WO1998019708A2 - Procede pour ameliorer la solubilite de composes sensiblement insolubles dans l'eau - Google Patents

Procede pour ameliorer la solubilite de composes sensiblement insolubles dans l'eau Download PDF

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Publication number
WO1998019708A2
WO1998019708A2 PCT/US1997/019831 US9719831W WO9819708A2 WO 1998019708 A2 WO1998019708 A2 WO 1998019708A2 US 9719831 W US9719831 W US 9719831W WO 9819708 A2 WO9819708 A2 WO 9819708A2
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WO
WIPO (PCT)
Prior art keywords
water
solubility
melt
drug
soluble polymer
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Application number
PCT/US1997/019831
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English (en)
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WO1998019708A3 (fr
Inventor
David H. Donabedian
Lawrence Marlin
Elke M. A. Clark
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Union Carbide Chemicals & Plastics Technology Corporation
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Application filed by Union Carbide Chemicals & Plastics Technology Corporation filed Critical Union Carbide Chemicals & Plastics Technology Corporation
Priority to EP97950577A priority Critical patent/EP0891190A2/fr
Publication of WO1998019708A2 publication Critical patent/WO1998019708A2/fr
Publication of WO1998019708A3 publication Critical patent/WO1998019708A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • the present invention generally relates to methods for enhancing the water-solubility of substantially water-insoluble compounds by combining such compounds with certain water-soluble polymers.
  • PEG polyethylene glycol
  • PEG polyethylene glycol
  • Polyvinyl pyrrolidone Kollidon® Polyvinylpyrrolidone for the Pharmaceutical Industry, Volker Buhler, BASF, Ludwigshafen, 88, 1993
  • cyclodextrin El Banna et al. Pharmazie 30, 788, 1985.
  • These materials often have relatively low molecular weights, e.g., less than about 80,000 grams per gram mole and can have insufficient effectiveness in acidic environments, e.g., pH of less than about 5.
  • compositions having such enhanced solubility are desired which can be delivered from both solid and liquid forms.
  • improved methods for enhancing the water solubility of substantially water-insoluble compounds involve combining the substantially water-insoluble compounds with an effective amount of a water-soluble polymer having a weight average molecular weight from about 50,000 to about 7,000,000 grams/gram mole in an amount effective to enhance the water solubility of compound in an acidic environment, e.g., less than a pH of about 5.
  • the present invention it is now possible to enhance the water solubility of such substantially water-insoluble compounds by at least about 10 percent and up to about 500 percent or more.
  • substantially water-insoluble drugs such as, for example, ibuprofen or tolbutamide
  • the amount of ibuprofen or tolbutamide necessary to treat a patient can be reduced while still providing an effective amount of the drug to treat the condition.
  • the release profile of the compound in solution can be adjusted to the desired rate.
  • compositions comprising the substantially water-insoluble compounds in combination with the water-soluble polymers are also provided by the present invention.
  • substantially water-insoluble compounds suitable for use in accordance with the present invention are not critical. Typically, such compounds will have a water solubility of less than 1,000 parts per million by weight (“ppmw”) and preferably less than about 600 ppmw.
  • Typical water-insoluble compounds include for example, drugs, i.e., compounds which have a medicinal, pharmaceutical, therapeutic or diagnostic effect on mammals as well as other compounds, such as, for example, antimicrobials, biocides, inks, colorants, preservatives, additives and the like.
  • drugs which may be utilized in the methods and compositions of the present invention, include for example, abortifacients, hypnotics, sedatives, tranquilizers, anti-inflammatory agents, antihistamines, anti-tussives, anti-convulsants, muscle relaxants, anti-tumor agents; for example those of the treatment of malignant neoplasia, local anaesthetics, anti-par kinson agents, topical or dermatological agents, diuretics, for example those containing potassium, such as potassium iodide preparations, for example those of the treatment of mental illness, for example preparations containing lithium for use in the treatment of manic depression, anti-spasmodics, anti-ulcer agents, preparation containing various substances for the treatment of infection by pathogens including anti-fungal agents, for example metronidazole, anti-parasitic agents and other antimicrobials, antibiotic agents, antibacterial agents, antiseptic agents, anti- malarials, cardiovascular agents preparations containing hormones,
