleptics; neuromuscular drugs; non-steroidal anti-inflammatories (NSAIDs); nutritional additives; peripheral vasodilators; polypeptides; prostaglandins; psychotropics; renin inhibitors; respiratory stimulants; sedatives; steroids; stimulants; sympatholytics; thyroid preparations; tranquilizers; uterine relaxants; vaginal preparations; vasoconstrictors; vasodilators; vertigo agents; vitamins; wound healing agents; and others. Active agents which may be used in the invention include: acetaminophen; acetic acid; acetylsalicylic acid, including its buffered forms; acrivastine; albuterol and its sulfate; alcohol; alkaline phosphatase; allantoin; aloe; aluminum acetate, carbonate, chlorohydrate and hydroxide; alprozolam; amino acids; aminobenzoic acid; amoxicillin; ampicillin; amsacrine; amsalog; anethole; ascorbic acid; aspartame; astemizole; atenolol; azatidine and its maleate; bacitracin; balsam peru; BCNU (carmustine); beclomethasone diproprionate; benzocaine; benzoic acid; benzophenones; benzoyl peroxide; benzquinamide and its hydrochloride; bethanechol; biotin; bisacodyl; bismuth subsalicylate; bornyl acetate; bromopheniramine and its maleate; buspirone; caffeine; calamine; calcium carbonate, casinate and hydroxide; camphor; captopril; cascara sagrada; castor oil; cefaclor; cefadroxil; cephalexin; centrizine and its hydrochloride; cetyl alcohol; cetylpyridinium chloride; chelated minerals; chloramphenicol; chlorocyclizine hydrochloride; chlorhexidine gluconate; chloroxylenol; chloropentostatin; chlorpheniramine and its maleates and tannates; chlorpromazine; cholestyramine resin; choline bitartrate; chondrogenic stimulating protein; cimetidine and its hydrochloride; cinnamedrine hydrochloride; citalopram; citric acid; clarithromycin; clemastine and its fumarate; clonidine and its hydrochloride salt; clorfibrate; cocoa butter; cod liver oil; codeine and its fumarate and phosphate; cortisone acetate; ciprofloxacin HCI; cyanocobalamin; cyclizine hydrochloride; cyproheptadine and its hydrochloride; danthron; dexbromophenhamine maleate; dextromethorphan and its hydrohalides; diazepam; dibucaine; dichloralphenazone; diclofen and its alkali metal sales; diclofenac sodium; digoxin; dihydroergotamine and its hydrogenates/mesylates; diltiazem; dimethicone; dioxybenzone; diphenhydramine and its citrate; diphenhydramine and its hydrochloride; divalproex and its alkali metal salts; docusate calcium, potassium, and sodium; doxycycline hydrate; doxylamine succinate; dronabinol; efaroxan; enalapril; enoxacin; ergotamine and its tartrate; erythromycin; estropipate; ethinyl estradiol; ephedrine; epinephrine bitartrate; erythropoietin; eucalyptol; famotidine; fenoprofen and its metal salts; ferrous fumarate, gluconate and sulfate; fluoxetine; folic acid; fosphenytoin; 5-fluorouracil (5-FU); fluoxetine and its hydrochloride; flurbiprofen; furosemide; gabapentan; gentamicin; gemfibrozil; glipizide; glycerine; glyceryl stearate; granisetron and its hydrochloride; griseofulvin; growth hormone; guafenesin; hexylresorcinol; hydrochlorothiazide; hydrocodone and its tartrates; hydrocortisone and its acetate; 8-hydroxyquinoline sulfate; hydroxyzine and its pamoate and hydrochloride salts; ibuprofen; indomethacin; inositol; insulin; iodine; ipecac; iron; isosorbide and its monoand dinitrates; isoxicam; ketamine; kaolin; ketoprofen; lactic acid; lanolin; lecithin; leuprolide acetate; lidocaine and its hydrochloride salt; lifinopril; liotrix; loratadine; lovastatin; luteinizing hormone; LHRH (luteinizing hormone replacement hormone); magnesium carbonate, hydroxide, salicylate, and trisilicate; meclizine and its hydrochloride; mefenamic acid; meclofenamic acid; meclofenamate sodium; medroxyprogesterone acetate; methenamine mandelate; menthol; meperidine hydrochloride; metaproterenol sulfate; methscopolamine and its nitrates; methsergide and its maleate; methyl nicotinate; methyl salicylate; methyl cellulose; methsuximide; metoclopramide and its halides/hydrates; metronidazole and its hydrochloride; metoprotol tartrate; miconazole nitrate; mineral oil; minoxidil; morphine; naproxen and its alkali metal sodium salts; nifedipine; neomycin sulfate; niacin; niacinamide; nicotine; nicotinamide; nimesulide; nitroglycerine; nonoxynol-9; norethindrone and its acetate; nystatin; octoxynol; octoxynol-9; octyl dimethyl PABA; octyl methoxycinnamate; omega-3 polyunsaturated fatty acids; omeprazole; ondansetron and its hydrochloride; oxolinic acid; oxybenzone; oxtriphylline; para-aminobenzoic acid (PABA); padimate-O; paramethadione; pentastatin; peppermint oil; pentaerythritol tetranitrate; pentobarbital sodium; perphenazine; phenelzine sulfate; phenindamine and its tartrate; pheniramine maleate; phenobarbital; phenol; phenolphthalein; phenylephrine and its tannates and hydrochlorides; phenylpropanolamine and its hydrochloride salt; phenytoin; pirmenol; piroxicam and its salts; polymicin B sulfate; potassium chloride and nitrate; prazepam; procainamide hydrochloride; procaterol; promethazine and its hydrochloride; propoxyphene and its hydrochloride and napsylate; pramiracetin; pramoxine and its hydrochloride salt; prochlorperazine and its maleate; propanolol and its hydrochloride; promethazine and its hydrochloride; prop anolol; pseudoephedrine and its sulfates and hydrochlorides; pyridoxine; pyrolamine and its hydrochlorides and tannates; quinapril; quinidine gluconate and sulfate; quinestrol; ralitoline; ranitadine; resorcinol; riboflavin; salicylic acid; scopolamine; sesame oil; shark liver oil; simethicone; sodium bicarbonate, citrate, and fluoride; sodium monofluorophosphate; sucralfate; sulfanethoxazole; sulfasalazine; sulfur; sumatriptan and its succinate; tacrine and its hydrochloride; theophylline; terfenadine; thiethylperazine and its maleate; timolol and its maleate; thioperidone; tramadol; trimetrexate; triazolam; tretinoin; tetracycline hydrochloride; tolmetin; tolnaftate; triclosan; trimethobenzamide and its hydrochloride; tripelennamine and its hydrochloride; tripolidine hydrochloride; undecylenic acid; vancomycin; verapamil HCI; vidaribine phosphate; vitamins A, B, C, D, BI, B2, B6, B,2, E, and K; witch hazel; xylometazoline hydrochloride; zinc; zinc sulfate; zinc undecylenate. Mixtures and pharmaceutically acceptable salts of these and other actives can be used. 
         [0064]    Particularly useful active agents are sparingly soluble solid agents whose dissolution and release properties are enhanced by the solubilizing agents used herein. These agents include HZ antagonists, analgesics, including non-steroidal anti-inflammatory drugs (NSAIDs), anticholesterolemics, anti-allergy agents, and anti-migraine agents. 
         [0065]    Analgesics include aspirin, acetaminophen, acetaminophen plus caffeine, and non-steroidal anti-inflammatory drugs (NSAIDS), e.g., ibuprofen and nimesulide. 
         [0066]    Useful NSAIDs include ibuprofen; diclofenac and its alkali metal salts; fenoprofen and its metal salts; fluriprofen; ketoprofen; naproxen and its alkali metal salts; nimesulide; and piroxicam and its salts. 
         [0067]    H 2 -antagonists which are contemplated for use in the present invention include cimetidine, ranitidine hydrochloride, famotidine, nizatidine, ebrotidine, mifentidine, roxatidine, pisatidine and aceroxatidine. 
         [0068]    Useful anti-allergy agents include hydricodone and its tartrates; clemastine and its fumarate; azatadine and its maleate; acetaminophen; hydroxyzine and its pamoate and hydrochloride salts; chlorpheniramine and its maleates and tannates; pseudoephedrine and its sulfates and hydrochlorides; broinopheniramine and its maleate; dextromethorphan and its hydrohalides; loratadine; phenylephrine and its tannates and hydrochlorides; methscopolamine and its nitrates; phenylpropanolamine and its hydrochlorides; codeine and its hydrochloride; codeine and its phosphate; terfenadine; acrivastine; astemizole; cetrizine and its hydrochloride; phenindamine and its tartrate; tripelennamine and its hydrochloride; cyproheptadine and its hydrochloride; promethazine and its hydrochloride; and pyrilamine and its hydrochlorides and tannates. 
         [0069]    Useful antimigraine agents include divalproex and its alkali metal salts; timolol and its maleate; propanolol and its hydrohalides; ergotamine and its tartrate; caffeine; sumatriptan and its succinate; dihydroergotamine, its hydrogenates/mesylates; methsergide and its maleate; isometheptene mucate; and dichloralphenazone. 
         [0070]    Another class of drugs which can be used are antiemetics. Useful antiemetics include: meclizine and its hydrochloride; hydroxyzine and its hydrochloride and pamoate; diphenhydramine and its hydrochloride; prochlorperazine and its maleate; benzquinamide and its hydrochloride; granisetron and its hydrochloride; dronabinol; bismuth sub salicylate; promethazine and its hydrochloride; metoclopramide and its halides/hydrates; chlorpromazine; trimethobenzamide and its hydrochloride; thiethylperazine and its maleate; scopolamine; perphenazine; and ondansetron and its hydrochloride. 
         [0071]    Other active ingredients for use in the present invention include antidiarrheals such as immodium AD, antihistamines, antitussives, decongestants, vitamins, and breath freshners. Also contemplated for use herein are anxiolytics such as Xanax; antipsychotics such as Clozaril and Haldon; antihistamines such as Seldane, Hismanal, Relafen, and Tavist; antiemetics such as Kytril and Cesamet; bronchodilators such as Bentolin, Proventil; antidepressants such as Prozac, Zoloft, and Paxil; antimigranes such as Imigran, ACE-inhibitors such as Vasotec, Capoten and Zestril; Anti-Alzheimers agents such as Nicergoline; and Call-Antagonists such as Procardia, Adalat, and Calan. 
         [0072]    Among the anticholesterolemics, the statins, e.g., lovastatin, provastatin and the like are notable. 
         [0073]    Fluoxetine, paroxetine and zolpidem are preferred active agents. 
         [0074]    Combinations of various types of drugs, as well as combinations of individual drugs, are contemplated. 
         [0075]    B. Processing Aids 
         [0076]    The processing aids of the invention include high molecular weight polyethylene glycols (PEG&#39;s) and/or polyethylene glycol glyceryl esters. When microspheres are made, these materials can be called “spheronization aids.” 
         [0077]    By “high molecular weight polyethylene glycols (PEG),” applicants mean PEG&#39;s having molecular weights of about 3,000 to about 8,000. “PEG 4600,” having an average molecular weight of about 4400 to 4800, is a preferred material. Mixtures can be used. 
         [0078]    In chemical terms, useful PEGs are those molecules having the structural formula HOCH 2  (CH 2 OCH 2 ) m  CH 2 OH, wherein m is the average number of oxyethylene groups. PEG&#39;s used for this invention are those in which m is from about 0 to about 13. 
         [0079]    Useful PEGS are solids. They are discussed on pages 355-361 of the  Handbook of Pharmaceutical Excipients,  2 nd  ed. (1994). 
         [0080]    The polyethylene glycol glyceryl esters useful herein are selected from those containing about 30 to about 35 oxyethylene groups. Polyethylene glycol 32 glyceryl ester sold as “GELUCIRE 50/13” by Gattefosse S.A. of France is a preferred ester. Mixtures are operable. 
         [0081]    The amounts of ingredients used in the compositions are generally within those shown in the following table. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 Broad range 
                 Narrow range 
                 Preferred range 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 Bio-affecting 
                 1-50% 
                  5-40% 
                 20-30% 
               
               
                 agent(s) 
               
               
                 PEG 
                 0-90% 
                 60-90% 
                 60-80% 
               
               
                 Glyceryl ester 
                 0-60% 
                  1-10% 
                 2.5-7.5%  
               
               
                 Excipient(s) 
                 0-98% 
                 10-50% 
                 10-30% 
               
               
                   
               
             
          
         
       
     
