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WO2016201119A1 - Excipient et formes galéniques solides orales pour médicaments huileux - Google Patents

Excipient et formes galéniques solides orales pour médicaments huileux Download PDF

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Publication number
WO2016201119A1
WO2016201119A1 PCT/US2016/036728 US2016036728W WO2016201119A1 WO 2016201119 A1 WO2016201119 A1 WO 2016201119A1 US 2016036728 W US2016036728 W US 2016036728W WO 2016201119 A1 WO2016201119 A1 WO 2016201119A1
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WO
WIPO (PCT)
Prior art keywords
excipient
silicate
carrier
oily
composition
Prior art date
Application number
PCT/US2016/036728
Other languages
English (en)
Inventor
Anthony CARPANZANO
Michael Nagel
Original Assignee
J. Rettenmaier & Söhne Gmbh + Co Kg
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by J. Rettenmaier & Söhne Gmbh + Co Kg filed Critical J. Rettenmaier & Söhne Gmbh + Co Kg
Publication of WO2016201119A1 publication Critical patent/WO2016201119A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/20—Agglomerating; Granulating; Tabletting
    • 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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
    • A23L29/206—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin
    • A23L29/262—Cellulose; Derivatives thereof, e.g. ethers
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • 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

Definitions

  • the present invention is related to a novel excipient for use in the manufacture of pharmaceuticals and nutraceuticals, and in particular, solid dosage forms such as tablets which include one or more active ingredients which are water-insoluble or oil-dissolved, or are themselves oils.
  • the present invention relates to a novel excipient for use in the manufacture of pharmaceuticals and/or nutraceuticals, and in particular, solid dosage forms such as tablets which include one or more active ingredients.
  • the material to be compressed into the dosage form possess certain physical characteristics which lend themselves to processing in such a manner.
  • the material to be compressed must be free-flowing, must be lubricated, and, importantly, must possess sufficient cohesiveness to insure that the solid dosage form remains intact after compression.
  • the tablet is formed by pressure being applied to the material to be tableted on a tablet press.
  • a tablet press includes a lower punch which fits into a die from the bottom and an upper punch having a corresponding shape and dimension which enters the die cavity from the top after the tableting 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.
  • 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 drug(s) which is being formulated into a dosage form.
  • Lubricants are typically added to avoid the materials) being tabletted from sticking to the punches.
  • Commonly used lubricants include magnesium stearate and calcium stearate. Such lubricants are commonly included in the final tabletted product in amounts of less than 1% by weight.
  • solid dosage forms In addition to lubricants, solid dosage forms often contain 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.
  • Binders are agents which impart cohesive qualities to the powdered material(s). Commonly used binders include starch, and sugars such as sucrose, 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.
  • Dry granulation procedures may be utilized where one of the constituents, either the drug or the diluent, has insufficient cohesive or flow properties to be tabletted.
  • the method includes mixing the ingredients, slugging the ingredients, dry screening, lubricating and finally compressing the ingredients.
  • the powdered material(s) 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, radio-frequency dryer, microwave, vacuum, or infra-red dryer.
  • excipients are added to the formulation in order to 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.
  • Useful direct compression excipients include processed forms of cellulose, sugars, and dicalcium phosphate dihydrate, among others.
  • a 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.
  • 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 acceptable solid dosage form.
  • wet granulation provides the material to be compressed with better wetting properties, particularly in the case of hydrophobic drug substances.
  • a hydrophilic excipient makes the surface of a hydrophobic drug more hydrophilic, easing disintegration and dissolution.
  • 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 problem with the direct compression method.
  • 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 form granules which when dried exhibit enhanced flow and compression characteristics.
  • microcrystalline cellulose Due to the popularity of microcrystalline cellulose, pharmaceutical formulators have deemed it desirable to include this excipient in a formulation which is wet granulated prior to tabletting. [019] 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 Emcocel ® from JRS Pharma and as Avicel ® from FMC Corp. Compared to other directly compressible excipients, microcrystalline cellulose is generally considered to exhibit superior compressibility and disintegration properties.
  • Silicified microcrystalline cellulose is commercially available as Prosolv ® SMCC and is a high functionality excipient that imparts superior flow, compaction and dispersion to a formulation. When used in direct compression, Prosolv ® SMCC can replace granulations and provide uniform tablets, while significantly reducing excipient numbers and levels.
  • Prosolv ® SMCC may enable direct compression while avoiding wet granulation, and may provide increased production capacity and improved compactibility. On the other hand, Prosolv ® SMCC provides excellent compressibility even when wet granulated, and so is useful in wet granulated formulations, as well.
  • Neusilin® is a totally synthetic magnesium aluminometasilicate (MAS) with exceptional excipient properties to improve API delivery and the quality of oral solid dosage forms, commercially available from Fuji Chemical Industry Co., Ltd.
  • Neusilin is a multifunctional excipient that can be used in both direct compression and wet granulation of solid dosage forms.
  • Neusilin is widely used for improvement of the quality of tablets, powder, granules and capsules.
  • the most suitable grade for converting oil to powder is Neusilin® US2.
  • an addition of 0.S to 2% UFL2 is said to improve fiowability substantially.
  • Neusilin® UFL2 alone at 0.5% can resolve sticking issues of oily formulations.
  • Neusilin® is said to potentially resolve problems associated with tabletting and improve efficiency of poorly water soluble drugs in a solid dispersion, as well as improve dissolution and bioavailability.
  • Neusilin® is also said to be useful in developing a Self Emulsifying Drug Delivery System (SEDDS) or a Self Nano-Emulsifying Drug Delivery System (SNEDDS), by aiding in the conversion of the liquid SEDDS/SNEDDS into a solid one.
  • SEDDS Self Emulsifying Drug Delivery System
  • SNEDDS Self Nano-Emulsifying Drug Delivery System
  • Oily drugs or drugs which are dissolvable in oil, are typically prepared as soft gel capsules. Although there are many commonly used excipients that will absorb oils or oily drugs, these excipients can only absorb a limited amount of oil when the goal is to
  • oily active ingredients e.g., drugs
  • the present invention is directed to an excipient which comprises or consists of microcrystalline cellulose and a silicate-based adsorbent carrier for an oily active ingredient.
  • the excipient further comprises or consists of an optional
  • the silicate based absorbant carrier is a magnesium aluminometasilicate, a granular or fine powder grade of a hydrophilic silica, or a mixture thereof.
  • the granular or fine powder grade of hydrophilic silica is a granular hydrophilic fumed silica.
  • the silicate-based carrier may alternatively or further comprise hydrophilic mixed oxides of silicon dioxide (Si ⁇ 3 ⁇ 4) and aluminum oxide (A1 2 0 3 ).
  • the silicate-based carrier may
  • a hydrophobic grade of a granular or fine powder silica e.g., a hydrophobic fumed silica
  • the excipient comprises a magnesium aluminometasilicate as the silicate-based adsorb ant carrier.
  • the excipient further includes a colloidal silicon dioxide as a compressibility enhancing agent.
  • the excipient comprises a granulated hydrophilic fumed silica as the silicate-based adsorbent carrier.
  • the excipient further includes a colloidal silicon dioxide as a compressibility enhancing agent.
  • the excipient of the present invention comprises a particulate agglomerate of coprocessed microcrystalline cellulose, from about 0.5% to about 50% silicate-based adsorbent carrier, by weight of the microcrystalline cellulose, and optionally from about 0.1% to about 20% colloidal silicon dioxide, by weight.
  • the excipient particles have an average particle size of from about 10 microns to about 500 microns. In certain embodiments, the excipient particles have an average particle size of from about 10 microns to about 500 microns.
  • the microcrystalline cellulose and silicate-based adsorbent carrier are in intimate association with each other (e.g., are co-processed), in the form of agglomerated particles, e.g., as attainable via a spray-drying technique.
  • the (optional) colloidal silicon dioxide portion of the agglomerate being derived from a colloidal silicon dioxide having a particle size from about 1 nanometer (nm) to about 100 microns, based on average primary particle size.
  • the silicon dioxide has a particle from about 5 nm to about 50 microns.
  • the (optional) colloidal silicon dioxide component comprises from about 0.5% to about 15% of the excipient, and most preferably from about 1% to about 5% by weight relative to the total weight of the excipient.
  • the colloidal silicon dioxide is further characterized by a surface area from about 10 m 2 /g to about 500 m 2 /g, preferably from about 50 m 2 /g to about 500 m 2 /g, and more preferably from about 175 m 2 /g to about 350 m 2 /g.
  • the compressibility enhancing agent is a colloidal silicon dioxide as described herein.
  • the colloidal silicon dioxide has surface area from about 10 m 2 /g to about 500 m 2 /g, and more preferably from about 175 m 2 /g to about 350 m 2 /g.
  • the silicate-based adsorbent carrier is a magnesium aluminometasilicate.
  • the magnesium aluminometasilicate is, e.g., Neusilin® US2 or UFL2.
  • the silicate-based adsorbant carrier is a granulated hydrophilic fumed silica.
  • the granulated hydrophilic fumed silica is, e.g.,Aeroperl ® 300, commercially available from Evonik.
  • the excipient comprises (in addition to the silicate-based adsorbant carrier) Prosolv ® SMCC 50 (silicified microcrystalline cellulose) commercially available from JRS Pharma. This product typically has a particle size ranging from about 45 to about 80 ⁇ .
  • the compressibility augmenting agent is selected from the group consisting of silicon dioxide, a surfactant, a highly polar compound, and mixtures thereof. In certain embodiments when the compressibility augmenting agent consists of said surfactant, said surfactant is present in an amount from about 0.1% to about 0.5% by weight of said microcrystalline cellulose.
  • the excipient composition comprises agglomerated particles of said microcrystalline cellulose, the optional compressibility augmenting agent and the silicate-based adsorbant carrier in intimate association with each other.
  • the agglomerated particles of the excipient composition further comprise a member of the group consisting of non-silicon metal oxides, starches, starch derivatives, polyalkylene oxides, stearic acid, kaolin, polydimethylsiloxane, silica gel, diatomaceous earth, and mixtures thereof.
  • the excipient composition is a physical admixture comprising microcrystalline cellulose, the silicate-based adsorbant carrier for an oily active ingredient and the (optional) compressibility augmenting agent.
  • the microcrystalline cellulose, a compressibility augmenting agent and a silicate or silicon dioxide based adsorbant carrier are in the form of agglomerated particles comprising the same. In certain preferred embodiments, therefore, the excipient composition is pre-agglomerated prior to the incorporation of an oily active ingredients).
  • the agglomerated particles may have an average particle size, e.g., of from about 10 microns to about 1,000 microns, more preferably from about 10 microns to about 150 microns or may be spheronized for use in capsules.
  • the excipient composition comprises a particulate agglomerate as described in the above paragraph
  • the excipient composition is prepared by preparing an aqueous slurry of microcrystalline cellulose in the form of a wet cake, compressibility augmenting agent(s), silicate or silicon dioxide based adsorbant carrier, and other optional ingredients, and spray-drying the ingredients to form agglomerated particles comprising the same.
