ES2199281T3

Pharmaceutical excipient having improved compressibility

Abstract

AN EXCIPIENT BASED ON THE MICROCRYSTALLINE CELLULATED WITH IMPROVED COMPRESSIBILITY IS SHOWN BOTH IF USED IN DIRECT COMPRESSION, DRY GRANULATION OR HUMID GRANULATION FORMULAS. THE EXCIPIENT IS AN AGLOMERATE OF MICROCRYSTALLINE CELLULOSE PARTICLES AND SILICON DIOXIDE PARTICLES OF 0.1 TO 20% IN MICROCRYSTALLINE CELL WEIGHT, WITH THE MICROCRYSTALLINE CELLULOSE AND INTIMATE SILENT MUTURE SILICON DIOXIDE. THE SILICON DIOXIDE USED IN THIS NEW EXCIPIENT HAS A PARTICULAR SIZE OF APPROXIMATELY 1 NANOMETER TO APPROXIMATELY 100 MICRONS AND PREFERIBLY IT WILL BE A GRADE OF COLOID SILICON DIOXIDE.

ES2199281T3, drawing sheet 1 — Sheet 1 of 5

Term

Term ended

Projected expiry passed 5 January 2016, 10.7 years ago.

61 claims: 17 independent, 44 dependent

1
ES 2 199 281 T3 IS 2 199 281 T3 CLAIMS REIVINDICACIONES 1. An excipient, which comprises, in the absence of a therapeutically active ingredient, a particulate agglomerate of microcrystalline cellulose co-processed with between 0.1% and 20% of silicon dioxide by weight of the microcrystalline cellulose, the microcrystalline cellulose and the dioxide being found of silicon in intimate association with each other, so that said silicon dioxide integrates with or partially coats said microcrystalline cellulose, said portion of silicon dioxide being derived from said agglomerate of a silicon dioxide having a mean primary particle size of between 1 nm and 100 µm. 1. Un excipiente, que comprende, en ausencia de un ingrediente terapéuticamente activo, un aglomerado particulado de celulosa microcristalina co-procesada con entre 0,1% y 20% de dióxido de silicio en peso de la celulosa microcristalina, encontrándose la celulosa microcristalina y el dióxido de silicio en asociación íntima entre sí, de modo que dicho dióxido de silicio se integra con o reviste parcialmente dicha celulosa microcristalina, derivándose dicha porción de dióxido de silicio de dicho aglomerado de un dióxido de silicio que posee un tamaño de partícula primario medio de entre 1 nm y 100 μm.
2
Un excipiente, que comprende, en ausencia de un ingrediente terapéuticamente activo, un aglomerado particulado de celulosa microcristalina integrada con entre 0,1% y 20% de dióxido de silicio en peso de dicha celulosa microcristalina, en el que dicho dióxido de silicio está co-procesado con dicha celulosa microcristalina y la reviste parcialmente, y dicha porción de dióxido de silicio de dicho excipiente se deriva de un dióxido de silicio que posee un área superficial de entre 10 m2/g y 500 m2/g. two. An excipient, comprising, in the absence of a therapeutically active ingredient, a particulate agglomerate of microcrystalline cellulose integrated with 0.1% to 20% silicon dioxide by weight of said microcrystalline cellulose, wherein said silicon dioxide is co -processed with said microcrystalline cellulose and partially covers it, and said silicon dioxide portion of said excipient is derived from a silicon dioxide that has a surface area of between 10 μm2/ g and 500 m2/ g.
5
The solid dosage form according to any of claims 3 to 4, wherein the silicon dioxide portion of said agglomerate is derived from a silicon dioxide having an average primary particle size of between 5 nm and 50 μη . 5. La forma de dosificación sólida de acuerdo con cualquiera de las reivindicaciones 3 a 4, en la que la porción de dióxido de silicio de dicho aglomerado se deriva de un dióxido de silicio que posee un tamaño de partícula primario medio de entre 5 nm y 50 μη.
6
The excipient or solid dosage form according to any one of the preceding claims, wherein said silicon dioxide portion of said agglomerate is derived from a silicon dioxide having a mean primary particle size of between 5 and 40 nm μm. 6. El excipiente o forma de dosificación sólida de acuerdo con una cualquiera de las reivindicaciones precedentes, en el que dicha porción de dióxido de silicio de dicho aglomerado se deriva de un dióxido de silicio que posee un tamaño de partícula primario medio de entre 5 nm y 40 μm.
7
The excipient or solid dosage form according to any one of the preceding claims, wherein said silicon dioxide portion of said agglomerate is derived from colloidal silicon dioxide. 7. El excipiente o forma de dosificación sólida de acuerdo con una cualquiera de las reivindicaciones precedentes, en el que dicha porción de dióxido de silicio de dicho aglomerado se deriva de un dióxido de silicio coloidal.
8
The excipient or solid dosage form according to any one of the preceding claims, wherein said silicon dioxide constitutes between 0.5% and 10% by weight, relative to the weight of said microcrystalline cellulose. 8. El excipiente o forma de dosificación sólida de acuerdo con una cualquiera de las reivindicaciones precedentes, en el que dicho dióxido de silicio constituye entre 0,5% y 10% en peso, respecto al peso de dicha celulosa microcristalina.
10
The excipient or solid dosage form according to any one of the preceding claims, wherein said excipient particles have an average particle size of between 10 µm and 1,000 µm. 10. El excipiente o forma de dosificación sólida de acuerdo con una cualquiera de las reivindicaciones precedentes, en el que dichas partículas de excipiente poseen un tamaño de partícula medio de entre 10 μm y 1.000 μm.
13
The excipient or solid dosage form according to any one of the preceding claims, wherein said excipient particles have a moisture content of between 0.5% and 15%. 13. El excipiente o forma de dosificación sólida de acuerdo con una cualquiera de las reivindicaciones precedentes, en el que dichas partículas de excipiente poseen un contenido de humedad de entre 0,5% y 15%.
14
The excipient or solid dosage form according to any one of the preceding claims, wherein said excipient particles further comprise a member of the group consisting of non-siliceous metal oxides, starches, starch derivatives, surfactants, polyalkylene oxides, celluloses, cellulose ethers, cellulose esters, and mixtures of these. 14. El excipiente o forma de dosificación sólida de acuerdo con una cualquiera de las reivindicaciones precedentes, en el que dichas partículas de excipiente comprenden además un miembro del grupo formado por óxidos metálicos no silíceos, almidones, derivados de almidones, tensioactivos, óxidos polialquilénicos, celulosas, éteres de celulosa, ésteres de celulosa, y mezclas de éstos.
15
El excipiente o forma de dosificación sólida de acuerdo con una cualquiera de las reivindicaciones precedentes, en el que dicha porción de dióxido de silicio de dicho aglomerado se deriva de un dióxido de silicio que posee un área superficial de entre 10 m2/g y 500 m2/g. fifteen. The excipient or solid dosage form according to any one of the preceding claims, wherein said silicon dioxide portion of said agglomerate is derived from a silicon dioxide having a surface area of between 10 μm2/ g and 500 m2/ g.
17
The excipient or solid dosage form according to any one of the preceding claims, wherein said excipient has a bulk density of between 0.2 g / ml and 0.6 g / ml. 17. El excipiente o forma de dosificación sólida de acuerdo con una cualquiera de las reivindicaciones precedentes, en el que dicho excipiente posee una densidad aparente de entre 0,2 g/ml y 0,6 g/ml.
19
The excipient according to any one of the preceding claims, which has been wet granulated. 19. El excipiente de acuerdo con una cualquiera de las reivindicaciones precedentes, que ha sido granulado en húmedo.
20
El excipiente de acuerdo con una cualquiera de las reivindicaciones precedentes, que se ha incorporado en una forma sólida. twenty. The excipient according to any one of the preceding claims, which has been incorporated in a solid form.
21
El excipiente de acuerdo con una cualquiera de las reivindicaciones precedentes, que ha sido granulado en húmedo con un agente activo. twenty-one. The excipient according to any one of the preceding claims, which has been wet granulated with an active agent.
22
An aqueous paste useful in the preparation of a compressible pharmaceutical excipient, which comprises a mixture of microcrystalline cellulose in the form of a wet cake, and between 0.1% and 20% by weight of silicon dioxide, relative to the weight of said microcrystalline cellulose , said silicon dioxide having an average primary particle size of between 1 nm and 100 μm, the solids content of said aqueous paste being between 0.5% and 25% by weight, and said silicon dioxide being present in an amount between 0.5% and 10% by weight, relative to the weight of said microcrystalline cellulose. 22. Una pasta acuosa útil en la preparación de un excipiente farmacéutico comprimible, que comprende una mezcla de celulosa microcristalina en forma de un pastel húmedo, y entre 0,1% y 20% en peso de dióxido de silicio, respecto al peso de dicha celulosa microcristalina, teniendo dicho dióxido de silicio un tamaño de partícula primario medio de entre 1 nm y 100 μm, siendo el contenido de sólidos de dicha pasta acuosa entre 0,5% y 25% en peso, y estando dicho dióxido de silicio presente en una cantidad entre 0,5% y 10% en peso, respecto al peso de dicha celulosa microcristalina.
39
A process for improving the compressibility of microcrystalline cellulose in wet granulation products, comprising:39. Un procedimiento para mejorar la compresibilidad de la celulosa microcristalina en los productos de granulación en húmedo, que comprende: (i) formación de una pasta acuosa que contiene una mezcla de celulosa microcristalina y dióxido de silicio que posee un tamaño primario medio de partícula de 1 nm a 100 μm, siendo la cantidad de dióxido de silicio entre 0,1% y 20% respecto a la cantidad de celulosa microcristalina, en peso, en la que dicha pasta comprende entre 0,5% y 25% en peso de celulosa microcristalina;y (ii) secado de dicha pasta para obtener un excipiente que comprende una pluralidad de partículas aglomeradas de dicha celulosa microcristalina en asociación íntima con dicho dióxido de silicio. (i) formation of an aqueous paste containing a mixture of microcrystalline cellulose and silicon dioxide that has an average primary particle size of 1 nm to 100 μm, the amount of silicon dioxide being between 0.1% and 20% with respect to to the amount of microcrystalline cellulose, by weight, wherein said pulp comprises between 0.5% and 25% by weight of microcrystalline cellulose;and (ii) drying said paste to obtain an excipient comprising a plurality of agglomerated particles of said microcrystalline cellulose in intimate association with said silicon dioxide.
50
Un procedimiento de preparación de una forma de dosificación sólida que comprende:fifty. A method of preparing a solid dosage form comprising: (i) formación de una pasta acuosa que contiene una mezcla de celulosa microcristalina y dióxido de silicio que posee un tamaño de partícula de 1 nm a 100 μm, en la que la cantidad de dióxido de silicio se encuentra entre 0,1% y 20% respecto a la cantidad de celulosa microcristalina, en peso;(i) formation of an aqueous paste containing a mixture of microcrystalline cellulose and silicon dioxide having a particle size of 1 nm to 100 μm, in which the amount of silicon dioxide is between 0.1% and 20 % relative to the amount of microcrystalline cellulose, by weight;(ii) drying said paste to obtain an excipient comprising a plurality of agglomerated particles of said microcrystalline cellulose in intimate association with said silicon dioxide;(ii) secado de dicha pasta para obtener un excipiente que comprende una pluralidad de partículas aglomeradas de dicha celulosa microcristalina en asociación íntima con dicho dióxido de silicio;(iii) mezclado del ingrediente activo con dicho excipiente, en una proporción entre aproximadamente 1:99 y 99:1;(iii) mixing the active ingredient with said excipient, in a ratio between approximately 1:99 and 99: 1;(iv) incorporación de dicha mezcla obtenida en la etapa (iii) en una pluralidad de formas de dosificación sólidas. (iv) incorporation of said mixture obtained in step (iii) in a plurality of solid dosage forms.