       III. Processes 
       [0082]    Useful processes for making the microparticles of the invention include liquiflash conditions as well as other thermoforming processes known in the art, eg., extrusion. “Liquiflash conditions” are generally those under which the material, called a feedstock, is rapidly heated just to the point at which it undergoes intraparticulate flow and partially deforms or liquifies so that it can pass through openings in a suitable spinning device. The passage of the liquiflash particles through openings is in response to centrifugal forces within the spinning head, which forces “expel” the particles, as discrete solids out of the device and into the atmosphere. The expelled materials instantly reform into particles, without the application of external shaping forces, which particles have different morphologies from those of the feedstocks. 
         [0083]    Applicants have found that one particular spinning device is highly useful in making the microspheres of the invention. In U.S. Pat. No. 5,458,823, a spinning device is described which uses a spinning head including a base and a cover. A plurality of closely spaced heating elements are positioned between the base and cover, forming a barrier through which the material to be processed passes. In use, the head rotates and the heating elements are heated to temperatures that bring about liquiflash conditions in the materials being processed. As the spinning head rotates, the centrifugal force created by its rotation expels the material through spaces between the heating elements. The material forms discrete, generally spherical particles as it exits. 
         [0084]    The production of microspheres for use in the subject invention may be optimized by the use of a V-groove insert inside the spinner head. The insert is described in pending U.S. patent application Ser. No. 08/874,515, filed Jun. 13, 1997 The insert has grooves therein, which grooves have a uniform depth and width through their length, so that highly uniform discrete microspheres or other particles are produced. Using this or a similar insert, the spinning device is operated at 50 to 75 Hz, at about 10 to 25% power, and at temperatures which yield liquiflash conditions. 
         [0085]    It should be noted that “liquiflash conditions” vary with the properties of the material, or feedstock, being processed. Since the feedstocks contain many substances in varying amounts, the parameters need to yield “liquiflash conditions” for a particular mixture must be ascertained by processing small quantities or samples before processing large ones. Typically, the feedstocks contain active agent(s) and processing aids. 
         [0086]    Among the co-assigned patents and patent applications which describe the preparations of microspheres containing bio-affecting agents re: U.S. Pat. No. 5,458,823; U.S. Pat. No. 5,0q,720; and U.S. Ser. No. 08/874,215, filed Jun. 13, 1997. 
       III. Microparticles 
       [0087]    While particulates made using various thermoprocessing technologies are useful, microspheres described below are preferred. 
         [0088]    The microspheres or other particulates are generally solid spherical bodies of about 150 to about 250 microns mean particle diameter. 
         [0089]    It is preferred that they be produced via a direct spheronization process, such as liquiflash or other suitable techniques. However, they may be made by physically altering the size and/or shape of non-spherical particles by extrusion/spheronization or melt granulation processes. 
         [0090]    When microspheres are made by direct spheronization of compositions containing active agent(s), the fatty esters and optional emulsifiers/surfactants, the fatty esters function as spheronization aids. 
         [0091]    The microspheres may be used as is, i.e., in powder or sachet products for delivering active agents. Alternatively, they may be used in the production of solid, liquid (suspensions), or semi-solid (e.g., gel-like) comestible units, etc. Tablets and capsules are preferred. 
         [0092]    It is preferred that the microspheres of the invention be used in combination with. excipients which have been formed into floss or matrix particles. Useful flosses are generally made from saccharide based carriers. See U.S. Pat. Nos. 5,622,719 and 5,587,172. 
         [0093]    Once the floss and microsphere ingredients are combined, they can be shaped into comestible units. 
       IV. Coatings 
       [0094]    One or both of the microspheres and the dosage units can be coated or encapsulated with at least one coating. Useful coating formulations contain polymeric ingredients as well as excipients conventionally employed in such coatings. The coatings are generally used for such purposes as taste-masking, controlling release and the like. 
         [0095]    Useful taste-masking coatings can include (meth)acrylate/cellulosic polymers. Ethylcellulose (EC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), and polymethacrylate polymers, such as Eudragit RS, Eudragit RL or mixtures thereof are useful. Preferred combinations include EC/HPC and Eudragit RS/Eudragit RL. 
         [0096]    Controlled release coatings generally contain at least one of: ethylcellulose (EC), hydroxypropylcellulose hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, and the like. The “Eudragits” designated as NE 300, RS, L 30 D, are useful. Mixtures are operable. 
         [0097]    Coating levels of about 0 to about 150% are effective, with levels of about 5% to about 30% being preferred. 
         [0098]    Coating devices include those conventionally used in pharmaceutical processing, with fluidized bed coating devices being preferred. 
         [0099]    Formulations according to the invention are illustrated by the examples provided below, which should in no way limit the scope of the appended claims. The friability results shown below correspond to Drop tests conducted with a Roche drum equipped with two separate drums, the motor rotate the drum at 100 revolution/min. the actual drums is made from plexiglass and is separated into parts, the drum body and removable cover, which opens to fill, discharge and clean the drum. For the Abrasion tests one of the two drums is replaced with an abrasion drum. 
       EXAMPLES 
       [0100]    The examples and counterexamples provided below illustrate formulations and processing conditions for forming dosage forms according to the invention. 
       Formulation No 1 
       [0101]    CEFORM™ or other coated particle: 5-45% W/W, preferred 5-35%, (35-45% is fast tablet but gritty) 
       Mannitol*: 29.1-77.1% 
     Microcrystalline Cellulose**: 12-18% 
     1-HPC, LH-11: 2-4% 
     Citric Acid: 1.5% 
     Acesulfame K: 0.2% 
     Magnasweet 100: 0.2% 
     Flavor: 0.5% 
     Syloid: 0.5% 
     Pruv: 1.0% 
     Formulation NO 2 
       [0102]    CEFORM™ or other coated particle: 5-45% W/W, preferred 5-35%, (35-45% is fast tablet but gritty) 
       Mannitol*: 29.1-77.1% 
       [0103]    Microcrystalline Cellulose**: 12-18%, preferably 15%-18% 
       Kollidon CL: 2-4% 
     Citric Acid: 1.5% 
     Acesulfame K: 0.2% 
     Magnasweet 100: 0.2% 
     Flavor: 0.5% 
     Syloid: 0.5% 
     Pruv: 1.0% 
     Formulation No 3 (More Referred Platform): 
       [0104]    CEFORM™ or other coated particle: 5-45% W/W, preferred 5-35%, (35-45% is fast tablet but gritty) 
       Mannitol*: 27.1-83.6% 
       [0105]    Microcrystalline Cellulose**: 5-20%, preferably 15-18% 
       Kollidon CL: 2% 
     1-HPC, LH-11: 2% 
     Citric Acid: 1.5% 
     Acesulfame K: 0.2% 
     Magnasweet 100: 0.2% 
     Flavor: 0.5% 
     Syloid: 0.5% 
       [0106]    Pruv: 1.0% *Mannitols evaluated and found acceptable: Pearlitol 400DC, 300DC, Parteck M200, Parteck M300, Roquette Lab 3038. No differences were observed in disintegration time.**Microcrystalline cellulose evaluated and found acceptable: Avicel PH 101, 102, 113, Prosolv 50, Prosolv 90. No differences were observed in disintegration time. 
         [0107]    Other preferred formulations based on model drug fluoxetine: 
         [0000]    
       
         
               
               
               
               
               
             
           
               
                   
               
               
                   
                 Hardness 
                 Disintegration 
                   
                   
               
               
                 Formulation Lot# 
                 (N) 
                 time 
                 Friability % 
                 Comments 
               
               
                   
               
             
             
               
                 FluoxetineTMMS: 
                 29.7 
                 Mouth: 10 s 
                 0.8 
                 Can be used with 
               
               
                 28.69 
                   
                 USP basket 
                   
                 any drug 
               
               
                 Pearlitol 400DC: 
                   
                 rack assembly: 
               
               
                 48.41 
                   
                 20 s 
               
               
                 Avicel PH 101: 16.0 
               
               
                 L-HPC 11: 4.0 
               
               
                 Citric acid: 1.0 
               
               
                 AsesulK: 0.2 
               
               
                 Tangerine: 0.2 
               
               
                 Syloid: 0.5 
               
               
                 Pruv: 1.0 
               
               
                 Avicel PH101/L- 
               
               
                 HPC11 ratio (80/20) 
               
               
                 Lot#/mfg date: 1242- 
               
               
                 124 
               
               
                 250 g batch/11 mm 
               
               
                 Flat Face Radial 
               
               
                 Edge/450 mg 
               
               
                 FluoxetineTMMS: 
                 34.0 
                 Mouth: 10 s 
                 0.8 
                 Can be used with 
               
               
                 28.69 
                   
                 USP basket 
                   
                 any drug 
               
               
                 Pearlitol 400DC: 
                   
                 rack assembly: 
               
               
                 48.41 
                   
                 20 s 
               
               
                 Avicel PH 101: 18.0 
               
               
                 L-HPC 11: 2.0 
               
               
                 Citric acid: 1.0 
               
               
                 AsesulK: 0.2 
               
               
                 Tangerine: 0.2 
               
               
                 Syloid: 0.5 
               
               
                 Pruv: 1.0 
               
               
                 Avicel PH101/L- 
               
               
                 HPC11 (90/10) ratio 
               
               
                 Lot#/mfg date: 1242- 
               
               
                 125 
               
               
                 250 g batch/11 mm 
               
               
                 Flat Face Radial 
               
               
                 Edge/450 mg 
               
               
                 FluoxetineTMMS: 
                 29.5 
                 Mouth: 10 s, 
                 0.3 
                 Can be used with 
               
               
                 28.69 
                 24.4 
                 15 s, 20 s, 10 s, 
                 0.3 
                 any drug 
               
               
                 Pearlitol 400DC: 
                 28.4 
                 10 s 
                 0.2 
               
               
                 51.41 
                 26.0 
                 USP basket 
                 0.2 
               
               
                 Avicel PH 101: 15.0 
                 28.3 
                 rack assembly: 
                 0.4 
               
               
                 L-HPC 11: 2.0 
                   
                 15 s, 20 s, —, 
               
               
                 Citric acid: 1.0 
                   
                 19 s, — 
               
               
                 AsesulK: 0.2 
               
               
                 Tangerine: 0.2 
               
               
                 Syloid: 0.5 
               
               
                 Pruv: 1.0 
               
               
                 *can be 
               
               
                 Avicel 113, 1242- 
               
               
                 140 
               
               
                 Avicel 102, 1242- 
               
               
                 139 
               
               
                 Prosolv 50, 1242- 
               
               
                 138 
               
               
                 Prosolv 90, 1242- 
               
               
                 137 
               
               
                 Lot#/mfg date: 1242- 
               
               
                 135, 140, 139, 138, 
               
               
                 137 
               
               
                 250 g batch/11 mm 
               
               
                 Flat Face Radial 
               
               
                 Edge/450 mg 
               
               
                 FluoxetineTMMS: 
                 28.4 
                 Mouth: 15 s. 
                 0.5 
                 Can be used with 
               
               
                 28.69 
                   
                 Good tablets 
                   
                 any drug except the 
               
               
                 Advantose 100: 
                   
                 No significant 
                   
                 drugs that have 
               
               
                 12.85 
                   
                 difference 
                   
                 amine group. 
               
               
                 Pearlitol 400DC: 
                   
                 between 1242- 
               
               
                 38.56 
                   
                 147 
               
               
                 Avicel PH 101: 15.0 
                   
                 USP basket 
               
               
                 L-HPC 11: 2.0 
                   
                 rack assembly: 
               
               
                 Citric acid: 1.0 
                   
                 19 s 
               
               
                 AsesulK: 0.2 
               
               
                 Tangerine: 0.2 
               
               
                 Syloid: 0.5 
               
               
                 Pruv: 1.0 
               
               
                 Advantose 
               
               
                 100/Pearlitol 400DC 
               
               
                 (25/75) ratio 
               
               
                 Lot#/mfg date: 1242- 
               
               
                 148/ 
               
               
                 Feb. 04, 2002 
               
               
                 250 g batch/11 mm 
               
               
                 Flat Face Radial 
               
               
                 Edge/450 mg 
               
               
                 FluoxetineTMMS: 
                 33.9 
                 Mouth: 7-10 s 
                 0.6 
                 Can be used with 
               
               
                 28.69 
                   
                 very fast tablet 
                   
                 any drug 
               
               
                 Pearlitol 400DC: 
                   
                 USP basket 
               
               
                 51.41 
                   
                 rack assembly: 
               
               
                 Avicel PH 101: 15.0 
                   
                 31 s 
               
               
                 Kollidon CL: 2.0 
               
               
                 Citric acid: 1.0 
               
               
                 AsesulK: 0.2 
               
               
                 Syloid: 0.5 
               
               
                 Tangerine: 0.2 
               
               
                 Pruv: 1.0 
               
               
                 Lot#/mfg date: 1242- 
               
               
                 152/ 
               
               
                 Feb. 05, 2002 
               
               
                 250 g batch/11 mm Flat 
               
               
                 Face Radial 
               
               
                 Edge/450 mg 
               
               
                 FluoxetineTMMS: 
                 30.8 
                 Mouth: 10 s 
                 0.2 
                 Can be used with 
               
               
                 28.69 
                   
                 very fast tablet 
                   
                 any drug except the 
               
               
                 Pearlitol 400DC: 
                   
                 USP basket 
                   
                 drugs that have 
               
               
                 38.56 
                   
                 rack assembly: 
                   
                 amine group. 
               
               
                 Advantose 100: 12.85 
                   
                 19 s 
               
               
                 Avicel PH 101: 15.0 
               
               
                 Kollidon CL: 2.0 
               
               
                 Citric acid: 1.0 
               
               
                 AsesulK: 0.2 
               
               
                 Syloid: 0.5 
               
               
                 Tangerine: 0.2 
               
               
                 Pruv: 1.0 
               
               
                 Lot#/mfg date: 1242- 
               
               
                 153/ 
               
               
                 Feb. 05, 2002 
               
               
                 250 g batch/11 mm Flat 
               
               
                 Face Radial 
               
               
                 Edge/450 mg 
               
               
                 FluoxetineTMMS: 
                 29.4 
                 Mouth: 10 s 
                 0.6 
                 Can be used with 
               
               
                 28.69 
                   
                 very fast tablet, 
                   
                 any drug 
               
               
                 Pearlitol 400DC: 
                   
                 no difference 
               
               
                 49.41 
                   
                 between 1242- 
               
               
                 Avicel PH 101: 15.0 
                   
                 154 &amp; 140 
               
               
                 Kollidon CL: 2.0 
                   
                 batches 
               
               
                 L-HPC 11: 4.0 
                   
                 USP basket 
               
               
                 Citric acid: 1.0 
                   
                 rack assembly: 
               
               
                 AsesulK: 0.2 
                   
                 23 s 
               
               
                 Syloid: 0.5 
               
               
                 Tangerine: 0.2 
               
               
                 Pruv: 1.0 
               
               
                 Lot#/mfg date: 1242- 
               
               
                 157/ 
               
               
                 Feb. 06, 2002 
               
               
                 250 g batch/11 mm Flat 
               
               
                 Face Radial 
               
               
                 Edge/450 mg 
               
               
                 FluoxetineTMMS: 
                 33.1 
                 Mouth: 12-15 s 
                 0.6 
                 Can be used with 
               
               
                 28.69 
                   
                 good tablet 
                   
                 any drug except the 
               
               
                 Pearlitol 400DC: 
                   
                 USP basket 
                   
                 drugs that have 
               
               
                 37.06 
                   
                 rack assembly: 
                   
                 amine group. 
               
