WO2023118074A1 - Compressible and free flowing co-processed mesoporous silica - Google Patents

Compressible and free flowing co-processed mesoporous silica Download PDF

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Publication number
WO2023118074A1
WO2023118074A1 PCT/EP2022/086896 EP2022086896W WO2023118074A1 WO 2023118074 A1 WO2023118074 A1 WO 2023118074A1 EP 2022086896 W EP2022086896 W EP 2022086896W WO 2023118074 A1 WO2023118074 A1 WO 2023118074A1
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Prior art keywords
particulate material
material according
acid
soluble
silicon dioxide
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PCT/EP2022/086896
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French (fr)
Inventor
Odon Planinsek
Ana BAUMGARTNER
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Univerza V Ljubljani
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Publication of WO2023118074A1 publication Critical patent/WO2023118074A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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
    • 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
    • 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 relates to a co-processed mesoporous silica. More specifically, the present invention provides a particulate material comprising (or consisting essentially of) mesoporous silicon dioxide and a water-soluble or hydrophilic binder.
  • the particulate material of the present invention is particularly useful as excipient or carrier in the preparation of a pharmaceutical composition since it has improved compressibility and flow properties than in pure form and still has a high enough specific surface area to be impregnated with the active ingredient and to produce a solid dispersion and produce tablets or capsules.
  • Single unit dosage forms suitable for oral administration of the active pharmaceutical ingredients are usually formulated in the form of solid formulations.
  • these forms, tablets and capsules contain pharmaceutically acceptable substances, which are called excipients, which are not active and have no therapeutic effect.
  • the formulations give the ability to the active pharmaceutical ingredient to be incorporated into a pharmaceutical form by an industrially feasible process. They may also have the effect of increasing the bioavailability of the active substance mainly on the basis of its improved dissolution and absorption.
  • Untreated excipients may have poor flow properties and compressibility. Good flow properties are important in both the capsule filling process and direct compression. Direct compression is the most desirable method of tableting, as it requires only a good flowing and compressible mixture of powders; active pharmaceutical ingredients and excipients such as fillers, binders, disintegrants, glidants and antiadhesives. If such a mixture is not well flowable and compressible, a granulation step must be added when making the tablets. The same step is required when the powder mixture does not have good enough flow properties to fill the capsules. Granulation is divided into: (1) dry granulation; and (2) wet granulation.
  • the dry granulation method involves mixing the ingredients, pressing at high pressures with an apparatus called a roller compactor, grinding, sieving, the addition of a glidant, and finally pressing the finished granules.
  • the wet granulation process involves mixing some or all of the components of the formulation and adding a binder to this mixture to form granules in high shear mixer-granulator.
  • the wet mixture is sieved and dried in fluid bed apparatus with the help of heated air or dried on trays.
  • the wet granulation process can also be performed in fluidized bed process.
  • Direct compression involves fewer steps and is a cheaper process than granulation.
  • the mixture must be freely flowable.
  • sufficient bonds must form between the particles during the tableting process to keep the tablet intact after compression.
  • Tablets are formed by applying pressure to a tablet mixture using a tablet press.
  • the basic unit of any tablet press is tooling consisting of two punches and a die called a station.
  • the upper and lower punches come together in the die that contains the tablet formulation.
  • the ability of the powder to flow well into the dye is important for the uniform filling of the dye and the uniformity of the tablet mass in the process of continuous tableting.
  • Carriers of solid dispersion can be polymers, surface active agents or mesoporous materials.
  • Mesoporous silica has a large specific surface area of up to 1000 square meters per gram of narrow pores between 2 and 50 nanometers and a large total pore volume of up to 2 milliliters per gram.
  • An increase in the specific surface area of the active ingredient filled in the pores, the amorphous state of the active pharmaceutical ingredient and good wetting of the particles contribute to the improvement of the dissolution rate of poorly water soluble active pharmaceutical ingredient.
  • the pores of mesoporous silicon dioxide can be filled by the method of impregnation of the active pharmaceutical ingredient from solution or by impregnation with melt.
  • Solid dispersions of active pharmaceutical ingredient with mesoporous excipients are characterized by poor flowability and compressibility.
  • mesoporous silica which has good flow properties and compressibility and can be impregnated with the active pharmaceutical ingredient and is suitable for encapsulation and tableting.
  • the particulate material of the present invention has superior functionalities.
  • a water-soluble or hydrophilic binder such as a disaccharide, sugar alcohol or pharmaceutical polymer
  • the properties of the particulate material thus allow its impregnation with an active pharmaceutical ingredient, the production of a solid dispersion and the incorporation of formulations into a solid pharmaceutical form such as capsules or tablets without the need for additional glidants, binders and fillers.
  • the particulate material is suitable for the production of the tablets with direct compression.
  • the particulate material shows an advantageous inclease in the bulk density which minimizes the air entrapment and offsets the effect of high compression speeds. Moreover, inclease bulk density of the particulate material of the invention reduces capsule size required.
  • the present invention thus provides in a first aspect a particulate material comprising (or consisting essentially of) mesoporous silicon dioxide and a water-soluble or hydrophilic binder. More specifically, the particulate material of the present invention comprises (or consists essentially of) i) about 40% w/w to about 99% w/w of mesoporous silicon dioxide and ii) about 1% w/w to about 60% w/w of a water-soluble or hydrophilic binder.
  • the present invention provides in a further aspect a particulate material which is a granulate comprising i) about 40% w/w to about 99% w/w of mesoporous silicon dioxide and ii) about 1% w/w to about 60% w/w of a water-soluble or hydrophilic binder, having a bulk density of at least about 0.2 g/cm 3 , such as from about 0.20 to about 0.35 g/cm 3 or 0.20 to about 0.32 g/cm 3 (determined according to EU Pharmacopoeia), having a Hausner ratio of about 1.1 to about 1.4, such as of about 1.1 to about 1.3 (determined according to US Pharmacopoeia), and having a mesopore volume of more than 0.3 ml/g, such as more than 0.5 ml/g or more than 0.7 ml/g.
  • the present invention provides in a further aspect a solid dispersion comprising the particulate material according to the present invention.
  • the present invention provides a solid dispersion comprising the particulate material according to the present invention, at least one active ingredient, and optionally at least one pharmaceutically acceptable excipient.
  • the present invention provides in a further aspect a pharmaceutical composition comprising the solid dispersion according to present invention and at least one pharmaceutically acceptable excipient.
  • the present invention provides in a further aspect a process for producing the particulate material according to the present invention, the process comprising granulation of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder.
  • the present invention provides in a further aspect a process for producing a solid dispersion according to the present invention, the process comprising admixing the particulate material according to the present invention with at least one active ingredient and optionally at least one pharmaceutically acceptable excipient.
  • the present invention provides in a further aspect a process for producing a pharmaceutical composition according to the present invention, the process comprising admixing the solid dispersion according to the present invention with at least one pharmaceutically acceptable excipient.
  • the present invention provides in a further aspect a process for producing a tablet, the process comprising admixing the solid dispersion according to the present invention with at least one pharmaceutically acceptable excipient, and compressing said resulting mixture into a tablet.
  • the present invention provides in a further aspect the use of a particulate material according to the present invention as excipient or carrier in the preparation of a pharmaceutical composition.
  • Particulate material comprising (or consisting essentially of) i) mesoporous silicon dioxide and ii) a water-soluble or hydrophilic binder.
  • Particulate material according to item 1 comprising (or consisting essentially of) i) about 40% w/w to about 99% w/w of mesoporous silicon dioxide and ii) about 1% w/w to about 60% w/w of a water-soluble or hydrophilic binder binder.
  • the particulate material according to item 1 or 2 wherein the mesoporous silicon dioxide is present in a concentration of about 50% to about 90% w/w and the water soluble or hydrophilic binder binder is present in a concentration from about 10% w/w to about 50% w/w.
  • the particulate material according to item 7 wherein the sugar alcohol is selected from the group consisting of xylitol, sorbitol, mannitol, maltitol, lactitol, erythritol, inositol, isomalt, isomaltulose and mixtures thereof.
  • the particulate material according to item 8 wherein the sugar alcohol is isomalt.
  • the particulate material according to item 13, wherein the polymeric substance is polyvinylpyrrolidone F90 or K25.
  • the particulate material according to any one of items 6 to 9, comprising about 5% w/w to about 60% w/w of said polyol.
  • the particulate material according to any one of items 6 to 9, comprising about 10% w/w to about 50% w/w of said polyol.
  • a solid dispersion comprising the particulate material according to any one of items 1 to 31, at least one active ingredient, and optionally at least one pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising the solid dispersion according to item 32 or 33 and at least one pharmaceutically acceptable excipient.
  • composition according to item 34 which is in the form of a tablet, capsule, sachet, pellet, beadlet, granule, or granulate.
  • composition according to item 34 which is in the form of a tablet.
  • the process according to any one of items 38 to 41, wherein the wet granulation comprises applying, e.g., spraying an aqueous or organic solvent (or a mixture of an aqueous solvent and an organic solvent) onto a mixture of the mesoporous silicon dioxide and the water- soluble or hydrophilic binder.
  • the wet granulation comprises applying, e.g., spraying onto the mesoporous silicon dioxide a granulation liquid comprising the water-soluble or hydrophilic binder and an aqueous or organic solvent (or a mixture of an aqueous solvent and an organic solvent).
  • melt granulation is fluid bed granulation or high shear granulation.
  • melt granulation involves the use of a fluid bed apparatus.
  • Process for producing a solid dispersion according to items 32 or 33 comprising admixing the particulate material according to any one of items 1 to 31 with at least one active ingredient and optionally at least one pharmaceutically acceptable excipient.
  • Process for producing a pharmaceutical composition according to any one of items 34 to 36 comprising admixing the solid dispersion according to item 32 or 33 with at least one pharmaceutically acceptable excipient.
  • Process for producing a tablet comprising admixing the solid dispersion according to item 32 or 33 with at least one pharmaceutically acceptable excipient, and compressing said resulting mixture into a tablet.
  • Figure 1 Compressibility of co-processed granulate vs. physical blend.
  • Figure 3 Compressibility of co-processed granulate vs. physical blend.
  • Figure 4 Compressibility of co-processed granulate vs. physical blend.
  • mesoporous silica which has good flow properties and compressibility and can be impregnated with the active pharmaceutical ingredient and is suitable for encapsulation and tableting.
  • mesoporous silica co-processed with a water- soluble or hydrophilic binder such as a disaccharide, sugar alcohol or pharmaceutical polymer
  • a water- soluble or hydrophilic binder such as a disaccharide, sugar alcohol or pharmaceutical polymer
  • mesoporous silica co-processed with a water- soluble or hydrophilic binder has better compressibility and flow properties than in pure form and still has a high enough specific surface area to be impregnated with the active ingredient and to produce a solid dispersion and produce tablets or capsules.
  • Pores are not completely filled with excipient during granulation and are available for impregnation with active pharmaceutical ingredient to form amorphous solid dispersion.
  • the properties of the particulate material thus allow its impregnation with an active pharmaceutical ingredient, the production of a solid dispersion and the incorporation of formulations into a solid pharmaceutical form such as capsules or tablets without the actual need for additional glidants, binders and fillers.
  • the particulate material is particularly suitable for the production of the tablets with direct compression.
  • the present invention provides a particulate material comprising (or consisting essentially of) mesoporous silicon dioxide and a water-soluble or hydrophilic binder.
  • the particulate material of the present invention comprises (or consists essentially of) i) about 40% w/w to about 99% w/w of mesoporous silicon dioxide and ii) about 1% w/w to about 60% w/w of a water-soluble or hydrophilic binder.
  • the mesoporous silicon dioxide is present in a concentration of about 50% w/w to about 95% w/w and the water-soluble or hydrophilic binder is present in a concentration from about 5% w/w to about 50% w/w.
  • the mesoporous silicon dioxide is present in a concentration of about 50% to about 90% w/w and the water-soluble or hydrophilic binder is present in a concentration from about 10% w/w to about 50% w/w.
  • the mesoporous silicon dioxide is present in a concentration of about 60% to about 90% w/w and the water-soluble or hydrophilic binder is present in a concentration from about 10% w/w to about 40% w/w.
  • the mesoporous silicon dioxide is present in a concentration of about 65% to about 90% w/w and the water-soluble or hydrophilic binder is present in a concentration from about 10% w/w to about 35% w/w.
  • the mesoporous silicon dioxide is present in a concentration of about 67% w/w to about 90% w/w and the water-soluble or hydrophilic binder is present in a concentration from about 10% w/w to about 33% w/w.
  • the mesoporous silicon dioxide is present in a concentration of about 75% w/w to about 85% w/w and the water-soluble or hydrophilic binder is present in a concentration from about 15% w/w to about 25% w/w. According to some embodiments, the mesoporous silicon dioxide is present in a concentration of about 80% w/w and the water-soluble or hydrophilic binder is present in a concentration from about 20% w/w.
  • the mesoporous silicon dioxide and the water-soluble or hydrophilic binder are generally present at a weight ratio of 1:1 to 10:1 mesoporous silicon dioxide:binder, such as a weight ratio of 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1 or 9:1.
  • the mesoporous silicon dioxide and the water-soluble or hydrophilic binder are present at a weight ratio of 2:1.
  • the mesoporous silicon dioxide and the water-soluble or hydrophilic binder are present at a weight ratio of 3:1.
  • the mesoporous silicon dioxide and the water-soluble or hydrophilic binder are present at a weight ratio of 4:1.
  • the particulate material of the present invention may comprise impurities and/or water in the form of, e.g., moisture, which do not materially affect the basic and novel characteristic(s) of the particulate of the present invention.
  • the impurities will not make out more than about 5% w/w of the total weight of the particulate material, preferably will not make out more than about 3% w/w of the total weight of the particulate material.
  • water in the form of, e.g., moisture will not make out more than about 7% w/w of the total weight of the particulate material, preferably will not make out more than about 5% of the total weight of the particulate material.
  • the moisture content may be about 0.5% w/w to about 7% w/w, such as about 0.5% w/w to about 7% w/w.
  • Mesoporous silicon dioxide refers to any number of a variety of materials synthesised to produce a SiOj mesoporous structure.
  • Mesoporous silicon dioxide is divided into ordered and disordered. While in the ordered pores they are uniformly arranged in one direction, in the disordered carriers the pores are oriented randomly, and in both cases the material is amorphous.
  • MCM Mobil Composition of Matter
  • Disordered mesoporous silicon dioxide is prepared with the chemical reaction of sol-gel process.
  • the starting material is usually alkoxysilane, where the alkyl groups are first hydrolyzed to silanol groups. These can then be connected to each other via a siloxane bridge (Si - O - Si), which initially leads to the aggregation of colloidal-sized particles (salts) and later to the formation of a larger crosslinked structure (gel).
  • Si - O - Si siloxane bridge
  • AEROSIL® fumed silica
  • the mesoporous silicon dioxide employed in accordance with the present invention can be an ordered or disordered mesoporous silicon dioxide. According to some embodiments, the mesoporous silicon dioxide is an ordered mesoporous silicon dioxide. According to some embodiments, the mesoporous silicon dioxide is a disordered mesoporous silicon dioxide.
  • the mesoporous silicon dioxide generally has an average pore size of about 2 nm to about 50 nm. According to some embodiments, the mesoporous silicon dioxide has an average pore size of about 5 nm to about 35 nm. According to some embodiments, the mesoporous silicon dioxide has an average pore size of about 10 nm to about 30 nm.
  • the mesoporous silicon dioxide has a specific surface area in the range from about 100 m 2 /g to about 700 m 2 /g, such as from about 100 m 2 /g to about 500 m 2 /g. According to some embodiments, the mesoporous silicon dioxide has a specific surface area in the range from about 150 m 2 /g to about 400 m 2 /g. According to some embodiments, the mesoporous silicon dioxide has a specific surface area in the range from about 200 m 2 /g to about 400 m 2 /g.
  • the specific surface area may be measured by gas adsorption according to Ph. Eur., 6th edition, Chapter 2.9.26. multipoint method, volumetric determination. The specific surface area can be measured using a multipoint BET - Brunauer-Emmett-Teller apparatus 3P Nova 2000e.
  • the mesoporous silicon dioxide generally has a mean particle size (d50) of about 1 pm to about 200 pm (determined by laser diffraction). According to some embodiments, the mesoporous silicon dioxide has a mean particle size of about 1 pm to about 150 pm. According to some embodiments, the mesoporous silicon dioxide has a mean particle size of about 1 pm to about 120 pm.
  • the mesoporous silicon dioxide has a mean particle size of about 1 pm to about 70 pm. According to some embodiments, the mesoporous silicon dioxide has a mean particle size of about 1 pm to about 50 pm. According to some embodiments, the mesoporous silicon dioxide has a mean particle size of about 1 pm to about 20 pm. According to some embodiments, the mesoporous silicon dioxide has a mean particle size of about 1 pm to about 10 pm.
  • the mean particle size can be determined according to 2.9.31. PARTICLE SIZE ANALYSIS BY LASER LIGHT DIFFRACTION, Ph.Eur. 10.0. using, e.g., a Malvern Mastersizer 3000 apparatus.
  • the mesoporous silicon dioxide may be obtained commercially.
  • Non-limiting examples of commercially available mesoporous silicon dioxide include Aeroperl® 300, Parteck® SLC 500, Syloid® XDP 3050, Syloid® XDP 3150, Syloid® 244 FP, Syloid® AL-1 FP, and Sylysia® 350.
  • SYLOID® 244 FP is a high pore volume silica gel with a large internal surface area. It has a strong affinity for moisture and organic based liquids. SYLOID® 244 FP can adsorb up to 1.6 ml of liquid per gram. SYLOID® 244 FP is further characterized in that it has an average pore size of 16 nm, has a specific surface area of 379 m 2 /g, and has a mean particle size of 3.5 pm. According to some embodiments, the mesoporous silicon dioxide has an average pore size of 16 nm, has a specific surface area of 379 m 2 /g, and has a mean particle size of 3.5 pm, such as Syloid® 244 FP.
  • Sylysia® 350 is a mesoporous silicon dioxide having an average pore size of 21 nm, has a specific surface area of 300 m 2 /g, and has a mean particle size of 1.8 pm.
  • the mesoporous silicon dioxide has an average pore size of 21 nm, has a specific surface area of 300 m 2 /g, and has a mean particle size of 1.8 pm.
  • Aeroperl® 300 is a mesoporous silicon dioxide having an average pore size of 30 nm, has a specific surface area of 260-320 m 2 /g, and has a mean particle size of 20-60 pm. According to some embodiments, the mesoporous silicon dioxide has an average pore size of 30 nm, has a specific surface area of 260-320 m 2 /g, and has a mean particle size of 20-60 pm, such as Aeroperl® 300.
  • Parteck® SLC 500 is a mesoporous silicon dioxide having an average pore size of 6 nm, has a specific surface area of 500 m 2 /g, and has a mean particle size of 5-20 pm.
  • the mesoporous silicon dioxide has an average pore size of 6 nm, has a specific surface area of 500 m 2 /g, and has a mean particle size of 5-20 pm, such as Parteck® SLC 500.
  • Syloid® XDP 3050 is a mesoporous silicon dioxide having an average pore size of 22.9 nm, has a specific surface area of 287 m 2 /g, and has a mean particle size of 50 pm.
  • the mesoporous silicon dioxide has an average pore size of 22.9 nm, has a specific surface area of 287 m 2 /g, and has a mean particle size of 50 pm, such as Syloid® XDP 3050.
  • Syloid® XDP 3150 is a mesoporous silicon dioxide having an average pore size of 20 nm, has a specific surface area of 320 m 2 /g, and has a mean particle size of 150 pm.
  • the mesoporous silicon dioxide has an average pore size of 20 nm, has a specific surface area of 320 m 2 /g, and has a mean particle size of 150 pm, such as Syloid® XDP 3150.
  • Syloid® AL-1 FP is a mesoporous silicon dioxide having an average pore size of 2.9 nm, has a specific surface area of 650 m 2 /g, and has a mean particle size of 7.5 pm.
  • the mesoporous silicon dioxide has an average pore size of 2.9 nm, has a specific surface area of 650 m 2 /g, and has a mean particle size of 7.5 pm.
  • the present invention employs a binder, and more specifically a water-soluble or hydrophilic binder.
  • the water-solubility of the binder may be about 10 mg/ml or more such as, e.g., about 25 mg/ml or more, about 50 mg/ml or more, about 75 mg/ml or more, about 100 mg/ml or more, about 150 mg/ml or more, about 200 mg/ml or more, about 250 mg/ml or more, or about 300 mg/ml or more.
  • a hydrophilic binder generally has a water contact angle below 90 degrees, and preferably exhibits good water wettability.
  • Non-limiting examples of suitable water-soluble or hydrophilic binders for use according to the invention are polyols, carbohydrates, polymeric substances, and mixtures thereof.
  • the water-soluble or hydrophilic binder is selected from the group consisting of polyols, carbohydrates and polymeric substances.
  • the water-soluble or hydrophilic binder is a polyol.
  • the polyol is a sugar alcohol.
  • Non-limiting examples of suitable sugar alcohols for use according to the present invention are xylitol, sorbitol, mannitol, maltitol, lactitol, erythritol, inositol, isomalt, isomaltulose and mixtures thereof.
  • the sugar alcohol is selected from the group consisting of xylitol, sorbitol, mannitol, maltitol, lactitol, erythritol, inositol, isomalt, isomaltulose and mixtures thereof.
  • the sugar alcohol is isomalt. According to some embodiments, the sugar alcohol is xylitol. According to some embodiments, the sugar alcohol is sorbitol. According to some embodiments, the sugar alcohol is mannitol. According to some embodiments, the sugar alcohol is maltitol. According to some embodiments, the sugar alcohol is lactitol. According to some embodiments, the sugar alcohol is erythritol. According to some embodiments, the sugar alcohol is isomaltulose.
  • the polyol e.g. sugar alcohol
  • the polyol is present in a concentration of about 5% w/w to about 60% w/w.
  • the polyol e.g. sugar alcohol
  • the polyol is present in a concentration of about 10% w/w to about 50% w/w.
  • the polyol e.g. sugar alcohol
  • the polyol is present in a concentration of about 10% w/w to about 40% w/w.
  • the polyol (e.g. sugar alcohol) is present in a concentration of about 10% w/w to about 35% w/w.
  • the polyol e.g.
  • sugar alcohol is present in a concentration of about 10% w/w to about 33% w/w.
  • the polyol e.g. sugar alcohol
  • the polyol is present in a concentration of about 10% w/w to about 25% w/w.
  • the polyol e.g. sugar alcohol
  • the polyol is present in a concentration of about 10% w/w to about 20% w/w.
  • the water-soluble or hydrophilic binder is a carbohydrate.
  • the carbohydrate is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, polysaccharides, and mixtures thereof.
  • the carbohydrate is a monosaccharide. According to some embodiments, the carbohydrate is a disaccharide. According to some embodiments, the carbohydrate is an oligosaccharide. According to some embodiments, the carbohydrate is a polysaccharide.
  • Non-limiting examples of suitable monosaccharides for use according to the invention are glucose, mannose, fructose, galactose, and mixtures thereof.
  • the carbohydrate is glucose.
  • the carbohydrate is mannose.
  • the carbohydrate is fructose.
  • the carbohydrate is galactose.
  • suitable disaccharides for use according to the present invention are lactose, maltose, sucrose, trehalose, tagatose, and mixtures thereof.
  • the carbohydrate is lactose.
  • the carbohydrate is maltose.
  • the carbohydrate is sucrose.
  • the carbohydrate is trehalose.
  • the carbohydrate is tagatose.
  • Non-limiting examples of suitable oligosaccharides and polysaccharides for use according to the present invention are dextrose, oligofructose, dextrin, cyclodextrin, maltodextrin, and mixtures thereof.
  • the carbohydrate is dextrose.
  • the carbohydrate isoligofructose.
  • the carbohydrate is a dextrin.
  • the carbohydrate is a cyclodextrin.
  • the carbohydrate is maltodextrin.
  • the carbohydrate is selected from the group consisting of sucrose, glucose, fructose, trehalose, galactose, lactose, maltose, mannose, ribose, xylose, arabinose, dextrins and mixtures thereof.
  • the carbohydrate is present in a concentration of about 5% w/w to about 60% w/w. According to some embodiments, the carbohydrate is present in a concentration of about 10% w/w to about 50% w/w. According to some embodiments, the carbohydrate is present in a concentration of about 10% w/w to about 40% w/w. According to some embodiments, the carbohydrate is present in a concentration of about 10% w/w to about 35% w/w. According to some embodiments, the carbohydrate is present in a concentration of about 10% w/w to about 33% w/w. According to some embodiments, the carbohydrate is present in a concentration of about 10% w/w to about 25% w/w. According to some embodiments, the carbohydrate is present in a concentration of about 10% w/w to about 20% w/w.
