WO1998023270A1 - Formulation pharmaceutique - Google Patents
Formulation pharmaceutique Download PDFInfo
- Publication number
- WO1998023270A1 WO1998023270A1 PCT/DK1997/000543 DK9700543W WO9823270A1 WO 1998023270 A1 WO1998023270 A1 WO 1998023270A1 DK 9700543 W DK9700543 W DK 9700543W WO 9823270 A1 WO9823270 A1 WO 9823270A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formulation according
- formula
- compound
- formulation
- levormeloxifene
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
Definitions
- This invention relates to new pharmaceutical formulations for oral administration comprising certain 3,4-diarylchromans of formula I, or a pharmaceutically acceptable salt thereof, in combination with a hydrophilic binder and a water-soluble diluent.
- R is C.,. 6 alkyl, and pharmaceutically acceptable salts thereof are known to be useful for reducing bone loss.
- Centchroman which is 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-pyrrolidin-1- yl)ethoxy)phenyl]-7-methoxychroman, is a non-steroidal compound known to have antiestrogenic activity. It is in use in India as an oral contraceptive (see, for example, Salman et al., U.S. Patent No.
- Centchroman has also been investigated as an anti-cancer agent for treatment of advanced breast cancer (Misra ej aL, Int J Cancer 43 (1989), 781 - 783. Recently, centchroman as a racemate has been found as a potent cholesterol lowering pharmaceutical agent expressed by a significant decrease of the serum concentrations (S.D. Bain ei aL, J Min Bon Res 9 (1994), S 394).
- Levormeloxifene ( - ) - 3R,4R - trans- 7-methoxy-2,2-dimethyl-3-phenyl-4- ⁇ 4- [2-(pyrrolidin-1-yl)ethoxy]phenyl ⁇ chromane, is a particular preferred compound from this series of 3,4-diarylchromans.
- Levormeloxifene may be used in human and veterinary medicine for the regulation of bone metabolism.
- osteoporosis including post-menopausal osteoporosis and glucocorticoid-related osteoporosis
- Paget ' s disease hyperparathyroidism
- hypercalcemia of malignancy other conditions characterized by excessive rates of bone resorption and/or decreased rates of bone formation.
- the 3,4-diarylchromans are prepared according to known methods, such as those disclosed in U.S. Patent No. 3,340,276 to Carney ej al., U.S. Patent No. 3,822,287 to Bolger, and Ray ej aL, J Med Chem 19 (1976), 276 - 279, the contents of which are incorporated herein by reference. Conversion of the cis isomer to the trans configuration by means of an organometallic base-catalyzed rearrangement is disclosed in U.S. Patent No. 3,822,287.
- the optically active d- and l-enantiomers may be prepared as disclosed by Salman ej aj. in U.S. Patent No.
- levormeloxifene the compound of formula II is referred to as levormeloxifene.
- levormeloxifene the compound of formula II is referred to as levormeloxifene.
- the compounds of formula I may be administered as pharmaceutically acceptable salts.
- a particularly useful pharmaceutically acceptable salt of levormeloxifene is the hydrogen fumarate salt (in this specification, this compound is referred to as levormeloxifene fumarate.).
- This salt form is prepared by dissolving fumaric acid and (- ) -3R.4R- trans - 7-methoxy-2,2-dimethyl-3-phenyl-4- ⁇ 4-[2- (pyrrolidin-1-yl)ethoxy]phenyl ⁇ chromane in a common solvent such as e.g. methanol, and crystallizing the resulting salt from the solution.
- An object of the present invention is to provide a pharmaceutical formulation for oral administration which formulation has a favourable bioavailability.
- the present invention provides a pharmaceutical formulation for oral administration comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with a hydrophilic carrier composition.
- a pharmaceutical formulation for oral administration comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with a hydrophilic carrier composition.
- Such formulations have an increased solubility in aqueous media.
- the present invention provides a pharmaceutical formulation for oral administration which comprises a compound of formula I
- R is C ⁇ alkyl; or a pharmaceutically acceptable salt thereof, a hydrophilic binder and a water-soluble diluent.
