WO2013182169A1 - Procédé de préparation d'une formulation d'acétate de bazédoxifène sans anti-oxydant et stable du point de vue polymorphe et chimique - Google Patents

Procédé de préparation d'une formulation d'acétate de bazédoxifène sans anti-oxydant et stable du point de vue polymorphe et chimique Download PDF

Info

Publication number
WO2013182169A1
WO2013182169A1 PCT/CZ2012/000047 CZ2012000047W WO2013182169A1 WO 2013182169 A1 WO2013182169 A1 WO 2013182169A1 CZ 2012000047 W CZ2012000047 W CZ 2012000047W WO 2013182169 A1 WO2013182169 A1 WO 2013182169A1
Authority
WO
WIPO (PCT)
Prior art keywords
bazedoxifene acetate
wet
process according
dry
formulation
Prior art date
Application number
PCT/CZ2012/000047
Other languages
English (en)
Inventor
Abid Riaz AHMED
Pawel STASIAK
Original Assignee
Zentiva, K. S.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zentiva, K. S. filed Critical Zentiva, K. S.
Priority to PCT/CZ2012/000047 priority Critical patent/WO2013182169A1/fr
Publication of WO2013182169A1 publication Critical patent/WO2013182169A1/fr

Links

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
    • A61K9/14—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
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the invention deals with a stable antioxidant-free formulation of apeledoxifene acetate prepared by wet aqueous processes.
  • Osteoporosis is a gender-related disease that is especially prevalent in postmenopausal women. Postmenopausal osteoporosis is an increasing worldwide health concern affecting an estimated 200 million individuals. The ongoing need for new osteoporosis therapies has led to the development of new selective estrogen receptor modulators (SERMs) with an ideal tissue selectivity profile and beneficial effects on bone without undesirable effects on the endometrium and breast (Chines and Med, 2009).
  • SERMs selective estrogen receptor modulators
  • Bazedoxifene acetate (1 -[4-(2-azepan-1-yl-ethoxy)benzyl]-2-(4-hydroxyfenyl)-3-methyl-1 H-indol-5-ol acetic acid), having the chemical formula shown below, is a new, third-generation, oral, nonsteroidal, indole-based selective estrogen receptor modulator (SERM) being developed for the prevention and treatment of osteoporosis.
  • SERM selective estrogen receptor modulator
  • Bazedoxifene acetate form B is thermodynamically more stable than form A.
  • the polymorphic form A has higher solubility in aqueous and organic system than does form B. The higher solubility of polymorphic form A makes it potential candidate to prepare pharmaceutical formulations.
  • EP 2311805A1 reports the Bazedoxifene acetate polymorphic form C which can be used in the preparation of pharmaceutical formulations.
  • PCT application WO0203987A2 describes oral formulations of one or more poorly soluble estrogenic compounds comprising a carrier or excipient systems of a filler and disintegrant component and a lubricant component, preferably with an antioxidant.
  • the formulations may be in any conventionally used oral forms (tablets, capsules, buccal forms, troches, lozenges, suspensions) and may be prepared by any conventional method without any closer specification (compression, wet granulation, dry granulation), with standard or delayed release of the API.
  • the only example of formulation without antioxidant (Example 1 ) was shown to be chemically unstable (Example 5).
  • PCT application WO05099677A1 describes solid dispersion comprising apeledoxifene acetate and methods of their preparation.
  • the solid dispersions are prepared by combinig the apeledoxifene acetate either with a dispersing agent in solution and removing the solvent or with melted dispersing agent and solidifying the liquid mixture.
  • PCT application WO2007024961 describes oral formulations of apeledoxifene acetate polymorphic form A prepared by dry processes, preferably by direct mixing, comprising a carrier or excipient system that prevents or minimizes the polymorphic conversion of the active ingredient.
  • a carrier or excipient system that prevents or minimizes the polymorphic conversion of the active ingredient.
  • the usage of a surfactant was not recommended because it was believed to facilitate the polymorphic conversion of the API.
  • the formulations were prepared by the direct blending.
  • the present invention relates to the manufacturing process of a stable, antioxidant-free pharmaceutical formulation of apeledoxifene acetate which comprises preparation of a wet portion prepared by the wet aqueous granulation and preparation of a dry portion and mixing the portions in different ratios.
  • the aim of this invention was to find out a method of preparation of apeledoxifene acetate solid oral formulations where any polymorphic conversion would be prevented or minimized during the production as well as during the storage of the formulations, so that the desirable physico-chemical properties of the used active ingredient stay unaffected, while the resulting formulations being as well chemically stable against oxidation.
  • a process for preparation of formulations was found which fulfilled both these requirements, even without usage of any antioxidant in the composition of the tablets.
  • the present invention relates to the manufacturing process of a stable, antioxidant-free pharmaceutical composition of apeledoxifene acetate which comprises mixing of a first dry portion with a second portion of granules prepared by wet aqueous granulation, optionally with further admixing of other powdered excipients, wherein ratio between the dry portion and the granules prepared by wet aqueous granulation varies between 25:75 - 75:25.