  • the water-soluble or hydrophilic binder is a polymeric substance.
  • Non-limiting examples of polymeric substances that are suitable for use according to the present invention are cellulose polymers including microcrystalline cellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and carboxymethylcellulose, povidone including polyvinylpyrrolidone F-90, K-90, K-30, K-25, K-17 or K- 12, copovidones including vinylpyrrolidone-vinyl acetate copolymer, agar, gelatin, gummi arabicum, xanthan gum, chitosan, alginates including sodium alginate and polyetylene glycol alginate, polyethylene glycols, polyethylene oxids, polyvinyl alcohols, copolymers comprised of polyethylene glycol and polyvinyl alcohol, , polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, poly(ethylene glycol)-block-poly(prop
  • the polymeric substance is a povidone. According to some embodiments, the polymeric substance is polyvinylpyrrolidone F90 or K25. According to some embodiments, the polymeric substance is polyvinylpyrrolidone F90. Accordinging to some embodiments, the polymeric substance is polyvinylpyrrolidone K25.
  • the polymeric substance is a copovidone. According to some embodiments, the polymeric substance is vinylpyrrolidone-vinyl acetate copolymer.
  • the polymeric substance is a cellulose polymer, such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose or carboxymethylcellulose.
  • the cellulose polymer is microcrystalline cellulose.
  • the cellulose polymer is methylcellulose.
  • the cellulose polymer is ethylcellulose.
  • the cellulose polymer is hydroxypropylmethylcellulose.
  • the cellulose polymer is hydroxyethylcellulose.
  • the cellulose polymer is hydroxypropylcellulose.
  • the cellulose polymer is carboxymethylcellulose.
  • the polymeric substance is a polyethylene glycol, polyvinyl alcohol or graft copolymer comprised of polyethylene glycol and polyvinyl alcohol.
  • the polymeric substance is a polyethylene glycol.
  • the polymeric substance is a polyethylene oxide.
  • the polymeric substance is a polyvinyl alcohol.
  • the polymeric substance is a graft copolymer comprised of polyethylene glycol and polyvinyl alcohol.
  • the polymeric substance is a polyethylene glycol having an average molecular weight from 1,000 g/mol to 20,000 g/mol. According to some embodiments, the polymeric substance is a polyethylene glycol having an average molecular weight from 2,000 g/mol to 15,000 g/mol. According to some embodiments, the polymeric substance is a polyethylene glycol having an average molecular weight from 2,000 g/mol to 10,000 g/mol. According to some embodiments, the polymeric substance is a polyethylene glycol having an average molecular weight from 4,000 g/mol to 6,000 g/mol. According to some embodiments, the polymeric substance is a polyethylene glycol having an average molecular weight of 4000 g/mol. According to some embodiments, the polymeric substance is a polyethylene glycol having an average molecular weight of 6000 g/mol.
  • the polymeric substance is a polyethylene oxide having an average molecular weight of 20,000 g/mol or above. According to some embodiments, the polymeric substance is a polyethylene oxide having an average molecular weight from 50,000 g/mol to 1,000,000 g/mol. According to some embodiments, the polymeric substance is a polyethylene oxide having an average molecular weight from 50,000 g/mol to 500,000 g/mol. According to some embodiments, the polymeric substance is a polyethylene oxide having an average molecular weight from 100,000 g/mol to 300,000 g/mol. According to some embodiments, the polymeric substance is a polyethylene oxide having an average molecular weight from 150,000 g/mol to 350,000 g/mol. According to some embodiments, the polymeric substance is a polyethylene oxide having an average molecular weight of 200,00 g/mol.
  • the polymeric substance is present in a concentration of about 5% w/w to about 60% w/w. According to some embodiments, the polymeric substance is present in a concentration of about 10% w/w to about 50% w/w. According to some embodiments, the polymeric substance is present in a concentration of about 10% w/w to about 40% w/w. According to some embodiments, the polymeric substance is present in a concentration of about 10% w/w to about 35% w/w. According to some embodiments, the polymeric substance is present in a concentration of about 10% w/w to about 33% w/w. According to some embodiments, the polymeric substance is present in a concentration of about 10% w/w to about 25% w/w. According to some embodiments, the polymeric substance is present in a concentration of about 10% w/w to about 20% w/w.
  • the particulate material according to the present invention has a particle size distribution that is suitable for use within the pharmaceutical field especially in connection with further processing of the particulate material into a solid dosage form.
  • the mean particle size d50 (determined by laser diffraction) of the particulate material according to the present invention is normally about 30 pm or above, such as at least about 40 pm, at least about 50 pm, at least about 80 pm, at least about 100 pm or at least about 120 pm.
  • the particle size analysis may generally performed on a Malvern Mastersizer 3000 apparatus where dlO, d50 and d90 give the particle sizes for which 10%, 50% and 90% of the total particles have sizes below the given value.
  • d50 is the mean particle size, and can be determined according to 2.9.31. PARTICLE SIZE ANALYSIS BY LASER LIGHT DIFFRACTION, Ph.Eur. 10.0.
  • the mean particle size d50 (determined by laser diffraction) is in the range of about 30 pm to about 1000 pm, such as of about 50 pm to about 1000 pm, of about 80 pm to about 1000 pm, such as of 120 pm to about 800 pm or of about 150 pm to about 600 pm.
  • the particulate material according to the present invention may have a Hausner ratio of about 1.1 to about 1.4, such as of about 1.1 to about 1.3. According to some embodiments, the particulate material according to the present invention has a Hausner ratio of about 1.1 to about 1.2. According to some embodiments, the particulate material according to the present invention has a Hausner ratio of about 1.10 to about 1.25. According to some embodiments, the particulate material according to the present invention has a Hausner ratio of about 1.10 to about 1.23. According to some embodiments, the particulate material according to the present invention has a Hausner ratio of about 1.10 to about 1.20. According to some embodiments, the particulate material according to the present invention has a Hausner ratio of about 1.10 to about 1.18. According to some embodiments, the particulate material according to the present invention has a Hausner ratio of about 1.12 to about 1.18.
  • the Hausner ratio can be determined according to 2.9.34 BULK DENSITY AND TAPPED DENSITY OF POWDERS, METHOD 1, Ph Eur 10.0 using 100 ml cylinder and Setling device for powder sample.
  • a particulate material according to the present invention may (further) have a specific surface area of at least about 100 m 2 /g. According to some embodiments, the particulate material according to the present invention has a specific surface area in the range from about 100 m 2 /g to about 600 m 2 /g, such as from about 150 m 2 /g to about 400 m 2 /g. According to some embodiments, the particulate material according to the present invention has a specific surface area in the range from about 200 m 2 /g to about 400 m 2 /g.
  • the specific surface area may be measured by gas adsorption according to Ph. Eur., 6th edition, Chapter 2.9.26. multipoint method, volumetric determination.
  • the specific surface area can be measured using a multipoint BET - Brunauer-Emmett-Teller apparatus 3P Nova 2000e.
  • a particulate material according to the present invention may (further) have a bulk density of at least about 0.2 g/cm 3 (determined according to EU Pharmacopoeia). According to some embodiments, the particulate material according to the present invention has a bulk density from about 0.20 to about 0.35 g/cm 3 . According to some embodiments, the particulate material according to the present invention has a bulk density from about 0.20 to about 0.32 g/cm 3 .
  • the bulk density can be determined according to 2.9.34. BULK DENSITY AND TAPPED DENSITY OF POWDERS, METHOD 1, Ph.Eur. 10.0 using 100 ml cylinder.
  • a particulate material according to the present invention may (further) be mesoporous. According to some embodiments, the particulate material according to the present invention has a mesopore volume of more than 0.3 ml/g. According to some embodiments, the particulate material according to the present invention has a mesopore volume of more than 0.5 ml/g. According to some embodiments, the particulate material according to the present invention has a mesopore volume of more than 0.7 ml/g.
  • Mesopores presence and their volume can be determined with complete gas physisorption analysis, wherein the adsorption isotherm is collected under both ascending pressure (adsorption) and descending pressure (desorption) conditions on the basis of hysteresis presence according to recommendations of the International Union of Pure and Applied Chemistry (IUPAC) or other interntional standards.
  • adsorption ascending pressure
  • desorption descending pressure
  • the particulate material may be obtained by way of granulation, such as wet or melt granulation, and more specifically is obtainable by a process according to present invention, which is described in more detail below.
  • the particulate material may have any suitable form, but preferably is a granulate.
  • the superior properties of the particulate material of the present invention allow its impregnation with an active pharmaceutical ingredient, the production of a solid dispersion and the incorporation of formulations into a solid pharmaceutical form such as capsules or tablets without the need for additional glidants, binders and fillers.
  • the particulate material is especially suitable in the preparation of tablets with direct compression.
  • the present invention provides a solid dispersion comprising the particulate material according to the present invention, at least one active ingredient, and optionally at least one pharmaceutically acceptable excipient.
  • solid dispersion generally refers to a solid mixture of one or more active ingredients and a hydrophilic backbone, i.e., a carrier.
  • Active pharmaceutical ingredient in the carrier can be molecularly dispersed or arranged in the form of amorphous or crystalline particles, and the carrier matrix can be both amorphous or crystalline (KT Kim et al. Solid dispersions as a drug delivery system Journal of Pharmaceutical Investigation 2011, Volume 41, Issue 3, Pages, 125-142).
  • the particulate material is impregnated with said at least one active ingredient.
  • Non-limiting example include rotary evaporation, vacuum drying and spray drying.
  • the active ingredient may be any desirable active ingredient.
  • Non-limiting examples include (-)- amlodipine, (-)-halofenate, (R)-salbutamol, (R)- salbutamol, (R,R)-formoterol, (S)-doxazosin, (S)-fluoxetine, (S)-oxybutynin, 1,2-naphthoquinone, 17-methyl testosterone, 17a- hydroxyprogesterone, 195mPt-cisplatin, 1- naphthyl salicylate, l-naphthylamine-4-, 1- theobromineacetic, la-hydroxy cholecalciferol, 2,4,6-tribromo-m-cresol, 2,6-diamino-2'-butyloxy- 3,5'-azopyridine, 2-[[[(lr)-2-(lh- imidazol-4-yl)-l-methylethyl]imino]phenylmethyl]-phenol,
  • pharmaprojects no. 4994 pharmaprojects no. 5325, pharmaprojects no. 5972, pharmaprojects no. 6446, pharmaprojects no. 6590, pharmaprojects no. 6656, pharmaprojects no. 6691, pharmaprojects no. 6743, pharmaprojects no.
  • phenacaine phenacemide, phenacetin, phenadoxone, phenallymal, phenamet, phenamide, phenazocine, phenazopyridine, phenbutamide, phencyclidine, phendimetrazine, phenelzine, phenesterine, phenetharbital, phenethicillin, pheneturide, phenformin, phenglutarimide, phenindamine, phenindione, pheniprazine, pheniramine, phenmetrazine, phenobarbital, phenobutiodil, phenocoll, phenoctide, phenolphthalein, phenolphthalol, phenolsulfonphthalein, phenol-tetrachlorophthalein, phenoperidine, phenosulfazole, phenoxybenzamine, phenoxypropazine, phenprobamate, phenprocoumon, phenserine, phenallymal,
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the solid dispersion according to the present invention and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition is an oral dosage form, and more specifically a solid dosage form, such as a tablet, capsule, sachet, pellet, beadlet, granule, or granulate.
  • the pharmaceutical composition is a tablet.
  • a "pharmaceutically acceptable excipient” is intended to denote any material, which is inert in the sense that it substantially does not have any therapeutic and/or prophylactic effect per se.
  • a pharmaceutically acceptable excipient may be added to the solid dispersion or pharmaceutical composite with the purpose of making it possible to obtain a solid dispersion or pharmaceutical composition having acceptable technical properties.
  • Suitable pharmaceutically acceptable excipients are well-known to the skilled person and have been described in the literature, such as in Remington's Pharmaceutical Sciences, the Handbook of Pharmaceutical Additives or the Handbook of Pharmaceutical Excipients.
  • suitable pharmaceutically acceptable excipients include diluents, fillers, binding agents, disintegrating agents, lubricants, fluidizers, granulating agents, coating materials, wetting agents, solvents, co-solvents, suspending agents, emulsifying agents, sweetening agents, flavoring agents, odor masking agents, coloring agents, anti-caking agents, chelating agents, plasticisers, viscosifiers, antioxidants, antiseptics, stabilizing agents, surfactants and buffer agents.
  • the present invention is generally based on the co-processing of a mesoporous silicon dioxide and a water-soluble or hydrophilic binder, resulting in particulate material having superior functionalities.
  • the process for preparing a particulate material of the present invention generally involves the granulation of a blend of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder.
  • Granulation has been employed within the pharmaceutical industry for decades. An essential manufacturing process which is used to form aggregated granules from a powder, it enhances the properties of a drug through material densification and is widely used as an intermediate process within Solid Dosage manufacturing.
  • wet granulation methods offer greater scalability than dry granulation, alongside enhanced reproducibility and significant cost-savings.
  • wet granulation involves four key mechanisms or rate processes that take place simultaneously and continuously inside the granulator. These are wetting (also referred to as nucleation), growth, consolidation and breakage. The interaction between these different mechanisms determines the final size distribution of the granulated product, in addition to controlling important attributes such as density and porosity.
  • fluid bed granulation high velocity air is used to suspend powdered material within a fluid bed granulator.
  • This specialized, multi-purpose piece of equipment is capable of mixing, granulating and drying, obviating the requirement to use separate instrumentation for each stage of the process.
  • the fluid bed granulator expands the bed upwards to provide high heat and mass transfer surface area. This process can also be microwave-assisted to provide much faster drying rates and lower operating temperatures.
  • a binder is sprayed on to the powder, causing the particles to stick together and form granules. This occurs via a stage-wise process of moistening and solidifying to give rise to agglomerates.
  • binders can be employed, including aqueous or organic solvents, as well as dissolved polymeric materials.
  • the granules are subsequently dried using hot air. Since the temperature of the air flow can be tightly regulated, fluid bed granulation is highly suitable for granulation of heat-sensitive materials.
  • melt granulation is the process of combining the material of interest with a binder which melts at a relatively low temperature (50- 90°C). Upon cooling, the material solidifies to form granules.
  • Melt granulation is a technique by which pharmaceutical powders are efficiently agglomerated by a meltable binder. The advantage of this technique compared to wet granulation is that no water or organic solvents is needed. Because there is no drying step, the process is less time consuming and uses less energy than wet granulation.
  • granulation may be carried out in a high shear mixer or any other type of granulator such as fluid bed or roller compactor and, depending on the technique used, involves subsequent drying when needed.
  • the present invention provides a process for producing the particulate material according to the present invention, the process comprising granulation of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder.
  • the process comprises wet granulation of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder.
  • the wet granulation comprises applying, e.g., spraying an aqueous or organic solvent (or a mixture of an aqueous solvent and an organic solvent) onto a mixture of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder.
  • the wet granulation comprises applying, e.g., spraying onto the mesoporous silicon dioxide a granulation liquid comprising the water-soluble or hydrophilic binder and an aqueous or organic solvent (or a mixture of an aqueous solvent and an organic solvent).
  • a non-limiting example of an aqueous solvent is water.
  • Non-limiting examples of an organic solvent include Acetic acid Acetone, Anisole, 1-Butanol, 2- Butanol, Butyl acetate, tert-Butylmethyl ether, Cumene, Dimethyl sulfoxide, Ethanol, Ethyl acetate, Ethyl ether, Ethyl formate, Formic acid, Heptane, Isobutyl acetate, Isopropyl acetate, Methyl acetate, 3-Methyl-l-butanol, Methylethyl ketone, Methylisobutyl ketone, 2-Methyl-l-propanol, Pentane, 1-Pentanol, 1-Propanol, 2-Propanol, Propyl acetate, Tetrahydrofuran, Acetonitrile, Chlorobenzene, Chloroform, Cyclohexane, 1,2-Dichloroethene, Dichloromethane
  • the process further comprises drying the obtained particulate material.
  • the process comprises melt granulation of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder.
  • wet or melt granulation can be carried out in a high shear mixer or any other type of granulator such as fluid bed or roller compactor.
  • the wet or melt granulation is fluid bed granulation or high shear granulation.
  • the wet or melt granulation involves the use of a fluid bed apparatus.
  • the wet or melt granulation involves the use of a high shear mixer.
  • the process comprises extrusion granulation of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder.
  • the process comprises extrusion granulation of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder using melt extrusion.
  • the extrusion granulation involves the use of a twin screw extruder.
  • the water-soluble or hydrophilic binder is ideally a meltable binder.
  • a meltable binder may for example by any one of the polymeric substances mentioned above, notably hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copovidone, polyethylene glycol or polyethylene oxid, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, poly(ethylene glycol)-block-poly(propylene glycol)- block-poly(ethylene glycol), poly(lactic-co-glycolic acid), and polylactic acid.
  • the particulate material may further be processed to form, e.g., solid dispersions.
  • the present invention provides a process for producing a solid dispersion (according to the present invention) comprising admixing the particulate material according to the present invention with at least one active ingredient and optionally at least one pharmaceutically acceptable excipient.
  • the particulate material may be impregnated with the at least one active ingredient.
  • the present invention provides in a further aspect a process for producing a pharmaceutical composition (according to the present invention) comprising admixing the solid dispersion according to the present invention with at least one pharmaceutically acceptable excipient.
  • the present invention provides in a process for producing a tablet (according to the present invention) comprising admixing the solid dispersion according to the present invention with at least one pharmaceutically acceptable excipient, and compressing said resulting mixture into a tablet.
  • the present invention provides in a further aspect the use of a particulate material according to the present invention as excipient or carrier in the preparation of a pharmaceutical composition.
  • the term "about” means plus or minus 10% of the numerical value of the number with which it is being used. Where a numerical limit or range is stated herein, the endpoints are included. Also, all values and sub-ranges within a numerical limit or range are specifically included as if explicitly written out.
  • the term "consisting essentially of” generally means that additional materials, features, components, elements or steps may be included that do not materially affect the basic and novel characteristic(s) of the claimed invention.
  • the term means that the particulate material may contain additional features, components or elements in addition to those literally disclosed provided that these additional features, components or elements do not materially affect the basic and novel characteristic(s) of the claimed particle.
  • the particulate material may include additional non-essential elements such as water (e.g., in form of moisture) and/or impurities.
  • the total amount of all ingredients making out the particulate material will normally add up to 100% of the total weight of the particulate material. In other words, the total amount of all ingredients will not exceed 100% of the total weight of the particulate material.
  • This example illustrates properties of mesoporous silica Syloid 244 FP, binder excipients from the group of sugar alcohols (isomalt erythritol, xylitol, mannitol), two component physical blends and co-processed granules composed of silica and binder in proportion 2:1.
  • Co-processed material was made by granulation in Procept laboratory granulator-Formatrix (vessel volume 1.5 L). 45 g of Syloid 244 FP was blended with 22.5 g of binder for two minutes prior to granulation with pure water. Impeller speed was 100 RPM and chopper speed was 1000 RPM. 109-115 g of water was added during granulation at rate 4.8 g/min.
  • Table 1 lists properties of pure mesoporous silica, binders (sugar alcohols) and co-processed particles.
  • Table 1 pure mesoporous silica, binders (sugar alcohols) and co-processed particles properties
  • Co-processed granules give tablets in broad ranges of compression pressures.
  • Figure 1 shows the improved compressibility of the co-processed granules compared to the mere physical blends of the mesoporous silica and binder.
  • This example illustrates properties of mesoporous silica Syloid 244 FP, binder excipients from the group of sugars (Lactose monohydrate 200 mesh, sucrose and maltodextrin), two component physical blends and co-processed granules composed of silica and binder in proportion 2:1.
  • Coprocessed material was made with granulation in Procept laboratory granulator-Formatrix (vessel volume 1.5 L).
  • 45 g of Syloid 244 FP was blended with 22.5 g of binder for two minutes prior to granulation with pure water.
  • Impeller speed was 100 RPM and chopper speed was 1000 RPM.
  • 109- 115 g of water was added during granulation at rate 4.8 g/min.
  • Table 2 lists properties of pure mesoporous silica, binders (sugars) and co-processed particles.
  • Table 2 pure mesoporous silica, binders (sugars) and co-processed particles properties
  • Co-processed granules give tablets in broad ranges of compression pressures.
  • Figure 2 shows the improved compressibility of the co-processed granules compared to the mere physical blends of the mesoporous silica and binder.
  • Co-processing This example illustrates properties of mesoporous silica Syloid 244 FP, binder excipients from the group of polymers (Kollidon VA64 ( vinylpyrrolidone-vinyl acetate copolymer), Avicel PH101 (microcrystalline cellulose), Kollicoat IR (graft copolymer comprised of polyethylene glycol and polyvinyl alcohol) and Pharmacoat 606 (hydroxypropyl methylcellulose)), two component physical blends and co-processed granules composed of silica and binder in proportion 2:1. Co-processed material was made with granulation in Procept laboratory granulator-Formatrix (vessel volume 1.5 L).
  • Syloid 244 FP was blended with 22.5 g of binder for two minutes prior to granulation with pure water. Impeller speed was 100 RPM and chopper speed was 1000 RPM. 109-115 g of water was added during granulation at rate 4.8 g/min. Wet granulate was pushed through 2 milimeter mesh size sieve and dried in hot air oven at 65 °C for six hours (final moisture content of the coprocessed material was below 2% and was determined according to US pharmacopoei USP 29-NF 24 using following conditions: sample mass between 2 and 3 grams, measurement temperature 85 °C, measurement time 15 minutes -BUCHI Moisture analyzer B-302).
  • Co-processed granules give tablets in broad ranges of compression pressures.
  • Figure 3 shows the improved compressibility of the co-processed granules compared to the mere physical blends of the mesoporous silica and binder.
  • This example illustrates properties of mesoporous silica Syloid 244 FP, binder excipients from the group of polymers (Polyethylene glycole 4000, Polyethylene oxide 200 000, Polyvinylpyrrolidone- PVP and polyvinylpyrrolidone-PVP K25), two component physical blends and co-processed granules composed of silica and binder in proportion 2:1.
  • Co-processed material was made with granulation in Procept laboratory granulator-Formatrix (vessel volume 1.5L).
  • 45 g of Syloid 244 FP was blended with 22.5 g of binder for two minutes prior to granulation with pure water. Impeller speed was 100 RPM and chopper speed was 1000 RPM.
  • Table 4 lists properties of pure mesoporous silica, binders (polymers) and co-processed particles.
  • Co-processed granules give tablets in broad ranges of compression pressures.
  • Figure 4 shows the improved compressibility of the co-processed granules compared to the mere physical blends of the mesoporous silica and binder.
  • Bulk density was determined according to European pharmacopoeia (Method 1). 80-100 ml of powder was passed into 100 ml plastic cylinder. Mass was weighted and untapped bulk density was calculated as sample mass divided by sample volume. This sample was then used to measure tapped volume and calculate tapped density. The tapped bulk density is an increased bulk density attained after mechanically tapping a cylinder containing the powder sample. A tapping apparatus capable of producing, per minute, nominally 300 ⁇ 15 taps was used. A tapped bulk density in grams per millilitre was calculated after volume reading using 1250 taps. Hausner ratio was calculated by dividing bulk density with tapped density. Hausner ratio determine in which class is the powder studied as a relation to flowability.
  • Table 5 Bulk density and Hausner ratio of co-processed Syloid 244FP with different binders and physical blends of the same composition in the proportion 2:1

Abstract

The present invention relates to a co-processed mesoporous silica. More specifically, the present invention provides a particulate material comprising (or consisting essentially of) mesoporous silicon dioxide and a water-soluble or hydrophilic binder. The particulate material of the present invention is particularly useful as excipient or carrier in the preparation of a pharmaceutical composition since it has improved compressibility and flow properties than in pure form and still has a high enough specific surface area to be impregnated with the active ingredient and to produce a solid dispersion and produce tablets or capsules. The present invention also relates to a process for producing the particulate material.

Description

Compressible and free flowing co-processed mesoporous silica
Field of the invention
The present invention relates to a co-processed mesoporous silica. More specifically, the present invention provides a particulate material comprising (or consisting essentially of) mesoporous silicon dioxide and a water-soluble or hydrophilic binder. The particulate material of the present invention is particularly useful as excipient or carrier in the preparation of a pharmaceutical composition since it has improved compressibility and flow properties than in pure form and still has a high enough specific surface area to be impregnated with the active ingredient and to produce a solid dispersion and produce tablets or capsules.
