+

WO2010112203A1 - Comprimés contenant de la dapoxétine et procédé de traitement à sec pour leur préparation - Google Patents

Comprimés contenant de la dapoxétine et procédé de traitement à sec pour leur préparation Download PDF

Info

Publication number
WO2010112203A1
WO2010112203A1 PCT/EP2010/002025 EP2010002025W WO2010112203A1 WO 2010112203 A1 WO2010112203 A1 WO 2010112203A1 EP 2010002025 W EP2010002025 W EP 2010002025W WO 2010112203 A1 WO2010112203 A1 WO 2010112203A1
Authority
WO
WIPO (PCT)
Prior art keywords
dapoxetine
tablets
adhesive
amorphous
steps
Prior art date
Application number
PCT/EP2010/002025
Other languages
German (de)
English (en)
Inventor
Frank Muskulus
Jana Pätz
Original Assignee
Ratiopharm Gmbh
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 Ratiopharm Gmbh filed Critical Ratiopharm Gmbh
Priority to EP10711165A priority Critical patent/EP2413910A1/fr
Publication of WO2010112203A1 publication Critical patent/WO2010112203A1/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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—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
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives

Definitions

  • the invention relates to tablets containing dapoxetine or a pharmaceutically acceptable salt thereof and pharmaceutical excipients, in particular adhesives, wherein the tablets have a uniformity of the content of preferably 95% to 105% and dry processing process for their preparation.
  • the tablets of the invention may contain dapoxetine in crystalline or amorphous form. Consequently, the invention further relates to an intermediate containing dapoxetine in amorphous form and a process for its preparation.
  • Dapoxetine belongs broadly to the group of Selective Serotonin Re-uptake Inhibitors (SSRIs), in particular it inhibits the transport molecule of serotonin.
  • SSRIs Selective Serotonin Re-uptake Inhibitors
  • dapoxetine (S) - (+) - N, N-dimethyl-1-phenyl-3- (1-naphthalenyloxy) -propanamine.
  • the chemical structure of dapoxetine is shown in formula (1) below:
  • EP 1 225 881 B1 relates to the use of dapoxetine for the treatment or management of sexual dysfunction.
  • Capsule and tablet formulations with a dapoxetine content of about 2.5 to 10% by weight are proposed for this purpose.
  • Hard gelatin capsules are often perceived by patients as unpleasant to the oral.
  • the tablet formulations it has been found during pressing that crystalline dapoxetine (in particular during the transition from an eccentric press to a rotary press) tends to adhere. This leads to undesirable negative qualitative changes of the tablet surface, which complicate a subsequent uniform coating and lead in extreme cases to cover the tablets, especially during prolonged run the Tablettlermaschinen. This leads to undesirable fluctuations in the active ingredient content in the resulting tablets.
  • dosage forms of dapoxetine are to be provided which ensure good solubility and bioavailability with simultaneously good storage stability.
  • the tasks could be solved unexpectedly by providing dapoxetine tablets with a high content of content uniformity at medium to high drug content.
  • the objects can be solved particularly advantageously by four preferred inventive aspects, which can be implemented individually or in combination.
  • the amount of lubricant (compared with the amount of lubricant used in EP 1 225 881 Bl) is increased.
  • dapoxetine preferably crystalline dapoxetine, having a specific particle size distribution is used.
  • the conversion of dapoxetine, especially crystalline dapoxetine, into a stabilized amorphous state occurs.
  • the processing of dapoxetine into tablets is by dry processing, in particular dry granulation with crystalline dapoxetine or dry granulation or direct compression with stabilized amorphous dapoxetine.
  • the invention therefore relates to tablets containing dapoxetine or a pharmaceutically acceptable salt thereof and pharmaceutical auxiliaries, in particular adhesives, the tablets having a uniformity of the content of 85% to 115%, determined in accordance with Ph. Eur.6.0, Section 2.9.6, and wherein in particular the active ingredient content is more than 10 to 60 wt .-%.
  • the Active ingredient content in the case of coated tablets refers to the total weight of the tablet core.
  • the active ingredient content refers to the total weight of the tablet.
