CA2183882C - Pharmaceutical excipient having improved compressibility - Google Patents
Pharmaceutical excipient having improved compressibility Download PDFInfo
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- CA2183882C CA2183882C CA002183882A CA2183882A CA2183882C CA 2183882 C CA2183882 C CA 2183882C CA 002183882 A CA002183882 A CA 002183882A CA 2183882 A CA2183882 A CA 2183882A CA 2183882 C CA2183882 C CA 2183882C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
- A61K9/2036—Silicones; Polysiloxanes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/906—Drug delivery
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/915—Therapeutic or pharmaceutical composition
Abstract
A microcrystalline cellulose-based excipient having improved compressibility, whether utilized in direct compression. Figure graphically shows a comparison of the tensile strength of tablets prepared in accordance with the invention and prior art tablets. Dry granulation or wet granulation formulations, is disclosed. The excipient is an agglomerate of microcrystalline cellulose particles and an effective amount of a surfactant, which in preferred embodiments is an anionic surfactant present in amounts ranging from about 0.1% to about 0.5 %, by weight of the microcrystalline cellulose, wherein the microcrystalline cellulose and surfactant are in intimate association with each other. One preferred anionic surfactant utilized in the novel excipient is sodium lauryl sulfate.
Description
2~.~~~~~
PT~ARMACEiITTCAL EaCTPTENT TTAVTNG
IMI'RO~'FD COMPRE IBTLTTY
BACKGROitND OF TTIE INVENTION
The present invention relates to a novel excipient for use in the manufacture of pharmaceuticals, and in particular, solid dosage forms such as tablets which 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 into the dosage form possess certain physical characteristics which lend themselves to processing in such a manner. Among other things, the material to be compressed must be free-flowing, must be lubricated, an<i, importantly, must possess sufficient cohesiveness to insure that the solid dosage form remains intact after compression.
In the case of tablets, the tablet is formed by pressure being applied to the material to be tabletted on a tablet press. A tablet press includes a lower punch which fits into a die from the bottom and a upper punch having a corresponding shape and dimension which enters the die cavity from the top after the tabletting material fills the die cavity. The tablet is formed by pressure applied on the lower and upper punches. The ability of the material to flow freely into the die is important in order to insure that there is a uniform filling of the die and a continuous movement of the material from the source of the material, e.g. a feeder hopper. The lubricity of the material is crucial in the preparation of the solid dosage forms since the compressed material must be readily ejected from the punch faces.
Since most drugs have none or only some of these properties, methods of tablet formulation have been developed in order to impart these desirable character-istics to the materials) which is to be compressed into a solid dosage form.
Typically, the material to be compressed into a solid dosage form includes one or more excipients which impart the free-flowing, lubrication, and cohesive properties to the drugs) which is being formulated into a dosage form.
Lubricants are typically added to avoid the materials) being tabletted from sticking to the punches. Connnonly used lubricants include magnesium stearate and WO 96122080 PCTlUS96100539 calcium stearate. Such lubricants are commonly included in the final tabletted product in amounts of less than l% by weight.
In addition to lubricants, solid dosage forms often conrain diluents. Diluents are frequently added in order to increase the bulk weight of the material to be tabletted in order to make the tablet 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 forms are binders. Binders are agents which impart cohesive qualities to the powdered material(s). Commonly used binders include starch, and sugars such as sucrose, lp glucose, dextrose, and lactose.
Disintegrants are often included in order to ensure that the ultimately prepared compressed solid dosage form has an acceptable disintegration rate in an environment of use (such as the gastrointestinal tract). Typical disintegrants include starch derivatives and salts of carboxymethylcellulose.
15 There are three general methods of preparation of the materials to be included in the solid dosage form prior to compression: (1) dry granulation;
(2) direct compression; and (3) v,~et granulation.
Dry granulation procedures may be utilized where one of the constituents, either the drug or the diluent, has sufficient cohesive properties to be tabletted. The Zp method includes mixing the ingredients, slugging the ingredients, dry screening, lubricating and finally compressing the ingredients.
In direct compression, the powdered materials) to be included in the solid dosage form is compressed directly without modifying the physical nature of the material itself.
The wet granulation procedure includes mixing the powders to be incorporated into the dosage form in, e.g.,,a twin shell blender or double-cone blender and thereafter adding solutions of a binding agent to the mixed powders to obtain a granulation. Thereafter, the damp mass is screened, e.g., in a 6- or 8-mesh screen and then dried, e.g., via tray drying, the use of a fluid-bed dryer, spray-dryer, radio-frequency dryer, microwave, vacuum, or infra-red dryer.
The use of direct compression is limited to those situations where the drug or active ingredient has a requisite crystalline structure and physical characteristics required for formation of a pharmaceutically acceptable tablet. On the other hand, it is well known in the art to include one or more excipients which make the direct compression method applicable to drugs or active ingredients which do not possess the requisite 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 tablet weight), it is necessary that the drugs) itself have sufficient physical characteristics (e.g., cohesiveness) for the ingredients to be directly compressed.
Typically, however, excipients are added to the formulation which impart good flow and compression characteristics to the material as a whole which is to be compressed. Such properties are typically imparted to these excipients via a pre-processing step such as wet granulation, slugging, spray drying, spheronization, or crystallization. Usel..l direct compression excipients include processed forms of cellulose, sugars, and dicalcium phosphate dehydrate, among others.
A processed cellulose, microcrystalline cellulose, has been utilized extensively in the pharmaceutical industry as a direct compression vehicle for solid dosage forms. Microcrystalline cellulose is commercially available under the tradename EMCOCELO from Edward Mendell Co., Inc. and as Avicelm from FMC Corp. Compared to other directly compressible excipients, microcrystalline cellulose is generally considered to exhil~~t superior compressibility and disin-tegration properties.
Another limitation of direct compression as a method of tablet manufacture is the size of the tablet. if the amount of active ingredient is high, a pharmaceutical formulator may choose to wet granulate the active with other excipients to attain an acceptably sized tablet with the desired compact strength. Usually the amount of filler/binder or excipierits needed in wet granulation is less than that required for WO 96122080 PCTIUS96f00539 21~~R8~
direct compression since the process of wet granulation contributes to some extent toward the desired physical properties of a tablet. Thus, despite the advantages of direct compression (such as reduced processing times and costs), wet granulation is widely used in the industry in the preparation of solid dosage forms. Many of those skilled in the art prefer wet granulation as compared to direct compression because this method has a greater probability of overcoming any problems associated with the physical characteristics of the various ingredients in the formulation, thereby providing a material which has the requisite flow and cohesive characteristics necessary to obtain an acceptahle solid dosage form.
l0 The popularity ofthe wet granulation process as compared to the direct compression process is based on at least three advantages. First, wet granulation provides the material to be compressed with better wetting properties, particularly in the case of hydrophobic drug substances. The addition of a hydrophilic excipient makes the surface of a hydrophobic drug more hydrophilic, easing disintegration 15 and dissolution. Second, the content uniformity of the solid dosage forms is generally improved. Via the wet granulation method, all of the granules thereby 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 20 problem with the direct compression method. Finally, the particle size and shape of the particles comprising the granulate to be compressed are optimized via the wet granulation process. This is due to the fact that when a dry solid is wet granulated, the binder "glues" particles together, so that they agglomerate in the granules which are more or less spherical.
25 Due to the popularity of microcrystalline cellulose, pharmaceutical fornutlators have deemed it desirable to include this excipient in a formulation which is wet granulated prior to tabletting. Unfortunately, currently-available microcrystalline cellulose does not hold to the typical principle that the amount of filler/binder needed in wet granulation is less than that in direct compression. It is WO 9GI22080 PCTlf1596ID0539 ..
known that the exposure of the microcrystalline cellulose to moisture in the wet 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 desires to prepare a solid oral dosage form of a high dose drug, and the use ofthe wet granulation technique is deemed necessary, the loss of compressibility of the microcrystalline cellulose dictates that a larger amount of this material may be needed to obtain an acceptably compressed final product. The additional amount of microcrystalline cellulose needed adds cost to the preparation, but more importantly adds bulk, making the product morn 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 there has been no satisfactory solution.
IS Attempts have been made to provide an excipient having high compressibility, a small bulk (high apparent density), and good flowability, while being capable of providing satisfactory disintegration of the solid dosage form, which is applicable to wet granulation as well as to dry granulation and direct compression methods for preparation of solid dosage forms.
For example, U.S. Patent No. 4,159,345 (Taken, et al.) describes an excipient which consists essentially ofa 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 linters, pulps and regenerated fibers. The microcrystalline cellulose is said to be a white cellulosic powder having an apparent specific volume of 1.6-3.I cc/g, a repose angle of 35°
to 4?°, a 200-mesh sieve residue oft to 80% by weight and a tapping apparent specific vol!mte of at least 1.4 ccJg.
In U.S. Patent No. 4,744,987 (Mehra, et al.), a particulate co-processed microcrystalline cellulose and calcium carbonate composition is described wherein r, 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 slurry of microcrystalline cellulose and calcium carbonate and then drying the slurry to yield a particulate product. The combination of these two ingredients is said to provide a lower cost excipient which has tabletting characteristics similar to those. .
of microcrystalline cellulose and which would satisfy a need for an economical excipient with good performance that is desired by the vitamin market.
European Patent Application EP 0609976AI (assigned to Asahi Kasei Kahushiki Kaisha) describes an excipienf comprising white powdery microcrystalline cellulose having an average degree of polymerization of from to 375, preferably from 190 to 210, and an acetic acid holding capacity of 280% or more, preferably from 290 to 370%. The ehcipient is said to exhibit high compactability and a high rate of disintegration and is said to be obtained by heat-treating an aqueous dispersion of purified cellulose particles, which has a solids 1 S ' content of 40% or less by weight, at 100°C or more, followed by drying, or by sub-jecting an aqueous dispersion of purified cellulose particles having a solids content of23% or less by weigi~t to thin qlm-forming treatment and drying the resultant thin film. The excipient is said to possess a high compressibility, and a good balance of compactability an<I rate of disintegration.
There still remains a need in the industry for a pharmaceutical excipient which possesses excellent compressibility whether utilized in a direct compression or wet granulation procedure.
OI3,IECTS AND SIIA1~1AR1' Or Tllr INVENTION
It is an object of the present invention to provide an excipient which is useful in a variety of applications, and which may be utilized in direct compression or wet granulation methods.
It is a Further object of the present invention to provide an excipient useful in direct compression methods which has improved compressibility relative to WO 96!22080 PCT/IJS96/00539 2I8~g8~
microcrystalline cellulose.
It is a further object of the present invention to provide an excipient useful in wet granulation methods which has improved compressibility relative to microcrystnlline cellulose.
It is a further object ofthe present invention to provide a free-flowing excipient which has excellent compressibility properties when utilized in direct com-pression or wet granulation methods, and which furthermore possesses pharma-ceutically 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 has improved compressibility relative to "off the-shelf' commercially available microcrystalline cellulose.
It is a further object of the present invention to provide a solid dosage form which includes one or more active ingredients and the improved microcrystalline cellulose excipient of the present invention.
It is a fiirther 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 exposed, e.g., to gastrointestinal fluid.
1n accordance with the above ~hjects 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 coprocessed microcrystalline cellulose and a surfactant.
Preferably, the surfactant is an ionic surfactant and most preferably, the surfactant is an anionic surfactant.
The amount of surfactant coprocessed with the microcrystalline cellulose is dependent, in part, upon the type of surfactant selected. Por purposes of the present invention, the amount is generally described as an effective amount, i.e. an amount which enhances or augments the compressibility of the microcrystalline cellulose. One particularly preferred surfactant is the anionic surfactant sodium WO 96!22080 PCT/U596/00539 lauryl sulfate (SLS). This surfactant is present in an amount of from about 0.1% to about 0.5% by weight of the microcrystalline cellulose. Preferably, however, the surfactant is present in amounts of from about 0.15 to about 0.4% and most preferably, in amounts ranging from about 0.2 to about 0.3% by weight.
The microcrystalline cellulose and surfactant are in intimate association with each other, and the surfactant portion of the agglomerate is in the form of an aqueous solution prior to being coprocessed with microcrystalline cellulose.
The present invention is further directed to an aqueous slurry useful in the preparation of a compressible excipient useful in dry and wet granulation formulation methods, comprising a mixture of microcrystalline cellulose and from about 0.1%to about 0.5% of a surfactant such as sodium lauryl sulfate, by weight relative to the microcrystalline cellulose. The solids content of the aqueous slurry is from about 0.5% to about 25%, by weight, preferably from about 15% to about 20% by weight, an<l most preferably from about 17% to about 19% by weight.
The present invention is further directed to a mixture of an active ingredients) and an excipient comprising a particulate agglomerate of coprocessed microcrystalline cellulose and a surfactant, the surfactant being present in an amount of from about 0.1 % to about 0.5% by weight based on the weight of the microcrystaliine cellulose. The microcrystaliine cellulose and surfactant are in intimate association with each other and the ratio of active ingredient to excipient is from about 1:99 to about 99:1, by weight.
The present invention is further directed to a granulate of an active ingredients) and the novel excipient described herein, wherein the active ingredients) and excipient have been subjected to a wet granulation procedure.
The present invention is also directed to a compressed solid dosage form comprising an active ingredients) and the novel excipient described herein, wherein the active ingredients) and excipient have been directly compressed into the solid dosage form or have been subjected to a wet granulation procedure and thereafter compressed into the solid dosage form. The compressed solid dosage form WO 96f22080 PCTlUS96/00539 provides a suitable immediate release dissolution profile of the active ingredients) when exposed to aqueous solutions during in-vitro dissolution testing, and provides a release of drug in an environment of use which is considered bioavailable.