Independent claims17

226 paragraphs in 3 sections, as filed

IS 2 199 281 T3

DESCRIPTION

Pharmaceutical excipient that has improved comprehensibility.

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 that include one or more active ingredients.

In order to prepare a solid dosage 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 that allow it to be processed in such a way. Among other things, the material to be compressed must be easy to slide, must be lubricated and, most importantly, must possess sufficient cohesion to ensure that the solid dosage form remains intact after compression.

In the case of tablets, the tablet is formed by applying pressure to the material from which the tablets will be made on a tablet press. A tablet press includes a lower punch that fits into a die from below and an upper punch, having corresponding shape and dimensions, that enters the die cavity from above after the tabletting material fills the die cavity. matrix. The tablet is formed by the action of pressure applied to the lower and upper punches. The ability of the material to flow freely in the die is important to ensure uniform filling of the die and that the material is in continuous motion from the source of the material, eg from an automatic loader. The lubricity of the material is crucial in the preparation of solid dosage forms, as the compressed material must be rapidly expelled from the faces of the punches.

Since most drugs do not possess any or only some of these properties, tablet formulation procedures have been developed in order to impart these desirable characteristics to the material (s) to be compressed into a solid dosage form. . Typically, the material to be compressed into the solid dosage form includes one or more excipients that confer the properties of ease of sliding, lubrication and cohesion to the drug / drugs that are formulated to obtain a dosage form.

Lubricants are typically added to prevent the material (s) from which the tablets are to be made from sticking to the punches. Commonly used lubricants include magnesium stearate and calcium stearate. Typically these lubricants are included in the final compressed product in amounts less than 1% by weight.

In addition to lubricants, solid dosage forms often contain diluents. Diluents are often added in order to increase the apparent weight of the material to be compressed, to achieve a practical tablet size for compression. This is often necessary when the dose of the drug is relatively small.

Another type of excipient in common use in solid dosage forms are binders. Binders are agents that confer cohesive properties to material / powders. Commonly used binders include starch, and sugars such as sucrose, glucose, dextrose, and lactose.

Disintegrants are often included in order to ensure that the freshly prepared compressed solid dosage form possesses an acceptable rate of disintegration in an environment of use (eg, the gastrointestinal tract). Typical disintegrants include starch derivatives and carboxymethylcellulose salts.

There are three general procedures for preparing the materials to be included in the solid dosage form prior to compression: (1) dry granulation; (2) direct compression; and (3) wet granulation.

Dry granulation processes can be used when one of the constituents, either the drug or the diluent, has sufficient cohesion properties to form tablets. The procedure includes mixing of the ingredients, stagnation of the ingredients, dry screening, lubrication, and finally compression of the ingredients.

In direct compression, the material (s) to be included in the solid dosage form are directly compressed without modifying the physical nature of the material itself.

The wet granulation process includes mixing the powders to be incorporated into the dosage form in, for example, a twin drum mixer or a double cone drum mixer, and then adding the solutions of a binding agent to the mixed powders to obtain granulation. The wet mass is then screened, for example, on a 6 or 8 mesh size screen, and dried, for example, by rack drying, using a fluid bed dryer, spray, radio-frequency dryer, microwave, vacuum or infrared dryer.

The use of direct compression is limited to those situations where the drug or active ingredient has a crystalline structure and physical characteristics required for the formation of a pharmaceutically acceptable tablet. Furthermore, it is well known in the art to include one or more excipients that make direct compression a procedure applicable to drugs or active ingredients that do not possess the required physical properties. For solid dosage forms in which the drug itself must be administered in a relatively high dose (i.e., when the drug comprises a substantial part of the total weight of the tablet), it is necessary that the drug (s) possess a Sufficient physical characteristics (eg, cohesion) for the ingredients to be compressed directly.

Typically, however, excipients are added to the formulation to impart good flow and compression properties to all of the material to be compressed. Such properties are typically imparted to these excipients by a pre-processing step such as wet granulation, stagnation, spray drying, spheronization, or crystallization. Among the excipients of com2

Useful direct pressure forms include processed forms of cellulose, sugars, and dicalcium phosphate dihydrate, among others.

Microcrystalline, processed cellulose has been widely used in the pharmaceutical industry as a direct compression vehicle for solid dosage forms. Microcrystalline cellulose is commercially available under the trade name EMCOCEL® by Edward Mendell Co., Inc. and as Avicel® from FMC Corp. Compared to other directly compressible excipients, microcrystalline cellulose is generally considered to exhibit superior compressibility and disintegration properties.

Another limitation of direct compression as a tabletting method is tablet size. If the amount of active ingredient is high, a pharmaceutical formulator may be chosen to wet granulate the active with other excipients, to obtain a tablet of acceptable size with the desired compact strength. Typically, the amount of filler / binder or excipients needed for wet granulation is less than that required for direct compression, as the wet granulation process contributes in some way to achieving the desired physical properties for a compressed. Thus, despite the advantages of direct compression (such as reduced processing times and costs), wet granulation is widely used in industry for the preparation of solid dosage forms. Wet granulation is preferred by many of those skilled in the art over direct compression, as this process is more likely to overcome any problems associated with the physical characteristics of the various ingredients in the formulation, thus providing a material that It meets the flow and cohesion requirement necessary to obtain an acceptable solid dosage form.

The popularity of the wet granulation process compared to the direct compression process is based on at least three advantages. First, wet granulation gives the material to be compressed better moisture properties, especially 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 content uniformity of solid dosage forms is generally improved. By the wet granulation process, all the granules thus obtained should contain approximately the same amount of drug. Thus, 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 in the direct compression procedure. Finally, the particle size and shape of the particles comprising the granulate to be compressed are optimized by the wet granulation process. This is due to the fact that when a dry solid is wet granulated, the binder "sticks" the particles together, so that they agglomerate into granules that will be more or less spherical.