  • the invention is further directed in part to a pharmaceutical solid dosage form, comprising an excipient composition comprising microcrystalline cellulose, a silicate-based adsorbant carrier for an oily active ingredient and an (optional) compressibility augmenting agent; and from about from about 0.5% to about 50%, or from about 1% to about 25%, and in certain embodiments from about 1% to about 35%, or from about 1% to about 22.5%, or from about 10% to about 30%, or from about 10% to about 20%, or from about 15% to about 30% of an oily active ingredient, the oily active ingredient being adsorbed onto the excipient composition.
  • the compressibility augmenting agent comprises from about 0.1% to about 20% by weight of the excipient.
  • the compressibility augmenting agent is colloidal silicon dioxide.
  • the silicate-based adsorbant carrier is a magnesium
  • aluminometasilicate a granulated hydrophilic fumed silica, or a mixture thereof.
  • the microcrystalline cellulose, (optional) colloidal silicon dioxide and magnesium aluminometasilicate are in the form of agglomerated particles comprising the same, i.e., the excipient composition is a pre-agglomerated mixture of these ingredients and any further optional excipient composition ingredients as described herein.
  • the excipient particles have an average particle size of from about 10 microns to about 500 microns.
  • the colloidal silicon dioxide has surface area from about 10 m 2 /g to about 500 m 2 /g.
  • the particles comprising the oily active agent (adsorbed onto) and the excipient composition are compressed into tablets.
  • the tablets preferably have a hardness from about 0.7 to about 1.4 g/cm 3 .
  • the oily active ingredient is an oily material in and of itself.
  • the oily active agent comprises a low-solubility drug dissolved or dispersed in an oily solvent as described herein.
  • the low-solubility drug has a solubility, e.g., of less than 10 mg/mL, less than 1 mg/mL, or less than 0.1 mg/mL.
  • the oil active ingredient is a drug which exists in a waxy state at room temperature, but becomes oily when warmed or heated.
  • the invention is further directed in part to a pharmaceutical solid dosage form, comprising an excipient composition comprising pre-agglomerated particles comprising microcrystalline cellulose, (optional) colloidal silicon dioxide in an amount from about 0.1% to about 20% by weight of the microcrystalline cellulose, and a magnesium
  • the pharmaceutical composition comprises particles of the oily active ingredient adsorbed onto the excipient composition, which are compressed into tablets.
  • the oily active ingredient may be an oily material in and of itself, or the oily active ingredient may comprise a low-solubility drug dissolved or dispersed in an oily solvent.
  • the low-solubility drug has a solubility, e.g., of less than 10 mg/mL, less than 1 mg/mL, or less than 0.1 mg/mL.
  • the invention is further directed to a pharmaceutical solid dosage form, comprising an excipient composition comprising microcrystalline cellulose, a silicate-based adsorbant carrier selected from the group consisting of a magnesium aluminometasilicate, a granular hydrophilic silica, or a mixture thereof, and at least about 10% of an oily active ingredient, the oily active ingredient being adsorbed onto the excipient composition.
  • a pharmaceutical solid dosage form comprising an excipient composition comprising microcrystalline cellulose, a silicate-based adsorbant carrier selected from the group consisting of a magnesium aluminometasilicate, a granular hydrophilic silica, or a mixture thereof, and at least about 10% of an oily active ingredient, the oily active ingredient being adsorbed onto the excipient composition.
  • the pharmaceutical solid dosage form further comprises from about 0.1% to about 20% by weight compressibility augmenting agent, which may be, e.g., colloidal silicon dioxide.
  • the pharmaceutical solid dosage form may comprise from about 0.5% to about 50% silicate-based adsorbant carrier, by weight.
  • silicate-based adsorbant carrier is a magnesium aluminometasilicate
  • the oily active ingredient may be present in an amount from, e .g., about 10% to about 22.5%, by weight.
  • the silicate-based adsorbant carrier is a granular hydrophilic fumed silica
  • the oily active ingredient may be present in an amount from about 10% to about 50%, by weight.
  • the oily active agent is oily by nature or is dissolved or dispersed in an oily solvent.
  • the oily active ingredient is present in an amount up to about 35% by weight. This amount of oily active ingredient may be increased when the pharmaceutical solid dosage form is not compressed and is instead incorporated in granular or powder form into a capsule.
  • the microcrystalline cellulose, and silicate-based adsorbant carrier which comprise the excipient composition may be a physical admixture, and in certain preferred embodiments are in the form of pre-agglomerated particles comprising the same (microcrystalline cellulose and silicate-based adsorbant carrier).
  • the excipient particles preferably have an average particle size of from about 10 microns to about 500 microns.
  • the oily active agent comprises a low-solubility drug dissolved or dispersed in an oily solvent, e.g, wherein the low-solubility drug has a solubility of less than 10 mg/mL, or less than 1 mg/mL, or less than 0.1 mg/mL.
  • the tablets When the pharmaceutical composition is compressed into tablets, the tablets preferably have a hardness from about 0.7 g/cm 3 to about 1.4 g cm 3 , or a hardness of from about 50 newtons to about 150 newtons, or preferably from about 80 to about 120 newtons.
  • 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 in the form of a wet cake (i.e.
  • hydrocellulose or hydrolyzed cellulose from about 0.1% to about 20% colloidal silicon dioxide by weight relative to the excipient, and from about 0.5% to about 50% silicate-based adsorbant carrier, by weight of the excipient.
  • 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, and most preferably from about 17% to about 19% by weight.
  • the present invention is further directed to a mixture of an oily active ingredient(s) and an excipient comprising a mixture of coprocessed microcrystalline cellulose, from about 0.1% to about 20% compressibility augmenting agent by weight of the excipient, and from about 0.5% to about 50% silicate-based adsorbent carrier, by weight of the excipient.
  • the microcrystalline cellulose, compressibility augmenting agent and silicate-based adsorbent carrier are in intimate association with each other (e.g., are in a particulate agglomerate form) prior to the introduction of the oily active ingredient.
  • the compressibility augmenting agent is a silicon dioxide, preferably having a particle size from about 1 nm to about 100 microns.
  • the silicate-based adsorbent carrier is a magnesium aluminometasilicate (e.g., Neusilin US2 or UFL2), a hydrophilic fumed silica (e.g., Aerosil fumed silica).
  • the oily active ingredient may comprise from about 0.1% to about 50% of the excipient, by weight.
  • the present invention is further directed to a granulate of an active ingredient(s) and the novel excipient described herein, wherein the active ingredients) and excipient have been subjected to a wet granulation procedure.
  • the present invention is further 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.
  • the compressed solid dosage form 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.
  • 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 in an excipient which is particularly adapted for tableting oil active agents.
  • the method includes forming an aqueous slurry containing a mixture of microcrystalline cellulose in the form of a wet cake (i.e. hydrocellulose or hydrolyzed cellulose) and the silicate-based adsorbent carrier and (optional) colloidal silicon dioxide having a particle size from about 1 nm to about 100 microns, end drying the slurry to obtain microcrystalline cellulose-based excipient particles in which the silicon dioxide particles have been integrated with the microcrystalline cellulose particles.
  • a wet cake i.e. hydrocellulose or hydrolyzed cellulose
  • colloidal silicon dioxide having a particle size from about 1 nm to about 100 microns
  • the slurry contains from about 0.5% to about 25% by weight microcrystalline cellulose in the form of a wet cake, with amounts of from about 15% to about 20% being preferred. Furthermore, the slurry contains from about 0.25% to about 5% by weight colloidal silicon dioxide.
  • the excipient composition provides improved bioavailability for an oily active ingredient (drug) which is adsorbed onto the excipient composition and formulated into an oral solid dosage form.
  • the excipient composition is incorporated together with one or more oily active ingredients (e.g., drugs) into a Self Emulsifying Drug Delivery System (SEDDS) or a Self Nano-Emulsifying Drug Delivery System (SNEDDS).
  • the oil is incorporated with an oily solvent as a Self Emulsifying Drug
  • SEDDS Self Nano-Emulsifying Drug Delivery System
  • SNEDDS Self Nano-Emulsifying Drug Delivery System
  • oily active ingredient it is meant for purposes of the invention that the active ingredient that is oily in and of itself, or which is relatively insoluble in water and which dissolves in oil or is dissolved in oil, or the drug is a waxy material that is an oil when heated.
  • oily active ingredients include but are not limited to drugs and nutraceuticals.
  • oily active ingredient includes but is not limited to low-solubility drugs having a solubility of less than 10 mg/mL, more preferred for low-solubility drugs having a solubility of less than 1 mg/mL, and even more preferred for low-solubility drugs having a solubility of less than 0.1 mgmL.
  • low-solubility drug is that the drug may be either “substantially water-insoluble,” which means that the drug has a minimum aqueous solubility at
  • physiologically relevant pH e.g., pH 1-8
  • “sparingly water-soluble” that is, has an aqueous solubility up to about 1 to 2 mgmL, or even low to moderate aqueous- solubility, having an aqueous-solubility from about 1 mg/mL to as high as about 20 to 40 mg/mL.
  • the oily active ingredient is a low-solubility active ingredient (e.g., drug)
  • the term further encompasses the drug being dissolved or dispersed in an oily solvent.
  • oily solvent is meant for purposes of the present invention to encompass any pharmaceutical or food approved substance which is oily in its nature that is not mixing or dissolving with water or hydrous mediums.
  • oily solvent may be natural or synthetic or semi-synthetic, in the form of liquid, semi-solid or solid at room temperature.
  • oily solvents are mineral oil, vegetable oil, silicon oil, lanolin, refined animal oil, hydrocarbon esters derived from vegetable animal or marine origin.
  • vegetable oils are:
  • the oil may be saponifiable or unsaponifiable and liquid or solid at room temperature.
  • Special oils are essential oils or poly unsaturated fatty acid or oils or etherified oils and modified semi-synthetic oils.
  • Example of semi-synthetic oil is a product of inter-esterification of hydro genated palm oil palm kernel oil (Cg-Cig triglycerides) with melting point at about 30°C to about 50°C.
  • a further preferred class of hydrophobic solvents may be selected from the group comprising isostearic acid derivatives, isopropyl palmitate, lanolin oil, diisopropyl dimerate, maleated soybean oil, octyl palmitate, isopropyl isostearate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolin alcohol, cetyl acetate, glyceryl oleate, tocopheryl linoleate, wheat germ glycerides, arachidyl propionate, myristyl lactate, isopropyl palmitate, decyl oleate, propylene glycol ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate, neopentylglycol dicaprylate/dicaprate, hydrogenated coco- glycerides, isononyl isonon
  • a further class are fatty acids include, but are not limited to, caproic acid, capric acid, caprylic acid, oleic acid, palmoic acid, stearic acid, linoleic acid, octanoic acid, decanoic acid, linolenic acid, palmitic acid, palmitoleic acid, arachidic acid, myristic acid, behenic acid and lignic acid, or fatty alcohols, and also mono and diglycerides.
  • 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 12 hour or a 24 hour dosage form.