               
                 Advantose 100: 12.35 
                   
                 12 s 
               
               
                 Avicel PH 101: 15.0 
               
               
                 Kollidon CL: 2.0 
               
               
                 L-HPC 11: 2.0 
               
               
                 Citric acid: 1.0 
               
               
                 AsesulK: 0.2 
               
               
                 Syloid: 0.5 
               
               
                 Tangerine: 0.2 
               
               
                 Pruv: 1.0 
               
               
                 Lot#/mfg date: 1242- 
               
               
                 158/ 
               
               
                 Feb. 06, 2002 
               
               
                 250 g batch/11 mm Flat 
               
               
                 Face Radial 
               
               
                 Edge/450 mg 
               
               
                   
               
             
          
         
       
     
       Fast Disintegrating Non Floss Tablet Additional Preferred Formulation 
       [0108]      
         [0000]    
       
         
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 FluoxetineTMMS: 
                 28.4 
                 Mouth: 8-10 s 
                 0.5 
                 Can be used with 
               
               
                 28.69 
                   
                 very good 
                   
                 any drug 
               
               
                 Pearlitol 400DC: 
                   
                 tablet 
               
               
                 48.41 
                   
                 USP basket 
               
               
                 Avicel PH 101: 16.0 
                   
                 rack assembly: 
               
               
                 Kollidon CL: 2.0 
                   
                 12 s 
               
               
                 L-HPC 11: 2.0 
               
               
                 Citric acid: 1.0 
               
               
                 AsesulK: 0.2 
               
               
                 Magnasweet 100: 0.2 
               
               
                 Tangerine: 0.2 
               
               
                 Syloid: 0.5 
               
               
                 Pruv: 1.0 
               
               
                 Lot#/mfg date: 1242- 
               
               
                 167/ 
               
               
                 Feb. 13, 2002 
               
               
                 250 g batch/11 mm Flat 
               
               
                 Face Radial 
               
               
                 Edge/450 mg 
               
               
                   
               
             
          
         
       
     
       Additional Formulations: 
       [0109]      
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
               
               
                   
                   
                 Mixing procedure &amp; 
                 Hardness 
                 Disintegration 
                   
               
               
                 Formulation Lot# 
                 Objective 
                 Equipment used 
                 (N) 
                 Time 
                 Friability % 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Fluoxetine TMMS: 
                 Investigate 
                  1/2  Pearlitol 400DC, 
                 32.4 
                 Mouth: 10 S 
                 Abrasion: 
               
               
                 28.69 
                 high level 
                 all MS 
                   
                   
                 0.3 
               
               
                 Pearlitol 400DC: 
                 of Kollidon 
                  1/2  Pearlitol 400DC, 
                   
                   
                 Drop: 
               
               
                 58.41 
                 XL for fast 
                 mix for 3 min. Add 
                   
                   
                 2.1 
               
               
                 Kolidon XL: 10 
                 disintegration 
                 all Citric acid, all 
               
               
                 Citric acid: 1.0 
                 using 
                 AcesuK, all syloid, 
               
               
                 AsesulK: 0.2 
                 high 
                 all Kollidon, all 
               
               
                 Tangerine: 0.2 
                 compression. 
                 tangerine, mix for 
               
               
                 Syloid: 0.5 
                   
                 5 min. Then pour all 
               
               
                 Pruv: 1.0 
                   
                 pruv and mix for 2 min 
               
               
                 Lot#/mfg date: 
                   
                 using Turbula 
               
               
                 1242-117/Jan. 14, 2002 
                   
                 mixer. 
               
               
                 250 g batch 
                   
                 Piccola tablets press 
               
               
                   
                   
                 11 mm punch FFRE 
               
               
                   
                   
                 450 mg table 
               
               
                 Fluoxetine TMMS: 
                 Evaluate 
                  1/2  Parteck M200, all 
                 22.2 
                 Mouth: 10 S 
                 Abrasion: 
               
               
                 28.69 
                 different 
                 MS, 
                   
                   
                 1.4 
               
               
                 Pearlitol 400DC: 
                 from 
                  1/2  Parteck M200 mix 
                   
                   
                 Drop: 
               
               
                 58.41 
                 different 
                 for 3 min. Add all 
                   
                   
                 4.1 
               
               
                 Kolidon XL: 10 
                 suppliers. 
                 Citric acid, all 
               
               
                 Citric acid: 1.0 
                   
                 AcesuK, all syloid, 
               
               
                 AsesulK: 0.2 
                   
                 all Kollidon, all 
               
               
                 Tangerine: 0.2 
                   
                 tangerine, mix for 5 min. 
               
               
                 Syloid: 0.5 
                   
                 Then pour all 
               
               
                 Pruv: 1.0 
                   
                 pruv and mix for 2 min. 
               
               
                 Lot#/mfg date: 
                   
                 using Turbula 
               
               
                 1242-118/Jan. 14, 2002 
                   
                 mixer. 
               
               
                 250 g batch 
                   
                 Piccola tablets press 
               
               
                   
                   
                 11 mm punch FFRE 
               
               
                   
                   
                 450 mg tablet 
               
               
                 Fluoxetine TMMS: 
                 Evaluate 
                  1/2  Parteck M300, all 
                 29.9 
                 Mouth: 10 S 
                 Abrasion: 
               
               
                 28.69 
                 different 
                 MS 
                   
                   
                 0.8 
               
               
                 Pearlitol 400DC: 
                 mannitol 
                  1/2  Parteck M300, mix 
                   
                   
                 Drop: 
               
               
                 58.41 
                 from 
                 for 3 min. Add all 
                   
                   
                 3.0 
               
               
                 Kolidon XL: 10 
                 different 
                 Citric acid, all 
               
               
                 Citric acid: 1.0 
                 suppliers. 
                 AcesuK, all syloid, 
               
               
                 AsesulK: 0.2 
                   
                 all Kollidon, all 
               
               
                 Tangerine: 0.2 
                   
                 tangerine, mix for 5 min. 
               
               
                 Syloid: 0.5 
                   
                 Then pour all 
               
               
                 Pruv: 1.0 
                   
                 pruv and mix for 2 min. 
               
               
                 Lot#/mfg date: 
                   
                 using Turbula 
               
               
                 1242-119/Jan. 14, 2002 
                   
                 mixer. 
               
               
                 250 g batch 
                   
                 Piccola tablets press 
               
               
                   
                   
                 11 mm punch FFRE 
               
               
                   
                   
                 450 mg tablet 
               
               
                 Fluoxetine TMMS: 
                 Increase 
                  1/2  Pearlitol 400DC, 
                 29.6 
                 Mouth: 10 S 
                 Abrasion: 
               
               
                 28.69 
                 the 
                 all MS 
                   
                   
                 0.4 
               
               
                 Pearlitol 400DC: 
                 Kollidon 
                  1/2  pearlitol 400DC, 
                   
                   
                 Drop: 
               
               
                 48.41 
                 XL from 
                 mix for 3 min. Add 
                   
                   
                 2.3 
               
               
                 Kolidon XL: 20 
                 10% to 
                 all Citric acid, all 
               
               
                 Citric acid: 1.0 
                 20% to 
                 AcesuK, all syloid, 
               
               
                 AsesulK: 0.2 
                 determine 
                 all Kollidon, all 
               
               
                 Tangerine: 0.2 
                 the effect 
                 tangerine, mix for 
               
               
                 Syloid: 0.5 
                 of 
                 5 min. Then pour all 
               
               
                 Pruv: 1.0 
                 disintegrant 
                 pruv and mix for 2 min 
               
               
                 Lot#/mfg date: 
                 concentration 
                 using Turbula 
               
               
                 1242-120/Jan. 15, 2002 
                 on 
                 mixer. 
               
               
                 250 g batch 
                 disintegration 
                 Piccola tablets press 
               
               
                   
                 time 
                 11 mm punch FFRE 
               
               
                 Fluoxetine TMMS: 
                 Investigate 
                  1/2  Pearlitol 400DC, 
                 16.2 
                 Mouth: 20 S, 
                 Abrasion: 
               
               
                 28.69 
                 alternative 
                 all MS 
                   
                 at 20 and 30 
                 14.8 
               
               
                 Pearlitol 400DC: 
                 distintegrant 
                  1/2  Pearlitol 400DC, 
                   
                 N tablets 
                 Drop: 
               
               
                 48.41 
                 like L- 
                 mix for 3 min. Add 
                   
                 very slow to 
                 Powder 
               
               
                 L-HPC 11: 2.0 
                 HPC11 
                 all Citric acid, all 
                   
                 disintegrate 
                 collection 
               
               
                 Citric acid: 1.0 
                   
                 AcesuK, all syloid, 
               
               
                 AsesulK: 0.2 
                   
                 all L-HPC, all 
               
               
                 Tangerine: 0.2 
                   
                 tangerine, mix for 5 min. 
               
               
                 Syloid: 0.5 
                   
                 Then pour all 
               
               
                 Pruv: 1.0 
                   
                 pruv and mix for 2 min 
               
               
                 Lot#/mfg date: 
                   
                 using Turbula 
               
               
                 1242-123/Jan. 16, 2002 
                   
                 mixer. 
               
               
                 250 g batch 
                   
                 Piccola tablets press 
               
               
                   
                   
                 11 mm punch FFRE 
               
               
                   
                   
                 450 mg tablet 
               
               
                 Fluoxetine TMMS: 
                 Increase 
                  1/2  Pearlitol 400DC, 
                 29.7 
                 Mouth: 10 S 
                 Abrasion: 
               
               
                 28.69 
                 the 
                 all MS 
                   
                   
                 0.2 
               
               
                 Pearlitol 400DC: 
                 Kollidon 
                  1/2  pearlitol 400DC, 
                   
                   
                 Drop: 
               
               
                 48.41 
                 XL from 
                 mix for 3 min. Add 
                   
                   
                 0.8 
               
               
                 Avicel PH 101: 16.0 
                 10% to 
                 all Citric acid, all 
               
               
                 L-HPC 11: 4.0 
                 20% to 
                 AcesuK, all syloid, 
               
               
                 Citric acid: 1.0 
                 determine 
                 all avicel, all L-HPC, 
               
               
                 AsesulK: 0.2 
                 the effect 
                 all tangerine, mix for 
               
               
                 Tangerine: 0.2 
                 of 
                 5 min. Then pour all 
               
               
                 Syloid: 0.5 
                 disintegrant 
                 pruv and mix for 2 min 
               
               
                 Pruv: 1.0 
                 concentration 
                 using Turbula 
               
               
                 Lot#/mfg date: 
                 on 
                 mixer. 
               
               
                 1242-124/Jan. 16, 2002 
                 disintegration 
                 Piccola tablets press 
               
               
                 250 g batch 
                 time 
                 11 mm punch FFRE 
               
               
                 Avicel PH101/L- 
                   
                 450 mg tablet 
               
               
                 HPC11 ratio 
               
               
                 (80/20) 
               
               
                 Fluoxetine TMMS: 
                 Evaluate 
                  1/2  Pearl 400DC, all 
                 34.0 
                 Mouth: 10 S 
                 Abrasion: 
               
               
                 28.69 
                 different 
                 MS 
                   
                   
                 0.2 
               
               
                 Pearlitol 400DC: 
                 ratio of 
                  1/2  Pearlitol 400DC, 
                   
                   
                 Drop: 
               
               
                 48.41 
                 avicel PH 
                 mix for 3 min. Add 
                   
                   
                 0.8 
               
               
                 Avicel PH 101: 18.0 
                 101/L-HPC 
                 all Citric acid, all 
               
               
                 L-HPC 11: 2.0 
                 11 to 
                 AcesuK, all syloid, 
               
               
                 Citric acid: 1.0 
                 determine 
                 all avicel, all L0HPC, 
               
               
                 AsesulK: 0.2 
                 which 
                 all tangerine, mix for 
               
               
                 Tangerine: 0.2 
                 excipient 
                 5 min. Then pour all 
               
               
                 Syloid: 0.5 
                 affect more 
                 pruv and mix for 2 min 
               
               
                 Pruv: 1.0 
                 the 
                 using Turbula 
               
               
                 Lot#/mfg date: 
                 disintegration 
                 mixer. 
               
               
                 1242-125/Jan. 16, 2002 
                 in the 
                 Piccola tablets press 
               
               
                 250 g batch 
                 mouth. 
                 11 mm punch FFRE 
               
               
                 Avicel PH 101/L- 
                   
                 450 mg table 
               
               
                 HPC11 ratio 
               
               
                 (90/10) 
               
               
                 Fluoxetine TMMS: 
                 Evaluate 
                  1/2  Pearlitol 400DC, 
                 31.0 
                 Mouth: 10 S 
                 Abrasion: 
               
               
                 28.69 
                 different 
                 all MS, 
                   
                   
                 0.2 
               
               
                 Pearlitol 400DC: 
                 ratio of 
                  1/2  Pearlitol 400DC, 
                   
                   
                 Drop: 
               
               
                 48.41 
                 avicel PH 
                 mix for 3 min. Add 
                   
                   
                 1.0 
               
               
                 Avicel PH 101: 18.0 
                 101/L-HPC 
                 all Citric acid, all 
               
               
                 L-HPC 11: 2.0 
                 11 to 
                 AcesuK, all syloid, 
               
               
                 Citric acid: 1.0 
                 determine 
                 all Kollidon, all 
               
               
                 AsesulK: 0.2 
                 which 
                 tangerine, mix for 5 min. 
               
               
                 Tangerine: 0.2 
                 excipient 
                 Then pour all 
               
               
                 Syloid: 0.5 
                 affect more 
                 pruv and mix for 2 min. 
               
               
                 Pruv: 1.0 
                 the 
                 using Turbula 
               
               
                 Lot#/mfg date: 
                 disintegration 
                 mixer. 
               
               
                 1242-129/Jan. 19, 2002 
                 in the 
                 Piccola tablets press 
               
               
                 250 g batch 
                 mouth. 
                 11 mm punch FFRE 
               
               
                 Avicel PH 101/L- 
                   
                 450 mg tablet 
               
               
                 HPC11 ratio 
               
               
                 (90/10) 
               
               
                 Fluoxetine TMMS: 
                 Comparative 
                  1/2  Pearlitol 400DC, 
                 33.8 
                 Mouth 10: 
                 Abrasion: 
               
               
                 28.69 
                 study of 
                 all MS, 
                   
                 10 S 
                 0.1 
               
               
                 Pearlitol 400DC: 
                 disintegration 
                  1/2  Pearlitol 400DC, 
                   
                   
                 Drop: 
               
               
                 48.41 
                 time of 
                 mix for 3 min. Add 
                   
                   
                 1.5 
               
               
                 Avicel PH 101: 16.0 
                 avicel PH 
                 all Citric acid, all 
               
               
                 Kollidon XL: 4.0 
                 101/L- 
                 Acesu K, all syloid, 
               
               
                 Citric acid: 1.0 
                 HPC11 
                 all avicel, all 
               
               
                 AsesulK: 0.2 
                 formulation 
                 Kollidon, all 
               
               
                 Tangerine: 0.2 
                 versus 
                 tangerine, mix for 5 min. 
               