Due to the popularity of microcrystalline cellulose, pharmaceutical formulators have found it desirable to include this excipient in a formulation that is wet granulated prior to tableting. Unfortunately, commonly available microcrystalline cellulose does not meet the typical principle that the amount of filler / binder needed in wet granulation is less than that of direct compression. Exposure of microcrystalline cellulose to moisture in the wet granulation process is known to severely reduce the compressibility of this excipient. The loss of compressibility of microcrystalline cellulose is especially problematic when the formulation dictates the final product must be relatively large in the environment of use. For example, if a pharmaceutical formulator wishes to prepare a high drug content solid oral dosage form, and the use of the wet granulation technique is deemed necessary, the loss of compressibility of microcrystalline cellulose dictates that it may be necessary. a larger quantity of this material to obtain an acceptably compressed final product. The additional amount of microcrystalline cellulose that is needed adds cost to the preparation, but it also adds bulk, more importantly, making the product more difficult to swallow.

The loss of compressibility of microcrystalline cellulose when exposed to wet granulation has long been considered a problem in the art, for which no satisfactory solution has been found.

Attempts have been made to provide an excipient possessing high compressibility, small volume (high bulk density), and good flow properties, while being capable of providing satisfactory disintegration of the solid dosage form, which is applicable in wet granulation processes as well as dry granulation and direct compression, for the preparation of solid dosage forms.

For example, United States Patent No. 4,159,345 (Takeo et al.) Describes an excipient consisting essentially of a microcrystalline cellulose having an average degree of polymerization between 60 and 375, and which is obtained by acid hydrolysis or the alkaline oxidative degradation of a cellulosic substance chosen from liquors, pulps and regenerated fibers. Microcrystalline cellulose is a white cellulosic powder that has an apparent specific volume of 1.6-3.1 cc / g, an angle of repose between 35 ° and 42 °, a sieve residue of 200 pore size from between 2 and 80% by weight and an apparent specific volume of bleed of at least 1.4 cc / g.

In US Patent No. 4,744,987 (Mehra, et al.), A co-processed and particulate composition of microcrystalline cellulose and calcium carbonate is described, in which the respective components are present in a weight ratio of 75:25 to 35:65. The co-processed composition is prepared by forming a well dispersed aqueous slurry of microcrystalline cellulose and calcium carbonate, followed by drying the slurry to give a particulate product. The combination of these two ingredients provides a lower cost excipient that has tablet characteristics similar to those of microcrystalline cellulose and that would satisfy the need for excipients.

ES 2 199 281 T3 economical and well-functioning product demanded by the vitamin market.

European Patent Application EP-0609976A1 (by Asahi Kasel Kabushiki Kaisha) describes an excipient comprising microcrystalline cellulose in white powder, which has an average degree of polymerization of between 100 and 375, preferably between 190 and 210, and a capacity of support acetic acid of 280% or more, preferably 290 to 370%. The excipient shows high compactness and high disintegration speed, and is obtained by heat treatment of an aqueous dispersion of purified cellulose particles, having a solids content of 40% or less by weight, at 100 ° C or more. , followed by drying, or by subjecting an aqueous dispersion of purified cellulose particles having a solids content of 23% or less by weight to a thin layering treatment and drying the resulting thin layer. The excipient has high compressibility and a good balance between compactness and disintegration speed.

US Patent No. 4,533,674 describes spray drying an aqueous paste of ascorbic acid and binder in the presence of an absorbent.

There still remains a need in the industry for a pharmaceutical excipient that possesses excellent compressibility when used in both direct compression and wet granulation processes.

Objects and summary of the invention

It is an object of the present invention to provide an excipient useful in a variety of applications, and which can be used in direct compression or wet granulation processes.

It is a further object of the present invention to provide an excipient useful in direct compression processes, which possesses improved compressibility over microcrystalline cellulose.

It is a further object of the present invention to provide an excipient useful in wet granulation processes, which possesses improved compressibility over microcrystalline cellulose.

It is a further object of the present invention to provide a free flowing excipient which possesses excellent compressibility properties when used in direct compression or wet granulation processes, and which further possesses pharmaceutically acceptable disintegration properties.

It is a further object of the present invention to provide an improved microcrystalline cellulose excipient, in which the microcrystalline cellulose has not been chemically altered, and which possesses improved compressibility over commercially available "stock" microcrystalline cellulose.

It is a further object of the present invention to provide a solid dosage form that includes one or more active ingredients and the improved microcrystalline cellulose excipient of the present invention.

It is a further object of the present invention 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 used. expose, for example, to gastrointestinal fluids.

In accordance with the foregoing objects and others that will be obvious to those skilled in the art, the present invention is directed towards an excipient comprising, in the absence of a therapeutically active ingredient, a particulate agglomerate of co-processed microcrystalline cellulose and between 0, 1% to 20% of silicon dioxide, by weight of the microcrystalline cellulose, the microcrystalline cellulose and the silicon dioxide being in close association with each other, and the silicon dioxide part of the agglomerate is derived from a silicon dioxide of particle size between 1 nanometer (nm) and 100 micrometers (μιη), based on the mean primary particle size.

In preferred embodiments, silicon dioxide represents between 0.5% to 10% of the excipient, and most preferably between 1.25% to 5% by weight relative to microcrystalline cellulose.

In other preferred embodiments of the invention, silicon dioxide has a particle size between 5nm and 40 µm, and preferably between 5 nm and 50 µm.

In preferred embodiments of the invention, silicon dioxide is further characterized by having a surface area between 10 µm2/ g and 500 m2/ g, preferably between 50 m2/ g and 500 m2/ g, and preferably between 175 m2/ g and 350 m2/ g.

The present invention is further directed towards an aqueous paste useful in the preparation of a compressible excipient useful in dry and wet granulation formulation processes, comprising a mixture of microcrystalline cellulose and between 0.1% and 20% dioxide. silicon, by weight with respect to microcrystalline cellulose, silicon dioxide having a particle size between 1 nm and 100 µm. The solids content of the slurry is 0.5% to 25% by weight, preferably 15% to 20% by weight, and preferably 17% to 19% by weight.

The present invention is further directed towards mixing an active ingredient (s) and an excipient comprising, in the absence of a therapeutically active ingredient, a particulate agglomerate of co-processed microcrystalline cellulose and between 0.1% and 20%. % silicon dioxide, by weight microcrystalline cellulose, the microcrystalline cellulose and the silicon dioxide being in close association with each other, and the silicon dioxide having a particle size between 1 nm and 100 µm. The ratio of active ingredient to excipient is 1:99 to about 99: 1, by weight.

The present invention is further directed towards a granulate of an active ingredient (s) and the new excipient described herein, in which the active ingredient (s) and the excipient have been subjected to a process of wet granulation.

The present invention is further directed towards a solid dosage form comprising an active ingredient (s) and the new excipient described herein, wherein the active ingredient (s) and the excipient have been compressed. directly into solid dosage form, or have been subjected to a wet granulation process and subsequently compressed into solid dosage form. The solid compressed dosage form provides an adequate dissolution and immediate release profile of the active ingredient (s) when exposed to aqueous solutions during assays for

ES 2 199 281 T3 dissolution in vitro, and provides drug release in an environment of use that is considered bioavailable. In further embodiments of the invention, the dissolution profile of the solid dosage form is modified to result in a controlled or sustained dissolution and release profile.

The present invention is further directed towards a process for maintaining and / or enhancing the compressibility of microcrystalline cellulose. The process includes the formation of an aqueous paste containing a mixture of microcrystalline cellulose and silicon dioxide having a particle size of 1 nm to 100 μm, and drying the paste to obtain excipient particles based on microcrystalline cellulose in the that the silicon dioxide particles have integrated with the microcrystalline cellulose particles. In this aspect of the invention, the pulp contains between 0.5% and 25% by weight of microcrystalline cellulose, with amounts between 15% and 20% being preferred. Furthermore, the pulp contains between 0.25% and 5% silicon dioxide by weight of microcrystalline cellulose.

The new excipient described in the present invention is easy to glide, has excellent disintegration properties, and importantly, in certain embodiments it has improved compressibility over commercially available microcrystalline cellulose "in stock" when directly compressed. . The advantages of the new excipient described in the present invention are realized especially in pharmaceutical formulations prepared using wet granulation techniques. When used in wet granulation techniques, the new excipient surprisingly provides a compressibility that is substantially improved in preferred embodiments, compared to the compressibility of normal commercially available "stock" microcrystalline cellulose used in wet granulation, and is even comparable to microcrystalline cellulose "in stock" used in direct compression techniques. In other embodiments, the new excipient surprisingly provides a compressibility that is substantially superior to the compressibility of normal commercially available "in stock" microcrystalline cellulose used in direct compression techniques.