  • the invention likewise provides a dry granulation process for the production of tablets containing dapoxetine or a pharmaceutically acceptable salt thereof and an adhesion agent comprising the steps
  • the invention further provides an intermediate containing amorphous dapoxetine and an adhesive.
  • the intermediate represents amorphous dapoxetine in stabilized form.
  • the invention further provides various processes for the preparation of stabilized amorphous dapoxetine in the form of the intermediate according to the invention.
  • tablettes are to be understood as meaning solid pharmaceutical preparations which contain one dose of an active substance (here: dapoxetine) and usually one or more pharmaceutical excipients. Tablets are usually made by pressing a constant volume of substance particles. Tablets are usually for oral use. They are usually either chewed or swallowed preferably chewed, dissolved in water before dissolution or disintegrated or retained for release of the drug in the oral cavity.
  • active substance here: dapoxetine
  • Tablets are usually for oral use. They are usually either chewed or swallowed preferably chewed, dissolved in water before dissolution or disintegrated or retained for release of the drug in the oral cavity.
  • the tablets according to the invention are preferably tablets which are swallowed whole.
  • they are coated tablets which are composed of a tablet core and a layer applied thereto.
  • the tablets according to the invention contain dapoxetine.
  • dapoxetine comprises (S) - (+) - N, N-dimethyl-1-phenyl-3- (1-naphthalenyloxy) propanamine according to formula (1) above.
  • dapoxetine includes all pharmaceutically acceptable salts as well as hydrates and solvates thereof.
  • the salts may be acid addition salts.
  • suitable salts are hydrochlorides, carbonates, bicarbonates, acetates, lactates, butyrates, Propionates, sulfates, methanesulfonates, citrates, tartrates, nitrates, sulfonates, oxalates and / or succinates.
  • Dapoxetine is preferably used in the context of this invention in the form of the hydrochloride.
  • the tablets according to the invention have a uniformity of the content of 85% to 115%. (That is, all tablets have an active ingredient content between 85% and 15% of the average active ingredient content.) Preferably, the tablets according to the invention have a uniformity of content of from 90 to 110%, more preferably from 95% to 105%, even more preferably from 96% to 104%, more preferably from 97% to 103% and especially from 98% to 102%.
  • Content Unjformity is determined according to the European Pharmacopoeia (hereafter Ph. Eur.), Issue 6.0, 2008, Section 2.9.6, Examination A. The stated values of the uniformity of the content refer in the context of this invention to a tablet production on a production scale. For this purpose, the dapoxetine content determined by HPLC / UV in 10 randomly sampled from a production batch of 100,000 tablets individually:
  • the following measuring conditions are to be selected.
  • the tablets according to the invention (or the tablets produced by the method according to the invention) usually have an active ingredient content of more than 10 to 60 wt .-%, preferably from 12 to 55 wt .-%, more preferably from 15 to 50 wt .-%, more preferably from 20 to 45 wt .-%, in particular from 22 to 40 wt .-%, on.
  • the active ingredient content relates, as already explained above, in the case of coated tablets to the total weight of the tablet core. In the case of uncoated tablets, the active ingredient content refers to the total weight of the tablet.
  • the tablets according to the invention (or the tablets produced by the process according to the invention) contain 1, 0 to 5.0 wt .-%, more preferably 1, 1 to 4.0 wt .-%, even more preferably 1 , 2 to 3.0 parts by weight, particularly preferably 1, 3 to 2.5 wt .-%, in particular 1, 5 to 2.0 wt .-%, lubricant.
  • the lubricant content refers in the case of coated tablets on the total weight of the tablet core. In the case of uncoated tablets, the lubricant content refers to the total weight of the tablet.
  • Lubricants are generally agents that lead to a reduction in static friction, sliding friction and / or rolling friction. In particular, lubricants reduce the shear forces occurring at the interface between the tablet and the die. Preferably, lubricants are used in solid form. Preference is given to lubricants which lead to an R value of 0.90 to 0.99, in particular 0.92 to 0.98. The so-called
  • R value is a measure of the effectiveness of the lubricant. The R value is measured on instrumented eccentric presses by comparing the force on the upper punch with the
  • R force at upper punch / force at lower punch.