In 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 of maintaining and/or enhancing the compressibility of microcrystalline cellulose. The method includes forming an aqueous slurry containing a mixture of microcrystalline cellulose and a surfactant, and drying the slurry to obtain microcrystalline cellulose-based excipient particles in which the surfactant has been integrated with the microcrystalline cellulose particles. Within this aspect of the invention, the slurry contains from about 0.5% to about 25% by weight microcrystalline cellulose, with amounts of from about 1 S% to about 20% being preferred. Furthermore, the surfactant included in the slurry is preferably an anionic surfactant such as SLS and is present in amounts ranging from about 0.1% to about 0.5% by weight of the MCC.
The novel excipient described herein is free-flowing, possesses excellent disintegration properties, and importantly, in certain embodiments possesses improved compressibility relative to normal "ofT=the-shelf' commercially available microcrystalline cellulose when directly compressed. The advantages of the novel excipient described herein are especially realized in pharmaceutical formulations prepared using wet granulation techniques. When utilized in wet granulation techniques, the novel excipient surprisingly provides a compressibility which is substantially improved in preferred embodiments in comparison to the compress-ibility of normal "off=the-shelf' commercially available microcrystalline cellulose used in wet granulation and is even comparable to "ofF the-shelf' microcrystalline cellulose used in direct compression techniques. In other embodiments, the novel excipient surprisingly provides a compressibility which is substantially superior to the compressibility of normal "off the-shelf" commercially available microcrystalline cellulose used in direct compression techniques.
The term "environn,_ntal fluid" is meant for purposes of the invention to encompass, e.g., an aqueous solution, or gastrointestinal fluid.
By "sustained release" it is meant for purposes of the invention that the therapeutically active medicament is released from the formulation at a controlled rate such that therapeutically beneficial blood levels (but below toxic levels) of the medicament are maintained over an extended period of time, e.g., providing a hour or a 24 hour dosage form.
By "bioavailable" it is meant for purposes of the invention that the therapeutically active medicament is absorbed from the sustained release formulation and becomes available in the body at the intended site of drug action.
By "surfactant" it is meant for purposes of the present invention that the material is a surface active agent which displays wetting, detergent or soap-like qualities as those agents are understood by those of ordinary skill in the art.
BRIEF DI:SCRTPTION OF TFIE DRA~'VINGS
The following drawings are illustrative of embodiments of the invention and are not meant to limit the scope of the invention as encompassed by the claims.
Figure 1 graphically shows a comparison of the tensile strength of tablets prepared in accordance with the invention and prior art tablets.
Figure 2 graphically shows a comparison of the tensile strength of tablets prepared in accordance with the invention to contain MCC coprocessed with SLS, tablets containing MCC coprocessed with docusate sodium and prior art tablets prepared to contain only unmodified MCC.
Figure 3 graphically illustrates a comparison of the tensile strength of tablets prepared using MCC coprocessed with polysorbate 40, tablets prepared with the novel SLS coprocessed MCC and tablets prepared with MCC alone.
Figure 4 graphically illustrates a comparison of the tensile strength of tablets prepared using MCC coprocessed with polydimethyl siloxane (simethicone) , tablets prepared using coprocessed MCC-SLS and prior art tablets prepared to contain WO 96/22080 PCTlUS96I00539 only unmodified MCC.
DETATLF DESCRIPTION OF THE INVENTION
Microcrystalline cellulose is a well-known tablet diluent, binder and disintegrant. Its chief advantage over other excipients is that it can be directly compressed into self binding tablets which disintegrate rapidly when placed into water. This widely-used ingredient is prepared by partially depolymerizing cellulose obtained as a pulp from fibrous plant material with dilute mineral acid solutions.
Following hydrolysis, the hydrocellulose thereby obtained is purified via filtration and an aqueous slurry is spray dried to form dry, white odorless, tasteless crystalline powder of porous particles ofvarir:us sizes. Another method of preparing microcrystalline cellulose is disclosed in U.S. Patent No. 3,141,875. This reference discloses subjecting cellulose to the hydrolytic action of hydrochloric acid at boiling temperatures so that 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 called cellulose crystallites by vigorous mechanical means such as a blender.
Microcrystalline cellulose is commercially available in several grades which range in average particle size from 20 to 200 microns.
Microcrystalline cellulose is water-insoluble, but the material has the ability to draw fluid into a tablet ! capillary action. The tablets then swell on contact and the microcrystalline cellulose thus acts as a disintegrating agent. The material has sufficient self lubricating qualities so as to allow a lower level of lubricant as compared to other excipients.
Typically, microcrystalline cellulose has an apparent density of about 0.28 g/cm' and a tap density of about 0.43 g/cm'. ~ndbook of Pharmaceutical Exci ail ents. pages 53-55.
When utilized in pharmaceutical applications, microcrystalline cellulose is typically used as a tablet binder/diluent in wet granulation and direct compression ,,..
. .
formulations in amounts of 3-30% of the formulation, or more. However, it is known to use more or less microcrystalline cellulose in pharmaceutical products, depending upon the requirements of the formulation.
The surfactants which may be used in the present invention generally include all pharmaceutically-acceptable surfactants. Preferably, however, the surfactant is .
an ionic surfactant and most preferably, the surfactant is an anionic surfactant.
Suitable pharmaceutically-acceptable anionic surfactants include, for example, those containing carboxylate, sulfonate, and sulfate ions. Those containing carboxylate ions are sometimes referred to as soaps and are generally prepared by saponification lp of natural fatty acid glycerides in alkaline solutions. The most common canons associated with these surfactants are sodium, potassium, ammonium and triethanolamine. The chain length of the fatty acids range from 12 to 18.
Although a large number of alkyl sulfates are available as surfactants, one particularly preferred surfactant is sodium lauryl sulfate.
In the pharmaceutical arts, sodium lauryl sulfate has been used as an emulsifying agent in amounts of up to about 0.1°~o by weight of the formulation. It is not believed that surfactants such as SLS have been included in coprocessed MCC compositions. Moreover, it is not believed that surfactants have been used in the amounts described herein to improve the compressibility of MCC especially in 2p wet granulations.
Sodium lauryl sulfate is a water-soluble salt, produced as a white or cream powder, crystals, or flakes and is used as a wetting agent and detergent. Also known as dodecyl sodium sulfate, SLS is actually a mixture of sodium alkyl sulfates consisting chiefly of sodium lauryl sulfate. Sodium lauryl sulfate is also known as sulfuric acid monododecyl ester sodium salt. Furthermore,.sodium lauryl sulfate is readily available from commercial sources such as Sigma or Aldrich in both solid form and as a solution. The solubility of SLS is about 1 gm per 10 ml/water.
The fatty acids of coconut oil, consisting chiefly of lauric acid, are catalytically hydrogenated to form the corresponding alcohols. The alcohols are then esterified with sulfuric acid (sulfated) and the resulting mixture of alkyl bisulfates (alkyl sulfuric acids) is converted into sodium salts by reacting with alkali under controlled conditions of pH.
Alternative anionic surfactants include, without limitation, alkyl carboxylates, acyl lactylates, alkyl ether carboxylates, N-acyl sarcosinates, polyvalent alkyl carbonates, N-acyl glutamates, fatty acid, polypeptide condensates and sulfuric acid esters.
In other aspects of the invention amphoteric (amphipathic/amphiphilic surfactants), non-ionic surfactants and/or cationic surfactants are included in the coprocessed compositions of the invention. These alternative surfactants can be included to replace some or even all of the preferred anionic surfactant. It is preferred, however, that the surfactant comprise an anionic surfactant.
Suitable pharmaceutically-acceptable non-ionic surfactants such as, for example, polyoxyethylene compounds, lecithin, ethoxylated alcohols, ethoxylated esters, ethoxylated amides, polyoxypropylene compounds, propoxylated alcohols, ethoxylated/propoxylated block polymers, propoxylated esters, alkanolamides, amine oxides, fatty acid esters of polyhydric alcohols, ethylene glycol esters, diethylene glycol esters of polyhydric alcohols, ethylene glycol esters, diethylene glycol esters, propylene glycol esters, glycerol esters, polyglycerol fatty acid esters, SPAN's~ (e.g., sorbitan esters), TWEEN's~ (i.e., sucrose esters), glucose (dextrose) esters and simethicone.
Other suitable pharmaceutically-acceptable surfactants include acacia, benzalkonium chloride, cholesterol, emulsifying wax, glycerol monostearate, lanolin alcohols, lecithin, poloxamer, polyoxyethylene, and castor oil derivatives.
Those skilled in the art will further appreciate that the name and/or method of preparation of the surfactant utilized in the present invention is not determinative of the usefulness of the product. Rather, as previously mentioned, it has been surprisingly discovered that it is the physical characteristics of surfactants, especially those of the anionic class such as sodium lauryl sulfate, which are critical.
In ~~s~s~~
particular, it has been discovered that when an anionic surfactant such as SLS
is coprocessed .with microcrystalline cellulose in the amounts described herein, improved microcrystalline cellulose products q~the invention result.
When the novel excipient of the invention utilizes an anionic surfactant, it has been found that the resultant excipient product surprisingly provides a com-pressibility which is substantially improved in preferred embodiments even in comparison to the compressibility of normal "ofi-the-shelf' commercially available microcrystalline cellulose used in direct compression techniques.
In other embodiments of the present invention, it has been discovered that the compressibility of microcrystalline cellulose which is wet granulated is significantly improved by coprocessing the MfCC with an anionic surfactant such as sodium lauryl sulfate.
Since microcrystalline cellulose is substantially water insoluble, the particle size of this ingredient in the well-dispersed aqueous slurry is directly related to its particle size as it was introduced into the aqueous solution. Most surfactants, on the other hand, tend to be water soluble. Sodium lauryl sulfate, for example, is relatively soluble in water (I gllOml) and, therefore, dissolves in the aqueous slurry.
It should be understood, however, that the coprocessed products of the present invention are not solely limited to those which contain a dissolved surfactant. The ?0 contemplated compositions can also be prepared from slurries which contain a dispersion of the surfactant as well as the MCC.
After a uniform mixture of the ingredients is obtained in the suspension, the suspension is dried to provide a plurality of microcrystalline cellulose-based excipient particles having enhanced compressibility.
~5 In the spray-drying process, the aqueous dispersion of microcrystalline cellulose and surfactant is brouglU together with a sufficient volume of hot air to produce evaporation and drying of the liquid droplets. The higi~ly dispersed slurry of microcrystalline cellulose and surfactant is pumpable and capable ofbeing atomized. It is sprayed into a current of warm filtered air, which supplies the heat WO 96/22080 PCTlIJS96I00539 '~l ~~~82 for evaporation and conveys a dried product to a collecting device. The air is then exhausted with the removed moisture. The resultant spray-dried powder particles are approximately spherical in shape and are relatively tmiform in size, thereby possessing excellent flowability. The coprocessed product consists of microcrystalline cellulbse and surfactant in int?mate association with each other.
The exact relationship of the two ingredients of the excipients after coprocessing is not presently understood; however, for puiposes of description the coprocessed particles are described herein as including an agglomerate of microcrystalline cellulose and surfactant in intimate association with each other. By "intimate association", it is meant that the surfactant has in some manner been integrated with the microcrystalline cellulose particles, e.g., via a partial coating of the microcrystalline particles, as opposed to a chemical interaction of the two ingredients. The term "intimate association" is therefore deemed for purposes of the present description as being synonymous with "integrated" or "united". The I S coprocessed particles are not necessarily uniform or homogeneous.
It is most preferred in the present invention that the microcrystalline cellulose and SLS are coprocessed, resulting in an intimate association of these in-gredients, rather than being combined, e.g., as a dry mixture. In preferred embodiments of the present invention, the aqueous slurry of the microcrystalline cellulose and surfactant are introduced into the spray dryer as a single.
aqueous medium, However, it is possible to separately introduce each ingredient into separate aqueous media which are then combined. Other procedures for combining the microcrystalline cellulose and surfactant known to those skilled in the art are deemed to be equivalent to the spray-drying technique described above, and are further deemed to be encornpasse,. by the appended claims.
In certain preferred embodiments of the present invention, the coprocessing of the microcrystalline cellulose and SLS is accomplished by forming a well-dispersed aqueous slurry of microcrystalline cellulose in which the SLS has been dissolved, and thereafter drying the slurry and forming a plurality of microcrystalline 2~ 838~~
cellulose-based excipient particles. Typically, microcrystalline cellulose is first added to an aqueous solution so that a slurry or suspension containing from about 0.5% to about 25% microcrystalline cellulose in the form of solids is obtained.
Preferably, the slurry or suspension contains from about I S% to 20% microcrys-talline cellulose and most preferably from about 17% to about 19%
microcrystalline cellulose. At this stage, it is often desirable to adjust the pH of the slurry to about neutral with ammonium hydroxide, sodium hydroxide, and mixtures thereof or the like. The suspension is kept under constant agitation for a sufficient time to assure a uniform distribution of the solids prior to being combined with the SLS.
1 p At this point, the SLS is added to the suspension or slurry in amounts ranging from O.l% to about 0.5% by weight, based on the amount of microcrystalline cellulose, amounts from about 0.15% to about 0.4% are preferred while amounts of from about 0.2°ro to about 0.3% by weight are especially preferred. The SLS can be added to the suspension as either a solid or in solution form. The microcrystalline cellulose is thus well-dispersed in the slurry or suspension and the surfactant is dissolved therein prior drying and forming the novel particles. It will be understood that other useful surfactants can be used in like amounts or even greater amounts, i.e. up to 5% by weight or even more. The usable concentration range for the selected surfactant depends in part upon not only its molecular weiglu but also its degree of foaming, particularly when present in agitated slurries which will be spray dried to form the desired particulate. Thus, in those aspects of the invention where surfactants other than SLS are coprocessed with the microcrystalline cellulose, it is to be understood that the surfactant will be present in an amount which enhances the compressibility of the MCC and yet does not have a degree of foaming which would substantially inhibit spray drying.
It is preferred that the suspension be dried using spray-drying techniques, as they are known in the art. Other drying techniques, however, such as flash drying, ring drying, micron drying, tray drying, vacuum drying, radio-frequency drying, and possibly microwave drying, can also be used. The exact manner in which the suspension is dried is not believed to be critical for the microcrystalline cellu(ose/SLS particles to demonstrate enhanced compressibility after wet granulating.