The term "ambient fluid" refers, for the purposes of the invention, to encompass, for example, an aqueous solution, or a gastrointestinal fluid.

By "sustained release" is meant, for the 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 toxic levels) of the drug are maintained at over an extended period of time, for example, resulting in a 12 hour or 24 hour dosage form.

By "bioavailable" is meant, for the purposes of the invention, that the therapeutically active drug is absorbed from the sustained release formulation and becomes present in the body at the intended drug site of action.

By "primary particle size" it is meant, for the purposes of the invention, that the particles are not agglomerated. Agglomeration is common for silicon dioxide particles, resulting in a comparatively large agglomerated particle size.

Brief description of the drawings

The following drawings are illustrative of embodiments of the invention, and are not intended to limit the scope of the invention as contemplated in the claims.

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

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

Figure 3 graphically shows a comparison of the tensile strength of the tablets containing CMC co-processed with diatomaceous earths prepared according to the invention, the tablets containing CMC co-processed with 2% w / w SiO2 and the Prior art tablets prepared to contain only unmodified CMC.

Figure 4 graphically shows a comparison of the tensile strength of tablets prepared using CMC co-processed with silica gel, tablets prepared with the new CMC co-processed, and tablets prepared only with CMC.

Figure 5 graphically shows a comparison of the tensile strength of tablets prepared using CMC co-processed with HS 5 grade SiO2, tablets prepared using CMC-SiO2 co-processed, and prior art tablets prepared to contain only CMC not modified.

Detailed description of the invention

Microcrystalline cellulose is a well known tablet diluent and disintegrant. Its main advantage over other excipients is that it can be directly compressed into self-binding tablets that rapidly disintegrate when in contact with water. This widely used ingredient is prepared by partial depolymerization of cellulose obtained as a pulp from fibrous plant material, with dilute mineral acid solutions. After hydrolysis, the hydrocellulose thus obtained is purified by filtration, and the slurry is spray-dried to form a tasteless, odorless white, dry crystalline powder of wide-size distribution porous particles. Another process for preparing microcrystalline cellulose is described in US Patent No. 3,141,875. This reference describes how cellulose is subjected to the hydrolytic action of hydrochloric acid at boiling temperatures, so that amorphous cellulosic material can be removed, and crystalline cellulose aggregates are formed. The aggregates are collected by filtration, washed with water and aqueous ammonia, and disintegrated into small fragments, often referred to as cellulose micelles, by vigorous mechanical means such as mixers. Microcrystalline cellulose is commercially available in various grades, ranging in particle size from 20 to 200 microns.

IS 2 199 281 T3

Microcrystalline cellulose is insoluble in water, but the material has the ability to direct fluid into a tablet by capillary action. The tablets then swell on contact with it, and thus the microcrystalline cellulose acts as a disintegrating agent. The material possesses sufficient self-lubricating qualities to allow a lower lubricant level when compared to other excipients.

Typically, microcrystalline cellulose has a bulk density of 0.28 g / cm3 and a bleed density of about 0.43 g / cm3. Handbook of Pharmaceutical Excipients, pages 53-55.

When used in pharmaceutical applications, microcrystalline cellulose is typically used as a tablet binder / diluent in wet granulation and direct compression formulations, in amounts of 5-30% 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 insolubilizing silica dissolved in a sodium silicate solution. When obtained by adding sodium silicate to a mineral acid, the product is called silica gel. When obtained by destabilizing a sodium silicate solution in such a way as to result in very fine particles, the product is called precipitated silica. Silicon dioxide is insoluble in water. Before the present invention, silicon dioxide, and in particular colloidal silicon dioxide, was used mainly as a slip and non-stick agent in the preparation and encapsulation of tablets, promoting the plasticity 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

Pharmaceuticals), 1986, American Pharmaceutical Association, page 255. This is in part due to the fact that increasing the amount of silicon dioxide in the mixture to be tabletted causes the mixture to flow too well, causing a a phenomenon known to tabletting experts as "flooding". If the mixture flows too well, a variable weight tablet with uneven content uniformity may result.

Those skilled in the art will appreciate that the name and / or process of preparation of the silicon dioxide used in the present invention does not determine the usefulness of the product. Rather, as mentioned above, it has surprisingly been discovered that it is the physical characteristics of silicon dioxide that are critical. In particular, silicon dioxide having a relatively large particle size (and therefore a small surface area), such as silica gel, has been found to be not useful in the preparation of improved microcrystalline cellulose products. of the invention. The appended claims are considered to encompass all forms of silicon dioxide having a mean primary particle size of between 1 nm and 100 μη, and / or a surface area of 10 μm.2/ g at 500 m2/ g.

The silicon dioxide used in the invention is of the very small particle size variety. In the most preferred embodiments of the invention, the silicon dioxide used is colloidal silicon dioxide. Colloidal silicon dioxide is a sub-micron particle size fumed silica prepared by vapor phase hydrolysis (eg at 1110 ° C) of a silicon compound, eg silicon tetrachloride. The product itself is a fluffy, light, loose, bluish-white, odorless, tasteless, amorphous sub-micron particle size powder that is commercially available from many sources, including Cabot Corporation (under the name commercial cabo-sil); Degussa, Inc. (tradename Aerosil); EI DuPont & Co.; And silicon dioxide from W.R. Grace & Co. Colloidal is also known as colloidal silica, fumed silica, light anhydrous silicic acid, silicic anhydride, and fumed silicon dioxide, among others. By varying manufacturing procedures, a variety of commercial colloidal silicon dioxide-based products can be produced. These modifications do not affect the silica content, specific gravity, refractive index, color or amorphous form. However, these modifications are known to change the particle size, surface areas, and bulk density of colloidal silicon dioxide products.

The surface area of the preferred type of silicon dioxide used in the invention ranges from 50 µm2/ g and 500 m2/ g. The mean primary particle diameter of the preferred type of silicon dioxide used in the invention ranges from 5 nm to 50 nm. However, in commercial colloidal silicon dioxide products, these particles agglomerate or aggregate to varying limits. The bulk density of the preferred class of silicon dioxides used in the invention ranges from 20 g / l to 100 g / l.

Commercially available colloidal silicon dioxide products have, for example, a BET surface area ranging from 50 ± 15 μm2/ g (Aerosil 0X50) and 400 ± 20 m2/ g (Cab-O-Sil S-17) or 390 ± 40 m2/ g (Cab-O-Sil EH-5). Commercially available particle sizes range from a nominal particle diameter of 7 nm (e.g. CabO-Sil S-17 or Cab-O-Sil EH-5) to a mean primary particle size of 40 nm (Aerosil OX50) . The density of these products ranges from 72.0 ± 8 g / l (Cab-O-Sil S-17) to 36.8 g / l (for example, Cab-OSil M-5). The pH of these products at 4% aqueous dispersion ranges between pH 3.5-4.5. These commercially available products are described solely for the purpose of exemplifying the acceptable properties of the preferred class of silicon dioxides, and this description is not intended to limit the scope of the invention in any way whatsoever.

It has been found that, when the novel excipient of the invention uses colloidal silicon dioxide, the resulting excipient surprisingly provides substantially improved compressibility in preferred embodiments, even when compared to the compressibility of available normal microcrystalline cellulose. commercially "in stock" used in direct compression techniques.

In other embodiments of the present invention, it has been found that the compressibility of microcrystalline cellulose that is wet granulated is significantly improved by a greater range of silicon dioxide products. Thus, in the for6

ES 2 199 281 T3 further embodiment of the present invention in which it is not important to achieve an improvement in the overall compressibility of the microcrystalline cellulose (both used in wet granulation and in dry granulation), and the cellulose product microcrystalline is subjected to wet granulation, it has been found that the surface area of silicon dioxide can be as low as 50 μm2 / g, and the mean primary particle diameter can be as large as

100 μ / m. Such silicon dioxide products are also considered to be within the scope of the invention.

Both microcrystalline cellulose and silicon dioxide are substantially insoluble in water. Therefore, the particle size of these ingredients present in the well dispersed aqueous paste is directly related to the particle size of these two ingredients when they are introduced into the aqueous solution. There is no appreciable dissolution of any of the ingredients in the aqueous paste.

After obtaining a uniform mixture of the ingredients in the suspension, the suspension is dried to provide a plurality of microcrystalline cellulose-based excipient particles possessing enhanced compressibility.

