MXPA96003745A

MXPA96003745A - Pharmaceutical excipient that has compressibility best

Info

Publication number: MXPA96003745A
Authority: MX

Abstract

Disclosed is an excipient based on microcrystalline cellulose having improved compressibility, used in either direct decompression, dry granulation or wet granulation formulations. The excipient is an agglomerate of microcrystalline cellulose particles and from about 0.1% to about 20% silicon dioxide particles, by weight of the microcrystalline cellulose, wherein the microcrystalline cellulose and the silicon dioxide are intimately associated with one another . The silicon dioxide used in the new excipient has a particle size from about 1 nm to about 100 microns. More preferably, silicon dioxide is a grade of coloid silicon dioxide

Description

PHARMACEUTICAL EXCIPIENT THAT HAS IMPROVED COMPRESSIBILITY BACKGROUND OF THE INVENTION The present invention relates to a new excipient for use in the manufacture of pharmaceutical products, and in particular, to solid dosage forms such as tablets, which include one or more active ingredients. In order to prepare a solid dose form containing one or more active ingredients (such as drugs), it is necessary that the material to be compressed in the dosage form possess certain physical characteristics which lend themselves to processing in such a way . Among other things, the material to be compressed must be free-flowing, must be lubricated, and, importantly, must possess sufficient cohesiveness to ensure that the solid dosage form remains intact after compression. In the case of tablets, the tablet is formed by the pressure applied to the material to be formed into a tablet on a tablet-forming press.

A tablet forming press includes a lower punch which fits within a die or die REF: 22991 from the bottom, and an upper punch having a corresponding shape and dimension, which enters the cavity of the die from the top after the tablet forming material fills the cavity of the die or die. The tablet is formed by the pressure applied to the upper and lower punches. The ability of the material to flow freely within the matrix is important in order to ensure that there is a uniform filling of the matrix and a continuous movement of the material from the source of the material, for example, a feeder hopper. The lubricity of the material is crucial in the preparation of the solid dosage forms, since the compressed material must be easily ejected from the faces of the punch. Since most drugs do not have any or only some of these properties, the methods for tablet formulation have been developed in order to impart these desirable characteristics to the material or materials, which will be compressed into a form of solid dose. Typically, the material to be compressed in a solid dose form includes one or more excipients that impart the free-flowing, lubricating and cohesive properties to the drug or drugs which are to be formulated in a dosage form.

Lubricants are typically added to prevent the material (s) that are formed into tablets from adhering to the punches. Commonly used lubricants include magnesium stearate and calcium stearate. Such lubricants are commonly included in the final product formed into a tablet, in amounts of less than 1% by weight. In addition to lubricants, solid dosage forms often contain diluents. The diluents are added frequently in order to increase the bulk weight of the material to be formed into a tablet, in order to make the tablet of a practical size for compression. This is often necessary where the dose of the drug is relatively small. Another commonly used class of excipients in solid dosage form are the binders. Binders are agents that impart cohesive qualities to powdered material or materials. Commonly used binders include starch, and sugars such as sucrose, glucose, dextrose and lactose. Disintegrators are often included in order to ensure that the compressed solid dosage form, prepared at the end, has an acceptable disintegration ratio in an environment of use (such as the gastrointestinal tract). Typical disintegrators include starch derivatives and salts of carboxymethylcellulose. There are three general methods of preparing the materials to be included in the solid dose form, before compression: (1) dry granulation; (2) direct compression; and (3) wet base granulation. Dry granulation procedures can be used where one of the constituents, either the drug or the diluent, has sufficient cohesive properties to be formed into a tab The method includes the mixing of the ingredients, the ingredients are strongly pounded, sifted dry, lubricated and finally the ingredients are compressed. In direct compression, the powder material or materials to be included in the solid dose form are compressed directly without modification of the physical nature of the material itself. The wet-based granulation process includes the mixing of the powders to be incorporated in the dosage form into, for example, a twin shell mixer or double cone mixer and thereafter solutions of a binder agent are added to the powders. mixed, to obtain a granulation. After this, the wet mass is screened, for example, in a 6 or 8 mesh screen and then dried, for example, by pan drying, the use of a fluidized bed drier, spray drier, dryer of radio frequency, microwave dryer, vacuum or infrared. The use of direct compression is limited to those situations where the drug or active ingredient has a required crystal structure and physical characteristics required for the formation of a pharmaceutically acceptable tab On the other hand, it is well known in the art to dilute one or more excipients that make the direct compression method applicable to drugs or active ingredients which do not possess the required physical properties. For solid dosage forms wherein the drug itself is to be administered in a relatively high dose (e.g., the drug itself comprises a substantial portion of the total weight of the tab, it is necessary that the drug or drugs themselves have sufficient characteristics physical (for example, cohesiveness) for the ingredients to be directly compressed. Typically, however, excipients that impart good flow and compression characteristics to the material, as a whole which will be compressed, are added to the formulation. Such properties are typically imparted to these excipients by means of a pre-processing step such as wet base granulation, beating, spray drying, spheronization, or crystallization. Useful excipients for direct compression include processed forms of cellulose, sugars and dicalcium phosphate dihydrate, among others. A processed cellulose, micro-crystalline cellulose, has been used extensively in the pharmaceutical industry as a direct compression vehicle for solid dosage forms. Microcrystalline cellulose is commercially available under the trade name EMCOCEL from Edward Mendell Co., Inc. and as Avicel® from FMC Corp. Compared to other directly compressible excipients, it is generally considered that microcrystalline cellulose exhibits superior compressibility and disintegration properties. Another limitation of direct compression as a method for making tab is the size of the tab If the amount of active ingredient is high, a pharmaceutical formulator may choose to granulate on a wet basis the active ingredient with other excipients, to achieve a tabof acceptable size with the resistance to compaction, desired. Usually the amount of filler / binder or excipients needed in the wet-based granulation is less than that required for direct compression, since the wet-based granulation process contributes to some degree to the desired physical properties of a tab Thus, despite direct compression sales (such as reduced processing times and costs), wet base granulation is widely used in the industry in the preparation of solid dosage forms. Many of those skilled in the art prefer wet-based granulation compared to direct compression, because this method has a higher probability of overcoming any problems associated with the physical characteristics of the various ingredients in the formulation, thereby providing a material having the flow requirement and the cohesive characteristics necessary to obtain a form of acceptable solid dose. The popularity of the wet-based granulation process compared to the direct compression process is based on at least three advantages. First, the wet-based granulation provides the material to be compressed, with better wetting properties, particularly in the case of hydrophobic medicinal substances. The addition of a hydrophilic excipient makes the surface of a drug more hydrophobic, hydrophilic, facilitating disintegration and dissolution. Second, the uniformity of the content of the solid dosage forms is generally improved. Via the wet-based granulation method, all granules obtained by this method should contain approximately the same amount of drug. In this way, the segregation of the different ingredients of the material to be compressed (due to different physical characteristics such as density) is avoided. Segregation is a potential problem with the direct compression method. Finally, the particle size and the shape of the particles comprising the granulate to be compressed are optimized by means of the wet base granulation process. This is due to the fact that when a dry solid is granulated on a wet basis, the binder "adheres" the particles together, so that they agglomerate in the granules that are more or less spherical. Due to the popularity of micro-crystalline cellulose, pharmaceutical formulators have found it desirable to include this excipient in a formulation that is wet-granulated prior to tabletting. Unfortunately, the currently available microcrystalline cellulose does not maintain the typical principle that the amount of filler / binder, necessary in the wet-based granulation, is less than that in direct compression. It is known that the exposure of microcrystalline cellulose to moisture in the wet-based granulation process severely reduces the compressibility of this excipient. The loss of compressibility of microcrystalline cellulose is particularly problematic where the formulation dictates that the final product will be relatively large in the environment of use. For example, if a pharmaceutical formulator wishes to prepare a solid oral dosage form of a drug at a high dose, and the use of the wet-based granulation technique is considered necessary, the loss of compressibility of microcrystalline cellulose dictates that it may be necessary. a greater quantity of this material to obtain a final product acceptably compressed. The additional amount of microcrystalline cellulose needed adds cost to the preparation, but more importantly adds volume, making the product more difficult to swallow. The loss of compressibility of microcrystalline cellulose, when exposed to wet-based granulation, has long been considered a problem in the art for which there has been no satisfactory solution. Attempts have been made to provide an excipient having high compressibility, a small volume (high bulk density), and good flowability, while being able to provide satisfactory disintegration of the solid dose form, which is applicable to granulation on a wet basis, as well as dry granulation and direct compression methods for the preparation of solid dosage forms. For example, U.S. Patent No. 4,159,345 (Ta eo et al.) Discloses an excipient consisting essentially of a microcrystalline cellulose having an average degree of polymerization of 60 to 375, and obtained through acid hydrolysis or alkaline oxidative degradation of a cellulosic substance selected from cotton lint, pulps and regenerated fibers. It is said that the microcrystalline cellulose is a white cellulosic powder having an apparent specific volume of 1.6 - 3.1 cm3 / g, an angle of repose of 35 ° to 42 °, a residue on 200 mesh sieve of 2 to 80% by weight and an apparent specific volume of the powder, after vibrating the content, of at least 1.4 cc / gram. In US Patent No. 4,744,987 (Mehra et al.), A co-processed particulate microcrystalline cellulose composition and calcium carbonate is disclosed, wherein the respective components are present in a weight ratio of 75:25 to 35: 65 The co-processed composition is said to be prepared by forming a well-dispersed aqueous suspension of microcrystalline cellulose and calcium carbonate, and then drying the suspension to produce a particulate product. It is said that the combination of these two ingredients provides a low cost excipient which has characteristics of tablet formation, similar to those of microcrystalline cellulose and which could satisfy a need for a well functioning economic excipient, which is desired by the market of vitamins. European Patent Application EP 0609976A1 (assigned to Asahi Kasei Kabushiki Kaisha) discloses an excipient comprising white microcrystalline powdered cellulose, having an average degree of polymerization from 100 to 375, preferably from 190 to 210, and a maintenance capacity of acetic acid of 280% or more, preferably from 290 to 370%. The excipient is said to exhibit high compactability and a high rate of disintegration, and is said to be obtained by heat treatment of an aqueous dispersion of purified cellulose particles, which has a solids content of 40% or less by weight, at 100 ° C or more, followed by drying, or by holding an aqueous dispersion of purified cellulose particles having a solids content of 23% or less, by weight, to the treatment of thin film formation and thin film drying resulting. It is said that the excipient has a high compressibility and a good balance of compactness and speed of disintegration. There remains a need still in the industry for a pharmaceutical excipient that possesses excellent compressibility whether it is used in a direct compression process or in a wet-based granulation process.