Depending upon the amount and type of drying, the concentration of the S microcrystalline cellulose and SLS in the suspension, the novel compressible particles will have different particle sizes, densities, pH, moisture content, etc.
The particulate coprocessed product of the present invention possesses desirable performance attributes that are not present when the combination of microcrystalline cellulose and SLS and optionally present other surfactants are combined as a dry 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 each other. It has also been found that intimate association of MCC and other detergent-like materials such as simethicone, even when they are dissolved/dispersed in the aqueous solutions which form the MCC
slurry, fail to provide MCC with enhanced compressibility.
The average particle size of the integrated excipient of the present invention ranges from about 10 microns to about 1000 microns. Particle sizes of about 10-500 microns are preferred, particle sizes of about 30-250 microns are more preferred and particle sizes of about 40-200 microns are most preferred. It will be appreciated by those of ordinary skit( in the art that the drying of the micro-crystalline cellulose-SLS suspension results in a random size distribution of the novel excipient particles being produced. For example if spray drying techniques are used, droplet size, temperatures, agitation, dispersion, air flow, atomizer wheel speed, etc. will effect final particle size. Furthermore, it is within the scope of the invention to sort or mechanically alter the dried particles according to ranges of particle sizes depending upon end uses. The particle size of the integrated excipient is not narrowly critical, the important parameter being that the average size of the particle must permit the formation of a directly compressible excipient which forms pharmaceutically acceptable tablets.
W0 96122080 PCTlU596100539 The novel excipient has a bulk (loose) density ranging from about 0.2 g/ml to about 0.5 g/ml, and most preferably from about 0.22 g/ml to about 0.35 g/ml.
The novel excipient has a tapped density ranging from about 0.30 g/ml to about 0.70 g/ml, and most preferably from about 0.35 g/ml to about 0.60 g/ml. The pH
of the particles is most preferably about neutral, although granulates having a pH of from about 3.0 to about 8.5 are possible. The moisture content of the excipient particles will broadly range from about 0.5% to about 15%, preferably from about 2.5% to about 6%, and most preferably from about 3.0% to about 5% by weight.
The novel excipient of!he invention is free-flowing and directly compressible. Accordingly, the excipient may be mixed in the desired proportion with an active agent and optional lubricant (dry granulation), and then directly compressed into solid dosage forms. In preferred embodiments of the present invention wherein the surfactant is sodium lauryi sulfate, the novel excipient comprising the coprocessed microcrystalline cellulose and SLS integrated together represents an augmented microcrystalline cellulose having improved compressibility as compared to standard commercially available grades of microcrystalline cellulose.
Alternatively, all or part of the excipient may be subjected to a wet granulation with the active ingredient. A representative wet granulation includes loading the novel excipient particles into a suitable granulator, such as those available from Baker-T'erkins, and granulating the particles together with the active ingredient, preferably using an aqueous granulating liquid. The granulating liquid is added to the mixture with stirring until the powdery mass has the consistency of damp snow and then wet screened through a desired mesh screen, for example, having a mesh from about 12 to about 16. The screened granulate is then dried, using standard drying apparatus such as a convection oven before undergoing a final screening. Additional dry screening of this material is possible, such as by using screens of from about 40 to about 200 mesh. Those materials flowing through 40 and 60 mesh screens may be further ground prior to ultimate tablet formulation. The thus obtained granulate containing the novel excipient is now capable of undergoing tabletting or otherwise placed into a unit dosage form.
In certain preferred embodiments, a portion of the total amount of the novel excipient is wet granulated with the active ingredient, and thereafter the additional portion of the novel excipient is added to the granulate. In yet other embodiments, the additional portion of the novel excipient to be added to the excipient/active ingredient granulate may be substituted with conventional microcrystalline cellulose, .
or other excipients commonly used by those skilled in the art, depending of course upon the requirements ofthe particular formulation.
By virtue of the novel excipie~i of the present invention, the amount of the novel excipient compared to the amount of microcrystalline cellulose which must be used in a wet granulation technique to obtain an acceptable solid dosage form is substantially reduced.
In other embodiments ofthe invention, a further material is added to the slurry of microcrystalline cellulose and SLS. Such additional materials include ' silicon dioxides, non-silicon metal oxides, starches, starch derivatives, surfactants, polyalkylene oxides, cellulose ethers, celluloses esters and mixtures thereof.
These additives may be included in desired amounts which will be apparent to those skilled in the art.
In one preferred aspect of the invention, however, there are provided MCC-based compositions which contain not only a surfactant but also from about 0.1 to about 20% by weight silicon dioxide. The silicon dioxide utilized in this aspect of the invention is preferably of the very fine particle size variety.
In the most preferred embodiments of the invention, the silicon dioxide utilized is a colloidal silicon dioxide. Colloidal silicon dioxide is a submicron fumed silica prepared by the vapor-phase hydrolysis (e.g., at 1110° C) of a silicon compound, such as silicon tetrachloride. The product itself is a submicron, fluffy, light, loose, bluish-white, odorless and tasteless amorfuous powder which is commercially available from a number of sources, including Cabot Corporation (under the tradename Cab-O-Sil); Degussa, Inc. (under the tradename Aerosil); E.I. DuPont &:
Co.; and W.R. Grace & Co. Colloidal silicon dioxide is also known as colloidal silica, fumed silica, light anhydrous silicic acid, silicic anhydride, and silicon dioxide fumed, 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 conteht, specific gravity, refractive index, color or amorphous form.
However, these modifications are known to change the particle size, surface areas, and bulk densities of the colloidal silicon dioxide products.
The surface area ofthe preferred class of silicon dioxides utilized in the invention ranges from about 50 m=/gm to about 500 mv/gm. The average primary particle diameter of the preferred class of silicon dioxides utilized in the invention ranges from about 5 nm to about 50 nm. However, in commercial colloidal silicon dioxide products, these particles are agglomerated or aggregated to varying extents.
The bulk density of the preferred class of silicon dioxides utilized in the invention ranges from about 20 gll to about 100 g/1.
Commercially available colloidal silicon dioxide products have, for example, a BET surface area ranging from about 50 t 15 m'/gm (Aerosil OX50) to about 400 t 20 (Cab-O-Sil S-17) or 390 f 40 mv/gm (Cab-O-Sil ET-1-5). Commercially available particle sizes range from a nominal particle diameter of 7 nm (e.g., Cab-O-Sil S-17 or Cab-0-Sil ET-T-S) to an average primary particle size of 40 nm (Aerosil 0X50). The density of these products range from 72.0 f 8 g/I (Cab-.0-Sil S-17) to 3G.8 g/1 (e.g., Cab-O-Sil M-5). The pi-T of the these products at 4% aqueous !~~s-persion ranges from pHl 3.5-4.5. These commercially available products are described for exemplification purposes of acceptable properties of the preferred class of silicon dioxides only, and this description is not meant to limit the scope of the invention in any manner whatsoever. Thus, in embodiments of the present invention where an improvement in overall compressibility of the microcrystalline cellulose (whether utilized in wet granulation or dry granulation) is important, and the microcwstalline cellulose product is to be subjected to wet granulation, it has been discovered that coprocessing the MCC with SLS can provide improvements in compressibility.
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 (for non-pharmaceutical applications) can be added to the novel excipient prior to preparation of the final product. For example, if desired, any generally accepted soluble or insoluble inert pharmaceutical fitter (diluent) material can be included in the final product (e.g., 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, "off the-shelf' microcrystalline cellulose, mixtures thereof, and the like.
An effective amount of any generally accepted pharmaceutical lubricant, including the calcium or magnesium soaps may optionally be added to the novel excipient at the time the medicament is added, or in any event prior to compression into a solid dosage form. The lubricant may comprise, for example, magnesium stearate in any amount of about 0.5-3% by weight of the solid dosage form.
The complete mixture, in an amount sufficient to make a uniform batch of tablets, may then subjected to tabletting in a conventional production scale tabletting machine at normal compression pressures for that machine, e.g., about 1500-10,000 Ibs/sq in. 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 tablet size for round tablets is preferably about 50 mg to 500 mg and for capsule-shaped tablets about 200 mg to 2000 mg. However, other formulations prepared in accardance with the present invention may be suitably shaped for other uses or locations, such as other bodv cavities, e.g., periodontal pockets, surgical wounds, vaginally. It is contemplated that for certain uses, e.g., antacid tablets, vaginal tablets and possibly implants, that the tablet will be larger.
In certain embodiments of the invention, the tablet is coated with a sufficient WO 96!22080 PCTIU596100539 amount of a hydrophobic polymer to render the formulation capable of providing a release of the medicament such that a l2~or 24 hour formulation is obtained.
The hydrophobic polymer which included in the tablet coating may be the same or different material as compared to the hydrophobic polymeric material which is optionally granulated with the sustained release excipient. In other embodiments of the present invention, the tablet coating may comprise an enteric coating material in addition to or instead or the hydrophobic polymer 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 available under the trade name EudragitT"~ L 100-555.-In further embodiments, the dosage form may be coated with a hydrophilic coating in addition to or instead of the above-mentioned coatings. An example of a suitable material which may be used for such a hydrophilic coating is hydroxy-propylmethylcellulose (e.g., Opadry~, 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 pan. For example, the coated tablets may be dried, e.g., at about GO-70° C for about 3-4 hours in a coating pan.
The solvent for the hydrophobic polymer or enteric coating may be organic, aqueous, or a mixture of an organic and an aqueous solvent. The organic solvents may be, e.g., isopropyl alcohol, ethanol, and the like, with or without water.
The coatings which may be optionally applied to the compressed solid dosage form of the invention may comprise from about 0.5% to about 30% by weight of the final solid dosage form.
In additional embodiments of the present invention, a support platform is applied to the tablets manufactured in accordance with the present invention.
Suitable support platforms are well known to those skilled in the art. An example of suitable support platforms is set forth, e.g., in U.S. Patent No. 4,839,177.
In that patent, the support platform partially coats 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 may be applied to the tablets, e.g., via compression coating onto part of the tablet surface, by spray coating the polymeric materials comprising the support platform onto all or part of the tablet surface, or by immersing the tablets in a solution of the polymeric materials.
The support platform may have a thickness of, e.g., about 2 mm if applied by compression, and about 10 ~,m if applied via spray-coating or immersion-coating.
Generally, in embodiments of the invention wherein a hydrophobic polymer or enteric coating is applied to the tablets, the tablets are coated to a weight gain from about 1% to about 20%, and in certain embodiments preferably from about 5% to about 10%.
Material useful in the hydrophobic coatings and support platforms of the present invention include derivatives of acrylic acid (such as esters of acrylic acid, methacrylic acid, and copolymers thereof) celluloses and derivatives thereof (such as ethylcellulose), polyvinyl alcohols, and the like.
In certain embodiments of the present invention, the tablet core includes an additional dose of the medicament included in either the hydrophobic or enteric coating, or in an additional overcoating coated on the outer surface of the tablet core (without the hydrophobic or enteric coating) or as a second coating layer coated on the surface of the base coating comprising the hydrophobic or enteric coating material. This may be desired when, for example, a loading dose of a therapeutically active agent is needed to provide therapeutically effective blood levels of the active agent when the formulation is first exposed to gastric fluid. The loading dose of medicament included in the coating layer may be, e.g., from about 10% to about 40% of the total amount of medicament included in the formulation.
The active agents) which may be incorporated with the novel excipient described herein into solid dosage forms invention include systemically active therapeutic agents, locally active therapeutic agents, disinfecting agents, chemical impregnants, cleansing agent, deodorants, fragrances, dyes, animal repellents, insect repellents, 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. The therapeutically active agents (e.g.
pharmaceutical agents ) which may be used in the compositions of the present invention include both water soluble and water insoluble drugs. Examples of the such therapeutically active 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 (e.g., metoclopramide), anti-epileptics (e.g., phenytoin, meprobamate and nitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardirine), anti-tussive agents and expectorants (e.g., codeine phosphate), anti-asthmatics (e.g., theophylline), antacids, anti-spasmodics (e.g., atropine, scopolamine), antidiabetics (e.g., insulin), diuretics (e.g., ethacrynic acid, bendrofluazide), anti-hypotensives (e.g., propranolol, clonidine), antihypertensives (e.g., clonidine, methyldopa), bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline), antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine). The above list is not meant to be exclusive.
A wide variety of locally active agents can be used in conjunction wih the novel excipient described herein, and include both water soluble and water insoluble agents. The locally active agents) which may be included in the controlled release formulation of the present invention is intended to exert its effect in the environment of use, e.g., the oral cavity, although in some instances the active agent may also have systemic activity via absorption into the blood via the surrounding mucosa.
The locally active agents) include antifungal agents (e.g., amphotericin B, clotrimazole, nystatin, ketoconazole, miconazol, etc.), antibiotic agents (penicillins, cephalosporins, erythromycin, tetracycline, aminoglycosides, etc.), antiviral agents (e.g., acyclovir, idoxuridine, etc.), breath fresheners (e.g., chlorophyll), antitussive agents (e.g., dextromethorphan hydrochloride), anti-cariogenic compounds (e.g., metallic salts of fluoride, sodium monofluorophosphate, stannous fluoride, amine fluorides), analgesic agents (e.g., methylsalicylate, salicylic acid, etc.), local anesthetics (e.g., benzocaine), oral antiseptics (e.g., chlorhexidine and salts thereof, hexylresorcinol, dequalinium chloride, cetylpyridinium chloride), anti-inflammatory agents (e.g., dexamethasone, betamethasone, prednisone, prednisolone, triamcinolone, hydrocortisone, etc.), hormonal agents (oestriol), antiplaque agents (e.g., methylsalicylate, eucalyptol), acidity reducing agents (e.g., buffering agents such as potassium phosphate dibasic, calcium carbonate, sodium bicarbonate, sodium and potassium hydroxide, etc.) and tooth desensitizers (e.g., potassium nitrate). This list is not meant to be exclusive. The solid formulations of the invention may also include other locally active agents, such as flavorants and sweeteners. Generally any flavoring or food additive such as those described in Chemicals Used in Food Processing, pub 1274 by the National Academy of Sciences, pages 63-258 may be used. Generally, the final product may include from about 0.1%
to about 5% by weight flavorant.