- the formulation further comprises a surfactant.
- the present invention also provides pharmaceutical formulations further comprising a lubricant and/or disintegrant.
- a suitable antioxidant or a combination of antioxidants may be used. It is preferred to use the compounds of formula I in the trans configuration. The I enantiomeric forms are preferred over racemic mixtures.
- R is methyl.
- C ⁇ alkyl includes straight and branched chain alkyl radicals containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-amyl, sec-amyl, n-hexyl, 2-ethylbutyl, 2,3-dimethylbutyl and the like.
- pharmaceutically acceptable salt represents salt forms of a compound of formula I that are physiologically suitable for pharmaceutical use.
- the pharmaceutically acceptable salts can exist in conjunction with a compound of formula I as acid addition primary, secondary, tertiary, or quaternary ammonium, alkali metal, or alkaline earth metal salts.
- the acid addition salts are prepared by the reaction of an acid with a compound of formula I, wherein R is as defined previously.
- the alkali metal and alkaline earth metal salts are generally prepared by the reaction of the metal hydroxide of the desired metal salt with a compound of formula I, wherein R is hydrogen.
- the compounds of formula I may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids.
- salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like.
- Suitable inorganic acid- addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like.
- the acid addition salts may be obtained as the direct products of compound synthesis.
- the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
- hydrophilic binder represents binders commonly used in the formulation of pharmaceuticals, such as polyvinylpyrrolidone, copolyvidone (cross- linked polyvinylpyrrolidone), polyethylene glycol, sucrose, dextrose, corn syrup, polysaccharides (including acacia, tragacanth, guar, and alginates), gelatin, and cellulose derivatives (including hydroxypropyl methylcellulose, hydroxypropyl cellulose, and sodium carboxymethylcellulose).
- pharmaceuticals such as polyvinylpyrrolidone, copolyvidone (cross- linked polyvinylpyrrolidone), polyethylene glycol, sucrose, dextrose, corn syrup, polysaccharides (including acacia, tragacanth, guar, and alginates), gelatin, and cellulose derivatives (including hydroxypropyl methylcellulose, hydroxypropyl cellulose, and sodium carboxymethylcellulose).
- water-soluble diluent represents compounds typically used in the formulation of pharmaceuticals, such as sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), and cyclodextrins.
- non water-soluble diluent represents compounds typically used in the formulation of pharmaceuticals, such as calcium phosphate, calcium sulfate, starches, modified starches and microcrystalline cellulose.
- non water-soluble diluent with non-swelling properties represents the non water-soluble diluents as indicated above, but excluding starches and modified starches and the like.
- surfactant represents ionic and nonionic surfactants or wetting agents commonly used in the formulation of pharmaceuticals, such as ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives, monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, sodium docusate, sodium laurylsulfate, cholic acid or derivatives thereof, lecithins, alcohols and phospholipids.
- antioxidant represents the three groups of antioxidants, true antioxidants, reducing agents and antoxidant synergists, such as tocopherols, tocopherolesters, alkyl gallates, butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, citric acid, edetic acid and its salts, lecithin and tartaric acid.
- disintegrant represents compounds such as starches, clays, celluloses, alginates, gums, cross-linked polymers (such as cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose), sodium starch glycolate, low-substituted hydroxypropyl cellulose, and soy polysaccharides.
- the disintegrant is a modified cellulose gum such as e.g. cross-linked sodium carboxymethylcellulose.
- lubricant represents compounds frequently used as lubricants or glidants in the preparation of pharmaceuticals, such as talc, magnesium stearate, calcium stearate, stearic acid, colloidal silicon dioxide, magnesium carbonate, magnesium oxide, calcium silicate, microcrystalline cellulose, starches, mineral oil, waxes, glyceryl behenate, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, sodium laurylsulfate, sodium stearyl fumarate, and hydrogenated vegetable oils.
- the lubricant is magnesium stearate or talc, more preferably magnesium stearate and talc in combination.
- the hydrophilic binder is gelatin, cellulose derivative, polyvinylpyrrolidone or copolyvidone.