  • Suitable lubricants are for example stearic acid, adipic acid, behenic acid, myristic acid, lauric acid, capric acid, palmitic acid and derivatives thereof, particularly Esterderivate are examples of suitable lubricants are glycerol monostearate, glycerol monopalmitate, sorbitan fatty acid ester (Arlacel ® - products), Polyethylenoxidfettklaer (Ethofats ®), Polyvinylmyristat,
  • Polyvinyl stearate Polyvinyl stearate, diglycol stearate, stearic acid, adipic acid, stearyl alcohol, myristyl alcohol, cetyl alcohol, sodium stearyl fumarate, calcium stearate,
  • Aluminum stearate, zinc stearate and / or magnesium stearate are used.
  • polyethylene glycol having a weight average molecular weight of 1000 to 10,000 g / mol, in particular in the form of a particulate composition having a volume average particle size of 0, 1 to 20 microns, more preferably from 1 to 10 ⁇ a than Lubricants are used.
  • talc or defatted milk powder can be used.
  • inorganic lubricants may be used based on aluminum silicates, for example aluminum hydrosilicates (Gleitol ®) or bolus alba.
  • the tablets according to the invention are obtainable by compressing dapoxetine in the form of a particulate active ingredient composition having an average particle size (D50) of 0.5 to 150 .mu.m, more preferably from 1 to 80 .mu.m, even more preferably from 2 to 50 .mu.m , particularly preferably from 3 to 35 .mu.m, in particular from 4 to 20 .mu.m, together with pharmaceutical excipients.
  • D50 average particle size
  • dapoxetine is in the form of the particulate Composition having the above-defined particle size is preferably used in the process according to the invention.
  • the particle sizes given above are based on dapoxetine in crystalline or amorphous form.
  • mean particle diameter in the context of this invention always refers to the D50 value of the volume-average particle diameter, which was determined by means of laser diffractometry.
  • the average particle diameter also referred to as the D50 value of the integral volume distribution, is defined in the context of this invention as the particle diameter at which 50% by volume of the particles have a smaller diameter than the diameter corresponding to the D50 value. Likewise, then 50% by volume of the particles have a larger diameter than the D50 value.
  • average particle size and average particle diameter are used interchangeably throughout this application.
  • the tablets according to the invention (or the tablets produced by the process according to the invention) preferably have a tablet height to weight ratio of 0.005 to 0.3 mm / mg, more preferably 0.01 to 0.2 mm / mg.
  • the tablets according to the invention preferably have a hardness of from 50 to 150 N, particularly preferably from 60 to 120 N, on. Hardness is calculated according to Ph.Eur. 6.0, section 2.9.8.
  • the tablets of the present invention have the above-mentioned hardness, in particular, by using the aforementioned preferred amount of lubricant (e.g., 1 to 3% by weight).
  • the tablets according to the invention (or the tablets produced by the process according to the invention) preferably show a friability of less than 5%, more preferably less than 3.0%, in particular less than 1.0%.
  • the friability is calculated according to Ph.Eur. 6.0, Section 2.9.7.
  • the tablets according to the invention contain dapoxetine in amorphous form.
  • Solid amorphous materials are isotropic in contrast to the anisotropic crystals. They usually have no defined melting point, but gradually go over slow softening in the liquid state. Their experimental differentiation of crystalline materials can be done by X-ray diffraction, which gives them no sharp, but usually only a few diffuse interferences at small diffraction angles.
  • the amorphous dapoxetine is in stabilized form, i. in the form of an intermediate containing amorphous dapoxetine and adhesive.
  • the intermediate according to the invention can generally be used for the formulation of medicaments. It is preferably used in the dry processing method according to the invention, in particular dry granulation method or in a direct compression.
  • the dry granulation process of the present invention is a process for producing tablets containing dapoxetine or a pharmaceutically acceptable salt thereof and adhesives comprising the steps
  • dapoxetine e.g., amorphous dapoxetine in the form of the intermediates of the invention or crystalline dapoxetine
  • Adhesion agents and optionally further pharmaceutical excipients (U) compaction into a scab; (iii) granulation of the slug;
  • the tablet can also be produced by direct compression.
