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]    The present application is a continuation in part 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 organoliptically 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. 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.  
           [0004]    There has been widespread use of tablets since the latter part of the 19.sup.th 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.  
           [0005]    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.  
           [0006]    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.  
           [0007]    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.  
           [0008]    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.  
           [0009]    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.  
           [0010]    Disintegrants are often included to ensure that the tablet has an acceptable rate of disintegration. Typical disintegrants include starch derivatives and salts of carboxymethylcellulose.  
           [0011]    Other desirable characteristics of excipients include the following:  
           [0012]    High compressibility to allow strong tablets to be made at low compression forces.  
           [0013]    Good flow properties that can improve the flow of other excipients in the formula.  
           [0014]    Cohesiveness (to prevent tablet from crumbling during processing, shipping and handling).  
           [0015]    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.  
           [0016]    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.  
           [0017]    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. 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.  
           [0018]    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.  
           [0019]    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.  
           [0020]    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.  
           [0021]    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.  
           [0022]    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.  
           [0023]    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.  
           [0024]    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.  
           [0025]    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”).  
           [0026]    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).  
           [0027]    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.  
           [0028]    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.” 
           [0029]    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.” 
           [0030]    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).  
           [0031]    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).  
           [0032]    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).  
           [0033]    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.  
           [0034]    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.  
           [0035]    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.” 
           [0036]    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.  
           [0037]    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.  
           [0038]    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.  
           [0039]    Co-owned U.S. patent applications 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.  
           [0040]    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.  
           [0041]    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.  
           [0042]    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.  
           [0043]    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.  
           [0044]    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.  
           [0045]    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 R P Scherer, Yamanouchi and Takada technoligies 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.  
           [0046]    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.  
           [0047]    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  
         [0048]    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. Pat. 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.  
           [0049]    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.  
           [0050]    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.  
           [0051]    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.  
           [0052]    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 manitol, alone or in combination with sorbitol.  
           [0053]    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.  
           [0054]    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  
         [0055]    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.  
           [0056]    Unless stated otherwise, all percentages recited herein are weight percentages, based on total composition weight.  
           [0057]    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.  
                                       Crosscarmelose sodium   High swelling capacity, effective at low 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 which leads to rapid       Glycolate   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 25C/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                                Eq. Moisture           Brand   Common       Functional       content at       name   name   Classification   Category   Properties   25C/90% RH   Typical uses               CL-   Crospovidone   Polyvinyl-   Tablet   Hygroscopic   62%   Disintegrant in       Kollidon       polypyrrolidone   super   Swelling-       dry                   disintegrant   18% in 10 s,       and wet                       45% in 20 s       granulation       Ac-   Croscarmellose   Cellulose,   Tablet   Hygroscopic   88%   Disintegrant for       Disol   sodium   carboxymethyl   and   Wicking       capsules,       Primellose       ether,   capsule   and       tablets               sodium salt,   super   swelling-       and granules               crosslinked   disintegrant   12% in 10 s,                       23% in 20 s       Explotab   Sodium   Sodium   Tablet   Swelling       Disintegrant in       Primojel   starch   carboxymethyl   and   capacity: in       dry and wet           glycolate   starch   capsule   water swells       granulation                   super   up to 300                   disintegrant   times its                       volume       Explotab   Sodium   (Cross   Super   Swells to       Disintegration       V17   starch   linked low   disintegrant   greater       and dissolution           glycolate   substituted       extent than       aid. Not for use               carboxymethyl       explotab       in wet               ether)Sodium               granulation               carboxymethyl               starch       Explotab   Sodium   (Cross   Super           Designed for       CLV   starch   linked low   disintegrant           wet granulation           glycolate   substituted               that utilize high               carboxymethyl               shear               ether)Sodium               equipment               carboxymethyl               starch,               highly cross               linked       L-HPC   Hydroxypropyl   Cellulose,   Tablet   Hygroscopic   37%   Tablet           cellulose,   2-   and   Swelling-       disintegrant,           low -   hydroxypropyl   capsule   13% in 10 s,       binder in wet           substituted   ether   disintegrant,   50% in 20 s       granulation               (low   tablet               substituted)   binder       Amberlite   Polacrilin   Cation   Tablet   Swelling       Tablet       IRP   Potassium   exchange   disintegrant   ability       disintegrant       88       resin       Starch   Starch,   Pregelatinized   Tablet   Hygroscopic   22%   Capsule and       1500   pregelatinized   starch   and           tablet binder,                   capsule           diluent,                   diluent,           disintegrant                   disintegrant,                   tablet                   binder       Avicel   Microcrystalline   Cellulose   Tablet   Hygroscopic   18%   Binder/diluent,           cellulose       and   Swelling-       has also some                   capsule   12% in 10 s,       lubricant and                   diluent,   18% in 20 s       disintegrant                   tablet           properties                   disintegrant                  
 
           [0060]    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; cholecystekinin 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; bomyl 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; chlorcyclizine 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 flumarate; 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 hyddrochloride; danthron; dexbromopheniramine 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 hormore; LHRH (lutenizing hormone replacement hormone); magnesium carbonate, hydroxide, salicylate, and trisilicate; meclizine and its hyddrochloride; 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; propanolol; pseudoephedrine and its sulfates and hydrochorides; 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 subsalicylate; 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.  