  • the active compound may be incorporated either into the wet granules or into the dry portion. This mixture can be filled into capsules or compressed into tablets.
  • the process of the preparation of the antioxidant-free chemically and polymorphically stable pharmaceutical composition of the present invention comprises following steps:
  • wet portion used in the text of this application means the part of the formulation that is in the form of granules prepared by the wet aqueous granulation.
  • the mixture for preparation of the portion of granules prepared by the wet granulation may or may not comprise the active compound apeledoxifene acetate. If the apeledoxifene acetate is present, the mixture comprises also at least one hydrophilic filler which is intensively blended with the apeledoxifene acetate prior addition of the rest of excipients.
  • the mixture further comprises at least one additional filler, at least one binder, at least one disintegrant selected from the group of sodium starch glycolate, sodium croscarmellose and crospovidone and at least one surfactant.
  • the wet granules can be prepared in a high shear mixer or by a fluid bed granulation process.
  • the high shear mixer first the micronized apeledoxifene acetate (if present) and the hydrophilic filler (if apeledoxifene acetate is present in the wet portion of granules) are intensively blended and after that this mixture is intensively blended with the rest of the excipients in a manner commonly known to a skilled person. Without or with few experiments a skilled person can adjust the necessary conditions (premixing time, speed of granulation liquid addition, amount of the liquid, speed of the mixture etc.).
  • the amount of granulation water and time of granulation was adjusted so that the granulate was of a size that did not require wet milling prior to drying.
  • the wet-granulate was dried in a fluid bed dryer at less than 40 °C to obtain dried granulate and the granules were milled through 1.0 mm sieve after drying.
  • the milled dried granulate had excellent flow ability and could be easily compressed into tablets with a suitable hardness and friability.
  • the fluid bed granulation process was used to prepare the wet aqueous granulation portion.
  • the pre-mix of apeledoxifene acetate (if present in the wet portion of granules) with at least one hydrophilic filler (if apeledoxifene acetate is present in the wet portion of granules) was intensively blended with at least one additional filler, at least one binder, at least one disintegrant selected form the group of sodium starch glycolate, sodium croscarmellose and crospovidone and at least one surfactant in fluid bed before the start of the liquid spraying.
  • the mixture was then sprayed with water, optionally comprising dissolved and/or dispersed one or more binders.
  • the necessary process parameter can be adjusted by a skilled person with or without few experiments.
  • the amount of water with or without binders and time of spray were adjusted to avoid agglomerate formation.
  • the wet- granulate was further dried in a fluid bed dryer at less than 40 °C to obtain dried granulate and the dried granules were milled through 1.0 mm sieve.
  • the milled dried granulate had excellent flow ability and could be easily compressed into tablets with a suitable hardness and friability.
  • dry portion used in the text of this application means the part of the formulation that is prepared by a dry process (direct blending, dry granulation, roller compaction).
  • the dry portion may or may not comprise the active compound apeledoxifene acetate. If the apeledoxifene acetate is present in the wet granules portion, it is not present in the dry portion and vice versa, if the apeledoxifene acetate is not present in the wet granules portion, it is present in the dry portion.
  • the mixture for the dry portion comprises further at least one hydrophilic filler (if apeledoxifene acetate is present), at least one additional filler, at least one binder, at least one disintegrant selected from the group of sodium starch glycolate, sodium croscarmellose and crospovidone, at least one surfactant and optionally a lubricant.
  • the dry portion of the final formulation can be produced either by direct blending of the ingredients or by a roller compaction, i.e. the ingredients are blended and compacted using the roller compactor with a force of 1 -20 KN/cm, most preferably between 3-7 KN/cm.
  • the bazadoxifene acetate and the hydrophilic filler are first intensively pre-blended and only after that the rest of excipient is added and intensively blended with the pre-mix of apeledoxifene acetate and the hydrophilic filler.
  • the blend Prior to the compaction, the blend is to be lubricated by a lubricant. If the final formulation is in a form of tablet, the amount of the lubricant used in the dry portion is approximately one quarter of the total amount of the lubricant in the final formulation.
  • the final blend for the final formulation comprises a wet portion and a dry portion wherein the ratio between the wet portion and the dry portion varies between 25:75 - 75:25.
  • the active compound may be incorporated into the wet portion or into the dry portion. Both portions are blended together and optionally further powdered excipients, such as glidants, lubricants and fillers, can be admixed.
  • This final blend can be filled into moisture protective capsules or compressed into tablet cores and coated with a moisture protection polymer.
  • the formulation is in a form of tablets prepared by blending of a wet portion and a dry portion wherein the ratio between the wet portion and the dry portion varies between 25:75 - 75:25 and to this blend is further admixed a lubricant and optionally a glidant.