  • Direct compression is particularly preferred when dapoxetine is used in amorphous form or when dapoxetine is given in crystalline form together with the amount of lubricant indicated above as preferred (eg 1 to 3%).
  • the direct compression corresponds to the method described above, omitting the steps (ii) and (Ui).
  • the subject of the invention is a process for the preparation of dapoxetine tablets by direct compression, comprising the steps
  • the invention likewise provides a process for the preparation of dapoxetine tablets by direct compression, comprising the steps of (i) mixing crystalline dapoxetine with adhesion agent, lubricant and, if appropriate, further pharmaceutical excipients, the amount of lubricant being from 1 to 5% by weight, preferably 1, From 1 to 4.0% by weight, more preferably from 1.2 to 3.0% by weight, particularly preferably from 1.3 to 2.5% by weight, in particular from 1.5 to 2.0% by weight , is; (iv) compression of the resulting mixture into tablets, optionally with the addition of further pharmaceutical excipients; and (v) optionally overdrawing, in particular filming the tablets.
  • the lubricant content refers in the case of coated tablets on the total weight of the tablet core. In the case of uncoated tablets, the lubricant content refers to the total weight of the tablet.
  • step (i) dapoxetine and adhesives, and optionally other pharmaceutical excipients (described below) are mixed.
  • the mixing can be done in conventional mixers.
  • the mixing in positive mixers or gravity mixers can be done, for example by Turbula ® T 1Ob (Bachofen AG, Switzerland).
  • Turbula ® T 1Ob Turbula ® T 1Ob (Bachofen AG, Switzerland).
  • the dapoxetine is first mixed with only a part of the excipients (eg 50 to 95%) before compaction (ii) and that the remaining part of the adjuvants is added after the granulation step (iii).
  • the admixing of the excipients should preferably take place before the first compaction step, between several compaction steps or after the last granulation step.
  • the mixing conditions in step (i) and / or the compacting conditions in step (ii) are usually selected to cover at least 30% of the surface area of the resulting dapoxetine particles with adhesive, more preferably at least 60% of the surface, most preferably at least 80 % of the surface, in particular at least 95% of the surface.
  • step (U) of the process according to the invention the mixture from step (i) is compacted into a rag.
  • This is dry compaction, i. the compaction is preferably carried out in the absence of solvents, in particular in the absence of organic solvents.
  • the compaction is preferably carried out in a roll granulator.
  • the rolling force is usually 3 to 70 kN / cm, preferably 5 to 40 kN / cm, more preferably 10 to 30 kN / cm.
  • the gap width of the rolling granulator is, for example, 0.8 to 5 mm, preferably 1 to 4 mm, more preferably 1.5 to 3 mm, in particular 1.8 to 2.8 mm.
  • the compacting device used preferably has a cooling device. In particular, it is cooled in such a way that the temperature of the compactate 50 0 C, in particular 40 0 C, does not exceed.
  • step (iii) of the process the slug is granulated.
  • the granulation can be carried out by methods known in the art.
  • the granulation is carried out with the device Comil ® U5 (Quadro Engineering, USA).
  • the granulation conditions are selected such that the resulting particles (granules) have a volume average particle size ((D 50 ) value) of 50 to 800 microns, more preferably 100 to 550 microns, even more preferably 150 to 400 microns , in particular from 200 to 350 microns.
  • D 50 volume average particle size
  • the granulation conditions can be selected so that not more than 55% of the particles have a size of less than 200 microns or the average particle diameter (D50) is between 100 and 450 microns.
  • the granulation conditions are preferably selected so that the resulting granules have a bulk density of 0.2 to 0.85 g / ml, more preferably 0.3 to 0.8 g / ml, especially 0.4 to 0.7 g / ml exhibit.
  • the Hausner factor is usually in the range of 1, 03 to 1, 3, more preferably from 1, 04 to 1, 20 and in particular from 1, 04 to 1, 15.
  • "Hausner factor” is the ratio of tamped density understood to bulk density.