                                               Broad range   Narrow range   Preferred range                   Bio-affecting agent(s)   1-50%    5-40%   20-30%       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%                  
 
           [0082]    III. Processes  
           [0083]    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.  
           [0084]    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.  
           [0085]    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.  
           [0086]    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.  
           [0087]    Among the co-assigned patents and patent applications which describe the preparations of microspheres containing bio-affecting agents re: U.S. 5,458,823; 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.  
           [0088]    III. Microparticles  
           [0089]    While particulates made using various thermoprocessing technologies are useful, microspheres described below are preferred.  
           [0090]    The microspheres or other particulates are generally solid spherical bodies of about 150 to about 250 microns mean particle diameter.  
           [0091]    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.  
           [0092]    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.  
           [0093]    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.  
           [0094]    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.  
           [0095]    Once the floss and microsphere ingredients are combined, they can be shaped into comestible units.  
           [0096]    IV. Coatings  
           [0097]    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.  
           [0098]    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.  
           [0099]    Controlled release coatings generally contain at least one of: ethylcellulose (EC), hydroxypropylcellulose (HPC), 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.  
           [0100]    Coating levels of about 0 to about 150% are effective, with levels of about 5% to about 30% being preferred.  
           [0101]    Coating devices include those conventionally used in pharmaceutical processing, with fluidized bed coating devices being preferred.  
           [0102]    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 equiped with two seperatedrums, the motor rotate the drum at 100 revolution/min. the actual drums is made from plexiglass and is seperated 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  
       [0103]    The examples and counterexamples provided below illustrate formulations and processing conditions for forming dosage forms according to the invention.  
         [0104]    Formulatin No 1  
         [0105]    CEFORM™ or other coated particle: 5-45% W/W, preferred 5-35%, (35-45% is fast tablet but gritty)  
         [0106]    Mannitol*: 29.1-77.1%  
         [0107]    Microcrystalline Cellulose**: 12-18%  
         [0108]    1-HPC, LH-11: 2-4%  
         [0109]    Citric Acid: 1.5%  
         [0110]    Acesulfame K: 0.2%  
         [0111]    Magnasweet 100: 0.2%  
         [0112]    Flavor: 0.5%  
         [0113]    Syloid: 0.5%  
         [0114]    Pruv: 1.0%  
         [0115]    Formulation NO 2  
         [0116]    CEFORM™ or other coated particle: 5-45% W/W, preferred 5-35%, (35-45% is fast tablet but gritty)  
         [0117]    Mannitol*: 29.1-77.1%  
         [0118]    Microcrystalline Cellulose**: 12-18%, preferably 15%-18%  
         [0119]    Kollidon CL: 2-4%  
         [0120]    Citric Acid: 1.5%  
         [0121]    Acesulfame K: 0.2%  
         [0122]    Magnasweet 100: 0.2%  
         [0123]    Flavor: 0.5%  
         [0124]    Syloid: 0.5%  
         [0125]    Pruv: 1.0%  
         [0126]    Formulation No 3 (more referred platform):  
         [0127]    CEFORM™ or other coated particle: 5-45% W/W, preferred 5-35%, (35-45% is fast tablet but gritty)  
         [0128]    Mannitol*: 27.1-83.6%  
         [0129]    Microcrystalline Cellulose**: 5-20%, preferably 15-18%  
         [0130]    Kollidon CL: 2%  
         [0131]    1-HPC, LH-11: 2%  
         [0132]    Citric Acid: 1.5%  
         [0133]    Acesulfame K: 0.2%  
         [0134]    Magnasweet 100: 0.2%  
         [0135]    Flavor: 0.5%  
         [0136]    Syloid: 0.5%  
         [0137]    Pruv: 1.0%  
         [0138]    *Mannitols evaluated and found acceptable: Pearlitol 400DC, 300DC, Parteck M200, Parteck M300, Roquette Lab 3038. No differences were observed in disintegration time.  