OBJECTIVES AND BRIEF DESCRIPTION OF THE INVENTION An object of the present invention is to provide an excipient that is useful in a variety of applications, and which can be used in direct compression or wet base granulation methods. A further objective of the present invention is to provide a useful excipient in direct compression methods, which has improved compressibility with respect to microcrystalline cellulose. A further objective of the present invention is to provide an excipient useful in wet base granulation methods, which has improved compressibility relative to microcrystalline cellulose. A further object of the present invention is to provide a free-flowing excipient, which has excellent compressibility properties when used in direct compression or wet-base granulation methods, and which further possesses pharmaceutically acceptable disintegration properties. A further object of the present invention is to provide an improved microcrystalline cellulose excipient in which the microcrystalline cellulose has not been chemically altered, and which has improved compressibility relative to commercially available microcrystalline cellulose "off the shelf". A further object of the present invention is to provide a solid dosage form that includes one or more active ingredients and the microcrystalline cellulose excipient of the present invention. A further object of the present invention is to provide an oral solid dosage form for one or more drugs, which is economical to manufacture, which maintains its integrity during storage, and which possesses excellent disintegration and dissolution properties when exposed. , for example, to the gastrointestinal fluid. In accordance with the above objectives and others which will be obvious to those skilled in the art, the present invention is directed to an excipient comprising a particulate agglomerate of co-processed microcrystalline cellulose, and from 0.1% to about 20% dioxide of silicon, by weight of the microcrystalline cellulose, the microcrystalline cellulose and the silicon dioxide being in intimate association with each other, and the silicon dioxide portion of the agglomerate is derived from a silicon dioxide having a particle size of about 1 nanometer (nm) to about 100 microns (μm), based on the primary, average particle size. In the preferred embodiments, the silicon dioxide comprises from about 0.5% to about 10% of the excipient, and more preferably from about 1.25% to about 5% by weight relative to the microcrystalline cellulose. In the preferred further embodiments of the invention, the silicon dioxide has a particle size from about 5 nm to about 40 microns, and more preferably from about 5 nm to about 50 microns.

In preferred embodiments of the present invention, silicon dioxide is further characterized by a surface area of about 10 m / g to about 500 m2 / g, preferably from about 50 m3 / g to about 500 ma / g , and more preferably from about 175 m2 / g to about 350 m2 / g. The present invention is further directed to an aqueous suspension useful in the preparation of a The compressible excipient, useful in dry and wet granulation formulation methods, comprises a mixture of microcrystalline cellulose and from about 0.1% to about 20% silicon dioxide, by weight, relative to microcrystalline cellulose, The silicon dioxide having a particle size from about 1 nm to about 100 microns. The solids content of the aqueous suspension is from about 0.5% to about 25% by weight, preferably from about 15% up to 2o about 20% by weight, and more preferably from about 17% to about 19% by weight. The present invention is further directed to a mixture of an active ingredient or ingredients and an excipient comprising a particulate agglomerate 25 of co-processed microcrystalline cellulose and from about 0.1% to about 20% silicon dioxide, by weight of the microcrystalline cellulose, the microcrystalline cellulose and the silicon dioxide being in intimate association with each other, and the silicon dioxide it has a particle size from about 1 nm to about 100 microns. The ratio of the active ingredient to the excipient is from about 1:99 to about 99: 1, by weight. The present invention is further directed to a granulate of an active ingredient or ingredients and to the new excipient described herein, wherein the active ingredient or ingredients and the excipient have been subjected to a wet-based granulation process. The present invention is further directed to a compressed solid dosage form, comprising one (several) active ingredient (s) and the new excipient described herein, wherein the active ingredient (s) ) and the excipient have been directly purchased in the solid dosage form, or have been subjected to a wet-based granulation process and thereafter compressed into the solid dosage form. The compressed solid dosage form provides an appropriate immediate release solution profile of the active ingredient (s), when exposed to aqueous solutions during the in vitro dissolution test, and provides a release of the drug into the solution. an environment of use, which is considered bioavailable. In the further embodiments of the invention, the dissolution profile of the solid dosage form is modified to provide a controlled or sustained release dissolution profile. The present invention is further directed to a method for maintaining and / or improving the compressibility of microcrystalline cellulose. The method includes forming an aqueous suspension containing a mixture of microcrystalline cellulose and silicon dioxide having a particle size from about 1 nm to about 100 microns, and drying the suspension to obtain excipient particles based on microcrystalline cellulose. in which the silicon dioxide particles have been integrated with the microcrystalline cellulose particles. Within this aspect of the invention, the suspension contains from about 0.5% to about 25% by weight of microcrystalline cellulose, with amounts from about 15% to about 20%, which are preferred. In addition, the suspension contains from about 0.25% to about 5% by weight of silicon dioxide.

The new excipient described herein is free flowing, possesses excellent disintegration properties, and importantly, in certain embodiments it has improved compressibility relative to commercially available microcrystalline cellulose, "off-shelf", when directly compressed. The advantages of the new excipient described herein are especially realized in pharmaceutical formulations prepared using wet base granulation techniques. When used in wet base granulation techniques, the new excipient surprisingly provides a compressibility that is substantially improved in the preferred embodiments, compared to the compressibility of the commercially available, normal, "off-shelf" microcrystalline cellulose used in granulation on a wet basis and is even comparable to the "off-shelf" microcrystalline cellulose used in direct compression techniques. In other embodiments, the new excipient surprisingly provides a compressibility that is substantially superior to the compressibility of commercially available "off-shelf" microcrystalline cellulose., used in direct compression techniques. The term "environmental fluid" means, for purposes of the invention, encompassing, for example, an aqueous solution, or gastrointestinal fluid. By "sustained release" it is meant, for purposes of the invention, that the therapeutically active drug is released from the formulation at a controlled rate, such that therapeutically beneficial blood levels (but below the toxic levels) of the drug are maintained, at a prolonged period of time, for example, by providing a 12-hour or a 24-hour dose form. By "bioavailable" is meant, for purposes of the invention, that the therapeutically active drug is absorbed from the sustained release formulation and becomes available in the body at a specific site of drug action. By "primary particle size" is meant, for purposes of the invention, that the particles are not agglomerated. Agglomeration is common with respect to the silicon dioxide particles, resulting in an agglomerated, average, comparatively large particle size.

BRIEF DESCRIPTION OF THE DRAWINGS The following drawings are illustrative of the embodiments of the invention, and are not intended to limit the scope of the invention as encompassed by the claims.

Figure 1 graphically shows a comparison of the tensile strength of the tablets prepared according to the invention, and the tablets of the prior art.

Figure 2 graphically shows a comparison of the tensile strength of the tablets containing APAP, prepared according to the invention, and the tablets containing APAP, of the prior art.