Background of the invention
Single unit dosage forms suitable for oral administration of the active pharmaceutical ingredients are usually formulated in the form of solid formulations. In addition to the active pharmaceutical ingredients these forms, tablets and capsules, contain pharmaceutically acceptable substances, which are called excipients, which are not active and have no therapeutic effect. The formulations give the ability to the active pharmaceutical ingredient to be incorporated into a pharmaceutical form by an industrially feasible process. They may also have the effect of increasing the bioavailability of the active substance mainly on the basis of its improved dissolution and absorption.
Untreated excipients may have poor flow properties and compressibility. Good flow properties are important in both the capsule filling process and direct compression. Direct compression is the most desirable method of tableting, as it requires only a good flowing and compressible mixture of powders; active pharmaceutical ingredients and excipients such as fillers, binders, disintegrants, glidants and antiadhesives. If such a mixture is not well flowable and compressible, a granulation step must be added when making the tablets. The same step is required when the powder mixture does not have good enough flow properties to fill the capsules. Granulation is divided into: (1) dry granulation; and (2) wet granulation. The dry granulation method involves mixing the ingredients, pressing at high pressures with an apparatus called a roller compactor, grinding, sieving, the addition of a glidant, and finally pressing the finished granules. The wet granulation process involves mixing some or all of the components of the formulation and adding a binder to this mixture to form granules in high shear mixer-granulator. The wet mixture is sieved and dried in fluid bed apparatus with the help of heated air or dried on trays. The wet granulation process can also be performed in fluidized bed process.
Direct compression involves fewer steps and is a cheaper process than granulation. For this process, the mixture must be freely flowable. In addition, sufficient bonds must form between the particles during the tableting process to keep the tablet intact after compression.
Tablets are formed by applying pressure to a tablet mixture using a tablet press. The basic unit of any tablet press is tooling consisting of two punches and a die called a station. The upper and lower punches come together in the die that contains the tablet formulation. The ability of the powder to flow well into the dye is important for the uniform filling of the dye and the uniformity of the tablet mass in the process of continuous tableting.
For filling hard gelatine capsules with powder formulations, good flow properties are important, which ensure satisfactory control over the mass or volume of filling.
Large percentage of active pharmaceutical ingredients on the market and in development phase is water poorly soluble, dissolve slowly in mater media and have low bioavailability: These properties can be improved with solid dispersions formation. Carriers of solid dispersion can be polymers, surface active agents or mesoporous materials. Mesoporous silica has a large specific surface area of up to 1000 square meters per gram of narrow pores between 2 and 50 nanometers and a large total pore volume of up to 2 milliliters per gram. An increase in the specific surface area of the active ingredient filled in the pores, the amorphous state of the active pharmaceutical ingredient and good wetting of the particles contribute to the improvement of the dissolution rate of poorly water soluble active pharmaceutical ingredient. The pores of mesoporous silicon dioxide can be filled by the method of impregnation of the active pharmaceutical ingredient from solution or by impregnation with melt. Solid dispersions of active pharmaceutical ingredient with mesoporous excipients are characterized by poor flowability and compressibility.
Thus, there is a need for improved functionality of mesoporous silica, which has good flow properties and compressibility and can be impregnated with the active pharmaceutical ingredient and is suitable for encapsulation and tableting.
Summary of the invention The particulate material of the present invention has superior functionalities. The inventors surprisingly found that mesoporous silica co-processed with a water-soluble or hydrophilic binder, such as a disaccharide, sugar alcohol or pharmaceutical polymer, has better compressibility and flow properties than in pure form and still has a high enough specific surface area to be impregnated with the active ingredient and to produce a solid dispersion and produce tablets or capsules. Pores are not completely filled with excipient during granulation and are available for impregnation with active pharmaceutical ingredient to form amorphous solid dispersion.
The properties of the particulate material thus allow its impregnation with an active pharmaceutical ingredient, the production of a solid dispersion and the incorporation of formulations into a solid pharmaceutical form such as capsules or tablets without the need for additional glidants, binders and fillers. The particulate material is suitable for the production of the tablets with direct compression.
Further, the particulate material shows an advantageous inclease in the bulk density which minimizes the air entrapment and offsets the effect of high compression speeds. Moreover, inclease bulk density of the particulate material of the invention reduces capsule size required.
The present invention thus provides in a first aspect a particulate material comprising (or consisting essentially of) mesoporous silicon dioxide and a water-soluble or hydrophilic binder. More specifically, the particulate material of the present invention comprises (or consists essentially of) i) about 40% w/w to about 99% w/w of mesoporous silicon dioxide and ii) about 1% w/w to about 60% w/w of a water-soluble or hydrophilic binder.
The present invention provides in a further aspect a particulate material which is a granulate comprising i) about 40% w/w to about 99% w/w of mesoporous silicon dioxide and ii) about 1% w/w to about 60% w/w of a water-soluble or hydrophilic binder, having a bulk density of at least about 0.2 g/cm3, such as from about 0.20 to about 0.35 g/cm3 or 0.20 to about 0.32 g/cm3 (determined according to EU Pharmacopoeia), having a Hausner ratio of about 1.1 to about 1.4, such as of about 1.1 to about 1.3 (determined according to US Pharmacopoeia), and having a mesopore volume of more than 0.3 ml/g, such as more than 0.5 ml/g or more than 0.7 ml/g.
The present invention provides in a further aspect a solid dispersion comprising the particulate material according to the present invention. Particularly, the present invention provides a solid dispersion comprising the particulate material according to the present invention, at least one active ingredient, and optionally at least one pharmaceutically acceptable excipient. The present invention provides in a further aspect a pharmaceutical composition comprising the solid dispersion according to present invention and at least one pharmaceutically acceptable excipient.
The present invention provides in a further aspect a process for producing the particulate material according to the present invention, the process comprising granulation of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder.
The present invention provides in a further aspect a process for producing a solid dispersion according to the present invention, the process comprising admixing the particulate material according to the present invention with at least one active ingredient and optionally at least one pharmaceutically acceptable excipient.
The present invention provides in a further aspect a process for producing a pharmaceutical composition according to the present invention, the process comprising admixing the solid dispersion according to the present invention with at least one pharmaceutically acceptable excipient.
The present invention provides in a further aspect a process for producing a tablet, the process comprising admixing the solid dispersion according to the present invention with at least one pharmaceutically acceptable excipient, and compressing said resulting mixture into a tablet.
The present invention provides in a further aspect the use of a particulate material according to the present invention as excipient or carrier in the preparation of a pharmaceutical composition.
The present invention can be further characterized by the following items:
1. Particulate material comprising (or consisting essentially of) i) mesoporous silicon dioxide and ii) a water-soluble or hydrophilic binder.
2. Particulate material according to item 1, comprising (or consisting essentially of) i) about 40% w/w to about 99% w/w of mesoporous silicon dioxide and ii) about 1% w/w to about 60% w/w of a water-soluble or hydrophilic binder binder.
3. The particulate material according to item 1 or 2, wherein the mesoporous silicon dioxide is present in a concentration of about 50% to about 90% w/w and the water soluble or hydrophilic binder binder is present in a concentration from about 10% w/w to about 50% w/w. The particulate material according to any one of items 1 to 3 wherein the mesoporous silica has a specific surface area in the range from about 100 m2/g to about 600 m2/g, such as from about 150 m2/g to about 400 m2/g. The particulate material according to any one of items 1 to 4, wherein the water-soluble or hydrophilic binder is selected from the group consisting of polyols, carbohydrates and polymeric substances. The particulate material according to any one of items 1 to 5, wherein the water-soluble or hydrophilic binder is a polyol. The particulate material according to item 6, wherein the polyol is a sugar alcohol. The particulate material according to item 7 , wherein the sugar alcohol is selected from the group consisting of xylitol, sorbitol, mannitol, maltitol, lactitol, erythritol, inositol, isomalt, isomaltulose and mixtures thereof. The particulate material according to item 8, wherein the sugar alcohol is isomalt. The particulate material according to any one of items 1 to 5, wherein the water-soluble or hydrophilic binder is a carbohydrate. The particulate material according to item 10, wherein the carbohydrate is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, polysaccharides, and mixtures thereof. The particulate material according to item 10 or 11, wherein the carbohydrate is selected from the group consisting of sucrose, glucose, fructose, trehalose, galactose, lactose, maltose, mannose, ribose, xylose, arabinose, maltodextrin, dextrin, cyclodextrin and mixtures thereof. The particulate material according to any one of items 1 to 5, wherein the water-soluble or hydrophilic binder is a polymeric substance. The particulate material according to item 13, wherein the polymeric substance is selected from the group consisting of cellulose polymers including microcrystalline cellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and carboxymethylcellulose, povidone including polyvinylpyrrolidone (PVP), copovidones, agar, gelatin, gummi arabicum, xanthan gum, chitosan, alginates including sodium alginate and polyetylene glycol alginate, polyethylene glycols, polyethylene oxids, polyvinyl alcohols, copolymers comprised of polyethylene glycol and polyvinyl alcohol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), poly(lactic-co-glycolic acid), polylactic acid, cross-linked polyacrylic acid (Carbopol ), starches and modified starches including potato starch, maize starch, rice starch, cross-linked amylase starch and pre-gelatinised starch, and mixtures thereof. The particulate material according to item 13, wherein the polymeric substance is a povidone. The particulate material according to item 13, wherein the polymeric substance is polyvinylpyrrolidone F90 or K25. The particulate material according to any one of items 6 to 9, comprising about 5% w/w to about 60% w/w of said polyol. The particulate material according to any one of items 6 to 9, comprising about 10% w/w to about 50% w/w of said polyol. The particulate material according to any one of items 10 to 12, comprising about 5% w/w to about 60% w/w of said carbohydrate. The particulate material according to any one of items 10 to 12, comprising about 10% w/w to about 50% w/w of said carbohydrate. The particulate material according to any one of items 13 to 16, comprising about 5% w/w to about 60% w/w of said polymeric substance. The particulate material according to any one of items 13 to 16, comprising about 10% w/w to about 50% w/w of said polymeric substance. The particulate material according to any one of items 1 to 22, having a mean particle size d50 of at least about 50 pm, such as about 80 pm to about 1000 pm, such as of 120 pm to about 800pm or of about 150 pm to about 600 pm (determined by laser diffraction). The particulate material according to any one of items 1 to 23, having a Hausner ratio of about 1.1 to about 1.4, such as of about 1.1 to about 1.3 (determined according to US Pharmacopoeia). 25. The particulate material according to any one of items 1 to 24, having a bulk density of at least about 0.2 g/cm3, such as from about 0.20 to about 0.35 g/cm3 or 0.20 to about 0.32 g/cm3 (determined according to EU Pharmacopoeia).
26. The particulate material according to any one of items 1 to 24, which is mesoporous.
27. The particulate material according to any one of items 1 to 2, having a mesopore volume of more than 0.3 ml/g, such as more than 0.5 ml/g or more than 0.7 ml/g.
28. The particulate material according to any one of items 1 to 27, which is a granulate.
29. The particulate material according to any one of items 1 to 28, which is obtainable by using granulation, such as fluid bed or high shear granulation.
30. The particulate material according to any one of items 1 to 29, which is obtainable by using wet granulation or melt granulation.
31. The particulate material according to any one of items 1 to 30, which is obtainable by a process according to any one of items 37 to 51.
32. A solid dispersion comprising the particulate material according to any one of items 1 to 31, at least one active ingredient, and optionally at least one pharmaceutically acceptable excipient.
33. The solid dispersion according to item 32, wherein the particulate material is impregnated with said at least one active ingredient.
34. A pharmaceutical composition comprising the solid dispersion according to item 32 or 33 and at least one pharmaceutically acceptable excipient.
35. The pharmaceutical composition according to item 34, which is in the form of a tablet, capsule, sachet, pellet, beadlet, granule, or granulate.
36. The pharmaceutical composition according to item 34, which is in the form of a tablet.
37. Process for producing the particulate material according to any one of items 1 to 31, the process comprising granulation of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder.
38. The process according to item 37, wherein the process comprises wet granulation of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder. 39. The process according to item 38, wherein the granulation is wet granulation is fluid bed granulation or high shear granulation.
40. The process according to item 38 or 39, wherein the wet granulation involves the use of a fluid bed apparatus.
41. The process according to item 38 or 39, wherein the wet granulation involves the use of a high shear mixer.
42. The process according to any one of items 38 to 41, wherein the wet granulation comprises applying, e.g., spraying an aqueous or organic solvent (or a mixture of an aqueous solvent and an organic solvent) onto a mixture of the mesoporous silicon dioxide and the water- soluble or hydrophilic binder.
43. The process according to any one of items 38 to 41, wherein the wet granulation comprises applying, e.g., spraying onto the mesoporous silicon dioxide a granulation liquid comprising the water-soluble or hydrophilic binder and an aqueous or organic solvent (or a mixture of an aqueous solvent and an organic solvent).
44. The process according to item 42 and 43, wherein the organic solvents are selected from the group consisting of Acetic acid Acetone, Anisole, 1-Butanol, 2-Butanol, Butyl acetate, tert- Butylmethyl ether, Cumene, Dimethyl sulfoxide, Ethanol, Ethyl acetate, Ethyl ether, Ethyl formate, Formic acid, Heptane, Isobutyl acetate, Isopropyl acetate, Methyl acetate, 3- Methyl-l-butanol, Methylethyl ketone, Methylisobutyl ketone, 2-Methyl-l-propanol, Pentane, 1-Pentanol, 1-Propanol, 2-Propanol, Propyl acetate, Tetrahydrofuran, Acetonitrile, Chlorobenzene, Chloroform, Cyclohexane, 1,2-Dichloroethene, Dichloromethane, 1,2- Dimethoxyethane, N,N-Dimethylacetamide, N,N-Dimethylformamide, 1,4-Dioxane, 2- Ethoxyethanol, Ethyleneglycol, Formamide, Hexane, Methanol, 2-Methoxyethanol, Methylbutyl ketone, Methylcyclohexane, N-Methylpyrrolidone, Nitromethane, Pyridine, Sulfolane, Tetralin, Toluene, 1,1,2-Trichloroethene, and Xylene.
45. The process according to item 37, wherein the process comprises melt granulation of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder.
46. The process according to item 45, wherein the melt granulation is fluid bed granulation or high shear granulation. 47. The process according to item 45 or 46, wherein the melt granulation involves the use of a fluid bed apparatus.
48. The process according to item 45 or 46, wherein the melt granulation involves the use of a high shear mixer.
49. The process according to item 37, wherein the process comprises extrusion granulation of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder.
50. The process according to item 49, wherein the process comprises extrusion granulation of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder using melt extrusion.
51. The process according to item 49 or 50, wherein the extrusion granulation involves the use of a twin screw extruder.
52. Process for producing a solid dispersion according to items 32 or 33, the process comprising admixing the particulate material according to any one of items 1 to 31 with at least one active ingredient and optionally at least one pharmaceutically acceptable excipient.
53. The process according to item 52, comprising impregnating the particulate material with the at least one active ingredient.
54. Process for producing a pharmaceutical composition according to any one of items 34 to 36, the process comprising admixing the solid dispersion according to item 32 or 33 with at least one pharmaceutically acceptable excipient.
55. Process for producing a tablet, the process comprising admixing the solid dispersion according to item 32 or 33 with at least one pharmaceutically acceptable excipient, and compressing said resulting mixture into a tablet.
56. Use of a particulate material according to any one of items 1 to 31 as excipient or carrier in the preparation of a pharmaceutical composition.
Brief description of the drawings
Figure 1: Compressibility of co-processed granulate vs. physical blend. A) Syloid 244FP + isomalt.
B) Syloid 244FP + erythriol. C) Syloid 244FP + xylitol. D) Syloid 244FP + mannitol Figure 2: Compressibility of co-processed granulate vs. physical blend. A) Syloid 244FP + lactose.
B) Syloid 244FP + sucrose. C) Syloid 244FP + maltodextrin
Figure 3: Compressibility of co-processed granulate vs. physical blend. A) Syloid 244FP + Kollidon VA64. B) Syloid 244FP + Avicel PH101. C) Syloid 244FP + Kollicoat IR. D) Syloid 244FP + Pharmacoat 606
Figure 4: Compressibility of co-processed granulate vs. physical blend. A) Syloid 244FP + PEG 4000.
B) Syloid 244FP + PEG 200000. C) Syloid 244FP + PVP K90. D) Syloid 244FP + PVP K25
The present invention is now described in more detail below.
Detailed description of the invention
Unless specifically defined herein, all technical and scientific terms used have the same meaning as commonly understood by a skilled person.
All methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, with suitable methods and materials being described herein. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will prevail. Further, the materials, methods, and examples are illustrative only and are not intended to be limiting, unless otherwise specified.
Particulate material of the present invention
As mentioned above, there is a need for improved functionality of mesoporous silica, which has good flow properties and compressibility and can be impregnated with the active pharmaceutical ingredient and is suitable for encapsulation and tableting.
This need is addressed by the present invention by providing a particulate material having superior functionalities. The inventors surprisingly found that mesoporous silica co-processed with a water- soluble or hydrophilic binder, such as a disaccharide, sugar alcohol or pharmaceutical polymer, has better compressibility and flow properties than in pure form and still has a high enough specific surface area to be impregnated with the active ingredient and to produce a solid dispersion and produce tablets or capsules. Pores are not completely filled with excipient during granulation and are available for impregnation with active pharmaceutical ingredient to form amorphous solid dispersion. The properties of the particulate material thus allow its impregnation with an active pharmaceutical ingredient, the production of a solid dispersion and the incorporation of formulations into a solid pharmaceutical form such as capsules or tablets without the actual need for additional glidants, binders and fillers. The particulate material is particularly suitable for the production of the tablets with direct compression.
Thus, according to one aspect, the present invention provides a particulate material comprising (or consisting essentially of) mesoporous silicon dioxide and a water-soluble or hydrophilic binder.
More specifically, the particulate material of the present invention comprises (or consists essentially of) i) about 40% w/w to about 99% w/w of mesoporous silicon dioxide and ii) about 1% w/w to about 60% w/w of a water-soluble or hydrophilic binder.
According to some embodiments, the mesoporous silicon dioxide is present in a concentration of about 50% w/w to about 95% w/w and the water-soluble or hydrophilic binder is present in a concentration from about 5% w/w to about 50% w/w.
According to some embodiments, the mesoporous silicon dioxide is present in a concentration of about 50% to about 90% w/w and the water-soluble or hydrophilic binder is present in a concentration from about 10% w/w to about 50% w/w.
According to some embodiments, the mesoporous silicon dioxide is present in a concentration of about 60% to about 90% w/w and the water-soluble or hydrophilic binder is present in a concentration from about 10% w/w to about 40% w/w.
According to some embodiments, the mesoporous silicon dioxide is present in a concentration of about 65% to about 90% w/w and the water-soluble or hydrophilic binder is present in a concentration from about 10% w/w to about 35% w/w.
According to some embodiments, the mesoporous silicon dioxide is present in a concentration of about 67% w/w to about 90% w/w and the water-soluble or hydrophilic binder is present in a concentration from about 10% w/w to about 33% w/w.
According to some embodiments, the mesoporous silicon dioxide is present in a concentration of about 75% w/w to about 85% w/w and the water-soluble or hydrophilic binder is present in a concentration from about 15% w/w to about 25% w/w. According to some embodiments, the mesoporous silicon dioxide is present in a concentration of about 80% w/w and the water-soluble or hydrophilic binder is present in a concentration from about 20% w/w.
The mesoporous silicon dioxide and the water-soluble or hydrophilic binder are generally present at a weight ratio of 1:1 to 10:1 mesoporous silicon dioxide:binder, such as a weight ratio of 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1 or 9:1.
According to some embodiments, the mesoporous silicon dioxide and the water-soluble or hydrophilic binder are present at a weight ratio of 2:1.
According to some embodiments, the mesoporous silicon dioxide and the water-soluble or hydrophilic binder are present at a weight ratio of 3:1.
According to some embodiments, the mesoporous silicon dioxide and the water-soluble or hydrophilic binder are present at a weight ratio of 4:1.
Depending on the material and method used in the preparation of the particulate material, the particulate material of the present invention may comprise impurities and/or water in the form of, e.g., moisture, which do not materially affect the basic and novel characteristic(s) of the particulate of the present invention. Generally, if present, the impurities will not make out more than about 5% w/w of the total weight of the particulate material, preferably will not make out more than about 3% w/w of the total weight of the particulate material. Likewise, if present, water in the form of, e.g., moisture, will not make out more than about 7% w/w of the total weight of the particulate material, preferably will not make out more than about 5% of the total weight of the particulate material. The moisture content may be about 0.5% w/w to about 7% w/w, such as about 0.5% w/w to about 7% w/w.
Mesoporous silicon dioxide (SiOj) refers to any number of a variety of materials synthesised to produce a SiOj mesoporous structure. Mesoporous silicon dioxide is divided into ordered and disordered. While in the ordered pores they are uniformly arranged in one direction, in the disordered carriers the pores are oriented randomly, and in both cases the material is amorphous.
The first example of ordered mesoporous silica marked as MCM (Mobil Composition of Matter) was presented in 1991, and since then it has been used very often in many fields. Such material is of interest for pharmaceutical development mainly because, in addition to all the already mentioned advantages of mesoporous carriers, ordered pores also enable highly controlled and reproducible active pharmaceutical ingredient release. Non-limiting examples of ordered mesoporous silica include SBA-15, TUD-1, H M M-33, and FSM-16.
Disordered mesoporous silicon dioxide is prepared with the chemical reaction of sol-gel process. The starting material is usually alkoxysilane, where the alkyl groups are first hydrolyzed to silanol groups. These can then be connected to each other via a siloxane bridge (Si - O - Si), which initially leads to the aggregation of colloidal-sized particles (salts) and later to the formation of a larger crosslinked structure (gel). By changing the reaction conditions, one can influence the properties of the obtained material, but always at the end a few silanol groups remain free, which is crucial for the subsequent occurrence of interactions between the carrier and the active pharmaceutical ingredient. Material with similar properties (high specific surface area and high amount of mesopores) can be obtained also with granulation of fumed silica (AEROSIL®). Many such materials are commercially available and are used in pharmaceutical and cosmetic products (Aeroperl® 300, Parteck® SLC 500, Syloid® XDP 3050, Syloid® XDP 3150, Syloid® 244 FP, Syloid® AL-1 FP, Sylysia® 350).
The mesoporous silicon dioxide employed in accordance with the present invention can be an ordered or disordered mesoporous silicon dioxide. According to some embodiments, the mesoporous silicon dioxide is an ordered mesoporous silicon dioxide. According to some embodiments, the mesoporous silicon dioxide is a disordered mesoporous silicon dioxide.
The mesoporous silicon dioxide generally has an average pore size of about 2 nm to about 50 nm. According to some embodiments, the mesoporous silicon dioxide has an average pore size of about 5 nm to about 35 nm. According to some embodiments, the mesoporous silicon dioxide has an average pore size of about 10 nm to about 30 nm.
According to some embodiments, the mesoporous silicon dioxide has a specific surface area in the range from about 100 m2/g to about 700 m2/g, such as from about 100 m2/g to about 500 m2/g. According to some embodiments, the mesoporous silicon dioxide has a specific surface area in the range from about 150 m2/g to about 400 m2/g. According to some embodiments, the mesoporous silicon dioxide has a specific surface area in the range from about 200 m2/g to about 400 m2/g.
The specific surface area may be measured by gas adsorption according to Ph. Eur., 6th edition, Chapter 2.9.26. multipoint method, volumetric determination. The specific surface area can be measured using a multipoint BET - Brunauer-Emmett-Teller apparatus 3P Nova 2000e. The mesoporous silicon dioxide generally has a mean particle size (d50) of about 1 pm to about 200 pm (determined by laser diffraction). According to some embodiments, the mesoporous silicon dioxide has a mean particle size of about 1 pm to about 150 pm. According to some embodiments, the mesoporous silicon dioxide has a mean particle size of about 1 pm to about 120 pm. According to some embodiments, the mesoporous silicon dioxide has a mean particle size of about 1 pm to about 70 pm. According to some embodiments, the mesoporous silicon dioxide has a mean particle size of about 1 pm to about 50 pm. According to some embodiments, the mesoporous silicon dioxide has a mean particle size of about 1 pm to about 20 pm. According to some embodiments, the mesoporous silicon dioxide has a mean particle size of about 1 pm to about 10 pm.
The mean particle size can be determined according to 2.9.31. PARTICLE SIZE ANALYSIS BY LASER LIGHT DIFFRACTION, Ph.Eur. 10.0. using, e.g., a Malvern Mastersizer 3000 apparatus.