         [0139]    **Microcrystalline cellulose evaluated and found acceptable: Avicel PH 101, 102, 113, Prosolv 50, Prosolv 90. No differences were observed in disintegration time.  
         [0140]    Other preferred formulations based on model drug fluoxetine:  
                                                                                                                                                   Formulation Lot#   Hardness (N)   Disintegration time   Friability %   Comments               FluoxetineTMMS:   29.7   Mouth: 10 s   0.8   Can be used with any drug       28.69       USP basket       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 any drug except       28.69       Good tablets       the drugs that have amine group.       Advantose 100:       No significant       12.85       difference       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. 4, 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. 5, 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. 5, 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. 6, 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. 6, 2002       250 g batch/11 mm Flat       Face Radial       Edge/450 mg            Fast Disintegrating Non Floss Tablet Additional Preferred Formulation            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:                    Mixing procedure &amp;   Hardness   Disintegration   Friability       Formulation Lot#   Objective   Equipment used   (N)   Time   %               Fluoxetine TMMS:   Investigate   ½ Pearlitol 400DC,   32.4   Mouth: 10 S   Abrasion:       28.69   high level   all MS           0.3       Pearlitol 400DC:   of Kollidon   ½ 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       Lot#/mfg date:       min using Turbula       1242-117/Jan. 14, 2002       mixer.       250 g batch       Piccola tablets press               11 mm punch FFRE               450 mg table       Fluoxetine TMMS:   Evaluate   ½ Parteck M200, all   22.2   Mouth: 10 S   Abrasion:       28.69   different   MS,           1.4       Pearlitol 400DC:   from   ½ 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       Syloid: 0.5       min. Then pour all       Pruv: 1.0       pruv and mix for 2       Lot#/mfg date:       min. using Turbula       1242-118/Jan. 14, 2002       mixer.       250 g batch       Piccola tablets press               11 mm punch FFRE               450 mg tablet       Fluoxetine TMMS:   Evaluate   ½ Parteck M300, all   29.9   Mouth: 10 S   Abrasion       28.69   different   MS           0.8       Pearlitol 400DC:   mannitol   ½ 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       Syloid: 0.5       min. Then pour all       Pruv: 1.0       pruv and mix for 2       Lot#/mfg date:       min. using Turbula       1242-119/Jan. 14, 2002       mixer.       250 g batch       Piccola tablets press               11 mm punch FFRE               450 mg tablet       Fluoxetine TMMS:   Increase   ½ Pearlitol 400DC,   29.6   Mouth: 10 S   Abrasion       28.69   the   all MS           0.4       Pearlitol 400DC:   Kollidon   ½ 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       Lot#/mfg date:   concentration   min using Turbula       1242-120/Jan. 15, 2002   on   mixer.       250 g batch   disintegration   Piccola tablets press           time   11 mm punch FFRE       Fluoxetine TMMS:   Investigate   ½ Pearlitol 400DC,   16.2   Mouth: 20 S   Abrasion       28.69   alternative   all MS       at 20 and 30   14.8       Pearlitol 400DC:   distintegran   ½ Pearlitol 400DC,       N tablets   Drop:       48.41   t like L-   mix for 3 min. Add       Verty slow to       L-HPC 11: 2.0   HPC11   all Citric acid, all       disintegrate   Powder       Citric acid: 1.0       AcesuK, all syloid,           collection       AsesulK: 0.2       all L-HPC, all       Tangerine: 0.2       tangerine, mix for 5       Syloid: 0.5       min. Then pour all       Pruv: 1.0       pruv and mix for 2       Lot#/mfg date:       min using Turbula       1242-123/Jan. 16, 2002       mixer.       250 g batch       Piccola tablets press               11 mm punch FFRE               450 mg tablet       Fluoxetine TMMS:   Increase   ½ Pearlitol 400DC,   29.7   Mouth: 10 S   Abrasion       28.69   the   all MS           0.2       Pearlitol 400DC:   Kollidon   ½ 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       Pruv: 1.0   concentration   min 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   ½ Pearl 400DC, all   34.0   Mouth: 10 S   Abrasion       28.69   different   MS           0.2       Pearlitol 400DC:   ratio of   ½ 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       Pruv: 1.0   the   min 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   ½ Pearlitol 400DC,   31.0   Mouth: 10 S   Abrasion       28.69   different   all MS,           0.2       Pearlitol 400DC:   ratio of   ½ 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       Tangerine: 0.2   excipient   min. Then pour all       Syloid: 0.5   affect more   pruv and mix for 2       Pruv: 1.0   the   min. 