  • This final blend exhibits excellent flow ability and can be easily compressed into tablets with suitable hardness and friability.
  • the tablets are coated with a moisture protection polymer.
  • the final formulation can be packed into PVC, PVC-AI or AI-AI blisters, or into, bottles, in normal atmosphere (air) or under an inert atmosphere (nitrogen, argon).
  • composition of the formulation is composed of two portions, the wet portion and the dry portion.
  • the apeledoxifene acetate may be incorporated either into the wet portion or into the dry portion.
  • composition of the portion (either wet or dry) comprising the apeledoxifene acetate is following: a/ 7 - 25% micronized apeledoxifene acetate
  • disintegrant selected from sodium starch glycolate, sodium
  • g/ optionally up to 2% glidant The percentages listed above indicate percentages by weight of the total weight of the components of the portion comprising the apeledoxifene actetate.
  • composition of the portion (either wet or dry) without the apeledoxifene acetate is following: a/ 65 - 87% filler
  • disintegrant selected from sodium starch glycolate, sodium
  • the active compound of the formulations according to the invention is micronized apeledoxifene acetate with D90 particle size of (i.e. 90 percent of the particle size distribution lies below) about 100 ⁇ , preferably about 50 ⁇ , more preferably about 20 ⁇ and still more preferably about 15 ⁇ .
  • the polymorphic form of the apeledoxifene acetate shall be substantially pure and will stay stable when formulated according to this invention. Without limiting the technical effect of the present invention, the polymorphic form C was used herein as the most preferred for its suitable physic-chemical properties.
  • any reference to apeledoxifene acetate is intended to include apeledoxifene acetate polymorphic form C, if not explicitly indicated to the contrary.
  • Polymorphic form C of Bazedoxifene acetate was selected and used because it was proved to exhibit the best combination of the physico-chemical properties that are advantageous for the pharmaceutical formulations compared to polymorphic forms A, B and amorphous form (Table 1 ).
  • the polymorphic form C of Bazedoxifene acetate together with form B is chemically more stable, has higher polymorphic stability and is less hygroscopic than form A and amorphous.
  • Hygroscopicity is the ability of a substance to attract and hold water molecules (e.g.
  • Hygroscopic substances need to be specifically stored (e.g. aluminium foil + desiccant) to remain unchanged.
  • Hygroscopicity of polymorphic form C of Bazedoxifene acetate is comparable with form B whereas form A sorbed significantly higher amount of water.
  • Hygroscopicity of amorphous form is immense.
  • the hydrophilic filler can be selected from those known in the art, including lactose (e.g. anhydrous or monohydrate), saccharose, raffinose, compressible sugar (commercially available combination of 95.0 to 98.0% sucrose and 2 to 5% dried glucose syrup or maltodextrin), fructose, dextrose and other sugars and mixtures thereof, and sugar alcohols such as mannitol, sorbitol, maltitol, xylitol, lactitol, and mixtures thereof.
  • lactose e.g. anhydrous or monohydrate
  • saccharose e.g. anhydrous or monohydrate
  • raffinose e.g. anhydrous or monohydrate
  • compressible sugar commercially available combination of 95.0 to 98.0% sucrose and 2 to 5% dried glucose syrup or maltodextrin
  • fructose dextrose and other sugars and mixtures thereof
  • sugar alcohols such as mannitol
  • the filler can comprise any substance of this function known in the art for the preparation of the solid oral forms, including the hydrophilic fillers.
  • the pharmaceutically acceptable filler can be selected for example from microcrystalline cellulose, powdered cellulose, siliconized microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate, lactose (e.g. anhydrous or monohydrate), saccharose, raffinose, compressible sugar, fructose, dextrose and other sugars, sugar alcohols such as mannitol, sorbitol, maltitol, xylitol, lactitol, and mixtures thereof.
  • Preferred excipients are microcrystalline cellulose, lactose and mannitol and any mixtures thereof.
  • binders examples include (but not limited to) polyvinylpyrrolidones of different K-values (i.e. exhibiting different viscosities in solution), microcrystalline cellulose, hydroxypropylmethylcellulose or other cellulose esters, cellulose ethers, starch, pre-gelatinized starch, polymethacrylate and any mixtures thereof.
  • the preferred binders are povidone and pregelatinized starch, the most preferred is pregelatinized starch.
  • the disintegrant shall be selected from the group of sodium starch glycolate, croscarmellose sodium, crospovidone and any their mixture.
  • the surfactant can be selected form the group of sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols, sugar esters of fatty acids and glycerides of fatty acids or mixtures thereof.
  • the preferred surfactant is sodium lauryl sulfate.
  • the glidant can be selected from the group of stearic acid and its metallic salts, magnesium palmitate, magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, macrogols, colloidal silica and any mixtures of thereof.
  • the preferred glidants are metallic stearates and colloidal silica, the most preferred is colloidal silica.
  • Examples of lubricants as excipients include stearic acid or stearic acid salts, such as magnesium stearate, magnesium palmitate, magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, macrogols, and any mixtures thereof.
  • Preferred are magnesium stearate or sodium stearyl fumarate, mostly magnesium stearate.
  • the tablet mixture was prepared by direct blending.