               
                 Syloid: 0.5 
                 avicel PH 
                 Then pour all 
               
               
                 Pruv: 1.0 
                 101/Kollidon 
                 pruv and mix for 2 min 
               
               
                 Lot#/mfg date: 
                 XL 
                 using Turbula 
               
               
                 1242-126/Jan. 17, 2002 
                   
                 mixer. 
               
               
                 250 g batch 
                   
                 Piccola tablets press 
               
               
                 Avicel PH 
                   
                 11 mm punch FFRE 
               
               
                 101/Kollidon ratio 
                   
                 450 mg tablet 
               
               
                 (80/20 
               
               
                 Fluoxetine TMMS: 
                 Comparative 
                  1/2  Pearlitol 400DC, 
                 31-37 
                 Mouth 10: 
                 Abrasion: 
               
               
                 28.69 
                 study of 
                 all MS, 
                   
                 10 S 
                 0.04 
               
               
                 Pearlitol 400DC: 
                 disintegration 
                  1/2  Pearlitol 400DC, 
                   
                   
                 Drop: 
               
               
                 48.41 
                 time of 
                 mix for 3 min. Add 
                   
                   
                 1.6 
               
               
                 Avicel PH 101: 4.0 
                 avicel PH 
                 all Citric acid, all 
               
               
                 Kollidon XL: 16.0 
                 101/L- 
                 Acesu K, all syloid, 
               
               
                 Citric acid: 1.0 
                 HPC11 
                 all avicel, all 
               
               
                 AsesulK: 0.2 
                 formulation 
                 Kollidon, all 
               
               
                 Tangerine: 0.2 
                 versus 
                 tangerine, mix for 5 min. 
               
               
                 Syloid: 0.5 
                 avicel PH 
                 Then pour all 
               
               
                 Pruv: 1.0 
                 101/Kollidon 
                 pruv and mix for 2 min 
               
               
                 Lot#/mfg date: 
                 XL 
                 using Turbula 
               
               
                 1242-127/Jan. 17, 2002 
                   
                 mixer. 
               
               
                 250 g batch 
                   
                 Piccola tablets press 
               
               
                 Avicel PH 
                   
                 11 mm punch FFRE 
               
               
                 101/Kollidon ratio 
                   
                 450 mg tablet 
               
               
                 (20/80) 
               
               
                 Fluoxetine TMMS: 
                 Comparative 
                  1/2  Pearlitol 400DC, 
                 36.4 
                 Mouth 10: 
                 Abrasion: 
               
               
                 28.69 
                 study of 
                 all MS, 
                   
                 10 S 
                 1.0 
               
               
                 Pearlitol 400DC: 
                 disintegration 
                  1/2  Pearlitol 400DC, 
                   
                   
                 Drop: 
               
               
                 52.41 
                 time of 
                 mix for 3 min. Add 
                   
                   
                 2.5 
               
               
                 Kollidon XL: 16.0 
                 16% 
                 all Citric acid, all 
               
               
                 Citric acid: 1.0 
                 Kollidon to 
                 Acesu K, all syloid, 
               
               
                 AsesulK: 0.2 
                 10 and 
                 all avicel, all 
               
               
                 Tangerine: 0.2 
                 20% 
                 Kollidon, all 
               
               
                 Syloid: 0.5 
                   
                 tangerine, mix for 5 min. 
               
               
                 Pruv: 1.0 
                   
                 Then pour all 
               
               
                 Lot#/mfg date: 
                   
                 pruv and mix for 2 min 
               
               
                 1242-130/Jan. 19, 2002 
                   
                 using Turbula 
               
               
                 250 g batch 
                   
                 mixer. 
               
               
                   
                   
                 Piccola tablets press 
               
               
                   
                   
                 11 mm punch FFRE 
               
               
                   
                   
                 450 mg tablet 
               
               
                 Fluoxetine TMMS: 
                 Increase 
                  1/2  Pearlitol 400DC, 
                 29.4 
                 Mouth: 10 S 
                 Abrasion: 
               
               
                 28.69 
                 the level of 
                 all MS, 
                   
                   
                 1.7 
               
               
                 Pearlitol 400DC: 
                 avicel to 
                  1/2  Pearlitol 400DC, 
                   
                   
                 Drop: 
               
               
                 26.25 
                 improve 
                 mix for 3 min. Add 
                   
                   
                 1.8 
               
               
                 Avicel PH 101: 
                 the 
                 all Citric acid, all 
               
               
                 26.25 
                 disintegration 
                 Acesu K, all syloid, 
               
               
                 L-HPC: 16 
                 time. 
                 all avicel, all L-HPC, 
               
               
                 Citric acid: 1.0 
                 Avicel is 
                 all tangerine, mix for 
               
               
                 AsesulK: 0.2 
                 porous and 
                 5 min. Then pour all 
               
               
                 Tangerine: 0.2 
                 therefore, it 
                 pruv and mix for 2 min 
               
               
                 Syloid: 0.5 
                 absorbs lot 
                 using Turbula 
               
               
                 Pruv: 1.0 
                 of water 
                 mixer. 
               
               
                 Lot#/mfg date: 
                 which 
                 F tablets press 
               
               
                 1242-131/Jan. 21, 2002 
                 helps the 
                 11 mm punch FFRE. 
               
               
                 250 g batch 
                 swelling of 
                 450 mg tablet 
               
               
                   
                 L-HPC 
               
               
                 Fluoxetine TMMS: 
                 Same 
                  1/2  Pearlitol 400DC, 
                 29.7 
                 Mouth: 10 S 
                 Abrasion: 
               
               
                 28.69 
                 objective 
                 all MS 
                   
                   
                 0.3 
               
               
                 Pearlitol 400DC: 
                 as 1242- 
                  1/2  Pearlitol 400DC, 
                   
                   
                 Drop: 
               
               
                 26.25 
                 131, except 
                 mix for 3 min. Add 
                   
                   
                 1.8 
               
               
                 Avicel PH 101: 
                 Kollidon 
                 all Citric acid, all 
               
               
                 26.25 
                 was used. 
                 AcesuK, all syloid, 
               
               
                 Kolidon XL: 16 
                   
                 all Kollidon, all 
               
               
                 Citric acid: 1.0 
                   
                 tangerine, mix for 5 min. 
               
               
                 AsesulK: 0.2 
                   
                 Then pour all 
               
               
                 Tangerine: 0.2 
                   
                 pruv and mix for 2 min 
               
               
                 Syloid: 0.5 
                   
                 using Turbula 
               
               
                 Pruv: 1.0 
                   
                 mixer. 
               
               
                 Lot#/mfg date: 
                   
                 F tablets press 
               
               
                 1242-132/Jan. 21, 2002 
                   
                 11 mm punch FFRE 
               
               
                 250 g batch 
                   
                 450 mg table 
               
               
                 Ireland Formulation 
                 Enalapril 
                   
                 26 
                 Mouth: 10 S 
                 Abrasion: 
               
               
                   
                 FD tablets 
                   
                   
                   
                 2.5 
               
               
                   
                 36 mg 
                   
                   
                   
                 Drop: 
               
               
                   
                   
                   
                   
                   
                 0.3 
               
               
                 Fluoxetine TMMS: 
                 Investigate 
                  1/2  Pearlitol 400DC, 
                 28.3 
                 Mouth: 15-20 S 
                 Abrasion: 
               
               
                 28.69 
                 the effect 
                 all MS 
                   
                 Slower than 
                 0.3 
               
               
                 Pearlitol 400DC: 
                 of MCC on 
                  1/2  Pearlitol 400DC, 
                   
                 1242-125 
                 Drop: 
               
               
                 54.41 
                 the 
                 mix for 3 min. Add 
                   
                   
                 0.3 
               
               
                 Avicel PH 101: 12.0 
                 disintegration 
                 all Citric acid, all 
               
               
                 L-HPC 11: 2.0 
                 of the 
                 AcesuK, all syloid, 
               
               
                 Citric acid: 1.0 
                 tablets. 
                 all avicel, all L- 
               
               
                 AsesulK: 0.2 
                 Decrease 
                 HPCn, all tangerine, 
               
               
                 Tangerine: 0.2 
                 MCC from 
                 mix for 5 min. Then 
               
               
                 Syloid: 0.5 
                 18 to 12% 
                 pour all pruv and mix 
               
               
                 Pruv: 1.0 
                   
                 for 2 min using 
               
               
                 Lot#/mfg date: 
                   
                 Turbula mixer. 
               
               
                 1242-133/Jan. 23, 2002 
                   
                 F tablets press 
               
               
                 250 g batch 
                   
                 11 mm punch FFRE 
               
               
                   
                   
                 450 mg table 
               
               
                 Fluoxetine TMMS: 
                 Investigate 
                  1/2  Pearlitol 400DC, 
                 28.1 
                 Mouth: 20 S 
                 Abrasion: 
               
               
                 28.69 
                 the effect 
                 all MS 
                   
                 Slower than 
                 0.4 
               
               
                 Pearlitol 400DC: 
                 of MCC on 
                  1/2  Pearlitol 400DC, 
                   
                 1242-133 
                 Drop: 
               
               
                 60.41 
                 the 
                 mix for 3 min. Add 
                   
                   
                 0.4 
               
               
                 Avicel PH 101: 6.0 
                 disintegration 
                 all Citric acid, all 
               
               
                 L-HPC 11: 2.0 
                 of the 
                 AcesuK, all syloid, 
               
               
                 Citric acid: 1.0 
                 tablets. 
                 all avicel, all L-HPC, 
               
               
                 AsesulK: 0.2 
                 Decrease 
                 all tangerine, mix for 
               
               
                 Tangerine: 0.2 
                 MCC from 
                 5 min. Then pour all 
               
               
                 Syloid: 0.5 
                 18 to 6% 
                 pruv and mix for 2 min 
               
               
                 Pruv: 1.0 
                   
                 using Turbula 
               
               
                 Lot#/mfg date: 
                   
                 mixer. 
               
               
                 1242-134/Jan. 23, 2002 
                   
                 F tablets press 
               
               
                 250 g batch 
                   
                 11 mm punch FFRE 
               
               
                   
                   
                 450 mg table 
               
               
                 Fluoxetine TMMS: 
                 Decreasing 
                  1/2  Pearlitol 400DC, 
                 29.5 
                 Mouth: 10 S 
                 Abrasion: 
               
               
                 28.69 
                 the level of 
                 all MS 
                   
                 As good as 
                 0.3 
               
               
                 Pearlitol 400DC: 
                 MCC from 
                  1/2  Pearlitol 400DC, 
                   
                 1242-125 
                 Drop: 
               
               
                 51.41 
                 18 to 12% 
                 mix for 3 min. Add 
                   
                   
                 0.3 
               
               
                 Avicel PH 101: 15.0 
                 in the 
                 all Citric acid, all 
               
               
                 L-HPC 11: 2.0 
                 formulation 
                 AcesuK, all syloid, 
               
               
                 Citric acid: 1.0 
                 slowed 
                 all avicel, all L-HPC, 
               
               
                 AsesulK: 0.2 
                 down 
                 all tangerine, mix for 
               
               
                 Tangerine: 0.2 
                 slightly the 
                 5 min. Then pour all 
               
               
                 Syloid: 0.5 
                 disintegration 
                 pruv and mix for 2 min 
               
               
                 Pruv: 1.0 
                 of the 
                 using Turbula 
               
               
                 Lot#/mfg date: 
                 tablets, but 
                 mixer. 
               
               
                 1242-135/Jan. 24, 2002 
                 it appeared 
                 F tablets press 
               
               
                 250 g batch 
                 to be an 
                 11 mm punch FFRE 
               
               
                   
                 optimum 
                 450 mg table 
               
               
                   
                 level in 
               
               
                   
                 between. 
               
               
                   
                 The level 
               
               
                   
                 of MCC 
               
               
                   
                 was 
               
               
                   
                 decreased 
               
               
                   
                 to 15% 
               
               
                   
                 instead. 
               
               
                 Fluoxetine TMMS: 
                 To 
                  1/2  Pearlitol 400DC, 
                 27.5 
                 Mouth: 20 S 
                 Abrasion: 
               
               
                 28.69 
                 investigate 
                 all MS 
                   
                 Disintegrate 
                 0.2 
               
               
                 Pearlitol 400DC: 
                 if the use 
                  1/2  Pearlitol 400DC, 
                   
                 with a core 
                 Drop: 
               
               
                 53.41 
                 of L-HPC 
                 mix for 3 min. Add 
                   
                   
                 0.4 
               
               
                 Avicel PH 101: 15.0 
                 is 
                 all Citric acid, all 
               
               
                 Citric acid: 1.0 
                 necessary 
                 AcesuK, all syloid, 
               
               
                 AsesulK: 0.2 
                 in the 
                 all avicel, all 
               
               
                 Tangerine: 0.2 
                 formulation 
                 tangerine, mix for 5 min. 
               
               
                 Syloid: 0.5 
                 to enhance 
                 Then pour all 
               
               
                 Pruv: 1.0 
                 the 
                 pruv and mix for 2 min 
               
               
                 Lot#/mfg date: 
                 disintegration 
                 using Turbula 
               
               
                 1242-136/Jan. 24, 2002 
                 of the 
                 mixer. 
               
               
                 250 g batch 
                 tablet. 
                 F tablets press 
               
               
                   
                   
                 11 mm punch FFRE 
               
               
                   
                   
                 450 mg table 
               
               
                 Fluoxetine TMMS: 
                 Investigate 
                  1/2  Pearlitol 400DC, 
                 28.3 
                 Mouth: 20 S 
                 Abrasion: 
               
               
                 28.69 
                 other 
                 all MS 
                   
                 As good as 
                 0.2 
               
               
                 Pearlitol 400DC: 
                 grades of 
                  1/2  Pearlitol 400DC, 
                   
                 1242-125 
                 Drop: 
               
               
                 51.41 
                 MCC 
                 mix for 3 min. Add 
                   
                   
                 0.4 
               
               
                 Prosolv 90: 15.0 
                   
                 all Citric acid, all 
               
               
                 L-HPC 11: 2.0 
                   
                 AcesuK, all syloid, 
               
               
                 Citric acid: 1.0 
                   
                 all prosolv, all 
               
               
                 AsesulK: 0.2 
                   
                 tangerine, mix for 5 min. 
               