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   ½ Pearlitol 400DC,   33.8   Mouth 10:   Abrasion       28.69   study of   all MS,       10 S   0.1       Pearlitol 400DC:   disintegration   ½ 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       Syloid: 0.5   avicel PH   min. Then pour all       Pruv: 1.0   101/Kollid   pruv and mix for 2       Lot#/mfg date:   on XL   min 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   ½ Pearlitol 400DC,   31-37   Mouth 10:   Abrasion       28.69   study of    all MS,       10 S   0.04       Pearlitol 400DC:   disintegration   ½ 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       Syloid: 0.5   avicel PH   min. Then pour all       Pruv: 1.0   101/Kollid   pruv and mix for 2       Lot#/mfg date:   on XL   min 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   ½ Pearlitol 400DC,   36.4   Mouth 10:   Abrasion       28.69   study of   all MS,       10 S   1.0       Pearlitol 400DC:   disintegration   ½ 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       Pruv: 1.0       min. Then pour all       Lot#mfg date:       pruv and mix for 2       1242-130/Jan. 19, 2002       min using Turbula       250 g batch       mixer.               Piccola tablets press               11 mm punch FFRE               450 mg tablet       Fluoxetine TMMS:   Increase   ½ Pearlitol 400DC,   29.4   Mouth: 10 s   Abrasion       28.69   the level of   all MS,           1.7       Pearlitol 400DC:   avicel to   ½ 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       Syloid: 0.5   absorbs lot   min 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   ½ Pearlitol 400DC,   29.7   Mouth: 10 S   Abrasion       28.69   objective   all MS           0.3       Pearlitol 400DC:   as 1242-   ½ 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       AsesulK: 0.2       min. Then pour all       Tangerine: 0.2       pruv and mix for 2       Syloid: 0.5       min 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   ½ Pearlitol 400DC,   28.3   Mouth: 15-   Abrasion       28.69   the effect   all MS       20 S   0.3       Pearlitol 400DC:   of MCC on   ½ Pearlitol 400DC,       Slower than   Drop       54.41   the   mix for 3 min. Add       1242-125   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   ½ Pearlitol 400DC,   28.1   Mouth: 20 S   Abrasion       28.69   the effect   all MS       Slower than   0.4       Pearlitol 400DC:   of MCC on   ½ 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       Pruv: 1.0       min 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   ½ Pearlitol 400DC,   29.5   Mouth: 10 S   Abrasion       28.69   the level of   all MS       As good as   0.3       Pearlitol 400DC:   MCC from   ½ 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       Pruv: 1.0   of the   min 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   ½ Pearlitol 400DC,   27.5   Mouth: 20 S   Abrasion       28.69   investigate   all MS       Disintegrate   0.2       Pearlitol 400DC:   if the use   ½ 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       Syloid: 0.5   to enhance   min. Then pour all       Pruv: 1.0   the   pruv and mix for 2       Lot#/mfg date:   disintegration   min 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   ½ Pearlitol 400DC,   28.3   Mouth: 20 S   Abrasion       28.69   other   all MS       As good as   0.2       Pearlitol 400DC:   grades of   ½ 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       Tangerine: 0.2       min. Then pour all       Syloid: 0.5       pruv and mix for 2       Pruv: 1.0       min 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   ½ Pearlitol 400DC,   26.0   Mouth: 10 S   Abrasion       28.69   other   all MS       Better than   0.3       Pearlitol 400DC:   grades of   ½ 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 EFRE               450 mg table       Fluoxetine TMMS:   Investigate   ½ Pearlitol 400DC,   28.4   Mouth: 15S —   Abrasion       28.69   other   all MS       20 S   0.2       Pearlitol 400DC:   greades of   ½ 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       Syloid: 0.5       min 