The tablets of the present invention may also contain effective amounts of coloring agents, (e.g., titanium dioxide, F.D. & C. and D. & C. dyes; see the Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 5, pp. 857-884), stabilizers, binders, odor controlling agents, and preservatives.
Alternatively, the novel excipient can be utilized in other applications wherein it is not compressed. For example, the granulate can be admixed with an active ingredient and the mixture then filled into capsules. The granulate can further be molded into shapes other than those typically associated with tablets. For S example, the granulate together with active ingredient can be molded to "fit" into a particular area in an environment of use (e.g., an implant). All such uses would be contemplated by those skilled in the art and are deemed to be encompassed within the scope of the appended claims.
nETAII~EII DESCRIPTION OF TIfE PREFERRED EM130DIMENTS
The following examples illusu,ae various aspects of the present invention.
Thoy are not to be construed to limit the claims in any manner whatsoever.
The examples set forth the preparation of various microcrystalline cellulose/
anionic surfactant compositions. Tablets were prepared using each of the compositions and each of tablet preparations was tested for tensile strength.
EXAMPLES l-3 PREPARATION OF COPROCESSED MCC-SI,S COMPOSITIONS AND
G.RANULATIQNS TI(EREOF
14TCC-SLS Product - 0.25~/. w/w SL,S
A. EXCIPIENT PARTICLES
In this example, about 6.2 kilograms of microcrystalline cellulose (hICC), (Mendell Co., Inc. Patterson, NY) in the form of a wet cake was combined with 5.2 kilograms of water in a mix rank to form a slurry containing about 15% solids.
The pFI
was adjusted to about neutral with about 3 ml of ammonitun hydroxide. The slurry was allowed to mix for about IS minutes before being combined with 0.25% w/w W 0 96122080 PCTlUS96100539 sodium lauryl sulfate (SLS) powder (available from Spectrum Chemical, Gardena, CA.) After allowing the materials to become intimately combined, the slurry was spray dried using a Nro Production Minor (Niro, Columbia, MD), inlet temperature-215 °C, outlet temperature-125°C, atomizer wheel speed 22,300 rpm, to provide MCC-SLS
having an average particle size of 40-60 microns.
B. GRANULATION OF EXCIPIENT PARTICLES
The MCC-SLS particles obtained as a result of step 1 A. were wet granulated in a Baker-Perkins 10 liter high-sheer granulator for 3 minutes using water as the granulating fluid. The resultant product was wet screened through a 12 mesh screen, tray dried in a convection oven for about 2-3 hours until a moisture content of less than 5% was obtained, dry screened and sieved to obtain an average particle size of From about 55 to about 70 microns.
MCC-SLS Products The processes of Example IA and B were repeated except that 0.5% w/w sodium lauryl sulfate was used to form the product of Example 2; 0.1 % w/w SLS
was used to form the product of Example 3; 0.2% w/w SL5 was used to form the Product of Example 4; and 0.3% w/w SLS was used to, form the product of Example 5.
E?~AMPLE 6 Dry blend mix of MCC and SLS (0.25'% w/wl - Comn:~rative As a control, E11ICOCEL~ grade 50 M microcrystalline cellulose (Mendell Co., Inc.) and 0.25% w/w SLS powder were dry blended. No spray drying or other treatment of the mixture was undertaken. The method of Example 1 B, however, was repeated.
WO 96122080 ' PCTIUS96100539 Processed MCC without SLS
As a second control, the process described in Example 1 B was repeated except that no SLS was added.
In this example, batches of compressed tablets were prepared using each of the products obtained as a result of Examples 1-7. The tablets were prepared using a Korsch tablet press having a punch size of 3/8" and an aim weight of about 245 mg.
The granulations were included in five separate tabletting runs using compression forces of 6, 12, 18, 24 and 30 kN respectively. Ten tablets from each run were weighed, measured for diameter and tested for thickness and hardness on the Erweka TBH 30 tablet hardness tester to determine the compressibility of the microcrystalline cellulose as measured by tensile strength. The results of the analysis for the products of Examples l, 3-7 are graphically illustrated in Figure 1 as a comparison of tensile strength versus compression force. The results obtained using the product of Example 2 were determined to be comparable to that obtained for the product of Example (0.1% SLS).
As can be seen from the graph, substantial benefits are obtained by coprocessing MCC with SLS. The tablets prepared using the products of comparative examples 6 and 7 demonstrated poor tensile strength. The novel excipient is superior and demonstrates approximately the same relative improvement across the entire range of compression forces. Furthermore, the graph also illustrates that tablets prepared with a mere dry admixture of MCC and SLS (Example G formulation) failed to demonstrate acceptable tensile strengths. Thus, the coprocessed MCC-SLS
described herein provides significant retention ofMCC compressibility.
2s ~ ~ I ~'~~~2 DOCUSATE SODIUM
In these examples, the coprocessing method described in Example 1 A was " repeated except that docusate sodium (Spectrum Chemical) was used as the S coprocessing agent).
Example I Docusate Sodium 0.25 l0 ~ O.SO
The resultant granulates prepared according to Example IB were tabletted according to the same method described in Example 8 and evaluated for tensile strength. The products of inventive Example 4 (MCC-SLS 0.20%w/w) and Example 7 (MCC alone) were included in Figure 2 for comparison purposes.
I S Referring now to Figure 2, it can be seen that coprocessing MCC with docusate sodium also affords the retention of MCC compressibility.
EXAMPLES ll-l4 In these examples, the coprocessing method described in Example IA was repeated using the non-ionic surfactant polysorbate 40 (Spectrum Chemical) as the coprocessing agent.
~1~38~'~
Exam le Polysorbate 40 wt %) 11 0.25 12 0.50 13 1.0 S 14 2.0 The resultant granulates prepared according to Example IB were tabletted according to the same method described in Example 8 and evaluated for tensile strength. The products of inventive Example 4 (MCC-SLS 0.2%w/w) and Example 7 (MCC alone) were included in Figure 3 for comparison purposes.
Referring now to Figure 3, it can be seen that the retention of compressibility afforded by coprocessing with polysorbate 40 is well below that provided by sodium lauryl sulfate. 1n fact, MCC cop~ocessed with polysorbate 40 demonstrates compressibility properties about the same as off the-shelf MCC in wet granulation formulations.
Simetbiconc In these examples, the coprocessing method described in example 1 was repeated using simethicone '(Dow Corning, Midland. M1.) as the surfactant coprocessing agent.
Exam le Simethicnne (wt %) 15 0.5 ' 16 1.0 17 2.0 WO 96(22080 PCT/US96/00539 The resultant granulates prepared according to Example 1B were tabletted according to the same method described in Example 8 and evaluated for tensile strength. The products of inventive Example 4 (MCC-SLS 0.2%w/w) and Example 7 (oil=the-shelf MCC) were included in Figure 4 for comparison purposes.
Referring now to 1 figure 4, it can he seen that this surfactant provides little, if any, improvement in the retention of MCC compressibility. It can, therefore, be seen that mere addition of any lubricant in any amount is not sufficient to allow MCC to retain its compressibility in wet granulations. Rather, selected surfactants, present .
within the claimed ranges, provide the desirable compressibility characteristics to the MCC.
While there have been described what are presently believed to be the preferred embodiments of the invention, those skilled in the art will realize that changes and modifications may be made thereto without departing from the spirit of the invention.
I S It is intended to claim all such changes and modifications that fall within the true scope of the invention.
PT~ARMACEiITTCAL EaCTPTENT TTAVTNG
IMI'RO~'FD COMPRE IBTLTTY
BACKGROitND OF TTIE INVENTION
The present invention relates to a novel excipient for use in the manufacture of pharmaceuticals, and in particular, solid dosage forms such as tablets which 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 into the dosage form possess certain physical characteristics which lend themselves to processing in such a manner. Among other things, the material to be compressed must be free-flowing, must be lubricated, an<i, importantly, must possess sufficient cohesiveness to insure that the solid dosage form remains intact after compression.
In the case of tablets, the tablet is formed by pressure being applied to the material to be tabletted on a tablet press. A tablet press includes a lower punch which fits into a die from the bottom and a upper punch having a corresponding shape and dimension which enters the die cavity from the top after the tabletting material fills the die cavity. The tablet is formed by pressure applied on the lower and upper punches. The ability of the material to flow freely into the die is important in order to insure that there is a uniform filling of the die and a continuous movement of the material from the source of the material, e.g. a feeder hopper. The lubricity of the material is crucial in the preparation of the solid dosage forms since the compressed material must be readily ejected from the punch faces.
Since most drugs have none or only some of these properties, methods of tablet formulation have been developed in order to impart these desirable character-istics to the materials) which is to be compressed into a solid dosage form.
Typically, the material to be compressed into a solid dosage form includes one or more excipients which impart the free-flowing, lubrication, and cohesive properties to the drugs) which is being formulated into a dosage form.
Lubricants are typically added to avoid the materials) being tabletted from sticking to the punches. Connnonly used lubricants include magnesium stearate and WO 96122080 PCTlUS96100539 calcium stearate. Such lubricants are commonly included in the final tabletted product in amounts of less than l% by weight.
In addition to lubricants, solid dosage forms often conrain diluents. Diluents are frequently added in order to increase the bulk weight of the material to be tabletted in order to make the tablet 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 forms are binders. Binders are agents which impart cohesive qualities to the powdered material(s). Commonly used binders include starch, and sugars such as sucrose, lp glucose, dextrose, and lactose.
Disintegrants are often included in order to ensure that the ultimately prepared compressed solid dosage form has an acceptable disintegration rate in an environment of use (such as the gastrointestinal tract). Typical disintegrants include starch derivatives and salts of carboxymethylcellulose.
15 There are three general methods of preparation of the materials to be included in the solid dosage form prior to compression: (1) dry granulation;
(2) direct compression; and (3) v,~et granulation.
Dry granulation procedures may be utilized where one of the constituents, either the drug or the diluent, has sufficient cohesive properties to be tabletted. The Zp method includes mixing the ingredients, slugging the ingredients, dry screening, lubricating and finally compressing the ingredients.
In direct compression, the powdered materials) to be included in the solid dosage form is compressed directly without modifying the physical nature of the material itself.
The wet granulation procedure includes mixing the powders to be incorporated into the dosage form in, e.g.,,a twin shell blender or double-cone blender and thereafter adding solutions of a binding agent to the mixed powders to obtain a granulation. Thereafter, the damp mass is screened, e.g., in a 6- or 8-mesh screen and then dried, e.g., via tray drying, the use of a fluid-bed dryer, spray-dryer, radio-frequency dryer, microwave, vacuum, or infra-red dryer.
The use of direct compression is limited to those situations where the drug or active ingredient has a requisite crystalline structure and physical characteristics required for formation of a pharmaceutically acceptable tablet. On the other hand, it is well known in the art to include one or more excipients which make the direct compression method applicable to drugs or active ingredients which do not possess the requisite 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 tablet weight), it is necessary that the drugs) itself have sufficient physical characteristics (e.g., cohesiveness) for the ingredients to be directly compressed.
Typically, however, excipients are added to the formulation which impart good flow and compression characteristics to the material as a whole which is to be compressed. Such properties are typically imparted to these excipients via a pre-processing step such as wet granulation, slugging, spray drying, spheronization, or crystallization. Usel..l direct compression excipients include processed forms of cellulose, sugars, and dicalcium phosphate dehydrate, among others.
A processed cellulose, microcrystalline cellulose, has been utilized extensively in the pharmaceutical industry as a direct compression vehicle for solid dosage forms. Microcrystalline cellulose is commercially available under the tradename EMCOCELO from Edward Mendell Co., Inc. and as Avicelm from FMC Corp. Compared to other directly compressible excipients, microcrystalline cellulose is generally considered to exhil~~t superior compressibility and disin-tegration properties.
Another limitation of direct compression as a method of tablet manufacture is the size of the tablet. if the amount of active ingredient is high, a pharmaceutical formulator may choose to wet granulate the active with other excipients to attain an acceptably sized tablet with the desired compact strength. Usually the amount of filler/binder or excipierits needed in wet granulation is less than that required for WO 96122080 PCTIUS96f00539 21~~R8~
direct compression since the process of wet granulation contributes to some extent toward the desired physical properties of a tablet. Thus, despite the advantages of direct compression (such as reduced processing times and costs), wet granulation is widely used in the industry in the preparation of solid dosage forms. Many of those skilled in the art prefer wet granulation as compared to direct compression because this method has a greater probability of overcoming any problems associated with the physical characteristics of the various ingredients in the formulation, thereby providing a material which has the requisite flow and cohesive characteristics necessary to obtain an acceptahle solid dosage form.
l0 The popularity ofthe wet granulation process as compared to the direct compression process is based on at least three advantages. First, wet granulation provides the material to be compressed with better wetting properties, particularly in the case of hydrophobic drug substances. The addition of a hydrophilic excipient makes the surface of a hydrophobic drug more hydrophilic, easing disintegration 15 and dissolution. Second, the content uniformity of the solid dosage forms is generally improved. Via the wet granulation method, all of the granules thereby 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 20 problem with the direct compression method. Finally, the particle size and shape of the particles comprising the granulate to be compressed are optimized via the wet granulation process. This is due to the fact that when a dry solid is wet granulated, the binder "glues" particles together, so that they agglomerate in the granules which are more or less spherical.