In the spray drying process, the aqueous dispersion of microcrystalline cellulose and silicon dioxide is treated together with a sufficient volume of hot air to cause evaporation and drying of the liquid droplets. The highly dispersed pulp of microcrystalline cellulose and silicon dioxide is pumpable and capable of being atomized. It is sprayed into a stream of hot filtered air, which supplies the heat for evaporation and drives the dried product to a collection device. The air with the removed mixture is then discharged. The resulting spray-dried powder particles are approximately spherical in shape, and relatively uniform in size, thus possessing excellent plasticity. The co-processed product consists of microcrystalline cellulose and silicon dioxide in close association with each other. The enlargement of the resulting particles indicates that the silicon dioxide has integrated with the surface of the microcrystalline cellulose particles, or has partially coated them. When the amount of silicon dioxide, including the excipient, is greater than about 20% by weight with respect to microcrystalline cellulose, the silicon dioxide appears to substantially coat the surfaces of the microcrystalline cellulose particles. The exact relationship between the two excipient ingredients after co-processing has not yet been understood; however, for the purpose of description, the present invention discloses that the co-processed particles include an agglomerate of microcrystalline cellulose and silicon dioxide in intimate association with each other. By "intimate association" it is meant that the silicon dioxide has been integrated in some way with the microcrystalline cellulose particles, eg, by a partial coating of the microcrystalline particles, as opposed to the chemical interaction of the two ingredients. The term "intimate association" is therefore considered a synonym for "integrated" or "united", for the purposes of the present description. The co-processed particles are not necessarily uniform or homogeneous. Rather, when enlarged, for example by an electron microscope at 500x, the silicon dioxide at the preferred inclusion percentage appears to be an "edge coating".

In the present invention it is more preferred that microcrystalline cellulose and silicon dioxide are co-processed, resulting in an intimate association of these ingredients, rather than a combination, eg, as a dry mix. In preferred embodiments of the present invention, the aqueous pulp of microcrystalline cellulose and silicon dioxide is introduced into the spray dryer as a single aqueous medium. However, it is possible to introduce each ingredient separately, in the absence of a therapeutically active ingredient, into separate aqueous media, which are then combined.

In certain preferred embodiments of the present invention, the co-processing of the microcrystalline cellulose and silicon dioxide is accomplished by forming a well-dispersed aqueous paste of microcrystalline cellulose and silicon dioxide , and then drying the pulp and forming a plurality of excipient particles based on microcrystalline cellulose. Typically, microcrystalline cellulose is first added to an aqueous solution, so as to obtain a paste or suspension containing 0.5% to 25% microcrystalline cellulose as solids. Preferably, the paste or suspension contains 15% to 20% microcrystalline cellulose, and more preferably 17% to 19% microcrystalline cellulose. At this point, it is often desirable to adjust the pH of the pulp to approximately neutral pH with ammonium hydroxide, sodium hydroxide, and mixtures of these or the like. The suspension is kept under constant agitation for a sufficient time to ensure a uniform distribution of the solids before combining them with the silicon dioxide.

At this point, the silicon dioxide is added to the suspension or paste in amounts ranging from 0.1% to 20% by weight, relative to the amount of microcrystalline cellulose; Amounts between 0.5% and 10% are preferred, although especially preferred amounts are between 1.25% and 5% by weight. Preferably, the silicon dioxide is in colloidal form prior to addition to the CMC paste. The microcrystalline cellulose and colloidal silicon dioxide are well dispersed in the paste or suspension prior to drying and formation of the new particles.

It is preferred that the suspension is dried by spray drying techniques, as they are known in the art. However, other drying techniques can also be used, such as flake drying, ring drying, micron drying, rack drying, vacuum drying, radio frequency drying, and possibly microwave drying. The exact manner in which the suspension is dried is not believed to be critical for the microcrystalline cellulose / silicon dioxide particles to demonstrate enhanced compressibility after wet granulation.

Depending on the amount and type of drying, and the concentration of microcrystalline cellulose and silicon dioxide in 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

ES 2 199 281 T3 microcrystalline cellulose and silicon dioxide are combined as a dry mixture. The beneficial result obtained by combining these two materials is believed to be due to the fact that both materials are closely associated with each other.

The mean particle size of the integrated excipient of the present invention ranges from 10 microns to 1000 microns. Particle sizes of 10-500 microns are preferred, particle sizes of 30-250 microns are more preferred, and particle sizes of 40-200 microns are most preferred. Those skilled in the art will appreciate that drying of the microcrystalline cellulose and silicon dioxide suspension results in a random particle size distribution of the newly produced excipient. For example, if spray drying techniques are used, the final particle size will be affected by droplet size, temperatures, agitation, dispersion, air flow, atomization wheel speed, etc. Furthermore, it is within the scope of the invention to classify or mechanically alter dry particles according to particle size ranges based on their end uses. The particle size of the integrated excipient is not narrowly critical, the important parameter being that the mean particle size should allow the formation of a directly compressible excipient, which forms pharmaceutically acceptable tablets.

The new excipient has an apparent (dispersed) density ranging between 0.2 g / ml and 0.6 g / ml, and preferably between 0.35 g / ml and 0.55 g / ml. The new excipient has a bleed density ranging from 0.2 g / ml to 0.6 g / ml, and more preferably from 0.35 g / ml to 0.55 g / ml. The pH of the particles is most preferably approximately neutral, although it is possible to obtain granules having a pH of between 3.0 and 8.5. The moisture content of the excipient particles will range widely between 0.5% and 15%, preferably between 2.5% and 6%, and more preferably between 3.0% and 5% by weight.

Angle of repose is a measurement used to determine the flow characteristics of a powder. The angle of repose depends on the experiment and the experimenter, but in a comparative analysis, the new excipient is superior.

The new excipient of the invention is easy to slide and directly compressible. Thus, the excipient can be mixed in the desired ratio with an active agent and an optional lubricant (dry granulation), and then directly compressed into solid dosage forms. In preferred embodiments of the present invention, in which the silicon dioxide is colloidal silicon dioxide, the novel excipient, comprising the microcrystalline cellulose and the colloidal silicon dioxide integrated together represents an augmented microcrystalline cellulose, which possesses improved compressibility when compared to the quality of conventional commercially available microcrystalline celluloses.

Alternatively, all or part of the excipient may be wet granulated with the active ingredient. Representative wet granulation includes loading the new excipient particles into a suitable granulator, such as those available from Baker-Perkins, and granulating the particles together with the active ingredient, preferably using an aqueous liquid granulator. The granulating liquid is added to the mixture with stirring, until the powder mass acquires the consistency of wet snow, and is then wet sieved through a sieve of the desired mesh size, for example with an aperture size 12 to 16 mesh. The screened granulate is then dried, using a conventional drying apparatus, such as a convection oven, before performing a final screening. Additional dry screening is possible, using 40 to 200 mesh size sieves. These materials flowing through 40 to 60 mesh size sieves can be further ground prior to formulating the final tablet. The wet granulate thus obtained, which contains the new excipient, may be tableted, or otherwise placed in unit dosage form.

In certain preferred embodiments, a part of the total amount of the new excipient is wet granulated with the active ingredient, and then the additional part of the new excipient is added to the granulate. In still other embodiments, the additional part of the new excipient to be added to the excipient / active ingredient granulate can be replaced by conventional microcrystalline cellulose, or other excipients commonly used by those skilled in the art, depending of course on the requirements. of the particular formulation.

By virtue of the new excipient of the present invention, the amount of new excipient compared to the amount of microcrystalline cellulose that must be used in a wet granulation technique to obtain an acceptable solid dosage form is substantially reduced.

In other embodiments of the invention, additional material is added to the pulp of microcrystalline cellulose and silicon dioxide. These additional materials include non-siliceous metal oxides, starches, starch derivatives, surfactants, polyalkylene oxides, cellulose ethers, cellulose esters, and mixtures of these. These additives can be included in the desired amounts, which will be apparent to those skilled in the art.

In addition to one or more active ingredients, other pharmaceutically acceptable excipients (in the case of pharmaceuticals) or other additives known to those skilled in the art (in the case of non-pharmaceutical applications). For example, if desired, any generally accepted inert, soluble or insoluble pharmaceutical filler (diluent) (eg, a solid dosage form) can be included in the final product. Preferably, the inert pharmaceutical filler comprises a monosaccharide, a disaccharide, a polyhydric alcohol, inorganic phosphates, sulfates or carbonates, and / or mixtures of these. Examples of suitable inert pharmaceutical fillers include sucrose, dextrose, lactose, xylitol, fructose, sorbitol, calcium phosphate, calcium sulfate, calcium carbonate, "in stock" microcrystalline cellulose, mixtures of these, and the like.

Optionally, an effective amount of any generally accepted pharmaceutical lubricant, including calcium or magnesium soaps, may be added to the new excipient at the time the drug is added, or at any time before.

ES 2 199 281 T3 of compression into a solid dosage form. The lubricant can comprise, for example, magnesium stearate in any amount between 0.5-3% by weight of the solid dosage form.