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   ½ Pearlitol 400DC,   24.4   Mouth: 15 S   Abrasion       28.69   other   all MS           0.3       Pearlitol 400DC:   greades of   ½ 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       Pruv: 1.0       min 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   ½ advantose, all MS   26.9   Mouth: 20 S   Abrasion       28.69   investigate   ½ 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   ½ advantose, all MS   27.9   Mouth: 10 S   Abrasion       28.69   investigate   ½ 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       AsesulK: 0.2   determine   min. Then pour all       Tangerine: 0.2   the   pruv and mix for 2       Syloid: 0.5   compressibility   min 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   ½ advantose, all MS   27.9   Mouth: 10 S   Abrasion       28.69   investigate   ½ 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       Citric acid: 1.0   determine   min. Then pour all       AsesulK: 0.2   the   pruv and mix for 2       Tangerine: 0.2   compressibility   min 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   ½ advantose, all MS   26.3   Mouth: 15 S   Abrasion       28.69   investigate   ½ 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   ½ advantose, all MS       Mouth: 10-   Abrasion       28.69   investigate   ½ advantose, mix for       25 S   0.0       Advantose 100:   the effect of   3 min. Add all Citric       Not as good   Drop:       56.41   MCC on the   acid, all AcesuK, all       as 1242-   1.0       Prosolv 50: 10.0   disintegration   syloid, all Prosolv, all       143.       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   ½ advantose, all MS   29.0   Mouth: 10-   Abrasion       28.69   the use of   ½ advantose, mix for       15 S   1.0       Advantose 100:   avicel to   3 min. Add all Citric       Good tablets   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   ½ advantose, ½   27.8   Mouth: 10S   Abrasion       28.69   investigate   Pearlitol, all MS, ½       Good tablets   0.5       Advantose 100:   the   Peqrlitol, ½           Drop:       25.70   combination   advantose, mix for 3           1.9       Pearlitol 400DC:   of 2 polyols   min. 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   ½ advantose, ½   28.4   Mouth: 15 S   Abrasion       28.69   investigate   Pearlitol, all MS, ½       Good tablets   0.3       Advantose 100:   the   Pearlitol, ½       No   Drop:       12.85   combination   advantose, mix for 3       significant   0.5       Pearlitol 400DC:   of 2 polyols   min. 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   ½ advantose, ½   28.4   Mouth: 10 S   Abrasion       28.69   investigate   Pearlitol, all MS, ½       Good tablets   n:       Advantose 100:   the   Pearlitol, ½       Faster than   0.5       38.56   combination   advantose, mix for 3       1242-147 &amp;   Drop:       Pearlitol 400DC:   of 2 polyols   min. Add all Citric       148   1.6       12.85   at different   acid, all Acesu K, all       1242-147 &amp;       Avicel PH 101:   ratio and   syloid, all avicel, all       148       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   ½ Pearlitol, all MS   27.1   Mouth: 35 S   Abrasion       28.69   the physical   ½ Pearlitol, mix for 3       Very slow   0.2       Pearlitol 400DC:   properties of   min. 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       Tangerine: 0.2       min. Then pour all       Syloid: 0.5       pruv and mix for 2       Pruv: 1.0       min 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   ½ Pearlitol, all MS   33.9   Mouth: 7-   Abrasion       28.69   the Kollidon   ½ Pearlitol, mix for 3       10 S   0.2       Pearlitol 400DC:   CL and its   min. Add all Citric       Very fast   Drop:       51.41   effect on   acid, all AcesuK, all       tablet   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       Tangerine: 0.2       min 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   ½ advantose, ½   30.8   Mouth: 10 S   Abrasion       28.69   the Kollidon   Pearlitol, all MS, ½       Very fast   0.2       Pearlitol 400Dc:   CL and its   Pearlitol, ½       tablet no   Drop:       38.56   effect on   advantose, mix for 3       difference no   0.2       Advantose 100:   disintegration   min. 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       Tangerine: 0.2       min 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   ½ Pearlitol, all MS   35.7   Mouth: 15 S   Abrasion       28.69   the avicel   ½ Pearlitol, mix for 3       Not as fast   0.2       Pearlitol 400DC:   level   min. 