Figure 3 shows graphically a comparison of tensile strength of tablets prepared according to the invention, containing MCC co-processed with diatomaceous earth, tablets containing MCC co-processed with 2% w / w Si0" , and the prior art tablets prepared containing only unmodified MCC.

Figure 4 graphically illustrates a comparison of the tensile strength of the tablets prepared using the MCC co-processed with silica gel, tablets prepared with the new, co-processed MCC, and the tablets prepared with MCC alone.

Figure 5 graphically illustrates a comparison of the tensile strength of the tablets prepared using MCC co-processed with SiO "grade HS5, tablets prepared using co-processed MCC-SiO2, and prior art tablets prepared containing only MCC not modified.

DETAILED DESCRIPTION OF THE INVENTION Microcrystalline cellulose is a well-known diluent and disintegrator for tablets. Its main advantage over other excipients is that it can be directly compressed into autoagglutination tablets, which disintegrate rapidly when placed in water. This widely used ingredient is prepared by the partial polymerization of the cellulose obtained as a pulp from fibrous plant material with diluted solutions of mineral acid. After hydrolysis, the hydrocellulose obtained therefrom is purified via filtration and the aqueous suspension is spray dried to form an anhydrous, white, odorless, tasteless crystalline powder of porous particles of a wide size distribution. Yet another method of preparing microcrystalline cellulose is described in US Patent No. 3,141,875. This reference describes attaching the cellulose to the hydrolytic action of hydrochloric acid at boiling temperatures, so that the amorphous cellulosic 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 referred to as cellulose crystallites, by vigorous mechanical means such as a mixer. Microcrystalline cellulose is commercially available in various grades, which are in the range of average particle size from 20 to 200 microns. Microcrystalline cellulose is insoluble in water, but the material has the ability to pull fluid into a tablet by capillary action. The tablets then swell upon contact and the microcrystalline cellulose thus acts as a disintegrating agent. The material has sufficient self-lubrication qualities to allow a low level of lubricant compared to other excipients. Typically, the microcrystalline cellulose has a bulk density of about 0.28 g / cm 3 and a bulk density of the powder after vibrating the content of about 0.43 g / cm 3. Handbook of Pharmaceutical Excipients, pages 53-55. When used in pharmaceutical applications, microcrystalline cellulose is typically used as a tablet binder / diluent in wet base and direct compression granulation formulations, in amounts of 5 to 30% of the formulation, or more. However, it is known to use more or less microcrystalline cellulose in pharmaceutical products, depending on the requirements of the formulation. Silicon dioxide is obtained by insolubilization of the dissolved silica, in sodium silicate solution. When it is obtained by the addition of sodium silicate to a mineral acid, the product is called silica gel. When obtained by destabilizing a sodium silicate solution, in a manner such as to produce very fine particles, the product is called precipitated silica. Silicon dioxide is insoluble in water. Prior to the present invention, silicon dioxide, and in particular colloidal silicon dioxide, was used primarily as a glidant and anti-adherent in the tabletting process and in encapsulation, promoting the flowability of the granulation. The amount of silicon dioxide included in such tablets for these applications is very limited, 0.1 - 0.5% by weight. Handbook of Pharmaceutical Excipients, 1986 American Pharmaceutical Association, page 255. This is due in part to the fact that by increasing the amount of silicon dioxide in the mixture to be formed into tablets, it causes the mixture to flow too well, causing a known to those skilled in the art of forming tablets as "flood". If the mixture flows too well, a variant weight of the tablet with uneven content uniformity may result. Those skilled in the art will appreciate that the name and / or method of preparation of the silicon dioxide used in the present invention is not determinative of the utility of the product. Rather, as mentioned previously, it has surprisingly been discovered that it is the physical characteristics of silicon dioxide that are critical. In particular, it has been found that silicon dioxide having a relatively large particle size (and correspondingly small surface area) such as silica gel is not useful in the preparation of the improved microcrystalline cellulose products of the invention. . The appended claims are considered to encompass all forms of silicon dioxide having a primary particle size of about 1 nm to about 100 microns, and / or a surface area of about 10 m2 / g to about 500 m2 / g. The silicon dioxide used in the invention is of the very fine particle size variety. In the most preferred embodiments of the invention, the silicon dioxide used is a colloidal silicon dioxide. The colloidal silicon dioxide is a submicron smoked silica prepared by the vapor phase hydrolysis (eg, at 1110 ° C) of a silicon compound, such as silicon tetrachloride. The product itself is a submicron, spongy, light, loose, bluish-white, odorless and tasteless amorphous powder, which is commercially available from a number of sources, including Cabot Corporation (under the trade name Cab-0-Sil); Degussa, Inc. (under the trade name Aerosil); E.I. DuPont & Co.; and .R. Grace & Co. Colloidal silicon dioxide is also known as colloidal silica, fumed silica, light anhydrous silicic acid, silicic anhydride and smoked silicon dioxide, among others. A variety of commercial grades of colloidal silicon dioxide are produced by varying the manufacturing process. These modifications do not affect the silica content, the specific gravity, the refractive index, the color or the amorphous form.

However, it is known that these modifications change the particle size, the surface areas and the apparent densities of the colloidal silicon dioxide products. The surface area of the preferred class of silicon dioxides used in the present invention is in the range of about 50 m2 / g to about 500 m2 / g. The average diameter of the primary particle of the preferred class of silicon dioxides used in the invention is in the range of about 5 nm to about 50 nm. However, in commercial products of colloidal silicon dioxide, these particles agglomerate or aggregate to varying degrees. The bulk density of the preferred class of silicon dioxides used in the invention is in the range of about 20 grams / liter to approximately 100 grams / liter. Commercially available colloidal silicon dioxide products have, for example, a BET surface area in the range of about 50 ± 15 m2 / g (Aerosil 0X50) to about 400 ± 20 (Cab-0-Sil S-17) or 390 ± 40 m2 / g (Cabo-0-Sil EH-5). The commercially available particle sizes are in the range of a nominal particle diameter of 7 nm (eg, Cab-0-Sil S-17 or Cab-0-Sil EH-5) at an average primary particle size of 40. nm (Aerosil 0X50). The density of these products is in the range of 72.0 ± 8 g / 1 (Cab-0-Sil S-17) to 36.8 g / 1 (for example, Cab-0-Sil M-5). The pH of these products in 4% aqueous dispersion is in the range of 3.5 to 4.5. These commercially available products are described for the purposes of exemplifying the acceptable properties of the preferred class of silicon dioxides only, and this disclosure is not intended to limit the scope of the invention in any way whatsoever. When the novel excipient of the invention uses a colloidal silicon dioxide, it has been found that the resulting excipient product surprisingly provides a compressibility that is substantially improved in the preferred embodiments, even compared to the compressibility of commercially available microcrystalline cellulose "outside of shelf "used in direct compression techniques. In other embodiments of the present invention, it has been found that the compressibility of microcrystalline cellulose, which is granulated on a wet basis, is significantly improved by a wider range of silicon dioxide products. Thus, in the embodiments of the present invention, where an improvement in the total compressibility of microcrystalline cellulose (whether used in wet granulation or in dry granulation) is not important, and the microcrystalline cellulose product goes to being subjected to wet-based granulation, it has been found that the surface area of the silicon dioxide can be as low as about 50 m2 / g, and the average primary particle diameter can be as large as about 100 microns. It is also considered that such silicon dioxide products are encompassed within the scope of the invention. Microcrystalline cellulose and silicon dioxide are both substantially insoluble in water.

