MXPA97005281A - Formulations of acetaminofen of high cargo, compresible directame - Google Patents

Abstract

The solid, direct compression dosage forms containing: a) from about 40 to about 95% by weight of acetaminophen, b) from about 1 to about 60% by weight of a direct compression vehicle comprising microcrystalline cellulose are presented and c) from about 0.01 to about 4.0% by weight of a pharmaceutically acceptable lubricant. acetaminophen and the direct compression vehicle are combined under high shear conditions that are sufficient to transform the acetaminophen and the direct compression vehicle into a homogeneous granulate without degradation. In preferred aspects of the invention, the lubricant is also combined with the acetaminophen and direct compression vehicle under high shear conditions. Also presented are the methods of preparation of the solid dosage forms, directly compressed and the methods of treatment with the dosage forms. The methods are particularly suitable for preparing directly compressed dose forms containing high loading amounts (ie up to 80% or greater) of acetaminophen based on the total weight of the tablet.

Description

FORMULATIONS OF ACETAMINOJFEN OF HIGH LOAD, COMPRESSIBLE DIRECTLY BACKGROUND OF THE INVENTION The present invention relates to methods for preparing solid dosage forms using direct compression techniques. In particular, the present invention relates to direct tablet compression methods that contain relatively high amounts of acetaminophen based on the total weight of the tablet. In order to prepare the solid dose form containing one or more active ingredients (such as drugs), it is necessary that the materials to be compressed in dosage form have certain physical characteristics that allow them to be processed in dosage form. solid Among other things, the material to be compressed must be free flowing, must be lubricated and, very important, must possess sufficient cohesion to ensure that the solid dose form remains intact after compression. In the case of tablets, this is formed by the pressure applied to the material to be tabletted, in a tablet dam. A dam for tablets includes a lower perforator, which fits or fits into a die from the bottom and an upper perforator having a corresponding shape and the dimension that enters the die cavity from above after the cavity is filled of the die with the material to be tableted. The tablet is formed by the pressure applied in the upper and lower perforators. The ability of the material to flow freely in the die is important because it ensures that there is a uniform filling of the die and a continuous movement of the material from the source of material, for example ur. feeder tank The lubrication of the material is crucial in the preparation of the solid dose forms since the material that is compressed must come out quickly from the perforation faces. Because most drugs only exhibit some of these properties, if any, methods for formulating tablets to impart these desirable characteristics to the material or materials to be compressed in the solid dosage form have been developed. Typically, excipients are added to the formulation that imparts good fluidity and compression characteristics to the material as a whole to be compressed. Typically, these properties are imparted to these excipients through the pre-processing step such as wet granulation, slugging, spray drying, spheronization or crystallization. The excipients useful in direct compression include the processed forms of cellulose, sugars and dehydrated calcium phosphate, among others. Typically, the lubricants are added to prevent the material or materials that are to be formed in the tablet from sticking to the perforators. Commonly used lubricants include magnesium stearate and calcium stearate. These lubricants are commonly included in the final tablet product in amounts usually less than 1% by weight. In addition, solid dosage forms frequently contain diluents. The diluents are frequently added in order to increase the weight of the mass of the material to be compressed in the tablet in order to make the tablet of a practical size for compression. Frequently, these are necessary when the dose of the drugs is relatively small. Another class of excipients that is commonly used in solid dosage forms are binders. The agglutinating agents that impart cohesion qualities to the material or powder materials. The binders that are commonly used include starch, and sugars such as sucrose, glucose, dextrose and lactose.

The disintegrants that are used more frequently, in order to ensure that the compressed solid dose form that is finally prepared has an acceptable average disintegration in the environment of use (such as the gastrointestinal tract). Typical disintegrants include starch derivatives and salts of carboxymethylcellulose. There are three general methods of preparing materials that are included in the solid dosage form before performing compression: (1) dry granulation; (2) wet granulation, and (3) direct compression. Dry granulation processes can be used when one of the constituents, be it the drug or the diluent, has sufficient cohesion properties to be compressed into tablets. The method includes mixing the ingredients with a lubricant, if required, spraying the ingredients, drying by sieving, lubricating and finally compressing the ingredients. The wet granulation process includes mixing the powders to be incorporated in the dosage form, for example, in a double layer mixer or in a double cone mixer under shear mixing conditions and then adding the solutions of an agent binder to the mixed powders to obtain the granulation. Then, the wet mass is screened, for example in a 6- or 8-mesh screen, and then dried, for example by drying and tray or fluid bed drying. The wet granulation technique is practically a time consuming due to its procedural steps and can also be considered as a relative expense. Furthermore, it is known that wet granulation reduces the compressibility of some pharmaceutical ingredients including microcrystalline cellulose. Direct compression, on the other hand, is considered to be a relatively rapid process in which powdered materials that are included in the solid dose form are compressed directly without modifying their physical nature. Usually, the active ingredient, the direct compression vehicle and other auxiliary substances, such as glidant to improve the average flow of the granulation of the tablet and the lubricant to prevent the adhesion of the material of the tablet on the surface of the dies and the tablet prey borers, are mixed in a double layer mixer or a similar low shear apparatus prior to tablet compression. This type of mixing of the ingredients is believed essential for preparing the pharmaceutically acceptable dosage forms. For example, Remington's Pharmaceutical Sciences, 16th edition (1980), Arthur Osol, ED, warns processors that the way in which the lubricant is added to the formulation must be controlled very carefully. Consequently, lubricants are generally added to the granulation by a gentle mixing. On page 1556, Remington 's warns: "Prolonged blending of a coating with a granulation can, theoretically, affect the hardness and disintegration time of the resulting tablets. In addition, those skilled in the art have long believed that excessive mixing of a lubricant with the granulated ingredients coats the granulates and reduces the hardness of the tablet or the strength of the tablets of the compressed tablets. Therefore, at least for these reasons, the shear mixing conditions have not been used to prepare dosage forms with direct compression. Pharmaceutical producers often prefer the use of direct compression techniques instead of dry or wet granulation techniques due to their processing time and cost advantages. However, direct compression is usually limited to those situations wherein the medicament or active ingredient has a crystal structure requirement and the physical characteristics that are required for the formation of a pharmaceutically acceptable tablet. However, often one or more excipients must be combined with the active ingredient before the direct compression method can be used since the active ingredients do not have the necessary properties. Because each of the excipients that is added to the formulation necessarily increases the size of the tablet of the final product, often, producers are limited to using direct compression techniques in formulations that contain a practically low load of the ingredient. active per compressed tablet. The solid dosage forms of the medicament are administered at a relatively high load or dose (eg, medicaments comprising a substantial portion of the total weight of the compressed tablet), it could only be compressed directly if the medication itself had enough physical characteristics (eg cohesion) for the ingredients to be directly compressed. For example, acetaminophen, which is widely used as an analgesic, is considered as a high load active ingredient. Most formulations of commercial compressed tablets include from 70% to 85% by weight of acetaminophen per finished tablet. This high load of active ingredient combined with the practically poor physical characteristics for direct compression have not allowed pharmaceutical manufacturers to use direct compression techniques to prepare final tablets. Previous attempts to directly compress acetaminophen with microcrystalline cellulose have failed to provide an acceptable product. The final products have to be soft, prone to encapsulate and for this reason they are not commercially desirable, that is, they are difficult to swallow due to their large size. Consequently, granulation techniques that require more time and are expensive must be used. Therefore, another limitation of direct compression as the method for tablet production is the potential size of the compressed tablet. If the amount of active ingredient is high, the pharmaceutical formulator can select the wet granulation with other excipients to achieve the acceptable size of the tablet with the desired amount of acetaminophen. Usually, the amount of filler / binder or excipients that are needed in the wet granulation is less than that required for direct compression since the wet granulation process contributes to a certain extent, towards the physical properties of a tablet. In the pharmaceutical industry, microcrystalline cellulose, a cellulose processed as a direct compression vehicle for solid dosage forms, has been widely used. Crystalline cellulose is commercially available under the trademark EMCOCEL® from Edward Mendell Co. , Ine and as Avicel® by EMC Corp. When compared to other directly compressible excipients, microcrystalline cellulose is generally considered to have superior compression and disintegration properties as long as it is not granulated by moisture prior to compression. Therefore, in spite of the advantages of direct compression such as for example the reduction of time and process costs, wet granulation is widely used in the industry to prepare solid dosage forms. Currently, many experts in the art also prefer wet granulation to direct compression because wet granulation is more likely to overcome any problems associated with the physical characteristics of the different ingredients in the formulation, therefore a material is provided. that has the characteristics of flow and cohesion that are necessary requirements to obtain an acceptable solid dose form. The popularity of the wet granulation process when compared to the direct compression process is based on at least three advantages. First, the wet granulation provides the material to be compressed with better moisture properties, particularly in the case of hydrophobic drug substances. The addition of a hydrophilic excipient makes the surface of a hydrophobic drug more hydrophilic, facilitating disintegration and dissolution. Second, the uniform content of solid dosage forms is generally improved with the wet granulation method because all the granulates that are obtained, therefore, usually contain approximately the same amount of medicament. Thus, segregation of the different ingredients of the material to be compressed is avoided (due to different physical characteristics, such as density). Segregation is a potential problem with the direct compression method. Finally, the size of the particle and the shape of the particles comprising the granulate to be compressed is optimized by the wet granulation process. This is due to the fact that when the dry solid is granulated with moisture, the binder "sticks" the particles, so that they agglutinate in the granules that are more or less spherical. Despite the advantages presented by the granulation methods, many producers accept the opportunity to directly compress tablets containing acetaminophen, especially those containing high charges of inofen acetates and / or microcrystalline cellulose. Therefore, the need remains in the industry for pharmaceutical techniques and excipients that allow producers to prepare different compressed dose forms containing relatively high amounts of acetaminophen by weight and thus avoid the time required and the costs of wet granulations. .