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       Tangerine: 0.2       min 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   ½ advantose, ½   26.7   Mouth: 10-   Abrasion       28.69   the avicel   Pearlitol, all MS ½       15 S   0.3       Pearlitol 400DC:   level   Pearlitol, ½       Not as fast   Drop:       42.31       advantose, mix for 3       15% avicel   0.8       Advantose 100:       min. 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       Citric acid: 1.0       min. Then pour all       AsesulK: 0.2       pruv and mix for 2       Tangerine: 0.2       min 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   ½ advantose, ½   21.6   Mouth: 35 S   Abrasion       28.69   the level of   Pearlitol, all MS, ½       Very slow   0.2       Pearlitol 400DC:   avicel   Pearlitol, ½           Drop:       49.81       advantose mix for 3           0.3       Advantose 100:       min. 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   ½ Pearlitol, all MS   29.4   Mouth: 10 S   Abrasion       28.69   the   ½ Pearlitol, mix for 3       Very fast   0.4       Pearlitol 400DC:   combination   min. 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       AsesulK: 0.2   and   min 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   ½ advantose, ½   33.1   Mouth: 12-   Abrasion       28.69   the   Pearlitol, all MS, ½       15 S   0.3       Pearlitol 400DC:   combination   Pearlitol, ½       Good tablets   Drop:       37.06   of Kollidon   advantose, mix for 3           0.6       Advantose 100:   CL/L0HPC   min. 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       L-HPC 11: 2.0   and   min. Then pour all       Citric acid: 1.0   friability   pruv and mix for 2       AsesulK: 0.2   formulation.   min 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   ½ lab, all MS ½ 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       AsesulK: 0.2       min. Then pour all       Tangerine: 0.2       pruv and mix for 2       Syloid: 0.5       min 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   ½ lab, all MS ½ 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       Tangerine: 0.2       min 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                    Mixing                               procedure &amp;               Equipment   Hardness   Disintegration   Friability   Dissolution       Formulation Lot#   Objective   Used   (N)   time   %   %               Fluoxetine TMMS:   Investigate   ½ Pearl   32   Mouth: 10 S   Abrasion       28.69   high   400DC, all           0.3       Pearlitol 400DC:   level of   MS ½ pearlitol           Drop:       58.41   Kollidon   400DC, mix           2.1       Kolidon XL: 10   XL for   for 3 min. Add       Citric acid: 1.0   fast   all Citric acid,       AsesulK: 0.2   disintegration   all AcesuK, all       Syloid: 0.5   using   syloid, all       Tangerine: 0.2   high   Kollidon, all       Pruv: 1.0   for 5 min.   tangerine, mix       Lot#1242-117   compression.   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: 0.2       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   400DC, all           0.4       Pearlitol 400DC:   Kollidon   MS,           Drop:       48.41   XL from   ½ Pearlitol           2.3       Kolidon XL: 20   10% to   400DC, 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: 0.2   effect of   syloid, all       Pruv: 1.0   disintegrant   Kollidon, all       Lot#1242-120   concentration   tangerine, mix           on   for 5 min.           disintegration.   Then pour all           time   pruv and mix               for 2 min.               using Turbula               mixer.               Piccola tablets               press               11 mm punch               FFRE       FluoxetineTMMS:   Investigate   ½ Pearlitol   16.2   Mouth   Abrasion       28.69   alternative   400DC, all       20 S, at 20   14.8       Pearlitol 400DC:   disintegrant   MS,       and 30 N   Drop:       48.41   like L-   ½ Pearlitol       tables very   powder       L-HPC11: 20   HPC11   400DC, mix       slow to   collection       Citric acid: 1.0       for 3 min. Add       disintegrate       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   microcrys-   400DC, all           0.2       Pearlitol 400DC:   talline   MS,           Drop:       48.41   cellulose   ½ Pearlitol           0.8       Avicel PH 101: 16.0   as a   400DC, mix       L-HPC 11: 4.0   wicking   for 3 min. Add       Citric acid: 1.0   and   all Citric acid,       AsesulK: 0.2   dispersin   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   disintegration   tangerine, mix       Avicel PH101/L-   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   400DC, all           0.2       Pearlitol 400DC:   ratio of   MS,           Drop:       48.41   avicel PH   ½ Pearlitol           0.8       Avicel PH 101: 18.0   101/L-   400DC mix       L-HPC 11: 2.0   HPC 11   for 3 min. Add       Citric acid: 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-   disintegration   for 5 min.       