The entire blend, in an amount sufficient to make a uniform series of tablets, can then be tableted in a tableting machine on a conventional production scale, at compression pressures normal for that machine, for example, 10,342 MPa-68,948 MPa (1500-10,000 pounds / square inch). The mixture should not be compressed to such an extent that subsequent difficulties in hydration arise when exposed to gastric fluids.

The average tablet size for round tablets is preferably between 50 mg and 500 mg, and for capsule-shaped tablets, from 200 mg to 2000 mg. However, other formulations prepared in accordance with the present invention may be appropriately shaped for other uses or positions, such as body cavities, eg, in the periodontium pocket, surgical dressings, vaginally. It is contemplated that for certain uses, eg antacid tablets, vaginal tablets and possibly implants, the tablet is larger.

In certain embodiments of the invention, the tablet is coated with a sufficient amount of a hydrophobic polymer to render the formulation capable of providing drug release such that a 12 or 24 hour formulation is obtained. The hydrophobic polymer included in the tablet coating can be the same or a different material, when compared to the hydrophobic polymeric material which is optionally granulated with the controlled release excipient. In other embodiments of the present invention, the tablet coating may comprise an enteric coating material in addition to or in place of the hydrophobic polymeric coating. Examples of suitable enteric polymers include cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate, methacrylic acid copolymer, shellac, hydroxypropylmethylcellulose succinate, cellulose acetate trimellitate, and mixtures of any of the foregoing. An example of a suitable commercially available enteric material is found under the trade name Eudragil.TM L 100-555.

In further embodiments, the dosage form may be coated with a hydrophilic coating in addition to or in place of the aforementioned coatings. An example of a suitable material that can be used for these hydrophilic coatings is hydroxypropylmethylcellulose (e.g. Opadry® commercially available from Colorcon, West Point, Pennsylvania).

The coatings can be applied in any pharmaceutically acceptable manner known to those of skill in the art. For example, in one embodiment the coating is applied through a fluidized bed or in a feed vat. For example, coated tablets can be dried at 60-70 ° C for 3-4 hours in a feed vat. The solvent for the hydrophobic polymer or enteric coating can be organic, aqueous, or a mixture of an organic and aqueous solvent. Organic solvents can be, for example, isopropyl alcohol, ethanol, and the like, with or without water.

Coatings that can optionally be applied to the compressed solid dosage form of the invention may comprise from 0.5% to 30% by weight of the final solid dosage form.

In further embodiments of the present invention, a support platform is applied to the tablets made in accordance with the present invention. Suitable support platforms are well known to those of skill in the art. For example, an example of a suitable support platform is set forth in US Patent No. 4,839,177. In that patent, the support platform partially covers the tablet, and consists of a polymeric material insoluble in aqueous liquids. The support platform can, for example, be designed to maintain its waterproof characteristics during transfer of the therapeutically active drug. The support platform can be applied to the tablets, for example, by compression coating on a portion of the tablet surface, by spray coating the polymeric materials comprising the support platform on all or part of the tablet surface , or by dipping the tablets in a solution of the polymeric materials.

The support platform can be, for example, 2 µm thick if applied by compression and 10 µm if applied by spray coating or dip coating. Generally, in embodiments of the invention in which a hydrophobic polymer or an enteric coating is applied to the tablets, the tablets are coated to a weight gain of between 1% and 20%, and in certain embodiments, preferably between 5% and 10%.

Materials useful 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 coating on the outer surface of the core of the tablet (without the hydrophobic or enteric coating). or as a second coating layer on the surface of the base coat comprising the hydrophobic or enteric coating material. This may be desirable when, for example, a loading dose of a therapeutically active agent is needed to produce therapeutically effective blood levels of the active agent, when the formulation is first exposed to gastric fluids. The loading dose of the drug included in the coating layer can be, for example, between 10% and 40% of the total amount of the drug included in the formulation.

The active agent (s) that can be incorporated with the new excipient described herein in the solid dosage forms of the invention include systemically active therapeutic agents, locally active therapeutic agents, disinfecting agents9

ES 2 199 281 T3 tes, chemical impregnants, cleaning agents, deodorizers, fragrances, dyes, animal repellants, insect repellants, fertilizing agents, pesticides, herbicides, fungicides, and plant growth stimulants, and the like.

A wide variety of therapeutically active agents can be used in conjunction with the present invention. Therapeutically active agents (eg, pharmaceutical agents) that can be used in the compositions of the present invention include water-soluble and insoluble drugs. Examples of such therapeutically active agents include antihistamines (eg, dimenhydrine, diphenhydramine, chlorpheniramine, and dexchlorpheniramine maleate), analgesics (eg, aspirin, codeine, morphine, dihydromorphone, oxycodone, etc.), non-steroidal anti-inflammatory agents (for example, naproxin, diclofenac, indomethacin, ibuprofen, sulindac), antiemetics (for example, metoclopramide), antiepileptics (for example, phenytoin, meprobamate and nitrezepam), vasodilators (eg, nifedipine, papaverine, diltiazem, and nicardyrine), antitussive agents and expectorants (eg, codeine phosphate), antiasthmatics (eg, theophylline), antacids, antispasmodics (eg, atropine, scopolamine, scopolamine ), antidiabetic drugs (eg insulin), diuretics (eg ethacrynic acid, bendrofluazide), antihypotensive (eg propranolol, clonidine), antihypertensive (eg clonidine, methyldopa), bronchodilators (eg, albuterol), steroids (eg, hydrocortisone, triamcinolone, prednisone), antibiotics (eg, tetracycline), antihemorrhoids, psychotropic hypnotics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, stimulants (including drug suppressants appetite such as phenylpropanolamine). The above 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 insoluble agents. The locally active agent (s) that can be included in the controlled release formulation of the present invention are understood to exert their effect in the environment of use, for example, the oral cavity, although in some cases the agent Active may possess systemic activity by absorption into the bloodstream through the surrounding mucosa.

Locally active agent (s) include antifungal agents (eg, amphotericin B, clotrimazole, mystatin, ketoconazole, miconazole, etc.), antibiotic agents (penicillins, cephalosporins, erythromycins, tetracycline, aminogrosides, etc.) , antiviral agents (for example, acyclovir, idoxuridine, etc.), elixirs (for example, chlorophyll), antitussive agents (for example, dextromethorphan hydrochloride), anticariogenic compounds (for example, metal salts of fluorides, sodium monofluorophosphate, stannous fluoride, amine fluorides), analgesic agents (for example, methyl salicylate, salicylic acid, etc.), local anesthetics (for example, benzocaine), oral antiseptics (for example, chlorhexidine and salts thereof, hexylresorcinol, dequalinium chloride, cetylpyridinium chloride), anti-inflammatory agents (for example, dexamethasone, betamethasone, prednisone, prednisolone, trimicinolone, hydrocortisone, etc.), hormonal agents (oestriol), antiplaque agents (eg, chlorhexidine and its salts, octenidine, and mixtures of thymol, menthol, methyl salicylate, eucalyptol), acid-reducing agents (eg, buffering agents such as dibasic potassium phosphate, calcium carbonate, sodium bicarbonate , sodium and potassium hydroxide, etc.), and dental desensitizers (eg, potassium nitrate). This list is not intended to be exclusive. Solid formulations of the invention may also include other locally active agents, such as flavorings and sweeteners. Generally, any of the flavorings and food additives described in Chemicals Used In Food Processing, pub 1274, of the National Academy of Sciences, pages 63-258 can be used. Generally, the final product can include 0.1% to 5% by weight of flavor.

The tablets of the present invention may also contain effective amounts of coloring agents, (for example, titanium dioxide, FD&C and D.&C dyes; see Kirk-Othmer Encyclopedia of Chemical Technology. Chemistry), Vol. 5, pp. 857-884, incorporated herein by reference), stabilizers, binders, odor regulating 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 can then fill capsules. The granulate can further be molded into shapes other than those typically associated with tablets. For example, the granulate, along with the active ingredient, can be molded to "fit" a specific area in a use environment (eg, on an implant).

Detailed description of the preferred embodiments

The following examples illustrate various aspects of the present invention.

The examples set out the preparation of various microcrystalline cellulose / silicon dioxide compositions. Tablets were prepared using each of the compositions, and the tensile strength of each of the tablet preparations was tested.

Examples 1-3

Preparation of co-processed compositions of

CMC-SiO2 and granulations of these

Example 1

Product CMC-SiO2 -5% w / w SiO2

A. Excipient particles

In this example, 6.2 kilograms of microcrystalline cellulose (CMC), (Mende3ll Co., Inc., Patterson, New York) were combined in the form of a wet cake, with 5.2 kilograms of water in a mixing tank, to form a paste containing approximately 15% solids. The pH was adjusted to approximately neutral, with approximately 3 ml of ammonium hydroxide. The paste was allowed to mix for 15 minutes before combining with 5% w / w silicon dioxide (SiO2), 200 m2/ g (CaboSil, PTG grade, available from Cabot Corp., Tuscola, Illinois). After allowing the materials to combine intimately, the paste was spray dried using a Niro Production Minor (Niro, Columbia, MD), with an inlet temperature of 215 ° C, outlet temperature of 125 ° C, speed of spinning atomiza10

ES 2 199 281 T3 dor 22,300 rpm, to give CMC-SiO2 with a mean particle size of 40-60 microns.