OBJECTIVES AND SUMMARY OF THE INVENTION It is an object of the present invention to provide improvements in direct compression techniques. Furthermore, it is an object of the present invention to provide an effective alternative for the costs of acetaminophen formulations by wet granulation to prepare solid dosage forms containing a relatively high proportion of the drugs when compared to the total weight of the dosage form. . It is still another object of the present invention to provide solid dosage forms for oral administration of compressed acetaminophen which disintegrates rapidly in vivo and in vitro. It is also an object of the present invention to provide directly compressed dose forms that provide a controlled release of acetaminophen without relying on the fluid bed or granulation techniques. Another object of the present invention is to provide the solid dosage forms which include acetaminophen and which are prepared according to the methods described herein. In accordance with the aforementioned objectives and others that will be obvious to those skilled in the art, the present invention includes a direct, solid, pharmaceutical dosage form containing: a) from about 40 to about 95% by weight of acetaminophen; b) from about 1 to about 60% by weight of a direct compression vehicle comprising microcrystalline cellulose; and c) from about 0.01 to 4.0-8 by weight of a pharmaceutically acceptable lubricant. The acetaminophen and direct compression vehicle included in the directly compressed dose form are combined under shear mixing conditions which are sufficient to transform the acetaminophen and the direct compression vehicle into a homogeneous granulate without degradation. In preferred embodiments of these aspects of the invention, the solid dosage form comprises from about 60% to about 85% by weight of acetaminophen and the acetaminophen is in granular form. In this manner, solid dosage forms can contain from about 10 to about 1000 milligrams of acetaminophen. In a particular preferred embodiment, the direct compression vehicle includes microcrystalline cellulose which has been coprocessed with from about 0.1 to about 20% by weight of silicon dioxide in such a way that the microcrystalline cellulose and the silicone dioxide are in intimate association each other and provide improved compression properties for direct compressed dosage forms. A further preferred embodiment includes preparing the solid dosage form directly compressed to include from about 0.1 to about 1% by weight of a pharmaceutically acceptable lubricant such as for example sodium fumarate stearate. The lubricant is included as part of the homogeneous mixture containing acetaminophen and the vehicle for direct compression and is preferably mixed with these ingredients under high shear conditions equal or similar to those used to form the homogeneous mixture. In another embodiment, the directly compressed dose forms of the present invention include from about 0.1 to about 5.0% by weight of silicone dioxide. The silicone dioxide is preferably combined with the homogenous mixture containing the acetaminophen and the direct compression vehicle during the same high shear conditions that are used to transform the ingredients into the homogeneous mixture. In another embodiment of the invention, directly compressed dosage forms include a desizing agent that has preferably been mixed with the aforementioned acetaminophen, the direct compression vehicle and the lubricant. A particularly preferred solid dosage form of the present invention, includes at least about 75% by weight of acetaminophen and has an average tablet hardness of approximately 6.5 kP when the homogeneous granulate containing acetaminophen and microcrystalline cellulose is directly compressed with a compression force of approximately 25 kN. The tablets of the present invention also have a relatively fast disintegration average which compares favorably with acetaminophen tablets prepared using the wet granulation techniques. In certain preferred embodiments, the average disintegration for the tablets of the present invention meets the requirements set forth in USP 23 © 1994 United States Pharmacopeial Convention, Inc. In addition, it is believed that the comparison of the average disintegration of the tablets of the invention is also favorable, and in certain embodiments, still exceeds that of APAP products granulated by moisture. In certain preferred embodiments, the tablets of the invention also meet dissolution requirements for acetaminophen tablets as set forth in the official USP 23 monograph. For example, directly compressed APAP tablets will preferably dissolve in 900 ml of pH 5.8 of phosphate buffer in 30 minutes. The "dissolution requirements" and the "disintegration requirements" referred to herein are made using the equipment and tests specified in USP 23 mentioned above. In another aspect of the present invention, methods of preparing directly compressed solid pharmaceutical dosage forms containing acetaminophen are provided. This aspect of the invention includes a first combination of an effective amount of acetaminophen and a direct compression vehicle comprising microcrystalline cellulose under shear conditions that are sufficient to transform the acetaminophen and the direct compression vehicle into a homogeneous first granulate without degradation. Then, the homogeneous granulate is combined with a pharmaceutically acceptable lubricant, either by a similar shear or with other dry mixing conditions and thus compressing the resulting homogeneous granulate containing a lubricant in pharmaceutically solid dosage forms. Alternative aspects of the methods of the invention described herein include forming a mixture with high shear including silicone dioxide, preferably in the form of colloidal silicon dioxide. A particularly preferred method includes forming a first high shear mixture containing acetaminophen and a direct compression vehicle including microcrystalline cellulose and silicon dioxide before adding the lubricant under high shear conditions. Yet another aspect of the method of the invention includes preparing the solid dosage forms of direct compression when preparing a first high shear mix with the combination of acetaminophen, the direct compression vehicle and optionally, silicone dioxide and / or a disintegrating Then, the first high shear mix is combined with a lubricant in a separate high shear mixing step to form a final homogeneous granulate. In this aspect of the invention, however, the second shear mixing step is carried out under conditions, which are milder than those used to carry out the first step of the shear mix. For the purposes of the present invention, the term "high load" is meant to indicate that acetaminophen comprises a substantial portion of a solid oral dosage form based on weight. Those who are familiar with the art will recognize that compressed tablets containing at least 40% by weight of acetaminophen are "high load" tablets. The term "granular" for the purposes of the present invention is meant to connote the particles having a transverse average diameter of from about 50 to about 500 microns. The granulated particles are distinguished from the powdered particles because they have a particle size of less than about 50 microns and even more in the range of 10-20 microns. The term "environmental fluid", for the purposes of the invention, is used to include or encompass, for example, an aqueous solution, or gastrointestinal fluid. By the term "sustained release" it is meant, for the purposes of the invention, that acetaminophen is released from the solid dose form to an controlled average such that blood levels therapeutically beneficial (but below toxic levels) of the active ingredient are maintained for an extended period of time, for example, by providing a dosage form of 12 hours or 24 hours. For the purposes of the invention, "controlled release" means that acetaminophen is released from the solid dosage form to a predetermined average, such that beneficially therapeutically beneficial blood levels are maintained for a period of time. By "bioavailable", it is meant, for the purposes of the invention that a is absorbed from the dosage form and becomes available in the body at an intended place of action. With the term "primary particle size", according to the purposes of the invention, it is meant that the particles are not agglomerated. Agglomeration is common with respect to silicon dioxide particles, resulting in a large agglomerated particle size, relative to the comparative average. The methods and compositions of the present invention provide several advantages to pharmaceutical producers in relation to direct compression techniques. For example, the methods give producers the ability to include large amounts of acetaminophen in direct compression dosage forms. In the past, only solid dosage forms for oral administration, of high loading, containing acetaminophen, could be prepared, using wet granulation techniques due to the amount of additional excipients that are required to impart the necessary physical characteristics, such as example hardness and size, giving final formulas of unacceptable doses for both manufacturers and consumers.