- the water-soluble diluent is a sugar, a polysaccharide or cyclodextrin.
- the formulation further comprises a non water-soluble diluent.
- the non water- soluble diluent is a non water-soluble diluent with non-swelling properties, preferably microcrystalline cellulose.
- the formulation further comprises an antioxidant.
- the antioxidant is tocopherols and tocopherolesters, such as alpha-tocopherol succinate.
- the formulation further comprises a surfactant.
- a surfactant preferably it is an anionic or nonionic surfactant.
- Representative surfactants from this preferred group include sodium laurylsulfate, polyglycolyzed glycerides, polyoxyethylene sorbitan fatty acid esters, monoglycerides, diglycerides or glycerol.
- the formulation further comprises a lubricant(s) and/or a disintegrant.
- the hydrophilic binder is polyvinylpyrrolidone or copolyvidone.
- the water-soluble diluent is a sugar, such as lactose, sucrose, dextrose.
- the surfactant is a nonionic surfactant, such as polyoxyethylene sorbitan fatty acid esters or glycerol.
- the hydrophilic binder is copolyvidone.
- the water-soluble diluent is lactose.
- the surfactant, when present, is glycerol.
- the amount of hydrophilic binder in the pharmaceutical formulation according to the invention is preferably from about 1% to about 25% (w/w), more preferably from about 1% to about 15% (w/w), most preferably from about 2,5% to about 15% (w/w).
- the amount of water-soluble diluent in the pharmacutical formulation according to the invention is preferably from about 20% to about 98% (w/w), more preferred from about 20% to about 80% (w/w).
- the amount of non water-soluble diluent in the pharmacutical formulation according to the invention is preferably from about 1% to about 50% (w/w), more preferred from about 5% to about 30% (w/w).
- the amount of the compound of formula I in the pharmaceutical formulation according to the invention is preferably from about 0,05% to about 50% (w/w), such as from about 0,1% to about 40% (w/w).
- compositions of the present invention are prepared and administered according to methods well known in pharmaceutical chemistry, see Remington's Pharmaceutical Sciences, 17 th ed. (A. Osol ed., 1985).
- the compositions of the present invention may be administered by means of solid dosage forms such as tablets and capsules.
- the compositions are formulated as tablets. These tablets may be prepared by wet granulation, by dry granulation, or by direct compression.
- Tablets for this invention are prepared utilizing conventional tabletting techniques.
- a general method of manufacture involves blending of a compound of formula I, or a salt thereof, the water-soluble diluent, hydrophilic binder and optionally a portion of a disintegrant. This blend is then granulated with an aqueous solution of the hydrophilic binder or an aqueous solution of the hydrophilic binder and surfactant and milled, if necessary. The granules are dried and reduced to a suitable size. Any other ingredients, such as lubricants, (e.g. magnesium stearate) and additional disinteg rants, are added to the granules and mixed. This mixture is then compressed into a suitable size and shape using conventional tabletting machines such as a rotary tablet press. The tablets may be film coated by techniques well known in the art.
- Capsules for this invention are prepared utilizing conventional methods.
- a general method of manufacture involves blending of a compound of formula I, or a salt thereof, the water-soluble diluent, a hydrophilic binder, and optionally a portion of a disintegrant. This blend is then granulated with an aqueous solution of the hydrophilic binder or an aqueous solution of the hydrophilic binder and surfactant in water, and milled, if necessary.
- the granules are dried and reduced to a suitable size. Any other ingredients, such as a lubricant, are added to the granules and mixed. The resulting mixture is then filled into a suitable size hard-shell gelatin capsule using conventional capsule- filling machines.
- a suitable size hard-shell gelatin capsule using conventional capsule- filling machines.
- the preferred range of pharmaceutical formulation (such as solid dosage form, e.g. capsule or tablet) strength may be from about 0.125 mg to about 40 mg of a compound of formula I, more preferred from about 0.25 mg to about 5 mg of a compound of formula I, preferably levormeloxifene.
- the preferred range of total mass may be from about 40 mg to about 500 mg depending on the strength of the formulation, more preferred from about 80 mg to about 320 mg.