  • First blend was prepared by blending of micronized apeledoxifene acetate, lactose and sodium lauryl sulphate for 10 min.
  • Second blend was prepared by addition of the remaining excipients except lubricant to the first blend and blending for 15 min. After that lubricant was added to the second blend, followed by mixing for 3 min.
  • the core tablets were then coated with a moisture protection polymer.
  • Example 1 Composition of 20 mq film coated tablet prepared by direct compression
  • Example 2 Composition of 20 mq film coated tablet prepared by direct compression
  • a first blend was prepared by mixing of micronized apeledoxifene and rest of excipients in a blender for 10 min.
  • a second blend was prepared by blending 1/4 th lubricant (e.g. magnesium stearate) of the composition with the first blend for 3 min.
  • the second blend was compacted with a force of 1 -20 KN/cm, the most preferable between 3-7 KN/cm.
  • the compacts were milled to granules by sieving through 1 .0 mm sieve. The resulted dry granulate further lubricated with rest of the lubricant and compressed in to tablet cores.
  • the tablet cores were coated with a moisture protection polymer.
  • the granules prepared by compaction had excellent flow ability and could be easily compressed into tablets with suitable hardness and friability.
  • granules were difficult to compress on a fast rotary tableting machine due to loss of rework ability. Due to this disadvantage there is limitation of selection of suitable excipients. Further, variation in content uniformity was observed, the micronized apeledoxifene acetate segregated from the excipients during blending and no robust formulation was achieved.
  • Example 3 Composition of 20 mq film coated tablet prepared by granulation by roller compaction
  • Example 4 Composition of 20 mq film coated tablet prepared by granulation by roller compaction
  • Bazedoxifene acetate was intensively mixed with lactose for 10 min. After that all the other excipients except the magnesium stearate were added and the mixture was blended for additional 15 min. Finally, the magnesium stearate was admixed for 3 min. The blend was then granulated in the high shear mixture by water. The granulate was dried at 40°C, milled to through 1.0 mm sieve and compressed into the tablet cores. The tablet cores were then film-coated.
  • Example 5 Composition of 20 mq film coated tablet prepared by wet aqueous granulation
  • Bazedoxifene acetate was intensively mixed with lactose for 10 min. After that all the other excipients of the wet portion (as indicated in the table of composition) were added and the mixture was blended for additional 15 min. The blend was then granulated by water in the high shear mixture. The granulate was dried at 40°C and milled to 1.0 mm sieve.
  • the wet portion and the dry portion were blended together for 15 min.
  • the resulting bled was lubricated with the rest of the lubricant and compressed in to tablet cores.
  • the tablet cores were coated with a moisture protection polymer.
  • Example 6 Composition of 20 mq film coated tablet prepared by combining of 25% wet portion comprising apeledoxifene acetate with 75% dry portion
  • Lactose monohydrate 1 19.60 39.5
  • Colloidal anhydrous silica 1.00 0.3
  • Example 7 Composition of 20 mq film coated tablet prepared by combining of 75% wet portion comprising apeledoxifene acetate with 25% dry portion
  • Examples 8 and 9 Formulations prepared from a wet portion and a dry portion comprising apeledoxifene acetate
  • Bazedoxifene acetate was intensively mixed with lactose for 10 min. After that all the other excipients of the wet portion (as indicated in the table of composition) were added and the mixture was blended for additional 15 min. After that 1/4 th of the total amount of magnesium stearate was added and the blend was mixed for additional 3 min. This blend was compacted with a force between 3-7 KN/cm. The compacts were milled to granules through 1.0 mm sieve.
  • the wet portion and the dry portion were blended together for 15 min.
  • the resulting blend was lubricated with the rest of the lubricant and compressed into tablet cores.
  • the tablet cores were coated with a moisture protection polymer.
  • Example 8 Composition of 20 mq film coated tablet prepared by combining of 25% wet portion with 75% dry portion comprising apeledoxifene acetate
  • Example 9 Composition of 20 mq film coated tablet prepared by combining of 75% wet portion with 25% dry portion comprising apeledoxifene acetate
  • Example 10 Composition of 20 mq film coated tablet prepared by combining of 40% wet portion comprising adoxifene acetate with 60% dry portion
  • Colloidal anhydrous silica 1.00 0.3
  • Example 1 1 Composition of 20 mq film coated tablet prepared by combining of 60% wet portion comprising apeledoxifene acetate with 40% dry portion
  • Colloidal anhydrous silica 1.00 0.6
  • Examples 6, 7 and 8 were exposed to dry- and humid-heat conditions.
  • the total amount of impurities was measured by the HPLC method. The results are shown in the Table 2. In all cases the formulations according to the invention were chemically stable and exhibited lower contents of total impurities than the comparative formulations even under the hard conditions of temperature of 80°C at the relative humidity of 75% for 48 h. All the samples were tested on the apeledoxifene acetate polymorphic form. In all the samples no conversion to other form was detected. The results of the coated tablets according to Examples 6, 7 and 8 exposed to the temperature of 80°C at the relative humidity of 75% for 48 h are shown in the Figure 2.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)