A further advantage of the present invention is that it is now possible to increase the tablet hardness of solid dosage forms containing acetaminophen by subjecting the formulation to high shear mixing. This technique is especially advantageous in situations where one or more of the ingredients of the formulation, such as for example an active ingredient, is unable to cope with the wet granulation. For a better understanding of the present invention, together with other additional objectives, reference is made to the following description, accompanied by the following figures, and the scope of the invention is pointed out in the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS The following drawings illustrate the embodiments of the invention and do not limit the scope of the invention as it is encompassed in the claims. Figure 1 illustrates, graphically, the tensile strength of the high load APAP tablets prepared according to Examples 3-5,7,8, a control of high load APAP tablets made according to Examples 6 and a second control prepared using the prior techniques. Figure 2 illustrates, graphically, a comparison of the tensile strength of the tablets prepared according to Examples 8 and 9-11 and obtained for a high load APAP formulation as a control. Figure 3 is a graphic illustration of the differences in disintegration time for a mixture mixture of tablets prepared according to the present invention and commercially available APAP tablets. DETAILED DESCRIPTION OF THE INVENTION In one aspect of the invention, directly compressed solid pharmaceutical dosage forms are provided comprising: a) from about 40 to about 95% by weight of acetaminophen; b) from about 1 to about 60% by weight of a direct compression vehicle comprising microcrystalline cellulose; and c) from about 0.01 to about 4.0% by weight of a pharmaceutically acceptable lubricant. The acetaminophen and the direct compression vehicle are combined under shear mixing conditions that are sufficient to transform the acetaminophen and the direct compression vehicle into a homogeneous granulate without degradation. The lubricant that is included in the dosage forms is also combined with the homogeneous granulate. In this sense, high shear conditions are preferred although they are not required. ACETAMINOFEN Acetaminophen, hereinafter referred to as APAP, used in the directly compressed dosage forms of the present invention is preferably in granular form and has an average cross-sectional diameter from about 50 to about 500 microns. However, more preferably, the granular APAP has a cross-sectional diameter of from about 250 to 300 microns. Acetaminophen having these physical characteristics is available, for example from Mallinkrodt, St. Louis, MO USA. An alternative acetamofen is also available from Mallinkrodt is DC-90. It is understood that the present invention is not limited to this type of granular APAP. Other sources of APAP are also contemplated, as long as the APAP has the granular characteristics that were previously established. The preferred granular APAP that is used in the dosage forms of the present invention is in contrast to the powder forms of the active ingredients. These powder forms of APAP have a cross-sectional diameter of from about 10 to 20 microns and are not contemplated for use herein. While the applicants are not limited by theory, it is believed that a critical particle size is required to successfully support the shear mixing conditions that transform the APAP into high load quantities, and the direct compression vehicle into a flowable granulate capable of being directly compressed into solid dose forms having sufficient hardness and other physical qualities associated with the acceptable dosage forms. In an aspect of the invention that is preferred, solid dosage forms contain from about 60 to about 85% by weight of acetaminophen. Of course, the exact amount of acetaminophen that is included in the dosage forms of the present invention will depend on the size of the tablet and the amount of the dose that the producer contemplates. Currently, APAP tablets are frequently formulated to contain from about 160 to about 650 milligrams of medicine. Tablets containing about 325 and about 500 milligrams are also commonly found. Many other formulations of APAP are commercially available. The tablets of the present invention contain from about 10 to about 1000 milligrams of APAP, preferably from about 80 to about 750 milligrams of APAP and more preferably from about 120 to about 650 milligrams of APAP.