Therefore, the particle size of these ingredients as they are present in the well-dispersed aqueous suspension is directly related to the particle size of these two ingredients as if they were introduced into the aqueous solution. There is no appreciable dissolution of any ingredient in the aqueous suspension. After a uniform mixture of the ingredients in the suspension is obtained, the suspension is dried to provide a plurality of excipient particles based on microcrystalline cellulose having improved compressibility. In the spray drying process, the aqueous dispersion of microcrystalline cellulose and silicon dioxide is carried along with a sufficient volume of hot air to produce evaporation and drying of the liquid droplets. The highly dispersed suspension of raicrocrystalline cellulose and silicon dioxide is pumpable and capable of being atomized. This is sprayed into a stream of hot filtered air, which supplies the heat for evaporation and transports a dry product to a collection device. The air is then extracted with the moisture removed. The resulting spray-dried powder particles are approximately spherical in shape and relatively uniform in size, thereby possessing excellent fluidity. The co-processed product consists of microcrystalline cellulose and silicon dioxide in intimate association with one another. The amplifications of the resulting particles indicate that the silicon dioxide is integrated with, or partially coats, the surfaces of the microcrystalline cellulose particles. When the amount of silicon dioxide that is included in the excipient is greater than about 20% by weight relative to the microcrystalline cellulose, the silicon dioxide appears to substantially coat the surfaces of the microcrystalline cellulose particles. The exact ratio of the two ingredients of the excipients after co-processing is not currently understood; however, for purposes of describing the particles co-processed herein it is disclosed that they include an agglomerate of microcrystalline cellulose and silicon dioxide in intimate association with one another. By "intimate association", it is understood that silicon dioxide has been integrated in some way with the microcrystalline cellulose particles, for example, via a partial coating of the microcrystalline cellulose particles, as opposed to a chemical interaction of the two ingredients The term "intimate association" is therefore considered for purposes of the present invention as synonymous with "integrated" or "joined". The co-processed particles are not necessarily uniform or homogeneous. Rather, under amplification, for example, with scanning electron microscopy at 500x, the silicon dioxide at the preferred percentage inclusion appears to be a "coating on the edge". It is more preferred in the present invention that microcrystalline cellulose and silicon dioxide be co-processed, resulting in an intimate association of these ingredients, rather than being combined, for example, as a dry mixture. In the preferred embodiments of the present invention, the aqueous suspension of the microcrystalline cellulose and the silicon dioxide are introduced into the spray dryer as a simple aqueous medium, however, it is possible to separately introduce each ingredient into the separated aqueous medium. , which are then combined Other processes for the combination of microcrystalline cellulose and silicon dioxide, known to those skilled in the art, are considered as equivalent to the spray drying technique described above, and are considered moreover they are encompassed by the appended claims.10 In certain preferred embodiments of the present invention, the co-processing of microcrystalline cellulose and silicon dioxide is achieved by the formation of a well-dispersed aqueous suspension of microcrystalline cellulose and silicon dioxide. , and then 5 of this the drying of the suspension and the formation of u a plurality of excipient particles based on microcrystalline cellulose. Typically, the microcrystalline cellulose is first added to an aqueous solution, so that a suspension is obtained containing or from about 0.5% to about 25% microcrystalline cellulose in the form of solids. Preferably, the mixture or suspension contains from about 15% to 20% microcrystalline cellulose, and more preferably from about 17% to about 19% microcrystalline cellulose. In this step, it is often desirable to adjust the pH of the suspension to approximately neutral pH with ammonium hydroxide, sodium hydroxide, and mixtures thereof or the like. The suspension is maintained under constant agitation for a sufficient time to ensure a uniform distribution of the solids before being combined with the silicon dioxide. At this point, the silicon dioxide is added to the suspension or mixture in amounts ranging from 0.1% to about 20% by weight, based on the amount of microcrystalline cellulose, amounts from about 0.5% to about 10% are preferred. , while amounts from about 1.25% to about 5% by weight are especially preferred. The silicon dioxide is preferably in colloidal form prior to the addition to the suspension of microcrystalline cellulose. The microcrystalline cellulose and the colloidal silicon dioxide are well dispersed in the mixture or suspension before drying and forming the new particles. It is preferred that the suspension be dried using spray drying techniques, as these are known in the art. Other drying techniques can also be used, however, such as instant drying, ring drying, micron drying, pan drying, vacuum drying, radiofrequency drying, and possibly microwave drying. The exact manner in which the suspension is dried is not believed to be critical for the microcrystalline cellulose particles / silicon dioxide to demonstrate improved compressibility after wet base granulation. Depending on the amount and type of drying, the concentration of the microcrystalline cellulose and the silicon dioxide in the suspension, the new compressible particles will have different particle sizes, densities, pH, moisture content, etc. The particulate co-processed product of the present invention possesses desirable performance attributes that are not present when the combination of microcrystalline cellulose and silicon dioxide are combined as an anhydrous mixture. It is believed that the beneficial result obtained by the combination of these two materials is due to the fact that the two materials are intimately associated with one another. The average particle size of the integrated excipient of the present invention is in the range of about 10 microns to about 1,000 microns. Particle sizes of about 10 to 500 microns are preferred, particle sizes of about 30 to 250 microns are more preferred, and particle sizes of about 40 to 200 microns are still more preferred. It will be appreciated by those skilled in the art that the drying of the microcrystalline cellulose-silicon dioxide suspension results in a random size distribution of the new excipient particles that are produced. For example, if spray drying techniques are used, droplet size, temperature, agitation, dispersion, air flow, atomizer wheel speed, etc. will affect the final size of the particles. Furthermore, it is within the scope of the invention to choose or mechanically alter the dried particles according to the particle size ranges, depending on the end uses. The particle size of the integrated excipient is not narrowly critical, the important parameter being that the average size of the particles should allow the formation of a directly compressible excipient which forms pharmaceutically acceptable tablets. The new excipient has a bulk density (loose) in the range 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 new excipient has a powder density compacted by vibration in the range of 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 pH of the particles is more preferably close to neutral, although granulates having a pH from about 3.0 to about 8.5 are possible. The moisture content of the excipient particles will vary widely from about 0.5% to about 15%, preferably from 2.5% to about 6%, and more preferably from about 3% to about 5% by weight. The angle of repose is a measurement used to determine the flow characteristics of a powder. The angle of repose is subject to the experiment and the experimenter, but in a comparative test, the new excipient is superior. The new excipient of the invention is free to flow and directly compressible. Accordingly, the excipient can be mixed in the desired ratio with an active agent and optional lubricant (dry granulation), and then directly compressed into solid dosage forms. In the preferred embodiments of the present invention, wherein the silicon dioxide is colloidal silicon dioxide, the new excipient comprising the co-processed microcrystalline cellulose and the colloidal silicon dioxide integrated together, represents an increased microcrystalline cellulose having improved compressibility compared to the commercially available standard grades of microcrystalline cellulose. Alternatively, all or part of the excipient may be subjected to wet-based granulation with the active ingredient. A representative wet base granulation includes loading the new excipient particles into an appropriate granulator, such as those available from Baker-Perkins, and granulating the particles together with the active ingredient, preferably using an aqueous granulation liquid. The granulation liquid is added to the mixture with agitation, until the powder mass has the wet snow content and is then screened in wet form through a desired mesh screen, for example, having a mesh from about 12 to about 16. The sifted granulate is then dried, using standard drying apparatuses such as a convection oven, before undergoing final sieving. Further dry screening of this material is possible, such as by the use of mesh screens from about 40 to about 200. Those materials flowing through the 40 and 60 mesh screens can be further ground before the last formulation of the tablets. The wet granulate thus obtained containing the new excipient is now capable of undergoing tabletting or otherwise being placed into a unit dosage form. In certain preferred embodiments, a portion of the total amount of the new excipient is granulated in wet form with the active ingredient, and thereafter the additional portion of the new excipient is added to the granulate. In other embodiments, the additional portion of the new excipient to be added to the excipient / active ingredient granulate, can be substituted with conventional microcrystalline cellulose, or other excipients commonly used by those skilled in the art, depending of course on the requirements of the formulation particular. By virtue of the new excipient of the present invention, the amount of the new excipient in comparison to the amount of microcrystalline cellulose to be used in a wet granulation technique, to obtain an acceptable solid dosage form, is substantially reduced. In other embodiments of the invention, an additional material is added to the suspension of microcrystalline cellulose and silicon dioxide. Such additional materials include non-silicon metal oxides, starches, starch derivatives, surfactants, polyalkylene oxides, cellulose ethers, cellulose esters and mixtures thereof. These additives may be included in desired amounts which will be apparent to those skilled in the art. In addition to one or more active ingredients, additional pharmaceutically acceptable excipients (in the case of pharmaceuticals) or other additives known to those skilled in the art may be added to the new excipient prior to the preparation of the final product (for non-pharmaceutical applications). pharmaceuticals). For example, if desired, any pharmaceutically inert, soluble or insoluble filler (diluent) material, generally accepted, can be included in the final product (eg, a solid dosage form). Preferably, the inert pharmaceutical filler comprises a monosaccharide, a disaccharide, a polyhydric alcohol, inorganic phosphates, sulfates or carbonates, and / or mixtures thereof. Examples of suitable inert pharmaceutical fillers include sucrose, dextrose, lactose, xylitol, fructose, sorbitol, calcium phosphate, calcium sulfate, calcium carbonate, microcrystalline cellulose "off-shelf", mixtures thereof, and the like. An effective amount of any generally accepted pharmaceutical lubricant, including calcium or magnesium soaps, can optionally be added to the new excipient at the time the drug is added, or in any case before compression in a solid dosage form. The lubricant may comprise, for example, magnesium stearate in any amount from about 0.5 to 3% by weight of the solid dosage form. The complete mixture, in an amount sufficient to make a uniform batch of tablets, can be subjected to tabletting in a tablet-making machine, at conventional production scale, at normal compression pressures for that machine, for example, from approximately 105.5 to 703.1 kg / cm2 (1,500 to 10,000 pound / inch2). The mixture should not be compressed to such a degree that there is subsequent difficulty in its hydration, when exposed to gastric fluid. The average size of the tablet for round tablets is preferably about 50 mg to 500 mg and for tablets in capsule form of about 200 mg to 2,000 mg. However, other formulations prepared according to the present invention may be suitably shaped for other uses or sites, such as other body cavities, eg, periodontal pockets, surgical wounds, vaginally, etc. It is contemplated that for certain uses, for example, antacid tablets, vaginal tablets and possibly implants, the tablet must be larger. In certain embodiments of the invention, the tablet is coated with a sufficient amount of a hydrophobic polymer to make the formulation capable of providing a release of the drug, such that a formulation of 12 or 24 hours is obtained. The hydrophobic polymer that is included in the coating of the tablet can be the same or of a different material compared to the hydrophobic polymeric material, which is optionally granulated with the sustained-release excipient. In other embodiments of the present invention, the coating of the tablet may comprise an enteric coating material in addition to or instead of the hydrophobic polymeric coating. Examples of suitable enteric polymers include cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, methacrylic acid copolymer, shellac, hydroxypropylmethylcellulose succinate, cellulose acetate trimellitate, and mixtures of any of the foregoing. . An example of a commercially available, appropriate enteric material MR is available under the trade name Eudragit L 100-555.