               
                 Tangerine: 0.2 
                   
                 Then pour all 
               
               
                 Syloid: 0.5 
                   
                 pruv and mix for 2 min 
               
               
                 Pruv: 1.0 
                   
                 using Turbula 
               
               
                 Lot#/mfg date: 
                   
                 mixer. 
               
               
                 1242-137/Jan. 24, 2002 
                   
                 F tablets press 
               
               
                 250 g batch 
                   
                 11 mm punch FFRE 
               
               
                   
                   
                 450 mg table 
               
               
                 Fluoxetine TMMS: 
                 Investigate 
                  1/2  Pearlitol 400DC, 
                 26.0 
                 Mouth: 10 S 
                 Abrasion: 
               
               
                 28.69 
                 other 
                 all MS 
                   
                 Better than 
                 0.3 
               
               
                 Pearlitol 400DC: 
                 grades of 
                  1/2  Pearlitol 400DC, 
                   
                 1242-124 
                 Drop: 
               
               
                 51.41 
                 MCC 
                 mix for 3 min. Add 
                   
                   
                 0.2 
               
               
                 Prosolv 90: 15.0 
                   
                 all Citric acid, all 
               
               
                 L-HPC 11: 2.0 
                   
                 AcesuK, all syloid, 
               
               
                 Citric acid: 1.0 
                   
                 all prosolv, all L- 
               
               
                 AsesulK: 0.2 
                   
                 HPC, all tangerine, 
               
               
                 Tangerine: 0.2 
                   
                 mix for 5 min. Then 
               
               
                 Syloid: 0.5 
                   
                 pour all pruv and mix 
               
               
                 Pruv: 1.0 
                   
                 for 2 min using 
               
               
                 Lot#/mfg date: 
                   
                 Turbula mixer. 
               
               
                 1242-138/Jan. 24, 2002 
                   
                 F tablets press 
               
               
                 250 g batch 
                   
                 11 mm punch FFRE 
               
               
                   
                   
                 450 mg table 
               
               
                 Fluoxetine TMMS: 
                 Investigate 
                  1/2  Pearlitol 400DC, 
                 28.4 
                 Mouth: 15 S-20 S 
                 Abrasion: 
               
               
                 28.69 
                 other 
                 all MS 
                   
                   
                 0.2 
               
               
                 Pearlitol 400DC: 
                 greades of 
                  1/2  Pearlitol 400DC, 
                   
                   
                 Drop: 
               
               
                 51.41 
                 MCC 
                 mix for 3 min. Add 
                   
                   
                 0.2 
               
               
                 Avicel PH 102″ 
                   
                 all Citric acid, all 
               
               
                 15.0 
                   
                 AcesuK, all syloid, 
               
               
                 L-HPC 11: 2.0 
                   
                 all avicel, all L-HPC, 
               
               
                 Citric acid: 1.0 
                   
                 all tangerine, mix for 
               
               
                 AsesulK: 0.2 
                   
                 5 min. Then pour all 
               
               
                 Tangerine: 0.2 
                   
                 pruv and mix for 2 min 
               
               
                 Syloid: 0.5 
                   
                 using Turbula 
               
               
                 Pruv: 1.0 
                   
                 mixer. 
               
               
                 Lot#/mfg date: 
                   
                 F tablets press 
               
               
                 1242-139/Jan. 24, 2002 
                   
                 11 mm punch FFRE 
               
               
                 250 g batch 
                   
                 450 mg table 
               
               
                 Fluoxetine TMMS: 
                 Investigate 
                  1/2  Pearlitol 400DC, 
                 24.4 
                 Mouth: 15 S 
                 Abrasion: 
               
               
                 28.69 
                 other 
                 all MS 
                   
                   
                 0.3 
               
               
                 Pearlitol 400DC: 
                 greades of 
                  1/2  Pearlitol 400DC, 
                   
                   
                 Drop: 
               
               
                 53.41 
                 MCC 
                 mix for 3 min. Add 
                   
                   
                 0.3 
               
               
                 Avicel PH 113: 15.0 
                   
                 all Citric acid, all 
               
               
                 L-HPC 11: 2.0 
                   
                 AcesuK, all syloid, 
               
               
                 Citric acid: 1.0 
                   
                 all avicel, all L-HPC, 
               
               
                 AsesulK: 0.2 
                   
                 all tangerine, mix for 
               
               
                 Tangerine: 0.2 
                   
                 5 min. Then pour all 
               
               
                 Syloid: 0.5 
                   
                 pruv and mix for 2 min 
               
               
                 Pruv: 1.0 
                   
                 using Turbula 
               
               
                 Lot#/mfg date: 
                   
                 mixer. 
               
               
                 1242-140/Jan. 25, 2002 
                   
                 F tablets press 
               
               
                 250 g batch 
                   
                 11 mm punch FFRE 
               
               
                   
                   
                 450 mg table 
               
               
                 Fluoxetine TMMS: 
                 To 
                  1/2  advantose, all MS 
                 26.9 
                 Mouth: 20 S 
                 Abrasion: 
               
               
                 28.69 
                 investigate 
                  1/2  advantose, mix for 
                   
                 with a core. 
                 0.8 
               
               
                 Advantose 100: 
                 alternative 
                 3 min. Add all Citric 
                   
                 Tablet sweet 
                 Drop: 
               
               
                 68.41 
                 polyols. In 
                 acid, all AcesuK, all 
                   
                 and have 
                 2.0 
               
               
                 Citric acid: 1.0 
                 this 
                 syloid, all tangerine, 
                   
                 good 
               
               
                 AsesulK: 0.2 
                 experiment, 
                 mix for 5 min. Then 
                   
                 mouthfeel. 
               
               
                 Tangerine: 0.2 
                 determine 
                 pour all pruv and mix 
               
               
                 Syloid: 0.5 
                 the 
                 for 2 min using 
               
               
                 Pruv: 1.0 
                 compressibility 
                 Turbula mixer. 
               
               
                 Lot#/mfg date: 
                 of 
                 F tablets press 
               
               
                 1242-141/Jan. 25, 2002 
                 maltose 
                 11 mm punch FFRE 
               
               
                 250 g batch 
                 (advantose 
                 450 mg table 
               
               
                   
                 100) 
               
               
                 Fluoxetine TMMS: 
                 To 
                  1/2  advantose, all MS 
                 27.9 
                 Mouth: 10 S 
                 Abrasion: 
               
               
                 28.69 
                 investigate 
                  1/2  advantose, mix for 
                   
                 Not as good 
                 1.0 
               
               
                 Advantose 100: 
                 alternative 
                 3 min. Add all Citric 
                   
                 as 1242-143 
                 Drop: 
               
               
                 53.41 
                 polyols. In 
                 acid, all AcesuK, all 
                   
                   
                 4.2 
               
               
                 Prosolv 50: 15 
                 this 
                 syloid, all Prosolv, all 
               
               
                 Citric acid: 1.0 
                 experiment, 
                 tangerine, mix for 5 min. 
               
               
                 AsesulK: 0.2 
                 determine 
                 Then pour all 
               
               
                 Tangerine: 0.2 
                 the 
                 pruv and mix for 2 min 
               
               
                 Syloid: 0.5 
                 compressibility 
                 using Turbula 
               
               
                 Pruv: 1.0 
                 of 
                 mixer. 
               
               
                 Lot#/mfg date: 
                 maltose 
                 F tablets press 
               
               
                 1242-142/Jan. 27, 2002 
                 (advantose 
                 11 mm punch FFRE 
               
               
                 250 g batch 
                 100) and 
                 450 mg table 
               
               
                   
                 MCC 
               
               
                 Fluoxetine TMMS: 
                 To 
                  1/2  advantose, all MS 
                 27.9 
                 Mouth: 10 S 
                 Abrasion: 
               
               
                 28.69 
                 investigate 
                  1/2  advantose, mix for 
                   
                 Good tablets 
                 1.0 
               
               
                 Advantose 100: 
                 alternative 
                 3 min. Add all Citric 
                   
                   
                 Drop: 
               
               
                 51.41 
                 poyols. In 
                 acid, all AcesuK, all 
                   
                   
                 3.7 
               
               
                 Prosolv 50: 15 
                 this 
                 syloid, all Prosolv, all 
               
               
                 L-HPC 11: 2.0 
                 experiment, 
                 tangerine, mix for 5 min. 
               
               
                 Citric acid: 1.0 
                 determine 
                 Then pour all 
               
               
                 AsesulK: 0.2 
                 the 
                 pruv and mix for 2 min 
               
               
                 Tangerine: 0.2 
                 compressibility 
                 using Turbula 
               
               
                 Syloid: 0.5 
                 of 
                 mixer. 
               
               
                 Pruv: 1.0 
                 maltose 
                 F tablets press 
               
               
                 Lot#/mfg date: 
                 (advantose 
                 11 mm punch FFRE 
               
               
                 1242-143/Jan. 27, 2002 
                 100)/ 
                 450 mg table 
               
               
                 250 g batch 
                 MCC/L- 
               
               
                   
                 HPC 
               
               
                 Fluoxetine TMMS: 
                 To 
                  1/2  advantose, all MS 
                 26.3 
                 Mouth: 15 S 
                 Abrasion: 
               
               
                 28.69 
                 investigate 
                  1/2  advantose, mix for 
                   
                 Not as good 
                 0.6 
               
               
                 Advantose 100: 
                 the effect of 
                 3 min. Add all Citric 
                   
                 as 1242- 
                 Drop: 
               
               
                 61.41 
                 MCC on the 
                 acid, all AcesuK, all 
                   
                 143. 
                 1.8 
               
               
                 Prosolv 50: 5 
                 disintegration 
                 syloid, all Prosolv, all 
               
               
                 L-HPC 11: 2.0 
                 of the 
                 L-HPC, all tangerine, 
               
               
                 Citric acid: 1.0 
                 tablets 
                 mix for 5 min. Then 
               
               
                 AsesulK: 0.2 
                   
                 pour all pruv and mix 
               
               
                 Tangerine: 0.2 
                   
                 for 2 min using 
               
               
                 Syloid: 0.5 
                   
                 Turbula mixer. 
               
               
                 Pruv: 1.0 
                   
                 F tablets press 
               
               
                 Lot#/mfg date: 
                   
                 11 mm punch FFRE 
               
               
                 1242-144/Jan. 27, 2002 
                   
                 450 mg table 
               
               
                 250 g batch 
               
               
                 Fluoxetine TMMS: 
                 To 
                  1/2  advantose, all MS 
                   
                 Mouth: 20-25 S 
                 Abrasion: 
               
               
                 28.69 
                 investigate 
                  1/2  advantose, mix for 
                   
                 Not as good 
                 0.0 
               
               
                 Advantose 100: 
                 the effect of 
                 3 min. Add all Citric 
                   
                 as 1242- 
                 Drop: 
               
               
                 56.41 
                 MCC on the 
                 acid, all AcesuK, all 
                   
                 143. 
                 1.0 
               
               
                 Prosolv 50: 10.0 
                 disintegration 
                 syloid, all Prosolv, all 
               
               
                 L-HPC 11: 2.0 
                 of the 
                 L-HPC, all tangerine, 
               
               
                 Citric acid: 1.0 
                 tablets 
                 mix for 5 min. Then 
               
               
                 AsesulK: 0.2 
                   
                 pour all pruv and mix 
               
               
                 Tangerine: 0.2 
                   
                 for 2 min using 
               
               
                 Syloid: 0.5 
                   
                 Turbula mixer. 
               
               
                 Pruv: 1.0 
                   
                 F tablets press 
               
               
                 Lot#/mfg date: 
                   
                 11 mm punch FFRE 
               
               
                 1242-145/Jan. 27, 2002 
                   
                 450 mg table 
               
               
                 250 g batch 
               
               
                 Fluoxetine TMMS: 
                 To compare 
                  1/2  advantose, all MS 
                 29.0 
                 Mouth: 10-15 S 
                 Abrasion: 
               
               
                 28.69 
                 the use of 
                  1/2  advantose, mix for 
                   
                 Good tablets 
                 1.0 
               
               
                 Advantose 100: 
                 avicel to 
                 3 min. Add all Citric 
                   
                   
                 Drop: 
               
               
                 51.41 
                 prosolv and 
                 acid, all AcesuK, all 
                   
                   
                 2.0 
               
               
                 Avicel PH 101: 
                 their effect 
                 syloid, all syloid, all 
               
               
                 15.0 
                 on friability 
                 avicel, all tangerine, 
               
               
                 L-HPC 11: 2.0 
                   
                 mix for 5 min. Then 
               
               
                 Citric acid: 1.0 
                   
                 pour all pruv and mix 
               
               
                 AsesulK: 0.2 
                   
                 for 2 min using 
               
               
                 Tangerine: 0.2 
                   
                 Turbula mixer. 
               
               
                 Syloid: 0.5 
                   
                 F tablets press 
               
               
                 Pruv: 1.0 
                   
                 11 mm punch FFRE 
               
               
                 Lot#/mfg date: 
                   
                 450 mg table 
               
               
                 1242-146/Feb. 4, 2002 
               
               
                 250 g batch 
               
               
                 Fluoxetine TMMS: 
                 To 
                  1/2  advantose, 1/2  
                 27.8 
                 Mouth: 10 S 
                 Abrasion: 
               
               
                 28.69 
                 investigate 
                 Pearlitol, all MS, 1/2  
                   
                 Good tablets 
                 0.5 
               
               
                 Advantose 100: 
                 the 
                 Peqrlitol, 1/2  
                   
                   
                 Drop: 
               
               
                 25.70 
                 combination 
                 advantose, mix for 3 min. 
                   
                   
                 1.9 
               
               
                 Pearlitol 400DC: 
                 of 2 polyols 
                 Add all Citric 
               
               
                 25.71 
                 at different 
                 acid, all Acesu K, all 
               
               
                 Avicel PH 101: 
                 ratio and 
                 syloid, all avicel, all 
               
               
                 15.0 
                 their effect 
                 L-HPC, all tangerine, 
               
               
                 L-HPC 11: 2.0 
                 on 
                 mix for 5 min. Then 
               
               
                 Citric acid: 1.0 
                 disintegration 
                 pour all pruv and mix 
               
               
                 AsesulK: 0.2 
                 and 
                 for 2 min using 
               
               
                 Tangerine: 0.2 
                 friability. 
                 Turbula mixer. 
               