  • Preferred drugs suitable for use in accordance with the present invention are selected from the group consisting of ibuprofen, tolbutamide, sulfathiazole, and hydroflumethazide, and mixtures thereof.
  • the water-soluble polymers suitable for use in accordance with the present invention have a water-solubility (as defined above) of at least about 1.0 weight, and preferably at least about 2.0 weight percent.
  • the water-soluble polymers have a molecular weight of from about 50,000 to 7,000,000, preferably from about 80,000 to 4,000,000, more preferably from about 100,000 to 750,000 grams/gram mole.
  • molecular weight refers to weight average molecular weight. Methods for determining the weight average molecular weight are known to those skilled in the art, and include for example, the method known as low angle light scattering.
  • the average particle size of the water-soluble polymers is not critical to the present invention, but is typically from about 0.01 microns to 1000 microns and preferably from about 50 microns to 150 microns.
  • the water-soluble polymers have alkylene oxide functionality. More preferably, the alkylene oxide is selected from the group consisting of ethylene oxide, propylene oxide and mixtures thereof. Especially preferred polymers include polyalkylene oxides and alkoxylated polysaccharides.
  • Polyalkylene oxide polymers typically having from about 2 to about 4 carbon atoms per monomeric molecule polymers may be used in accordance with the present invention. Ethylene oxide and propylene oxide monomers are preferred. Polyethylene oxide polymers are especially preferred for use in accordance with the present invention.
  • the polyethylene oxide polymers include, for example, homopolymers of ethylene oxide and copolymers of ethylene oxide with one or more polymerizable olefin oxide comonomers.
  • the particular comonomer, when used in accordance with the present invention, is not critical and may contain hydrocarbon substituents such as alkyl, cycloalkyl, aromatic, alkene and branched alkyl groups.
  • comonomer e.g., 1,2-propylene oxide
  • Typical olefin oxide comonomers include 1,2-propylene oxide, 2,3-butylene oxide, 1,2-butylene oxide, styrene oxide, 2,3-epoxy hexane, 1,2-epoxy octane, butadiene monomside, cyclohexene monoxide, epichlorohydrin, and the like.
  • Polyalkylene oxides such as for example polyethylene oxide, suitable for use in accordance with the present invention are available from Union Carbide Corporation, Danbury, CT. Further details concerning the polyalkylene oxide polymers suitable for use in accordance with the present invention are known to those skilled in the art.
  • Alkoxylated polysaccharides also referred to as polysaccharide ethers, are suitable for use in accordance with the present invention.
  • the polysaccharide starting materials suitable for use in accordance with the present invention include naturally occurring, biosynthesized and derivatized carbohydrate polymers or mixtures thereof. Such materials encompass high molecular weight polymers composed of monosaccharide units joined by glycosidic bonds. These materials may include, for example, the entire starch and cellulose families; pectin, chitosan; chitin; the seaweed products such as agar and carrageenan; alginate; the natural gums such as guar, arabic and tragacanth; bio-derived gums such as xanthan; and the like.
  • Preferred starting materials include cellulosics conventionally employed for the preparation of cellulose ethers, such as, for example, chemical cotton, cotton linters, wood pulp, alkali cellulose and the like. Such materials are commercially available.
  • the molecular weight of the polysaccharides suitable for use in accordance with the present invention typically ranges from about 50,000 to 2,000,000 grams per gram mole and preferably ranges from about 80,000 to 250,000 grams per gram mole.
  • the particular derivatizing agent, e.g., alkyl halides or alkylene oxides, used to derivatize the polysaccharides is not critical to the present invention.
  • Suitable alkylene oxides for use in accordance with the present invention comprise from about 2 to 24, preferably from about 2 to 5 carbon atoms per molecule. Examples include ethylene oxide, propylene oxide and butylene oxide.
  • the ether substituent is derivatized onto the cellulose by reacting the polysaccharide with an alkylene oxide, preferably ethylene oxide.
  • the amount of ether substitution is typically from about 1.5 to 6 and preferably from about 2 to 4 moles of ether substituent per mole of polysaccharide ether.
  • Suitable alkyl halides include, for example, ethyl chloride or methyl chloride.
  • the polysaccharide ethers may be substituted with one or more desired substituents, e.g., cationic, anionic and/or hydrophobic substituents.