  • the granulation is carried out in a sieve mill.
  • the mesh size of the sieve insert is usually 0.1 to 5 mm, preferably 0.5 to 3 mm, more preferably 0.75 to 2 mm, in particular 0.8 to 1, 8 mm.
  • the method is adapted such that a multiple compaction takes place, wherein the granulate resulting from step (111) is recycled once or several times for compaction (U).
  • the granules from step (iii) are preferably recycled 1 to 5 times, in particular 2 to 3 times.
  • the granules resulting from step (iii) can be processed into pharmaceutical dosage forms.
  • the granules are filled, for example, in sachets or stickpacks.
  • the invention therefore also relates to stick packs and sachets containing a granulated pharmaceutical composition obtainable by the dry granulation process according to the invention.
  • step (iv) compression into tablets occurs.
  • the compression can be done with tableting machines known in the art.
  • the compression is preferably carried out in the absence of solvents.
  • Suitable tableting machines are eccentric presses or concentric presses.
  • a fats ® 102i (Fette GmbH, Germany) are used.
  • step (iv) of the process pharmaceutical excipients may optionally be added to the granules of step (iii).
  • the amounts of excipients added in step (iv) usually depend on the type of tablet to be prepared and on the amount of excipients already added in steps (i) or (ii).
  • step (v) of the process according to the invention the tablets from step (iv) are coated, preferably film-coated.
  • coatings without influence on the drug release, enteric coatings, and delayed-release coatings are possible.
  • Coatings that do not affect drug release are usually water-soluble (preferably have a water solubility greater than 250 mg / ml).
  • Enteric coatings have a pH-dependent solubility.
  • Retarded coatings are usually not water-soluble (preferably they have a water solubility of less than 10 mg / ml at 20 0 C).
  • the coating (e) preferably for the coating (e), usually macromolecular substances are used, for example modified celluloses, polymethacrylates, polyvinylpyrrolidone, polyvinyl acetate phthalate, zein and / or shellac or natural gums, such as carrageenan.
  • macromolecular substances for example modified celluloses, polymethacrylates, polyvinylpyrrolidone, polyvinyl acetate phthalate, zein and / or shellac or natural gums, such as carrageenan.
  • film-forming agents which have no effect on drug release are methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), polyvinylpyrrolidone (PVP), polyvinyl acetate (PVA) and mixtures thereof.
  • the polymers mentioned should usually have a weight-average molecular weight of 10,000 to 150,000 g / mol.
  • HPMC in particular HPMC having a weight-average molecular weight of 10,000 to 150,000 g / mol and / or an average degree of substitution of -OCH 3 groups of 1.2 to 2.0.
  • the layer thickness of the coating (e) is usually 0.5 to 100 ⁇ m, in particular 2 to 60 ⁇ m. In the case of immediate-release coatings, the layer thickness is preferably from 1 to 5 ⁇ m. In the case of slow-release coatings, the layer thickness is preferably 10 to 80 ⁇ m, in particular 15 to 60 ⁇ m.
  • an "adhesive" is used in the process according to the invention and the intermediate according to the invention.
  • an adhesion agent is preferably used in the tablet according to the invention.
  • the adhesive is generally a substance capable of stabilizing dapoxetine in compacted or compressed form.
  • the addition of the adhesion agent usually leads to an enlargement of the interparticle surfaces on which bonds can form (for example during the compression process).
  • adhesives are characterized by the fact that they increase the plasticity of the tableting mixture, so that solid tablets are formed during the compression.
  • suitable adhesives are capable of stabilizing dapoxetine in amorphous form.
  • the adhesive is a polymer.
  • the term "adhesive" also includes substances that behave polymer similar. Examples are fats and waxes.
  • the adhesive comprises solid, non-polymeric compounds which preferably have polar side groups. Examples of these are sugar alcohols or disaccharides.
  • the adhesive used in the context of this invention is preferably a polymer having a glass transition temperature (Tg) of greater than 15 0 C, more preferably from 30 0 C to 150 0 C, in particular from 40 0 C to 100 0 C.