               
                 Syloid: 0.5 
                   
                 F tablets press 
               
               
                 Pruv: 1.0 
                   
                 11 mm punch FFRE 
               
               
                 Lot#/mfg date: 
                   
                 450 mg table 
               
               
                 1242-147/Feb. 4, 2002 
               
               
                 250 g batch 
               
               
                 Advantose 
               
               
                 100/Perlitol 
               
               
                 400DC (50/50) 
               
               
                 ratio 
               
               
                 Fluoxetine TMMS: 
                 To 
                  1/2  advantose, 1/2  
                 28.4 
                 Mouth: 15 S 
                 Abrasion: 
               
               
                 28.69 
                 investigate 
                 Pearlitol, all MS, 1/2  
                   
                 Good tablets 
                 0.3 
               
               
                 Advantose 100: 
                 the 
                 Pearlitol, 1/2  
                   
                 No 
                 Drop: 
               
               
                 12.85 
                 combination 
                 advantose, mix for 3 min. 
                   
                 significant 
                 0.5 
               
               
                 Pearlitol 400DC: 
                 of 2 polyols 
                 Add all Citric 
                   
                 difference 
               
               
                 38.56 
                 at different 
                 acid, all Acesu K, all 
                   
                 between 
               
               
                 Avicel PH 101: 
                 ratio and 
                 syloid, all avicel, all 
                   
                 1242-147 
               
               
                 15.0 
                 their effect 
                 L-HPC, all tangerine, 
               
               
                 L-HPC 11: 2.0 
                 on 
                 mix for 5 min. Then 
               
               
                 Citric acid: 1.0 
                 disintegration 
                 pour all pruv and mix 
               
               
                 AsesulK: 0.2 
                 and 
                 for 2 min using 
               
               
                 Tangerine: 0.2 
                 friability. 
                 Turbula mixer. 
               
               
                 Syloid: 0.5 
                   
                 F tablets press 
               
               
                 Pruv: 1.0 
                   
                 11 mm punch FFRE 
               
               
                 Lot#/mfg date: 
                   
                 450 mg table 
               
               
                 1242-148/Feb. 4, 2002 
               
               
                 250 g batch 
               
               
                 Advantose 
               
               
                 100/Perlitol 
               
               
                 400DC (25/75) 
               
               
                 ratio 
               
               
                 Fluoxetine TMMS: 
                 To 
                  1/2  advantose, 1/2  
                 28.4 
                 Mouth: 10 S 
                 Abrasion: 
               
               
                 28.69 
                 investigate 
                 Pearlitol, all MS, 1/2  
                   
                 Good tablets 
                 0.5 
               
               
                 Advantose 100: 
                 the 
                 Pearlitol, 1/2  
                   
                 Faster than 
                 Drop: 
               
               
                 38.56 
                 combination 
                 advantose, mix for 3 min. 
                   
                 1242-147 &amp; 
                 1.6 
               
               
                 Pearlitol 400DC: 
                 of 2 polyols 
                 Add all Citric 
                   
                 148 
               
               
                 12.85 
                 at different 
                 acid, all Acesu K, all 
               
               
                 Avicel PH 101: 
                 ratio and 
                 syloid, all avicel, all 
               
               
                 15.0 
                 their effect 
                 L-HPC, all tangerine, 
               
               
                 L-HPC 11: 2.0 
                 on 
                 mix for 5 min. Then 
               
               
                 Citric acid: 1.0 
                 disintegration 
                 pour all pruv and mix 
               
               
                 AsesulK: 0.2 
                 and 
                 for 2 min using 
               
               
                 Tangerine: 0.2 
                 friability. 
                 Turbula mixer. 
               
               
                 Syloid: 0.5 
                   
                 F tablets press 
               
               
                 Pruv: 1.0 
                   
                 11 mm punch FFRE 
               
               
                 Lot#/mfg date: 
                   
                 450 mg table 
               
               
                 1242-149/Feb. 4, 2002 
               
               
                 250 g batch 
               
               
                 Advantose 
               
               
                 100/Perlitol 
               
               
                 400DC (75/25) 
               
               
                 ratio 
               
               
                 Fluoxetine TMMS: 
                 To compare 
                  1/2  Pearlitol, all MS 
                 27.1 
                 Mouth: 35 S 
                 Abrasion: 
               
               
                 28.69 
                 the physical 
                  1/2  Pearlitol, mix for 3 min. 
                   
                 Very slow 
                 0.2 
               
               
                 Pearlitol 400DC: 
                 properties of 
                 Add all Citric 
                   
                   
                 Drop: 
               
               
                 68.41 
                 pearlitol to 
                 acid, all AcesuK, all 
                   
                   
                 0.3 
               
               
                 Citric acid: 1.0 
                 advantols 
                 syloid, all syloid, all 
               
               
                 AsesulK: 0.2 
                   
                 tangerine, mix for 5 min. 
               
               
                 Tangerine: 0.2 
                   
                 Then pour all 
               
               
                 Syloid: 0.5 
                   
                 pruv and mix for 2 min 
               
               
                 Pruv: 1.0 
                   
                 using Turbula 
               
               
                 Lot#/mfg date: 
                   
                 mixer. 
               
               
                 1242-151/Feb. 4, 2002 
                   
                 F tablets press 
               
               
                 250 g batch 
                   
                 11 mm punch FFRE 
               
               
                   
                   
                 450 mg table 
               
               
                 Fluoxetine TMMS: 
                 To evaluate 
                  1/2  Pearlitol, all MS 
                 33.9 
                 Mouth: 7-10 S 
                 Abrasion: 
               
               
                 28.69 
                 the Kollidon 
                  1/2  Pearlitol, mix for 3 min. 
                   
                 Very fast 
                 0.2 
               
               
                 Pearlitol 400DC: 
                 CL and its 
                 Add all Citric 
                   
                 tablet 
                 Drop: 
               
               
                 51.41 
                 effect on 
                 acid, all AcesuK, all 
                   
                   
                 0.6 
               
               
                 Avicel PH 101: 
                 disintegration 
                 syloid, all syloid, all 
               
               
                 15.0 
                 and 
                 avicel, all kollidon, 
               
               
                 Kollidon CL: 2.0 
                 friability in 
                 all tangerine, mix for 
               
               
                 Citric acid: 1.0 
                 the pearlitol 
                 5 min. Then pour all 
               
               
                 AsesulK: 0.2 
                 formulation. 
                 pruv and mix for 2 min 
               
               
                 Tangerine: 0.2 
                   
                 using Turbula 
               
               
                 Syloid: 0.5 
                   
                 mixer. 
               
               
                 Pruv: 1.0 
                   
                 F tablets press 
               
               
                 Lot#/mfg date: 
                   
                 11 mm punch FFRE 
               
               
                 1242-152/Feb. 5, 2002 
                   
                 450 mg table 
               
               
                 250 g batch 
               
               
                 Fluoxetine TMMS: 
                 To evaluate 
                  1/2  advantose, 1/2  
                 30.8 
                 Mouth: 10 S 
                 Abrasion: 
               
               
                 28.69 
                 the Kollidon 
                 Pearlitol, all MS, 1/2  
                   
                 Very fast 
                 0.2 
               
               
                 Pearlitol 400Dc: 
                 CL and its 
                 Pearlitol, 1/2  
                   
                 tablet no 
                 Drop: 
               
               
                 38.56 
                 effect on 
                 advantose, mix for 3 min. 
                   
                 difference to 
                 0.2 
               
               
                 Advantose 100: 
                 disintegration 
                 Add all Citric 
                   
                 1242-152. 
               
               
                 51.41 
                 and 
                 acid, all AcesuK, all 
                   
                 At 40N, 
               
               
                 Avicel PH 101: 
                 friability in 
                 syloid, all syloid, all 
                   
                 tablets 
               
               
                 15.0 
                 the pearlitol 
                 avicel, all kollidon, 
                   
                 disintegrate 
               
               
                 Kollidon CL: 2.0 
                 formulation. 
                 all tangerine, mix for 
                   
                 within 15 s. 
               
               
                 Citric acid: 1.0 
                   
                 5 min. Then pour all 
               
               
                 AsesulK: 0.2 
                   
                 pruv and mix for 2 min 
               
               
                 Tangerine: 0.2 
                   
                 using Turbula 
               
               
                 Syloid: 0.5 
                   
                 mixer. 
               
               
                 Pruv: 1.0 
                   
                 F tablets press 
               
               
                 Lot#/mfg date: 
                   
                 11 mm punch FFRE 
               
               
                 1242-153/Feb. 4, 2002 
                   
                 450 mg table 
               
               
                 250 g batch 
               
               
                 Fluoxetine TMMS: 
                 Optimize 
                  1/2  Pearlitol, all MS 
                 35.7 
                 Mouth: 15 S 
                 Abrasion: 
               
               
                 28.69 
                 the avicel 
                  1/2  Pearlitol, mix for 3 min. 
                   
                 Not as fast 
                 0.2 
               
               
                 Pearlitol 400DC: 
                 level 
                 Add all Citric 
                   
                 as 15% 
                 Drop: 
               
               
                 56.41 
                   
                 acid, all AcesuK, all 
                   
                 avicel 
                 0.3 
               
               
                 Avicel PH 101: 
                   
                 syloid, all syloid, all 
               
               
                 10.0 
                   
                 avicel, all kollidon, 
               
               
                 Kollidon CL: 2.0 
                   
                 all tangerine, mix for 
               
               
                 Citric acid: 1.0 
                   
                 5 min. Then pour all 
               
               
                 AsesulK: 0.2 
                   
                 pruv and mix for 2 min 
               
               
                 Tangerine: 0.2 
                   
                 using Turbula 
               
               
                 Syloid: 0.5 
                   
                 mixer. 
               
               
                 Pruv: 1.0 
                   
                 F tablets press 
               
               
                 Lot#/mfg date: 
                   
                 11 mm punch FFRE 
               
               
                 1242-154/Feb. 5, 2002 
                   
                 450 mg table 
               
               
                 250 g batch 
               
               
                 Fluoxetine TMMS: 
                 Optimize 
                  1/2  advantose, 1/2  
                 26.7 
                 Mouth: 10-15 S 
                 Abrasion: 
               
               
                 28.69 
                 the avicel 
                 Pearlitol, all MS 1/2  
                   
                 Not as fast 
                 0.3 
               
               
                 Pearlitol 400DC: 
                 level 
                 Pearlitol, 1/2  
                   
                 15% avicel 
                 Drop: 
               
               
                 42.31 
                   
                 advantose, mix for 3 min. 
                   
                   
                 0.8 
               
               
                 Advantose 100: 
                   
                 Add all Citric 
               
               
                 51.41 
                   
                 acid, all AcesuK, all 
               
               
                 Avicel PH 101: 
                   
                 syloid, all syloid, all 
               
               
                 15.0 
                   
                 avicel, all kollidon, 
               
               
                 Kollidon CL: 2.0 
                   
                 tangerine, mix for 5 min. 
               
               
                 Citric acid: 1.0 
                   
                 Then pour all 
               
               
                 AsesulK: 0.2 
                   
                 pruv and mix for 2 min 
               
               
                 Tangerine: 0.2 
                   
                 using Turbula 
               
               
                 Syloid: 0.5 
                   
                 mixer. 
               
               
                 Pruv: 1.0 
                   
                 F tablets press 
               
               
                 Lot#/mfg date: 
                   
                 11 mm punch FFRE 
               
               
                 1242-155/Feb. 5, 2002 
                   
                 450 mg table 
               
               
                 250 g batch 
               
               
                 Fluoxetine TMMS: 
                 Optimize 
                  1/2  advantose, 1/2  
                 21.6 
                 Mouth: 35 S 
                 Abrasion: 
               
               
                 28.69 
                 the level of 
                 Pearlitol, all MS, 1/2  
                   
                 Very slow 
                 0.2 
               
               
                 Pearlitol 400DC: 
                 avicel 
                 Pearlitol, 1/2  
                   
                   
                 Drop: 
               
               
                 49.81 
                   
                 advantose mix for 3 min. 
                   
                   
                 0.3 
               
               
                 Advantose 100: 
                   
                 Add all Citric 
               
               
                 16.60 
                   
                 acid, all AcesuK, all 
               
               
                 Kollidon CL: 2.0 
                   
                 syloid, all syloid, all 
               
               
                 Citric acid: 1.0 
                   
                 kollidon, tangerine, 
               
               
                 AsesulK: 0.2 
                   
                 mix for 5 min. Then 
               
               
                 Tangerine: 0.2 
                   
                 pour all pruv and mix 
               
               
                 Syloid: 0.5 
                   
                 for 2 min using 
               
               
                 Pruv: 1.0 
                   
                 Turbula mixer. 
               
               
                 Lot#/mfg date: 
                   
                 F tablets press 
               
               
                 1242-156/Feb. 5, 2002 
                   
                 11 mm punch FFRE 
               
               
                 250 g batch 
                   
                 450 mg table 
               
               
                 Fluoxetine TMMS: 
                 To evalute 
                  1/2  Pearlitol, all MS 
                 29.4 
                 Mouth: 10 S 
                 Abrasion: 
               
               
                 28.69 
                 the 
                  1/2  Pearlitol, mix for 3 min. 
                   
                 Very fast 
                 0.4 
               
               
                 Pearlitol 400DC: 
                 combination 
                 Add all Citric 
                   
                 tablet, no 
                 Drop: 
               
               
                 49.41 
                 of Kollidon 
                 acid, all AcesuK, all 
                   
                 difference 
                 0.6 
               
               
                 Avicel PH 101: 
                 CL/L0HPC 
                 syloid, all syloid, all 
                   
                 between 
               
               
                 15.0 
                 and their 
                 kollidon, all-HPC, 
                   
                 1242-154 &amp; 
               
               
                 Kollidon CL: 2.0 
                 synergetic 
                 all tangerine, mix for 
                   
                 140 batches 
               
               
                 L-HPC 11: 2.0 
                 effect on 
                 5 min. Then pour all 
               
               
                 Citric acid: 1.0 
                 disintegration 
                 pruv and mix for 2 min 
               
               
                 AsesulK: 0.2 
                 and 
                 using Turbula 
               
               
                 Tangerine: 0.2 
                 friability 
                 mixer. 
               