  • Hydrophobic substituents are known in the art and typically comprise alkyl, alkene, aryl-alkene or aryl-alkyl groups having about 8 to 24 carbon atoms per molecule.
  • Hydrophobically- modified cellulose ethers are described, for example, in U.S. Patent Nos. 4,228,277, 5,120,328 and 5,504,123 and European Patent Publication 0 384 167 BI.
  • Cationic, hydrophobically modified cellulose ethers are described, for example, in U.S. Patent No. 4,663,159.
  • substitution level of each such substituent on the polysaccharide ether is typically from about 0.001 to 0.1 and preferably from about 0.004 to about 0.05 moles of substituent per mole of polysaccharide ether. More than one particular substituent can be substituted onto the polysaccharide ether.
  • the viscosity of the polysaccharide ethers typically ranges from about 1 to 8000 centipoise, preferably from about 100 to 3000 centipoise. Unless otherwise indicated, as used herein the term “viscosity” refers to the viscosity of a 1.0 weight percent aqueous solution of the polymer measured at 25°C with a Brookfield viscometer. Such viscosity measuring techniques are known in the art and are described in ASTM D 2364-89.
  • the average particle size of the polysaccharide ethers is not critical, but is preferably from about 0.01 to 1000 microns and more preferably from about 50 to 400 microns.
  • Preferred polysaccharide ethers produced in accordance with the present invention are cellulose ethers, including for example, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, hydroxyethyl carboxylmethyl cellulose, and derivatives thereof.
  • the amount of the water-soluble polymer effective to enhance the water solubility of the substantially water insoluble compound typically ranges from about 1 to 500, preferably from about 20 to 300 and more preferably from about 50 to 250 grams of polymer per gram of compound. Such concentrations typically correspond to polymer concentrations of from about 0.1 weight percent up to about the solubility limit of the polymer in the aqueous liquid, e.g., 25 weight percent or less. More typically, the concentration of polymer ranges from about 0.1 to 5 weight percent, preferably from about 0.1 to 2 weight percent based on the total weight of the aqueous liquid.
  • the water-soluble polymer can be combined with the compound by physical mixing in a dry state, wet state or by melting the polymer, when a thermoplastic polymer is used either before or during the combination with the compound and melt blending the polymer with the compound. Further details concerning such blending techniques and apparatus suitable therefor are known to those skilled in the art.
  • polymers include for example, those selected from the group consisting of hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, cationic cellulose ethers, polyvinyl pyrrolidone, carboxyvinyl polymer, hydroxypropylmethyl cellulose phthalate, acetate phthalate, methyl meta-acrylate meta-acyrlic acid copolymer, polyvinylacetal dialkylaminoacetate, dimethylaminoalkyl meta-acrylate meta-acrylic acid copolymer, 2-methyl-5-vinylpyridinemethyl acrylate meta-acrylic acid copolymer, citric acid, urea, succinic acid and amino acid.
  • the concentration of polymers other than the water-soluble polymers suitable for use in accordance with the present invention is not critical and typically ranges from about 0.1 to 99 weight percent based on the total weight of water-soluble polymers, the compound and the other polymers. Further details concerning the selection and use of such other polymers are known to those skilled in the art.
  • the amount of water-soluble polymer which is combined with the substantially water-insoluble compound in solution is effective to provide a solubility enhancement of at least 10 percent, preferably at least 20 percent, more preferably at least 30 percent, even more preferably at least about 50 percent, still more preferably at least about 100 percent, even further more preferably at least about 200 percent. More than one water-soluble polymer may be employed.
  • Such solubility enhancements generally correspond to concentrations of soluble compound of at least 100 ppmw, preferably at least 150 ppmw and more preferably at least about 300 ppmw when prepared in aqueous liquid form.
  • compositions of the present invention can be provided as either liquids, solids or combinations thereof. Typical forms can be films, tapes, laminates, gels, tablets, particles, aqueous solutions, dispersions and other pourable liquids.
  • the physical characteristics of the compositions of the present invention will depend on the relative amounts of the polymers and compounds used in the compositions. For example, the concentration of polyalkylene oxide or the water-soluble polymer in a solid composition can range broadly from a very low concentration, e.g., 0.1 weight percent, to a very high concentration of 99 weight percent or more.