  • Tg glass transition temperature
  • the "glass transition temperature” (Tg) is the temperature at which amorphous or partially crystalline polymers change from the solid state to the liquid state. In this case, a significant change in physical characteristics, z. As the hardness and elasticity, a. Below the Tg, a polymer is usually glassy and hard, above the Tg it turns into a rubbery to viscous state.
  • DSC differential scanning calorimetry
  • z. B a device from Mettler Toledo DSC 1 can be used. It is at a heating rate of 1 -20 ° C / min, preferably 5-15 ° C / min or with a cooling rate of 5-25, preferably 10-20 ° C / min, worked.
  • the polymer usable as the adhesive agent preferably has a weight average or number average molecular weight of from 1,000 to 500,000 g / mol, more preferably from 2,000 to 90,000 g / mol.
  • the resulting solution preferably exhibits a viscosity of from 0.1 to 8 mPa * s, more preferably from 0.3 to 7 mPa * s , in particular from 0.5 to 4 mPa-s, measured at 25 0 C, and preferably according to Ph. Eur., 6th edition, Chapter 2.2.10 determined.
  • hydrophilic polymers for the preparation of the intermediate. These are polymers which have hydrophilic groups. Examples of suitable hydrophilic groups are hydroxy, alkoxy, acrylate, methacrylate, sulfonate, carboxylate and quaternary ammonium groups.
  • the intermediate according to the invention may comprise, for example, the following polymers as adhesion agents: polysaccharides, such as hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC, in particular sodium and calcium salts), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), preferably low-substituted hydroxypropylcellulose (L- HPC); microcrystalline cellulose, guar gum, alginic acid and / or alginates; synthetic polymers such as polyvinylpyrrolidone, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and salts thereof, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers (e.g., Kollidon ® VA64, BASF), polyalkylene glycols such as polypropylene glycol or, preferably, polyethylene
  • Polyvinylpyrrolidone preferably having a weight-average molecular weight of from 10,000 to 60,000 g / mol, in particular from 12,000 to 40,000 g / mol, of a copolymer of vinylpyrrolidone and vinyl acetate, in particular having a weight-average molecular weight of, is particularly preferably used as the adhesive 40,000 to 70,000 g / mol and / or polyethylene glycol, in particular having a weight-average molecular weight of 2,000 to 10,000 g / mol, and HPMC, in particular having a weight-average molecular weight of 20,000 to 90,000 g / mol and / or preferably a proportion of methyl groups of 10 to 35% and a proportion of hydroxy groups from 1 to 35%.
  • microcrystalline cellulose in particular those having a specific surface area of 0.7-1.4 m 2 / g.
  • the specific surface area was determined by gas adsorption method according to Brunauer, Emmet and Teller.
  • the determination of the weight-average molecular weight is preferably carried out by gel permeation chromatography.
  • the adhesive also includes solid, non-polymeric compounds which preferably have polar side groups.
  • these are sugar alcohols or disaccharides.
  • suitable sugar alcohols and / or disaccharides are lactose, mannitol, sorbitol, xylitol, isomalt, glucose, fructose, maltose and mixtures thereof.
  • sugar alcohols here also includes monosaccharides. In particular, lactose and mannitol are used as adhesives.
  • dapoxetine and adhesives are used in an amount wherein the weight ratio of dapoxetine to adhesive is 10: 1 to 1:20, more preferably 5: 1 to 1:10, even more preferably 2: 1 to 1: 5 , in particular 1: 1 to 1: 3.
  • the adhesive is used in particulate form and the volume-average particle size (D50) of the adhesive is less than 500 ⁇ m, preferably 5 to 300 ⁇ m, in particular 50 to 250 ⁇ m.
  • Another object of the invention is a method for identifying a pharmaceutical excipient which is suitable as an adhesion agent for amorphous dapoxetine, and thus can be used for the preparation of the intermediate according to the invention.
  • the method comprises the steps:
  • a device of Mettler Toledo DSC 1 can be used. It is at a heating rate of 1 -20 ° C / min, preferably 5-15 ° C / min, or at a cooling rate of 5-25 ° C / min, preferably 10 -20 ° C / min, worked.