25 Due to the popularity of microcrystalline cellulose, pharmaceutical fornutlators have deemed it desirable to include this excipient in a formulation which is wet granulated prior to tabletting. Unfortunately, currently-available microcrystalline cellulose does not hold to the typical principle that the amount of filler/binder needed in wet granulation is less than that in direct compression. It is WO 9GI22080 PCTlf1596ID0539 ..
known that the exposure of the microcrystalline cellulose to moisture in the wet 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 desires to prepare a solid oral dosage form of a high dose drug, and the use ofthe wet granulation technique is deemed necessary, the loss of compressibility of the microcrystalline cellulose dictates that a larger amount of this material may be needed to obtain an acceptably compressed final product. The additional amount of microcrystalline cellulose needed adds cost to the preparation, but more importantly adds bulk, making the product morn 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 there has been no satisfactory solution.
IS Attempts have been made to provide an excipient having high compressibility, a small bulk (high apparent density), and good flowability, while being capable of providing satisfactory disintegration of the solid dosage form, which is applicable to wet granulation as well as to dry granulation and direct compression methods for preparation of solid dosage forms.
For example, U.S. Patent No. 4,159,345 (Taken, et al.) describes an excipient which consists essentially ofa 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 linters, pulps and regenerated fibers. The microcrystalline cellulose is said to be a white cellulosic powder having an apparent specific volume of 1.6-3.I cc/g, a repose angle of 35°
to 4?°, a 200-mesh sieve residue oft to 80% by weight and a tapping apparent specific vol!mte of at least 1.4 ccJg.
In U.S. Patent No. 4,744,987 (Mehra, et al.), a particulate co-processed microcrystalline cellulose and calcium carbonate composition is described wherein r, 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 slurry of microcrystalline cellulose and calcium carbonate and then drying the slurry to yield a particulate product. The combination of these two ingredients is said to provide a lower cost excipient which has tabletting characteristics similar to those. .
of microcrystalline cellulose and which would satisfy a need for an economical excipient with good performance that is desired by the vitamin market.
European Patent Application EP 0609976AI (assigned to Asahi Kasei Kahushiki Kaisha) describes an excipienf comprising white powdery microcrystalline cellulose having an average degree of polymerization of from to 375, preferably from 190 to 210, and an acetic acid holding capacity of 280% or more, preferably from 290 to 370%. The ehcipient is said to exhibit high compactability and a high rate of disintegration and is said to be obtained by heat-treating an aqueous dispersion of purified cellulose particles, which has a solids 1 S ' content of 40% or less by weight, at 100°C or more, followed by drying, or by sub-jecting an aqueous dispersion of purified cellulose particles having a solids content of23% or less by weigi~t to thin qlm-forming treatment and drying the resultant thin film. The excipient is said to possess a high compressibility, and a good balance of compactability an<I rate of disintegration.
There still remains a need in the industry for a pharmaceutical excipient which possesses excellent compressibility whether utilized in a direct compression or wet granulation procedure.
OI3,IECTS AND SIIA1~1AR1' Or Tllr INVENTION
It is an object of the present invention to provide an excipient which is useful in a variety of applications, and which may be utilized in direct compression or wet granulation methods.
It is a Further object of the present invention to provide an excipient useful in direct compression methods which has improved compressibility relative to WO 96!22080 PCT/IJS96/00539 2I8~g8~
microcrystalline cellulose.
It is a further object of the present invention to provide an excipient useful in wet granulation methods which has improved compressibility relative to microcrystnlline cellulose.
It is a further object ofthe present invention to provide a free-flowing excipient which has excellent compressibility properties when utilized in direct com-pression or wet granulation methods, and which furthermore possesses pharma-ceutically 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 has improved compressibility relative to "off the-shelf' commercially available microcrystalline cellulose.
It is a further object of the present invention to provide a solid dosage form which includes one or more active ingredients and the improved microcrystalline cellulose excipient of the present invention.
It is a fiirther 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 exposed, e.g., to gastrointestinal fluid.
1n accordance with the above ~hjects 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 coprocessed microcrystalline cellulose and a surfactant.
Preferably, the surfactant is an ionic surfactant and most preferably, the surfactant is an anionic surfactant.
The amount of surfactant coprocessed with the microcrystalline cellulose is dependent, in part, upon the type of surfactant selected. Por purposes of the present invention, the amount is generally described as an effective amount, i.e. an amount which enhances or augments the compressibility of the microcrystalline cellulose. One particularly preferred surfactant is the anionic surfactant sodium WO 96!22080 PCT/U596/00539 lauryl sulfate (SLS). This surfactant is present in an amount of from about 0.1% to about 0.5% by weight of the microcrystalline cellulose. Preferably, however, the surfactant is present in amounts of from about 0.15 to about 0.4% and most preferably, in amounts ranging from about 0.2 to about 0.3% by weight.
The microcrystalline cellulose and surfactant are in intimate association with each other, and the surfactant portion of the agglomerate is in the form of an aqueous solution prior to being coprocessed with microcrystalline cellulose.
The present invention is further directed to an aqueous slurry useful in the preparation of a compressible excipient useful in dry and wet granulation formulation methods, comprising a mixture of microcrystalline cellulose and from about 0.1%to about 0.5% of a surfactant such as sodium lauryl sulfate, by weight relative to the microcrystalline cellulose. The solids content of the aqueous slurry is from about 0.5% to about 25%, by weight, preferably from about 15% to about 20% by weight, an<l most preferably from about 17% to about 19% by weight.
The present invention is further directed to a mixture of an active ingredients) and an excipient comprising a particulate agglomerate of coprocessed microcrystalline cellulose and a surfactant, the surfactant being present in an amount of from about 0.1 % to about 0.5% by weight based on the weight of the microcrystaliine cellulose. The microcrystaliine cellulose and surfactant are in intimate association with each other and the ratio of active ingredient to excipient is from about 1:99 to about 99:1, by weight.
The present invention is further directed to a granulate of an active ingredients) and the novel excipient described herein, wherein the active ingredients) and excipient have been subjected to a wet granulation procedure.
The present invention is also directed to a compressed solid dosage form comprising an active ingredients) and the novel excipient described herein, wherein the active ingredients) and excipient have been directly compressed into the solid dosage form or have been subjected to a wet granulation procedure and thereafter compressed into the solid dosage form. The compressed solid dosage form WO 96f22080 PCTlUS96/00539 provides a suitable immediate release dissolution profile of the active ingredients) when exposed to aqueous solutions during in-vitro dissolution testing, and provides a release of drug in an environment of use which is considered bioavailable.
In 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 of maintaining and/or enhancing the compressibility of microcrystalline cellulose. The method includes forming an aqueous slurry containing a mixture of microcrystalline cellulose and a surfactant, and drying the slurry to obtain microcrystalline cellulose-based excipient particles in which the surfactant has been integrated with the microcrystalline cellulose particles. Within this aspect of the invention, the slurry contains from about 0.5% to about 25% by weight microcrystalline cellulose, with amounts of from about 1 S% to about 20% being preferred. Furthermore, the surfactant included in the slurry is preferably an anionic surfactant such as SLS and is present in amounts ranging from about 0.1% to about 0.5% by weight of the MCC.
The novel excipient described herein is free-flowing, possesses excellent disintegration properties, and importantly, in certain embodiments possesses improved compressibility relative to normal "ofT=the-shelf' commercially available microcrystalline cellulose when directly compressed. The advantages of the novel excipient described herein are especially realized in pharmaceutical formulations prepared using wet granulation techniques. When utilized in wet granulation techniques, the novel excipient surprisingly provides a compressibility which is substantially improved in preferred embodiments in comparison to the compress-ibility of normal "off=the-shelf' commercially available microcrystalline cellulose used in wet granulation and is even comparable to "ofF the-shelf' microcrystalline cellulose used in direct compression techniques. In other embodiments, the novel excipient surprisingly provides a compressibility which is substantially superior to the compressibility of normal "off the-shelf" commercially available microcrystalline cellulose used in direct compression techniques.
The term "environn,_ntal fluid" is meant for purposes of the invention to encompass, e.g., an aqueous solution, or gastrointestinal fluid.
By "sustained release" it is meant for purposes of the invention that the therapeutically active medicament is released from the formulation at a controlled rate such that therapeutically beneficial blood levels (but below toxic levels) of the medicament are maintained over an extended period of time, e.g., providing a hour or a 24 hour dosage form.
By "bioavailable" it is meant for purposes of the invention that the therapeutically active medicament is absorbed from the sustained release formulation and becomes available in the body at the intended site of drug action.
By "surfactant" it is meant for purposes of the present invention that the material is a surface active agent which displays wetting, detergent or soap-like qualities as those agents are understood by those of ordinary skill in the art.
BRIEF DI:SCRTPTION OF TFIE DRA~'VINGS
The following drawings are illustrative of embodiments of the invention and are not meant to limit the scope of the invention as encompassed by the claims.
Figure 1 graphically shows a comparison of the tensile strength of tablets prepared in accordance with the invention and prior art tablets.
Figure 2 graphically shows a comparison of the tensile strength of tablets prepared in accordance with the invention to contain MCC coprocessed with SLS, tablets containing MCC coprocessed with docusate sodium and prior art tablets prepared to contain only unmodified MCC.
Figure 3 graphically illustrates a comparison of the tensile strength of tablets prepared using MCC coprocessed with polysorbate 40, tablets prepared with the novel SLS coprocessed MCC and tablets prepared with MCC alone.
Figure 4 graphically illustrates a comparison of the tensile strength of tablets prepared using MCC coprocessed with polydimethyl siloxane (simethicone) , tablets prepared using coprocessed MCC-SLS and prior art tablets prepared to contain WO 96/22080 PCTlUS96I00539 only unmodified MCC.
DETATLF DESCRIPTION OF THE INVENTION
Microcrystalline cellulose is a well-known tablet diluent, binder and disintegrant. Its chief advantage over other excipients is that it can be directly compressed into self binding tablets which disintegrate rapidly when placed into water. This widely-used ingredient is prepared by partially depolymerizing cellulose obtained as a pulp from fibrous plant material with dilute mineral acid solutions.
Following hydrolysis, the hydrocellulose thereby obtained is purified via filtration and an aqueous slurry is spray dried to form dry, white odorless, tasteless crystalline powder of porous particles ofvarir:us sizes. Another method of preparing microcrystalline cellulose is disclosed in U.S. Patent No. 3,141,875. This reference discloses subjecting cellulose to the hydrolytic action of hydrochloric acid at boiling temperatures so that 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 called cellulose crystallites by vigorous mechanical means such as a blender.
Microcrystalline cellulose is commercially available in several grades which range in average particle size from 20 to 200 microns.
Microcrystalline cellulose is water-insoluble, but the material has the ability to draw fluid into a tablet ! capillary action. The tablets then swell on contact and the microcrystalline cellulose thus acts as a disintegrating agent. The material has sufficient self lubricating qualities so as to allow a lower level of lubricant as compared to other excipients.
Typically, microcrystalline cellulose has an apparent density of about 0.28 g/cm' and a tap density of about 0.43 g/cm'. ~ndbook of Pharmaceutical Exci ail ents. pages 53-55.
When utilized in pharmaceutical applications, microcrystalline cellulose is typically used as a tablet binder/diluent in wet granulation and direct compression ,,..
. .
formulations in amounts of 3-30% of the formulation, or more. However, it is known to use more or less microcrystalline cellulose in pharmaceutical products, depending upon the requirements of the formulation.
The surfactants which may be used in the present invention generally include all pharmaceutically-acceptable surfactants. Preferably, however, the surfactant is .
an ionic surfactant and most preferably, the surfactant is an anionic surfactant.
Suitable pharmaceutically-acceptable anionic surfactants include, for example, those containing carboxylate, sulfonate, and sulfate ions. Those containing carboxylate ions are sometimes referred to as soaps and are generally prepared by saponification lp of natural fatty acid glycerides in alkaline solutions. The most common canons associated with these surfactants are sodium, potassium, ammonium and triethanolamine. The chain length of the fatty acids range from 12 to 18.
Although a large number of alkyl sulfates are available as surfactants, one particularly preferred surfactant is sodium lauryl sulfate.
In the pharmaceutical arts, sodium lauryl sulfate has been used as an emulsifying agent in amounts of up to about 0.1°~o by weight of the formulation. It is not believed that surfactants such as SLS have been included in coprocessed MCC compositions. Moreover, it is not believed that surfactants have been used in the amounts described herein to improve the compressibility of MCC especially in 2p wet granulations.
Sodium lauryl sulfate is a water-soluble salt, produced as a white or cream powder, crystals, or flakes and is used as a wetting agent and detergent. Also known as dodecyl sodium sulfate, SLS is actually a mixture of sodium alkyl sulfates consisting chiefly of sodium lauryl sulfate. Sodium lauryl sulfate is also known as sulfuric acid monododecyl ester sodium salt. Furthermore,.sodium lauryl sulfate is readily available from commercial sources such as Sigma or Aldrich in both solid form and as a solution. The solubility of SLS is about 1 gm per 10 ml/water.
The fatty acids of coconut oil, consisting chiefly of lauric acid, are catalytically hydrogenated to form the corresponding alcohols. The alcohols are then esterified with sulfuric acid (sulfated) and the resulting mixture of alkyl bisulfates (alkyl sulfuric acids) is converted into sodium salts by reacting with alkali under controlled conditions of pH.
Alternative anionic surfactants include, without limitation, alkyl carboxylates, acyl lactylates, alkyl ether carboxylates, N-acyl sarcosinates, polyvalent alkyl carbonates, N-acyl glutamates, fatty acid, polypeptide condensates and sulfuric acid esters.
In other aspects of the invention amphoteric (amphipathic/amphiphilic surfactants), non-ionic surfactants and/or cationic surfactants are included in the coprocessed compositions of the invention. These alternative surfactants can be included to replace some or even all of the preferred anionic surfactant. It is preferred, however, that the surfactant comprise an anionic surfactant.