Abstract

Cette invention concerne un procédé aqueux de préparation d'une formulation orale solide d'acétate de bazédoxifène, sans anti-oxydant et stable du point de vue polymorphe et chimique, ledit procédé consistant à : a. préparer une fraction humide de la formulation sous forme de granulés obtenus par granulation humide; b. préparer une fraction sèche de la formulation finale obtenue par mélange direct ou par granulation sèche; c. mélanger les fractions en un rapport de 25:75 à 75:25; d. ajouter facultativement des excipients en poudre, par exemple une ou plusieurs charges, un ou plusieurs agents d'écoulement et/ou un ou plusieurs lubrifiants; e. fabriquer la formulation finale i/ en comprimant le mélange sous forme de noyaux de comprimés et en enrobant lesdits noyaux d'une pellicule comprenant des polymères protégeant de l'humidité, ii/ en remplissant le mélange dans des capsules protégeant de l'humidité, ledit composé actif acétate de bazédoxifène étant incorporé dans la fraction humide ou dans la fraction sèche, et ladite préparation de la fraction contenant le composé actif acétate de bazédoxifène comprenant, comme première étape, le prémélange d'acétate de bazédoxifène avec une charge hydrophile.
PCT/CZ2012/000047 2012-06-07 2012-06-07 Procédé de préparation d'une formulation d'acétate de bazédoxifène sans anti-oxydant et stable du point de vue polymorphe et chimique WO2013182169A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CZ2012/000047 WO2013182169A1 (fr) 2012-06-07 2012-06-07 Procédé de préparation d'une formulation d'acétate de bazédoxifène sans anti-oxydant et stable du point de vue polymorphe et chimique