The mesoporous silicon dioxide may be obtained commercially. Non-limiting examples of commercially available mesoporous silicon dioxide include Aeroperl® 300, Parteck® SLC 500, Syloid® XDP 3050, Syloid® XDP 3150, Syloid® 244 FP, Syloid® AL-1 FP, and Sylysia® 350.
SYLOID® 244 FP is a high pore volume silica gel with a large internal surface area. It has a strong affinity for moisture and organic based liquids. SYLOID® 244 FP can adsorb up to 1.6 ml of liquid per gram. SYLOID® 244 FP is further characterized in that it has an average pore size of 16 nm, has a specific surface area of 379 m2/g, and has a mean particle size of 3.5 pm. According to some embodiments, the mesoporous silicon dioxide has an average pore size of 16 nm, has a specific surface area of 379 m2/g, and has a mean particle size of 3.5 pm, such as Syloid® 244 FP.
Sylysia® 350 is a mesoporous silicon dioxide having an average pore size of 21 nm, has a specific surface area of 300 m2/g, and has a mean particle size of 1.8 pm. According to some embodiments, the mesoporous silicon dioxide has an average pore size of 21 nm, has a specific surface area of 300 m2/g, and has a mean particle size of 1.8 pm.
Aeroperl® 300 is a mesoporous silicon dioxide having an average pore size of 30 nm, has a specific surface area of 260-320 m2/g, and has a mean particle size of 20-60 pm. According to some embodiments, the mesoporous silicon dioxide has an average pore size of 30 nm, has a specific surface area of 260-320 m2/g, and has a mean particle size of 20-60 pm, such as Aeroperl® 300.
Parteck® SLC 500 is a mesoporous silicon dioxide having an average pore size of 6 nm, has a specific surface area of 500 m2/g, and has a mean particle size of 5-20 pm. According to some embodiments, the mesoporous silicon dioxide has an average pore size of 6 nm, has a specific surface area of 500 m2/g, and has a mean particle size of 5-20 pm, such as Parteck® SLC 500.
Syloid® XDP 3050 is a mesoporous silicon dioxide having an average pore size of 22.9 nm, has a specific surface area of 287 m2/g, and has a mean particle size of 50 pm. According to some embodiments, the mesoporous silicon dioxide has an average pore size of 22.9 nm, has a specific surface area of 287 m2/g, and has a mean particle size of 50 pm, such as Syloid® XDP 3050.
Syloid® XDP 3150 is a mesoporous silicon dioxide having an average pore size of 20 nm, has a specific surface area of 320 m2/g, and has a mean particle size of 150 pm. According to some embodiments, the mesoporous silicon dioxide has an average pore size of 20 nm, has a specific surface area of 320 m2/g, and has a mean particle size of 150 pm, such as Syloid® XDP 3150.
Syloid® AL-1 FP is a mesoporous silicon dioxide having an average pore size of 2.9 nm, has a specific surface area of 650 m2/g, and has a mean particle size of 7.5 pm. According to some embodiments, the mesoporous silicon dioxide has an average pore size of 2.9 nm, has a specific surface area of 650 m2/g, and has a mean particle size of 7.5 pm.
In order to build up agglomerates of the powdered mesoporous silicon dioxide, the present invention employs a binder, and more specifically a water-soluble or hydrophilic binder.
The water-solubility of the binder may be about 10 mg/ml or more such as, e.g., about 25 mg/ml or more, about 50 mg/ml or more, about 75 mg/ml or more, about 100 mg/ml or more, about 150 mg/ml or more, about 200 mg/ml or more, about 250 mg/ml or more, or about 300 mg/ml or more.
A hydrophilic binder generally has a water contact angle below 90 degrees, and preferably exhibits good water wettability.
Non-limiting examples of suitable water-soluble or hydrophilic binders for use according to the invention are polyols, carbohydrates, polymeric substances, and mixtures thereof.
According to some embodiments, the water-soluble or hydrophilic binder is selected from the group consisting of polyols, carbohydrates and polymeric substances.
According to some embodiments, the water-soluble or hydrophilic binder is a polyol.
According to some embodiments, the polyol is a sugar alcohol.
Non-limiting examples of suitable sugar alcohols for use according to the present invention are xylitol, sorbitol, mannitol, maltitol, lactitol, erythritol, inositol, isomalt, isomaltulose and mixtures thereof. According to some embodiments, the sugar alcohol is selected from the group consisting of xylitol, sorbitol, mannitol, maltitol, lactitol, erythritol, inositol, isomalt, isomaltulose and mixtures thereof.
According to some embodiments, the sugar alcohol is isomalt. According to some embodiments, the sugar alcohol is xylitol. According to some embodiments, the sugar alcohol is sorbitol. According to some embodiments, the sugar alcohol is mannitol. According to some embodiments, the sugar alcohol is maltitol. According to some embodiments, the sugar alcohol is lactitol. According to some embodiments, the sugar alcohol is erythritol. According to some embodiments, the sugar alcohol is isomaltulose.
According to some embodiments, the polyol (e.g. sugar alcohol) is present in a concentration of about 5% w/w to about 60% w/w. According to some embodiments, the polyol (e.g. sugar alcohol) is present in a concentration of about 10% w/w to about 50% w/w. According to some embodiments, the polyol (e.g. sugar alcohol) is present in a concentration of about 10% w/w to about 40% w/w. According to some embodiments, the polyol (e.g. sugar alcohol) is present in a concentration of about 10% w/w to about 35% w/w. According to some embodiments, the polyol (e.g. sugar alcohol) is present in a concentration of about 10% w/w to about 33% w/w. According to some embodiments, the polyol (e.g. sugar alcohol) is present in a concentration of about 10% w/w to about 25% w/w. According to some embodiments, the polyol (e.g. sugar alcohol) is present in a concentration of about 10% w/w to about 20% w/w.
According to some embodiments, the water-soluble or hydrophilic binder is a carbohydrate.
According to some embodiments, the carbohydrate is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, polysaccharides, and mixtures thereof.
According to some embodiments, the carbohydrate is a monosaccharide. According to some embodiments, the carbohydrate is a disaccharide. According to some embodiments, the carbohydrate is an oligosaccharide. According to some embodiments, the carbohydrate is a polysaccharide.
Non-limiting examples of suitable monosaccharides for use according to the invention are glucose, mannose, fructose, galactose, and mixtures thereof. According to some embodiments, the carbohydrate is glucose. According to some embodiments, the carbohydrate is mannose. According to some embodiments, the carbohydrate is fructose. According to some embodiments, the carbohydrate is galactose. Non-limiting examples of suitable disaccharides for use according to the present invention are lactose, maltose, sucrose, trehalose, tagatose, and mixtures thereof. According to some embodiments, the carbohydrate is lactose. According to some embodiments, the carbohydrate is maltose. According to some embodiments, the carbohydrate is sucrose. According to some embodiments, the carbohydrate is trehalose. According to some embodiments, the carbohydrate is tagatose.
Non-limiting examples of suitable oligosaccharides and polysaccharides for use according to the present invention are dextrose, oligofructose, dextrin, cyclodextrin, maltodextrin, and mixtures thereof. According to some embodiments, the carbohydrate is dextrose. According to some embodiments, the carbohydrate isoligofructose. According to some embodiments, the carbohydrate is a dextrin. According to some embodiments, the carbohydrate is a cyclodextrin. According to some embodiments, the carbohydrate is maltodextrin.
According to some embodiments, the carbohydrate is selected from the group consisting of sucrose, glucose, fructose, trehalose, galactose, lactose, maltose, mannose, ribose, xylose, arabinose, dextrins and mixtures thereof.
According to some embodiments, the carbohydrate is present in a concentration of about 5% w/w to about 60% w/w. According to some embodiments, the carbohydrate is present in a concentration of about 10% w/w to about 50% w/w. According to some embodiments, the carbohydrate is present in a concentration of about 10% w/w to about 40% w/w. According to some embodiments, the carbohydrate is present in a concentration of about 10% w/w to about 35% w/w. According to some embodiments, the carbohydrate is present in a concentration of about 10% w/w to about 33% w/w. According to some embodiments, the carbohydrate is present in a concentration of about 10% w/w to about 25% w/w. According to some embodiments, the carbohydrate is present in a concentration of about 10% w/w to about 20% w/w.
According to some embodiments, the water-soluble or hydrophilic binder is a polymeric substance.
Non-limiting examples of polymeric substances that are suitable for use according to the present invention are cellulose polymers including microcrystalline cellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and carboxymethylcellulose, povidone including polyvinylpyrrolidone F-90, K-90, K-30, K-25, K-17 or K- 12, copovidones including vinylpyrrolidone-vinyl acetate copolymer, agar, gelatin, gummi arabicum, xanthan gum, chitosan, alginates including sodium alginate and polyetylene glycol alginate, polyethylene glycols, polyethylene oxids, polyvinyl alcohols, copolymers comprised of polyethylene glycol and polyvinyl alcohol, , polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), poly(lactic-co-glycolic acid), polylactic acid, cross-linked polyacrylic acid (Carbopol ), starches and modified starches including potato starch, maize starch, rice starch, cross-linked amylase starch and pre-gelatinised starch, and mixtures thereof.
According to some embodiments, the polymeric substance is a povidone. According to some embodiments, the polymeric substance is polyvinylpyrrolidone F90 or K25. According to some embodiments, the polymeric substance is polyvinylpyrrolidone F90.According to some embodiments, the polymeric substance is polyvinylpyrrolidone K25.
According to some embodiments, the polymeric substance is a copovidone. According to some embodiments, the polymeric substance is vinylpyrrolidone-vinyl acetate copolymer.
According to some embodiments, the polymeric substance is a cellulose polymer, such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose or carboxymethylcellulose. According to some embodiments, the cellulose polymer is microcrystalline cellulose. According to some embodiments, the cellulose polymer is methylcellulose. According to some embodiments, the cellulose polymer is ethylcellulose. According to some embodiments, the cellulose polymer is hydroxypropylmethylcellulose. According to some embodiments, the cellulose polymer is hydroxyethylcellulose. According to some embodiments, the cellulose polymer is hydroxypropylcellulose. According to some embodiments, the cellulose polymer is carboxymethylcellulose.
According to some embodiments, the polymeric substance is a polyethylene glycol, polyvinyl alcohol or graft copolymer comprised of polyethylene glycol and polyvinyl alcohol. According to some embodiments, the polymeric substance is a polyethylene glycol. According to some embodiments, the polymeric substance is a polyethylene oxide. According to some embodiments, the polymeric substance is a polyvinyl alcohol. According to some embodiments, the polymeric substance is a graft copolymer comprised of polyethylene glycol and polyvinyl alcohol.
According to some embodiments, the polymeric substance is a polyethylene glycol having an average molecular weight from 1,000 g/mol to 20,000 g/mol. According to some embodiments, the polymeric substance is a polyethylene glycol having an average molecular weight from 2,000 g/mol to 15,000 g/mol. According to some embodiments, the polymeric substance is a polyethylene glycol having an average molecular weight from 2,000 g/mol to 10,000 g/mol. According to some embodiments, the polymeric substance is a polyethylene glycol having an average molecular weight from 4,000 g/mol to 6,000 g/mol. According to some embodiments, the polymeric substance is a polyethylene glycol having an average molecular weight of 4000 g/mol. According to some embodiments, the polymeric substance is a polyethylene glycol having an average molecular weight of 6000 g/mol.
According to some embodiments, the polymeric substance is a polyethylene oxide having an average molecular weight of 20,000 g/mol or above. According to some embodiments, the polymeric substance is a polyethylene oxide having an average molecular weight from 50,000 g/mol to 1,000,000 g/mol. According to some embodiments, the polymeric substance is a polyethylene oxide having an average molecular weight from 50,000 g/mol to 500,000 g/mol. According to some embodiments, the polymeric substance is a polyethylene oxide having an average molecular weight from 100,000 g/mol to 300,000 g/mol. According to some embodiments, the polymeric substance is a polyethylene oxide having an average molecular weight from 150,000 g/mol to 350,000 g/mol. According to some embodiments, the polymeric substance is a polyethylene oxide having an average molecular weight of 200,00 g/mol.
According to some embodiments, the polymeric substance is present in a concentration of about 5% w/w to about 60% w/w. According to some embodiments, the polymeric substance is present in a concentration of about 10% w/w to about 50% w/w. According to some embodiments, the polymeric substance is present in a concentration of about 10% w/w to about 40% w/w. According to some embodiments, the polymeric substance is present in a concentration of about 10% w/w to about 35% w/w. According to some embodiments, the polymeric substance is present in a concentration of about 10% w/w to about 33% w/w. According to some embodiments, the polymeric substance is present in a concentration of about 10% w/w to about 25% w/w. According to some embodiments, the polymeric substance is present in a concentration of about 10% w/w to about 20% w/w.
Normally, the particulate material according to the present invention has a particle size distribution that is suitable for use within the pharmaceutical field especially in connection with further processing of the particulate material into a solid dosage form. To be more specific, the mean particle size d50 (determined by laser diffraction) of the particulate material according to the present invention is normally about 30 pm or above, such as at least about 40 pm, at least about 50 pm, at least about 80 pm, at least about 100 pm or at least about 120 pm. The particle size analysis may generally performed on a Malvern Mastersizer 3000 apparatus where dlO, d50 and d90 give the particle sizes for which 10%, 50% and 90% of the total particles have sizes below the given value. d50 is the mean particle size, and can be determined according to 2.9.31. PARTICLE SIZE ANALYSIS BY LASER LIGHT DIFFRACTION, Ph.Eur. 10.0.
According to some embodiments, the mean particle size d50 (determined by laser diffraction) is in the range of about 30 pm to about 1000 pm, such as of about 50 pm to about 1000 pm, of about 80 pm to about 1000 pm, such as of 120 pm to about 800 pm or of about 150 pm to about 600 pm.
Further, the particulate material according to the present invention may have a Hausner ratio of about 1.1 to about 1.4, such as of about 1.1 to about 1.3. According to some embodiments, the particulate material according to the present invention has a Hausner ratio of about 1.1 to about 1.2. According to some embodiments, the particulate material according to the present invention has a Hausner ratio of about 1.10 to about 1.25. According to some embodiments, the particulate material according to the present invention has a Hausner ratio of about 1.10 to about 1.23. According to some embodiments, the particulate material according to the present invention has a Hausner ratio of about 1.10 to about 1.20. According to some embodiments, the particulate material according to the present invention has a Hausner ratio of about 1.10 to about 1.18. According to some embodiments, the particulate material according to the present invention has a Hausner ratio of about 1.12 to about 1.18.
The Hausner ratio can be determined according to 2.9.34 BULK DENSITY AND TAPPED DENSITY OF POWDERS, METHOD 1, Ph Eur 10.0 using 100 ml cylinder and Setling device for powder sample.
A particulate material according to the present invention may (further) have a specific surface area of at least about 100 m2/g. According to some embodiments, the particulate material according to the present invention has a specific surface area in the range from about 100 m2/g to about 600 m2/g, such as from about 150 m2/g to about 400 m2/g. According to some embodiments, the particulate material according to the present invention has a specific surface area in the range from about 200 m2/g to about 400 m2/g.
The specific surface area may be measured by gas adsorption according to Ph. Eur., 6th edition, Chapter 2.9.26. multipoint method, volumetric determination. The specific surface area can be measured using a multipoint BET - Brunauer-Emmett-Teller apparatus 3P Nova 2000e.
A particulate material according to the present invention may (further) have a bulk density of at least about 0.2 g/cm3 (determined according to EU Pharmacopoeia). According to some embodiments, the particulate material according to the present invention has a bulk density from about 0.20 to about 0.35 g/cm3. According to some embodiments, the particulate material according to the present invention has a bulk density from about 0.20 to about 0.32 g/cm3.
The bulk density can be determined according to 2.9.34. BULK DENSITY AND TAPPED DENSITY OF POWDERS, METHOD 1, Ph.Eur. 10.0 using 100 ml cylinder.
A particulate material according to the present invention may (further) be mesoporous. According to some embodiments, the particulate material according to the present invention has a mesopore volume of more than 0.3 ml/g. According to some embodiments, the particulate material according to the present invention has a mesopore volume of more than 0.5 ml/g. According to some embodiments, the particulate material according to the present invention has a mesopore volume of more than 0.7 ml/g.
Mesopores presence and their volume can be determined with complete gas physisorption analysis, wherein the adsorption isotherm is collected under both ascending pressure (adsorption) and descending pressure (desorption) conditions on the basis of hysteresis presence according to recommendations of the International Union of Pure and Applied Chemistry (IUPAC) or other interntional standards.
The particulate material may be obtained by way of granulation, such as wet or melt granulation, and more specifically is obtainable by a process according to present invention, which is described in more detail below. The particulate material may have any suitable form, but preferably is a granulate.
Solid dispersions and pharmaceutical compositions according to the present invention
As mentioned above, the superior properties of the particulate material of the present invention allow its impregnation with an active pharmaceutical ingredient, the production of a solid dispersion and the incorporation of formulations into a solid pharmaceutical form such as capsules or tablets without the need for additional glidants, binders and fillers. The particulate material is especially suitable in the preparation of tablets with direct compression.
Thus, in a further aspect, the present invention provides a solid dispersion comprising the particulate material according to the present invention, at least one active ingredient, and optionally at least one pharmaceutically acceptable excipient. The term "solid dispersion" generally refers to a solid mixture of one or more active ingredients and a hydrophilic backbone, i.e., a carrier. Active pharmaceutical ingredient in the carrier can be molecularly dispersed or arranged in the form of amorphous or crystalline particles, and the carrier matrix can be both amorphous or crystalline (KT Kim et al. Solid dispersions as a drug delivery system Journal of Pharmaceutical Investigation 2011, Volume 41, Issue 3, Pages, 125-142). Since Segikuchi and Obi first introduced solid dispersion in 1961 (Keiji Sekiguchi, Noboru Obi, Studies on Absorption of Eutectic Mixture. I. A Comparison of the Behavior of Eutectic Mixture of Sulfathiazole and that of Ordinary Sulfathiazole in Man. Chemical and Pharmaceutical Bulletin 1961, Volume 9, Issue 11, Pages 866-872), a good number of drugs based on this approach have appeared on the market (Kaletra- FDA approval in 2007, Norvir- FDA approval in 2010). The main purpose of making solid dispersions is to convert the active ingredient into an amorphous state to improve dissolution and increase bioavailability.
According to some embodiments, the particulate material is impregnated with said at least one active ingredient.
Techniques for impregnation are well-know to the skilled person. Non-limiting example include rotary evaporation, vacuum drying and spray drying.