In an alternative aspect of the invention, directly compressed acetaminophen tablets are prepared to contain an additional active ingredient such as those commonly found in APAP products. A list, without limitation, of suitable ingredients that can be combined with APAP includes narcotic analgesics such as codeine phosphate, oxycodone and hydromorphone, decongestant nasal and / or sinus ingredients, such as pseudoephedrine and antihistamines, such as, for example, phenyldramine. . DIRECT COMPRESSION VEHICLES The direct compression vehicles used in the solid dosage forms of the present invention represent from about 1 to about 60% by weight of the solid dosage form containing from about 2 to about 25 and more preferably from 5 to about approximately 20% by weight of the direct compression vehicle. Microcrystalline cellulose is a well-known tablet diluent and disintegrant. Its main advantage over other excipients is that it can be compressed directly into self-binding tablets, which disintegrate rapidly when placed in water. This widely used ingredient is prepared by the partial depolymerization of the cellulose obtained as a pulp of the fibrous plant material with acid solutions of dilute mineral. After hydrolysis, the hydrocellulose obtained in this way is purified by filtration and the aqueous suspension is spray dried to form a crystalline, tasteless, odorless, dry white powder of porous particles of a broad size distribution . Another method for preparing microcrystalline cellulose is presented in U.S. Patent No. 3,141,875. This reference presents the subjecting the cellulose to the hydrolytic action of a hydrochloric acid at boiling temperatures in such a way that the amorphous cellulose material can be removed and aggregates of crystalline cellulose are formed. The aggregates are collected by filtration, washed with water and aqueous ammonia and disintegrated into small fragments, often called cellulose crystallites by means of vigorous mechanics such as for example mixing. Microcrystalline cellulose is commercially available in different grades with a range in average particle size from 20 to 200 microns. The crystalline cellulose is soluble in water, but the material has the ability to flow in the tablet by capillary action. Then, the tablets are incised in contact and the microcrystalline cellulose acts as a disintegrating agent. The material has sufficient self-lubricating qualities in a way that allows a lower level of lubricant compared to other excipients. Typically, the volume powder of the microcrystalline cellulose has a bulk density of about 0.28 g / cm 3 and a capsule density of about 0.43 g / cm 2. Handbook of Pharmaceutical Excipients, pages 53-55. When used in pharmaceutical applications, microcrystalline cellulose is typically used, as a binding agent / diluent in wet granulation and in direct compression formulations in amounts of 5-30% of the formulation, or more. However, it is well known that the use of more or less microcrystalline cellulose in pharmaceutical products depends on the requirements of the formulation. Although it is known to include MCC in direct compression formulations, the simple double-layer mixture of APAP and MCC has not provided a mixture that can be directly compressed into an acceptable solid dose form. In a preferred embodiment of the invention, the direct compression vehicle includes microcrystalline cellulose which has been coprocessed with from about 0.1 to about 20% silicon dioxide. This coprocessed direct compression vehicle is an agglomerate of microcrystalline cellulose and silicon dioxide in which microcrystalline cellulose and silicon dioxide are intimately associated with each other, as described in commonly assigned U.S. Patent Application Serial No. 08 / 370,576, the disclosure of which is incorporated herein by reference. The magnifications of these coprocessed particles indicate that the silicone dioxide is integrated with, or partially covers, the surfaces of the microcrystalline cellulose particles. This exact relationship of the two ingredients in the excipient, after the coprocess is not currently understood; however, for the purpose of the description, the coprocessed particles are described herein as including an agglomerate of microcrystalline cellulose and silicon dioxide in an intimate association with each other. By "intimate association" is meant that silicon dioxide, in some form, is integrated with the microcrystalline cellulose particles, for example, by the partial coating of the microcrystalline particles, as opposed to the chemical interaction of two ingredients. The term "intimate association" is therefore considered, for the purposes of the present description, as a synonym for "integrated" or "joined". Co-processed particles are not necessarily uniform or homogenous. Under magnification, for example analysis with a microscope at 500x, the silicon dioxide, in a preferred percentage inclusion, appears to be a "coating-edge". The compressed excipients have a (free) volume of density ranging from about 0.2 g / ml to about 0.6 g / ml, and more preferably from about 0.35 g / ml to about 0.55 g / ml. The coprocessed excipients have an encapsulation density ranging from about 0.25 g / ml to about 0.65 g / ml and more preferably from about 0.35 g / ml to about 0.55 g / ml. The pH of the particles is more preferably approximately neutral. Although, it is possible for the granulates to have a pH from about 3.0 to about 8.5. The moisture content of the excipient particles will vary widely from about 0.5% to about 15%, preferably from about 1.5% to about 7% and more preferably from about 3.0% to about 5% by weight. The coprocessed excipient can be used alone or in combination with MCC "outside the layer" in any desired ratio to form the direct compression vehicle included in the new dosage forms. The silicone dioxide coprocessed with microcrystallines in this aspect of the invention preferably has an average primary particle size from about 1 nm to 1,000 μm. However, more preferably, the silicone dioxide has a primary particle average from about 5 nm to 40 μm. In silicon dioxide co-processed with MCC it is derived, preferably from colloidal silicon dioxide, and preferably comprises from about 0.5 to 10-by-weight of the co-processed material based on the weight of the microcrystalline cellulose and, more preferably, comprises from about 1.25 to about 5% by weight of the agglomerate based on the weight of the microcrystalline cellulose. LUBRICANTS The solid dosage forms of the present invention also include a sufficient amount of a lubricant. In preferred aspects of the invention, the selected lubricant is sodium fumarate stearate. Alternatives, however, include magnesium stearate, hydrogenated vegetable oil, LUBRI ® (Edward Mendell Co., Inc.), stearic acid, PEG and other lubricants known to those skilled in the art. In this regard, the lubricant will be present in amounts from about 0.01 to about 4% by weight of the dosage form. Amounts from about 0.1 to about 1.0% by weight are preferred and amounts from about 0.2 to about 0.45% are most preferred. In accordance with the present invention, the lubricant is combined with a homogeneous mixture containing the APAP and the direct compression vehicle. Surprisingly, it has been found that high shear mixing of the lubricant with the homogeneous granulate does not adversely affect the hardness of the tablet of the directly compressed dosage forms. Since the applicants are not limited by the theory, it is proposed that the conditions of high shear mixing pass the physical conditions in the granulate containing the lubricant, which is completely contrary to what was expected and which is desired for the direct compression of the granulation. ADDITIONAL INGREDIENTS A. Silicon dioxide In certain preferred aspects of the invention, the pharmaceutical dosage forms, which are directly compressed, include silicone dioxide in an amount that is separated from and in addition to the silicon dioxide included with the co-processed MCC ( if it is used). In this regard, the silicone dioxide is preferably colloidal silicon dioxide and is present in an amount from about 0.1 to about 5% by weight of the dosage form. Preferably, however, silicone dioxide is present in an amount from about 0.15 to about 0.9% by weight and, more preferably in an amount from about 0.4 to about 0.75% by weight of the dosage form. Silicon dioxide is obtained by insolubilizing silica dissolved in a solution of sodium silicate. When it is obtained by the addition of sodium silicate in a mineral acid, it is product is finished silica gel. When it is obtained by the destabilization of a sodium silicate solution in such a way that very fine particles are produced, the product is finished precipitated silica. Silicon dioxide is insoluble in water. Silicon dioxide and in particular colloidal silicon dioxide, is mainly used as a glidant and anti-adherent in the process of forming the tablets and encapsulating to promote the fluidity of the granulation. Handbook of Pharmaceutical Excipients, © JL986 American Pharmaceutical Association, page 255. This is partly due to the fact that the increase in the amount of silicon dioxide in the mixture that is going to be formed into tablets causes the mixture to flow very well, causing the phenomenon known to those skilled in the art of forming tablets as "flood" (Flooding). If the mixture flows very well, a variation in the weight of the tablet with uneven uniformity content may result.

Those skilled in the art will appreciate that the name and / or method of preparation of silicon dioxide used in the present invention does not determine the usefulness of the product. Furthermore, it has been surprising to discover that the high shear mixing of Si02 with other ingredients of the formulation unexpectedly improves the hardness of the tablet in direct compression dosage forms. The present invention encompasses all forms of silicone dioxide having an average primary particle size from about 1 nm to about 100 μm, and / or a surface area of about 10 m2 / g to about 500 m2 / g. The silicone dioxide used in the invention is of the variety of a very fine particle size. In the most preferred embodiments of the invention, the silicone dioxide used is a colloidal silicon dioxide. The colloidal silicon dioxide is smoked silica, submicron prepared by the hydrolysis in vapor phase (for example 1110 ° C) of a silicone compound, such as for example silicon tetrachloride. The product itself in a submicron, fluffy, light, loose, bluish-white, odorless and tasteless amorphous powder form that is commercially available from a number of sources, including Cabot Corporation (under the trademark Cab-O -Sil); Degusa, Inc. (Under the trademark of Aerosil); E.I.