B. Granulation of excipient particles

The CMC-SiO2 particles obtained as a result of step 1A were granulated in a 10 liter Baker-Perkins high shear granulator for 3 minutes, using water as the granulating fluid. The resulting product was wet-sieved through a 12-mesh sieve, rack-dried in a convection oven for 2-3 hours to a moisture content of less than 5%, dry-sieved, and dried. sieved to obtain a mean particle size between 55 and 70 microns.

Example 2

Product CMC-SiO2 -20% w / w SiO2

The procedures of Examples 1A and B were repeated, except that 20% w / w silicon dioxide was used to form the product.

Example 3

Product CMC-SiO2 -2% w / w SiO2

In this example, the procedures of Examples 1A and B were repeated except that 2% w / w silicon dioxide was used to form the product. Example 4

Dry mix of CMC and SiO2 (5% w / w) Comparative

As a control, EMCOCEL microcrystalline cellulose was dry mixed.® 50M grade (Mendell Co., Inc.) and 5% w / w silicon dioxide, 200 m2/ g (CaboSil, PTG quality). Spray drying was not carried out, nor was any other treatment of the mixture carried out. However, the procedure of Example 1B was repeated.

Example 5

CMC processed without SiO2

As a second control, the procedure described in Example 1B was repeated, except that SiO2 was not added.

Example 6

In this example, series of compressed tablets were prepared using each of the products obtained as a result of Examples 1-5. Tablets were prepared using a Korsch tablet press with a punch size of 3/8 "and a target weight of 245 mg. The granulations were included in five different series of tableting, using compression forces of 6, 12, 18, 24 and 30 kN respectively. Ten tablets were weighed for each series, their diameter was measured, and their thickness and hardness were analyzed on the Erweka TBH 30 tablet hardness analyzer, to determine the compressibility of microcrystalline cellulose, measured as tensile strength. The results of the analyzes are graphically illustrated in Figure 1, as a comparison between tensile strength and compression force.

As can be seen from the graph, substantial benefits are obtained by co-processing CMC with SiO2. 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 compressive forces. In addition, the graph also illustrates that tablets prepared with a simple dry mix of CMC and

SiO2 (formulation of Example 4) failed to demonstrate acceptable tensile strengths. Thus, the co-processed CMC-SiO2 described in the present invention results in significant retention of the compressibility of CMC.

Examples 7-12

In these examples, compressed tablet products were prepared, containing 70% by weight CMC and 30% acetaminophen (APAP in the present invention). The products of Examples 7-9 are controls and were prepared without the co-processed CMCSiO2 of the present invention. The products of Examples 10-12, on the other hand, included 70% by weight of the new co-processed CMC-SiO2 and 30% APAP. Details concerning the preparation of each granulation product will be established later. A graphical comparison of tensile strength versus compression force is provided in Figure 2 for each compressed product.

Examples 7-12

Intragranulation and Extragranulation of APAP with CMC

In this example, tablets were prepared using CMC in stock (EMCOCEL® 50 M) according to the following formula:

<td>Ingredients</td><td>Weight (grams)</td>

<td>Deionized water</td><td> 165,8</td>

Half of the CMC was added to a 10 liter Baker-Perkins mixer, and mixed with all of the APAP. The mixer turbine was set at 200 rpm and the cutter at 1000 rpm. After one minute, water was added for 90 seconds using a rinse bottle. Then mixing was continued for an additional 90 seconds. The granulation was removed from the mixer, wet sieved 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 dry sieved through a 16 mesh screen, before being mixed for 10 minutes with the remaining portion of CMC in a 2 quart V-mixer. The granulation was removed from the mixer and compressed according to the procedure to be described below.

Tablet strength analysis

In order to prepare tablets for the formulations of Examples 7, 8, 10 and 11, the following procedure was followed:

The wet granulation products were weighed and mixed in a 2 quart V-mixer for 5 minutes with 0.2% PruvTM (Sodium stearyl fumarate, available from Mendell Co.,

Inc.).

Five series of tableting were carried out, with compression forces of 5, 10, 15, 20 and 25 kN respectively, using a Korsch tablet press with a punch size of 3/8 ". and a target weight of 245 mg. Ten tablets were chosen for each strength

ES 2 199 281 T3 compression and were used in the experiment set out in Example 13.

Example 8

Wet granulation of APAP with CMC In this example, only wet granulation or intra-granulation step as described above was carried out. The formulation was prepared according to the following formula, using CMC in stock EMCOCEL® 50 M:

<td>Ingredients</td><td>Weight (grams)</td>

<td>Deionized water</td><td> 170,1</td>

The CMC was added to a 10 liter Baker-Perkins mixer, and mixed with the APAP. The mixer turbine was set at 200 rpm and the cutter at 1000 rpm. After one minute, water was added for 90 seconds using a rinse bottle. Then, mixing was continued for an additional 90 seconds. The granulation was removed from the mixer, wet sieved 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. Then, the granulation was dry sieved through a 16 mesh screen, and tablets were formed according to the procedure described in Example 7. Example 9

Direct Compression Formulation of APAP with CMC

A direct compression formulation was prepared so that the tablets contained 70% CMC in stock EMCOCEL® 50 M and 30% APAP by weight. The tablets were prepared according to the following formula:

<td>Ingredients</td><td>Weight (grams)</td>

CMC and APAP were combined in a V-mixer and mixed for 15 minutes. Then Pruv was added and mixing was continued for another 5 minutes. The granulation was removed, and five separate series of tableting were carried out, with compression forces of 5, 10, 15, 20 and 25 kN respectively, using a Korsch tablet press. The punch size of the tablet press was 0.95 cm (3/8 ") and the target weight was 245 mg. Ten tablets were used for each compression force in the experiment set out in Example 13.

Example 10

Wet granulation of APAP with co-processed CMC-SiO2 (5% w / w)

In this example, tablets were prepared by granulation with the co-processed CMC (5% w / w SiO2) from Example 1A. The tablet granulation was prepared according to the following formula:

<td>Ingredients</td><td>Weight (grams)</td>

<td>Deionized water</td><td> 170,1</td>

The CMC-SiO2 was added to a 10 liter BakerPerkins mixer, and mixed with the APAP. The mixer turbine was set at 200 rpm and the cutter at 1000 rpm. After one minute, water was added for 90 seconds using a rinse bottle. Then mixing was continued for an additional 90 seconds. The granulation was removed from the mixer, wet sieved through a 12 mesh sieve and then 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 dry sieved through a 16 mesh screen, and tablets were formed according to the procedure described in Example 7.

Example 11

Intra- and extra-granulation of APAP with CMC-SiO2 (5% w / w)

A compressed tablet granulation was prepared according to the following formula:

<td>Ingredients</td><td>Weight (grams)</td>

<td>Deionized water</td><td> 165,8</td>

Half of the co-processed CMC-SiO2 (prepared as in Example 1A) was added to a 10 liter Baker-Perkins mixer, and combined with the APAP. The mixer turbine was set at 200 rpm and the cutter at 1000 rpm. After one minute, water was added for 90 seconds using a rinse bottle. Then mixing was continued for an additional 90 seconds. The granulation was removed from the mixer, wet sieved 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 dry screened through a 16 mesh sieve, before being mixed for 10 minutes with the remaining portion of the CMC-SiO2 co-processed in a 2 quart V-mixer, removed from the mixer and tablets were formed according to the procedure described in Example 7.

Example 12

Direct compression formulation of APAP with

CMC-SiO2 (5% w / w)

A direct compression formulation similar to that established in Example 9 was carried out, except that the tablets were prepared to contain the co-processed CMC-SiO2 from Example 12

ES 2 199 281 T3 plo 1A. The tablet granulation was prepared according to the following formula:

<td>Ingredients</td><td>Weight (grams)</td>

As in Example 9, five separate series of tableting were carried out, with compression forces of 5, 10, 15, 20 and 25 kN respectively, using a Korsch tablet press (punch size: 0, 95 cm (3/8 ") and target weight: 245 mg). Ten tablets were used for each compression force to carry out the experiment set out in Example 13.

Example 13

Tablet strength analysis

Ten tablets from each compression force series were weighed for each formulation prepared in Examples 7-12, their diameter was measured, and thickness and hardness were analyzed on the Erweka TBH 30 Tablet Hardness Analyzer to determine the compressibility of the tablet. microcrystalline cellulose. The results are graphically illustrated in Figure 2A, as a comparison between tensile strength and compression force.