  • biologically available it is meant for purposes of the invention that the therapeutically active medicament is absorbed from the formulation and becomes available in the body at the intended site of drug action.
  • microcrystalline cellulose in the form of a wet cake As one of ordinary skill in the art will appreciate, the terms “microcrystalline cellulose in the form of a wet cake”, “hydrocellulose”, and “hydrolyzed cellulose” are synonymous, and refer to the precursor of the (dried) microcrystalline cellulose product.
  • FIG. 1 graphically shows compression profiles of blended formulations of an excipient in accordance with the invention (also referred to herein as "Prosolv ® Oil Excipient' *) of Example 1;
  • FIG.2 graphically shows comparative compression profiles of the Prosolv Oil Excipient - Co-Processed (SD) versus Simple Blends (DC) of Example 2;
  • FIG.3 graphically shows comparative direct compression profiles of the Prosolv Oil Excipient in different ratios of ProSolv SO to Aeroperl 300 of Example 7 (physical blends);
  • FIG.4 graphically shows comparative compression profiles of the Prosolv Oil Excipient with oil loading of Example 8.
  • FIG. S graphically shows comparative compression profiles of the Prosolv Oil Excipient - co-processed of Example 9;
  • FIG. 6 graphically shows comparative compression profiles of the Prosolv Oil Excipient - co-processed with oil loading of Example 10;
  • FIG.7 graphically shows comparative compression profiles of the Prosolv Oil Excipient - co-processed with higher oil loadings of Example 11;
  • FIG. 8 graphically shows comparative compression profiles of the Prosolv Oil Excipient of Example 12 - co-processed with and without the presence of colloidal silicon dioxide, and with and without oil loading;
  • FIG.9 graphically shows comparative compression profiles of the Prosolv Oil Excipient of Example 13 co-processed with and without the presence of colloidal silicon dioxide.
  • the present invention is directed in part to a new excipient which can be used with oily active ingredients or active ingredients which are dissolved in an oil.
  • the excipient comprises microcrystalline cellulose, and a silicate-based adsorbant carrier (such as a magnesium aluminometasilicate and/or a hydrophilic fumed silica).
  • the excipient optionally further comprises a compressibility augmenting agent (such as colloidal silicon dioxide).
  • Microcrystalline cellulose is a well-known tablet diluent 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 the aqueous slurry is spray dried to form dry, white odorless, tasteless crystalline powder of porous particles of a broad size distribution.
  • hydrolyzed cellulose the terms "hydrolyzed cellulose"
  • hydrocellulose and "microcrystalline cellulose in the form of a wet cake” are synonymous and encompass materials prepared by partially depolymerizing cellulose obtained as pulp. Another method of preparing microcrystalline cellulose is disclosed in U.S. Pat. No.
  • 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 that 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 by 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.
  • microcrystalline cellulose has an apparent density of about 0.28 g/cm.sup.3 and a tap density of about 0.43 g/cm 3 . Handbook of Pharmaceutical Excipients, pages S3-SS.
  • microcrystalline cellulose 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 5-30% 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 novel agglomerated microcrystalline cellulose excipient optionally utilizes a compressibility augmenting agent which (i) physically restricts the proximity of the interlace between adjacent cellulose surfaces; (ii) inhibits interactions between adjacent cellulose surfaces, for example, via the creation of a hydrophobic boundary at cellulose surfaces; or (iii) accomplishes both (i) and (ii) above.
  • a compressibility augmenting agent which (i) physically restricts the proximity of the interlace between adjacent cellulose surfaces; (ii) inhibits interactions between adjacent cellulose surfaces, for example, via the creation of a hydrophobic boundary at cellulose surfaces; or (iii) accomplishes both (i) and (ii) above.
  • microcrystalline cellulose surfaces include silicon dioxide having a very fine particle size, e.g., from about 1 run to about 100 microns.
  • a most preferred silicon dioxide is colloidal silicon dioxide.
  • Other materials of similar size may also be used instead of silicon dioxide to create the aforementioned physical barrier.
  • such other physically-acting compressibility augmenting agents will have at least some physical characteristics similar to that of silicon dioxide.
  • Compressibility augmenting agents which inhibit surface-to-surface interactions between surfaces of the microcrystalline cellulose include any material which has the ability, via a portion of the molecule, to bind or interact with the surface of the microcrystalline cellulose and at the same time, via another portion of the molecule, to inhibit the attraction of the cellulose surfaces, e.g., via a hydrophobic portion or "tail".
  • Suitable compressibility augmenting agents will have an HLB value of at least 10, preferably at least about IS, and more preferably from about IS to about 40 or greater.
  • compressibility augmenting agents which have shown the greatest effect have had relatively high HLB values, and therefore an HLB value from about 30 to about 40 or greater is most preferred.
  • Agents which exhibit these properties include certain surfactants such as sodium lauryl sulfate and polysorbate 40, and highly polar compounds, including pharmaceutically acceptable dyes such as congo red.
  • the compressibility augmenting agent which provides a physical barrier between adjacent cellulose surfaces is a silicon dioxide, preferably colloidal silicon dioxide.
  • Silicon dioxide is obtained by insolubilizing dissolved silica in sodium silicate solution. When obtained by the addition of sodium silicate to a mineral acid, the product is termed silica gel. When obtained by the destabilization of a solution of sodium silicate in such a manner as to yield very fine particles, the product is termed precipitated silica. Silicon dioxide is insoluble in water. Prior to the present invention, silicon dioxide, and in particular colloidal silicon dioxide, was used mainly as a glidant and anti-adherent in tableting processes and encapsulation, promoting the flowability of the granulation.
  • 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 amorphous 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 content, 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.
  • colloidal silicon dioxide products have, for example, a BET surface area ranging from about 50 ⁇ 15 m 2 /g (Aerosil OXS0) to about 400 ⁇ 20 m 2 /g (Cab-O- Sil S-17) or 390 ⁇ 40 m 2 /g (Cab-O-Sil EH-5).
  • particle sizes range from a nominal particle diameter of 7 nm (e.g., Cab-O-Sil S-17 or Cab-O-Sil EH-5) to an average primary particle size of 40 nm (Aerosil OX50).
  • the density of these products range from 72.0 ⁇ 8 g/1 (Cab-O-Sil S-17) to 36.8 g1 (e.g., Cab-O-Sil M-5).
  • the pH of the these products at 4% aqueous dispersion ranges from pH 3.5-4.5.
  • microcrystalline cellulose product is to be subjected to wet granulation, it has been discovered that the surface area of the silicon dioxide can be as low as about SO m 2 /g and the average primary particle diameter can be as large as about 100 microns. Such silicon dioxide products are also deemed to be encompassed within the scope of the invention.
  • the compressibility augmenting agent is a material which inhibits interactions between adjacent cellulose surfaces, for example, via the creation of a hydrophobic boundary or barrier at cellulose surfaces.
  • compressibility augmenting agents which inhibit surface-to-surface interactions between surfaces of the microcrystalline cellulose include any material which has the ability, via a portion of the molecule, to bind or interact with the surface of the microcrystalline cellulose and at the same time, via another portion of the molecule, to inhibit the attraction of the cellulose surfaces, e.g., via a hydrophobic portion or "tail".
  • Suitable compressibility augmenting agents will have an HLB value of at least 10, preferably at least about IS, and more preferably from about IS to about 40 or greater. Compressibility augmenting agents having an HLB value from about 30 to about 40 or greater is most preferred.
  • Surfactants which may be used in the present invention as a compressibility augmenting agent generally include all pharmaceutically-acceptable surfactants, with the proviso that the surfactant have an HLB value of at least 10, and preferably at least about IS.
  • the HLB value of the surfactant is from about IS to SO, and in further embodiments is most preferably from about IS.6 to about 40.
  • 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 of natural fatty acid glycerides in alkaline solutions. The most common cations 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, which has an HLB value of about 40.
  • sodium lauryl sulfate has been used as an emulsifying agent in amounts of up to about 0.1% by weight of the formulation.
  • surfactants such as sodium lauryl sulfate have been included in coprocessed microcrystalline cellulose compositions.
  • surfactants have been used in the amounts described herein to improve the compressibility of microcrystalline cellulose especially in 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.
  • sodium lauryl sulfate 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.
  • 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 sodium lauryl sulfate is about 1 gm per 10 ml/water.
  • the fatty acids of coconut oil, consisting chiefly of lauric acid, are catalytically hydro genated 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 docusate salts such as the sodium salt thereof.
  • Other suitable 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.
  • amphoteric (amphipathic/amphiphilic surfactants), non-ionic surfactants and/or cationic surfactants are included in the coprocessed compositions of the invention.
  • Suitable pharmaceutically-acceptable non-ionic surfactants such as, for example, polyoxyethylene compounds, lecithin, ethoxylated alcohols, ethoxylated esters, ethoxyiated 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, 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.
  • the HLB for one acceptable non-ionic surfactant, polysorbate 40 is about IS.6.
  • Suitable pharmaceutically-acceptable surfactants include acacia, benzalkonium chloride, cholesterol, emulsifying wax, glycerol monostearate, lanolin alcohols, lecithin, poloxamer, polyoxyethylene, and castor oil derivatives.
  • 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 particular, it has been discovered that when an anionic surfactant such as sodium lauryl sulfate is coprocessed with microcrystalline cellulose in the amounts described herein, improved microcrystalline cellulose products of the invention result.
  • the novel excipient of the invention utilizes an anionic surfactant
  • the resultant excipient product surprisingly provides a compressibility which is substantially improved in preferred embodiments even in comparison to the compressibility of normal "off-the-shelf commercially available microcrystalline cellulose used in direct compression techniques.
  • an anionic surfactant such as sodium lauryl sulfate.
  • 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 tend to be water soluble.
  • Sodium lauryl sulfate for example, is relatively soluble in water (1 g 10 ml) and, therefore, dissolves in the aqueous slurry.
  • the coprocessed products of the present invention are not solely limited to those which contain a dissolved surfactant.
  • the contemplated compositions can also be prepared from slurries which contain a dispersion of the surfactant as well as the microcrystalline cellulose.
  • Highly polar molecules having the requisite HLB value range set form above may also be utilized as the compressibility augmenting agent.
  • Such highly polar molecules include certain dyes, particular those which may be capable of binding to the cellulose surface while thereafter creating a relatively hydrophobic environment due to the presence of a hydrophobic portion of the molecule (e.g., a hydrophobic tail) which "points away" from the cellulose surface and discourages hydrophilic surface-to-surface cellulose interactions, such as hydrogen-bonding.
  • the dye is one which is pharmaceutically acceptable for inclusion in solid dosage forms.
  • Suitable dyes include Congo Red (chemical name: 3 '-[[l,l' iphenyl]- 4,4'-diylbis-(azo)]bis[4-amino-l-naphthalenesulfonic acid] di sodium salt; FD&C Red No.40 (also known as "Allura Red”) (chemical name: Disodium salt of 6-hydroxy- 5 [(2-methyl-4- sulfophenyl)azo] -2-naphthalenesulfonic acid); FD&C Yellow No. 5 (common name:
  • tartrazine (chemical name: 5-oxo-l-(p-sulfophenyl)-4-[(p-sulfophenyl)azo]-2-pyrazoline-3- carboxylic acid, trisodium salt); FD&C Yellow No.