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CZ2012/000047 WO2013182169A1 (fr) 2012-06-07 2012-06-07 Procédé de préparation d'une formulation d'acétate de bazédoxifène sans anti-oxydant et stable du point de vue polymorphe et chimique

Publications (1)

Publication Number Publication Date
WO2013182169A1 true WO2013182169A1 (fr) 2013-12-12

Family

ID=46545576

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CZ2012/000047 WO2013182169A1 (fr) 2012-06-07 2012-06-07 Procédé de préparation d'une formulation d'acétate de bazédoxifène sans anti-oxydant et stable du point de vue polymorphe et chimique

Country Status (1)

Country Link
WO (1) WO2013182169A1 (fr)

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5998402A (en) 1996-04-19 1999-12-07 American Home Products Corporation 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents
WO2002003987A2 (fr) 2000-07-06 2002-01-17 Wyeth Compositions pharmaceutiques d'agents oestrogeniques
US6479535B1 (en) 1998-05-15 2002-11-12 Wyeth 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole and estrogen formulations
WO2003105834A1 (fr) * 2002-06-13 2003-12-24 Wyeth Schemas therapeutiques du bazedoxifene
WO2005070434A2 (fr) * 2004-01-13 2005-08-04 Wyeth Traitement de l'osteoporose liee a la therapie par un inhibiteur de l'aromatase
US20050227965A1 (en) 2004-04-07 2005-10-13 Wyeth Crystalline polymorph of bazedoxifene acetate
WO2005099677A1 (fr) 2004-04-08 2005-10-27 Wyeth Formulations a dispersion solide d'acetate de bazedoxifene
WO2007024961A2 (fr) 2005-08-24 2007-03-01 Wyeth Preparations de bazedoxifene acetate
EP2311805A1 (fr) 2007-07-25 2011-04-20 Zentiva, K.S. Nouvelle forme polymorphique de l'acetate de bazedoxifene
US8063041B2 (en) 2009-06-23 2011-11-22 Wyeth Llc Polymorphic Form D of bazedoxifene acetate and methods of preparing same
US10099805B2 (en) 2016-02-24 2018-10-16 The Boeing Company Artificial gravity system with rotating hub that is sealed with rotary seals
US10098305B1 (en) 2017-07-06 2018-10-16 Monsanto Technology Llc Soybean variety 01064403

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5998402A (en) 1996-04-19 1999-12-07 American Home Products Corporation 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents
US6479535B1 (en) 1998-05-15 2002-11-12 Wyeth 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole and estrogen formulations
WO2002003987A2 (fr) 2000-07-06 2002-01-17 Wyeth Compositions pharmaceutiques d'agents oestrogeniques
WO2003105834A1 (fr) * 2002-06-13 2003-12-24 Wyeth Schemas therapeutiques du bazedoxifene
WO2005070434A2 (fr) * 2004-01-13 2005-08-04 Wyeth Traitement de l'osteoporose liee a la therapie par un inhibiteur de l'aromatase
US20050227965A1 (en) 2004-04-07 2005-10-13 Wyeth Crystalline polymorph of bazedoxifene acetate
WO2005099677A1 (fr) 2004-04-08 2005-10-27 Wyeth Formulations a dispersion solide d'acetate de bazedoxifene
WO2007024961A2 (fr) 2005-08-24 2007-03-01 Wyeth Preparations de bazedoxifene acetate
US20070048374A1 (en) * 2005-08-24 2007-03-01 Wyeth Bazedoxifene acetate formulations
US7771744B2 (en) 2005-08-24 2010-08-10 Wyeth Llc Bazedoxifene acetate formulations
EP2311805A1 (fr) 2007-07-25 2011-04-20 Zentiva, K.S. Nouvelle forme polymorphique de l'acetate de bazedoxifene
US8063041B2 (en) 2009-06-23 2011-11-22 Wyeth Llc Polymorphic Form D of bazedoxifene acetate and methods of preparing same
US10099805B2 (en) 2016-02-24 2018-10-16 The Boeing Company Artificial gravity system with rotating hub that is sealed with rotary seals
US10098305B1 (en) 2017-07-06 2018-10-16 Monsanto Technology Llc Soybean variety 01064403