Suitable pharmaceutically-acceptable non-ionic surfactants such as, for example, polyoxyethylene compounds, lecithin, ethoxylated alcohols, ethoxylated esters, ethoxylated amides, polyoxypropylene compounds, propoxylated alcohols, ethoxylated/propoxylated block polymers, propoxylated esters, alkanolamides, amine oxides, fatty acid esters of polyhydric alcohols, ethylene glycol esters, diethylene glycol esters of polyhydric alcohols, ethylene glycol esters, diethylene glycol esters, propylene glycol esters, glycerol esters, polyglycerol fatty acid esters, SPAN's~ (e.g., sorbitan esters), TWEEN's~ (i.e., sucrose esters), glucose (dextrose) esters and simethicone.
Other suitable pharmaceutically-acceptable surfactants include acacia, benzalkonium chloride, cholesterol, emulsifying wax, glycerol monostearate, lanolin alcohols, lecithin, poloxamer, polyoxyethylene, and castor oil derivatives.
Those skilled in the art will further appreciate that the name and/or method of preparation of the surfactant utilized in the present invention is not determinative of the usefulness of the product. Rather, as previously mentioned, it has been surprisingly discovered that it is the physical characteristics of surfactants, especially those of the anionic class such as sodium lauryl sulfate, which are critical.
In ~~s~s~~
particular, it has been discovered that when an anionic surfactant such as SLS
is coprocessed .with microcrystalline cellulose in the amounts described herein, improved microcrystalline cellulose products q~the invention result.
When the novel excipient of the invention utilizes an anionic surfactant, it has been found that the resultant excipient product surprisingly provides a com-pressibility which is substantially improved in preferred embodiments even in comparison to the compressibility of normal "ofi-the-shelf' commercially available microcrystalline cellulose used in direct compression techniques.
In other embodiments of the present invention, it has been discovered that the compressibility of microcrystalline cellulose which is wet granulated is significantly improved by coprocessing the MfCC with an anionic surfactant such as sodium lauryl sulfate.
Since microcrystalline cellulose is substantially water insoluble, the particle size of this ingredient in the well-dispersed aqueous slurry is directly related to its particle size as it was introduced into the aqueous solution. Most surfactants, on the other hand, tend to be water soluble. Sodium lauryl sulfate, for example, is relatively soluble in water (I gllOml) and, therefore, dissolves in the aqueous slurry.
It should be understood, however, that the coprocessed products of the present invention are not solely limited to those which contain a dissolved surfactant. The ?0 contemplated compositions can also be prepared from slurries which contain a dispersion of the surfactant as well as the MCC.
After a uniform mixture of the ingredients is obtained in the suspension, the suspension is dried to provide a plurality of microcrystalline cellulose-based excipient particles having enhanced compressibility.
~5 In the spray-drying process, the aqueous dispersion of microcrystalline cellulose and surfactant is brouglU together with a sufficient volume of hot air to produce evaporation and drying of the liquid droplets. The higi~ly dispersed slurry of microcrystalline cellulose and surfactant is pumpable and capable ofbeing atomized. It is sprayed into a current of warm filtered air, which supplies the heat WO 96/22080 PCTlIJS96I00539 '~l ~~~82 for evaporation and conveys a dried product to a collecting device. The air is then exhausted with the removed moisture. The resultant spray-dried powder particles are approximately spherical in shape and are relatively tmiform in size, thereby possessing excellent flowability. The coprocessed product consists of microcrystalline cellulbse and surfactant in int?mate association with each other.
The exact relationship of the two ingredients of the excipients after coprocessing is not presently understood; however, for puiposes of description the coprocessed particles are described herein as including an agglomerate of microcrystalline cellulose and surfactant in intimate association with each other. By "intimate association", it is meant that the surfactant has in some manner been integrated with the microcrystalline cellulose particles, e.g., via a partial coating of the microcrystalline particles, as opposed to a chemical interaction of the two ingredients. The term "intimate association" is therefore deemed for purposes of the present description as being synonymous with "integrated" or "united". The I S coprocessed particles are not necessarily uniform or homogeneous.
It is most preferred in the present invention that the microcrystalline cellulose and SLS are coprocessed, resulting in an intimate association of these in-gredients, rather than being combined, e.g., as a dry mixture. In preferred embodiments of the present invention, the aqueous slurry of the microcrystalline cellulose and surfactant are introduced into the spray dryer as a single.
aqueous medium, However, it is possible to separately introduce each ingredient into separate aqueous media which are then combined. Other procedures for combining the microcrystalline cellulose and surfactant known to those skilled in the art are deemed to be equivalent to the spray-drying technique described above, and are further deemed to be encornpasse,. by the appended claims.
In certain preferred embodiments of the present invention, the coprocessing of the microcrystalline cellulose and SLS is accomplished by forming a well-dispersed aqueous slurry of microcrystalline cellulose in which the SLS has been dissolved, and thereafter drying the slurry and forming a plurality of microcrystalline 2~ 838~~
cellulose-based excipient particles. Typically, microcrystalline cellulose is first added to an aqueous solution so that a slurry or suspension containing from about 0.5% to about 25% microcrystalline cellulose in the form of solids is obtained.
Preferably, the slurry or suspension contains from about I S% to 20% microcrys-talline cellulose and most preferably from about 17% to about 19%
microcrystalline cellulose. At this stage, it is often desirable to adjust the pH of the slurry to about neutral with ammonium hydroxide, sodium hydroxide, and mixtures thereof or the like. The suspension is kept under constant agitation for a sufficient time to assure a uniform distribution of the solids prior to being combined with the SLS.
1 p At this point, the SLS is added to the suspension or slurry in amounts ranging from O.l% to about 0.5% by weight, based on the amount of microcrystalline cellulose, amounts from about 0.15% to about 0.4% are preferred while amounts of from about 0.2°ro to about 0.3% by weight are especially preferred. The SLS can be added to the suspension as either a solid or in solution form. The microcrystalline cellulose is thus well-dispersed in the slurry or suspension and the surfactant is dissolved therein prior drying and forming the novel particles. It will be understood that other useful surfactants can be used in like amounts or even greater amounts, i.e. up to 5% by weight or even more. The usable concentration range for the selected surfactant depends in part upon not only its molecular weiglu but also its degree of foaming, particularly when present in agitated slurries which will be spray dried to form the desired particulate. Thus, in those aspects of the invention where surfactants other than SLS are coprocessed with the microcrystalline cellulose, it is to be understood that the surfactant will be present in an amount which enhances the compressibility of the MCC and yet does not have a degree of foaming which would substantially inhibit spray drying.
It is preferred that the suspension be dried using spray-drying techniques, as they are known in the art. Other drying techniques, however, such as flash drying, ring drying, micron drying, tray drying, vacuum drying, radio-frequency drying, and possibly microwave drying, can also be used. The exact manner in which the suspension is dried is not believed to be critical for the microcrystalline cellu(ose/SLS particles to demonstrate enhanced compressibility after wet granulating.
Depending upon the amount and type of drying, the concentration of the S microcrystalline cellulose and SLS in the suspension, the novel compressible particles will have different particle sizes, densities, pH, moisture content, etc.
The particulate coprocessed product of the present invention possesses desirable performance attributes that are not present when the combination of microcrystalline cellulose and SLS and optionally present other surfactants are combined as a dry 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 each other. It has also been found that intimate association of MCC and other detergent-like materials such as simethicone, even when they are dissolved/dispersed in the aqueous solutions which form the MCC
slurry, fail to provide MCC with enhanced compressibility.
The average particle size of the integrated excipient of the present invention ranges from about 10 microns to about 1000 microns. Particle sizes of about 10-500 microns are preferred, particle sizes of about 30-250 microns are more preferred and particle sizes of about 40-200 microns are most preferred. It will be appreciated by those of ordinary skit( in the art that the drying of the micro-crystalline cellulose-SLS suspension results in a random size distribution of the novel excipient particles being produced. For example if spray drying techniques are used, droplet size, temperatures, agitation, dispersion, air flow, atomizer wheel speed, etc. will effect final particle size. Furthermore, it is within the scope of the invention to sort or mechanically alter the dried particles according to ranges of particle sizes depending upon end uses. The particle size of the integrated excipient is not narrowly critical, the important parameter being that the average size of the particle must permit the formation of a directly compressible excipient which forms pharmaceutically acceptable tablets.
W0 96122080 PCTlU596100539 The novel excipient has a bulk (loose) density ranging from about 0.2 g/ml to about 0.5 g/ml, and most preferably from about 0.22 g/ml to about 0.35 g/ml.
The novel excipient has a tapped density ranging from about 0.30 g/ml to about 0.70 g/ml, and most preferably from about 0.35 g/ml to about 0.60 g/ml. The pH
of the particles is most preferably about neutral, although granulates having a pH of from about 3.0 to about 8.5 are possible. The moisture content of the excipient particles will broadly range from about 0.5% to about 15%, preferably from about 2.5% to about 6%, and most preferably from about 3.0% to about 5% by weight.
The novel excipient of!he invention is free-flowing and directly compressible. Accordingly, the excipient may be mixed in the desired proportion with an active agent and optional lubricant (dry granulation), and then directly compressed into solid dosage forms. In preferred embodiments of the present invention wherein the surfactant is sodium lauryi sulfate, the novel excipient comprising the coprocessed microcrystalline cellulose and SLS integrated together represents an augmented microcrystalline cellulose having improved compressibility as compared to standard commercially available grades of microcrystalline cellulose.
Alternatively, all or part of the excipient may be subjected to a wet granulation with the active ingredient. A representative wet granulation includes loading the novel excipient particles into a suitable granulator, such as those available from Baker-T'erkins, and granulating the particles together with the active ingredient, preferably using an aqueous granulating liquid. The granulating liquid is added to the mixture with stirring until the powdery mass has the consistency of damp snow and then wet screened through a desired mesh screen, for example, having a mesh from about 12 to about 16. The screened granulate is then dried, using standard drying apparatus such as a convection oven before undergoing a final screening. Additional dry screening of this material is possible, such as by using screens of from about 40 to about 200 mesh. Those materials flowing through 40 and 60 mesh screens may be further ground prior to ultimate tablet formulation. The thus obtained granulate containing the novel excipient is now capable of undergoing tabletting or otherwise placed into a unit dosage form.
In certain preferred embodiments, a portion of the total amount of the novel excipient is wet granulated with the active ingredient, and thereafter the additional portion of the novel excipient is added to the granulate. In yet other embodiments, the additional portion of the novel excipient to be added to the excipient/active ingredient granulate may be substituted with conventional microcrystalline cellulose, .
or other excipients commonly used by those skilled in the art, depending of course upon the requirements ofthe particular formulation.
By virtue of the novel excipie~i of the present invention, the amount of the novel excipient compared to the amount of microcrystalline cellulose which must be used in a wet granulation technique to obtain an acceptable solid dosage form is substantially reduced.
In other embodiments ofthe invention, a further material is added to the slurry of microcrystalline cellulose and SLS. Such additional materials include ' silicon dioxides, non-silicon metal oxides, starches, starch derivatives, surfactants, polyalkylene oxides, cellulose ethers, celluloses esters and mixtures thereof.
These additives may be included in desired amounts which will be apparent to those skilled in the art.
In one preferred aspect of the invention, however, there are provided MCC-based compositions which contain not only a surfactant but also from about 0.1 to about 20% by weight silicon dioxide. The silicon dioxide utilized in this aspect of the invention is preferably of the very fine particle size variety.
In the most preferred embodiments of the invention, the silicon dioxide utilized is a colloidal silicon dioxide. Colloidal silicon dioxide is a submicron fumed silica prepared by the vapor-phase hydrolysis (e.g., at 1110° C) of a silicon compound, such as silicon tetrachloride. The product itself is a submicron, fluffy, light, loose, bluish-white, odorless and tasteless amorfuous powder which is commercially available from a number of sources, including Cabot Corporation (under the tradename Cab-O-Sil); Degussa, Inc. (under the tradename Aerosil); E.I. DuPont &:
Co.; and W.R. Grace & Co. Colloidal silicon dioxide is also known as colloidal silica, fumed silica, light anhydrous silicic acid, silicic anhydride, and silicon dioxide fumed, 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 conteht, specific gravity, refractive index, color or amorphous form.
However, these modifications are known to change the particle size, surface areas, and bulk densities of the colloidal silicon dioxide products.
The surface area ofthe preferred class of silicon dioxides utilized in the invention ranges from about 50 m=/gm to about 500 mv/gm. The average primary particle diameter of the preferred class of silicon dioxides utilized in the invention ranges from about 5 nm to about 50 nm. However, in commercial colloidal silicon dioxide products, these particles are agglomerated or aggregated to varying extents.
The bulk density of the preferred class of silicon dioxides utilized in the invention ranges from about 20 gll to about 100 g/1.
Commercially available colloidal silicon dioxide products have, for example, a BET surface area ranging from about 50 t 15 m'/gm (Aerosil OX50) to about 400 t 20 (Cab-O-Sil S-17) or 390 f 40 mv/gm (Cab-O-Sil ET-1-5). Commercially available particle sizes range from a nominal particle diameter of 7 nm (e.g., Cab-O-Sil S-17 or Cab-0-Sil ET-T-S) to an average primary particle size of 40 nm (Aerosil 0X50). The density of these products range from 72.0 f 8 g/I (Cab-.0-Sil S-17) to 3G.8 g/1 (e.g., Cab-O-Sil M-5). The pi-T of the these products at 4% aqueous !~~s-persion ranges from pHl 3.5-4.5. These commercially available products are described for exemplification purposes of acceptable properties of the preferred class of silicon dioxides only, and this description is not meant to limit the scope of the invention in any manner whatsoever. Thus, in embodiments of the present invention where an improvement in overall compressibility of the microcrystalline cellulose (whether utilized in wet granulation or dry granulation) is important, and the microcwstalline cellulose product is to be subjected to wet granulation, it has been discovered that coprocessing the MCC with SLS can provide improvements in compressibility.
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 (for non-pharmaceutical applications) can be added to the novel excipient prior to preparation of the final product. For example, if desired, any generally accepted soluble or insoluble inert pharmaceutical fitter (diluent) material can be included in the final product (e.g., 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, "off the-shelf' microcrystalline cellulose, mixtures thereof, and the like.