  • compressibility augmenting agents encompassed herein include calcium carbonate, as described, e.g., in U.S. Patent No. 5,747,067, hereby incorporated by reference, (particulate pharmaceutical tablet excipient compositions comprising co-processed microcrystalline cellulose and particulate USP calcium carbonate having a particle size distribution of 7 to 22 microns wherein the range of calcium carbonate to microcrystalline cellulose is 70:30 to 90:10). Also encompassed within the term compressibility augmenting agents is calcium phosphate.
  • composition useful as a pharmaceutical excipient in the preparation of tablets that are prepared by multiple compaction steps consisting of a physical blend of particles of at least one calcium phosphate and particles of microcrystalline cellulose, wherein the particles of at least one calcium phosphate have a median particle size as measured by laser diffraction of not greater than about 20 microns, and wherein tablets containing said composition have a higher tensile strength after recompaction at a tableting pressure of 120 MPa than the same tablet consisting of a physical blend of microcrystalline cellulose and a calcium phosphate having a median particle size as measured by laser diffraction of greater than about 20 microns.
  • Yet another compressibility augmenting agent encompassed herein are sugar alcohols such as mannitol.
  • U.S. Patent No. 8,932,629 hereby incorporated by reference, describes a co-processed excipient composition consisting essentially of a spray dried particulate of co-processed microcrystalline cellulose and at least one sugar alcohol containing four to six carbon atoms, in which: the ratio of microcrystalline cellulose to the at least one sugar alcohol is 70:30 to 95:5.
  • Yet another compressibility augmenting agent encompassed herein is calcium alginate, as described in U.S. Patent No.
  • excipient composition comprising particles of a dried aqueous slurry consisting essentially of unattrited micro crystalline cellulose wetcake and a low viscosity alginate selected from the group consisting of low viscosity sodium alginate and a sodium, calcium salt complex of low viscosity sodium alginate in which the low viscosity alginate has a viscosity in the range of 40 to 80 cps).
  • This list is meant to be exemplary and is not meant to be limiting in any manner, whatsoever.
  • the silicate-based adsorbant carrier is a material that allows an oily active ingredient, (e.g., an active ingredient that is oily in and of itself, or which is relatively insoluble in water and which dissolves in oil or is dissolved in oil) to be adsorbed into the excipient and which allows for the composition (e.g., excipient of the invention plus one or more active agents plus any further optional pharmaceutically acceptable excipients) to be a free-flowing powder which can be tabletted or which can be filled into a capsule.
  • an oily active ingredient e.g., an active ingredient that is oily in and of itself, or which is relatively insoluble in water and which dissolves in oil or is dissolved in oil
  • the composition e.g., excipient of the invention plus one or more active agents plus any further optional pharmaceutically acceptable excipients
  • magnesium aluminometasilicate This material is described in US Patent Publication No.2010196475, hereby incorporated by reference in its entirety. Magnesium aluminometasilicate can be described by the chemical formula
  • the aluminium oxide is present in the range of from 25% to 40%
  • the magnesium oxide present in the range of from 10% to 15%
  • the silicon dioxide is present in the range of from 25% to 40%.
  • these percentages are based on drying the substance at 110° C for 7 hours.
  • the magnesium aluminometasilicate may be Neusilin® as produced and commercially available from Fuji Chemical Industry Co., Ltd.
  • the silicate-based adsorbant carrier is a magnesium aluminometasilicate commercially available under the tradename Neusilin® US2 or UFL2.
  • the silicate-based adsorbant carrier is a granular or fine powder grade of a hydrophilic silica (silicon dioxide). Particularly preferred in certain embodiments is a granular hydrophilic fumed silica.
  • a hydrophilic silica is a granular hydrophilic turned silica such as Aeroperl® (a granulated hydrophilic fumed silica (silicon dioxide) commercially available from Evonik Industries.
  • the silicate-based adsorbent carrier is Aeroperl® 300 Pharma or 300/30, which have an average particle size of about 30 ⁇ .
  • Other hydrophilic fumed silicas are commercially available from Cabot Corporation under the tradename Cab-O-Sil ® , such as Cab-O-Sil H-5, M-5, M-5DP, M-5F, M-5P, M-7D.
  • the granular or fine powder grade of a hydrophilic silica is a colloidal grade hydrophilic silica, such as one or more Aerosil ® products commercially available from Evonik Industries, e.g., Aerosil* 90, 130, 200, 255, 300, OX 50, TT 600, 200 F, 380 F, 200 Pharma, or 300 Pharma.
  • Such hydrophilic fumed silica products have BET surface areas from about 75 to about 410 m 2 /g.
  • the amount of granulated hydrophilic fumed silica contained in the excipient of the invention is from about 10% to about 50%, and in certain embodiments from about 20% to about 35%.
  • silicate-based adsorbent carriers that may be used include but are not limited to Zeofree® 80, 110SD, 200, 265, 5161, 5162, 5170, 5191 and/or 9193 (synthetic silicon dioxides commercially available from Huber), and Zeothix®177 (a synthetic amorphous silica with sodium sulfate commercially available from Huber). Also, Zeolex ® 7, 201, 23 A, 23D and/or 7A (synthetic sodium aluminosilicates) may be used. Also, commercially available products from Grace such as Syloid ® 244 FP and/or XDP.
  • the silicate-based carrier may alternatively or further comprise hydrophilic mixed oxides of silicon dioxide (S1O 2 ) and aluminum oxide (AI 2 O 3 ).
  • hydrophilic mixed oxides include those commercially available from Evonik as Aerosil ® MOX 80, MOX 170 and/or COK 84.
  • the silicate-based carrier may alternatively or further comprise a hydrophobic grade of a granular or fine powder silica (e.g., a hydrophobic fumed silica).
  • hydrophobic silica include hydrophobic fumed silica, such as those commercially available as Aerosil ® R 972, R974,m R 104, R 106, R202, R 208, R 805, R 812, R 812 S, R 816, R 7200, R 8200, R 9200, R 711, $Y 50, NY 50, NY 50 L, RY 200, RY 200 S, RX 50, NAX 50, RX 200, NA 50 H, RA 200 H, NA 130 K, NA 200 Y, NX 130, RY 200 L, R 709, and/or R 976 S.
  • the excipient is a physical mixture of microcrystalline cellulose, compressibility augmenting agent and a silicate-based adsorbent carrier.
  • the microcrystalline cellulose, compressibility augmenting agent and silicate- based adsorbent is a co-processed blend.
  • the co-processed blends generally show a slightly higher oil carrying capacity that the physical mixtures, and produce very satisfactory tablets.
  • the process for preparing the co-processed composition involves forming a well- dispersed aqueous slurry of microcrystalline cellulose, the optional compressibility augmenting agent, and the silicate-based adsorbent carrier.
  • the slurry may be formed by using microcrystalline cellulose wetcake formed in the hydrolysis step during the manufacture of microcrystalline cellulose, or in may be formed by re-slurrying dried microcrystalline cellulose. The relative amounts of the two components are adjusted in the slurry to yield the specific weight ratio desired in the final dried co-processed composition. In some instances, it may be desirable to form the slurry under conditions of low shear.
  • the aqueous slurry may be prepared by first preparing the slurry of microcrystalline cellulose and thereafter adding the compressibility augmenting agent and/or the silicate-based adsorbent carrier, or by mixing these ingredients together in a (e.g., pharmaceutically acceptable) aqueous medium to form the aqueous slurry.
  • a (e.g., pharmaceutically acceptable) aqueous medium to form the aqueous slurry.
  • microcrystalline cellulose in the form of a wet cake (i.e hydrolyzed cellulose or hydro cellulose) and silicon dioxide are substantially water insoluble. Therefore, the particle size of these ingredients as present in the well-dispersed aqueous slurry is directly related to the particle size of these two ingredients as they were introduced into the aqueous solution. There is no appreciable dissolution of either ingredient in the aqueous slurry.
  • the suspension is dried to provide a plurality of microcrystalline cellulose-based excipient particles having enhanced compressibility.
  • the slurry is dried using spray-drying techniques, which are well known to those skilled in the art.
  • Other drying techniques such as flash drying, ring drying, tray drying, vacuum drying, radio frequency drying, and microwave drying, may be alternatively used.
  • microcrystalline cellulose is preferably wetcake from a conventional
  • microcrystalline cellulose manufacturing process is microcrystalline cellulose that has not yet been dried to yield conventional microcrystalline cellulose as a free-flowing powder.
  • the particle size of the microcrystalline cellulose used in the aqueous slurry is ordinarily that which is encountered in conventional microcrystalline cellulose manufacture.
  • pH adjustment of the wetcake can be made before, during, or after the sugar alcohol addition, preferably before, as representative of conventional MCC manufacturing processes.
  • the total solids content of the aqueous slurry is preferably at least 10 wt %, based on the total slurry weight, and is more preferably at least 20 wt % solids.
  • the higher solids content levels are desirable since the amount of water that must be removed during the drying step is accordingly reduced.
  • the upper limit on solids content in the aqueous slurry is typically determined by the operating constraints of the drying apparatus used. With the preferred spray drying procedure, solids contents of about 20 to about 30 weight % are representative for aqueous slurries that can be readily processed. Ambient or elevated slurry temperatures, of from about 10°C to about 80°C may be used, and higher slurry temperatures may be desirable with certain types of drying equipment.
  • the drying of the well-dispersed aqueous slurry is preferably accomplished by spray drying.
  • Conventional spray drying equipment may be used. Operating procedures familiar to those skilled in the spray drying art are applicable to the spray drying step of this process.
  • Drier outlet temperature is ordinarily used to control the residual moisture level obtained in the co-processed composition.
  • the aqueous dispersion of microcrystalline cellulose in the form of a wet cake, (optional) compressibility augmenting agent (e.g., colloidal silicon dioxide) and silicate-based adsorbent carrier (e.g., magnesium alumino metasilicate) are brought together with a sufficient volume of hot air to produce evaporation and drying of the liquid droplets.
  • compressibility augmenting agent e.g., colloidal silicon dioxide
  • silicate-based adsorbent carrier e.g., magnesium alumino metasilicate
  • the coprocessed product comprises or consists of microcrystalline cellulose, compressibility augmenting agent (e.g., colloidal silicon dioxide) and silicate-based adsorbent carrier (e.g., magnesium alumino metasilicate) in intimate association with each other.
  • compressibility augmenting agent e.g., colloidal silicon dioxide
  • silicate-based adsorbent carrier e.g., magnesium alumino metasilicate
  • microcrystalline cellulose, (optional) compressibility augmenting agent (e.g., colloidal silicon dioxide) and silicate-based adsorbent carrier in the slurry may have different particle sizes, densities, pH and moisture content.
  • Spray drying is an especially preferred method for removing water from the aqueous slurry and thereby accomplishing the drying step.