DuPont & Co.; and .R. Grace & Co. Colloidal silicon dioxide is also known as colloidal silica, smoked silica, silica anhydride, silica anhydride and smoked silicon dioxide, among others. A variety of commercial grades of colloidal silicon dioxide are produced by a variety of manufacturing processes. These modifications do not affect the silica content, specific gravity, refractive index, color and amorphous form. However, it is known that these modifications change the particle size, the surface areas and the volume density of the colloidal silicon dioxide products. The surface area of the preferred kind of silicon dioxide used in the invention ranges from about 50 m2 / gm to about 500 m2 / gm. The primary average particle diameter of the preferred class of silicone dioxide used in the invention ranges from about 5 nm to about 50 nm. However, in commercial colloidal silicon dioxide products, these particles are agglomerated or aggregated to various degrees. The density the volume of the preferred kind of silicon dioxide used in the invention vary from about 20 g / 1 to about 100 g / 1. The colloidal silicon dioxide products have, for example, a Bet surface area ranging from about 50 + 15 m2 / gm (Aerosil OX50) to about 400 ± 20 (Cab-O-Sil S-17) or 390 ± 40 pr / gm (Cab-O-Sil EH-5). The commercially available particle sizes vary from a nominal particle diameter of 7 nm (eg Cab-O-Sil S-17 or Cab-O-Sil Eh-5) to an average primary particle size of 40 nm (Aerosil OX50). The density of these products varies from 72.0 ± 8 g / 1 (Cab-O-Sil S-17) to 36.8 g / 1 (for example Cab-O-Sil M-5). The pH of these products at 4% aqueous dispersion ranges from pH 3.5 to 4.5. These commercially available products are described to exemplify the acceptable properties of the preferred class of silicone dioxides only, and this disclosure is not intended to limit the scope of the invention in any way. In those aspects of the invention where the silicone dioxide is part of the pharmaceutical dosage form, it is preferred that the silicone dioxide be combined with acetaminophen, the direct compression vehicle and the lubricant under the same high shear conditions used for create the homogeneous mixture of ingredients in the solid dosage form. Alternatively, the silicone dioxide can be mixed by high shear with acetaminophen and the direct compression vehicle before the lubricant is combined therewith.

B. DISINFECTANT A disintegrant can also be included with other ingredients in a solid dosage form and is subjected to high shear mixing and, therefore, becomes part of the homogeneous mixture. In a preferred aspect of the invention, the disintegrant is sodium starch glycolate and will be present in amounts ranging from 0.01 to about 4.0% by weight of the dosage form, preferably from about 0.1 to about 2.0% and more preferably in amounts ranging from about 1.00 to about 1.50% by weight of the dosage form. A particularly useful disintegrant is available under the trademark Explotab® from Edward Mendell Co. , Inc. Alternate disintegrants include, for example, carboxymethylcellulose, crosslinked polyvinyl pyrrolidones in amounts similar to those set forth above or starches, in amounts of from about 4 to about 5%. C. AUXILIARY PHARMACEUTICAL INGREDIENTS The solid dosage form may also include an inert pharmaceutical filler such as for example a monosaccharide, a disaccharide, a polyhydric alcohol, inorganic phosphate, sulfates or carbonates, and / or mixtures thereof. Examples of inert pharmaceutical fillers include sucrose, dextrose, lactose, xylitol, fructose, calcium sorbitol phosphate, calcium sulfate, calcium carbonate, mixtures thereof and the like. The amount of inert filler, if included, will be an amount that does not impair the improved hardness of the tablet that is achieved by the process described herein. In this sense, the amount will be less than 10% by weight of the tablet. CONDITIONS OF SHEAR MIXING The present invention includes transforming acetaminophen, the direct compression vehicle and optionally, the pharmaceutically acceptable lubricant into a homogeneous granulate under shear conditions that do not degrade the ingredients. For the purposes of the present invention, the shear conditions under which the ingredients are combined can generally be described as a set of conditions that include a combination of temperature and mechanical forces that allow the formation of homogeneous granulate but does not break the materials that undergo the process. For the purposes of the present invention, the conditions are described as high shear to distinguish them from the normal mixture that is achieved by double-layer mixing or stirring. The high shear mixing apparatuses contemplated herein may include high speed mixers having an impeller or mixing blade rotating around a central arrow near the bottom of the mixer container and a shredder or a series of shredders that consist of fast rotating arms or blades that are inserted in the mixer containers. This combination of mixer and crusher confers a mechanical or force influence on the APAP and MCC that transforms them into a homogeneous mixture that can be directly compressed even if the APAP constitutes the majority of granules in the basic weight. A high shear granulate that has a high shear impeller and shredder is available from Baker-Perkins. While this apparatus is normally used to prepare wet granulations, it has been found that when operating the apparatus under dry mixing conditions, it is capable of transforming the ingredients of the solid dosage form under shear conditions into a homogeneous mixture. In this particular, the operation of the impeller in combination with the crusher creates an environment for the shear mixing. A set of parameters useful with this apparatus to give the necessary high shear conditions includes operating the impeller at approximately 100 to 300 rpm and the crusher at approximately 200 to approximately 1,200 rpm. It will be understood, however, that the The speeds of the impeller and the shredder can be extended beyond the averages provided in relation to the device illustrated and that the optimum operating conditions for the shear mixing apparatus will be apparent to those skilled in the art without proper experimentation. The simultaneous action of the impeller and the shredder has been found to uniquely transform the ingredients of the solid dose form into a mixture that can be directly compressed into solid dosage dosage forms having sufficient hardness and size characteristics desired for oral administration of tablets containing a high load. Nevertheless, it will be understood that the Baker-Perkins apparatus described above is a simple illustration of the type of apparatus useful in transforming the ingredients of the dosage form. Those skilled in the art will realize that other devices can be used for shear mixing, such as the Patterson-Kelly double-layer mixer apparatus equipped with an intensifier bar to facilitate mixing, grinding, strength shear and the rotation counter of the ingredients. You can also use the high shear mixer available from Machines Collette, Inc. Totowa, NJ that operates under dry conditions. In another aspect of the invention, the shear mixing conditions used to transform the APAP and the direct compression vehicle are expressed as a measure of the strength of the mechanical process. One of these measures is the relative sweep volume, an average of the volume through which the impeller travels every second for the volume of the vessels. The size of the sweep volume is calculated by dividing the areas of each impeller blade into vertical segments and the impeller speed, calculating the volume of impeller blades traveling through per second. In the preferred aspects of the invention, the solid dosage forms of the present invention are prepared from a homogeneous granulate prepared as a result of the technique of mixing by high shear in two steps. In the first step, the acetaminophen, the direct compression vehicle and, optionally, the disintegrant and / or the silicon dioxide are combined under high shear conditions to form a first high shear mix which preferably contains the ingredients in a distribution homogeneous The second step involves combining the high shear mix with the lubricant under the high shear conditions to form the final homogeneous granulate. In the preferred aspects of this embodiment, the shearing force used to combine the lubricant with the first high shear mix is less than that used to combine the ingredients of the first high shear mix. DIRECT COMPRESSION OF APAP GRANULATE The present invention also includes methods for preparing solid pharmaceutical dosage forms containing APAP by direct compression. As noted above, compression techniques include compressing the ingredients of the tablet directly without modifying the physical nature of any of the ingredients. Therefore, in this regard, the method includes: a) combining from about 40 to about 95% by weight of acetaminophen and from about 1 to about 60% by weight of a direct compression vehicle comprising microcrystallized cellulose under shear conditions which are sufficient to transform the acetaminophen and the direct compression vehicle into a homogeneous first granulate; b) combining the first homogeneous granulate with from about 0.01 to about 4.0% of a pharmaceutically acceptable lubricant; and c) compressing the homogeneous granulate containing the lubricant in a solid pharmaceutical dosage form. It will be understood that the combination steps described above are carried out, preferably in the high shear apparatus described above. In the preferred embodiments of the present invention, the APAP is in a granular form having a particle size from about 250 to about 500 microns and the direct compression vehicle includes co-processed MCC. An alternative method according to the present invention includes combining from about 0.1 to about 5% by weight of silicon dioxide with APAP and the direct compression vehicle and subjecting this mixture to the shear mixing conditions described above. A disintegrant may also be included in this high shear mixture designated herein as a first homogeneous granulate. The lubricant can be combined with the first homogenous granulate both by the high shear mixing and by other mixing techniques such as double layer mixing. However, it is preferred that the lubricant be combined with the first homogeneous granulate by mixing by additional high shear. In connection with this, it is preferable that the high shear mix used to incorporate the lubricant be carried out under high shear conditions which are less than those used to prepare the first homogeneous granulate. Thus, the lubricant will preferably be added under conditions that include one or more reductions in the parameters of the mixture, i.e., lower mix or rpm of the grind and / or shorter mixing times. Then, the homogenous full homogeneous high shear mix, in an amount sufficient to make a uniform mixture of tablets, is subjected to tabletting in a direct compression tablet machine at conventional production scale, at a compression pressure normal for this machine, for example approximately 1500 up to 10,000 lbs / sq. The mixture should not be compressed to the extent that a subsequent difficulty in hydration occurs when exposed to gastric fluid. As noted above, the solid dosage forms of the present invention will contain from 10 to about 1000 milligrams of APAP. The average size of the tablet for directly compressed tablets will vary, from about 50 mg to 2000 mg. Other formulations prepared in accordance with the present invention can be suitably formed for other uses or locations, such as for example other body cavities, i.e., periodontal pockets, surgical wounds, vaginally. It is contemplated that for certain uses, for example, antacid tablets, vaginal tablets and possible implants, that the tablets be larger. A particularly preferred solid dosage form of the present invention contains at least about 75% by weight of APAP and has an average tablet hardness of about 6.5 kP when the homogeneous granulate is compressed directly at a compression force of approximately 25 kN. In certain embodiments of the invention, the tablet is coated with a sufficient amount of hydrophobic polymer to give the formulation the ability to provide release of the medicament such that a formulation of 12 hours or 24 hours is obtained. The hydrophobic polymer can be selected from materials well known to those skilled in the art such as, for example, acrylic acid derivatives. In other embodiments of the present invention, the coating of the tablet comprises an additional enteric coating material or instead of a hydrophobic polymer coating. Examples of the enteric polymers include cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate, methacrylic acid copolymer, shellac, hydroxypropylmethylcellulose succinate, trimellitate acetate cellulose and mixtures of any of these. An example of commercially available, suitable enteric material is available under the trademark of Eudragit® L 100-555. In additional embodiments, the dosage form can be coated with a hydrophilic layer in addition to or in place of the aforementioned coatings. An example of a suitable material that can be used for this hydrophilic coating is hydroxypropylmethylcellulose (for example Opadry®, commercially available from Colorcon, West Point, Pennsylvania). The coatings can be applied in a pharmaceutically acceptable manner known to those skilled in the art. For example, in one embodiment, the coating is applied by the fluid bed in a coating tray. For example, the coated tablets may be dried, e.g., at about 60 to 70 ° C for about 3 to 4 hours in a coating pan. The solvent for the hydrophobic polymer or enteric coating may be organic, aqueous, or a mixture of an organic solvent and an aqueous one. The organic solvents may be, for example, isopropyl alcohol, ethanol, and the like, with or without water. Coatings that can be optionally applied to the compressed solid dose form of the invention can comprise from about 0.5% to about 30% by weight of the final solid dosage form. In additional embodiments of the present invention, a support platform is applied to tablets manufactured in accordance with the present invention. The desired support platforms are well known to those skilled in the art. An example of support platforms is set forth, for example, in U.S. Patent No. 4,839,177, which is incorporated herein by reference. In this patent, the support platform partially covers the tablets, and consists of a polymeric material insoluble in aqueous liquids. The support platform may, for example, be designed to maintain its waterproof characteristics during the transfer of a therapeutically active medicament. The support platform can be applied to the tablets, for example, by compressing the coating on part of the surface of the tablet, by spraying the coating of polymeric materials comprising the support platform in whole or in part on the surface of the tablet. the tablet, or by immersing the tablets in a solution of polymeric materials. The support platform may have a thickness of, for example, approximately 2 mm if applied by compression, and approximately 10 μm if applied by spraying the coating or coating by immersion. Generally, in the embodiments of the invention wherein the hydrophobic polymer or the enteric coating is applied to the tablets, the tablets are coated to a weight gained from about 1% to about 20% and in certain embodiments preferably from about 5% up to 10%.