HPC11 ratio (90/10)   in   Then pour all           the   pruv and mix           mouth   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   400DC, all           0.2       Pearlitol 400DC:   ratio of   MS,           Drop:       48.41   avicel PH   ½ Pearlitol           1.0       Avicel PH 101: 14.0   101/L-   400DC, mix       L-HPC 11: 6.0   HPC 11   for 3 min. Add       Citric acid: 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-   disintegration   for 5 min.       HPC11 ratio (70/30)   in   Then pour all           the   pruv and mix           mouth   for 2 min using               Turbula mixer.               Piccola tablets               press               11 mm punch               FFRE       Fluoxetine TMMS:   Comparative   ½ Pearlitol   34.0   Mouth: 10 S   Abrasion       28.69   study   400DC, all           0.1       Pearlitol 400DC:   of   MS,           Drop:       48.41   disintegration   ½ Pearlitol           1.5       Avicel PH 101: 16.0   time   400DC, mix       Kollidon XL: 4.0   of avicel   for 3 min. Add       Citric acid: 1.0   PH   all Citric acid,       AsesulK: 0.2   101/L-   all Acesu K, all       Syloid: 0.5   HPC11   syloid, all       Tangerine: 0.2   formulation   avicel, all       Pruv: 1.0   versus   Killidon, all       Lot#1242-126   avicel PH   tangerine, mix       Avicel PH   101/Kollidon   for 5 min.       101/Kollidon ratio   XL   Then pour all       (80/20)       pruv and mix               for 2 min using               Turbula mixer.               Piccola tablets               press               11 mm punch               FFRE       Fluoxetine TMMS:   Comparative   ½ Pearlitol   31-37   Mouth: 10 S   Abrasion       28.69   study   400DC, all           0.04       Pearlitol 400DC:   of   MS,           Drop:       48.41   disintegration   ½ Pearlitol           1.6       Avicel PH 101: 4.0   time   400DC, mix       Kollidon XL: 16.0   of avicel   for 3 min. Add       Citric acid: 1.0   PH   all Citric acid,       AsesulK: 0.2   101/L-   all Acesu K, all       Syloid: 0.5   HPC11   syloid, all       Tangerine: 0.2   formulation   avicel, all       Pruv: 1.0   versus   Kollidon, all       Lot#1242-127   avicel PH   tangerine, mix       Avicel PH   101/Kollidon   for 5 min.       101/Kollidon ratio       Then pour all       (20/80)       pruv and mix               for 2 min using               Turbula mixer.               Piccola tablets               press               11 mm punch               FFRE       Fluoxetine TMMS:   Comparative   ½ Pearlitol   33.3   Mouth: 10 S   Abrasion       28.69   study   400DC, all           1.0       Pearlitol 400DC:   of   MS,           Drop:       52.41   disintegration   ½ Pearlitol           2.5       Kollidon XL: 16.0   time   400DC, mix       Citric acid: 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   400DC, all           1.7       Pearlitol 400DC:   of avicel   MS,           Drop:       26.25   to   ½ Pearlitol           1.8       Avicel PH 101: 26.25   improve   400DC, mix       L-HPC: 16   the   for 3 min. Add       Citri ca cid: 1.0   disintegration   all Citric acid,       AsesulK: 0.2   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: 10 S   Abrasion       28.69   objective   400DC, all           0.3       Pearlitol 400DC:   as 1242-   MS,           Drop:       26.25   131,   ½ Pearlitol           0.8       Avicel PH 101: 26.25   except   400DC, 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   400DC, all       to 20 S   0.3       Pearlitol 400DC:   avicel on   MS,           Drop:       54.41   the   ½ Pearlitol           0.3       Avicel PH 101:12   tablets   400DC, mix       L-HPC: 2   formulation   for 3 min. Add       Citri ca cid: 1.0   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   400DC, all       slow   0.4       Pearlitol 400DC:   the   MS,       compared to   Drop:       60.41   mouth   ½ Pearlitol       1242-133   0.4       Avicel PH 101: 6   feel and   400DC, mix       L-HPC: 2   gritty   for 3 min. Add       Citri ca cid: 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           formulation   FFRE.       