- Tablets and capsules may be prepared using the ingredients and procedures as described below:
- the mixture of levormeloxifene fumarate, lactose, microcrystalline cellulose, and a portion of cross-carmellose sodium and copolyvidone is granulated with an aqueous solution of copolyvidone.
- the granules are dried, reduced to a suitable size and mixed with magnesium stearate, talc and remaining cross-carmellose sodium.
- the mixture is compressed into individual tablets yielding a tablet weight of 320 mg. It is possible to manufacture levormeloxifene tablet strengths in the range of 1.25 mg to 40 mg with a total mass of 320 mg.
- the mixture of levormeloxifene fumarate, lactose, microcrystalline cellulose, and a portion of cross-carmellose sodium and copolyvidone is granulated with an aqueous solution of copolyvidone.
- the granules are dried, reduced to a suitable size and mixed with magnesium stearate, talc and remaining cross-carmellose sodium.
- the mixture is compressed into individual tablets yielding a tablet weight of 160 mg. It is possible to manufacture levormeloxifene tablet strengths in the range of 0.25 mg to 40 mg with a total mass of 160 mg.
- the mixture of levormeloxifene fumarate, lactose, microcrystalline cellulose, and a portion of cross-carmellose sodium and copolyvidone is granulated with an aqueous solution of copolyvidone.
- the granules are dried, reduced to a suitable size and mixed with magnesium stearate, talc and remaining cross-carmellose sodium.
- the mixture is compressed into individual tablets yielding a tablet weight of 320 mg. It is possible to manufacture levormeloxifene tablet strengths in the range of 0.125 mg to 20 mg with a total mass of 120 mg.
- the mixture of levormeloxifene fumarate, lactose, microcrystalline cellulose, and a portion of cross-carmellose sodium and copolyvidone is granulated with an aqueous solution of copolyvidone containing dissolved sodium laurylsulfate.
- the granules are dried, reduced to a suitable size and mixed with magnesium stearate, talc and remaining cross-carmellose sodium.
- the mixture is compressed into individual tablets yielding a tablet weight of 320 mg. It is possible to manufacture levormeloxifene tablet strengths in the range of 1.25 mg to 40mg with a total mass of 320 mg.
- the mixture of levormeloxifene fumarate, dextrose, microcrystalline cellulose, and a portion of cross-carmellose sodium and copolyvidone is granulated with an aqueous solution of copolyvidone.
- the granules are dried, reduced to a suitable size and mixed with magnesium stearate, talc and remaining cross-carmellose sodium.
- the mixture is compressed into individual tablets yielding a tablet weight of 320 mg. It is possible to manufacture levormeloxifene tablet strengths in the range of 1.25 mg to 40 mg with a total mass of 320 mg.
- the mixture of levormeloxifene fumarate, lactose, microcrystalline cellulose, and a portion of cross-carmellose sodium is granulated with an aqueous solution of gelatine.
- the granules are dried, reduced to a suitable size and mixed with magnesium stearate, talc and remaining cross-carmellose sodium.
- the mixture is compressed into individual tablets yielding a tablet weight of 400 mg. It is possible to manufacture levormeloxifene tablet strengths in the range of 1.25 mg to 40 mg with a total mass of 400 mg.
- the mixture of levormeloxifene fumarate, dextrose, microcrystalline cellulose, and a portion of cross-carmellose sodium is granulated with an aqueous solution of gelatine.
- the granules are dried, reduced to a suitable size and mixed with magnesium stearate, talc and remaining cross-carmellose sodium.
- the mixture is compressed into individual tablets yielding a tablet weight of 400 mg. It is possible to manufacture levormeloxifene tablet strengths in the range of 1.25 mg to 40 mg with a total mass of 400 mg.
- the mixture of levormeloxifene fumarate, lactose, microcrystalline cellulose, and a portion of cross-carmellose sodium and copolyvidone is granulated with an aqueous solution of copolyvidone containing Tween 80.
- the granules are dried, reduced to a suitable size and mixed with magnesium stearate, talc and remaining cross- carmellose sodium.