               
                 Syloid: 0.5 
                 formulation. 
                 F tablets press 
               
               
                 Pruv: 1.0 
                   
                 11 mm punch FFRE 
               
               
                 Lot#/mfg date: 
                   
                 450 mg table 
               
               
                 1242-157/Feb. 6, 2002 
               
               
                 250 g batch 
               
               
                 Fluoxetine TMMS: 
                 To evalute 
                  1/2  advantose, 1/2  
                 33.1 
                 Mouth: 12-15 S 
                 Abrasion: 
               
               
                 28.69 
                 the 
                 Pearlitol, all MS, 1/2  
                   
                 Good tablets 
                 0.3 
               
               
                 Pearlitol 400DC: 
                 combination 
                 Pearlitol, 1/2  
                   
                   
                 Drop: 
               
               
                 37.06 
                 of Kollidon 
                 advantose, mix for 3 min. 
                   
                   
                 0.6 
               
               
                 Advantose 100: 
                 CL/L0HPC 
                 Add all Citric 
               
               
                 12.35 
                 and their 
                 acid, all AcesuK, all 
               
               
                 Avicel PH 101: 
                 synergetic 
                 syloid, all syloid, all 
               
               
                 15.0 
                 effect on 
                 kollidon, all 
               
               
                 Kollidon CL: 2.0 
                 disintegration 
                 tangerine, mix for 5 min. 
               
               
                 L-HPC 11: 2.0 
                 and 
                 Then pour all 
               
               
                 Citric acid: 1.0 
                 friability 
                 pruv and mix for 2 min 
               
               
                 AsesulK: 0.2 
                 formulation. 
                 using Turbula 
               
               
                 Tangerine: 0.2 
                   
                 mixer. 
               
               
                 Syloid: 0.5 
                   
                 F tablets press 
               
               
                 Pruv: 1.0 
                   
                 11 mm punch FFRE 
               
               
                 Lot#/mfg date: 
                   
                 450 mg table 
               
               
                 1242-158/Feb. 6, 2002 
               
               
                 250 g batch 
               
               
                 Fluoxetine TMMS: 
                 To evaluate 
                  1/2  lab, all MS 1/2  lab, 
                 25.3 
                 Mouth: 10 S 
                 Abrasion: 
               
               
                 28.69 
                 alternative 
                 mix for 3 min. Add 
                   
                 Good tablets 
                 0.6 
               
               
                 Lab 3038: 51.41 
                 polyols with 
                 all Citric acid, all 
                   
                   
                 Drop: 
               
               
                 Avicel PH 101: 
                 Kollidon 
                 AcesuK, all syloid, 
                   
                   
                 2.0 
               
               
                 15.0 
                 and their 
                 all syloid, all 
               
               
                 Kollidon CL: 2.0 
                 effect on 
                 kollidon, all 
               
               
                 Citric acid: 1.0 
                 disintegration 
                 tangerine, mix for 5 min. 
               
               
                 AsesulK: 0.2 
                   
                 Then pour all 
               
               
                 Tangerine: 0.2 
                   
                 pruv and mix for 2 min 
               
               
                 Syloid: 0.5 
                   
                 using Turbula 
               
               
                 Pruv: 1.0 
                   
                 mixer. 
               
               
                 Lot#/mfg date: 
                   
                 F tablets press 
               
               
                 1242-159/Feb. 6, 2002 
                   
                 11 mm punch FFRE 
               
               
                 250 g batch 
                   
                 450 mg table 
               
               
                 Fluoxetine TMMS: 
                 To evaluate 
                  1/2  lab, all MS 1/2  lab, 
                 32.4 
                 Mouth: 20 S 
                 Abrasion: 
               
               
                 28.69 
                 alternative 
                 mix for 3 min. Add 
                   
                   
                 0.2 
               
               
                 Lab 3038: 68.41 
                 polyols with 
                 all Citric acid, all 
                   
                   
                 Drop: 
               
               
                 Avicel PH 101: 
                 L-HPC and 
                 AcesuK, all syloid, 
                   
                   
                 0.8 
               
               
                 15.0 
                 their effect 
                 all syloid, all HPC, 
               
               
                 L-HPC 11: 2.0 
                 on 
                 all tangerine, mix for 
               
               
                 Citric acid: 1.0 
                 disintegration. 
                 5 min. Then pour all 
               
               
                 AsesulK: 0.2 
                   
                 pruv and mix for 2 min 
               
               
                 Tangerine: 0.2 
                   
                 using Turbula 
               
               
                 Syloid: 0.5 
                   
                 mixer. 
               
               
                 Pruv: 1.0 
                   
                 F tablets press 
               
               
                 Lot#/mfg date: 
                   
                 11 mm punch FFRE 
               
               
                 1242-160/Feb. 6, 2002 
                   
                 450 mg table 
               
               
                 250 g batch 
               
               
                   
               
             
          
         
       
     
       Additional Non-Floss Formulations 
       [0110]      
         [0000]                                                            Mixing                               procedure &amp;   Hard-           Disso-               Equipment   ness   Disintegra-   Friability   lution       Formulation Lot#   Objective   Used   (N)   tion time   %   %                   Fluoxetine TMMS:   Investigate   ½ Pearl   32   Mouth: 10 S   Abrasion:           28.69   high   400 DC, all           0.3           Pearlitol 400 DC:   level of   MS½ pearlitol           Drop:           58.41   Kollidon   400 DC, mix           2.1           Kolidon XL: 10   XL for   for 3 min. Add                       Citric acid: 1.0   fast   all Citric acid,                       AsesulK: 0.2   disintegra-   all AcesuK, all                       Syloid: 0.5   tion   syloid, all                       Tangerine: 0.2   using   Kollidon, all                       Pruv: 1.0   high   tangerine, mix                       Lot# 1242-117   compression   for 5 min. Then                               pour all pruv                               and mix for 2                               min using                               Turbula mixer.                               Piccola tablets                               press                               11 mm punch                               FFRE                       Fluoxetine TMMS:   Evaluate   ½ Parteck   22.2   Mouth: 10 S   Abrasion:           28.69   different   M200, all MS,           1.4           Parteck M200:   mannitol   ½ Parteck           Drop:           58.41   from   M200 mix for           4.1           Kolidon XL: 10   different   3 min. Add all                       Citric acid: 1.0   suppliers.   Citric acid, all                       AsesulK: 0.2       AcesuK, all                       Syloid: 0.5       syloid, all                       Tangerine: 0.2       Kollidon, all                       Pruv: 1.0       tangerine, mix                       Lot# 1242-118       for 5 min.                               Then pour all                               pruv and mix                               for 2 min.                               using Turbula                               mixer.                               Piccola tablets                               press                               11 mm punch                               FFRE                       Fluoxetine TMMS:   Evaluate   ½ Parteck   30.0   Mouth: 10 S   Abrasion:           28.69   different   M300, all MS,           0.8           Parteck M300:   mannitol   ½ Parteck           Drop:           58.41   from   M300, mix for           3.0           Kolidon XL: 10   different   3 min. Add all                       Citric acid: 1.0   suppliers.   Citric acid, all                       AsesulK: 0.2       Acesu K, all                       Syloid: 0.5       syloid, all                       Tangerine: 02       Kollidon, all                       Pruv: 1.0       tangerine, mix                       Lot# 1242-119       for 5 min.                               Then pour all                               pruv and mix                               for 2 min.                               using Turbula                               mixer.                               Piccola tablets                               press                               11 mm punch                               FFRE                       Fluoxetine TMMS:   Increase   ½ Pearlitol   27.0   Mouth: 10 S   Abrasion:           28.69   the   400 DC, all           0.4           Pearlitol 400 DC:   Kollidon   MS,           Drop:           48.41   XL from   ½ Pearlitol           2.3           Kolidon XL: 20   10% to   400 DC, mix                       Citric acid: 1.0   20% to   for 3 min. Add                       AsesulK: 0.2   determine   all Citric acid,                       Syloid: 0.5   the   all Acesu K, all                       Tangerine: 02   effect of   syloid, all                       Pray: 1.0   disintegrant   Kollidon, all                       Lot# 1242-120   concentra-   tangerine, mix                           tion on   for 5 min.                           disintegra-   Then pour all                           tion. time   pruv and mix                               for 2 min.                               using Turbula                               mixer.                               Piccola tablets                               press                               11 min punch                               FFRE                       FluoxetineTMMS:   Investi-   ½ Pearlitol   16.2   Mouth:   Abrasion:           28.69   gate   400 DC, all       20 S, at 20    14.8           Pearlitol 400 DC:   alternative    MS,       and 30 N   Drop:           48.41   disintegrant   ½ Pearlitol       tablets very   powder           L-HPC 11: 20   like L-   400 DC, mix       slow to   collec-           Citric acid: 1.0   HPC11   for 3 min. Add       disintegrate   tion           AsesulK: 0.2       all Citric acid,                       Syloid: 0.5       all Acesu K, all                       Tangerine: 0.2       syloid, all L-                       Pruv: 1.0       HPC, all                       Lot# 1242-123       tangerine, mix                               for 5 min.                               Then pour all                               pruv and mix                               for 2 min.                               using Turbula                               mixer.                               Piccola tablets                               press                               11 mm punch                               FFRE                       Fluoxetine TMMS:   Introduce   ½ Pearlitol   30.0   Mouth: 10 S   Abrasion:           28.69   microcry   400 DC, all           0.2           Pearlitol 400 DC:   stalline   MS,           Drop:           48.41   cellulose   ½ Pearlitol           0.8           Avicel PH 101: 16.0   as a   400 DC, mix                       L-HPC 11:4.0   wicking   for 3 min. Add                       Citric acid: 1.0   and   all Citric acid,                       AsesulK: 0.2   dispersing   all Acesu K, all                       Syloid: 0.5   agent to   syloid, all                       Tangerine: 0.2   improve   avicel, all L-                       Pruv: 1.0   the   HPC, all                       Lot# 1242-124   disintegra-   tangerine, mix                       Avicel PH101/L-   tion of   for 5 min..                       HPC11 ratio (80/20)   the   Then pour all                           tablets.   pruv and mix                               for 2 min using                               Turbula mixer.                               Piccola tablets                               press                               11 mm punch                               FFRE                       Fluoxetine TMMS:   Evaluate   ½ Pearlitol   34.0   Mouth: 10 S   Abrasion:           28.69   different   400 DC, all           0.2           Pearlitol 400 DC:   ratio of   MS,           Drop:           48.41   avicel PH   ½ Pearlitol           0.8           Avicel PH 101: 1 8.0   101/L-   400 DC, mix                       L-HPC 11: 2.0   HPC 11   for 3 min. Add                       Citri cacid: 1.0   to   all Citric acid,                       AsesulK: 0.2   determine   all Acesu K, all                       Syloid: 0.5   which   syloid, all                       Tangerine: 0.2   excipient   avicel, all L-                       Pruv: 1.0   affect   HPC, all                       Lot# 1242-125   more the   tangerine, mix                       Avicel PH 101/L-   disintegra-   for 5 min.                       HPC11 ratio (90/10)   tion in   Then pour all                           the mouth   pruv and mix                               for 2 min using                               Turbula mixer.                               Piccola tablets                               press                               11 mm punch                               FFRE                       Fluoxetine TMMS:   Evaluate   ½ Pearlitol   34.0   Mouth: 10 S   Abrasion:           28.69   different   400 DC, all           0.2           Pearlitol 400 DC:   ratio of   MS,           Drop:           48.41   avicel PH   ½ Pearlitol           1.0           Avicel PH 101: 14.0   101/L-   400 DC, mix                       L-HPC 11:6.0   HPC 11   for 3 min. Add                       Citri cacid: 1.0   to   all Citric acid,                       AsesulK: 0.2   determine   all Acesu K, all                       Syloid: 0.5   which   syloid, all                       Tangerine: 0.2   excipient   avicel, all L-                       Pruv: 1.0   affect   HPC, all                       Lot# 1242-129   more the   tangerine, mix                       Avicel PH 101/L-   disintegra-    for 5 min.                       HPC11 ratio (70/30)   tion in   Then pour all                           the   pruv and mix                           mouth   for 2 min using                               Turbula mixer.                               Piccola tablets                               press                               11 mm punch                               FFRE                       Fluoxetine TMMS:   Compara-   ½ Pearlitol   34.0   Mouth: 10 S   Abrasion:           28.69   tive study   400 DC, all           0.1           Pearlitol 400 DC:   of   MS,           Drop:           48.41   disintegra-   ½ Pearlitol           1.5           Avicel PH 101: 16.0   tion time   400 DC, mix                       Kollidon XL: 4.0   of avicel   for 3 min. Add                       Citri cacid: 1.0   PH   all Citric acid,                       AsesulK: 0.2   101/L-   all Acesu K, all                       Syloid: 0.5   HPC11   syloid, all                       Tangerine: 0.2   formula-   avicel, all                       Pruv: 1.0   tion versus   Killidon, all                       Lot# 1242-126   avicel PH   tangerine, mix                       Avicel P11   101/Kolli   for 5 min.                       101/Kollidon ratio   don XL   Then pour all                       (80/20)       pruv and mix                               for 2 min using                               Turbula mixer.                               Piccola tablets                               press                               11 mm punch                               FFRE                       Fluoxetine TMMS:   Compara-   ½ Pearlitol   31-37   Mouth: 10 S   Abrasion:           28.69   tive study   400 DC, all           0.04           Pearlitol 400 DC:   of   MS,           Drop:           48.41   disintegra-   ½ Pearlitol           1.6           Avicel PH 101: 4.0   tion time   400 DC, mix                       Kollidon XL: 16.0   of avicel   for 3 min. Add                       Citri cacid: 1.0   PH   all Citric acid,                       AsesulK: 0.2   101/L-   all Acesu K, all                       Syloid: 0.5   HPC11   syloid, all                       Tangerine: 0.2   formula-   avicel, all                       Pruv: 1.0   tion versus   Kollidon, all                       Lot# 1242-127   avicel PH   tangerine, mix                       Avicel P11   101/Kolli   for 5 min.                       101/Kollidon ratio   don   Then pour all                       (20/80)       pruv and mix                               for 2 min using                               Turbula mixer.                               Piccola tablets                               press                               11 mm punch                               FFRE                       Fluoxetine TMMS:   Compara-   ½ Pearlitol   33.3   Mouth: 10 S   Abrasion:           28.69   tive study   400 DC, all           1.0           Pearlitol 400 DC:   of   MS,           Drop:           52.41   disintegra-    ½ Pearlitol           2.5           Kollidon XL: 16.0   tion time   400 DC, mix                       Citri cacid: 1.0   of 16%   for 3 min. Add                       AsesulK: 0.2   Kollidon   all Citric acid,                       Syloid: 0.5   to 10 and   all Acesu K, all                       Tangerine: 0.2   20%   syloid, all                       Pruv: 1.0       Kollidon, all                       Lot# 1242-130       tangerine, mix                               for 5 min.                               Then pour all                               pruv and mix                               for 2 min using                               Turbula mixer.                               Piccola tablets                               press                               11 mm punch                               FFRE.                       FluoxetineTMMS:   Increase   ½ Pearlitol   29.4   Mouth: 10 S   Abrasion:           28.69   the level   400 DC, all           1.7           Pearlitol 400 DC:   of avicel   MS,           Drop:           26.25   to   ½ Pearlitol           1.8           Avicel PH 101: 26.25   improve   400 DC, mix                       Kolidon XL: 16   the   for 3 min. Add                       Citric acid: 1.0   disintegra-   all Citric acid,                       AsesulK: 0.2   tion time.   all Acesu K, all                       Syloid: 0.5   Avicel is   syloid, all                       Tangerine: 0.2   porous   avicel, all L-                       Pruv: 1.0   and   HPC, all                       Lot# 1242-131   therefore,   tangerine, mix                           it absorbs   for 5 min.                           lot of   Then pour all                           water   pruv and mix                           which   for 2 min                           helps the   using Turbula                           swelling   mixer.                           of L-HPC   F tablets press                               11 mm punch                               FFRE.                       FluoxetineTMMS:   Same   ½ Pearlitol   29.7   Mouth: 10S   Abrasion:           28.69   objective   400 DC, all           0.3           Pearlitol 400 DC:   as 1242-   MS,           Drop:           26.25   131,   ½ Pearlitol           0.8           Avicel PH 101: 26.25   except   400 DC, mix                       Kolidon XL: 16   Kollidon   for 3 min. Add                       Citri ca cid: 1.0   was used.   all Citric acid,                       AsesulK: 0.2       all Acesu K, all                       Syloid: 0.5       syloid, all                       Tangerine: 0.2       avicel, all                       Pruv: 1.0       Kollidon, all                       Lot# 1242-132       tangerine, mix                               for 5 min.                               Then pour all                               pruv and mix                               for 2 min.                               using Turbula                               mixer.                               F tablets press                               11 mm punch                               FFRE.                       Ireland Formulation   Enapril       26   Mouth: 10 S   Abrasion:           EXP 988   FD               2.5               tablets               Drop:               36 mg               13.5           FluoxetineTMMS:   Study the   ½ Pearlitol   28.3   Mouth: 15   Abrasion:           28.69   effect of   400 DC, all       to 20 S   0.3           Pearlitol 400 DC:   avicel on   MS,           Drop:           54.41   the   ½ Pearlitol           0.3           Avicel PH 101: 12   tablets   400 DC, mix                       L-HPC: 2   formula-   for 3 min. Add                       Citric acid: 1.0   tion at   all Citric acid,                       AsesulK: 0.2   differents   all Acesu K, all                       Syloid: 0.5   level   syloid, all                       Tangerine: 0.2   12% and   avicel, all L-                       Pruv: 1.0   6% as   HPC, all                       Lot# 1242-133   results of   tangerine, mix                           lot 1242-   for 5 min.                           125   Then pour all                               pruv and mix                               for 2 min                               using Turbula                               mixer.                               F tablets press                               11 mm punch                               FFRE.                       FluoxetineTMMS:   To   ½ Pearlitol   28.1   Mouth: 20 S   Abrasion:           28.69   improve   400 DC, all       slow   0.4           Pearlitol 400 DC:   the   MS,       compared to   Drop:           60.41   mouth   ½ Pearlitol       1242-133   0.4           Avicel PH 101: 6   feel and   400 DC, mix                       L-HPC: 2   gritty   for 3 min. Add                       Citric acid: 1.0   taste of   all Citric acid,                       AsesulK: 0.2   the   all Acesu K, all                       Syloid: 0.5   tablets.   syloid, all                       Tangerine: 0.2   Avicel   avicel, all L-                       Pruv: 1.0   was   HPC, all                       Lot# 1242-134   reduced   tangerine, mix                           from   for 5 min.                           18% to   Then pour all                           12% by   pruv and mix                           keeping   for 2 min                           L-HPC   using Turbula                           11 to 2%   mixer.                           level in   F tablets press                           tablets   11 mm punch                           formula-   FFRE.                           tion                           FluoxetineTMMS:   As results   ½ Pearlitol   29.5   Mouth: 10 S   Abrasion:           28.69   of   400 DC, all MS,           0.3           Pearlitol 400 DC:   1242-   ½ Pearlitol           Drop:           51.41   125 and   400 DC, mix for           0.3           Avicel PH 101: 15   1242-133   3 min. Add all                       L-HPC: 2   on the   Citric acid, all                       Citric acid: 1.0   tablets   Acesu K, all                       AsesulK: 0.2   disintegra-   syloid, all                       Syloid: 0.5   tion, is   avicel, all L-                       Tangerine: 0.2   been   HPC, all                       Pruv: 1.0   found that   tangerine, mix                       Lot# 1242-135   the lot   for 5 min. Then                           1242-125   pour all pruv                           gave   and mix for 2                           better   min using                           disintegra-   Turbula mixer.                           tion which   F tablets press                           the level   11 mm punch                           of Avicel   FFRE.                           was                               increased                               to 15%                           FluoxetineTMMS:   Evaluate   ½ Pearlitol   27.5   Mouth: 20 S   Abrasion:           28.69   the used   400 DC, all MS,           0.2           Pearlitol 400 DC:   of avicel   ½ Pearlitol           Drop:           53.41   alone in   400 DC, mix for           0.4           Avicel PH 101: 15   the tablets   3 min. Add all                       Citric acid: 1.0   formula-   Citric acid, all                       AsesulK: 0.2   tion. To   Acesu K, all                       Syloid: 0.5   determine   syloid,                       Tangerine: 02   the effect   all avicel, all                       Pruv: 1.0   of the   tangerine, mix                       Lot# 1242-136   disintegra-   for 5 min. Then                           tion while   pour all pruv                           L-HPC11   and mix for 2                           was   min using                           removed.   Turbula mixer.                               F tablets press                               11 mm punch                               FFRE.                       FluoxetineTMMS:   Investigate   ½ Pearlitol   28.3   Mouth: 10 S   Abrasion:           28.69   another   400 DC, all MS,       better disint    0.2           Pearlitol 400 DC:   disintegrant   ½ Pearlitol       than 1242-   Drop:           51.41   Prosolv90   400 DC, mix for       125   0.4           Prosolv90: 15   to study   3 min. Add all                       L_HPC11: 2   the   Citric acid, all                       Citric acid: 1.0   disintegra-   Acesu K, all                       AsesulK: 0.2   iton   syloid,                       Syloid: 0.5   properties   all Prosolv90,                       Tangerine: 0.2   and   all L_HPC11,                       Pruv: 1.0   compare   all tangerine,                       Lot# 1242-137   its   mix for 5 min.                           effective-   Then pour all                           ness with   pruv and mix for                           avicel in a   2 min using                           direct   Turbula mixer.                           compaction.   F tablets press                               11 mm punch                               FFRE.                    
Preferred Formulations Based on Directly Compressible Inorganic Salts, Alone or in Combination with a Cellulose Derivative:
 