  • Spray drying the well-dispersed aqueous slurry produces a co-processed composition having a loose bulk density of less than or equal to 0.60 g/cm 3 , suitably 0.20 g/cm 3 to 0.60 g/cm 3 .
  • This produces a composition having a preferred compactability in the presence of lubricant compared to either a dry blend of the materials or the corresponding wet granulate.
  • the loose bulk density may be less than 0.55 g/cm 3 , less than 0.50 g/cm 3 , less than 0.45 g/cm 3 , less than 0.40 g/cm 3 , less than 0.35 g/cm 3 , less than 0.30 g/cm 3 , and less than 0.25 g/cm 3 .
  • the co-processed composition recovered from the drying operation is a free-flowing particulate solid.
  • Particle size of the product is a function of the spray drier settings, which can be controlled by those skilled in the art such as adjusting feed rates and atomizer disc speeds during spray drying.
  • the microcrystalline cellulose, (optional) compressibility enhancing agent and the silicate-based adsorbent carrier are coprocessed, resulting in an intimate association of these ingredients, rather than being combined, e.g., as a dry mixture.
  • the aqueous slurry of the microcrystalline cellulose in the form of a wet cake, (optional) compressibility enhancing agent (e.g., colloidal silicon dioxide) and silicate-based adsorbent carrier (e.g., magnesium aluminometasilicate) are introduced into the spray dryer as a single aqueous medium. However, it is possible to separately introduce each ingredient into separate aqueous medium which are then combined. Other procedures for combining the
  • microcrystalline cellulose in the form of a wet cake i.e. hydrocellulose or hydrolyzed cellulose
  • silicon dioxide known to those skilled in the art
  • the coprocessing of the microcrystalline cellulose and silicon dioxide is accomplished by forming a well-dispersed aqueous slurry of microcrystalline cellulose in the form of a wet cake compressibility augmenting agent (e.g., colloidal silicon dioxide) and silicate-based adsorbent carrier (e.g., magnesium alumino metasilicate and/or hydrophilic fumed silica), and thereafter drying the slurry and forming a plurality of microcrystalline cellulose-based excipient particles.
  • a wet cake compressibility augmenting agent e.g., colloidal silicon dioxide
  • silicate-based adsorbent carrier e.g., magnesium alumino metasilicate and/or hydrophilic fumed silica
  • microcrystalline cellulose in the form of a wet cake 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.
  • the slurry or suspension contains from about 15% to 20% microcrystalline cellulose in the form of a wet cake and most preferably from about 17% to about 19% microcrystalline cellulose in the form of a wet cake.
  • the suspension is kept under constant agitation for a sufficient time to assure a uniform
  • the solids prior to being combined with the (optional) compressibility augmenting agent e.g., colloidal silicon dioxide
  • silicate-based adsorbent carrier e.g., magnesium alumino metasilicate
  • the (colloidal) silicon dioxide may be added to the suspension or slurry, e.g., in amounts ranging from 0.1% to about 20% by weight, based on the amount of microcrystalline cellulose. Amounts of silicon dioxide from about 0.5% to about 10% are preferred while amounts of from about 1.25% to about 5% by weight are especially preferred.
  • the silicon dioxide is preferably in colloidal form prior to addition to the slurry.
  • the microcrystalline cellulose in the form of a wet cake and colloidal silicon dioxide are well- dispersed in the slurry or suspension prior drying and forming the novel particles.
  • the amount of silicate-based adsorb ant carrier added to the slurry may be in an amount up to about 50% of the excipient, by weight.
  • the amount of silicate-based adsorbent carrier added to the slurry may be in an amount from about 5% to about 50% of the excipient, by weight, and in certain embodiments most preferably from about 12% to about 23% of the excipient, by weight.
  • the silicate-based adsorbent carrier may be added after the incorporation of the compressibility enhancing agent (e.g., silicon dioxide) to the slurry.
  • the average particle size of the 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 skill in the art mat the drying of the microcrystalline cellulose in the form of a wet cake-silicon dioxide 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.
  • 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.
  • the excipient of the present invention preferably has a bulk (loose) density ranging from about 0.2 g/ml to about 0.6 g/ml, and most preferably from about 0.35 g/ml to about 0.55 gml.
  • the novel excipient preferably has a tapped density ranging from about 0.2 g/ml to about 0.6 g/ml, and most preferably from about 0.35 g/ml to about 0.55 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 preferably 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 preferably comprises a particulate agglomerate of coprocessed microcrystalline cellulose, from about 5% to about 50%, or from about 10% to about 50% and in certain embodiments from about 20% to about 35%, and in other embodiments from about 25% to about 35%, and in certain embodiments preferably from about 12% to about 23% silicate-based adsorbent carrier (e.g., magnesium aluminometasilicate or granular hydrophilic silica), by weight.
  • the novel excipient may optionally further comprise from about 0.1% to about 20%, and preferably from about 0.25% to about 5% compressibility augmenting agent.
  • the novel excipient in accordance with the invention is free-flowing and directly compressible. Accordingly, the excipient may be mixed in the desired proportion with an active agent and optional lubricant (blended or dry granulated), and then directly compressed into solid dosage forms.
  • the excipient of the present invention represents an augmented microcrystalline cellulose having improved compressibility which allows for the tableting of an oily active agent as defined in herein. More particularly, the excipient of the present invention adsorbs oily active agents (e.g., oily drugs or oily compounds, or active agents/drugs/compounds dissolved in oil), resulting in a free-flowing powder that can be compressed into tablets or filled into capsules on a routine basis.
  • oily active agents e.g., oily drugs or oily compounds, or active agents/drugs/compounds dissolved in oil
  • conversion of this oil dosage form (excipient plus active agents) into tablets via this excipient may provide enhanced intrinsic solubility, and faster/better bioavailability. From a business standpoint this would be valuable to companies who could turn their problematic, slow to produce, relatively expensive soft-gel formulations into less problematic, faster and cheaper to produce tablets.
  • Adsorbant carriers generally have an ability to adsorb at least their own weight in oil (it has been found that Neusilin® adsorbs about 3.2 times its weight of oily drug, whereas common adsorbants only held 10% of their own weight of other products). With this in mind, the oil- carrying capacity of the present excipient is dictated, e.g., by how much silicate-based adsorbent carrier can be loaded into the excipient and still make robust tablets under normal operating ranges.
  • the excipient is combined with at least one oily active ingredient, optional additional (non-oily) active agent(s), and optional pharmaceutically acceptable excipients and tableted into suitably sized tablets. It has been determined that using just the dry blended excipient of the invention, the excipient alone functioned well with about a 20% load of silicate-based adsorbent carrier (e.g., Neusilin), and it was hypothesized that about 100 grams of excipient containing about 20 grams of silicate-based adsorbent carrier (e.g., Neusilin) could adsorb at least 60 grams of oil.
  • silicate-based adsorbent carrier e.g., Neusilin
  • the excipient is prepared by spray-drying (as opposed to a dry-blending process) and it was found that the oil-loading capacity (load at which oil would get expressed from the tablets) during compression was increased
  • the oil loading goal for the excipient of the invention is to provide a pharmaceutically acceptable tablet with up to about 20% oil loading (e.g., 100 mg oil in a 500 mg tablet), and even as high as about 22.5% oil loading or more.
  • the amount of oil loading of the oily active ingredient into the final product may be about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 20.5%, about 21%, about 21.5%, about 22%, about 22.5%, about 23%, about 23.5%, about 24%, about 24.5%, about 25%, about 25.5%, about 26%, about 26.5%, about 27%, about 28%, about 28.5%, about 29%, about 29.5%, about 30%, about 30.5%, about 31%, about 31.5%, about 32%, about 32.5%, about 33% about 33.5%, about 34%, about 34.5%, and about 35%, for example.
  • acceptable tablets are prepared which include the excipient of the present invention and an oil active ingredients), which can be manufactured, e.g, without fouling the press with oil.
  • Acceptable tablets (1/2" diameter @ 10-13kP) have been manufactured using compression forces of as low as about 8-10 kNewtons. This is in the low end of the forces commonly used in industry to produce acceptable tablets.
  • the excipient of the invention provides improved bioavailability for an oily drug when combined in the same in suitable proportions as described herein and prepared as a pharmaceutical dosage form for oral administration.
  • the excipient is combined with an active ingredients) that is an oily active ingredient agent or an active ingredient agent that is dissolvable in an oil.
  • oily active ingredients which may be incorporated together with the excipient of the present invention include but are not limited to systemically active therapeutic agents, locally active therapeutic agents, nutraceuticals, disinfecting agents, chemical impregnants, cleansing agents, deodorants, fragrances, dyes, animal repellents, insect repellents, a fertilizing agents, pesticides, herbicides, fungicides, and plant growth stimulants, and the like.
  • the active agent is one or more drug(s), a food supplements), a medical food(s), or a nutraceutical(s).
  • the term oily medicament means a medicament that is hydrophobic and that is liquid at physiological pH, temperature and osmolality.
  • Such soft gel capsules may be prepared, for example, without limitation, by dispersing the formulation in an appropriate vehicle (vegetable oils are commonly used) to form a high viscosity mixture. This mixture is then encapsulated with a gelatin based film using technology and machinery known to those in the soft gel industry. The industrial units so formed are then dried to constant weight.
  • an appropriate vehicle vegetable oils are commonly used
  • a few examples of therapeutic substances that are considered to be water insoluble are ibuprofen, diazepam, griseofulvin, cyclosporin, cortisone, proleukin, etoposide and paclitaxel.
  • Administration of chemotherapeutic or anti-cancer agents is particularly problematic. The majority of these agents are poorly soluble and thus are difficult to deliver in aqueous solvents and supply at therapeutically useful levels.
  • water-soluble anti-cancer agents are generally taken up by both cancer and non-cancer cells, thereby exhibiting non- specificity.
  • Oily drugs further include agents such as ubiquinone (CoQ-10), certain nutraceuticals, nutritional agents such betacarotene, various vitamins and vitamin derivatives such as vitamin A, vitamin B 2 , vitamin D, vitamin E, vitamin K, prebiotics, probiotics, antiviral HIV protease inhibitors (e.g., Ritonavir, Saquinavir), therapeutic agents for hyperlipidemia (e.g., clofibrate), iodine compounds (e.g., sodium iopodate, sodium iodide), polyunsaturated fatty acid derivatives (e.g., ethyl eicosapentaenoic acid (EPA),
  • agents such as ubiquinone (CoQ-10), certain nutraceuticals, nutritional agents such betacarotene, various vitamins and vitamin derivatives such as vitamin A, vitamin B 2 , vitamin D, vitamin E, vitamin K, prebiotics, probiotics, antiviral HIV protease inhibitors (e.g., Rit
  • DHA docosahexaenoic acid
  • carotenoids e.g., lycopene, bixin, beta-carotene, xanthophyll, lutein
  • ubiquinones coenzyme Q
  • Prostaglandin and/or derivatives thereof, and the freebase form of pilocarpine also constitute oily drugs.