- the mixture is compressed into individual tablets yielding a tablet weight of 400 mg. It is possible to manufacture levormeloxifene tablet strengths in the range of 1.25 mg to 40 mg with a total mass of 400 mg.
- the mixture of levormeloxifene fumarate, lactose, microcrystalline cellulose, and a portion of cross-carmellose sodium and copolyvidone is granulated with an aqueous solution of copolyvidone containing glycerol.
- the granules are dried, reduced to a suitable size and mixed with magnesium stearate, talc and remaining cross- carmellose sodium.
- the mixture is compressed into individual tablets yielding a tablet weight of 400 mg. It is possible to manufacture levormeloxifene tablet strengths in the range of 1.25 mg to 40 mg with a total mass of 400 mg.
- the mixture of levormeloxifene fumarate, dextrose, microcrystalline cellulose, and a portion of cross-carmellose sodium is granulated with an aqueous solution of gelatine and glycerol.
- the granules are dried, reduced to a suitable size and mixed with magnesium stearate, talc and remaining cross-carmellose sodium.
- the mixture is compressed into individual tablets yielding a tablet weight of 400 mg. It is possible to manufacture levormeloxifene tablet strengths in the range of 1.25 mg to 40 mg with a total mass of 400 mg.
- the mixture of levormeloxifene fumarate, dextrose, hydroxypropyl-betacyclodextrin microcrystalline cellulose, and a portion of cross-carmellose sodium is granulated with an aqueous solution of gelatine containing glycerol.
- the granules are dried, reduced to a suitable size and mixed with magnesium stearate, talc and remaining cross-carmellose sodium.
- the mixture is compressed into individual tablets yielding a tablet weight of 500 mg. It is possible to manufacture levormeloxifene tablet strengths in the range of 1.25 mg to 80 mg with a total mass of 500 mg.
- the mixture of levormeloxifene fumarate, lactose and microcrystalline cellulose is granulated with an aqueous solution of polyvinylpyrrolidone or copolyvidone.
- the granules are dried, reduced to a suitable size and mixed with magnesium stearate.
- the mixture is then filled into size 0 hard-shell gelatine capsules utilizing conventional encapsulating equipment. In order to obtain different capsule strenghts in the range of 1.25 mg to 20.0 mg, different quantities are weighed out in the range of 15 mg to 240 mg.
- the mixture of levormeloxifene fumarate, lactose, microcrystalline cellulose, antioxidant, and a portion of cross-carmellose sodium and copolyvidone is granulated with an aqueous solution of copolyvidone.
- the granules are dried, reduced to a suitable size and mixed with magnesium stearate, talc and remaining cross-carmellose sodium.
- the mixture is compressed into individual tablets yielding a tablet weight of 80 mg. It is possible to manufacture levormeloxifene tablet strengths in the range of 0.125 mg to 10 mg with a total mass of 80 mg.
- the mixture of levormeloxifene fumarate, lactose, microcrystalline cellulose, antioxidant, and a portion of cross-carmellose sodium and copolyvidone is granulated with an aqueous solution of copolyvidone.
- the granules are dried, reduced to a suitable size and mixed with magnesium stearate, talc and remaining cross-carmellose sodium.
- the mixture is compressed into individual tablets yielding a tablet weight of 100 mg. It is possible to manufacture levormeloxifene tablet strengths in the range of 0.125 mg to 20 mg with a total mass of 100 mg.