Useful materials, in the hydrophobic coatings and in the support platforms of the invention, include derivatives of acrylic acid (such as for example acrylic acid, methacrylic acid and copolymers thereof) cellulose and derivatives thereof (such as for example ethylcellulose) , polyvinyl alcohols and the like. In certain embodiments of the present invention, the core or core of the tablets includes an additional dose of medicament, i.e., APAP included both in the hydrophobic enteric coating or in an additional coating on the outermost surface of the tablet core (without the hydrophobic or enteric coating) or a second coating layer on the surface of the base coat comprising the hydrophobic or enteric coating material. This may be desired when, for example, the dose of APAP loading is needed to provide therapeutically effective blood levels when the formulation is first exposed to gastric fluid. The dose load of medicament included in the coating layer can be, for example, from about 10 *? up to approximately 40% of the total amount of medication included in the formulation. The solid formulations of the invention may also include other locally active agents, such as flavors or sweeteners. Generally, any flavor or food additive such as those described in Chemical Used in Food Processing (Chemicals used in food processing), pub 1274 by the National Academy of Sciences, pages 63-258 can be used. Generally, the final product may include from about 0.1 to about 5% by weight of flavor. The tablets of the present invention may also include effective amounts of coloring agents (eg, titanium dioxide, FD & C &D & C; see Chemical Encyclopedia Kirt-Othner, Vol 5, pp 857- 884, which is incorporated herein by reference), stabilizers, binders, controlled odor agents, and preservatives. Alternatively, the novel homogeneous high shear granulate can be used in other applications where it is not compressed. For example, the granulate can be filled into capsules. In addition, the granulate can be molded in other forms than those typically associated with the tablets. For example, the granulate together with acetaminophen can be molded to "fit" it in a particular area in an environment of use (eg, an implant). All of these uses can be contemplated by those skilled in the art are considered within the scope of the appended claims.

In another embodiment of the present invention, it is directed to the effect method of the analgesic in mammals. This method includes administering a dosage form as described herein that contains an effective amount of APAP to a mammal in need of this treatment. In preferred aspects of the embodiment, the dosage form containing from about 10 to about 1000 milligrams of APAP and more preferably, from about 120 to about 750 milligrams of APAP. For the purposes of the present invention, the term "effective amount" shall be understood to include a generally accepted amount of APAP for the purposes of effective analgesic to soothe to moderate pain. The method of treatment may also include administering an effective amount as a single dose or as multiple doses administered every four or six hours, as needed. Yet another aspect of the invention includes homogeneous high shear granulates that are useful as pharmaceutical intermediates. The granulates include: a) from about 94 to about 99.99% by weight of a direct compression vehicle that compresses microcrystalline cellulose; and b) from about 0.01 to about 6.0% by weight of a pharmaceutically acceptable lubricant. The direct compression vehicle and the pharmaceutically acceptable lubricant are combined under shear conditions which are sufficient to transform the direct compression vehicle and the pharmaceutically acceptable lubricant into a homogeneous granulate without degradation. The intermediates are, therefore, acceptable to be mixed with one or more active ingredients such as for example by the additional high shear mixing and therefore direct compression in a solid dosage form in direct compression. The shear conditions under which the intermediate ingredients are combined are similar to those used for the APAP formulations described above. Additionally, all direct compression ingredients, such as disintegrants, etc., can also be included in the intermediate product in the same way. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples illustrate various aspects of the present invention. This does not constitute a limitation of the claims in any way.