FluoxetineTMMS:   As results   ½ Pearlitol   29.5   Mouth: 10 S   Abrasion       28.69   of   400DC, all MS,           0.3       Pearlitol 400DC:   1242-   ½ Pearlitol           Drop:       51.41   125 and   400DC, mix for           0.3       Avicel PH 101:15   1242-133   3 min. Add all       L-HPC: 2   on the   Citric acid, all       Citri ca cid: 1.0   tablets   Acesu K all       AsesulK: 0.2   disintegration,   syloid, all       Syloid: 0.5   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           disintegration   Turbula mixer.           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   400DC, all MS,           0.2       Pearlitol 400DC:   of avicel   ½ Pearlitol           Drop:       53.41   alone in   400DC, mix for           0.4       Avicel PH 101: 15   the tablets   3 min. Add all       Citri ca cid: 1.0   formulation.   Citric acid, all       AsesulK: 0.2   To   Acesu K, all       Syloid: 0.5   determine   syloid,       Tangerine: 0.2   the effect   all avicel, all       Pruv: 1.0   of the   tangerine, mix       Lot#1242-136   disintegration   for 5 min. Then           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   400DC, all MS,       better disint   0.2       Pearlitol 400DC:   disintegrant   ½ Pearlitol       than 1242-   Drop:       51.41   Prosolv90   400DC, mix for       125   0.4       Prosolv90: 15   to   3 min. Add all       L_HPC 11: 2   study   Citric acid, all       Citri ca cid: 1.0   the   Acesu K, all       AsesulK: 0.2   disintegration   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.           effectiveness   Then pour all           with   pruv and mix for           avicel   2 min using           in a   Turbula mixer.           direct   F tablets press           compaction.   11 mm punch               FFRE.                  
 
         [0141]    Preferred oormulations based on directly compressible inorganic Salts, alone or in combination with a cellulose derivative:  
         [0142]    The present preferred illustartive embodiments of the invention relate to the introduction of directly compressible inorganic salt with a cellulose derivative.  
                                                                                                                                                                                                                                                       %                                    Formulation I:       This formulation is based on an excipient mass containing       a misture of dibasic calcium phosphate dihydrate       (Emcompress) and microcrystalline cellulose (Avicel).                FluoxetineTMMS*:   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           Citric Acid anhydrous:   1.50           Syloid 244FP:   0.50           Pruv:   1.00            Formulation II:       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           Citric Acid anhydrous:   1.50           Syloid 244FP:   0.50           Pruv:   1.00            Formulation III:       This formulation is based on an excipient mnass 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           Citric Acid anhydrous:   1.50           Syloid 244FP:   0.50           Pruv:   1.00            Formulation IV:       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           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:   0.20           Magnasweet 100:   0.20           Tangerine Flavor:   0.50           Citric Acid anhydrous:   1.50           Syloid 244FP:   0.50           Pruv:   1.00            Formulation VI:       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           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           Citric Acid anhydrous:   1.50           Syloid 244FP:   0.50           Pruv:   1.00            Formulation VIII:       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 therevy improve the patient&#39;s ability       to 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           Citric Acid anhydrous:   1.50           Syloid 244FP:   0.50           Pruv:   1.00            Formulation IX:                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           Citric Acid anhydrous:   1.50           Syloid 244FP:   0.50           Pruv:   1.00            Formulation X:                Fluoxetine TMMS*:   28.69           Pearlitol 400DC:   43.81           Emcompress:   12.10           Avicel PH 101:   7.50           Magnabrite F:   4.00           AcesulfameK:   0.20           Magnasweet100:   0.20           Tangerine Flavor:   0.50           Citric Acid anhydrous:   1.50           Syloid 244FP:   0.50           Pruv:   1.00