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Abstract
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU50490/98A AU5049098A (en) | 1996-11-28 | 1997-11-26 | Pharmaceutical formulation |
EP97913126A EP0959880A1 (fr) | 1996-11-28 | 1997-11-26 | Formulation pharmaceutique |
JP52416798A JP2001504502A (ja) | 1996-11-28 | 1997-11-26 | 薬学的製剤 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK1359/96 | 1996-11-28 | ||
DK135996 | 1996-11-28 | ||
DK1265/97 | 1997-11-07 | ||
DK126597 | 1997-11-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998023270A1 true WO1998023270A1 (fr) | 1998-06-04 |
Family
ID=26065492
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/DK1997/000543 WO1998023270A1 (fr) | 1996-11-28 | 1997-11-26 | Formulation pharmaceutique |
Country Status (4)
Country | Link |
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EP (1) | EP0959880A1 (fr) |
JP (1) | JP2001504502A (fr) |
AU (1) | AU5049098A (fr) |
WO (1) | WO1998023270A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999024031A1 (fr) * | 1997-11-07 | 1999-05-20 | Novo Nordisk A/S | Composition pharmaceutique comprenant de faibles doses de 3,4-diarylchromannes |
WO2001008686A1 (fr) * | 1999-08-03 | 2001-02-08 | Lilly Icos Llc | Compositions pharmaceutiques a base de beta-carboline |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4447622A (en) * | 1981-09-22 | 1984-05-08 | Council Of Scientific And Industrial Research Rafi Marg | Preparation of l- and d-isomers of dl-3,4-trans-2,2-disubstituted-3,4-diarylchromans and derivatives thereof |
US5407955A (en) * | 1994-02-18 | 1995-04-18 | Eli Lilly And Company | Methods for lowering serum cholesterol and inhibiting smooth muscle cell proliferation, restenosis, endometriosis, and uterine fibroid disease |
US5464862A (en) * | 1993-03-11 | 1995-11-07 | Zymogenetics, Inc. | Method for inhibiting bone loss using centchroman derivatives |
US5563133A (en) * | 1995-02-21 | 1996-10-08 | Eli Lilly And Company | Hexamethyleneiminyl tachykinin receptor antagonists |
-
1997
- 1997-11-26 JP JP52416798A patent/JP2001504502A/ja active Pending
- 1997-11-26 EP EP97913126A patent/EP0959880A1/fr not_active Withdrawn
- 1997-11-26 AU AU50490/98A patent/AU5049098A/en not_active Abandoned
- 1997-11-26 WO PCT/DK1997/000543 patent/WO1998023270A1/fr not_active Application Discontinuation
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4447622A (en) * | 1981-09-22 | 1984-05-08 | Council Of Scientific And Industrial Research Rafi Marg | Preparation of l- and d-isomers of dl-3,4-trans-2,2-disubstituted-3,4-diarylchromans and derivatives thereof |
US5464862A (en) * | 1993-03-11 | 1995-11-07 | Zymogenetics, Inc. | Method for inhibiting bone loss using centchroman derivatives |
US5407955A (en) * | 1994-02-18 | 1995-04-18 | Eli Lilly And Company | Methods for lowering serum cholesterol and inhibiting smooth muscle cell proliferation, restenosis, endometriosis, and uterine fibroid disease |
US5472977A (en) * | 1994-02-18 | 1995-12-05 | Eli Lilly And Company | Method for the treatment of uterine fibroid desease |
US5482958A (en) * | 1994-02-18 | 1996-01-09 | Eli Lilly And Company | Method for treating endometriosis |
US5563133A (en) * | 1995-02-21 | 1996-10-08 | Eli Lilly And Company | Hexamethyleneiminyl tachykinin receptor antagonists |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999024031A1 (fr) * | 1997-11-07 | 1999-05-20 | Novo Nordisk A/S | Composition pharmaceutique comprenant de faibles doses de 3,4-diarylchromannes |
WO2001008686A1 (fr) * | 1999-08-03 | 2001-02-08 | Lilly Icos Llc | Compositions pharmaceutiques a base de beta-carboline |
US7182958B1 (en) | 1999-08-03 | 2007-02-27 | Lilly Icos Llc. | β-carboline pharmaceutical compositions |
EP2338491A3 (fr) * | 1999-08-03 | 2011-11-30 | Lilly ICOS LLC | Composition pharmaceutique à base d'une beta-carboline |
HRP20020090B1 (hr) * | 1999-08-03 | 2014-03-28 | Icos Corporation | FARMACEUTSKI PRIPRAVCI S Ăź-KARBOLINOM |
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Publication number | Publication date |
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EP0959880A1 (fr) | 1999-12-01 |
AU5049098A (en) | 1998-06-22 |
JP2001504502A (ja) | 2001-04-03 |
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