In the further embodiments, the dosage form can be coated with a hydrophilic coating in addition to or instead of the aforementioned coatings. An example of an appropriate material that can be used for such hydrophilic coating is hydroxypropylmethylcellulose (e.g., Opadry MR, commercially available from Colorcon, West Point, Pennsylvania). The coatings may be applied in any pharmaceutically acceptable manner known to those skilled in the art. For example, in one embodiment, the coating is applied via a fluidized bed or in a coating drum or drum. For example, the coated tablets may be dried, for example, at about 60-70 ° C for about 3 to 4 hours in a coating drum or drum. The solvent for the hydrophobic polymer or the enteric coating may be organic, aqueous, or a mixture of an organic solvent and an aqueous one. The organic solvents can be, for example, isopropyl alcohol, ethanol and the like, with or without water. Coatings that may be optionally applied to the compressed solid dose form of the invention may comprise from about 0.5% to about 30% by weight of the final solid dosage form. In the additional embodiments of the present invention, a support platform is applied to the tablets manufactured according to the present invention. Appropriate support platforms are well known to those skilled in the art. An example of suitable support platforms is described in, for example, U.S. Patent No. 4,839,177, incorporated by reference herein. In that patent, the support platform partially covers the tablet, and consists of a polymeric material insoluble in aqueous liquids. The support platform may, for example, be designed to maintain its impermeability characteristics during the transfer of the therapeutically active medicament. The support platform can be applied to the tablets, for example, by means of compression coating on part of the surface of the tablet, by spray coating the polymeric materials comprising the support platform, on all or part of the surface of the tablet, or by immersing the tablets in a solution of the polymeric materials. The support platform may have a thickness of, for example, approximately 2 mm if applied by compression, and approximately 10 microns if applied by means of spray coating or dip coating. In general, in the embodiments of the invention, wherein a hydrophobic polymer or enteric coating is applied to the tablets, the tablets are coated at a weight gain of from about 1% to about 20%, and in certain embodiments preferably from about 5%. % up to approximately 10%. Useful materials in the hydrophobic coatings and support platforms of the present invention include acrylic acid derivatives (such as esters of acrylic acid, methacrylic acid, and copolymers thereof), celluloses and derivatives thereof (such as ethyl cellulose), polyvinyl alcohols, and the like. In certain embodiments of the present invention, the core of the tablet includes an additional dose of the drug, included either in the hydrophobic or enteric coating, or in an additional overcoat coated on the outer surface of the tablet core (without the hydrophobic coating). or enteric), or as a second coating layer coated on the surface of the base coat, comprising the hydrophobic or enteric coating material. This may be desired when, for example, a loading dose of a therapeutically active agent is necessary to provide therapeutically effective blood levels of the active agent, when the formulation is first exposed to the gastric fluid. The loading dose of the medicament included in the coating layer can be, for example, from about 10% to about 40% of the total amount of the medicament included in the formulation. The active agent or agents that can be incorporated with the new excipient described herein, in solid dosage forms of the invention, include systemically active therapeutics, locally active therapeutics, disinfectants, chemical impregners, cleaning agents, deodorants, fragrances, colorants, animal repellents, insect repellents, fertilizer agents, pesticides, herbicides, fungicides, and plant growth stimulators, and the like. A wide variety of therapeutically active agents can be used in conjunction with the present invention. Therapeutically active agents (e.g., pharmaceutical agents) that can be used in the compositions of the present invention include water-soluble and water-insoluble drugs. Examples of such active therapeutic agents include antihistamines (e.g., dimenhydrinate, diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate), analgesics (e.g., aspirin, codeine, morphine), dihydromorphone, oxycodone, etc.), non-steroidal anti-inflammatory agents (eg, naproxen, diclofenac * indomethacin, ibuprofen, sulindac), antiemetics (eg, metoclopramide), antiepileptics (eg, phenytoin, meprobamate and nitrezepam) ), vasodilators (e.g., nifedipine, papaverine, diltiazem and nicar-dirin), antitussive and expectorant agents (e.g., codeine phosphate), antiasthmatics (e.g., theo-phylline), antacids, antispasmodics (e.g., atropine, scopolamine), antidiabetics (eg, insulin), diuretics (eg, ethacrynic acid, bendrofluazide), anti-hypotensors (eg, pro-pranolol, clonidine), antihypertensives (eg, clonidine, methyldopa), bronchodilators (e.g. , albuterol), steroids (eg, hydrocortisone, triamcinolone, prednisone), antibiotics (eg, tetracycline), antihemorrhoidal, hypnotic, psychotropic, antidiarrheal, mucolytic, edatives, decongestants, laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanol-amine). The previous list is not intended to be exclusive.

A wide variety of locally active agents can be used, in conjunction with the new excipient described herein, and include water-soluble and water-insoluble agents. The locally active agent or agents that can be included in the controlled release formulation of the present invention is intended to exert its effect in the environment of use, for example, the oral cavity, although in some cases the active agent may also have activity. systemic via absorption in the blood by means of the surrounding mucosa. The locally active agent or agents include antifungal agents (e.g., amphotericin B, clotrimazole, nystatin, ketoconazole, miconazole, etc.), antibiotic agents (penicillins, cephalosporins, erythromycin, tetracycline, aminoglycosides, etc.), antiviral agents (e.g. , acyclovir, idoxuridine, etc.), breath fresheners (eg, chlorophyll), antitussive agents (eg, dextro-methorphan hydrochloride), anticariogenic compounds (eg, metal salts of fluoride, sodium monofluorophosphate, stannous fluoride, amine fluorides), analgesic agents (e.g., methyl salicylate, salicylic acid, etc.), local anesthetics (e.g., benzocaine), oral antiseptics (e.g., chlorhexidine and salts thereof, hexylresorcinol, decualinium chloride, cetylpyridinium chloride), anti-inflammatory agents (eg, dexamethasone, betamethasone, prednisone, prednisolone, triamcinolone, hydrocortisone, etc.). ), hormonal agents (estriol), antiplaque agents (for example, chlorhexidine and salts thereof, octeni-dine, and mixtures of thymol, menthol, methyl salicylate and eucalyptol), acidity reducing agents (for example, buffering agents) such as potassium dibasic phosphate, calcium carbonate, sodium bicarbonate, sodium and potassium hydroxide, etc.), and tooth desensitizers (eg, potassium nitrate). This list is not intended to be exclusive. The solid formulations of the invention may also include other locally active agents, such as flavorings and sweeteners. In general, any flavor or food additive such as those described in Chemical Used in Food Processing, pub 1274 by the National Academy of Sciences, pages 63-258 may be used. In general, the final product may include from about 0.1% to about 5% by weight of flavor. The tablets of the present invention may also contain effective amounts of coloring agents (e.g., titanium dioxide, FD &C. dyes, and D. & C; see the Kirk-Othmer Ency-clopedia of Chemical Technology , Vol. 5, pp. 857-884, incorporated by reference herein), stabilizers, binders, odor control agents, and preservatives. Alternatively, the new excipient can be used in other applications where it is not compressed. For example, the granulate can be mixed with an active ingredient and the mixture then filled into capsules. The granulate can also be molded in forms other than those typically associated with the tablets. For example, the granulate together with the active ingredient can be molded to "fit" to a particular area in an environment of use (e.g., an implant). All such uses could be contemplated by those skilled in the art, and are considered to be encompassed within the scope of the appended claims.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES The following examples illustrate various aspects of the present invention. These are not constructed to limit the claims in any way.