  • Liquid compositions especially for alkoxylated polysaccharide polymers will often comprise substantially smaller amounts of polymer often in the range 0.1 to about 5 weight percent.
  • the compositions of the present invention can also provide a sustained release of the compounds in the aqueous liquid. It has been found that when utilizing the water-soluble polymers having certain molecular weight ranges, the characteristics of the release profile can be adjusted as desired.
  • the water-soluble polymers in the molecular weight range of about 900,000 to 7,000,000 for the polyakylene oxide polymers and 500,000 to 1,000,000 for the alkoxylated polysaccharide polymers are preferred.
  • polymers having a molecular weight in the range of from about 100,000 to 600,000 for the polyalkylene oxide polymers are preferred and 100,000 to 400,000 for the alkoxylated polysaccharide polymers are preferred.
  • the methods and compositions of the present invention have a wide variety of end use applications, such as for example, industrial applications and personal care applications.
  • Typical industrial applications include, for example, the solubility enhancement of antimicrobial compounds, biocides, inks and colorants, preservatives, additives and the like.
  • Typical personal care applications include, for example, various pharmaceutical and cosmetic compositions.
  • Typical drug tablets which may be utilized in accordance with the present invention can be made by any technique known to those skilled in the art such as for example, by direct compression, granulation with a suitable solvent followed by compression, melt fabrication and or by fabrication in dosage forms.
  • Such drugs which are deliverable in solid form typically contain the compound, the water-soluble polymer and other known ingredients, including for example, lactose, magnesium or calcium stearate, dicalcium phosphate, mannitol, and microcrystalline cellulose.
  • the alkoxylated polysaccharide polymer compositions may also be delivered as a semi- solid/liquid dosage application such as often used for cold and headache medications.
  • the equipment conditions and techniques for forming such compositions are known to those skilled in the art. Note, for example, U.S. Patent No. 5,273,758, issued December 28, 1993, U.S. Patent No. 4,343,789 issued August 10, 1982, and U.S. Patent No. 5,116,145, issued November 24, 1992.
  • CELLOSIZE HEC WP-09L showed an increase in ibuprofen solubility, on the order of fourfold, for a 2.0% (w/v) solution.
  • HPMC had very little if any effect on increasing the water solubility of ibuprofen relative to CELLOSIZE HEC WP-09L.
  • CELLOSIZE HEC seems to enhance the solubility characteristics of poorly water soluble drugs like ibuprofen and tolbutamide in aqueous mediums with ranging pH profiles.
  • Polyethylene oxide another hydrophilic binder commonly used in the pharmaceutical industry, was investigated to determine if it could enhance the solubility of substantially water-insoluble compounds.
  • This material unlike hydroxyethyl cellulose is thermoplastic, that is, it can be re-melted and re-shaped without loss in molecular weight using conventional melt processing equipment.
  • melt-blends of polyethylene oxide and substantially water- insoluble compounds are described.
  • the melt fused materials obtained from the Brabender were compressed into plaques on a Greenard Press.
  • the plaques had dimensions of 63 mm x 63 mm x 3 mm.
  • the heating cycle for each system regardless of active was as follows: 1 min heat with no pressure at 80 °C, 1 min heat with pressure at 2,000 psi, followed by isothermal cooling to room temperature. Teflon® Release paper was used to separate the material from the top plaque in all cases. From these plaques, tablets were punched out that weighed 3.5 g.
  • EXAMPLE 8 To determine the dissolution profile or rate of drug release over time from the physical and melt blends, a dissolution apparatus used was similar to the one employed by Mura and co-workers (P. Mura et al. II Farmco.-Ed. Pr. vol. 42 6, 149, 1987).
  • the dissolution medium consisted of either 300 mL of distilled water or 0.1N HC1 (SGF) maintained at 23 °C in a 600 mL beaker covered with a glass plate.
  • the amount of drug in each POLYOX WSR matrix tablet was greater than 1000 ppm.
  • Two techniques were used to prepare tablets. The first technique produced tablets by directly compressing and had dimensions of 28 mm x 5 mm at a pressure of 2 tons and dwell time of 10 seconds on a Carver Press [Model C, Carver Lab Press, Menomokee Falls, WI].