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHINES, A.A.; KOMM, B.S.: "Bazedoxifene acetate: A novel selective estrogen receptor modulator for the prevention and treatment of postmenopausal osteopocosis", DRUGS TODAY (BARC)., vol. 45, no. 7, 2009, pages 507 - 20
KUNG, ANNIE W. C.; CHU; EVA Y. W.; XU, LING: "Bazedoxifene: a new selective estrogen receptor modulator for the treatment of postmenopausal osteoporosis", EXPERT OPINION ON PHARMACOTHERAPY, vol. 10, no. 8, 2009, pages 1377 - 1385
MILLER ET AL., BAZEDOXIFENE ACETATE, DRUGS OF THE FUTURE, vol. 27, no. 2, 2002, pages 117 - 121
MILLER, C. P.; COLLIN, M.D.; TRAN, B. D.: "Design, synthesis and preclinical characterization of novel, highly selective indole estrigens", J. MED. CHEM., vol. 44, 2001, pages 1654 - 7, XP002337303, DOI: doi:10.1021/jm010086m

Similar Documents

Publication Publication Date Title
KR100894027B1 (ko) 에스트로겐 제제의 약제학적 제형
US9186333B2 (en) Process for preparing pharmaceutical compositions of fingolimod
US20070048374A1 (en) Bazedoxifene acetate formulations
US20110136883A1 (en) Granulation of active pharmaceutical ingredients
EP3606511A1 (fr) Composition pharmaceutique comprenant du mésylate de lenvatinib
EP2323634B1 (fr) Composition à base de ropinirole
WO2013100112A1 (fr) Composition pharmaceutique solide contenant un composé ayant une activité antagoniste de l'angiotensine ii
EP2804588B1 (fr) Procédé de préparation de compositions de cinacalcet destinées à la fabrication directe de comprimés
US20120010216A1 (en) Pharmaceutical compositions containing vanoxerine
WO2012136839A1 (fr) Formulation sèche et composition pharmaceutique comprenant une fésotérodine ou un sel ou un solvate de celle-ci
EP3860606B1 (fr) Composition pharmaceutique comprenant esylate ou tosylate de lenvatinib
EP2276466A1 (fr) Granulés contenant de l'oxalate d'escitalopram
EP2101742B1 (fr) Composition pharmaceutique contenant de l'hydrogénosulfate de clopidogrel de forme polymorphe 1
US20160250192A1 (en) Production method of pharmaceutical composition containing candesartan cilexetil
EP3505158A1 (fr) Composition pharmaceutiquie comprenant des sels d'addition d'acide du lénalidomide
WO2013182169A1 (fr) Procédé de préparation d'une formulation d'acétate de bazédoxifène sans anti-oxydant et stable du point de vue polymorphe et chimique
EP2379061B1 (fr) Formulations de composés pré-comprimées à décomposition rapide à faible biodisponibilité orale
WO2013182170A1 (fr) Augmentation de la vitesse de dissolution d'une composition pharmaceutique comprenant de l'acétate de bazédoxifène
EP2153822A1 (fr) Granulation d'ingrédients pharmaceutiques actifs
EP4374856A1 (fr) Procédé pour comprimés comprenant du brexpiprazol
JP2022102543A (ja) オセルタミビルを含む錠剤及びその製造方法
EP4337175A1 (fr) Formulation pharmaceutique de valsartan et de sacubitril
EP3079672A1 (fr) Composition pharmaceutique comprenant un sel pharmaceutiquement acceptable de rasagiline
AU2012275036A1 (en) Bazedoxifene acetate formulations and manufacturing process thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12737466

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12737466

Country of ref document: EP

Kind code of ref document: A1