The active ingredient may be any desirable active ingredient. Non-limiting examples include (-)- amlodipine, (-)-halofenate, (R)-salbutamol, (R)- salbutamol, (R,R)-formoterol, (S)-doxazosin, (S)- fluoxetine, (S)-oxybutynin, 1,2-naphthoquinone, 17-methyl testosterone, 17a- hydroxyprogesterone, 195mPt-cisplatin, 1- naphthyl salicylate, l-naphthylamine-4-, 1- theobromineacetic, la-hydroxy cholecalciferol, 2,4,6-tribromo-m-cresol, 2,6-diamino-2'-butyloxy- 3,5'-azopyridine, 2-[[[(lr)-2-(lh- imidazol-4-yl)-l-methylethyl]imino]phenylmethyl]-phenol, 21- acetoxypregnenolone, 2- amino-4-picoline, 2-aminothiazole, 2-ethoxybenzoic acid, 2-naphthol, 2- naphthyl benzoate, 2-naphthyl lactate, 2-naphthyl salicylate, 2-p-sulfanilylanilinoethanol, 2- thiouracil, 3',3",5',5"-tetra-bromophenolphthalein, 3-amino-4-hydroxybutyric acid, 3- Bromo-D- camphor, 3-Hydroxycamphor, 3-O-Lauroylpyridoxol Diacetate, 3-pentadecylcatechol, 3- quinuclidinol, 4,4'-oxydi-2-butanol, 4, 4'-sulfmyl dianiline, 4-amino-3-hydroxybutyric acid, 4-amino- 3-phenylbutyric acid, 4-aminosalicylic acid, 4-chloro-m- cresol, 4-hexylresorcinol, 4- salicyloylmorpholine, 5'-nitro-2'-propoxyacetanilide, 5-aminolevulinic acid, 5-azacitidine, 5- bromosalicyl-hydroxamic acid, 5F-DF-203, 5-FU, 5-HT3 antagonists, 6-azauridine, 6- mercaptopurine, 8-hydroxyquinoline, 9- aminocamptothecin, A-151892, A-5021, abacavir, abaperidone, abarelix, abciximab, abecamil, abetimus, abiraterone, ABLC, ABT-751, AC-5216, acadesine, acamprosate, acamprosate, acarbose, acebrophylline, acebutolol, acecainide, acecarbromal, aceclofenac, acedapsone, acediasulfone, acefylline, aceglutamide, aceglutamide, acemetacin, acenocoumarol, aceponate, acetal, acetamidoeugenol, acetaminophen, acetaminosalol, acetanilide, acetarsone, acetazolamide, acetiamine, acetohexamide, acetohydroxamic acid, acetophenazine, acetophenide, acetophenone, acetosulfone, acetoxoIone, acetrizoat, acetyl, acetylcarnitine, acetylcholine, acetylcholine, acetylcysteine, acetylleucine, acetylpheneturide, acetylsalicylate, acetylsalicylic acid, aciclovir, acifran, acipimox, acitazanolast, acitretin, aclarubicin, aclatonium, aconitine, acranil®, acriflavine, acrisorcin, acrivastine, acrivastine, actagardine derivative, actarit, ACTH, acyclovir, adapalene, ADCON-L, adefovir, adefovir dipivoxil, adenoscan, adenosine triphosphate, ADEPT, adinazolam, adiphenine, ADL-10-0101, adrafmil, adrenal one, adrenochrome, adrogolide, AEOL-10150, aesthinol, AET, AF-2259, afloqualone, AG- 041R, AG-2037, AGN-194310, agomelatine, ahistan, AHL-157, AIT-034, AIT-202, AJ-9677, AJG-049, ajmaline, akzo desogestrel, alacepril, alapivoxil, albaconazole, albendazole, albuterol, albutoin, alclofenac, alclometasone, alcuronium, aldioxa, aldol, aldosterone, alendronate, alendronic acid, alexidine, alfacalcidol, alfadolone, alfaxalone, alfentanil, alfimeprase, alfuzosin, alfuzosin, algestone, algestone, algin, alglucerase, alibendol, aliskiren, alitertinoin, alizapride, alkannin, alkofanone, allantoin, allobarbital, allopurinol, allyl isothiocyanate, allylestrenol, almagate, alminoprofen, almitrine, almotriptan, aloe-emodin, aloin, alosetron, alovudine, aloxiprin, alpha-, alpha- 1 protease, alphaprodine, alpidem, alpiropride, alprazolam, alprenolol, alsactide, ALT-711, Althiazid, altinicline, altretamine, aluminium chloride hexahydrate, aluminon, aluminum acetate solution, aluminum chlorate, aluminum hydroxychloride, aluminum potassium sulfate, aluminum sodium sulfate, alusulf, alverine, alvimopan, alvocidib, ALX-0646, AM-24, AM-36, AM-477, amantadine, amantanium, ambazon, ambenonium, ambrisentan, ambroxol, ambucaine, ambuphylline, ambusid, ambutonium bromide, amcinonide, AMD-3100, amdinocillin, amdinocillin pivoxil, amdoxovir, amelubant, americaine, amezinium, amfenac, amidephrine, amidinomycin, amifostine, amiglumide, amikacin, amiloride, aminacrine, amineptine, aminitrozole, amino acid preparations, aminocaproic acid, aminoglutethimide, aminoguanidine, aminohippurate, aminometradine, aminopentamide, aminophylline, aminopromazine, aminopyrine, aminoquinuride, aminorex, amiodarone, amiodipine, amiphenazole, amiprilose, amisulpride, amitriptyline, amitriptyline + ketamine, amitriptylinoxide, amlexanox, ammoniacum, ammoniated mercuric chloride, ammonium benzoate, ammonium mandelate, ammonium salicylate, ammonium valerate, amobarbital, amocarzine, amodiaquin, amorolfme, amoscanat, amosulalol, amotriphene, amoxapine, amoxicillin, amoxicillin + potassium clavulan, AMP Alex, amphetamine, amphetaminil, amphotericin B, ampicillin, ampiroxicam, ampligen, amprenavir, amrinose, amrubicin, amsacrine, amtolmetin guacil, amylocaine, AN- 152, anabolic steroids, anagestone, anagrelide, anastrozole, anazolene, ancitabine, ancrod, andolast, androisoxazole, androstenediol, anecortave, anethole, anethole trithione, angiogenix, angiotensin, anhydrovinblastine, anidulafungin, anilerdine, aniracetam, anisindione, anisomycin, anisotropine, anistreplase, antazoline, anthiolimine, anthralin, anthramycin, anthrarobin, anthrax inhibitor, anti angiogenic, anticort, antidepressants, anti-invasins, antimony potassium tartrate, antimony sodium thioglycollate, antimony thioglycollamide, antiprogestin, antipyrine, antipyrine salicylate, antithrombin III, anxiolytics, AP- 521, AP- 5280, apalcil lin, apaziquone, apazone, apocodeine, apomine, apomorphine, apraclonidine, aprepitant, aprindine, aprobarbital, apronalide, aprotinin, aptiganel, AQ4N, aquavan, AR- 116081, AR-A2, arachidonic acid, arani dipine, arbekacin, arbidol, arbutamine, arcitumomab, ardeparin, arecoline, argatroban, arginine, Ariflo ®, aripiprazole, arofylline, arotinolol, arsacetin, arsenic trioxide, arsphenamine, arteether, arteflene, artemether, artemisinin, artemotil, artesunate, arzoxifene, AS-3201, ASA, ascaridole, ascorbic acid, asenapine, asimadoline, asocarboxazid, asoprisnil, asoxime, aspartic acid, aspidin, aspidinol, aspirin, aspirin dipyridamole, aspoxicillin, AST- 120, astemizole, asulacrine, AT-1015, atamestane, atazanavir, atenolol, atenolol + chlorthalidone, atenolol + nifedipine, atevirdine, atipamezole, atiprimod dimaleate, ATL-146e, atomoxetine, atorvastatin, atosiban, atovaquone, atovaquone + proguanil, atracurium, atrasentan, atrial natriuretic, atrolactamide, atropine, augmentin, auranofm, aurothioglucose, avasimibe, avobenzone, AWD- 12-281, azacitidine, azacyclonol, azanidazole, azapropazone, azaserine, azasertron, azatadine, azathipprine, AZD-4282, AZD-6140, azelaic acid, azelastine, azelnidipine, azidamfenicol, azidocillin, azimilide, azintamide, azithromycin, azlocillin, azosemide, aztreonam, azulene, bacampicillin, bacitracin, baclofen, baicalein, balofloxacin, balsalazide, bambuterol, bamethan, bamifylline, bamipine, barbital, barnidipine, BAS-118, basic alumina, baslilximab, batimastat, batroxobin, Bay-41-2272, Bay-41-8543, BAY-43-9006, BAY-57-1293, bazedoxifen, BBR- 3464, BBR-3576, BBR- 3610, BCH-1868, bebeerine, beclamide, beclometasone, befloxatone, befunolol, bemegride, benactyzine, benazepril, bencyclane, bendazac, bendroflumethiazide, benetonide, benexate, benfluorex, benfotiamine, benfurodil, benidipine, benorylate, benoxaprofen, benoxinate, benperidol, benproperine, benserazide, bentazepam, bentiromide, bentoquatam, benzafibrate, benzalkonium, benzarone, benzathine, benzbromarone, benzethonium, benzetimide, benzilonium, benziodarone, benznidazole, benzocaine, benzoctamine, benzonatate, benzoxonium chloride, benzoyl peroxide, benzoylpas, benzphetamine, benzpiperylon, benzquinamide, benzthiazide, benztropine, benzydamine, benzyl benzoate, benzylhydrochloro-thiazide, benzylmorphine, bephenium, bepotastine, bepridil, beraprost, berberine, bergapten, bermoprofen, besipirdine, betahistine, betaine, betamethasone, betamipron, betasine, betaxolol, betazole, bethanechol, bethanidine, betoxycaine, bevantolol, bevonium, bexarotene, bezitramide, BG-9928, BIA-2-024, BIA-2-093, BIA-3-202, bialamicol, biapenem, bibenzonium, bibrocathol, bicalutamide, bicifadine, bicisate, bicyclic, bidisomide, bietamiverine, bietanautine, bietaserpine, bifermelane, bifluranol, bifonazole, bimatoprost, bimoclomol, bimosiamose, binifibrate, binodenoson, biomed-101, biotin, biperiden, biriperone, birlcodar, bisacodyl, bisantrene, bisbentiamine, bisdequalinium, bismuth, bismuth, bismuth, bismuth aluminate, bismuth ethyl, bismuth sodium, bismuth sodium triglycollamate, bismuth subcarbonate, bismuth subgallate, bismuth subnitrate, bismuth subsalicylate, bisoprolol, bisoprolol + HCTZ, bisoprolol + trichloromethiazide, bisoxatin, bithionol, bitolterol, bitoscanat, BL-3875, bleomycin, blonanserin, BMS-184476, BMS- 387032, BN-82451, BNP-7787, BO-653, bolandiol, bolasterone, boldenone, bopindolol, bornyl chloride, bornyl salicylate, bortezomib, bosentan, bradycor, brain natriuretic, brallobarbital, brasofensine, brequinar, bretylium, brilliant green, brimonidine, brinzolamide, brivudin, brodimoprim, bromazepam, bromfenac, bromhexine bromide, bromindione, bromisovalum, bromocriptine, bromo-diphenhydramine, bromoform, bromopride, bromo-salicychloranilide, bromperidol, brompheniramine, broparoestrol, bropirimine, brostallicin, brotizolam, brovincamine, broxyquinoline, brozuridine, brucine, bucetin, bucillamine, bucindolol, bucladesine, buclizine, buclosamide, bucolome, bucricaine, bucumolol, budesonide, budesonide + formoterol, budipine, budralazine, bufeniode, bufetolol, bufexamac, buflomedil, buformin, bufuralol, bumadizon, bumetanide, bunaftine, bunamiodyl sodium, bunazosin, bunitrolol, bupivacaine, bupranolol, buprenorphine, bupropion, buramate, buserelin, buspirone, busulfan, busulfan, butabarbital, butacaine, butacetin, butalamine, butalbital, butallylonal, butamben, butamirate, butanilicaine, butaperazine, butaverine, butazolamide, butedronic acid, butenafme, butethal, butethamate, butethamine, buthalital, buthiazide, butibufen, butidrine, butobendine, butoconazole, butoctamide, butofilolol, butorphanol, butoxycaine, butriptyline, butropium, butylthiolaurate, butyrate propio, buzepide, BVT-5182, BXT- 51072, C-1311, cabergoline, cabergoline, cacodylic acid, cactinomycin, cadexomer iodine, cadmium salicylate, cadralazine, cafaminol, caffeine, calcifediol, calcipotriene, calcipotriol, calcipotriol + beclometasone, calcitriol, calcium 3-aurothio-2-propanol-l- sulfonate, calcium acetylsalicylate, calcium bromolactobionate, calcium carbonate, calcium gluconate, calcium glycerophosphate, calcium hopantothenate, calcium iodobehenate, calcium iodosterate, calcium lactate, calcium levulinate, calcium mesoxalate, calcium N-carbamoylaspartate, calcium polycarbophil, calcium propionate, calcium succinate, caldaret, calusterone, camazepam, camostat, camphor, camphorate, camphotamide, camptothecin, candesartan, candesartan cilexetil, candoxatril, canertinib, canrenone, cantharidin, cantuzumab mertansine, capecitabine, capobenic acid, capravirine, capromab, capsaicin cream, captodiamine, captopril, captopril + HCTZ, capuride, carabersat, caramiphen, carazolol, carbachol, carbamazepine, carbamide peroxide, carbarsone, carbaryl, carbazochrome, carbendazim, carbenicillin, carbenoxolone, carbetapentane, carbicarb, carbidopa, carbidopa + levodopa-1, carbimazole, carbinoxamine, carbocloral, carbocysteine, carbon tetrachloride, carbonate gel, carboplatin, carboprost, carboprost, carboquone, carbromal, carbubarb, carbutamide, carbuterol, carfimate, carglumic acid, cargutocin, carindacillin, cariporide, cariporide, carisoprodol, carmofur, carmoxirole, carmustine, carnitine, caroverine, caroxazone, carphenazine, carpipramine, carprofen, carsalam, carteolol, carticaine, carubicin, carumonam, carvacrol, carvedilol, carvone, cascarill in, caspofungin, catechin, cathepsin K inhibitors, cathepsin S inhibitors, CC-401, CCI-779, CCR5 antagonists, CDC-394, CDC- 801, CEE-03-310, cefactor, cefadroxil, cefalexin, cefalexin pivoxil, cefamandole, cefatrizine, cefazedone, cefazolin, cefbuperazone, cefcapene pivoxil, cefclidin, cefdinir, cefditoren pivoxil, cefepime, cefetamet, cefetamet pivoxil, cefixime, cefmenoxime, cefmetazole, cefminox, cefodizime, cefonicid, cefoperazone, cefoperazone + sulbactam, ceforanide, cefoselis, cefotazime, cefotetan, cefotiam, cefotiam hexetil, cefoxitin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefroxadine, cefsulodin, ceftazidime, cefteram, ceftezole, ceftibuten, ceftizoxime, ceftizoxime, ceftriaxone, cefuroxime, cefuroxime axetil, cefuzonam, celecoxib, celgosivir, cel iprolol, cellulose ethyl, CEP-1347, CEP-701, cephacetrile, cephaeline, cephalexin, cephaloglycin, cephaloridine, cephalosporin C, cephalothin, cephapirin, cephradine, cerivastatin, ceronapril, certoparin, ceruletide, cerviprost, cetalkonium, cetamolol, cethexonium, cethromycin, cetiedil, cetirizine, cetirizine, cetirizine + pseudoephedrine, cetotiamine, cetoxime, cetraxate, cetrimonium, cetrorelix, cetyldimethylethyl-ammonium, cetylpyridinium, cevimeline, CG-1521, chaulmoogric acid, chenodiol, CHF-3381, chlophedianol, chloracizine, chloral, chlorambucil, chloramine-B, chloramine-T, chloramino-chloramphenicol, chlorazanil, chlorbenzoxamine, chlorbetamide, chlorcyclizine, chlordantoin, chlorguanide, chlorhexadol, chlorhexidine, chloriazepoxide, chlorisondamine, chlormadinone, chlormerodrin, chlormezanone, chlormidazole, chlornaphazine, chloroazodin, chlorophyll, chloroprednisone, chloroprocaine, chloropyramine, chloroquine, chlorothen, chlorothiazide, chlorotrianisene, chloroxine, chloroxylenol, chlorozotocin, chlorphenamine, chlorphenesin, chlorpheniramine, chlorphenoxamide, chlorphenoxamine, chlorphentermine, chlorproethazine, chlorproguanil, chlorproguanil + dapsone, chlorpromazine, chlorpropamide, chlorprothixene, chlorquinaldol, chlortetracycline, chlorthalidone, chlorthenoxazine(e), chlorzoxazone, cholic acid, choline, choline theophyllinate, choline-L-alfoscerate, chromocarb, chromonar, chrysoidine, CHS-828, CI-1031, CI- 1040, cibenzoline, ciclesonide, cicletanine, ciclonicate, ciclopirox, ciclosidomine, ciclosporin A, cidofovir, cifenline, cilansetron, cilastatin, cilazapril, cilengitide, cilnidipine, cilomilast, cilostazol, cimetidine, cimetropium, cinacalcet, cinchonidine, cinchonine, cinchophen, cinepazet, cinepazide, cinepazide, cinitapride, cinmetacin, cinnamedrine, cinnarizine, cinolazepam, cinoxacin, cinoxate, cinromide, cioteronel, cipamfylline, cipralisant, ciprofibrate, ciprofloxacin, ciprofloxacin + ciramadol, cisapride, cisatracurium, cisplatin, citalopram, citicoline, Citiolone, citrate, citric acid, citrulline, cizolirtine, CJ-13610, CKD-602, cladribine, clanobutin, clarithromycin, clavulan, clavulanate disodium, clavulanic acid, clebopride, clemastine, clemizol, clenbuterol, clentiazem, clevidipine, clevudine, clidanac, clidinium, clinafloxacin, clindamycin, clindamycin, clindamycin + tretinoin, clinofibrate, clinprost, clobazam, clobenfurol, clobenoside, clobenzepam, clobenzorex, clobenztropine, clobetasol, clobetasone, clobutinol, clocapramine, clocinizine, cloconazole, clocortolone, clodronate, clodronic acid, clofarabine, clofazimine, clofenamide, clofibrat, clofibric acid, cloflucarban, clofoctol, cloforex, clomacran, clomestrone, clometacin, clomethiazole, clometocillin, clomiphene, clomipramine, clomocycline, clonazepam, clonidine, clonitazene, clonitrate, clonixin, clopamid, clopenthixol, cloperastine, clopidogrel, clopirac, cloprednol, cloranolol, clorazepic acid, clorexolone, cloricromene, clorindione, clorprenaline, clortermine, clospirazine, clostebol, clothiapine, clotiazepam, clotrimazole, clotrimazole + betamethasone, cioxacillin, cloxazolam, cloxotestosterone, cloxyquin, clozapine, CMI-392, CMT-3, CNI-1493, CNS- 5161, cobamamide, cocaethylene, cocaine, codeine, cofactor, colchicine, colesevelam, colestilan, colestipol, colforsin daropate, colfosceril, collagraft, colocynthin, colpormon, coluracetam, combretastatin A-4 prodrug, compound B, conivaptin conjugate, connettivina, convallatoxin, coparaffmate, corticorelin ovine, corticosterone, cortisone, cortivazol, cosyntropin, cotamine, cotinine, co-trimazine, coumetarol, CP-248, CP-461, CPC-211, CPI-1189, CRA-0450, creatinol-O- phosphate, CRL-5861, crobenetine, croconazole, cromoglicic acid, cromolyn, cropropamide, crotamiton, crotethamide, crystacide, CS-502, CS-758, CS-834, CT-052923, CT-32228, cupric citrate, cuproxoline, CVT-2584, CX-659S, cyacetacide, cyamemazine, cyanidin, CYC400, cyclacillin, cyclandelate, cyclazocine, cyclexanone, cyclexedrine, cyclidrol, cyclin DI inhibitors, cyclizine, cyclobarbital, cyclobendazole, cyclobenzaprine, cyclobutyrol, cyclocumarol, cyclodrine, cyclofenil, cycloguanil, cyclomethycaine, cycloniumelodide, cyclopentamine, cyclopenthiazide, cyclopentobarbital, cyclopentolate, cyclophosphamide, cyclopiroxalamine, cycloserine, 1 cyclothiazide, cyclovalone, cymarin, cymserine, cynarin(e), cyp26 inhibitors, cyproheptadine, cyproterone, cysteamine, cystic fibrosis ther, cytarabine, D-24851, D-4418, DA-5018, DA-6034, DA- 7867, DA-7911, DA- 8159, dacarbazine, daclizumab, dactinomycin, dalbavancin, dalfopristin, dalfopristin + quinupristin, dalteparin, daltroban, danaparoid, danazol, danthron, dantrolene, dapiprazole, dapivirine, dapoxetine, dapsone, daptomycin, darbepoetin alfa, darifenacin, daunorubicin, DAX< SciClone, DB-67, D-camphocarboxylic, DCF -987, DDT, deaminooxytocin, deanol, debrisoquin, decamethonium, decimemide, decitabine, declopramide, deferiprone, deferoxamine, deflazacort, defosfamide, degarelix, dehydroascorbic acid, dehydroemetine, dehyrdocholic acid, delapri + manidipine, delapril, delavirdine, delmadinone, delmopinol, delorazepam, delucemine, demanyl, demecarium, demeclocycline, demecolcine, demegestone, demexiptilline, denaverine, dendrimers, denileukin diftitox, denopamine, denopterin, deoxycholic acid, deoxycorticosterone, deoxydihydro-streptomycin, deoxyepinephrine, depreotide, depsipeptide, deptropine, dequalinium, dersalazine, deserpidine, desferrioxamine, desflurane, desipramine, deslanoside, desloratadine, deslorelin, desmopressin, desogestrel, desogestrel + estradiol, desogestrel + ethinylestrad (1), desomorphine, desonide, desoximetasone, detaxtran, devacade, dexamethasone, dexanabinol, dexecadotril, dexefaroxan, dexetimide, dexibuprofen, dexketoprofen, dexloxiglumide, dexmedetomidine, dexmethylphenidate, dexpanthenol, dexrazoxane, dextran-1, dextranomer, dextroamphetamine, dextromethorphan, dextromoramide, dextropropoxyphene, dezocine, DF-1012, DFA-IV, D-fenchone, D-glucuronolactone, Diab II, diacerein, diampromide, diamthazole, diathymosulfone, diatrizoate, diazepam, diaziquone, diazoxide, dibekacin, dibenzepin, dibromopropamidine, dibucaine, dichloralphenazone, dichloramine T, dichlorisone, dichlorobenzyl alcohol, dichlorohydrin, dichlorophen, dichlorophenarsine, dichlorphenamide, diclofenac, diclofenac + HA, dicloxacillin, dicoumarol, dicumarol, dicyclomine, didanosine, dideoxyadenosine, didox, dienestrol, dienogest, dienogest + estradiol, diethadione, diethazine, diethylamide, diethylbromo-acetamide, diethylcarbamazine, diethylpropion, diethylstilbestrol, difemerine, difenamizole, difenoxin, difenpiramide, diflomotecan, diflorasone, difloxacin, diflucortolone, diflunisal, difluprednate, digitalin, digitoxin, digoxin, dihexyverine, dihydralazine, dihydrocodeine, dihydrocodeinone enol, dihydroergocryptine, dihydroergocryptine, dihydroergotamine, dihydromorphine, dihydrostreptomycin, dihydrotachysterol, dihydroxyaluminum, diisopromine, diisopropyl paraoxon, diisopropylamine, dilazep, dilevalol, diloxanide, diltiazem, dimecrotic acid, dimefline, dimeglumine, dimemorfan, dimenhydrinate, dimenoxadol, dimepheptanol, dimercaprol, dimetacrine, dimethadione, dimethazan, dimethindene, dimethisoquin, dimethisterone, dimethocaine, dimethoxanate, dimethyl sulfoxide, dimethylthiambutene, dimetofrine, dimorpholamine, dinoprostone, diosmectite, diosmin, dioxadrol, dioxaphetyl, dioxethedrine, dioxybenzone, diphemanil, diphenadione, diphencyprone, diphenhydramine, diphenidol, diphenoxylate, diphenylpyraline, diphetarsone, diphtheria & tetanus toxoids and acellular pertussis vaccine adsorbed, dipipanone, dipivefrin, dipyridamole, dipyridamole, dipyrocetyl, dipyrone, diquafosol, dirithromycin, disodium pamidronate, disofenin, disopyramide, distigmine, disulfamide, disulfiram, ditazol, dithiazanine, dithranol, ditiocarb, dixanthogen, dixyrazine, DJ-927, DK-507k, DL-Lactic Acid, DM DC, DMXAA, DNA Stealth, dobesilate, dobutamine, docarpamine, docetaxel, docosahexaenoic acid, docosanol, docusate, dofetilide, dolasetron mesilate, domiodol, domiphen, domitroban, domperidone, donepezil, donitriptan, dopamine, dopexamine, doramapimod, doranidazole, doripenem, dorzolamide, dorzolamide + timolol, dosmalfate, dosulepine, dotarizine, dothiepin, doxacurium, doxapram, doxazosin, doxefazepam, doxenitoin, doxepin, doxercalciferol, doxifluridine, doxofylline, doxorubicin, doxycycline, doxylamine, DPC-817, DPI-3290, DQ-113, drofenine, droloxifene, drometrizole, dromostanolone, dronabinol, dronedarone, droperidol, droprenilamine, dropropizine, drospirenone, drotaverine, drotebanol, droxicam, droxidopa, droxidopa, DU-125530, duloxetine, duramycin, durapatite, dutasteride, DW- 1141, DW-286a, DW-471, DX-9065a, DY-9760e, dyclonine, dydrogesterone, dymanthine, dyphyllin, E-1010, E-2101, E2F antagonists, E-3620, E-5564, E-5842, E-6259, EAA-90, ebastine, eberconazole, ebrotidine, ebselen, eburnamonine, ecabapide, ecabet, ecadotril, ecgonidine, ecgonine, echothiophate, econazole, ecopipam, ecraprost, ectylurea, ED-71, edaravone, edatrexate, edetate calcium disodium, edetate disodium, edetate sodium, edetate trisodium, edonentan, edotreotide, edoxudine, edrecolomab, edrophonium, efalith, efaproxiral, efavirenz, efletirizine, eflomithine, efloxate, eflucimibe, efonidipine, EGIS-7229, eglumegad, egualen, elarofiban, elcatonin, eicosapentaenoic acid, eledoisin, eletriptan, elgodipine, ellagic acid, elliptinium, eltoprazine, elvucitabine, elzasonan, embelin, embramine, emedastine, emepronium, emetine, emitefur, EMM- 210525, emodin, emorfazone, EMR- 62203, emtricitabine, emylcamate, enalapril, enalaprilat, enallylpropymal, encainide, enciprazine, endralazine, enfenamic acid, enflurane, enilconazole, eniluracil, ENMD-0995, enocitabine, enol-3-IPA, enoxacin, enoxaparin, enoximone, enoxolone, enprostil, enrasentan, entacapone, entecavir, enviomycin, eoinephrine, epalrestat, epavir, EPC-K1, eperisone, epervudine, ephedrine, epicillin, epimestrol, epinastine, epirizole, epirubicin, epitiostanol, eplerenone, eplivanserin, epoprostenol, epostane, eprazinone, epristeride, eprosartan, eprozinol, eptapirone, eptaplatin, eptastigmine, eptazocine, eptifibatide, equilenin, equilin, ERA-923, erdosteine, ergocornine, ergocorninine, ergoloid