  • the tablets were placed in a beaker and stirring was conducted at 200 rpm using a 5-blade paddle mixer. At suitable time intervals, 5 mL aliquots were removed from the dissolution vessel (600 mL beaker) and filtered with 0.45m filters and replaced with 5 mL of fresh dissolution medium. The amount of drug in solution at each time interval was appropriately diluted and blanked for absorbance measurements using a UV-VIS. Drug solubility was determined from established calibration curves as a function of time.
  • Table 8 lists the rate of drug dissolution over time for polyethylene oxide samples in water prepared by melt blending and physical dispersion. From this table, it can be observed that the amount of drug released over time is much greater for the melt blends compared to the physical blends. Also, the total solubility of the melt blend system is greater than the physical blend system. This release rate data correlates well with the increase in solubility discussed in Example 5. Table 8.
  • Table 9 lists the rate of tolbutamide dissolution over time for polyethylene oxide samples in SGF prepared by melt blending and physical dispersion. From this table, it can be observed that the amount of drug released over time is much greater for the melt blends compared to the physical blends. Also, the total solubility of the melt blend system is much greater than the physical blend system. This release rate data correlates well with the increase in solubility discussed in Example 5. Table 9.
  • EXAMPLE 10 Table 10 lists the rate of sulfathiazole dissolution over time for polyethylene oxide samples in water prepared by melt blending and physical dispersion. From this table, it can be observed that the amount of drug released over time is somewhat greater for the melt blends compared to the physical blends. Also, the total solubility of the melt blend system is greater than the physical blend system. This release rate data correlates well with the increase in solubility discussed in Example 6. Table 10.
  • EXAMPLE 11 Table 11 lists the rate of hydroflumethazide dissolution over time for polyethylene oxide samples in water prepared by melt blending and physical dispersion. From this table, it can be observed that the amount of drug released over time is much greater for the melt blends compared to the physical blends. Also, the total solubility of the melt blend system is greater than the physical blend system. This release rate data correlates well with the increase in solubility discussed in Example 7. Table 11.
  • EXAMPLE 12 Table 12 lists the rate of hydroflumethazide dissolution over time for polyethylene oxide samples in SGF prepared by melt blending and physical dispersion. From this table, it can be observed that the amount of drug released over time is much greater for the melt blends compared to the physical blends. Also, the total solubility of the melt blend system is much greater, 4 to 5 times than the physical blend system. This release rate data correlates well with the increase in solubility discussed in Example 7. Table 12.
  • a critical parameter to the methods described above for enhancing the water solubility of substantially water-insoluble compounds with carriers like polyethylene oxides is the shelf-life stability of such compounds.
  • Certain carriers for example polyvinyl pyrrolidone and polyethylene glycols, when formulated with the substantially water-insoluble compounds, alter the structure of the substantially water-insoluble compound from the crystalline to the amorphous state.
  • the problem with such a morphological change is that the drug, over time, may re-crystallize, thus reducing it's water- solubility.
  • Such trends have been seen in PEG 6000-tolbutamide systems (Kedzierewicz et al. Int. J. Pharm. 117, 247, 1995).
  • N-80 stored at 23 °C for 335 days.
  • tolbutamide was formulated with both POLYOX WSR and a low molecular weight polyethylene glycol.
  • the POLYOX WSR sample was prepared as described in Example 5.
  • the polyethylene glycol sample was prepared as described in Example 1.
  • Table 15 From this table it can be seen that, at a relatively high polymer concentration of 5.0% (w/v), the polyethylene glycol did not substantially increase the solubility of tolbutamide (less than 10.0%). Quite surprisingly, this is not true for the high molecular weight polyethylene oxide.
  • the solubility enhancement of this system is over 800% at a polymer concentration of only 1.0% (w/v).
  • High molecular weight polyethylene oxides not only increase the solubility of substantially water-insoluble compounds like tolbutamide at low pH's, but also the amount of polymer needed for this enhancement is five times lower than what is needed for polyethylene glycols. Further, by using a high molecular weight polyethylene oxide, one can impart a controlled delivery of the substantially water- insoluble compound over a long period of time. Low molecular weight polyethylene glycols dissolve rapidly and can not afford such a delivery profile.