An effective amount of any generally accepted pharmaceutical lubricant, including the calcium or magnesium soaps may optionally be added to the novel excipient at the time the medicament is added, or in any event prior to compression into a solid dosage form. The lubricant may comprise, for example, magnesium stearate in any amount of about 0.5-3% by weight of the solid dosage form.
The complete mixture, in an amount sufficient to make a uniform batch of tablets, may then subjected to tabletting in a conventional production scale tabletting machine at normal compression pressures for that machine, e.g., about 1500-10,000 Ibs/sq in. 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 tablet size for round tablets is preferably about 50 mg to 500 mg and for capsule-shaped tablets about 200 mg to 2000 mg. However, other formulations prepared in accardance with the present invention may be suitably shaped for other uses or locations, such as other bodv cavities, e.g., periodontal pockets, surgical wounds, vaginally. It is contemplated that for certain uses, e.g., antacid tablets, vaginal tablets and possibly implants, that the tablet will be larger.
In certain embodiments of the invention, the tablet is coated with a sufficient WO 96!22080 PCTIU596100539 amount of a hydrophobic polymer to render the formulation capable of providing a release of the medicament such that a l2~or 24 hour formulation is obtained.
The hydrophobic polymer which included in the tablet coating may be the same or different material as compared to the hydrophobic polymeric material which is optionally granulated with the sustained release excipient. In other embodiments of the present invention, the tablet coating may comprise an enteric coating material in addition to or instead or the hydrophobic polymer 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 available under the trade name EudragitT"~ L 100-555.-In further embodiments, the dosage form may be coated with a hydrophilic coating in addition to or instead of the above-mentioned coatings. An example of a suitable material which may be used for such a hydrophilic coating is hydroxy-propylmethylcellulose (e.g., Opadry~, 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 pan. For example, the coated tablets may be dried, e.g., at about GO-70° C for about 3-4 hours in a coating pan.
The solvent for the hydrophobic polymer or enteric coating may be organic, aqueous, or a mixture of an organic and an aqueous solvent. The organic solvents may be, e.g., isopropyl alcohol, ethanol, and the like, with or without water.
The coatings which may be optionally applied to the compressed solid dosage form of the invention may comprise from about 0.5% to about 30% by weight of the final solid dosage form.
In additional embodiments of the present invention, a support platform is applied to the tablets manufactured in accordance with the present invention.
Suitable support platforms are well known to those skilled in the art. An example of suitable support platforms is set forth, e.g., in U.S. Patent No. 4,839,177.
In that patent, the support platform partially coats 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 may be applied to the tablets, e.g., via compression coating onto part of the tablet surface, by spray coating the polymeric materials comprising the support platform onto all or part of the tablet surface, or by immersing the tablets in a solution of the polymeric materials.
The support platform may have a thickness of, e.g., about 2 mm if applied by compression, and about 10 ~,m if applied via spray-coating or immersion-coating.
Generally, in embodiments of the invention wherein a hydrophobic polymer or enteric coating is applied to the tablets, the tablets are coated to a weight gain from about 1% to about 20%, and in certain embodiments preferably from about 5% to about 10%.
Material useful in the hydrophobic coatings and support platforms of the present invention include derivatives of acrylic acid (such as esters of acrylic acid, methacrylic acid, and copolymers thereof) celluloses and derivatives thereof (such as ethylcellulose), polyvinyl alcohols, and the like.
In certain embodiments of the present invention, the tablet core includes an additional dose of the medicament included in either the hydrophobic or enteric coating, or in an additional overcoating coated on the outer surface of the tablet core (without the hydrophobic or enteric coating) or as a second coating layer coated on the surface of the base coating comprising the hydrophobic or enteric coating material. This may be desired when, for example, a loading dose of a therapeutically active agent is needed to provide therapeutically effective blood levels of the active agent when the formulation is first exposed to gastric fluid. The loading dose of medicament included in the coating layer may be, e.g., from about 10% to about 40% of the total amount of medicament included in the formulation.
The active agents) which may be incorporated with the novel excipient described herein into solid dosage forms invention include systemically active therapeutic agents, locally active therapeutic agents, disinfecting agents, chemical impregnants, cleansing agent, deodorants, fragrances, dyes, animal repellents, insect repellents, 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. The therapeutically active agents (e.g.
pharmaceutical agents ) which may be used in the compositions of the present invention include both water soluble and water insoluble drugs. Examples of the such therapeutically active 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 (e.g., metoclopramide), anti-epileptics (e.g., phenytoin, meprobamate and nitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardirine), anti-tussive agents and expectorants (e.g., codeine phosphate), anti-asthmatics (e.g., theophylline), antacids, anti-spasmodics (e.g., atropine, scopolamine), antidiabetics (e.g., insulin), diuretics (e.g., ethacrynic acid, bendrofluazide), anti-hypotensives (e.g., propranolol, clonidine), antihypertensives (e.g., clonidine, methyldopa), bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics (e.g., tetracycline), antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine). The above list is not meant to be exclusive.
A wide variety of locally active agents can be used in conjunction wih the novel excipient described herein, and include both water soluble and water insoluble agents. The locally active agents) which may be included in the controlled release formulation of the present invention is intended to exert its effect in the environment of use, e.g., the oral cavity, although in some instances the active agent may also have systemic activity via absorption into the blood via the surrounding mucosa.
The locally active agents) include antifungal agents (e.g., amphotericin B, clotrimazole, nystatin, ketoconazole, miconazol, etc.), antibiotic agents (penicillins, cephalosporins, erythromycin, tetracycline, aminoglycosides, etc.), antiviral agents (e.g., acyclovir, idoxuridine, etc.), breath fresheners (e.g., chlorophyll), antitussive agents (e.g., dextromethorphan hydrochloride), anti-cariogenic compounds (e.g., metallic salts of fluoride, sodium monofluorophosphate, stannous fluoride, amine fluorides), analgesic agents (e.g., methylsalicylate, salicylic acid, etc.), local anesthetics (e.g., benzocaine), oral antiseptics (e.g., chlorhexidine and salts thereof, hexylresorcinol, dequalinium chloride, cetylpyridinium chloride), anti-inflammatory agents (e.g., dexamethasone, betamethasone, prednisone, prednisolone, triamcinolone, hydrocortisone, etc.), hormonal agents (oestriol), antiplaque agents (e.g., methylsalicylate, eucalyptol), acidity reducing agents (e.g., buffering agents such as potassium phosphate dibasic, calcium carbonate, sodium bicarbonate, sodium and potassium hydroxide, etc.) and tooth desensitizers (e.g., potassium nitrate). This list is not meant to be exclusive. The solid formulations of the invention may also include other locally active agents, such as flavorants and sweeteners. Generally any flavoring or food additive such as those described in Chemicals Used in Food Processing, pub 1274 by the National Academy of Sciences, pages 63-258 may be used. Generally, the final product may include from about 0.1%
to about 5% by weight flavorant.
The tablets of the present invention may also contain effective amounts of coloring agents, (e.g., titanium dioxide, F.D. & C. and D. & C. dyes; see the Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 5, pp. 857-884), stabilizers, binders, odor controlling agents, and preservatives.
Alternatively, the novel excipient can be utilized in other applications wherein it is not compressed. For example, the granulate can be admixed with an active ingredient and the mixture then filled into capsules. The granulate can further be molded into shapes other than those typically associated with tablets. For S example, the granulate together with active ingredient can be molded to "fit" into a particular area in an environment of use (e.g., an implant). All such uses would be contemplated by those skilled in the art and are deemed to be encompassed within the scope of the appended claims.
nETAII~EII DESCRIPTION OF TIfE PREFERRED EM130DIMENTS
The following examples illusu,ae various aspects of the present invention.
Thoy are not to be construed to limit the claims in any manner whatsoever.
The examples set forth the preparation of various microcrystalline cellulose/
anionic surfactant compositions. Tablets were prepared using each of the compositions and each of tablet preparations was tested for tensile strength.
EXAMPLES l-3 PREPARATION OF COPROCESSED MCC-SI,S COMPOSITIONS AND
G.RANULATIQNS TI(EREOF
14TCC-SLS Product - 0.25~/. w/w SL,S
A. EXCIPIENT PARTICLES
In this example, about 6.2 kilograms of microcrystalline cellulose (hICC), (Mendell Co., Inc. Patterson, NY) in the form of a wet cake was combined with 5.2 kilograms of water in a mix rank to form a slurry containing about 15% solids.
The pFI
was adjusted to about neutral with about 3 ml of ammonitun hydroxide. The slurry was allowed to mix for about IS minutes before being combined with 0.25% w/w W 0 96122080 PCTlUS96100539 sodium lauryl sulfate (SLS) powder (available from Spectrum Chemical, Gardena, CA.) After allowing the materials to become intimately combined, the slurry was spray dried using a Nro Production Minor (Niro, Columbia, MD), inlet temperature-215 °C, outlet temperature-125°C, atomizer wheel speed 22,300 rpm, to provide MCC-SLS
having an average particle size of 40-60 microns.
B. GRANULATION OF EXCIPIENT PARTICLES
The MCC-SLS particles obtained as a result of step 1 A. were wet granulated in a Baker-Perkins 10 liter high-sheer granulator for 3 minutes using water as the granulating fluid. The resultant product was wet screened through a 12 mesh screen, tray dried in a convection oven for about 2-3 hours until a moisture content of less than 5% was obtained, dry screened and sieved to obtain an average particle size of From about 55 to about 70 microns.
MCC-SLS Products The processes of Example IA and B were repeated except that 0.5% w/w sodium lauryl sulfate was used to form the product of Example 2; 0.1 % w/w SLS
was used to form the product of Example 3; 0.2% w/w SL5 was used to form the Product of Example 4; and 0.3% w/w SLS was used to, form the product of Example 5.
E?~AMPLE 6 Dry blend mix of MCC and SLS (0.25'% w/wl - Comn:~rative As a control, E11ICOCEL~ grade 50 M microcrystalline cellulose (Mendell Co., Inc.) and 0.25% w/w SLS powder were dry blended. No spray drying or other treatment of the mixture was undertaken. The method of Example 1 B, however, was repeated.
WO 96122080 ' PCTIUS96100539 Processed MCC without SLS
As a second control, the process described in Example 1 B was repeated except that no SLS was added.
In this example, batches of compressed tablets were prepared using each of the products obtained as a result of Examples 1-7. The tablets were prepared using a Korsch tablet press having a punch size of 3/8" and an aim weight of about 245 mg.
The granulations were included in five separate tabletting runs using compression forces of 6, 12, 18, 24 and 30 kN respectively. Ten tablets from each run were weighed, measured for diameter and tested for thickness and hardness on the Erweka TBH 30 tablet hardness tester to determine the compressibility of the microcrystalline cellulose as measured by tensile strength. The results of the analysis for the products of Examples l, 3-7 are graphically illustrated in Figure 1 as a comparison of tensile strength versus compression force. The results obtained using the product of Example 2 were determined to be comparable to that obtained for the product of Example (0.1% SLS).
As can be seen from the graph, substantial benefits are obtained by coprocessing MCC with SLS. The tablets prepared using the products of comparative examples 6 and 7 demonstrated poor tensile strength. The novel excipient is superior and demonstrates approximately the same relative improvement across the entire range of compression forces. Furthermore, the graph also illustrates that tablets prepared with a mere dry admixture of MCC and SLS (Example G formulation) failed to demonstrate acceptable tensile strengths. Thus, the coprocessed MCC-SLS
described herein provides significant retention ofMCC compressibility.
2s ~ ~ I ~'~~~2 DOCUSATE SODIUM
In these examples, the coprocessing method described in Example 1 A was " repeated except that docusate sodium (Spectrum Chemical) was used as the S coprocessing agent).
Example I Docusate Sodium 0.25 l0 ~ O.SO
The resultant granulates prepared according to Example IB were tabletted according to the same method described in Example 8 and evaluated for tensile strength. The products of inventive Example 4 (MCC-SLS 0.20%w/w) and Example 7 (MCC alone) were included in Figure 2 for comparison purposes.
I S Referring now to Figure 2, it can be seen that coprocessing MCC with docusate sodium also affords the retention of MCC compressibility.
EXAMPLES ll-l4 In these examples, the coprocessing method described in Example IA was repeated using the non-ionic surfactant polysorbate 40 (Spectrum Chemical) as the coprocessing agent.
~1~38~'~
Exam le Polysorbate 40 wt %) 11 0.25 12 0.50 13 1.0 S 14 2.0 The resultant granulates prepared according to Example IB were tabletted according to the same method described in Example 8 and evaluated for tensile strength. The products of inventive Example 4 (MCC-SLS 0.2%w/w) and Example 7 (MCC alone) were included in Figure 3 for comparison purposes.
Referring now to Figure 3, it can be seen that the retention of compressibility afforded by coprocessing with polysorbate 40 is well below that provided by sodium lauryl sulfate. 1n fact, MCC cop~ocessed with polysorbate 40 demonstrates compressibility properties about the same as off the-shelf MCC in wet granulation formulations.
Simetbiconc In these examples, the coprocessing method described in example 1 was repeated using simethicone '(Dow Corning, Midland. M1.) as the surfactant coprocessing agent.
Exam le Simethicnne (wt %) 15 0.5 ' 16 1.0 17 2.0 WO 96(22080 PCT/US96/00539 The resultant granulates prepared according to Example 1B were tabletted according to the same method described in Example 8 and evaluated for tensile strength. The products of inventive Example 4 (MCC-SLS 0.2%w/w) and Example 7 (oil=the-shelf MCC) were included in Figure 4 for comparison purposes.
Referring now to 1 figure 4, it can he seen that this surfactant provides little, if any, improvement in the retention of MCC compressibility. It can, therefore, be seen that mere addition of any lubricant in any amount is not sufficient to allow MCC to retain its compressibility in wet granulations. Rather, selected surfactants, present .
within the claimed ranges, provide the desirable compressibility characteristics to the MCC.