mesylates, ergonovine, ergosterol, ergotamine, eritadenine, erlotinib, ertapenem, erythrityl tetranitrate, erythrocentaurin, erythromycin acistrate, erythromycin erythrophleine, erythromycin estolate, erythromycin glucoheptonate, erythromycin lactobionate, erythromycin propionate, erythromycin stearate, erythromycin stinoprate, esaprazole, escitalopram, esculin, eseridine, esmolol, esomeprazole, estazolam, ester, estradiol, estradiol, estramustine, estriol, estrogen, estrone, eszopiclone, etafedrine, etafenone, etamiphyllin, etanercept, etanidazole, etaqualone, eterobarb, ethacridine, ethacrynic acid, ethadion, ethambutol, ethamivan, ethamsylate, ethanolamine, ethaverine, ethchlorvynol, ethenzamide, ethiazide, ethinamate, ethinyl estradiol, ethinyl estradiol, ethinyl estradiol, ethionamide, ethisterone, ethoheptazine, ethopropazine, ethosuximide, ethotoin, ethoxzolamide, ethybenztropine, ethyl alcohol, ethyl biscoumacetate, ethyl chloride, ethyl dibunate, ethyl ether, ethyl icosapentate, ethyl loflazepate, ethyl loflazepate, ethylamine, ethylene, ethylestrenol, ethylidene, ethylmethyl-thiambutene, ethylmorphine, ethylnorepinephrine, ethynodiol, ethynylcytidine, etidocaine, etidronate, etidronic acid, etifelmin, etifoxine, etilefrin, etilevodopa, etiprednol, etiroxate, etizolam, etodolac, etodroxizine, etofenamate, etofibrate, etofylline, etofylline clofibrate, etofylline nicotinate, etoglucid, etomidate, etomidoline, etonitazene, etonogestrel, etoperidone, etoposide, etoposide phosphate, etoricoxib, etoxadrol, etozolin, etretinate, etryptamine, etymemazine, eucatropine, eugenol, EUK-134, EUK-189, evans blue, everolimus, exalamide, exametazime, exatecan, exemestane, exifone, exisulind, Exosurf ®, ezetimibe, Factor IX, Factor VIII, Factor XIII, fadolmidine, fadrozole, falecalcitriol, famciclovir, famotidine, fampridine, fandofloxacin, fantofarone, faropenem, faropenem daloxate, fasidotril, fasudil, fazadinium bromide, febarbamate, febuprol, febuxostat, fedotozine, felbamate, felbinac, felodipine, felypressin, femoxetine, fenbenicillin, fenbufen, fenbutrazate, fencamfamine, fencamine, fenclozic acid, fendiline, fendosal, fenethylline, fenfluramine, fenipentol, fenofibrate, fenoldopam, fenoprofen, fenoterol, fenoverine, fenoxazoline, fenoxedil, fenozolone, fenpentadiol, fenpiprane, fenpiverinium, fenproporex, fenquizone, fenretinide, fenspiride, fentanyl, fentiazac, fenticlor, fenticonazole, fentonium bromide, fepradinol, feprazone, ferric sodium edetate, ferrioxamine B, ferrocholinate, ferrous gluconate, ferumoxytol, fesoterodine, fexofenadine, fibrostat, fidarestat, fiduxosin, finasteride, fmrozole, fipexide, FK-960, flavopiridol, flavoxate, flecainide, fleroxacin, flesinoxan, flibanserin, floctafenine, flomoxef, flopropione, florantyrone, flosequinan, floxacillin, floxuridine, fluacizine, fluanisone, fluarizine, fluasterone, fluazacort, flucloronide, flucloxacill in, fluconazole, flucytosine, fludarabine, fludeoxyglucose Fl 8, fludiazepam, fludrocortisone, flufenamic acid, fluindione, flumazenil, flumecinol, flumequine, flumethasone, flumethiazide, flunisolide, flunitrazepam, flunoxaprofen, fluocinolone acetonide, fluocinolone SAL, fluocinonide, fluocortin butyl, fluocortolone, fluorescein, fluoresone, fluoromethoIone, fluorosalan, fluorouracil, fluoxetine, fluoxymesterone, flupentixol, fluperolone, fluphenazine, flupirtine, fluprednidene acetate, fluprednisolone, fluproquazone, flurandrenolide, flurazepam, flurbiprofen, flurithromycin, flurogestone, flurothyl, fluroxen, fluspirilene, flutamide, flutazolam, fluticasone, flutoprazepam, flutrimazole, flutropium bromide, fluvastatin, fluvoxamine, folic acid, folinic acid, fomepizole, fominoben, fomivirsen, fomocaine, fonazine, fondaparinux, formebolone, formestane, formocortal, formoterol, fosamprenavir, foscamet, fosfestrol, fosfluconazole, fosfomycin, fosfomycin, fosfosal, fosinopril, fosphenytoin, fotemustine, fropenem, frovatriptan, fructose, fructose- 1,6-diphosphate, FTC, FTY-720, fudosteine, fulvestrant, fumagiline, fumagillin, furaltadone, furazabol, furazolidone, furazolium chloride, furonazide, furosemide, fursultiamine, furtrethonium, fusidic acid, Gl, YM BioSciences, G25, GABA-A Alphas, gabapentin, gabexate, gaboxadol, gadobenat, gadobutrol, gadodiamide, gadolinium, gadopentetic acid, gadoteridol, gadoversetamide, gadoxetic acid, galantamine, galanthamine, galarubicin, gallamine triethiodide, gallic acid, gallium maltolate, gallium nitrate, gallopamil, ganaxolone, ganciclovir, ganirelix, ganstigmine, gantofiban, garenoxacin, garnocestim, gatifloxacin, gefarnate, gefitinib, gemcabene, gemcitabine, gemeprost, gemfibrozil, gemifloxacin, gentamicin, gentian violet, gentiopicrin, gentisic acid, gepefrine, gepirone, gestodene, gestodene + ethinylest, gestonorone caproate, gestrinone, gimatecan, giractide, gitoxin, GL-406349, Glafenine, glatiramer, Glibornuride, gliclazide, glimepiride, glipizide, gliquidone, glisolamide, glisoxepid, globulin (human), glucametacin, glucoheptonic acid, gluconic acid, glucosamine, glucosulfone, glufosfamide, glutamic acid, glutaraldehyde, glutethimide, glyburide, glybuthiazol(e), glybuzole, glycerol, glycerophosphate, glycocyamine, glycol salicylate, glyconiazide, glycopyrrolate, glyhexamide, glymidine, glypinamide, GMDP, gold sodium, goserelin, GPI-1485, GPI-5693, graftskin, granisetron, grepafloxacin, griseofulvin, guaiacol, guaiapate, guaiazulene, guaifenesin, guaimesal, guaiacolsulfonate, guamecycline, guanabenz, guanadrel, guanethidine, guanfacine, guanoxabenz, guanoxan, gugulipid, gusperimus, GW-280430A, GW-320659, GYKI-16084, hachimycin, halazepam, halcinonide, halobetasol, halofantrine, halometasone, haloperidol, halopredone, haloprogin, halopropane, halothane, haloxazolam, harkoseride, HE-2000, healos, hematoporphyrin, hepronicate, heptabarbital, heptaminol, hetacillin, hetastarch, hexacetonide, hexachlorophene, hexadimethrine, hexafluorenium, hexamethonium, hexamidine, hexapropymate, hexedine, hexestrol, hexestrol Bis(P-di ethyl ami noethyl ether), hexethal, hexetidine, hexobarbital, hexobendine, hexocyclium methyl sulfate, hexoprenaline, hextend, hexyl caine, HF-0299, HGP-2, HGP-6A, hidrosmin, histamine, Histapyrrodine, histrelin, HM-101, HMN-214, homatropine, homocamfm, homochlorcyclizine, hopantenic acid, HP-228, huperzine A, hyaluronan, hycanthone, hydnocarpic acid, hydralazine, hydrastine, hydrastinine, hydrochlorothiazide, hydrocodone, hydrocortamate, hydrocortisone, hydrocortisone, hydroflumethiazide, hydromorphone, hydroquinidine, hydroquinine, hydroquinone, hydroxid, hydroxocobalamin, hydroxyamphetamine, hydroxychloroquine, hydroxydione, hydroxyethyl ether, hydroxynaphthoate, hydroxypethidine, hydroxyphenamate, hydroxypropyl cellulose, hydroxystilbamidine, hydroxytetracaine, hydroxyzine, Hylan G- F 20, hymecromone, hyoscyamine, hypericin, IACFT, ibandronic acid, bopamine, ibopamine, Ibritumomab, ibrolipim, ibudilast, Ibufenac, ibuprofen, ibuprofen piconol, buproxam, ibutilide, ICA-17043, icodextrin, idarubicin, Idazoxan, ldB-1016, idebenone, IDN-5109, doxifen, idraparinux, idrocilamide, ifenprodil, ifosfamide, iguratimod, ilaprazole, ilomastat, loperidone, iloprost trometamol, ILX23-7553, imatinib, imidapril, imidazole salicylate, imipenem, mipramine, imipramine N-Oxide, imiquimod, imolamine, implitapide, improsulfan, inactivated, naperisone, incadronate, incadronic acid, indalpine, indanazoline, indapamide, indecainid, ndeloxazine, indeloxazine, indenolol, indinavir, indiplon, indisetron, indisulam, indobufen, ndocyanine green, indometacin, indoprofen, indoramin, induclem, infliximab, inhibitor, inhibitors, nosine pranobex, inositol, inositol niacinate, inverse agonist Mer, iobenguane, iobenzamic acid, obitridol, iocarmic acid, iocetamic acid, iodamide, iodide, iodine, iodipamide, iodixanol, odoalphionic acid, iodochlorhydroxyquin, iodoform, iodopyracet, iodopyrrole, iodoquinol, odosubgallate, iofetamine 1231, ioglycamic acid, iohexol, iomeglamic acid, iomeprol, iopamidol, opanoic acid, iopentol, iophendylate, iophenoxic acid, iopromide, iopronic acid, iopydol, iopydone, othalamic acid, iotrolan, ioversol, ioxaglic acid, ioxilan, IP-751, ipidacrine, IPL-576092, ipodate, poniazid, ipratpopium, ipratropium, ipratropium bromide, iprazochrome, ipriflavone, iprindole, proclozid, ipsapiron, irbesartan, IRFI-042, IRFI-165, iridomyrmecin, irindalone, irinotecan, rofulven, iron sorbitex, irsogladine, IS-741, isaglitazone, ISAtx-247, isbogrel, isepamicin, isoaminile, sobutyl p-aminobenzoate, isoconazole, isoetharine, isofloxythepin, isoflurane, isoflurophate, soladol, isomethadone, isometheptene, isoniazid, isonixin, isopromethazine, isopropamide iodide, isopropyl alcohol, isopropyl unoprostone, isoproterenol, isosorbide, isosorbide dinitrate, isosorbide mononitrate, isothipendyl, isotretinoin, isovaleryl, isoxepac, isoxicam, isoxsuprine, isradipine, israpafant, ISV-403, itasetron, ITF-282, itopride, itraconazole, itramin, itriglumide, iturelix, ivabradine, ixabepilone, J-104132, J-107088, J-l 13397, Janex-1, josamycin, JTV-519, K-777, kainic acid, kalimate, kallidin, KB-130015, KCB-328, kebuzone, ketamine, ketanserin, ketazolam, kethoxal, ketobemidone, ketoconazole, ketoprofen, ketorolac, ketorolac, ketotifen, khellin, kinetin, KNI-272, KP-103, KP-157, KP-544, KRN-5500, KT-136, KUL-7211, KW-2170, KW-6002, KW-7158, L-365260, L- 5 -hydroxy-tryptophan, L-745337, L-758298, L-826141, labetalol, lacidipine, lactic acid, lactitol, lactulose, lafutidine, lamifiban, lamivudine, lamotrigine, landiolol, lanicemine, laniquidar, lanoconazole, lanoteplase, lanreotide, lansoprazole, lanthanum carbonate, lapatinib, laquinimod, lasofoxifene, latamoxef, latanoprost, lauroguadine, laurolinium acetate, lawsone, LAX-111, lazabemide, LB-30057, L-cysteine, lefetamine, leflunomide, leflunomide, leiopyrrole, lenampicillin, lentinan, lepirudin, lercanidipine, lerisetron, lesopitron, leteprinim, letosteine, letrozole, leucocyanidin, leuprolide, leuprolide acetate, leuprorelin, levallorphan, levaminsole, levcromakalim, levetiracetam, levobetaxolol, levobunolol, levobupivacaine, levocabastine, levocetirizine, levodopa, levodropropizine, levofloxacin, levomethadyl acetate, levomoprolol, levonorgestrel, levophacetoperane, levopropoxyphene, levorphanol, levosimendan, levosulpride, levothyroxine, levovirin, lexidronam, lexipafant, LF-15-0195, LF-16-0687, LGD-1550, LH, LH-RH, liarozote, licofelone, licostinel, lidadronate, lidamidine, lidocaine, lidofenin, lidoflazine, limaprost, lincomycin, lindan, linezolid, linoleic acid, linolenic acid, liothyronine, lipase, lipo- dexamethasone, lipo-flurbiprofen, Lipogel HA, LiquiVent, liranaftate, lisinopril, lisofyllin, lisuride, lithium, lithium citrate, lixivaptan, UP-1082, LLUAIpha, LMP-160, LMP-420, loanzapine, lobaplatin, lobeline, lobenzarit, lodoxamide, lofentanil, lofepramine, lofexidine, loflucarban, lomefloxacin, lomerizine, lomifylline, lomustine, lonafarnib, lonapalene, lonazolac, lonidamine, loperamide, loperamide oxide, loprazolam, loprinone, loracarbef, lorajmine, loratadine, lorazepam, lorcainide, lormetazepam, lornoxicam, losartan, loteprednol, lotrafiban, lovastatin, loxapine, loxiglumide, loxoprofen, Lu-35-138, lubeluzole, lubiprostone, lucanthone, lucanthone, lumefantrine, lumiracoxib, lurtotecan, lutetium texaphyrin, LV-216, LX-104, LY-156735, LY-293111, LY-293558, LY- 355703, lyapolate, lymecycline, lynestrenol, lypressin, lysine acetylsalicylate, lysine salicylate, lysophospholipids, M-40403, mabuprofen, mabuterol, macrophage colony-stimulating factor, MADU, mafenide, mafosfamide, magaldrate, magenta I, magnesium, magnesium carbonate, magnesium chloride, magnesium citrate, magnesium gluconate, magnesium lactate, magnesium salicylate, malathion, malotilate, mandelic acid, mandelic acid isoamyl, mangafodipir, manidipine, mannomustine, mannose-6-phosphate, maprotilline, maribavir, marimastat, maxacalcitol, mazindol, mazipredone, MC-5723, MCC-478, MCI- 154, m-cresyl acetate, MDAM, MDI-101, MDI- 403, MDL- 100907, mebendazole, mebeverine, mebhydroline, mebrofenin, mebutamate, mecamylamine, mechlorethamine, mechlorethamine oxide, mecillinam, meclizine, meclocycline, meclofenamate, meclofenamic acid, meclofenoxate, mecloqualone, mecysteine, medazepam, medifoxamine, medrogestone, medronic acid, medroxyprogesterone, medrysone, mefenamic acid, mefenorex, mefexamide, mefloquine, mefruside, megestrol, meglumin, meglutol, melagatran, melanocortin-4 agonist, melarsoprol, melengestrol, melevodopa, melinamide, melitracen, meloxicam, melperone, melphalan, meluadrine, memantine, MEN-10700, MEN-10755, menadiol, menadione, menadoxime, menbutone, menogaril, MENT, menthol, menthyl valerate, meobentine, meparfynol, mepartricin, mepazine, mepenzolate bromide, meperidine, mephenesin, mephenoxalone, mephentermine, mephenytoin, mephobarbital, mepindolol, mepitiostane, mepivacaine, mepixanox, meprednisone, meprobamate, meproscillarin, meptazinol, mequitazine, meralein, meralluride, merbromin, mercaptomerin, mercumallylic acid, mercuric oleate, mercuric oxycyanide, merimepodib, meropenem, mersalyl, mertiatide, mesalamine, mesalazine, mesna, mesoridazine, mestanolone, mesterolone, mestranol, mesulfen, metaclazepam, metampicillin, metapramine, metaproterenol, metaraminol, metazocine, metergoline, metformin, methacholine, methacycline, methadone, methafurylene, methamphetamine, methandriol, methandrostenolone, methantheline, methapyrilene, methaqualone, metharbital, methazolamide, methdilazine, methenamine, methenolone, methestrol, methetoin, methicillin, methimazole, methiodal, methionic acid, methionine, methisazone, methitural, methixene, methocarbamol, methohexital, methotrexate, methotrimeprazine, methoxamine, methoxsalen, methoxycinnamate, m eth oxyfl urane, methoxyphenamine, methoxypromazine, methscopolamine, methsuximide, methyclothiazide, methyl blue, methyl nicotinate, methyl propyl ether, methyl salicylate, methyl tert-butyl ether, methylbenzethonium chloride, methylbromide, methylcobalamin, methyldopa, methylene blue, methyl ergonovine, methylhexaneamide, methylphenidate, methylprednisolone, methylprednisolone, methylprednisolone, methylthiouracil, methyltrienolone, methyprylon, methysergide, metiazinic acid, metipranolol, metoclopramide, metocurine iodide, metofenazate, metolazone, metopimazine, metopon, metoprolol, metralindole, metrizamide, metrizoic acid, metron s, metyrapone, metyrosine, mexazolam, mexenone, mexiletine, mezlocillin, MFH-244, mianserin, mibefradil, miboplatin, micafungin, miconazole, micronomicin, midaxifyline, midazolam, midecamycin, midecamycin acetate, midesteine, midodrine, midostaurin, mifepristone, miglitol, miglustat, mildronate, milnacipran, miloxacin, milrinone, miltefosine, minaprine, minocycline, minodronic acid, minoxidil, miokamycin, mirtazapine, misoprostol, mitemcinal, mitiglinide, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mitoxantrone, MIV-210, mivacurium, mivazerol, mizolastine, mizoribine, MKC-733, MLN-519, MLN-576, moclobemide, modafinil, moexipril, mofarotene, mofebutazone, mofegiline, mofetil, mofezolac, MOL-6131, molindone, molsidomine, mometasone, monatepil, monobenzone, monoethanolamine, monolaurin, monoterpene diols, montelukast, monteplase, moperone, mopidamol, moprolol, moracizine, morazone, moricizine, moroxydine, morphazinamide, morphine, morphine-6-glucuronide, mosapramine, mosapride, motexafm, motretinide, moveltipril, moxalactam, moxastine, moxaverine, moxestrol, moxifloxacin, moxisylyte, moxonidine, M-PGA, MPI-5010, MPI-5020, MPL, MRS- 1754, MS-209, MS-275, MS- 325, MS-377, mupirocin, muscarin, muzolimine, MX-1013, mycophenolate, mycophenolic acid, myrophine, N-(hydroxymethyl)-nicotinamide, N,N,N',N'- tetraethylphthalamide, N-[4-[4-(2- methoxyphenyl)-l-piperazinyl]butyl]naphthalene-2- carboxamide, N2-formyl-sulfisomidine, N4- sulfanilylsulfanilamide, N4-b-u- glucosylsulfanilamide, nabilone, nabumetone, N-acetylcysteine, N- acetylmethionine, nadifloxacin, nadolol, nadoxolol, nafamostat, nafarelin, nafcillin, nafronyl, naftidofuryl, naftifme, naftopidil, nalbuphine, nalidixic acid, nalmefene, nalorphine, naloxone, naltrexone, NAMI, naminidil, nandrolone, napadisilate, naphazoline, naphthalene, naproxen, naproxen betainate, naratriptan, narceine, narcobarbital, natamycin, nateglinide, N-butyldeoxy- nojirimycin, N-butylscopolammonium Bromide, NC-503, NC-531, NCX- 1000, NCX-4016, NCX-456, NCX-950, n-docosanol, NE-100, nealbarbital, nebivolol, nebostinel, nebracetam, nedaplatin, nedocromil, nefazodone, nefiracetam, nefopam, negamycin, nelfmavir, nemonapride, neostigmine, nepadutant, neramexane, neridronic acid, neriifolin, N-ethylamphetamine, neticonazole, netilmicin, nevirapine, NGD-98-2, nialamide, niaprazine, nicametate, nicaraven, nicardipine, nicergoline, niceritrol, niclosamide, nicoclonate, nicofuranose, nicomol, nicomorphine, nicorandil, nicotinamide, nicotine, nicotinic acid, nicotinic acid benzyl ester, nicotinyl alcohol, nifedipine, nifekalant, nifenalol, niflumic acid, nifuratel, nifurfoline, nifuroxazide, nifuroxime, nifurpirinol, nifurprazine, nifurtimox, nifurtoinol, nifurzide, NIK-254, nikethamide, nilutamide, nilvadipine, nimesulide, nimetazepam, nimodipine, nimorazole, nimustine, ninopterin, NIP-142, NIP-531, niperotidine, nipradilol, niridazole, nisoldipine, nitazoxanide, nitisinone, nitracrine, nitrazepam, nitrendipine, nitroflurbiprofen, nitrofurantoin, nitrofurazone, nitroglycerin, nitromersol, nitronaproxen, nitroxazepine, nitroxoline, nizatidine, nizofenone, NM-3, NM-702, N- methylephedrine, N- methylepinephrine, N-methylglucamine, NN-414, NNC-05-1869, nobel, nogalamycin, nolatrexed, nolomirole, nolpitantium, nomegestrol, nomifensine, noprylsulfamide, norbolethone, nordazepam, nordefrin, nordihydroguaiaretic acid, norelgestromin, norepinephrine, norethandrolone, norethindrone, norethynodrel, norfenefrine, norfloxacin, norgesterone, norgestimate, norgestrel, norgestrienone, norlevorphanol, normethadone, normethandrone, normorphine, norphenazone, norpipanone, norpseudoephedrine, nortriptyline, norvinisterone, noscapine, novembichin, novobiocin, noxiptillin, noxythiolin, NS-1209, NS-1231, NS-126, NS-220, NS-2330, NS5A inhibitors, NS-7, NS- 8, NSC-330507, NSC-619534, NSC-697726, N-sulfanilyl-3,4- xylamide, NU-6027 nucleosides, NV-07, NVP-SRA880, NW-1029, NXY-059, Nylidrin, NZ-314, NZ-419, obidoxime chloride, OC-108, ocinaplon, octabenzone, octacaine, octamoxin, octaverine, octenidine, octodrine, octopamine, octotiamine, octreotide, octyl, ofloxacin, oleandrin, oleic acid, olmesartan - medoxomil, o-lodohippurate, olopatadine, olpadronic acid, olsalazine, oltipraz, OM- 294DP, omacor, omapatrilat, omeprazole, omiloxetine, omoconazole, onapristone, ondansetron, ONO-3403, ONO-4128, ONO-8815 Ly, ONT- 093, OPC-14523, OPC-31260, OPC-51803, OPC-6535, opiniazide, opioid analgesics, opipramol, orazamide, orazipone, Org-12962, Org-24448, oritavancin, orlistat, ormeloxifene, ornidazole, ornipressin, ornithine, omoprostil, orotic acid, orphenadrine, orthocaine, osalmid, osanetant, osaterone, oseltamivir, OSI-7836, OSI-7904, ospemifene, otilonium bromide, ouabain, oxaceprol, oxacillin, oxaflozane, oxaliplatin, oxalyt-C, oxamarin, oxametacine, oxamniquine, oxandrolone, oxantel, oxapropanium, oxaprozin, oxatomide, oxazepam, oxazolam, oxcarbazepine, oxeladin, oxendolone, oxethazaine, oxetoron, oxiconazole, oxidronic acid, oxiniacic acid, oxiracetam, oxitropium, oxolamin, oxolinix acid, oxophenarsine, oxprenolol, oxybenzone, oxybutynin, oxycinchophen, oxycodone, oxygent, oxymesterone, oxymetazoline, oxymethoIone, oxymethurea, oxymorphone, oxypendyl, oxypertine, oxyphenbutazone, oxyphencyclimine, oxyphenisatin, oxyphenonium, oxypinocamphone, oxypurinol, oxytedrine, oxytetracycline, ozagrel, p-(benzylsulfonamido)-benzoic acid, P-100, P-1202, P32/98, PA- 824, PACAP 38, pactitaxel, PADRE, pagoclone, PAI inhibs, palindore, palivizumab, palonosetron, pamabrom, pamaquine, pamicogral, pamidronate, p-aminobenzoic acid, p- aminohippuric acid, p-amino-propiophenone, p- aminosalicylic acid, panavir, pancuronium, panipenem, pantethine, pantoprazole, pantothenic acid, papain, papaverine, paracetamol, paraflutizide, paraldehyde, paramethadione, paramethasone, paranyline, parathyroid hormone, parecoxib, parethoxycaine, pargyline, paricalcitol, paromomycin, paroxetine, paroxypropione, parsalmide, patrin-2, pazinaclone, pazufloxacin, p- bromoacetanilide, PC-NSAIDs, PD-0166285, pecilocin, pefloxacin, pegvisomant, pelletierine, pemetrexed, pemirolast, pemoline, pempidine, PEN-203, penamecillin, penbutolol, penciclovir, penethamate, penfluridol, penicillamine, penicillin G, penicillin G Procaine, penicillin N, penicillin O, penicillin V, penimepicycline, penntuss, pentaerythritol, pentaerythritol, pentaerythritol chloral, pentagastrin, pentagestrone, pentalyte, pentam thonium, pentamidine, pentazocine, pentetate, pentetic acid, pentetreotide, penthienate, pentifyllin, pentigetide, pentisomide, pentobarbital, pentolinium, pentorex, pentosan, pentostatin, pentoxifylline, pentoxyl, pentrinitrol, pentylenetetrazole, peplomycin, peptide, peptide, perazine, perfiromycin, perflubron, perfosfamide, pergolide, perhexiline, pericyazine, perifosine, perillyl alcohol, perimethazine, perindopril, periodyl, perisoxal, perlapine, permanganate, permethrin, perospirone, perphenazine, petroleum benzin, PH-10, phanquinone, pharmacor, pharmaprojects no. 6362, pharmaprojects no. 4994, pharmaprojects no. 5325, pharmaprojects no. 5972, pharmaprojects no. 6446, pharmaprojects no. 6590, pharmaprojects no. 6656, pharmaprojects no. 6691, pharmaprojects no. 6743, pharmaprojects no. 6748, phenacaine, phenacemide, phenacetin, phenadoxone, phenallymal, phenamet, phenamide, phenazocine, phenazopyridine, phenbutamide, phencyclidine, phendimetrazine, phenelzine, phenesterine, phenetharbital, phenethicillin, pheneturide, phenformin, phenglutarimide, phenindamine, phenindione, pheniprazine, pheniramine, phenmetrazine, phenobarbital, phenobutiodil, phenocoll, phenoctide, phenolphthalein, phenolphthalol, phenolsulfonphthalein, phenol-tetrachlorophthalein, phenoperidine, phenosulfazole, phenoxybenzamine, phenoxypropazine, phenprobamate, phenprocoumon, phenserine, phensuximide, phentermine, phentetiothalein, phentolamine, phenyl