The examples describe the preparation of various microcrystalline cellulose / silicon dioxide compositions. The tablets were prepared using each of the compositions and each of the tablet preparations was tested for tensile strength.

EXAMPLES 1-3 PREPARATION OF MCC-SiQ2 COPROCESSED COMPOSITIONS AND GRANULATIONS OF THE SAME EXAMPLE 1 Product MCC-Si02 5% w / w of SiO ,, A. EXCIPIENT PARTICLES In this example, approximately 6.2 kilograms of microcrystalline cellulose (MCC), (Mendell Co., Inc. Patterson, NY) are combined in the form of a wet cake with 5.2 kilograms of water in a mixing tank, to form a suspension that It contains approximately 15% solids. The pH was adjusted approximately to neutral with approximately 3 ml of ammonium hydroxide. The suspension was allowed to mix for approximately 15 minutes before being combined with 5% w / w of silicon dioxide (SiO ^), 200 m2 / g (CaboS-il, PTG grade, available from Cabot Corp., Tuscola, IL). After allowing the materials to merge intimately, the suspension was spray dried using a Niro Production Minor (Niro, Columbia, MD), inlet temperature 215 ° C, outlet temperature 125 ° C, atomizer wheel speed 22,300 rpm , to provide MCC-Si02 having an average particle size of 40 to 60 microns.

B. GRANULATION OF EXCIPIENT PARTICLES The MCC-Si0 ~ particles obtained as a result of step 1 A were granulated on a humid basis in a 10 liter high cut granulator, Baker-Perkins, for 3 minutes using water as the granulation fluid. The resulting product was screened in a humid form through a 12 mesh screen, dried on a tray in a convection oven for approximately 2-3 hours until the moisture content was less than 5%, was filtered and sieved in dry to obtain an average particle size of about 55 to about 70 microns.

EXAMPLE 2 Product MCC-SiQ - 20% p / p of SiQ2 The processes of Examples IA and B were repeated, except that 20% w / w silicon dioxide was used to form the product.

EXAMPLE 3 MCC-SiQ product - 2% SiQ2 p / p In this example, the processes of Example IA and B were repeated, except that 2% w / w silicon dioxide was used to form the product.

EXAMPLE 4 Dry-mixed mixture of MCC and Si0 (5% w / w) - Comparativc As a control, microcrystalline cellulose EMCOCEL grade 50 M (Mendell) was mixed in dry base Co. , Inc.) and 5% silicon dioxide w / w, 200 m2 / g (CaboSil, PTG grade). No spray drying or other treatment of the mixture was undertaken. However, the method of Example IB was repeated.

EXAMPLE 5 MCC processed without SiO, As a second control, the process described in Example IB was repeated, except that Si02 was not added.

EXAMPLE 6 In this example, batches of compressed tablets were prepared using each of the products obtained as a result of Examples 1-5. The tablets were prepared using a Korsch tablet press having a punch size of 9.52 mm (3/8 inch) and a target weight of about 245 mg. The granulations were included in five separate runs of tablet formation using compression forces of 6, 12, 18, 24 and 30 KN, respectively. Ten tablets of each run were weighed, measured for diameter and tested for thickness and hardness on the tablet hardness tester Erweka TBH 30, to determine the compressibility of microcrystalline cellulose, measured by tensile strength. The results of the analysis are illustrated graphically in Figure 1, as a comparison of tensile strength versus compressive strength. As can be seen from the graph, substantial benefits are obtained through the co-processing of MCC with SiO ". Tablets prepared using the products of comparative examples 4 and 5, demonstrated poor tensile strength. The new excipient is superior and demonstrates approximately the same relative improvement over the entire range of compression forces. In addition, the graph also illustrates that tablets prepared merely with a dry mix of MCC and SiO? (formulation of Example 4) failed to demonstrate acceptable tensile strengths. Thus, the co-processed MCC-SiO described herein, provides significant retention of the compressibility of microcrystalline cellulose.

EXAMPLES 7-12 In these examples, compressed tablet products containing 70% by weight of microcrystalline cellulose and 30% acetaminophen (APAP in the present) were prepared. The products of Examples 7-9 were controls and were prepared without the co-processed MCC-SiO ™ of the present invention. The products of examples 10-12, on the other hand, included 70% by weight of the new co-processed MCC-Si02 and 30% of APAP. The details concerning the preparation of each granulation product are described below. Figure 2 provides a graphical comparison of the tensile strength versus the compressive force for each product formed into a tablet.

EXAMPLE 7 Intragranulation and Extragranulation of APAP with MCC In this example, tablets were prepared using off-rack MCC (EMCOCEL 50 M) according to the following formula: INGREDIENTS WEIGHT (GRAMS) MCC 267.9 APAP 114.8 Deionized water 165.8 Half of the MCC was added to a 10-liter Baker-Perkins mixer, and combined with the entire APAP. The mixer rotor was adjusted to 200 rpm and the chopper was adjusted to 10,000 rpm. After one minute, the water was added in 90 seconds using a bottle of rinse. After this, the mixing was continued for an additional period of 90 seconds. The granulation was removed from the mixer, screened in wet form through a 12 mesh screen and dried in a convection oven for 2-3 hours at 60 ° C, until a moisture content of less than 5 was obtained. %. The granulation was then screened dry through a 16 mesh screen before being mixed for 10 minutes with the remaining portion of the microcrystalline cellulose in a 2 compartment V mixer. The granulation was removed from the mixer and formed into tablets according to the method described below.

TABLET RESISTANCE TEST In order to prepare tablets for the formulations of Examples 7, 8, 10 and 11, the following procedure was used: the wet-based granulation products were weighed and mixed in a 2-compartment V-blender for 5 minutes with 0.2% of Pruv MR (sodium stearyl fumarate, available from Mendell Co., Inc.). Five tablet-forming runs were run separately with compression forces of 5, 10, 15, 20, and 25 kn respectively, using a Korsch tablet press having a punch size of 9,525 mm (3/8 inch) and a target weight of approximately 245 mg. Ten tablets of each compression force were selected and used in the experiment described in example 13.

EXAMPLE 8 Granulation on a wet basis of APAP with MCC In this example, only the wet base granulation or the intragranulation step was carried out as described above. The formulation was prepared according to the following formula using microcrystalline cellulose EMCOCEL MR 50 M off-shelf: INGREDIENTS WEIGHT (GRAMS) MCC 178.6 APAP 76.5 Deionized water 170.1 Microcrystalline cellulose was added to a 10-liter Baker-Perkins mixer and combined with APAP. The mixer rotor was adjusted to 200 rpm and the chopper or shredder was adjusted to 1,000 rpm. After one minute, water was added in 90 seconds using a bottle of rinse. After this, the mixing was continued for an additional period of 90 seconds. The granulation was removed from the mixer, screened through a 12 mesh screen and then dried in a convection oven at 60 ° C for 2 to 3 hours, until a moisture content of less than 5% was achieved. The granulation was then screened dry through a 16 mesh screen and tabletted according to the method described in Example 7.

EXAMPLE 9 Formulation of APAP Direct Compression with MCC A direct compression formulation for tablets containing 70% microcrystalline cellulose was prepared MR EMCOCEL 50 M off-shelf, and 30% APAP in weight.

The tablets were prepared according to the following formula: INGREDIENTS WEIGHT (GRAMS) MCC 175.0 APAP 74.5 PRUV 0.5 L MCC and APAP were combined in a V-blender and mixed for 15 minutes. After this, the Pruv was added and the mixing was continued for another 5 minutes. The granulation was removed and 5 tablet-forming runs were run separately, using compression forces of 5, 10, 15, 20 and 25 KN, respectively, in a Korsch tablet-forming press. The tablet-forming press had a punch size of 9,525 mm (3/8 inch) and a target weight of about 245 mg. Ten tablets of each compression force were used in the experiment described in example 13.

EXAMPLE 10 Granulation in Wet Base of APAP with MCC-SiOp co-processed (5% w / w) In this example, tablets were prepared by wet base granulation with the co-processed microcrystalline cellulose (5% w / w Si02) of Example IA. The granulation of tablets was prepared according to the following formula: INGREDIENTS WEIGHT (GRAMS) MCC-Si02 178.6 APAP 76.5 Deionized water 170.1 MCC-Si0 added? to a 10-liter mixer Baker-Perkins and was combined with the APAP. The mixer rotor was adjusted to 200 rpm and the chopper was adjusted to 1,000 rpm. After one minute, water was added in 90 seconds using a bottle of rinse. After this, mixing was continued for an additional 90 seconds. The granulation was removed from the mixer, screened wet through a 12 mesh screen and then dried in a convection oven for 2-3 hours at 60 ° C, until a moisture content of less than 5 was achieved. %. The granulation was then screened dry through a 16 mesh screen and made into tablets according to the method described in Example 7.