  • drugs which are included in or which are candidates for inclusion in a soft gelatin capsule would be considered an oily active ingredient as defined herein.
  • Other examples will be recognized by those skilled in the art.
  • Oily drugs present solubility problems in aqueous media, and they are not readily dispersed in such media.
  • surfactants have been employed to form emulsions in which the oily drugs are dissolved or suspended. See U.S. Patent No.4,347,238.
  • stability of the emulsion can then become a problem.
  • oily particles forming the disperse phase of the emulsion can agglomerate or coalesce and separate from the aqueous continuous phase.
  • the presence of salts and/or soluble polymers used to increase viscosity can exacerbate the problem by competing for water, thereby increasing the tendency of the oily disperse phase to separate from the aqueous continuous phase.
  • the oily drug(s) included in the compositions of the invention include compounds or compositions of matter which, when administered to an organism (human or animal) induce a desired pharmacological and/or physiologic effect by local and/or systemic action.
  • the terms include the therapeutic or prophylactic agents in all major therapeutic or prophylactic areas of medicine.
  • a bioactive agent may be a phyto-chemical, drug, nutrition agent, Vitamin, peptide, oligonucleotide or liposaccharide or combinations thereof.
  • Classes of drugs which may be incorporated with the excipient of the present invention include, but are not limited to, antihypertensives, antianxiety agents, anticlotting agents, anticonvulsants, blood glucose-lowering agents, decongestants, antihistamines, antitussives, antineoplastics, beta blockers, anti-inflammatories, antipsychotic agents, cognitive enhancers, anti-atherosclerotic agents, cholesterol-reducing agents, antiobesity agents, autoimmune disorder agents, anti-impotence agents, antibacterial and antifungal agents, hypnotic agents, anti-Parkinsonism agents, anti-Alzheimer's disease agents, antibiotics, anti-depressants, antiviral agents, glycogen phosphorylase inhibitors, antineoplastic agents, and cholesterol ester transfer protein inhibitors.
  • the present invention is useful with any drug capable of being formulated as an amorphous drug.
  • drug is conventional, denoting a compound having beneficial prophylactic and/or therapeutic properties when administered to an animal, especially humans.
  • the drug does not need to be a low-solubility drug in order to benefit from this invention, although low-solubility drugs represent a preferred class for use with the invention.
  • Even a drug that nonetheless exhibits appreciable solubility in the desired environment of use can benefit from the increased solubility/bioavailability made possible by this invention if the formulation and administration in the presented carrier can reduce the size of the dose needed for therapeutic efficacy or increase the rate of drug absorption in cases where a rapid onset of the drug's effectiveness is desired.
  • the active ingredients may further be any agent that is traditionally used as a medicament and lends itself to being administered through the oral cavity.
  • active agents may be vitamins, chemotherapeutics; antimycotics; oral contraceptives, nicotine or nicotine replacement agents, minerals, analgesics, antacids, muscle relaxants, antihistamines, decongestants, anesthetics, antitussives, diuretics, anti-inflammatories, antibiotics, antivirals, psychotherapeutic agents, anti-diabetic agents and cardiovascular agents, nutraceuticals and nutritional supplements.
  • Vitamins and co-enzymes that may be delivered using this invention include but are not limited to water or fat soluble vitamins such as thiamin, riboflavin, nicotinic acid, pyridoxine, pantothenic acid, biotin, flavin, choline, inositol and paraminobenzoic acid, carnitine, vitamin C, vitamin D and its analogs, vitamin A and the carotenoids, retinoic acid, vitamin E and vitamin K and Coenzyme Q10.
  • water or fat soluble vitamins such as thiamin, riboflavin, nicotinic acid, pyridoxine, pantothenic acid, biotin, flavin, choline, inositol and paraminobenzoic acid, carnitine, vitamin C, vitamin D and its analogs, vitamin A and the carotenoids, retinoic acid, vitamin E and vitamin K and Coenzyme Q10.
  • Example of botanical bioactive agents are: polyphenols, isoflavones, resveratrol, soy isoflavones, grape seed extract polyphenols, curcumin, epigenin.
  • Anti-inflammatory plant extracts such as aloe vera, echinacea and chamomile hammamelis extracts, anti-psoriatic such as Chinese zizipus jujuba.
  • Astringents such as hammamelis anti bacterial such as artemisia, chamomile, golden seal.
  • Immune modulators such as echinacea, anti-aging or anti-cancer or anti-photo damage, anti-inflammatory such as feverfew parthenolides, rejuvenation agents, carotenoids, beta-carotene, lycopene, astaxanthons, lutein, tocopheryl and retinol.
  • Coronary drugs including vasodilators such as nitroglycerin, isosorbide dinitrate, Calcium-antagonists such as verapamile, nifedipine and diltiazem, Cardiac-glycosides such as digoxine.
  • vasodilators such as nitroglycerin, isosorbide dinitrate, Calcium-antagonists such as verapamile, nifedipine and diltiazem, Cardiac-glycosides such as digoxine.
  • Analgesics eg. morphine, buprenorphine, etc
  • Local anaesthetics eg. lidocaine, etc;
  • Example of cholesterol and triglycerides lowering drug fenofibrate, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, or cerivastatin.
  • Anxiolytics, sedatives & hypnotics diazepam, nitrazepam, fhirazepam, estazolam, flunitrazepam, triazolam, alprazolam, midazolam, temazepam, lormetazepam, brotizolam, clobazam, clonazepam, lorazepam, oxazepam, buspirone, etc;
  • metoclopramide etc. Others: such as disulfuram, vitamin K, etc.
  • chemotherapeutics agents include but are not limited to cisplatin
  • CDDP procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, bisulfan, nitrosurea, dactinomycin, daunorubicm, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP 16), tamoxifen, taxol, transplatinum, 5- fluorouracil, vincristin, vinblastin and methotrexate or any analog or derivative variant thereof.
  • antibiotics drugs Tetracyclines such as tetracycline, doxycycline, oxytetracycline, chloramphenicol etc; Macrolides such as erythromycin and derivatives, etc; Antivirals: such as acyclovir, idoxuridine, tromantadine etc; Antimycotics: Miconazole, ketoconazole, fluconazole, itraconazole, econazole, terconazole, griseofulvin, and polyenes such as amphotericin B or nystatine etc; Anti - amoebic s: Metronidazole, metronidazole benzoate and tinidazole etc; Anti-inflammatory drugs: steroids or NSAID's such as indomethacin, ibuprofen, piroxicam, diclofenac etc; Anti-allergics: Di sodium cromoglycate etc; Immunosuppressive agents: cyclosporins etc;
  • Antimicrobial agents that may be used include but are not limited to naficillin, oxacillin, vancomycin, clindamycin, erythromycin, trimethoprim-sulphamethoxazole, rifampin, ciprofloxacin, broad spectrum penicillin, amoxicillin, gentamicin, ceftriazoxone, cefotaxime, chloramphenicol, clavunate, sulbactam, probenecid, doxycycline, spectinomycin, cefixime, penicillin G, minocycline, .beta.-lactamase inhibitors; meziocillin, piperacillin, aztreonam, norfloxacin, trimethoprim, ceftazidime, ceftriaxone and dapsone.
  • Antifungal agents that may be delivered include but are not limited to ketoconazole, fluconazole, nystatin, itraconazole, clomitrazole, and amphotericin B.
  • Antiviral agents that may be used include but are not limited to acyclovir, trifluridine, idoxorudine, foscarnet, ganciclovir, zidovudine, dideoxycytosine, dideoxyinosine, stavudine, famciclovir, didanosine, zalcitabine, rifimantadine, and cytokines.
  • Antihistamines are represented by but are not limited to cimetidine, ranitidine, diphenydramine, prylamine, promethazine, chloroheruramine, chlorcyclizine, terfenadine, carbinoxamine maleate, clemastine fumarate, diphenhydramine hydrochloride,
  • dimenhydrinate dimenhydrinate
  • prilamine maleate tripelennamine hydrochloride, tripelennamine citrate
  • chlorpheniramine maleate brompheniramine maleate
  • hydroxyzine pamoate hydroxyzine hydrochloride
  • cyclizine lactate cyclizine hydrochloride
  • meclizine hydrochloride meclizine hydrochloride, acrivastine, cetirizine hydrochloride, astemizole, levocabastine hydrochloride, and loratadine.
  • Decongestants and antitussives include agents such as dextromethorphan,
  • levopropoxyphene napsylate noscapine, carbetapentane, caramiphen, chlophedianol, pseudoephedrine hydrochloride, diphenhydramine, glaucine, pholcodine, and benzonatate.
  • Anesthetics include etomidate, ketamine, propofol, and benodiazapines (e.g., chlordiazepoxide, diazepam, clorezepate, halazepam, flurazepam, quazepam, estazolam, triazolam, alprozolm, midazolam, temazepam, oxazepam, lorazepam), benzocaine, dyclonine, bupivacaine, etidocaine, lidocaine, mepivacaine, promoxine, prilocalne, procaine,
  • benodiazapines e.g., chlordiazepoxide, diazepam, clorezepate, halazepam, flurazepam, quazepam, estazolam, triazolam, alprozolm, midazolam, temazepam, oxazepam,
  • proparcaine ropivacaine, tetracaine.
  • Other useful agents may include amobartital,
  • Analgesics include opioids such as morphine, mepidine, dentanyl, suientranil, alfentanil, aspirin, acetaminophen, ibuprofen, indomethacine, naproxen, atrin, isocome, midrin, axotal, firinal, phrenilin, ergot and ergot derivatives (wigraine, caiergot, ergostat, ergomar, dihydroergotamine), imitrex.
  • opioids such as morphine, mepidine, dentanyl, suientranil, alfentanil, aspirin, acetaminophen, ibuprofen, indomethacine, naproxen, atrin, isocome, midrin, axotal, firinal, phrenilin, ergot and ergot derivatives (wigraine, caiergot, ergostat, ergomar, dihydroergotamine),
  • Diuretics include but are not limited to acetazolamide, dichlorphenamide,
  • Antiinflammatories include but are not limited to salicylic acid derivatives (e.g. aspirin) paraminophenol derivative (e.g. acetaminophen) indole and indene acetic acids (indomethacin, sulindac and etodalac) heteroaryl acetic acids (tolmetin diclofenac and ketorolac) aryl propionic acid derivatives (ibuprofen, naproxen, ketoprofen, fenopren, oxaprozine), anthranilic acids (mefenamic acid, meclofenamic acid) enolic acids (piroxicam, tenoxicam, phenylbutazone and oxyphenthatrazone).