Abstract

Cette invention concerne des procédés pouvant améliorer la solubilité de composés sensiblement insolubles dans l'eau, par combinaison desdits composés avec un polymère soluble dans l'eau, par exemple un polymère de polyoxyde d'alkylène ou un éther de cellulose, ayant un poids moléculaire compris entre environ 50 000 et 7 000 000 grammes par gramme dans une quantité effective pour améliorer la solubilité desdits composés dans l'eau, en milieu acide à un pH inférieur à environ 5, par exemple. L'invention concerne également des compositions contenant les composés ayant une solubilité dans l'eau améliorée.
PCT/US1997/019831 1996-11-04 1997-10-31 Procede pour ameliorer la solubilite de composes sensiblement insolubles dans l'eau WO1998019708A2 (fr)

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EP97950577A EP0891190A2 (fr) 1996-11-04 1997-10-31 Procede pour ameliorer la solubilite de composes sensiblement insolubles dans l'eau

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Application Number Priority Date Filing Date Title
US3028296 1996-11-04
US60/030,282 1996-11-05

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WO1998019708A2 true WO1998019708A2 (fr) 1998-05-14
WO1998019708A3 WO1998019708A3 (fr) 1998-08-20

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6964978B2 (en) 1999-12-08 2005-11-15 Pharmacia Corporation Solid-state form of celecoxib having enhanced bioavailability
WO2013158992A1 (fr) * 2012-04-19 2013-10-24 Purdue Research Foundation Alpha-d-glucanes hautement ramifiés

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6818566B2 (en) 2002-10-18 2004-11-16 The Boc Group, Inc. Thermal activation of fluorine for use in a semiconductor chamber

Citations (4)

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Publication number Priority date Publication date Assignee Title
EP0012523A1 (fr) * 1978-11-20 1980-06-25 American Home Products Corporation Compositions thérapeutiques à biodisponibilité accrue et procédé pour leur préparation
EP0315964A1 (fr) * 1987-11-11 1989-05-17 Laboratoires Pharmascience Composition pharmaceutique comprenant l'exifone et un polymère soluble dans l'eau
WO1996032097A1 (fr) * 1995-04-14 1996-10-17 Pharma Pass Compositions solides contenant du polyethyleneoxyde et un principe actif non amorphe
WO1998011879A1 (fr) * 1996-09-19 1998-03-26 Depomed, Inc. Formes galeniques orales retenues dans l'estomac, pour la liberation controlee de medicaments faiblement solubles et de substance insoluble

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0012523A1 (fr) * 1978-11-20 1980-06-25 American Home Products Corporation Compositions thérapeutiques à biodisponibilité accrue et procédé pour leur préparation
EP0315964A1 (fr) * 1987-11-11 1989-05-17 Laboratoires Pharmascience Composition pharmaceutique comprenant l'exifone et un polymère soluble dans l'eau
WO1996032097A1 (fr) * 1995-04-14 1996-10-17 Pharma Pass Compositions solides contenant du polyethyleneoxyde et un principe actif non amorphe
WO1998011879A1 (fr) * 1996-09-19 1998-03-26 Depomed, Inc. Formes galeniques orales retenues dans l'estomac, pour la liberation controlee de medicaments faiblement solubles et de substance insoluble

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6964978B2 (en) 1999-12-08 2005-11-15 Pharmacia Corporation Solid-state form of celecoxib having enhanced bioavailability
WO2013158992A1 (fr) * 2012-04-19 2013-10-24 Purdue Research Foundation Alpha-d-glucanes hautement ramifiés
US10117937B2 (en) 2012-04-19 2018-11-06 Purdue Research Foundation Highly branched alpha-D-glucans

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CN1211928A (zh) 1999-03-24
EP0891190A2 (fr) 1999-01-20
WO1998019708A3 (fr) 1998-08-20

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