EXAMPLE 11 Intra- and Extragranulation of APAP with MCC-SiQ2 (5% w / w) A granulation was prepared for compressed tablets according to the following formula: INGREDIENTS WEIGHT (GRAMS) MCC-Si02 267.9 APAP 114.8 Deionized water 165.8 A co-processed MCC-Si02 medium (prepared as in Example IA) was added to a Baker-Perkins 10 liter mixer and combined with the entire APAP. The mixer rotor was adjusted to 200 rpm and the chopper or shredder was adjusted to 1,000 rpm. After one minute, the water was added in a period of 90 seconds using a rinse bottle. After this, the mixing was continued for an additional period of 90 seconds. The granulation was removed from the mixer, screened wet through a 12 mesh screen and then dried in a convection oven for 2-3 hours at 60 ° C, until a moisture content of less than 5 was achieved. %. The granulation was then sieved dry through a 16 mesh screen before being mixed for 10 minutes with the remaining portion of the MCC-Si02 co-processed in a 2-compartment V-mixer, removed from the mixer, and converted into tablets. according to the method of Example 7.

EXAMPLE 12 Formulation of APAP Direct Compression with MCC-SiQ (5% w / w) A direct compression formulation similar to that described in Example 9 was carried out, except that the tablets were prepared to contain MCC-Si02 co-processed from Example IA. Tablet granulation was prepared according to the following formula: INGREDIENTS WEIGHT (GRAMS) MCC-Si02 175.0 APAP 74.5 PRUV 0.5 As was the case in Example 9, five separate tabletting runs were carried out using compression forces of 5, 10, 15, 20 and 25 KN, respectively, on a Korsch tablet forming press (size punch: 9.525 mm (3/8 inch) and a target weight of approximately 245 mg). Ten tablets of each compression force were used to carry out the experiment described in Example 13.

EXAMPLE 13 TEST RESISTANCE TABLETS Ten tablets from each compression run for each formulation, prepared in Examples 7-12, were weighed, measured for diameter and tested for thickness and hardness on the tablet hardness tester Erweka TBH 30, to determine the compressibility of microcrystalline cellulose. The results are illustrated graphically in Figure 2 as a comparison of tensile strength versus compressive strength. Referring now to Figure 2, it can be seen that the compressed tablets made with the co-processed MCC-Si0 of the invention have relatively high tensile strengths, when compared to those made with off-rack MCC. The advantages of MCC-SiO-co-processed are clearly seen in direct compression and in wet granulation formulations, and especially in wet-based granulation products.

EXAMPLES 14-16 DIATOMACEOUS EARTH In these examples, the coprocessing method described in Example IA was repeated, except that the diatomaceous earth had a particle size of about 40 microns (J.T. Baker, Phillipsburg, NJ, was used as the source of Si0").

Example Diatomaceous earth (% weight) 14 2.0 15 1.0 16 0.5 The resulting granules prepared according to Example IB were tabletted according to the same method described in Example 6, and evaluated for tensile strength. The products of Example 3 of the invention (MCC-Si02 at 2% w / w) and Example 5 (MCC only) were included in Figure 3 for comparison purposes. Referring now to Figure 3, it can be seen that although the retention of compressibility provided by the co-processing of the diatomaceous earth is not as great as that provided by the colloidal Si02 having surface areas of approximately 200 m2 / g, however, the co-processed diatomaceous earth MCC mixture demonstrates improved compressibility in wet base granulation formulations.

EXAMPLES 17-19 SILICA GEL In these examples, the coprocessing method described in Example IA was repeated, using silica gel of particle size of 200 microns (VWR Corp., Piscataway, NJ, as the source of Si02).

Example Silica gel (% weight) 17 1 18 2 19 5 The resulting granules prepared according to Example IB were tabletted according to the same method described in Example 6, and evaluated for tensile strength. The products of Example 3 of the invention (MCC-Si0"at 2% w / w) and Example 5 (MCC alone) were included in Figure 4 for comparison purposes. Referring now to Figure 4, it can be seen that the retention of compressibility provided by co-processing with silica gel is well below that provided by colloidal Si02 having surface areas of approximately 200 m2 / g. In fact, the microcrystalline cellulose co-processed with silica gel demonstrates compressibility properties approximately the same as those of off-shelf microcrystalline cellulose in the wet-based granulation formulations.

EXAMPLES 20-22 Silicon dioxide grade HS-5 In these examples, the coprocessing method described in Example 1 was repeated, using Si02 grade HS-5 surface area of 325 m2 / g (Cabot Corp., Tuscola, IL).

Example Silica gel (% weight) 20 2 21 1 22 0.5 The resulting granules prepared according to Example IB were tabletted according to the same method described in Example 6, and evaluated for tensile strength. The products of Example 3 of the invention (MCC-Si02 at 2% w / w) and Example 5 (MCC off-shelf) are included in Figure 5 for comparison purposes. Referring now to Figure 5, the compressibility retention provided by the coprocessing with HS-5 is comparable to that obtained using Si02 having surface aeras of approximately 200 m2 / g. While what is currently believed to be the preferred embodiments of the invention have 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 is intended to claim all changes and modifications that fall within the true scope of the invention.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims

1. An excipient composition, characterized in that it comprises a particulate agglomerate of co-processed microcrystalline cellulose and from about 0.1% to about 20% by weight of silicon dioxide, the microcrystalline cellulose and the silicon dioxide being in intimate association with each other, the portion of The silicon dioxide of the agglomerate is derived from a silicon dioxide having an average primary particle size from about 1 nm to about 100 microns.

2. The composition according to claim 1, characterized in that the silicon dioxide portion of said agglomerate is derived from a silicon dioxide having an average primary particle size of from about 5 nm to about 40 microns.

3. The composition according to claim 1, characterized in that the silicon dioxide portion of the agglomerate is derived from colloidal silicon dioxide.

4. The composition according to claim 1, characterized in that the silicon dioxide is included in an amount from about 0.1% to about 20% by weight, based on the weight of the microcrystalline cellulose.

5. The composition according to claim 1, characterized in that the silicon dioxide is from about 0.5% to about 10% by weight, based on the weight of the microcrystalline cellulose.

6. The composition according to claim 1, characterized in that the silicon dioxide is included in an amount from about 1.25% to about 5% by weight, based on the weight of the microcrystalline cellulose.

7. The composition according to claim 1, characterized in that the excipient particles have an average particle size from about 10 microns to about 1,000 microns.

8. The composition according to claim 1, characterized in that the excipient particles have an average particle size from about 10 microns to about 500 microns.

9. The composition according to claim 1, characterized in that the excipient particles have an average particle size from about 30 microns to about 250 microns.

10. The composition according to claim 1, characterized in that the excipient particles have a moisture content from about 0.5% to about 15%.

11. The composition according to claim 1, characterized in that the excipient particles further comprise a member of the group consisting of non-silicon metal oxides, starches, starch derivatives, surfactants, poly-alkylene oxides, celluloses, cellulose ethers, cellulose esters and mixtures thereof.

12. The composition according to claim 1, characterized in that the silicon dioxide portion of the agglomerate is derived from a silicon dioxide having a surface area of about 10 m2 / g to about 500 m2 / g.

13. The composition according to claim 1, characterized in that the silicon dioxide portion of the agglomerate is derived from a silicon dioxide having a surface area from about 175 m2 / g to about 350 m2 / g.

14. The composition according to claim 1, characterized in that the excipient has a bulk density from about 0.2 g / ml to about 0.6 g / ml.

15. The composition according to claim 3, characterized in that the excipient has a bulk density from about 0.35 g / ml to about 0.55 g / ml.

16. An aqueous suspension useful in the preparation of a compressible pharmaceutical excipient, characterized in that it comprises a mixture of microcrystalline cellulose and from about 0.1% to about 20% by weight of silicon dioxide, based on the weight of the microcrystalline cellulose, the dioxide of silicon has an average primary particle size from about 1 nm to about 100 microns, the solids content of the aqueous suspension is from about 0.5% to about 25% by weight.

17. The suspension according to claim 16, characterized in that the silicon dioxide is present in an amount from about 0.5% to about 10% by weight, based on the weight of the microcrystalline cellulose.

18. The suspension according to claim 16, characterized in that the silicon dioxide is present in an amount from about 1.25% to about 5% by weight, based on the weight of the microcrystalline cellulose.