The examples establish the preparation of pharmaceutical compositions containing the high charge of an acetaminophen as an active ingredient (APAP) in combination with excipients based on microcrystalline cellulose. The tablets were prepared using each of the compositions and each of the tablet preparations were tested for tensile strength. EXAMPLES 1-2 PREPARATION OF MCC-SiQ2, THE COMPOSITIONS AND THE GRANULATIONS OF THE SAME Product at 5% by weight of SiQ2 ,, MCC-SiQ In this example, approximately 6.2 kilograms of microscrystalline cellulose (MCC) (Mendell Co., Ine Patterson , NY) in the form of a wet cake is combined with 5.2 kilograms of water in a mixing tank to form a suspension containing approximately 15% solids. The pH was adjusted to approximately a neutral value with approximately 3 ml of ammonium hydroxide. The suspension is allowed to mix for approximately 15 minutes before being combined with 5% by weight of colloidal silicon dioxide (CSD), 200 pr / g (CaboSil, PTG grade, available from Cabot Copr, Tuscola, IL). Afterwards the materials are allowed to mix more intimately, the spray suspension is dried using a Niro Production Mmor (Niro Columbia MD), the external temperature of 215 ° C, the external temperature 125 ° C, the speed of the atomizer wheel to 22,300 rpm, to provide MCC-SiO :, has an average particle size of 40-60 microns. EXAMPLE 2 2% by weight product of SiQ2 ,, MCC-SiQ2 In this example, the process of Example 1 is repeated except that colloidal silicon dioxide at 2 weight is used to form the product. EXAMPLES 3-11 In these examples batches of compressed tablets containing granular acetaminophen (APAP) in high load (80% by weight) were prepared, using the techniques described herein and compared to a high load (80% by weight) of the APAP formulation described above wherein all the ingredients are mixed in V before being compressed into tablets. In each case, the tablets were prepared using a Korsh tablet press which has a perforator size of 3/8"and a main weight of approximately 245 mg ± 5 mg Each of the above granulations was included in five runs for the Separate tablet formation using compression forces of 6, 12, 18, 24 and 30 kN, respectively Ten tables of each stroke was weighed, the diameter was measured and tested for the thickness and hardness in a tester for the hardness of Erweka TBH 30 tablets, to determine the tensile strength of the final product.The results of the analyzes were illustrated graphically in Figures 1-2 as a comparison of tensile strength versus compressive strength .The formula of batches for tablets of comparative control is established below: COMPARATIVE MIXING The MCC, APAP and SSG were added to two quarters of a V- mixer and mixed for 15 minutes. Then, the Mg sterearate was added to the mixer and the mixing was continued for an additional 5 minutes. All the mixture of the ingredients is carried out in a room that has a relative humidity of approximately 10%. The mixture was then removed from the mixer and formed into tablets in the same manner as was used to prepare the tablets of the invention.

EXAMPLE 3 In this example, compressed tablets containing APAP are prepared according to the formula of the mixture that was established above. The microcrystalline cellulose used was MCC co-processed with 5.0% Si02 as described in Example 1.

The tablets are prepared according to the following procedure: The co-processed MCC was added to a Baker-Perkins 10L shear can granulator together with APAP, CSD and SSG. The CSD was added in addition to that included in the co-processed MCC. The ingredients were mixed under high shear conditions, dry for 3 minutes with an impeller at 200 rpm and a 1-pounder, 000 rpm. Next, sodium stearyl fumarate, PRUV®, Edward Mendell Co. , Inc., was added to the high shear granulator and mixing is continued for an additional 25 seconds with the impeller at 200 rpm and the shredder at 500 rpm. At the conclusion of this mixing step, the granulate was removed and compressed directly into tablets using the aforementioned Korsch PH-100 tablet press and compression forces. EXAMPLE 4 In this example, the procedure of Example 3 was repeated except that the MCC used was MCC (EMCOCEL®, Edward Mendell Co., Ine) rather than the coprocessed silicone dioxide material of Example 1. The tablets were prepared using the following mixing formula: EXAMPLE 5 In this example the procedure of Example 3 was repeated, except that CSD was not included in the mixture by high shear of the ingredients. We used the formula of the mixture is established below.

EXAMPLE 6 In this example, an additional control granulation was prepared by the mixer V by mixing MCC with other ingredients in a control environment having a relative humidity of about 40%. The granulation also does not include any silicon dioxide. The formulation was prepared according to the following formula of the mixture EXAMPLE 7 In this example, the procedure of Example 3 was followed. However, in this mixture the MCC used was the coprocessed product of Example 2 containing 2.0% SiO2. The mixture also did not include a separate amount of CSD added in the mixture by high shear.

EXAMPLE 8 In this example, tablets that were directly compressed containing APAP were prepared using the procedure of Example 3, except that the MCC used was coprocessed with the microcrystalline cellulose of Example 2. The formula of the mixture which is set up was used. continuation.

DISCUSSION Referring now to Figure 1, the results of the tensile force test for high-load, directly compressed tablets were discussed. Each of the tablets containing a high APAP load was made according to the present invention had a desirable tablet hardness profile when compared to the comparative example of the V mixture.

It can also be appreciated that simply drying the mixture of the ingredients before performing the compression does not provide the acceptable tensile strength. Even in the case of Example 6, where the humidity is increased to about 40%, the results fail to match those obtained by high shear mixing of the present invention. In addition, the advantages of high shear mixing of APAP and MCC based on the compression vehicle is especially apparent at higher compression forces. The results point to the fact that those high loaded tablets prepared with MCC co-processed with SiO, ie Examples 3 and 8, as well as those containing an amount added separately from SiO, ie Example 4, have a profile tablet hardness particularly desirable. In general, the results obtained for the compositions of the invention were completely unexpected since those skilled in the art will be aware of the problems associated with the combination of tablet lubricants such as sodium fumarate with other ingredients under varying conditions. high shear Contrary to expectations, directly compressed high load tablets have a higher than low tension force. Furthermore, the coating of the granules with the lubricant that was expected and that would have significantly reduced the hardness of the tablets was not observed. Additionally, it was also unexpected that the APAP granular forms would provide sufficient physical characteristics for a formulation that would allow the formation of directly compressed high load tablets having acceptable levels of hardness. Therefore, it can be appreciated that the high shear mixing of MCC-based excipients as described hereinabove directly direct a reduction of the prior art. EXAMPLE 9 In this example, the tablets were prepared according to the following mixture of the formula: In this example, the initial high shear mixing of MCC, APAP, CSD and SSG was carried out in the same manner as described above in relation to Example 4 (ie using high shear mixer for 3 minutes to 200 minutes). rpm for the impeller and 1,000 rpm for the disposer). However, after the first step of mixing by high shear, all the ingredients were removed and transferred to a two-quart V mixer. No additional high shear mixing was carried out. Instead, sodium stearyl fumarate was added to the mixture and mixed in V for 5 minutes. Then, the tablets were made following the procedure described above. EXAMPLE 10 The procedure of Example 11 was repeated except that the equal amount of magnesium stearate was replaced by stearyl sodium fumarate which was used in Example 11 for the previous step to mix V for the direct compression of the tablets.