Referring to Figure 2, it can be seen that the compressed tablets made with co-processed CMC-SiO2 of the invention possess relatively high tensile strengths when compared to CMC in stock. The advantages of co-processed CMC-SiO2 are clearly seen in both direct compression and wet granulation formulations, and especially in wet granulation products.

Examples 14-16

Diatomaceous earth

In these examples, the co-processing procedure described in Example 1A was repeated, except that a 40 micron particle size diatomaceous earth was used as the source of SiO2 (JT Baker, Phillipsburg, NJ).

<td>Example</td><td>Diatomaceous earth (% weight)</td>

The resulting granules prepared according to Example 1B were tableted according to the same procedure described in Example 6, and their tensile strength was evaluated. The products of inventive Example 3 (CMCSiO2 2% w / w) and inventive Example 5 (CMC alone) were included in Figure 3 for comparison purposes.

Referring now to Figure 3, it can be appreciated that although the retention of compressibility achieved by co-processing diatomaceous earth is not as good as that provided by colloidal SiO2, which has surface areas of 200 m2/ g, the co-processed CMC-diatomaceous earth, however, demonstrated improved compressibility in wet granulation formulations.

Examples 17-19

Silica gel

In these examples, the co-processing procedure described in Example 1A was repeated, using 200 micron particle size silica gel (VWRCorp., Piscataway, NJ) as the source of SiO2.

<td>Example</td><td>Silica gel (% weight)</td>

The resulting granules prepared according to Example 1B were tableted according to the same procedure described in Example 6, and their tensile strength was evaluated. The products of Inventive Example 3 (CMCSiO2 2% w / w) and Inventive Example 5 (CMC alone) were included in Figure 4 for comparative purposes.

Regarding Figure 4, it can be seen that although the retention of compressibility achieved when co-processing with silica gel is much lower than that provided by colloidal SiO2, which has surface areas of 200 m2/ g. In fact, CMC co-processed with silica gel exhibited compressibility properties approximately equal to those of stock CMC in wet granulation formulations. Examples 20-22

HS-5 grade silicon dioxide

In these examples, the co-processing procedure described in Example 1 was repeated, using HS-5 grade SiO2 with a surface area of 325 µm.2/ g (Cabot Corp., Tuscola, Illinois).

<td>Example</td><td>Silica gel (% weight)</td>

The resulting granules prepared according to Example 1B were tableted according to the same procedure described in Example 6, and their tensile strength was evaluated. The products of inventive Example 3 (CMCSiO2 2% w / w) and inventive Example 5 (CMC in stock) were included in Figure 5 for comparison purposes.

Referring now to Figure 5, the retention of compressibility achieved by co-processing with HS-5 is comparable to that obtained using SiO2, which has surface areas of 200 µm.2/ g.

Contents3

97 members in 19 offices

This recordMember, by publication datePriority claim9 more offices are in the list below

Priority claims2

Priority claims
Document	Office	Kind	Date
19950370576	United States of America	–	1995-01-09
37057695	United States of America	A	1995-01-09

Members97

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Document	Office	Kind
IL116674D0	Israel	D0	1996-05-14
IL116675D0	Israel	D0	1996-05-14
CA2183881A1	Canada	A1	1996-07-18
WO9621429A1	World Intellectual Property Organization (WIPO)	A1	1996-07-18
CA2183882A1	Canada	A1	1996-07-25
WO9622080A1	World Intellectual Property Organization (WIPO)	A1	1996-07-25
AU4759896A	Australia	A	1996-07-31
AU5019996A	Australia	A	1996-08-07
NO963732D0	Norway	D0	1996-09-06
NO963733D0	Norway	D0	1996-09-06
NO963733L	Norway	L	1996-09-06
FI963496A	Finland	A	1996-11-06
FI963497A	Finland	A	1996-11-06
NO963732L	Norway	L	1996-11-08
HU9602360D0	Hungary	D0	1996-11-28
HU9602361D0	Hungary	D0	1996-11-28
US5585115A	United States of America	A	1996-12-17
EP0749300A1	European Patent Office (EPO)	A1	1996-12-27
EP0752848A1	European Patent Office (EPO)	A1	1997-01-15
MX9603745A	Mexico	A	1997-07-31
MX9603746A	Mexico	A	1997-07-31
HU9602360A2	Hungary	A2	1997-08-28
HU9602361A2	Hungary	A2	1997-08-28
HUP9602360A2	Hungary	A2	1997-08-28
HUP9602361A2	Hungary	A2	1997-08-28
BR9605245A	Brazil	A	1997-09-16
BR9605329A	Brazil	A	1997-09-16
JPH10500426A	Japan	A	1998-01-13
US5725883A	United States of America	A	1998-03-10
US5725884A	United States of America	A	1998-03-10
US5741524A	United States of America	A	1998-04-21
EP0752848A4	European Patent Office (EPO)	A4	1998-11-04
AU698667B2	Australia	B2	1998-11-05
JPH10512862A	Japan	A	1998-12-08
US5858412A	United States of America	A	1999-01-12
US5866166A	United States of America	A	1999-02-02
AU708346B2	Australia	B2	1999-08-05
US5948438A	United States of America	A	1999-09-07
TW372874B	Taiwan Province of China	B	1999-11-01
CA2183881C	Canada	C	2000-08-01
US6103219A	United States of America	A	2000-08-15
CA2183882C	Canada	C	2000-08-22
US6106865A	United States of America	A	2000-08-22
IL116675A	Israel	A	2000-10-31
US6217909B1	United States of America	B1	2001-04-17
US2001001664A1	United States of America	A1	2001-05-24
EP0749300A4	European Patent Office (EPO)	A4	2001-09-05
HU9602360A3	Hungary	A3	2001-12-28
HU9602361A3	Hungary	A3	2001-12-28
HUP9602360A3	Hungary	A3	2001-12-28
HUP9602361A3	Hungary	A3	2001-12-28
IL139728D0	Israel	D0	2002-02-10
US6358533B2	United States of America	B2	2002-03-19
US6395303B1	United States of America	B1	2002-05-28
JP3300364B2	Japan	B2	2002-07-08
US2002142032A1	United States of America	A1	2002-10-03
TW505529B	Taiwan Province of China	B	2002-10-11
US6471994B1	United States of America	B1	2002-10-29
KR100332337B1	Republic of Korea	B1	2002-11-11
US2002182259A1	United States of America	A1	2002-12-05
US6521261B2	United States of America	B2	2003-02-18
EP1287823A1	European Patent Office (EPO)	A1	2003-03-05
EP0752848B1	European Patent Office (EPO)	B1	2003-05-07
AT239450T	Austria	T	2003-05-15
ATE239450T1	Austria	T1	2003-05-15
US2003096005A1	United States of America	A1	2003-05-22
IL116674A	Israel	A	2003-05-29
US2003099702A1	United States of America	A1	2003-05-29
DE69627934D1	Germany	D1	2003-06-12
IL139728A	Israel	A	2003-06-24
US2003147949A1	United States of America	A1	2003-08-07
PT752848E	Portugal	E	2003-08-29
DK0752848T3	Denmark	T3	2003-09-01
DE69627934T2	Germany	T2	2004-02-12
ES2199281T3This record	Spain	T3	2004-02-16
US6746693B2	United States of America	B2	2004-06-08
US2004265374A1	United States of America	A1	2004-12-30
US2005013861A1	United States of America	A1	2005-01-20
US6858231B2	United States of America	B2	2005-02-22
US6866867B2	United States of America	B2	2005-03-15
US2005147673A1	United States of America	A1	2005-07-07
US6936277B2	United States of America	B2	2005-08-30
NO320533B1	Norway	B1	2005-12-19
JP3728321B2	Japan	B2	2005-12-21
US2006008522A1	United States of America	A1	2006-01-12
NO321771B1	Norway	B1	2006-07-03
FI118754B	Finland	B	2008-03-14
US2009169621A1	United States of America	A1	2009-07-02
EP1287823B1	European Patent Office (EPO)	B1	2009-09-02
AT441403T	Austria	T	2009-09-15
ATE441403T1	Austria	T1	2009-09-15
EP0749300B1	European Patent Office (EPO)	B1	2009-10-14
AT445391T	Austria	T	2009-10-15
ATE445391T1	Austria	T1	2009-10-15
DE69638015D1	Germany	D1	2009-10-15
DE69638054D1	Germany	D1	2009-11-26
BR9605329B1	Brazil	B1	2010-02-23

Pharmaceutical excipient having improved compressibility

Abstract

Term

IS 2 199 281 T3

DESCRIPTION

IS 2 199 281 T3

Priority claims2

Members97

Numbers

Titles2

Classification