19. The suspension according to claim 17, characterized in that it has a solids content from about 15% to about 20%.

20. The suspension according to claim 18, characterized in that it has a solids content from about 17% to about 19%.

21. The suspension according to claim 16, characterized in that the pH has been adjusted with a member of the group consisting of ammonium hydroxide, sodium hydroxide and mixtures thereof.

22. The suspension according to claim 16, further characterized in that it comprises a member of the group consisting of non-silicon metal oxides, starches, starch derivatives, surfactants, polyalkylene oxides, celluloses, cellulose ethers, cellulose esters and mixtures of the same.

23. An excipient composition, characterized in that it comprises from about 1% to about 99% of an excipient comprising a particulate agglomerate of co-processed microcrystalline cellulose and from about 0.1% to about 20% silicon dioxide by weight of the microcrystalline cellulose, the cellulose being micro-crystalline and silicon dioxide in intimate association with one another, and the silicon dioxide portion of said agglomerate is derived from a silicon dioxide having an average primary particle size from about 1 nm to about 100 microns, and from about 99% to about 1% of an active ingredient.

24. The composition according to claim 23, characterized in that the silicon dioxide portion of said agglomerate is derived from a silicon dioxide having an average primary particle size from about 5 nm to about 40 microns.

25. The composition according to claim 23, characterized in that the silicon dioxide portion of said agglomerate is derived from colloidal silicon dioxide.

26. The composition according to claim 23, characterized in that it has been granulated on a wet basis.

27. The composition according to claim 25, characterized in that it has been granulated on a wet basis.

28. The composition according to claim 23, characterized in that it has been incorporated in a solid form.

29. A solid dosage form of a compressed mixture, characterized in that it comprises from about 1% to about 99% of an excipient comprising a particulate agglomerate of co-processed microcrystalline cellulose and from about 0.1% to about 20% by weight of silicon dioxide, the microcrystalline cellulose and silicon dioxide are in intimate association with each other, the silicon dioxide portion of said agglomerate is derived from a silicon dioxide having an average primary particle size from about 1 nm to about 100 microns, and from about 99% to about 1% of a therapeutically active ingredient.

30. The composition according to claim 29, characterized in that the silicon dioxide portion of said agglomerate is derived from a silicon dioxide having an average primary particle size from about 5 nm to about 50 microns.

31. The composition according to claim 29, characterized in that the silicon dioxide portion of said agglomerate is derived from colloidal silicon dioxide.

32. The composition according to claim 31, characterized in that it has been granulated on a wet basis before compression.

33. The composition according to claim 29, characterized in that it is incorporated in an oral dosage form.

34. A method for improving the compressibility of microcrystalline cellulose in wet-based granulation products, characterized in that it comprises: (a) the formation of an aqueous suspension containing a mixture of microcrystalline cellulose and silicon dioxide, having a primary particle size average from about 1 nm to about 100 microns, the amount of silicon dioxide being from about 0.1% to about 20% by weight relative to the amount of the microcrystalline cellulose; and (b) drying the suspension to obtain an excipient comprising a plurality of agglomerated particles of microcrystalline cellulose in intimate association with the silicon dioxide.

35. The method according to claim 34, characterized in that the suspension comprises from about 0.5% to about 2% by weight of microcrystalline cellulose.

36. The method according to claim 34, characterized in that the suspension contains from about 15% to about 20% microcrystalline cellulose.

37. The method according to claim 34, characterized in that the suspension contains from about 17% to about 19% microcrystalline cellulose.

38. The method according to claim 34, characterized in that the silicon dioxide is colloidal silicon dioxide.

39. The method according to claim 34, further characterized in that it comprises drying the suspension of microcrystalline cellulose and silicon dioxide, by a method selected from the group consisting of instant drying, ring drying, spray drying, and micron drying.

40. The method according to claim 34, further characterized in that it comprises drying the suspension of microcrystalline cellulose and silicon dioxide, which is dried by spray drying.

41. The method according to claim 34, further characterized in that it comprises drying the suspension, such that the resulting excipient particles have an average particle size from about 10 microns to about 1,000 microns.

42. The method according to claim 34, further characterized in that the suspension is dried, such that the resulting excipient particles have a particle size from about 10 microns to about 500 microns.

43. The method according to claim 40, further characterized in that it comprises drying the suspension, such that the resulting excipient particles have a particle size from about 30 microns to about 250 microns.

44. The method according to claim 34, further characterized in that it comprises drying the suspension, such that the resulting excipient particles have a moisture content of from about 0.5 to about 15%.

45. The method according to claim 34, characterized in that the suspension further comprises a member of the group consisting of non-silicon metal oxides, starches, starch derivatives, surfactants, polyalkylene oxides, celluloses, cellulose ethers, cellulose esters and mixtures thereof.

46. The excipient particles based on microcrystalline cellulose, characterized in that they are prepared by the process according to claim 34

47. The excipient particles based on microcrystalline cellulose, characterized in that they are prepared by the process according to claim 43.

48. A method for the preparation of a solid dosage form, characterized in that it comprises: (a) the formation of an aqueous suspension containing a mixture of microcrystalline cellulose and silicon dioxide, having a particle size from about 1 nm to about 100 microns, the amount of silicon dioxide being from about 0.1% to about 20% relative to the amount of microcrystalline cellulose, by weight; (b) drying the suspension to obtain an excipient comprising a plurality of agglomerated particles of the microcrystalline cellulose, in intimate association with the silicon dioxide; (c) mixing an active ingredient with the excipient in a ratio of from about 1:99 to about 99: 1; (d) the incorporation of the mixture obtained in step (c) into a plurality of solid unit doses.

49. The method according to claim 48, characterized in that the silicon dioxide is colloidal silicon dioxide, further comprising the wet base granulation of the mixture obtained in step (c) before the incorporation of the mixture within the unit doses. solid.

50. The method according to claim 48, characterized in that the aqueous suspension prepared in step (a) comprises from about 0.5% to about 25% by weight of microcrystalline cellulose.

51. The method according to claim 48, characterized in that the drying of step (b) is achieved via spray drying, such that the resulting excipient particles have an average particle size from about 10 microns to about 1,000 microns.

52. The method according to claim 49, characterized in that the drying of step (b) is achieved via spray drying, such that the resulting excipient particles have an average particle size from about 30 microns to about 250 microns.

53. The method according to claim 48, characterized in that the resulting excipient particles have a bulk density from about 0.2 g / ml to about 0.6 g / ml.

54. The method according to claim 49, characterized in that the resulting excipient particles have a bulk density from about 0.35 g / ml to about 0.55 g / ml.

55. The method according to claim 49, further characterized in that it comprises wet granulation of the mixture of step (c), adding a further amount of the excipient obtained in step (b) to said granulation, and thereafter incorporated the mixture in a solid dosage form.

56. The method according to claim 49, further characterized in that it comprises the wet-based granulation of the mixture of step (b) before mixing the excipient with the active ingredient in step (c).

57. The method according to claim 56, further characterized in that it comprises adding a further amount of the excipient obtained in step (b) to the mixture of the granulation and the active ingredient, and thereafter the mixture is compressed into a form of solid dose.

58. The method according to claim 49, further characterized by comprising wet granulation of the mixture of step (c), adding an additional amount of a pharmaceutically acceptable excipient to said granulation, and thereafter compressing the mixture into a solid dosage form.

59. The method according to claim 56, further characterized in that it comprises adding an additional amount of a pharmaceutically acceptable excipient to the mixture of the granulation and the active ingredient, and thereafter the mixture is compressed into a solid dosage form.

60. An excipient composition, characterized in that it comprises a particulate excipient of co-processed microcrystalline cellulose, integrated with approximately 0.1% up to about 20% silicon dioxide, by weight of the microcrystalline cellulose, the silicon dioxide portion of said excipient being derived from dioxide silicon having a surface area of about 10 m2 / g to about 500 m2 / g.

61. The composition according to claim 60, characterized in that the silicon dioxide portion of the excipient is derived from silicon dioxide having a surface area of about 175 m2 / g to about 350 m2 / g.

62. The composition according to claim 60, characterized in that the silicon dioxide portion of the excipient is derived from colloidal silicon dioxide.

63. A pharmaceutical excipient suitable for compression in a solid dosage form when combined with an active ingredient, characterized in that it comprises a co-processed microcrystalline cellulose. integrated with about 0.1% to about 20% of colloidal silicon dioxide by weight of said microcrystalline cellulose.

64. An enhanced microcrystalline cellulose excipient, suitable for compression in a solid dose form with a therapeutically active agent via a wet-based granulation method, characterized in that it comprises micro-crystalline cellulose particles having from about 0.1% to about 20% of colloidal silicon dioxide by weight of said microcrystalline cellulose, integrated on a portion of the surface of the microcrystalline cellulose particles.