acetylsalicylate, phenyl aminosalicylate, phenyl salicylate, phenylbutazone, phenylephrine, phenylethanolamine, phenylmercury, phenylmethylbarbituric acid, phenylpropanolamine, phenylpropyl-methylamine, phenyltoloxamine, phenyramidol, phenytoin, phethenylate, phloroglucinol, pholcodine, pholedrine, phoramide, phosphate, phosphate, phosphocreatine, phosphocysteamine, phosphorylcholine, phthalylsulfathiazole, phthalysulfacetamide, p-hydroxyephedrine, phylloquinone, physostigmine, phytic acid, PI-88, piberaline, piboserod, picilorex, picloxydine, picoperine, picosulfate, picotamide, picumast, pidotimod, pifarnine, piketoprofen, pildralazine, pilocarpine, piloplex, pilsicainide, pimeclone, pimecrolimus, pimefylline, pimilprost, piminodine, pimobendan, pimozide, pinacidil, pinaverium, pinazepam, pindolol, pioglitazone, pipacycline, pipamazine, pipamperone, pipazethate, pipebuzone, pipecurium, pipecuronium, pipemidic acid, pipenzolate bromide, piperacetazine, piperacillin, piperazine adipate, piperidione, piperidolate, piperilate, pipeline analogues, piperocaine, piperonal, piperoxan, piperylone, pipobroman, piposulfan, pipotiazine, pipoxolan, pipradrol, piprozolin, piracetam, pirarubicin, pirazolac, pirbuterol, pirenoxine, pirenzepine, piretanide, pirfenidone, piribedil, piridocaine, pirifibrate, piritramide, piritrexim, pirlindole, pirmenol, piroctone, piroheptine, piromidic acid, piroxicam, piroxicam betadex, piroxicam cinnamate, pirozadil, pirprofen, pitavastatin, pivagabine, pivaloyloxymethyl, pivalylbenzhydrazine, pivampicillin, pivampicillin/pivmecillinam, pivcefalexin, pivmecillinam, pixantrone, pizotifen, pizotyline, PKI-166, p-lactophenetide, plafibride, plasminogen activator, plasmocid, platonin, plaunotol, PLD-118, PLD-147, pleconaril, plicamycin, p-methyl diphenhydramine, PMS-601, Pneumococcal, PNU- 288034, podophyllotoxin, polaprezinc, poldine methylsulfate, policresulen, polidexide, polidocanol, poliovirus vaccine, poly-ADPRT inhibitors, polyestradiol, polyphenon E, polythiazide, porfimer, posaconazole, posatirelin, potassium, potassium, potassium, potassium chloride, potassium gluconate, potassium p-aminobenzoate, povidone, povidone-iodine, PP-117, PR-2699, PR-608, practolol, prajmaline, pralidoxime, pralnacasan, pramipexole, pramiracetam, pramiverin, pramlintide, pramoxine, pranidipine, pranlukast, pranoprofen, prasterone, pratosartan, pravastatin, prazepam, praziquantel, prazosin, prednicarbate, prednimustine, prednisolone, prednisolone 21- diethylaminoacetate, prednisolone famesil, prednisolone sodium, prednisone, prednival, prednylidene, pregabalin, pregnan-3a-ol-20-one, premarin + trimegestone, prenalterol, prenoxdiazine, prenylamine, prezatide, pridinol, prifmium, prilocaine, primaquine, primidone, prinomastat, PRO-2000, probenecid, probucol, procainamide, procaine, procarbazine, procaterol, prochlorperazine, procodazol, procyclidine, procymate, prodipine, proflavine, progabide, progesterone, proglumetacin, proglumide, proheptazine, prolactin, prolintane, prolonium, promazine, promedol, promegestone, promestriene, promethazine, pronethalol, propacetamol, propafenone, propagermanium, propallylonal, propamidine, propane- 1,2-diol, propanidid, propantheline, proparacaine, propatyl, propenidazole, propentofylline, propicillin, propiomazine, propionic acid, propionyl 1- carnitine, propipocaine, propiram, propiverine, propizepine, propofol, propoxycaine, propoxyphene, propranolol, propylhexedrine, propyliodone, propylthiouracil, propyphenazone, proquazone, proscillaridin, prostacyclin, prostaglandin El, prostaglandin E2, prostaglandin F2a, prosultiamine, protein C, protheobromine, prothipendyl, protiofate, protionamide, protizinic acid, protoanemonin, protoklol, protoporphyrin IX, protriptyline, pro-urokinase, proxazole, proxetil, proxibarbal, proxigermanium, proxyphylline, prozapine, prucalopride, prulifloxacin, pseudococaine, pseudoephedrine, pseudoephedrine, pseudoephedrine + triprolidine, psilocybin, PSK-3841, p-sulfanilyl- benzylamine, PT-141, pteropterin, puromycin, PX-12, pyrantel, pyrazinamide, pyridinol carbamate, pyridostigmine, pyridoxal 5 -phosphate, pyridoxine, pyrilamine, pyrimethamine, pyrinoline, pyrisuccideanol, pyrithione, pyrithyldione, pyritinol, pyrocatechol, pyrogallol, pyronaridine, pyrophosphate, pyrovalerone, pyroxylin, pyrrobutamine, pyrrocaine, pyrrolntrin, pyrvinium pamoate, quazepam, quercetin, quetiapine, quinacillin, quinacrine, quinagolide, quinapril, quinaprilat, quinapyramine, quinbolone, quinestradiol, quinestrol, quinethazone, quinfamide, quinidine, quinine, quinocide, quinupramine, quinupristin, R-107500, R-667, rabeprazole, racecadotril, racemethorphan, raloxifene, raltitrexed, ramatroban, ramifenazone, ramipril, ramosetron, Ramot project No. 1097, ranimustine, ranitidine, ranitidine bismuth, ranolazine, ranpirnase, rapacuronium, rasagiline, raubasine, ravuconazole, raxofelast, razoxane, RC- 529, rebamipide, rebimastat, rebox etime, remacemide, remifentanil, reminetant, remoxipride, renzapride, repaglinide, repertaxin L-lysine salt, repinotan, repirinast, reposal, reproterol, rescimetol, rescinnamine, reserpiline, reserpine, resibufogenin, resiquimod, resorcinol, reteplase, retigabine, retinoic acid, revimid, R-flurbiprofen, rho (D) immune, rho-kinase inhibitors, ribavirin, riboflavin, ribostamycin, ricinoleic acid, ridogrel, rifabutin, rifalazil, rifametane, rifamide, rifampicin + trimethoprim, rifampin, rifamycin SV, rifapentine, rifaximin, rifaximine cream, rilmazafone, rilmenidine, riluzole, rimantadine, rimazolium, rimexolone, rimiterol, rimonabant, riodoxol, rioprostil, risedronate, risedronic acid, risperidone, ritanserin, ritipenem, ritodrine, ritonavir, rituximab, rivastigmine, rizatriptan, RJR- 2403, RNA Stealth, Ro-0094889, Ro-61-1790, rociverine, rocuronium, rofecoxib, roflumilast, rokitamycin, rolipram, rolitetracycline, romurtide, ronifibrate, ropinirole, ropivacaine, roquinimex, rosaprostol, rosaramicin, rose bengal, rosiglitazone, rosoxacin, rostaporfm, rosuvastatin, rotigotine, rotraxate, roxarsone, roxatidine, roxifiban, roxindol, roxithromycin, RPR-109881A, RPR- 130401, R- roscovitine, RS-0406, RSR-13, rubijervine, rubitecan, ruboxistaurin, rufmamide, rufloxacin, rupatadine, rutin, RWJ-54428, S-0139, S-15535, S-18886, S-34730, S-3578, S- 36496, S- 36527, S-5751, S-8510, S-8921, sabcomeline, sabeluzole, S- adenosylmethionine, safmamide, salacetamide, salazosulfadimidine, salbutamol, salicin, salicyl alcohol, salicylamide, salicylamide O- acetic acid, salicylanilide, salicylic acid, sal icylsilfuric acid, salinazid, salmeterol, salsalate, salverine, samarium 153Sm, sampatrilat, sancycline, saperconazole, sapropterin, saquinavir, saralasin, saredutant, saredutant, sarizotan, sarizotan, sarpogrelate, sarpogrelate, satigrel, satigrel, satraplatin, satraplatin, satumomab, satumomab, SB-237376, SB-237376, SB-238039, SB-238039, SB-277011, SB-277011, scarlet red, SCH-00013, SCH-00013, Sch-23863, Sch-23863, Sch-57790, Sch- 63390, scillarenin, scopolamine, scopolamine, scopolamine N-oxide, SCS technology, secalciferol, secnidazole, secobarbital, selegiline, selenomethionine, sematilide, semotiadil, seocalcitol, sepimostat, seratrodast, sertaconazole, sertaconazole, sertindole, sertindole, sertraline, sertraline, sestamibi, setastine, setastine, sevelamer, sevelamer, sevoflurane, sevoflurane, SG-210, sibutramine, siccanin, sildenafil, silodosin, silprostone, silver lactate, silver picrate, silver sulfadiazine, simetride, simfibrate, simvastatin, sincalide, sintropium bromide, sisomicin, sitafloxacin, sitamaquine, sitaxsentan, sivelestat, SJA-6017, SL-65-1498, SLV-306, SLV-308, Sml53 lexidronam, S-methylmethionine, SMP-300, SN-38, SNAP-7941, SOA-132, soblidotin, sobrerol, sobuzoxane, sodium arsanilate, sodium arsphenamine, sodium chloride, sodium dibunate, sodium folate, sodium formaldehydesulfoxylate, sodium hyaluronate, sodium iodomethamate, sodium nitrite, sodium nitroprusside, sodium oxybate, sodium phenol -sulfonate, sodium phenylbutyrate, sodium phosphate, sodium prasterone sulfate, sodium propionate, sodium salicylate, sodium tetradecyl sulfate, sofalcone, solasulfone, solifenacin, sorbinicate, sorbitol, sorivudine, sotalol, soterenol, sozoiodolic acid, spaglumic acid, sparfloxacin, sparteine, SPA-S-843, spasmolytol, SPD- 754, spectinomycin, SPI-339, spiperone, spirapril, spirogermanium, spironolactone, SR- 121463, SR- 144190, SR-146131, SR-271425, SR-27897, SR-31747, SR-58611, SS732, SS-750, SSR-149415, SSR- 180575, SSR-181507, SSR-591813, SST-101, SSY-726, ST-200, stachyfilin, stallimycin, stampidine, stannous, stannsoporfm, stanolone, stanozolol, staph aureus ther, STAT4 inhibitors, stavudine, stenbolone, stepronim, stibocaptate, stibophen, stilbamidine, stiripentol, streptodomase, streptomycin, streptonicozid, streptonigrin, streptozocin, strontium ranelate, strontium-89 chloride, succimer, succinimide, succinyl choline, succinylcholine, succinylsulfathiazole, succisulfone, suclofenide, sucralfate, sufentanil, sulbactam, sulbactam + ampicillin, sulbenicillin, sulbentine, sulbutiamine, sulconazole, suleptanate, sulesomab, sulfabenzamide, sulfacetamide, sulfachlorpyridazine, sulfachrysoidine, sulfacytine, sulfadiazine, sulfadicramide, sulfadimethoxine, sulfadoxine, sulfaethidole, sulfaguanidine, sulfaguanole, sulfalene, sulfaloxic acid, sulfamerazine, sulfameter, sulfamethazine, sulfamethizole, sulfamethomidine, sulfamethoxazole, sulfamethoxypyrazine, sulfamethoxypyridazine, sulfametrole, sulfamidochrysoidine, sulfamoxole, sulfanilamide, sulfanilic acid, sulfanilylurea, sulfaperine, sulfaphenazole, sulfaproxyline, sulfapyrazine, sulfapyridine, sulfarside, sulfarsphenamine, sulfasalazine, sulfasomizole, sulfasymazine, sulfathiazole, sulfathiourea, sulfmalol, sulfinpyrazone, sulfiram, sulfisomidine, sulfisoxazole, sulfobromophthalein, sulfonethylmethane, sulfoniazide, sulfonic acid, sulfonmethane, sulforidazine, sulfoxone, sulindac, sulisatin, sulisobenzone, sulmarin, sulmazole, suloctidil, sulphan blue, sulpiride, sultamicillin, sulthiame, suitopride, sultosilic acid, sumanirole, sumatriptan, SUN-N8075, suplatast, suprofen, suramin, surfactant TA, suriclone, suxibuzone, SYM- 1010, SYM-2081, SYM- 2207, symclosene, Syn-1253, Syn-2190, Syn-2869, synephrine, syrosingopine, T-1095, T- 1249, T-3912, T-588, T-67, T-82, TA-2005, TA-2005, TA-993, tabimorelin, tacalcitol, tacedinaline, tacrine, tacrolimus, tadalafil, tafenoquine, tafluposide, TAK-375, TAK-427, TAK-559, taka-diastase, talampanel, talampicill in, talaporfm, talastine, talbutal, talinolol, talipexole, talnetant, talniflumate, taltirelin, tamoxifen, tamsulosin, tandospirone, tannoform, taprostene, tariquidar, TAS-103, tasosartan, taurocholic acid, taurolidine, tazanolast, tazarotene, tazobactam, tazobactam + piperacillin, TBC-3711, TCH-346, tebipenem, teboroxime, tecadenoson, tecastemizole, Technetium "Tc, teclothi azide, teclozan, tedisamil, teflurane, tegafur, tegafur + uracil, tegaserod, teicoplanin, telbivudine, telenzepine, telithromycin, telmesteine, telmisartan, telomerase inhibs, temazepam, temiverine, temocapril, temocillin, temoporfm, temozolomide, tenatoprazole, tenecteplase, tenidap, teniposide, tenofovir, tenofovir disoproxil, tenonitrozole, tenoxicam, tenuazonic acid, teprenone, terazosin, terbinafme, terbutaline, terconazole, terfenadine, terguride, terlipressin, terodiline, terofenamate, terpin, tertalolol, tert-pentyl alcohol, tesaglitazar, tesmilifene, testolactone, testosterone, tetrabamate, tetrabarbital, tetrabenazine, tetracaine, tetrachloroethylene, tetracine, tetracycline, tetrahydrozoline, tetrandrine, tetrantoin, tetrazepam, tetrofosmin, tetroxoprim, Tevenel®, tezacitabine, tezosentan, thalidomide, thenaldine, thenyldiamine, theobromine, theofibrate, theophylline, thiabendazole, thiacetazone, thiacymserine, thialbarbital, thiamine, thiamiprine, thiamphenicol, thiamylal, thiazesim, thiazinamium, thiazolinobutazone, thiazolsulfone, thibenzazoline, thiemalat, thiethylperazine, thimerfonate, thimerosal, thiobarbital, thiobutabarbital, thiocarbamizine, thiocarbarsone, thiocolchicine, thiocresol, thioctic acid, thioglycerol, thioguanine, thioimrag, thiopental, thiophosphoramide, thiopropazate, thioproperazine, thioridazine, thiosulfate, thiothixene, thiovir, thiphenamil, thiram, thonzylamine, thozalinone, thromboplastin, thurfyl nicotinate, thymectacin, thymol, thymopentin, thymyl N- isoamylcarbamate, thyropropic acid, thyroxine, tiadenol, tiagabine, tiamenidine, tianeptine, tiapride, tiaprofenic acid, tiaramide, tiazofurin, tibezonium, tibolone, ticarcillin, ticlopidine, ticrynafen, tiemonium, tigecycline, tigemonam, tigloidine, tilidine, til isolol, tilmacoxib, tiludronic acid, timentin, timepidium, timiperone, timolol, timonacic, tin ethyl etiopurpurin, tinazoline, tinidazole, tinoridine, tiocarlide, tioclomarol, tioconazole, tiopronin, tiotropium, tioxolone, tipepidine, tipifarnib, tipranavir, tiquizium, tirapazamine, tiratricol, tirilazad, tirofiban, tiropramide, titanium sulfate, tiuxetan, tixocortol, tizanidine, TLK-199, TLK-286, TNF-b analogue, TNP-470, TO-186, tobramycin, tocainide, tocamphyl, tocladesine, tocoretinate, todralazine, tofenacin, tofimilast, tofisopam, tolazamid, tolazolin, tolbutamide, tolcapone, tolciclate, tolcyclamide, tolevamer, tolfenamic acid, tolindate, toliprolol, tolmetin, tolnaftate, tolonidine, tolonium, toloxatone, tolperisone, tolpropamine, tolrestat, tol serine, tolterodine, tolvaptan, tolycaine, topiramate, topoisomerase, topotecan, torasemide, torcetapib, torcitabine, toremifene, torsemide, tositumomab, tosulfloxacin, tramadol, tramazoline, trandolapril, tranexamic acid, tranilast, trans-retinoic acid, tranylcypromine, trapidil, trastuzumab, travoprost, traxanox, traxoprodil, trazodone, tremacamra, trenbolone, trengestone, treosulfan, trepibutone, treprostinol, tretinoin, tretoquinol, TRH, TRI-50b, triacetin, triamcinolone, triamcinolone, triamcinolone, triamcinolone acetonide, triamterene, triapine, triaziquone, triazolam, tribenoside, tribromophenate, trichlorfon, tri chi ormethi azide, trichlormethine, trichloroethylene, triclobisonium, triclocarban, triclofenol piperazine, triclofos, triclosan, tricromyl, tridihexethyl iodide, trientine, triethanolamine, triethylenemelamine, trifluoperazine, trifluperidol, triflupromazine, trifluridine, triflusal, triflutate, trihexyphenidyl, trimazosin, trimebutine, trimecaine, trimeprazine, trimetazidine, trimethadione, trimethaphan, trimethobenzamide, trimethoprim, trimetozine, trimetrexate, trimipramine, trimoprostil, triolstane, trioxsalen, tripamide, triparanol, tripelennamine, triprolidine, triptorelin, tritiozine, tritoqualine, TRK-530, TRK-820, troclosene, trofosfamide, troglitazone, troleandomycin, trolnitrate, tromantadine, trometamol, trometamol, tromethamine, tromethamine, tropacine, tropesin, tropicamide, tropine, tropisetron, trospectomycin, trospium, trovafloxacin, troxacitabine, troxerutin, troxipide, trypan red, tryparsamide, tryptophan, TSH, TSN-09, TU-2100, tuaminoheptane, tubercidin, tubocurarine chloride, tulobuterol, TV-3326, TY-11223, TY-12533, TYB- 3215, tybamate, tyloxapol, tymazoline, tyramine, tyropanoate, ubenimex, ufenamate, undecylenic acid, unoprostone, UR-8880, uracil mustard, uralyt-U, urapidil, urea, uredepa, urethan, uridine 5 '-triphosphate, urinastatin, ursodeoxycholic acid, ursodiol, ushercell, uzarin, vaccine, Diphtheria Vaccine, Polyvalent Vaccine, valacyclovir, valdecoxib, valdetamide, valethamate, valganciclovir, valnoctamide, valomaciclovir, valproate, valproic acid, valpromide, valrocemide, valrubicin, valsartan, valspodar, vardenafil, varespladib, varicella virus, vatanidipine, VEA, vecuronium, velnacrine, venlafaxine, veralipride, verapamil, verteporfm, vesnarinone, vetrabutine, VF-233, VI-0134, vidarabine, vigabatrin, vilazodone, viloxazine, viminol, vinbarbital, vinblastine, vinburnine, vincamine, vinconate, vincristine, vindesine, vinflunine, vinorelbine, vinpocetine, vinyl ether, vinylbital, viquidil, viridin, visnadine, vitamin A, vitamin B12, vitamin C, vitamin D2, vitamin D3, vitamin K5, prenatal vitamins, VLA-4 antagonists, VNP-4010M, voglibose, voriconazole, vorozole, VTJF-K-8788, warfarin, WF-10, WMC-79, wound healing matrix, WP-170, xaliproden, xamoterol, xanomeline, xanthinol niacinate, xemilofiban, xenbucin, xibenolol, xibomol, ximelagatran, ximoprofen, xipamide, xorphanol, XR- 5118, XR-5944, xylometazoline, xylose, YH-1885, YM-511, YM-598, yohimbine, YT-146, Z-321, Z- 335, zafirlukast, zalcitabine, zaldaride, zaleplon, zaltoprofen, zanamivir, zanapezil, zatebradine, ZD- 0473, ZD-0947, ZD-6126, ZD-9331, zebularine, zelandopam, zenarestat, ziconotide, zidovudine, zileuton, zimeldine, zinc acetate, zinc acexamate, zinc ibuprofenate, zinc p-phenolsulfonate, zinc salicylate, zinostatin, zinostatin stimalamer, zipeprol, ziprasidone, zofenopril, zofenpril + HCTZ, zoledronic acid, zolimidine, zolmitriptan, zolpidem, zomepirac, zonampanel, zoniporide, zonisamide, zopiclone, zopolrestat, zorubicin, zosuquidar, zotepine, ZP-123, Z-tamoxifen, zuclopenthixol, al-antitrypsin, a-bisabolol, a-chloralose, a-ethylbenzyl alcohol, a-glucose-1 - phosphate, a-phenylbutyramide, a-santonin, a-terpineol, a-tocopherol, b-alethine, b- benzalbutyramide, b-carotene, b-eucaine, b-propiolactone, b-sitosterol, g- aminobutyric acid, g- hydroxybutyrate, g-linolenic acid, d-aminolevulinic acid, e- acetamidocaproic, and e-aminocaproic acid.
In a further aspect, the present invention provides a pharmaceutical composition comprising the solid dispersion according to the present invention and at least one pharmaceutically acceptable excipient. Preferably, the pharmaceutical composition is an oral dosage form, and more specifically a solid dosage form, such as a tablet, capsule, sachet, pellet, beadlet, granule, or granulate.
According to some embodiments, the pharmaceutical composition is a tablet.
In the context of the present invention, a "pharmaceutically acceptable excipient" is intended to denote any material, which is inert in the sense that it substantially does not have any therapeutic and/or prophylactic effect per se. A pharmaceutically acceptable excipient may be added to the solid dispersion or pharmaceutical composite with the purpose of making it possible to obtain a solid dispersion or pharmaceutical composition having acceptable technical properties.
Suitable pharmaceutically acceptable excipients are well-known to the skilled person and have been described in the literature, such as in Remington's Pharmaceutical Sciences, the Handbook of Pharmaceutical Additives or the Handbook of Pharmaceutical Excipients. Non-limiting examples of suitable pharmaceutically acceptable excipients include diluents, fillers, binding agents, disintegrating agents, lubricants, fluidizers, granulating agents, coating materials, wetting agents, solvents, co-solvents, suspending agents, emulsifying agents, sweetening agents, flavoring agents, odor masking agents, coloring agents, anti-caking agents, chelating agents, plasticisers, viscosifiers, antioxidants, antiseptics, stabilizing agents, surfactants and buffer agents.
Processes of the present invention
The present invention is generally based on the co-processing of a mesoporous silicon dioxide and a water-soluble or hydrophilic binder, resulting in particulate material having superior functionalities. The process for preparing a particulate material of the present invention generally involves the granulation of a blend of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder.
Granulation has been employed within the pharmaceutical industry for decades. An essential manufacturing process which is used to form aggregated granules from a powder, it enhances the properties of a drug through material densification and is widely used as an intermediate process within Solid Dosage manufacturing.
There are various methods through which granulation can be achieved. Wet granulation methods offer greater scalability than dry granulation, alongside enhanced reproducibility and significant cost-savings. Various wet granulation methods exist, including steam granulation, which uses steam as the binding agent, and freeze granulation, a process which involves spray-freezing and subsequent freeze-drying. Fluid bed granulation is however the most popular technique.
Wet granulation involves four key mechanisms or rate processes that take place simultaneously and continuously inside the granulator. These are wetting (also referred to as nucleation), growth, consolidation and breakage. The interaction between these different mechanisms determines the final size distribution of the granulated product, in addition to controlling important attributes such as density and porosity.
During fluid bed granulation, high velocity air is used to suspend powdered material within a fluid bed granulator. This specialized, multi-purpose piece of equipment is capable of mixing, granulating and drying, obviating the requirement to use separate instrumentation for each stage of the process. Designed to introduce the air stream into the bed from below, the fluid bed granulator expands the bed upwards to provide high heat and mass transfer surface area. This process can also be microwave-assisted to provide much faster drying rates and lower operating temperatures.
Next, a binder is sprayed on to the powder, causing the particles to stick together and form granules. This occurs via a stage-wise process of moistening and solidifying to give rise to agglomerates. A wide variety of binders can be employed, including aqueous or organic solvents, as well as dissolved polymeric materials. The granules are subsequently dried using hot air. Since the temperature of the air flow can be tightly regulated, fluid bed granulation is highly suitable for granulation of heat-sensitive materials.
Another popular technique for granulating is melt granulation. Melt granulation is the process of combining the material of interest with a binder which melts at a relatively low temperature (50- 90°C). Upon cooling, the material solidifies to form granules. Melt granulation is a technique by which pharmaceutical powders are efficiently agglomerated by a meltable binder. The advantage of this technique compared to wet granulation is that no water or organic solvents is needed. Because there is no drying step, the process is less time consuming and uses less energy than wet granulation.