         [0111]    The present preferred illustrative embodiments of the invention relate to the introduction of directly compressible inorganic salt with a cellulose derivative. 
       Formulation I: 
       [0112]    This formulation is based on an excipient mass containing a mixture of dibasic calcium phosphate dihydrate (Emcompress) and microcrystalline cellulose (Avicel).
       %       
 
       Fluoxetine TMMS*: 28.69 
     Pearlitol 400DC 36.31 
     Emcompress: 12.10 
     Avicel PH 101: 15.00 
     L-HPC LH-11: 2.00 
     XL Kollidon: 2.00 
     Acesulfame K: 0.20 
     Magnasweet 100: 0.20 
     Tangerine Flavor: 0.50 
       [0114]    Citric Acid anhydrous: 1.50 
       Syloid 244FP: 0.50 
     Pruv: 1.00 
     Formulation II: 
       [0115]    This formulation is based on an excipient mass wherein mannitol is substituted with the dicalcium phosphate dihydrate.
       %       
 
       Fluoxetine TMMS*: 28.69 
     Emcompress: 48.41 
     Avicel PH 101: 15.00 
     XL Kollidon: 2.00 
     L-HPC LH-11: 2.00 
     Acesulfame K: 0.20 
     Magnasweet 100: 0.20 
     Tangerine Flavor: 0.50 
       [0117]    Citric Acid anhydrous: 1.50 
       Syloid 244FP: 0.50 
     Pruv: 1.00 
     Formulation III: 
       [0118]    This formulation is based on an excipient mass wherein microcrystalline cellulose (Avicel) is substituted with the dicalcium phosphate dihydrate (Emcompress)
       %       
 
       Fluoxetine TMMS*: 28.69 
     Pearlitol 400DC: 48.41 
     Emcompress: 15.00 
     L-HPC LH-11: 2.00 
     XL Kollidon: 2.00 
     Acesulfame K: 0.20 
     Magnasweet 100: 0.20 
     Tangerine Flavor: 0.50 
       [0120]    Citric Acid anhydrous: 1.50 
       Syloid 244FP: 0.50 
     Pruv: 1.00 
     Formulation IV: 
       [0121]    This formulation is based on an excipient mass containing a combination of Pearlitol 400DC/dicalcium phosphate dihydrate at ratio 75/25 
       Fluoxetine TMMS*: 28.69 
     Pearlitol 400DC: 36.69 
     Emcompress: 12.10 
     Avicel PH 101: 15.00 
     XL Kollidon: 2.00 
     L-HPC LH-11: 2.00 
     Acesulfame K: 0.20 
     Magnasweet 100: 0.20 
     Tangerine Flavor: 0.50 
       [0122]    Citric Acid anhydrous: 1.50 
       Syloid 244FP: 0.50 
     Pruv: 1.00 
     Formulation V: 
     Fluoxetine TMMS*: 28.69 
     Pearlitol 400DC: 36.31 
     Emcompress: 17.10 
     Avicel PH 101: 10.00 
     XL Kollidon: 2.00 
     L-HPC LH-11: 2.00 
     Acesulfame K: 020 
     Magnasweet 100: 0.20 
     Tangerine Flavor: 0.50 
       [0123]    Citric Acid anhydrous: 1.50 
       Syloid 244FP: 0.50 
     Pruv: 1.00 
     Formulation VI: 
       [0124]    This formulation is based on an excipient mass containing a combination of low level of Avicel with Emcompress. 
       Fluoxetine TMMS*: 28.69 
     Pearlitol 400DC: 43.81 
     Emcompress: 12.10 
     Avicel PH 101: 7.50 
     XL Kollidon: 2.00 
     L-HPC LH-11: 2.00 
     Acesulfame K: 0.20 
     Magnasweet 100: 0.20 
     Tangerine Flavor: 0.50 
       [0125]    Citric Acid anhydrous: 1.50 
       Syloid 244FP: 0.50 
     Pruv: 1.00 
     Formulation VII: 
     Fluoxetine TMMS*: 28.69 
     Pearlitol 400DC: 48.41 
     Emcompress 7.50 
     Avice PH 101: 7.50 
     XL Kollidon: 2.00 
     L-HPC LH-11: 2.00 
     Acesulfame K: 0.20 
     Magnasweet 100: 0.20 
     Tangerine Flavor: 0.50 
       [0126]    Citric Acid anhydrous: 1.50 
       Syloid 244FP: 0.50 
     Pray: 1.00 
     Formulation VIII: 
       [0127]    This formulation illustrates how the introduction of Clay (magnabrite) in tablet formulation according to the invention allows for covering the unpleasant and gritty taste of the microspheres and thereby improve the patient&#39;s ability to swallow a tablet based on this formulation.
       %       
 
       Fluoxetine TMMS*: 28.69 
     Pearlitol 400DC: 43.81 
     Emcompress: 12.10 
     Avicel PH 101: 6.50 
     XL Kollidon: 2.00 
     L-HPC LH-11: 2.00 
     Magnabrite F: 1.00 
     Acesulfame K: 0.20 
     Magnasweet 100: 0.20 
     Tangerine Flavor: 0.50 
       [0129]    Citric Acid anhydrous: 1.50 
       Syloid 244FP: 0.50 
     Pruv: 1.00 
     Formulation IX: 
       [0000]    
       
         
           
             % 
           
         
       
     
       Fluoxetine TMMS*: 28.69 
     Pearlitol 400DC: 43.81 
     Emcompress: 12.10 
     Avicel PH 101: 7.50 
     XL Kollidon: 2.00 
     Magnabrite F: 2.00 
     Acesulfame K: 0.20 
     Magnasweet 100: 0.20 
     Tangerine Flavor: 0.50 
       [0131]    Citric Acid anhydrous: 1.50 
       Syloid 244FP: 0.50 
     Pruv: 1.00 
     Formulation X: 
       [0000]    
       
         
           
             % 
           
         
       
     
       Fluoxetine TMMS*: 28.69 
     Pearlitol 400DC: 43.81 
     Emcompress: 12.10 
     Avicel PH 101: 7.50 
     Magnabrite F: 4.00 
     Acesulfame K: 0.20 
     Magnasweet 100: 0.20 
     Tangerine Flavor: 0.50 
       [0133]    Citric Acid anhydrous: 1.50 
       Syloid 244FP: 0.50 
       [0134]    Pruv: 1.00 *Note: TMMS=Taste Masked Microspheres. Fluoxetine was used as a model drug, but these formulas cover the use of any coated or uncoated CEFORM™ Microsphere. 
         [0135]    Reasonable variations, such as those which would occur to a skilled artisan, can be made herein without departing from the scope of the invention.