While there have been described what are presently believed to be the preferred embodiments of the invention, those skilled in the art will realize that changes and modifications may be made thereto without departing from the spirit of the invention.
I S It is intended to claim all such changes and modifications that fall within the true scope of the invention.
Claims (47)
1. An excipient composition comprising a particulate agglomerate of coprocessed microcrystalline cellulose and a surfactant, said surfactant being present in an amount from about 0.1% to about 0.5% by weight of the micro-crystalline cellulose, said microcrystalline cellulose and said surfactant being in intimate association with each other.
2. An augmented microcrystalline cellulose excipient composition suitable for compression into a solid dosage form with a therapeutically active agent via a wet granulation method, comprising particles of microcrystalline cellulose having from about 0.1% to about 0.5% of an anionic surfactant, by weight of said microcrystalline cellulose integrated with said microcrystalline cellulose particles.
3. An excipient composition, comprising from about 1% to about 99% of an excipient comprising a particulate agglomerate of coprocessed microcrystalline cellulose and from about 0.1% to about 0.5 % of a surfactant by weight of said microcrystalline cellulose, the microcrystalline cellulose and said surfactant being in intimate association with each other, and from about 99% to about 1%, by weight, of an active ingredient.
4. A solid dosage form composition of a compressed mixture of from about 1%
to about 99% of an excipient comprising a particulate agglomerate of coprocessed microcrystalline cellulose and from about 0.1% to about 0.5% by weight of a surfactant, the microcrystalline cellulose and surfactant being in intimate association with each other, and from about 99% to about 1%, by weight, of a therapeutically active ingredient.
to about 99% of an excipient comprising a particulate agglomerate of coprocessed microcrystalline cellulose and from about 0.1% to about 0.5% by weight of a surfactant, the microcrystalline cellulose and surfactant being in intimate association with each other, and from about 99% to about 1%, by weight, of a therapeutically active ingredient.
5. An excipient composition comprising a particulate agglomerate of coprocessed micro-crystalline cellulose, silicon dioxide, and surfactant, said silicon dioxide and said surfactant being present in an amount by weight of the microcrystalline cellulose which is effective to augment the compressibility of the microcrystalline cellulose, said microcrystalline cellulose, said silicon dioxide, and said surfactant being in intimate association with each other.
6. An excipient composition comprising:
(a) from about 1% to about 99% of an excipient including a particulate agglomerate of coprocessed microcrystalline cellulose, (b) from about 0.1% to about 5.0 % of a surfactant by weight, said surfactant comprising said microcrystalline cellulose and silicon dioxide, the microcrystalline cellulose, the silicon dioxide, and said surfactant being in intimate association with each other; and (c) from about 99% to about 1%, by weight, of an active ingredient.
(a) from about 1% to about 99% of an excipient including a particulate agglomerate of coprocessed microcrystalline cellulose, (b) from about 0.1% to about 5.0 % of a surfactant by weight, said surfactant comprising said microcrystalline cellulose and silicon dioxide, the microcrystalline cellulose, the silicon dioxide, and said surfactant being in intimate association with each other; and (c) from about 99% to about 1%, by weight, of an active ingredient.
7. The composition of claims 1, 3-6 wherein said surfactant is an ionic surfactant.
8. The composition of claims 1, 3-6, wherein said ionic surfactant is an anionic surfactant.
9. The composition of claim 8, wherein said anionic surfactant is sodium lauryl sulfate.
10. The composition of claim 8, wherein said anionic surfactant is docusate sodium.
11. The composition of claims 1-6, wherein said surfactant is included in an amount of from about 0.15% to about 0.4%, based on the weight of said microcrystalline cellulose.
12. The composition of claims 1-6, wherein said surfactant is included in an amount of from about 0.2% to about 0.3%, based on the weight of said microcrystalline cellulose.
13. The composition of claims 1, 3, 5, and 6, wherein said excipient composition comprises particles having an average particle size of from about 10 µm to about 1,000 µm.
14. The composition of claims 1, 3, 5, and 6, wherein said excipient composition comprises particles having an average particle size of from about 10 µm to about 500 µm.
15. The composition of claims 1 , 3, 5, and 6, wherein said excipient composition comprises particles having an average particle size of from about 30 µm to about 250 µm.
16. The composition of claims 1, 3, 5, and 6, wherein said excipient composition comprises particles having an average particle size of from about 40 µm to about 200 µm.
17. The composition of claims 1, 3, 5, and 6, wherein said excipient composition has a moisture content from about 0.5% to about 15%.
18. The composition of claims 1, 3, 5, and 6, wherein said excipient composition further comprises from about 0.1 to about 20% by weight silicon dioxide, based on the weight of the microcrystalline cellulose.
19. The composition of claims 1, 3, 5, and 6, wherein said excipient composition further comprises from about 0.5 to about 10% by weight silicon dioxide, based on the weight of the microcrystalline cellulose.
20. The composition of claims 1, 3, 5, and 6 wherein said excipient composition further comprises from about 1.25 to about 5% by weight silicon dioxide, based on the weight of the microcrystalline cellulose.
21. The composition of claim 20, wherein said silicon dioxide is derived from colloidal silicon dioxide.
22. The composition of claims 1, 3, 5, and 6 wherein said excipient composition has a bulk density from about 0.2 g/ml to about 0.5 g/ml.
23. The composition of claim 20, wherein said excipient composition has a bulk density from about 0.22 g/ml to about 0.35 g/ml.
24. The composition of claims 1, 3, 5, and 6 wherein said excipient composition comprises particles having a member of the group consisting of non-silicon metal oxides, starches, starch derivatives, polyalkylene oxides, celluloses, cellulose ethers, cellulose esters and mixtures thereof.
25. The composition of claim 3, further comprising silicon dioxide.
26. The composition of claims 3 and 6 which has been wet granulated.
27. The composition of claims 3 and 6 which has been incorporated into a solid form.
28. The composition of claim 4, which has been wet granulated prior to compression.
29. The composition of claim 4, which is incorporated into an oral dosage form.
30. The composition of claim 5, wherein said surfactant is included in an amount of from about 0.1% to about 5.0%, based on the weight of said microcrystalline cellulose.
31. The composition of claim 5, wherein said surfactant is included in an amount of from about 0.1% to about 0.5%, based on the weight of said microcrystalline cellulose.
32. A method of enhancing the compressibility of microcrystalline cellulose in wet granulation products, comprising:
a. forming an aqueous slurry containing a mixture of microcrystalline cellulose in the form of a wet cake and a surfactant; and b. drying said slurry to obtain an excipient comprising a plurality of agglomerated particles of microcrystalline cellulose in intimate association with said surfactant, said surfactant being present in an amount from about 0.1 to about 0.5%, based on the weight of said microcrystalline cellulose.
a. forming an aqueous slurry containing a mixture of microcrystalline cellulose in the form of a wet cake and a surfactant; and b. drying said slurry to obtain an excipient comprising a plurality of agglomerated particles of microcrystalline cellulose in intimate association with said surfactant, said surfactant being present in an amount from about 0.1 to about 0.5%, based on the weight of said microcrystalline cellulose.
33. The method of claim 32, wherein said slurry comprises from about 0.5% to about 25% by weight microcrystalline cellulose.
34. The method of claim 32, wherein said slurry contains from about 15% to about 20% microcrystalline cellulose.
35. The method of claim 32, wherein said slurry contains from about 17% to about 19% microcrystalline cellulose.
36. The method of claim 32, wherein said surfactant is an anionic surfactant.
37. The method of claim 36, wherein said anionic surfactant is sodium lauryl sulfate.
38. The method of claim 36, wherein said anionic surfactant is docusate sodium.
39. The method of claim 32, further comprising drying said slurry of microcrystalline cellulose and a surfactant by spray drying.
40. The microcrystalline cellulose-based excipient particles prepared by the process of claim 32.
41. A method of preparing a solid dosage form, comprising:
a. forming an aqueous slurry containing a mixture of microcrystalline cellulose in the form of a wet cake and a surfactant;
b. drying said slurry to obtain an excipient comprising a plurality of agglomerated particles of microcrystalline cellulose in intimate association with said surfactant, said surfactant being present in an amount from about 0.1 to about 0.5% based on the weight of said microcrystalline cellulose;
c. mixing an active ingredient with said excipient in a ratio from about 1:99 to about 99:1, by weight; and d. incorporating said mixture obtained in step (c) into a plurality of solid unit doses.
a. forming an aqueous slurry containing a mixture of microcrystalline cellulose in the form of a wet cake and a surfactant;
b. drying said slurry to obtain an excipient comprising a plurality of agglomerated particles of microcrystalline cellulose in intimate association with said surfactant, said surfactant being present in an amount from about 0.1 to about 0.5% based on the weight of said microcrystalline cellulose;
c. mixing an active ingredient with said excipient in a ratio from about 1:99 to about 99:1, by weight; and d. incorporating said mixture obtained in step (c) into a plurality of solid unit doses.
42. The method of claims 32 and 41, further comprising drying said slurry of microcrystalline cellulose and surfactant by a method selected from the group consisting of flash drying, ring drying, spray drying, and micron drying.
43. The method of claims 32 and 41, further comprising drying said slurry such that the resultant excipient particles have an average particle size from about µm to about 1,000 µm.
44. The method of claim 41, wherein said surfactant is an anionic surfactant.
45. The method of claim 44, wherein said anionic surfactant is sodium lauryl sulfate.
46. The method of claim 41, further comprising wet granulating said mixture obtained in step (c) prior to incorporating said mixture into said solid unit doses.
47. The method of claim 41, further comprising adding a further amount of excipient obtained in step (b) to said mixture obtained in step (c), and there-after incorporating the mixture into a solid dosage form.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/370,576 | 1995-01-09 | ||
US08/370,576 US5585115A (en) | 1995-01-09 | 1995-01-09 | Pharmaceutical excipient having improved compressability |
US08/486,183 US5725883A (en) | 1995-01-09 | 1995-06-07 | Pharmaceutical excipient having improved compressibility |
US08/486,183 | 1995-06-07 | ||
PCT/US1996/000539 WO1996022080A1 (en) | 1995-01-09 | 1996-01-05 | Pharmaceutical excipient having improved compressibility |
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CA2183882A1 CA2183882A1 (en) | 1996-07-25 |
CA2183882C true CA2183882C (en) | 2000-08-22 |
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CA002183882A Expired - Fee Related CA2183882C (en) | 1995-01-09 | 1996-01-05 | Pharmaceutical excipient having improved compressibility |
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US (3) | US5866166A (en) |
EP (1) | EP0749300B1 (en) |
JP (1) | JP3728321B2 (en) |
AU (1) | AU708346B2 (en) |
BR (1) | BR9605245A (en) |
CA (1) | CA2183882C (en) |
FI (1) | FI963496A (en) |
HU (1) | HUP9602361A3 (en) |
IL (3) | IL116674A (en) |
NO (1) | NO321771B1 (en) |
TW (1) | TW505529B (en) |
WO (1) | WO1996022080A1 (en) |
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-
1996
- 1996-01-04 IL IL11667496A patent/IL116674A/en not_active IP Right Cessation
- 1996-01-04 IL IL13972896A patent/IL139728A/en not_active IP Right Cessation
- 1996-01-05 EP EP96907007A patent/EP0749300B1/en not_active Expired - Lifetime
- 1996-01-05 HU HU9602361A patent/HUP9602361A3/en unknown
- 1996-01-05 WO PCT/US1996/000539 patent/WO1996022080A1/en active Application Filing
- 1996-01-05 CA CA002183882A patent/CA2183882C/en not_active Expired - Fee Related
- 1996-01-05 AU AU50199/96A patent/AU708346B2/en not_active Ceased
- 1996-01-05 JP JP52234796A patent/JP3728321B2/en not_active Expired - Lifetime
- 1996-01-05 BR BR9605245A patent/BR9605245A/en not_active Application Discontinuation
- 1996-01-06 TW TW085100140A patent/TW505529B/en not_active IP Right Cessation
- 1996-06-10 US US08/660,553 patent/US5866166A/en not_active Expired - Lifetime
- 1996-07-08 US US08/676,654 patent/US5741524A/en not_active Expired - Lifetime
- 1996-09-06 FI FI963496A patent/FI963496A/en unknown
- 1996-09-06 NO NO19963733A patent/NO321771B1/en not_active IP Right Cessation
-
1997
- 1997-12-17 US US08/982,224 patent/US5858412A/en not_active Expired - Lifetime
-
2000
- 2000-11-16 IL IL13972800A patent/IL139728A0/en unknown
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WO1996022080A1 (en) | 1996-07-25 |
TW505529B (en) | 2002-10-11 |
HU9602361D0 (en) | 1996-11-28 |
NO963733L (en) | 1996-09-06 |
US5866166A (en) | 1999-02-02 |
IL139728A (en) | 2003-06-24 |
HUP9602361A2 (en) | 1997-08-28 |
AU5019996A (en) | 1996-08-07 |
IL116674A0 (en) | 1996-05-14 |
CA2183882A1 (en) | 1996-07-25 |
IL139728A0 (en) | 2002-02-10 |
NO963733D0 (en) | 1996-09-06 |
BR9605245A (en) | 1997-09-16 |
IL116674A (en) | 2003-05-29 |
JP3728321B2 (en) | 2005-12-21 |
EP0749300A1 (en) | 1996-12-27 |
EP0749300A4 (en) | 2001-09-05 |
EP0749300B1 (en) | 2009-10-14 |
FI963496A0 (en) | 1996-09-06 |
AU708346B2 (en) | 1999-08-05 |
US5741524A (en) | 1998-04-21 |
FI963496A (en) | 1996-11-06 |
JPH10512862A (en) | 1998-12-08 |
HUP9602361A3 (en) | 2001-12-28 |
US5858412A (en) | 1999-01-12 |
NO321771B1 (en) | 2006-07-03 |
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