Generally, granulation may be carried out in a high shear mixer or any other type of granulator such as fluid bed or roller compactor and, depending on the technique used, involves subsequent drying when needed.
Another granulation technique is extrusion granulation, such as melt extrusion, using e.g., a Twin screw extruder. Thus, according to another aspect, the present invention provides a process for producing the particulate material according to the present invention, the process comprising granulation of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder.
According to some embodiments, the process comprises wet granulation of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder.
According to some embodiments, the wet granulation comprises applying, e.g., spraying an aqueous or organic solvent (or a mixture of an aqueous solvent and an organic solvent) onto a mixture of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder.
According to some embodiments, the wet granulation comprises applying, e.g., spraying onto the mesoporous silicon dioxide a granulation liquid comprising the water-soluble or hydrophilic binder and an aqueous or organic solvent (or a mixture of an aqueous solvent and an organic solvent).
A non-limiting example of an aqueous solvent is water.
Non-limiting examples of an organic solvent include Acetic acid Acetone, Anisole, 1-Butanol, 2- Butanol, Butyl acetate, tert-Butylmethyl ether, Cumene, Dimethyl sulfoxide, Ethanol, Ethyl acetate, Ethyl ether, Ethyl formate, Formic acid, Heptane, Isobutyl acetate, Isopropyl acetate, Methyl acetate, 3-Methyl-l-butanol, Methylethyl ketone, Methylisobutyl ketone, 2-Methyl-l-propanol, Pentane, 1-Pentanol, 1-Propanol, 2-Propanol, Propyl acetate, Tetrahydrofuran, Acetonitrile, Chlorobenzene, Chloroform, Cyclohexane, 1,2-Dichloroethene, Dichloromethane, 1,2- Dimethoxyethane, N,N-Dimethylacetamide, N,N-Dimethylformamide, 1,4-Dioxane, 2- Ethoxyethanol, Ethyleneglycol, Formamide, Hexane, Methanol, 2-Methoxyethanol, Methylbutyl ketone, Methylcyclohexane, N-Methylpyrrolidone, Nitromethane, Pyridine, Sulfolane, Tetralin, Toluene, 1,1,2-Trichloroethene, and Xylene.
According to some embodiments, the process further comprises drying the obtained particulate material.
According to some embodiments, the process comprises melt granulation of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder.
As noted above, the wet or melt granulation can be carried out in a high shear mixer or any other type of granulator such as fluid bed or roller compactor.
Thus, according to some embodiments, the wet or melt granulation is fluid bed granulation or high shear granulation. According to some embodiments, the wet or melt granulation involves the use of a fluid bed apparatus.
According to some embodiments, the wet or melt granulation involves the use of a high shear mixer.
According to some embodiments, the process comprises extrusion granulation of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder.
According to some embodiments, the process comprises extrusion granulation of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder using melt extrusion.
According to some embodiments, the extrusion granulation involves the use of a twin screw extruder.
In case of melt granulation and extrusion granulation, the water-soluble or hydrophilic binder is ideally a meltable binder. A meltable binder may for example by any one of the polymeric substances mentioned above, notably hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copovidone, polyethylene glycol or polyethylene oxid, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, poly(ethylene glycol)-block-poly(propylene glycol)- block-poly(ethylene glycol), poly(lactic-co-glycolic acid), and polylactic acid.
Once obtained, the particulate material may further be processed to form, e.g., solid dispersions.
Thus, according to another aspect, the present invention provides a process for producing a solid dispersion (according to the present invention) comprising admixing the particulate material according to the present invention with at least one active ingredient and optionally at least one pharmaceutically acceptable excipient. For example, the particulate material may be impregnated with the at least one active ingredient.
Methods for preparation of solid dispersion are well-known and can be divided into three categories: solvent evaporation methods, elevated temperature or melting methods, and mechanical methods (Vo CL, Park C, Lee BJ. Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs. European Journal of Pharmaceutics and Biopharmaceutics. 2013, volume 85, issue 3, pages 799-813; and Tran P, Pyo YC, Kim DH, Lee SE, Kim JK, Park JS. Overview of the Manufacturing Methods of Solid Dispersion Technology for Improving the Solubility of Poorly Water-Soluble Drugs and Application to Anticancer Drugs. Pharmaceutics. 2019, volume 11, isue 3 pages 132-158). There is also a combination of the first two methods.
The present invention provides in a further aspect a process for producing a pharmaceutical composition (according to the present invention) comprising admixing the solid dispersion according to the present invention with at least one pharmaceutically acceptable excipient.
In a more specific aspect, the present invention provides in a process for producing a tablet (according to the present invention) comprising admixing the solid dispersion according to the present invention with at least one pharmaceutically acceptable excipient, and compressing said resulting mixture into a tablet.
The present invention provides in a further aspect the use of a particulate material according to the present invention as excipient or carrier in the preparation of a pharmaceutical composition.
Certain definitions
As used herein, the term "about" means plus or minus 10% of the numerical value of the number with which it is being used. Where a numerical limit or range is stated herein, the endpoints are included. Also, all values and sub-ranges within a numerical limit or range are specifically included as if explicitly written out.
As used herein, the indefinite articles "a" and "an" mean "at least one" or "one or more" unless the context clearly dictates otherwise.
As used herein, the terms "comprising", "including", "having" and grammatical variants thereof are to be taken as specifying the stated features, steps, or components but do not preclude the addition of one or more additional features, steps, components or groups thereof. The use of "comprising" and "comprises" as used herein is to be understood as also disclosing "consisting essentially of" and "consists essentially of" as well as "consisting of" and "consists of", respectively.
As used herein, the term "consisting essentially of" (and grammatical variants thereof) generally means that additional materials, features, components, elements or steps may be included that do not materially affect the basic and novel characteristic(s) of the claimed invention. For example, when used in the context of the particulate material of the invention, the term means that the particulate material may contain additional features, components or elements in addition to those literally disclosed provided that these additional features, components or elements do not materially affect the basic and novel characteristic(s) of the claimed particle. For example, the particulate material may include additional non-essential elements such as water (e.g., in form of moisture) and/or impurities.
Furthermore, it will be understood by the skilled person that the total amount of all ingredients making out the particulate material will normally add up to 100% of the total weight of the particulate material. In other words, the total amount of all ingredients will not exceed 100% of the total weight of the particulate material.
Where a numerical limit or range is stated herein, the endpoints are included. Also, all values and sub ranges within a numerical limit or range are specifically included as if explicitly written out.
Having generally described this invention, a further understanding can be obtained by reference to certain specific examples, which are provided herein for purposes of illustration only, and are not intended to be limiting unless otherwise specified.
Examples
Example 1
Co-processing
This example illustrates properties of mesoporous silica Syloid 244 FP, binder excipients from the group of sugar alcohols (isomalt erythritol, xylitol, mannitol), two component physical blends and co-processed granules composed of silica and binder in proportion 2:1. Co-processed material was made by granulation in Procept laboratory granulator-Formatrix (vessel volume 1.5 L). 45 g of Syloid 244 FP was blended with 22.5 g of binder for two minutes prior to granulation with pure water. Impeller speed was 100 RPM and chopper speed was 1000 RPM. 109-115 g of water was added during granulation at rate 4.8 g/min. Wet granulate was pushed through 2 millimeter mesh size sieve and dried in a hot air oven at 65 °C for six hours (final moisture content of the co-processed material was below 2% and was determined according to US pharmacopoei USP 29-NF 24 using following conditions: sample mass between 2 and 3 grams, measurement temperature 85 °C, measurement time 15 minutes-BUCHI Moisture analyzer B-302).
Particle evaluation Excipient, binder and co-processed particles obtained with sieving with sizes between 180 micrometers and 500 micrometers were used for evaluation for specific surface area measurement (multipoint BET - Brunauer-Emmett-Teller apparatus 3P Nova 2000e), Hausner ratio (according to Ph. Eur. 2.9.34 BULK DENSITY AND TAPPED DENSITY OF POWDERS Method 1 using Micromeritics tap density tester after 1250 taps -powder was filled into 100 ml measuring cylinder), and particle size analysis with laser diffraction (dry measuring unit Malvern Mastersizer 3000, p=1.2 bar, 3 measurements).
For physical blends of mesoporous silica with sugar alcohol physical bends 270 mg of powder was compressed using 12 mm flat punch and dye accessory. Due to high bulk volume this was the maximal mass to obtain tablet. Physical blends were compressed in tablet press at various compression forces. When a tablet was formed, tablet hardness was measured with tablet hardness tester according to USP Pharmacopoeia.
For compression testing of co-processed particles 400 mg of powder was compressed. Powders were compressed using Killian 300 tablet press and 12 mm flat punch ant dye accessory which enables measurement of compression force. Tablet hardness of 400 mg tablets compressed at different compression pressures were measured with tablet hardness tester according to USP Pharmacopoeia.
Table 1 lists properties of pure mesoporous silica, binders (sugar alcohols) and co-processed particles.
Table 1: pure mesoporous silica, binders (sugar alcohols) and co-processed particles properties
Figure imgf000050_0001
Figure imgf000051_0001
Co-processed granules give tablets in broad ranges of compression pressures. Figure 1 shows the improved compressibility of the co-processed granules compared to the mere physical blends of the mesoporous silica and binder.
Example 2
Co-processing
This example illustrates properties of mesoporous silica Syloid 244 FP, binder excipients from the group of sugars (Lactose monohydrate 200 mesh, sucrose and maltodextrin), two component physical blends and co-processed granules composed of silica and binder in proportion 2:1. Coprocessed material was made with granulation in Procept laboratory granulator-Formatrix (vessel volume 1.5 L). 45 g of Syloid 244 FP was blended with 22.5 g of binder for two minutes prior to granulation with pure water. Impeller speed was 100 RPM and chopper speed was 1000 RPM. 109- 115 g of water was added during granulation at rate 4.8 g/min. Wet granulate was pushed through 2 milimeter mesh size sieve and dried in an hot air oven at 65 °C for six hours (final moisture content of the co-processed material was below 2% and was determined according to US pharmacopoei USP 29-NF 24 using following conditions: sample mass between 2 and 3 grams, measurement temperature 85 °C, measurement time 15 minutes-BUCHI Moisture analyzer B-302.
Particles evaluation
Excipient, binder and co-processed particles obtained with sieving with sizes between 180 micrometers and 500 micrometers were used for evaluation for specific surface area measurement (multipoint BET - Brunauer-Emmett-Teller apparatus 3P Nova 2000e), Hausner ratio (according to Ph. Eur. 2.9.34 BULK DENSITY AND TAPPED DENSITY OF POWDERS Method 1 using Micromeritics tap density tester after 1250 taps -powder was filled into 100 measuring cylinder), and particle size analysis with laser diffraction (dry measuring unit Malvern Mastersizer 3000, P=1.2 bar, 3 measurements). For physical blends of mesoporous silica with sugar alcohol physical bends 270 mg of powder was compressed using 12 mm flat punch and dye accessory. Due to low bulk volume this was the maximal mass to obtain tablet. Physical blends were compressed in tablet press at various compression forces. When a tablet was formed, tablet hardness was measured with tablet hardness tester according to USP Pharmacopoeia.
For compression testing of co-processed particles 400 mg of powder was compressed. Powders were compressed using Killian 300 tablet press and 12 mm flat punch ant dye accessory which enables measurement of compression force. Tablet hardness of 400 mg tablets compressed at different compression pressures were measured with tablet hardness tester according to USP Pharmacopoeia.
Table 2 lists properties of pure mesoporous silica, binders (sugars) and co-processed particles.
Table 2: pure mesoporous silica, binders (sugars) and co-processed particles properties
Figure imgf000052_0001
Co-processed granules give tablets in broad ranges of compression pressures. Figure 2 shows the improved compressibility of the co-processed granules compared to the mere physical blends of the mesoporous silica and binder.
Example 3
Co-processing This example illustrates properties of mesoporous silica Syloid 244 FP, binder excipients from the group of polymers (Kollidon VA64 ( vinylpyrrolidone-vinyl acetate copolymer), Avicel PH101 (microcrystalline cellulose), Kollicoat IR (graft copolymer comprised of polyethylene glycol and polyvinyl alcohol) and Pharmacoat 606 (hydroxypropyl methylcellulose)), two component physical blends and co-processed granules composed of silica and binder in proportion 2:1. Co-processed material was made with granulation in Procept laboratory granulator-Formatrix (vessel volume 1.5 L). 45 g of Syloid 244 FP was blended with 22.5 g of binder for two minutes prior to granulation with pure water. Impeller speed was 100 RPM and chopper speed was 1000 RPM. 109-115 g of water was added during granulation at rate 4.8 g/min. Wet granulate was pushed through 2 milimeter mesh size sieve and dried in hot air oven at 65 °C for six hours (final moisture content of the coprocessed material was below 2% and was determined according to US pharmacopoei USP 29-NF 24 using following conditions: sample mass between 2 and 3 grams, measurement temperature 85 °C, measurement time 15 minutes -BUCHI Moisture analyzer B-302).
Particle evaluation
Excipient, binder and co-processed particles obtained with sieving with sizes between 180 micrometers and 500 micrometers were used for evaluation for specific surface area measurement (multipoint BET Brunauer-Emmett-Teller apparatus 3P Nova 2000e), Hausner ratio (according to Ph. Eur. 2.9.34 BULK DENSITY AND TAPPED DENSITY OF POWDERS Method 1 using Micromeritics tap density tester after 1250 taps -powder was filled into 100 ml measuring cylinder), and particle size analysis with laser diffraction (dry measuring unit Malvern Mastersizer 3000, P=1.2 bar, 3 measurements).
For physical blends of mesoporous silica with sugar alcohol physical bends 270 mg of powder was compressed using 12 mm flat punch and dye accessory. Due to low bulk volume this was the maximal mass to obtain tablet. Physical blends were compressed in tablet press at various compression forces. When a tablet was formed, tablet hardness was measured with tablet hardness tester according to USP Pharmacopoeia.
For compression testing of co-processed particles 400 mg of powder was compressed. Powders were compressed using Killian 300 tablet press and 12 mm flat punch ant dye accessory which enables measurement of compression force. Tablet hardness of 400 mg tablets compressed at different compression pressures were measured with tablet hardness tester according to USP Pharmacopoeia. Table 3 lists properties of pure mesoporous silica, binders (polymers) and co-processed particles.
Table 3: pure mesoporous silica, binders (polymers) and co-processed particles properties
Figure imgf000054_0001
Co-processed granules give tablets in broad ranges of compression pressures. Figure 3 shows the improved compressibility of the co-processed granules compared to the mere physical blends of the mesoporous silica and binder.
Example 4 Co-processing
This example illustrates properties of mesoporous silica Syloid 244 FP, binder excipients from the group of polymers (Polyethylene glycole 4000, Polyethylene oxide 200 000, Polyvinylpyrrolidone- PVP and polyvinylpyrrolidone-PVP K25), two component physical blends and co-processed granules composed of silica and binder in proportion 2:1. Co-processed material was made with granulation in Procept laboratory granulator-Formatrix (vessel volume 1.5L). 45 g of Syloid 244 FP was blended with 22.5 g of binder for two minutes prior to granulation with pure water. Impeller speed was 100 RPM and chopper speed was 1000 RPM. 109-115 g of water was added during granulation at rate 4.8 g/min. Wet granulate was pushed through 2 milimeter mesh size sieve and dried in a hot air oven at 65 °C for six hours (final moisture content of the co-processed material was below 2% and was determined according to US pharmacopoei USP 29-NF 24 using following conditions: sample mass between 2 and 3 grams, measurement temperature 85 °C, measurement time 15 minutes - BUCHI Moisture analyzer B-302.
Particles evaluation
Excipient, binder and co-processed particles obtained with sieving with sizes between 180 micrometers and 500 micrometers were used for evaluation for specific surface area measurement (multipoint BET - Brunauer-Emmett-Teller apparatus 3P Nova 2000e), Hausner ratio (according to Ph. Eur. 2.9.34 BULK DENSITY AND TAPPED DENSITY OF POWDERS Method 1 using Micromeritics tap density tester after 1250 taps -powder was filled into 100 ml measuring cylinder), and particle size analysis with laser diffraction (dry measuring unit Malvern Mastersizer 3000, P=1.2 bar, 3 measurements).
For physical blends of mesoporous silica with sugar alcohol physical bends 270 mg of powder was compressed using 12 mm flat punch and dye accessory. Due to low bulk volume this was the maximal mass to obtain tablet. Physical blends were compressed in tablet press at various compression forces. When a tablet was formed, tablet hardness was measured with tablet hardness tester according to USP Pharmacopoeia.
For compression testing of co-processed particles 400 mg of powder was compressed. Powders were compressed using Killian 300 tablet press and 12 mm flat punch ant dye accessory which enables measurement of compression force. Tablet hardness of 400 mg tablets compressed at different compression pressures were measured with tablet hardness tester according to USP Pharmacopoeia.
Table 4 lists properties of pure mesoporous silica, binders (polymers) and co-processed particles.
Table 4: Pure mesoporous silica, binders (polymers) and co-processed particles
Figure imgf000055_0001
Figure imgf000056_0001
Co-processed granules give tablets in broad ranges of compression pressures. Figure 4 shows the improved compressibility of the co-processed granules compared to the mere physical blends of the mesoporous silica and binder.
Example 5
Bulk density was determined according to European pharmacopoeia (Method 1). 80-100 ml of powder was passed into 100 ml plastic cylinder. Mass was weighted and untapped bulk density was calculated as sample mass divided by sample volume. This sample was then used to measure tapped volume and calculate tapped density. The tapped bulk density is an increased bulk density attained after mechanically tapping a cylinder containing the powder sample. A tapping apparatus capable of producing, per minute, nominally 300 ± 15 taps was used. A tapped bulk density in grams per millilitre was calculated after volume reading using 1250 taps. Hausner ratio was calculated by dividing bulk density with tapped density. Hausner ratio determine in which class is the powder studied as a relation to flowability.
Flow Character Hausner Ratio
Excellent 1.00-1.11
Good 1.12-1.18
Fair 1.19-1.25
Passable 1.26-1.34
Poor 1.35-1.45
Very poor 1.46-1.59 Very, very poor >1.60
Table 5: Bulk density and Hausner ratio of co-processed Syloid 244FP with different binders and physical blends of the same composition in the proportion 2:1
Figure imgf000057_0001

Claims

Claims
1. Particulate material which is a granulate comprising i) about 40% w/w to about 99% w/w of mesoporous silicon dioxide and ii) about 1% w/w to about 60% w/w of a water-soluble or hydrophilic binder, having a bulk density of at least about 0.2 g/cm3, such as from about 0.20 to about 0.35 g/cm3 or 0.20 to about 0.32 g/cm3 (determined according to EU Pharmacopoeia), having a Hausner ratio of about 1.1 to about 1.4, such as of about 1.1 to about 1.3 (determined according to US Pharmacopoeia), and having a mesopore volume of more than 0.3 ml/g, such as more than 0.5 ml/g or more than 0.7 ml/g.
2. Particulate material according to claim 1, consisting essentially of i) about 40% w/w to about 99% w/w of mesoporous silicon dioxide and ii) about 1% w/w to about 60% w/w of a water- soluble or hydrophilic binder.
3. The particulate material according to claim 1 or 2, wherein the mesoporous silicon dioxide is present in a concentration of about 50% to about 90% w/w and the water soluble or hydrophilic binder is present in a concentration from about 10% w/w to about 50% w/w.
4. The particulate material according to any one of claims 1 to 3 wherein the mesoporous silica has a specific surface area in the range from about 100 m2/g to about 600 m2/g, such as from about 150 m2/g to about 400 m2/g.
5. The particulate material according to any one of claims 1 to 4, wherein the water-soluble or hydrophilic binder is selected from the group consisting of polyols, carbohydrates and polymeric substances.
6. The particulate material according to any one of claims 1 to 5, wherein the water-soluble or hydrophilic binder is a polyol.
7. The particulate material according to claim 6, wherein the polyol is a sugar alcohol.
8. The particulate material according to claim 7, wherein the sugar alcohol is selected from the group consisting of xylitol, sorbitol, mannitol, maltitol, lactitol, erythritol, inositol, isomalt, isomaltulose and mixtures thereof.
9. The particulate material according to claim 8, wherein the sugar alcohol is isomalt.
10. The particulate material according to any one of claims 1 to 5, wherein the water-soluble or hydrophilic binder is a carbohydrate.
57
11. The particulate material according to claim 10, wherein the carbohydrate is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, polysaccharides, and mixtures thereof.
12. The particulate material according to claim 10 or 11, wherein the carbohydrate is selected from the group consisting of sucrose, glucose, fructose, trehalose, galactose, lactose, maltose, mannose, ribose, xylose, arabinose, maltodextrin, dextrin, cyclodextrin and mixtures thereof.
13. The particulate material according to any one of claims 1 to 5, wherein the water-soluble or hydrophilic binder is a polymeric substance.
14. The particulate material according to claim 13, wherein the polymeric substance is selected from the group consisting of cellulose polymers including microcrystalline cellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and carboxymethylcellulose, povidone including polyvinylpyrrolidone (PVP), copovidones, agar, gelatin, gummi arabicum, xanthan gum, chitosan, alginates including sodium alginate and polyetylene glycol alginate, polyethylene glycols, polyethylene oxids, polyvinyl alcohols, copolymers comprised of polyethylene glycol and polyvinyl alcohol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), poly(lactic-co-glycolic acid), polylactic acid, cross-linked polyacrylic acid (Carbopol ), starches and modified starches including potato starch, maize starch, rice starch, cross-linked amylase starch and pre-gelatinised starch, and mixtures thereof.
15. The particulate material according to claim 13, wherein the polymeric substance is a povidone.
16. The particulate material according to claim 13, wherein the polymeric substance is polyvinylpyrrolidone F90 or K25.
17. The particulate material according to any one of claims 1 to 16, having a mean particle size d50 of at least about 50 pm, such as about 80 pm to about 1000 pm, such as of 120 pm to about 800pm or of about 150 pm to about 600 pm (determined by laser diffraction).
18. The particulate material according to any one of claims 1 to 17, which is obtainable by a process as defined in claim 19.
58 Process for producing the particulate material according to any one of claims 1 to 17, the process comprising granulation of the mesoporous silicon dioxide and the water-soluble or hydrophilic binder. Use of a particulate material according to any one of claims 1 to 18 as excipient or carrier in the preparation of a pharmaceutical composition.
59
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3156047A1 (en) * 2015-10-12 2017-04-19 Sandoz Ag Afatinib-containing formulation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3156047A1 (en) * 2015-10-12 2017-04-19 Sandoz Ag Afatinib-containing formulation

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
BAUMGARTNER ANA ET AL: "Application of commercially available mesoporous silica for drug dissolution enhancement in oral drug delivery", EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, ELSEVIER AMSTERDAM, NL, vol. 167, 20 September 2021 (2021-09-20), XP086860596, ISSN: 0928-0987, [retrieved on 20210920], DOI: 10.1016/J.EJPS.2021.106015 *
KEIJI SEKIGUCHINOBORU OBI: "Studies on Absorption of Eutectic Mixture. I. A Comparison of the Behavior of Eutectic Mixture of Sulfathiazole and that of Ordinary Sulfathiazole in Man", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 9, 1961, pages 866 - 872
KT KIM ET AL., SOLID DISPERSIONS AS A DRUG DELIVERY SYSTEM JOURNAL OF PHARMACEUTICAL INVESTIGATION, vol. 41, 2011, pages 125 - 142
PH. EUR.
SHEN SHOU-CANG ET AL: "Preparation and application of monodispersed mesoporous submicron carbon particles as a drug carrier", POWDER TECHNOLOGY, ELSEVIER, BASEL (CH), vol. 261, 18 April 2014 (2014-04-18), pages 241 - 249, XP029024935, ISSN: 0032-5910, DOI: 10.1016/J.POWTEC.2014.04.044 *
TRAN PPYO YCKIM DHLEE SEKIM JKPARK JS: "Overview of the Manufacturing Methods of Solid Dispersion Technology for Improving the Solubility of Poorly Water-Soluble Drugs and Application to Anticancer Drugs", PHARMACEUTICS, vol. 11, 2019, pages 132 - 158
VO CLPARK CLEE BJ: "Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs.", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS., vol. 85, 2013, pages 799 - 813, XP028791016, DOI: 10.1016/j.ejpb.2013.09.007
ZHANG SHIMING ET AL: "Osmotic pump tablets with solid dispersions synergized by hydrophilic polymers and mesoporous silica improve in vitro/in vivo performance of cilostazol", INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER, NL, vol. 588, 13 August 2020 (2020-08-13), XP086272420, ISSN: 0378-5173, [retrieved on 20200813], DOI: 10.1016/J.IJPHARM.2020.119759 *

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