INGREDIENT% GRAMS PER LOT LOT EXAMPLE 11 In this example, the two high shear mixing steps of the procedure of Example 4 were repeated except that the magnesium stearate was replaced by the sodium stearyl fumarate that was originally discovered. As was the case in Example 4, high shear mixing was used both to carry out the initial and final blends.

DISCUSSION Figure 2, graphically, provides the results for the comparison of the mixture by high shear in two steps, the tablets that are compressed directly from Example 8 with the high shear, then the formulations mixed by low shear of the examples 9 and 10 and the combined control formulation in V. The graph also provides the results for the high shear formulation in two steps of Example 11, which includes magnesium stearate in place of stearyl sodium fumarate in the second step of the mixture by high shear. In each case, improvements can be seen in the hardness of the tablets that can be made even if the lubricant is combined under low shear conditions. In all cases, tablets prepared from granulations that were prepared using at least one step of the high shear mix play the control of mixture V completely. EXAMPLE 12 In this example, the average disintegration time for the tablets prepared according to example 8 was determined and compared with commercially available APAP tablets, sold under the trademark Tylenol®. The test was carried out in accordance with the USP guidelines using the Van-Kel disintegration apparatus. In particular, six tablets according to the procedure of Example 8 as well as six tablets of Tylemol were evaluated individually in the apparatus to determine the disintegration time in deionized water at 37 ° C without using the basket disc in the apparatus. The average disintegration time for the six tablets in each group was calculated and illustrated as a graph presented in Figure 3. As can be seen in the graph, the tablets prepared according to the present invention have an average time of disintegration of less than half of that required for the formulation sold commercially. This rapid disintegration characteristic illustrates an additional advantage of the formulations of the present invention. While what is currently believed to be the preferred embodiments of the invention has been described, those skilled in the art will realize that changes and modifications can be made thereto without departing from the spirit of the invention. It attempts to claim all changes and modifications that fall within the true scope of the invention.

Claims (27)

1. CLAIMS 1. A solid dosage form, directly compressed, comprising: a) from about 40 to about 95% by weight of acetaminophen; b) from about 1 to about 60% by weight of a direct compression vehicle comprising microcrystalline cellulose; and c) from about 0.01 to about 4.0% by weight of a pharmaceutically acceptable lubricant; the acetaminophen and the direct compression vehicle are combined under sufficient shear conditions to transform the acetaminophen and the direct compression vehicle into a homogeneous granulate without degradation and which has been directly compressed into the solid pharmaceutical dosage form.
2. 2. The solid dosage form according to claim 1, wherein the pharmaceutical dosage form comprises from about 60% to about 85% by weight of acetaminophen.
3. 3. The solid dosage form according to claim 1, wherein the microcrystalline cellulose has been coprocessed with from about 0.1 to about 20% by weight of silicon dioxide, wherein the microcrystalline cellulose and the silicone dioxide are intimately associated each.
4. 4. The solid dosage form according to claim 3, wherein the silicone dioxide has an average particle size from 1 nm to about 100 μm. The solid dosage form according to claim 4, wherein the silicone dioxide is derived from colloidal silicon dioxide and wherein the silicone dioxide is present in an amount from about 0.
5. 5 to about 10% by weight, based on in the weight of microcrystalline cellulose.
6. 6. The solid dosage form according to claim 5, wherein the silicone dioxide is present in an amount from about 1.25 to about 5% by weight, based on the weight of the microcrystalline cellulose.
7. 7. The solid dosage form according to claim 1, wherein the lubricant is stearyl sodium fumarate and the lubricant is present in an amount from about 0.1 to about 1.0% by weight.
8. 8. The solid dosage form according to claim 1, wherein the homogeneous granulate further comprises silicon dioxide.
9. 9. The solid dosage form according to any of claims 3, 5 or 8, wherein the silicone dioxide is combined with acetaminophen and the direct compression vehicle under high shear conditions.
10. 10. The solid dosage form according to claim 8, wherein the silicone dioxide is colloidal silicon dioxide.
11. 11. The solid dosage form according to claim 8, wherein the amount of silicone dioxide is from about 0.1 to about 5% by weight of the dosage form.
12. 12. The solid dosage form according to claim 1, further comprising a desintegrant and the disintegrant is combined with acetaminophen and the direct compression vehicle under high shear conditions.
13. 13. The solid dosage form according to claim 12, wherein the direct compression vehicle is present in an amount of from about 2 to about 25% by weight of the solid dosage form.
14. 14. The solid dosage form according to claim 5, wherein the silicone dioxide is combined with acetaminophen and the direct compression vehicle to form a first shear mix and therefore combine the first high shear mix with the lubricant under high shear conditions to form a homogeneous granulate.
15. The solid dosage form according to claim 1, wherein the acetaminophen comprises at least 75% by weight of a solid dosage form and the solid dosage form has an average hardness of approximately 6.5 kP when the homogeneous granulate It is directly compressed to a compression force of approximately 25 kN.
16. 16. The solid dosage form according to claim 1, wherein the solid dosage form comprises from about 10 to about 1000 milligrams of acetaminophen.
17. 17. A method for preparing the pharmaceutical dosage form, solid, directly compressed, comprising: a) combining from about 40 to about 95% by weight of acetaminophen and from about 1 to about 60% by weight of a direct compression vehicle comprising microcrystalline cellulose under sufficient shear conditions to transform the acetaminophen and the direct compression vehicle into a first homogeneous granulate; b) combining the first homogeneous granulate with from about 0.01 to about 4.0% by weight of a pharmaceutically acceptable lubricant; and c) compressing the homogeneous granulate containing the lubricant in the solid pharmaceutical dosage form.
18. 18. The method according to claim 17, wherein the pharmaceutical dosage form comprises from about 60% to about 85- by weight of acetaminophen.
19. 19. The method according to claim 17, wherein the acetamofen is in granular form.
20. The method according to claim 17, wherein the microcrystalline cellulose has been coprocessed with from about 0.1 to about 20% by weight of silicon dioxide, wherein the microcrystalline cellulose and the silicone dioxide are intimately associated with each other.
21. The method according to claim 20, wherein the silicone dioxide is colloidal silicon dioxide and have an average primary particle size from 1 nm to about 100 μm and the silicone dioxide is present in an amount from about 0.5 to about 10% by weight, based on the weight of the microcrystalline cellulose.
22. 22. The method according to claim 18, wherein the lubricant is sodium stearyl fumarate which is present in an amount from about 0.01 to about 4.0% by weight.
23. 23. The method according to claim 1, wherein the first homogeneous granulate further comprises silicone dioxide in an amount from about 0.1 to about 5% by weight of the dosage form and the silicone dioxide is combined with acetic acid and the direct compression vehicle ba or high shear conditions.
24. 24. The method according to claim 22, wherein the silicone dioxide is colloidal silicon dioxide.
25. 25. The method according to claim 18, further comprising combining a disintegrant with acetamofen and a direct compression vehicle under high shear conditions.
26. 26. The method according to claim 17, wherein the direct compression vehicle is present in an amount from about 2 to about 25% by weight of the solid dosage form.
27. 27. The method according to claim 23, wherein the acetamofen and the direct compression vehicle are combined to form a high shear mix before it is combined with the lubricant.