  • salicylic acid derivatives e.g. aspirin
  • paraminophenol derivative e.g. acetaminophen
  • indole and indene acetic acids indomethacin, sulindac and e
  • Psychotherapeutic agents include thorazine, serentil, mellaril, millazine, tindal, pennitil, prolixin, trilafon, stelazine, suprazine, taractan, navan, Clozaril, haldol, halperon, loxitane, moban, orap, risperdal, alprazolam, chlordiaepoxide, clonezepam, clorezepate, diazepam, halazepam, lorazepam, oxazepam, prazepam, buspirone, elvavil, anafranil, adapin, sinequan, tofranil, surmontil, asendin, norpramin, pertofrane, ludiomil, pamelor, vivactil, prozac, luvox, paxil, Zoloft, effexor, welibutri
  • Cardiovascular agents include but are not limited to nitroglycerin, isosorbide dinitrate, sodium nitroprisside, captopril, enalapril, enalaprilat, quinapril, lisinopril, ramipril, losartan, aminone, lirinone, vesnerinone, hydralazine, nicorandil, prozasin, doxazosin, bunazosin, tamulosin, yohimbine, propanolol, metoprolol, nadolol, atenolol, timolol, esmolol, pindolol, acebutolol, labetalol, phentolamine, carvedilol, bucindolol, verapamil, nifedipine, amlodipine and dobutamine.
  • Anti-neoplastic agents and Immunosuppressants aminoglutethimide, amsacrine, azathioprine, busulphan, chlorambucil, cyclosporin, dacarbazine, estramustine, etoposide, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitozantrone, procarbazine HC1, tamoxifen citrate, testolactone.
  • the oil active ingredient may be disinfecting agents, chemical impregnants, cleansing agents, deodorants, fragrances, dyes, animal repellents, insect repellents, a fertilizing agents, pesticides, herbicides, fungicides, and plant growth stimulants, and the like.
  • the excipient of the present invention may be physically mixed with the oily active ingredient (e.g., oily drug) and other optional pharmaceutical excipients and thereafter either tableted or filled into a capsule in powder form. 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-Perkins, 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 wet granulate containing novel excipient is now capable of undergoing tableting or otherwise placed into a unit dosage form.
  • 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.
  • 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 of the particular formulation.
  • a further material is added to the slurry of microcrystalline cellulose in the form of a wet cake, silicate-based adsorb ant, and optional compressibility enhancing agent, prior to drying (e.g., spray-drying).
  • additional materials include 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.
  • 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.
  • the solid formulations prepared using the novel excipient may also include suitable quantities of pharmaceutical adjuvants, e.g., diluents, plasticizers, lubricants, binders, granulating aids, disintegrants (e.g., sodium starch glycolate (commercially available from JRS Pharma under the tradename Explotab ® ), colorants, flavorants and glidants that are conventional in the pharmaceutical art.
  • suitable adjuvants include spray dried lactose, polyvinylpyrrolidone (PVP), talc, magnesium stearate, and mixtures thereof. The quantities of these additional materials will be sufficient to provide the desired effect to the desired formulation.
  • PVP polyvinylpyrrolidone
  • talc talc
  • magnesium stearate magnesium stearate
  • suitable adjuvants include spray dried lactose, polyvinylpyrrolidone (PVP), talc, magnesium stearate, and mixtures thereof.
  • PVP polyvinylpyrrolidone
  • talc talc
  • magnesium stearate magnesium stearate
  • plasticizers includes include water insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin, although it is possible that other water-insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) may be used.
  • water insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin
  • Triethyl citrate is an especially preferred plasticizer.
  • the inert pharmaceutical filler comprises a monosaccharide, a disaccharide, apolyhydric alcohol, inorganic phosphates, sulfates or carbonates, and/or mixtures thereof.
  • suitable inert pharmaceutical fillers include sucrose, dextrose, lactose, xylitol, fructose, sorbitol, calcium phosphate, calcium sulfate, calcium carbonate, "off-the-shelf macrocrystalline 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 average tablet size for round tablets is preferably about SO mg to 500 mg and for capsule-shaped tablets about 200 mg to 2000 mg.
  • other formulations prepared in accordance with the present invention may be suitably shaped for other uses or locations, such as other body cavities, e.g., periodontal pockets, surgical wounds, vaginally. It is
  • the tablets prepared using the novel excipient may comprise a homogeneous mixture of the novel excipient, oily active ingredient(s), and optional further active ingredients) and optional further excipients (e.g., pharmaceutically acceptable excipients where the oily active ingredient and/or optional further active ingredients) are a drug), or may comprise a compression coated tablet, in which the active substance is contained within a core which is contained within an outer coating (either hydrophobic coating or hydrophilic coating, e.g., as described below). In some embodiments, the coating may be complete, in other embodiments, the coating may be partial.
  • the novel excipient and oily active ingredient are further prepared with one or more controlled or sustained release carriers to provide a delayed or sustained release of the active ingredient from the final product (e.g., oral tablet).
  • the final product e.g., oral tablet
  • This can be accomplished, e.g., by incorporating a sustained release carriers) together with the mixture of the novel excipient and oily drug(s) (with further optional active ingredients and or further optional pharmaceutically acceptable excipients) and then tableting the mixture, thereby obtained sustained release matrix tablets.
  • novel excipient and oily drug(s) may be tableted or filled into a capsule, which is then coated with one or more delayed (e.g., enteric) or sustained release carriers to thereby provide a delayed or sustained release final formulation.
  • delayed e.g., enteric
  • the tablet is coated with a sufficient amount of a hydrophobic polymer to render the formulation capable of providing a release of the active ingredient(s) such that a 12 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.
  • the tablet coating may comprise an enteric coating material in addition to or instead or the hydrophobic polymer coating.
  • enteric polymers examples 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 Eudragit®L 100-555.
  • the dosage form may be coated with a hydrophilic coating in addition to or instead of the above-mentioned coatings.
  • a hydrophilic coating is hydroxypropylmethylcellulose (e.g., Opadry®, commercially available from Colorcon, West Point, Pa.).
  • the coatings may be applied in any pharmaceutically acceptable manner known to those skilled in the art.
  • the coating is applied via a fluidized bed or in a coating pan.
  • the coated tablets may be dried, e.g., at about 60-70°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.
  • 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. Pat. No.4,839,177, hereby incorporated by reference. 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 microns if applied via spray-coating or immersion-coating.
  • 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%.
  • Materials 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), polyvinylalcohols, and the like.
  • the sustained-release carrier may be incorporated in a sustained-release matrix to impart sustained-release of the active agent from the final formulation.
  • the sustained release carrier may be hydrophobic or hydrophilic.
  • Suitable materials which may be included in the sustained release carrier of the present invention include alkylcelluloses such as natural or synthetic celluloses derivatives (e.g. ethylcellulose), acrylic and methacrylic acid polymers and copolymers, zein, and mixtures thereof.
  • Suitable biocompatible preferably
  • biodegradable polymers can be utilized as the sustained release carrier.
  • the biodegradable polymeric material may comprise a polylactide, a polyglycolide, a poly(lactide-co-glycolide), a polyanhydride, a polyorthoester, polycapro lactones, polyphosphazenes, polysaccharides, proteinaceous polymers, soluble derivatives of polysaccharides, soluble derivatives of proteinaceous polymers, polypeptides, polyesters, and polyorthoesters.
  • the polysaccharides may be poly-l,4-glucans, e.g., starch glycogen, amylose, amylopectin, and mixtures thereof.
  • the biodegradable hydrophilic or hydrophobic polymer may be a water-soluble derivative of a poly-l,4-glucan, including hydrolyzed amylopectin, hydroxyalkyl derivatives of hydrolyzed amylopectin such as hydroxyethyl starch (HES), hydroxyethyl amylose, dialdehyde starch, and the like.
  • HES hydroxyethyl starch
  • hydroxyethyl amylose dialdehyde starch
  • sustained-release carrier comprises a synthetic or naturally occurring gum.
  • naturally occurring gums include, e.g., the
  • heteropolysaccharides and homopolysaccharides.
  • heteropolysaccharide is xanthan gum, which is a high molecular weight (>10.sup.6) heteropolysaccharide.
  • Other preferred heteropolysaccharides include derivatives of xanthan gum, such as deacylated xanthan gum, the carboxymethyl ether, and the propylene glycol ester.
  • the homopolysaccharides useful in the present invention include galactomannan gums, which are polysaccharides composed solely of mannose and galactose. Preferred
  • galactomannan gums are those which are capable of cross-linking with the
  • heteropolysaccharide In particular, galactomannans which have higher proportions of unsubstituted mannose regions have been found to achieve more interaction with the heteropolysaccharide when exposed to an environmental fluid. Locust bean gum, which has a higher ratio of mannose to galactose, is especially preferred as compared to other
  • galactomannans such as guar and hydroxypropyl guar.
  • Other natural or synthetic gums known to those skilled in the food and pharmaceutical arts are also useful as the controlled release carrier of the invention.
  • Such gums include alginic acid derivatives, carageenan, tragacanth, acacia, karaya, guar gum, agar, acacia, galactans, mannans, and the like.
  • Water swellable polymers may be used in addition to or instead of gums to promote sustained- release of the active agent from the final formulation.
  • Such water swellable polymers include cellulose ethers, carboxyvinyl polymer and the like.
  • the sustained-release carrier includes a release modifying agent.
  • a release modifying agent according to the invention includes any pharmaceutically acceptable substance which my alter, e.g. prolong or increase, the release rate of the active agent form the formulation upon exposure to an aqueous environment, e.g. gastric fluid or dissolution medium.
  • Suitable release modifying agents which may be incorporated into the matrix formulations of the present invention include, e.g., monovalent or multivalent metal cations.
  • the salts are inorganic salts, including e.g., alkali metal and/or alkaline earth metal sulfates, chlorides, borates, bromides, citrates, acetates, lactates, etc.
  • these salts include, e.g., calcium sulfate, sodium chloride, potassium sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride, sodium bicarbonate, calcium chloride, magnesium chloride, sodium citrate, sodium acetate, calcium lactate, magnesium sulfate and sodium fluoride. Multivalent metal cations may also be utilized.
  • the release modifying agents are bivalent.
  • Particularly preferred salts are calcium sulfate and sodium chloride.
  • Other release modifying agents include sugars, e.g. sucrose, starches, water-soluble alkylcellulose derivatives such as hydroxypropylmethylcellulose, urea, and the like.
  • any effective amount may be employed (generally from about 0.1% to about 20%, by weight).
  • the final sustained-release oral dosage form may contain from about 1 to about 99% (by weight) of sustained release carrier.
  • the weight percent of the sustained release carrier ranges from about 1 to about 80%.
  • the sustained release carrier is a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and meth acrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate,
  • acrylic acid and meth acrylic acid copolymers including but not limited to acrylic acid and meth acrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid al
  • the sustained-release carrier may further include a relatively hydrophilic material, including but not limited to materials such as hydroxyalkylcelluloses such as hydroxypropylmethylcellulose and mixtures of the foregoing.
  • the sustained release cairier(s) (with or without optional release modifying agent(s)) is added into the aqueous slurry of the novel excipient, and the aqueous slurry is then dried in such a manner as to obtain
  • the tablet core includes an additional dose of the same or different active ingredient 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
  • 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 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
  • the excipient of the present invention provides significant advantages over the prior art with respect to oily active agents or drugs dissolved in an oil. For example, the excipient allows for a manufacturer to switch from expensive and slow soft-gel production to tableting. Also, physical stability issues often found with soft-gel capsules are avoided. Further, oily active agents can be administered in solution in a more dispersed fashion from a tablet than may be formulated to disintegrate faster than a bolus oil dose may disperse. The excipient of the present invention may also be used in allow for the use of SEDDS (self-emulsifying drug delivery system) and SMEDDS (self-microemulsifying drug delivery system) into tablets.
  • SEDDS self-emulsifying drug delivery system
  • SMEDDS self-microemulsifying drug delivery system
  • the novel excipient can be utilized in other applications wherein it is not compressed.
  • 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.
  • 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.
  • ProSolv SMCC SO is a silicified microcrystalline cellulose composed of 98%
  • the amount of silicate-based adsorbent carrier e.g., magnesium alumino metasilicate (e.g., Neusilin®)
  • silicate-based adsorbent carrier e.g., magnesium alumino metasilicate (e.g., Neusilin®)
  • the excipient included from about 18.5% to about 20.9% silicate-based adsorbent carrier (e.g., magnesium aluminometasilicate (e.g., Neusilin®)), and from about 1.58% to about 1.63% compressibility augmenting agent (e.g., CSD).
  • Formulations 1 and 2 were co-processed by combining the ingredients in a slurry with water at a solids content of 15-20%. Thereafter, additional water is added to bring the slurry to around 15% solids content. Thereafter, the slurry is spray-dried at 200° C inlet and 105° C outlet at 31.2 Hz.
  • the amount of Neusilin included in the excipient was about 25% of the MCC for formulation 1 and about 26% of the MCC for formulation 2.
  • the amount of Neusilin included in the excipient was about 19.66% in formulation 1 and about 20.28% in formulation 2.
  • the amount of MCC in the excipient of formulation 1 was about 78.73% and about 78.14% in formulation 2.
  • the amount of CSD in the excipient of formulation 1 was about 1.61% in formulation 1 and 1.59% in formulation 2.
  • the amount of MCC in the tablets was about 56.53% in formulation 1 and about 62.16% in formulation 2.
  • the amount of CSD in the tableted formulations of Example 2 was about 1.15% in formulation 1 and about 1.28% in formulation 2.
  • the amount of Neusilin in the tableted formulations was about 14.12% in formulation I and about 16.12% in formulation 2.
  • the amount of oily active agent (based on the olive oil surrogate) included in the tableted formulations was about 17.5% in formulation 1 and about 20% in formulation 2.
  • the microcrystalline cellulose (MCC) slurry was prepared.
  • the colloidal silicon dioxide (CSD) was added to the MCC slurry.
  • the Neusilin US2 was added to the slurry containing the MCC and CSD.
  • the required water was added to achieve the following:
  • the solids content of the MCC slurry was 18.60%.
  • the required weight of the MCC slurry in kg was 8.40%.
  • the MCC solids content was 11.32%.
  • the required water added (kg) was 5.4.
  • the total water weight (kg) was 12.23.
  • the total slurry weight (kg) was 13.79.
  • the overall slurry solids target was 14.50%. Thereafter, the slurry was spray-dried at 200° C inlet and 105° C outlet at 31.2 Hz.
  • the excipient will carry as much as lOOmg of oil or more (olive oil used as a surrogate for an oily active ingredient) in a 500mg tablet. Tablets can be compressed with high application of force without fouling the punches and result in trouble free compression. The presence of oil in the mix does reduce the hardness somewhat (as compared to a mixture not containing oil), but not to the extent that tablet quality is compromised. The co-processed (slurry) blends showed a slightly higher oil carrying capacity that the physical mixtures, and produced very satisfactory tablets.
  • An excipient in accordance with the present invention included the following ingredients set forth in Table 4.
  • the excipient is prepared by preparing an aqueous slurry of the Prosolv SO (containing MCC and 2% CSD). Thereafter, the magnesium alumino metasilicate (Neusilin US2) is added to the slurry. Then, the slurry containing all three ingredients (MCC, CSD and magnesium alumino metasilicate) is spray-dried to produce the ready-to-use excipient.
  • the amount of Neusilin included in the excipient was about 26% of the MCC for Example 4.
  • the amount of Neusilin included in the excipient was about 20.28%, the amount of CSD was about 1.59% and the amount of MCC was about 78.13% of the excipient.
  • An excipient in accordance with the present invention included the following ingredients set forth in Table 5.
  • the excipient is prepared by combining the ingredients in an aqueous slurry. Then, the slurry containing all three ingredients (MCC, CSD and magnesium alumino metasilicate) is spray-dried to produce the ready-to-use excipient.
  • Example 6 the excipient prepared in either of Examples 4 or 5 is added to a suitable high-shear mixer. The ingredients are combined in the proportions set forth in Table 6.
  • an oily active ingredient (olive oil can is used as a surrogate for an oily active ingredient) is added to the excipient and the ingredients are mixed until all of the oil is adsorbed and a free-flowing powder results, e.g., about 5 minutes.
  • the free-flowing powder is then compressed into a tablet or filled into capsules as desired. When compressed into a tablet, this can be accomplished, e.g., on a Piccola 284 automated press at 5 different forces: approximately 3, 6, 9, 12 and 15 N.
  • the tablet punch size is 0.5 inches and the targeted tablet weight is 500 mg using a gravity feeder and feed rate of 25 rpm.
  • the tablet hardness at each compression force is measured, e.g., on a Sotax HT10 hardness tester.
  • the amount of Neusilin included in the tablet was about 16% w/w.
  • Example 7 an excipient for an oily active ingredient is prepared in accordance with the above examples, except that Aeroperl ® is included in place of Neusilin ® .
  • Example 7 four formulations differing in ratios of Prosolv ® 50 to Aeroperl were physically blended and evaluated for compaction. The formulations are set forth in Table 7 below.
  • Example 8 the oil loading capacity of an excipient including Aeroperl was tested. Therein, physical blends of Prosolv: Aeroperl were prepared at 80:20, 73:25, 70:30, and 65:35 as physical blends, and then the oil loading capacity of these excipients were tested using an oily active ingredient (olive oil can) as a surrogate for an oily active ingredient.
  • an oily active ingredient oily active ingredient
  • the olive oil is added to the excipient and the ingredients are mixed until all of the oil is adsorbed and a f ee-flowing powder results, e.g., about 5 minutes.
  • the free-flowing powder is then compressed into a tablet or filled into capsules as desired.
  • Pruv® sodium stearyl fumarate lubricant commercially available from JRS Pharma
  • Pruv® sodium stearyl fumarate lubricant commercially available from JRS Pharma
  • the tablet punch size is 0.5 inches and the targeted tablet weight is 500 mg using a gravity feeder and feed rate of 25 rpm.
  • the tablet hardness at each compression force is measured, e.g., on a Sotax HT10 hardness tester.
  • Table 8 The formulations are provided in Table 8.
  • Example 9 the formulation blends of Example 8 were prepared again, this time as co-processed materials.
  • the spray drying process begins with an MCC slurry of a determined percent of solids about 19% in Example 9). Both CSD and adsorbent (Aeroperl 300 Pharma) were added to this slurry, along with additional water to yield a slurry with a final level of solids between about 14 - 15%.
  • the solids level may vary depending upon the capability of the spray dryer or the contribution of an adsorbent to the viscosity of the slurry to be sprayed. Three separate spray drying experiments were performed, altering the level of
  • PTosolv50/Aeroperl 300 75/25, 70/30, and 65/35, along with the standard 80/20 batch. All weights are based on 2.5kg batches, on a dried basis, and a final solids level of the slurry, of 14%. The formulations are further described in Table 9.
  • Example 10 the co-processed materials of Example 9 were loaded to a 20% level with olive oil.
  • the formulations of Example 10 are set forth in Table 10.
  • Example 11 having established that co-processed material prepared at the various ratios studied could produce satisfactory tablets at a 20% oil load, formulations having an oil loading mat exceeded the 20% limit of Example 9 were prepared and tested. For this, the co- processed material having the 65:35 ratio of MCC: Aeroperl was selected to give the highest chances for success.
  • the formulations are set forth in Table 11.
  • % of oil load refers to % of oil in the overall tablet
  • Example 12 an excipient product consisting of cellulose and granulated hydrophilic fumed silicate (Aeroperl 300 Pharma) (as compared to an excipient product consisting of cellulose, granulated hydrophilic fumed silicate and colloidal silicon dioxide in previous examples). Accordingly, a slurry was prepared as per the previous examples using only Cosmo 92-40 pulp and Aeroperol 300 Pharma in a ratio of 65:35 as shown in Tables 13 and 14 below. The desired solids content of the slurry was 14.00%.
  • Example 13 an excipient product consisting of cellulose and magnesium alumino metasilicate (Neusilin US2) (as compared to an excipient product consisting of cellulose, granulated hydrophilic fumed silicate and colloidal silicon dioxide in previous examples). Accordingly, a slurry was prepared as per the previous examples using only Cosmo 92-40 pulp (microcrystalline cellulose) and Neusilin US2 in a ratio of 80:20 microcrystalline cellulose to magnesium alumino metasilicate. As a comparison, an additional product was made with 2% colloidal silicon dioxide incorporated therein. Both products contained nominally 20% magnesium alumino metasilicate. The mixture was spray-dried and tableted.

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Abstract

La présente invention concerne un excipient qui peut être utilisé pour produire des comprimés contenant des principes actifs huileux, par exemple des médicaments huileux, et des compositions pharmaceutiques contenant ledit excipient.
PCT/US2016/036728 2015-06-09 2016-06-09 Excipient et formes galéniques solides orales pour médicaments huileux WO2016201119A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010001664A1 (en) * 1995-01-09 2001-05-24 Sherwood Bob E. Pharmaceutical excipient having improved compressibility
US20030091624A1 (en) * 2001-09-28 2003-05-15 Szymczak Christopher E. Simethicone solid oral dosage form
US20070190080A1 (en) * 2004-01-06 2007-08-16 Doron Friedman Non-aqueous compositions for oral delivery of insoluble bioactive agents
US20090324729A1 (en) * 2008-05-02 2009-12-31 Gilead Sciences, Inc. Use of solid carrier particles to improve the processability of a pharmaceutical agent
US20100196475A1 (en) * 2007-05-17 2010-08-05 Pascal Grenier Controlled release tablet formulation containing magnesium aluminometasilicate

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010001664A1 (en) * 1995-01-09 2001-05-24 Sherwood Bob E. Pharmaceutical excipient having improved compressibility
US20030091624A1 (en) * 2001-09-28 2003-05-15 Szymczak Christopher E. Simethicone solid oral dosage form
US20070190080A1 (en) * 2004-01-06 2007-08-16 Doron Friedman Non-aqueous compositions for oral delivery of insoluble bioactive agents
US20100196475A1 (en) * 2007-05-17 2010-08-05 Pascal Grenier Controlled release tablet formulation containing magnesium aluminometasilicate
US20090324729A1 (en) * 2008-05-02 2009-12-31 Gilead Sciences, Inc. Use of solid carrier particles to improve the processability of a pharmaceutical agent

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