  • the invention also relates to intermediates containing amorphous dapoxetine and a pharmaceutical excipient selected by means of the methods described above.
  • the type and amount of the adhesive agent be chosen so that the resulting intermediate has a glass transition temperature (Tg) of more than 20 0 C, preferably> 30 0 C.
  • the type and amount of the polymer be chosen so that the resulting intermediate is storage stable.
  • storage-stable is meant that in the intermediate according to the invention after 3 years storage at 25 0 C and 50% relative humidity, the proportion of crystalline dapoxetine - based on the total amount of dapoxetine - not more than 60% by weight, preferably not more than 30% by weight. %, more preferably at most 15 wt .-%, in particular at most 5 wt .-%, is.
  • the intermediates according to the invention additionally comprise, in addition to amorphous dapoxetine and adhesive, a crystallization inhibitor based on an inorganic salt, an organic acid or a polymer having a weight-average molecular weight (Mw) greater than 500,000 g / mol.
  • Mw weight-average molecular weight
  • these polymers which are suitable as crystallization inhibitors are also referred to as "highly viscous polymers.”
  • Their weight-average molecular weight is usually less than 5,000,000 g / mol
  • a preferred high-viscosity polymer is polyvinylpyrrolidone, preferably having the above-mentioned molecular weight, in particular having a weight-average molecular weight from 600,000 to 900,000 g / mol.
  • the crystallization inhibitor is preferably ammonium chloride, citric acid or povidone K 90 (according to Ph. Eur. 6.0).
  • the crystallization inhibitor may generally be used in an amount of from 1 to 30% by weight, preferably from 2 to 25% by weight, more preferably from 5 to 20% by weight, based on the total weight of the intermediate.
  • the intermediates according to the invention can be obtained by various preparation processes.
  • the invention further provides a process for the preparation of the intermediate according to the invention.
  • five preferred embodiments for such a method will be explained.
  • the invention relates to a freeze-drying method, i. a process for the preparation of the intermediate according to the invention, comprising the steps
  • step (a) dapoxetine, preferably crystalline dapoxetine and the above-described adhesive, dissolved in a solvent or solvent mixture, preferably completely dissolved.
  • Suitable solvents are e.g. Water, alcohol (e.g., methanol, ethanol, isopropanol), dimethyl sulfoxide (DMSO), acetone, butanol, ethyl acetate, heptane, pentanol, or mixtures thereof. Preference is given to water, in particular "Aqua purificata” according to Ph.Eur. 6.0 used.
  • Suitable adhesives in this embodiment are in particular modified celluloses such as HPMC and sugar alcohols such as isomalt, mannitol and sorbitol.
  • the intermediate to be prepared additionally contains a crystallization inhibitor based on an inorganic salt or an organic acid or a highly viscous polymer, this may likewise be added in step (a1).
  • a crystallization inhibitor based on an inorganic salt or an organic acid or a highly viscous polymer
  • the solution from step (al) is cooled to about 10 0 C to 50 ° C below the freezing point (ie brought to freezing). Subsequently, the solvent is removed by sublimation. This is preferably done when the conductivity of the solution is less than 2%.
  • the sublimation temperature is preferably determined by the intersection of product temperature and Rx - 10 0 C. Sublimation is preferably at a pressure of less than 0.1 mbar. After sublimation, the lyophilized intermediate is warmed to room temperature.
  • the process conditions in this first embodiment are preferably selected such that the resulting intermediate particles have a volume-average particle diameter (D50) of from 1 to 250 ⁇ m, more preferably from 2 to 15 ⁇ m, in particular from 3 to 30 ⁇ m.
  • D50 volume-average particle diameter
  • the invention relates to a "pellet layering process", i. a process for the preparation of the intermediate according to the invention, comprising the steps
  • step (b2) spraying the solution from step (a2) onto a carrier core.
  • step (a2) dapoxetine, preferably crystalline dapoxetine and the above-described adhesive, dissolved in a solvent or solvent mixture, preferably completely dissolved.
  • Suitable solvents are e.g. Water, alcohol (e.g., methanol, ethanol, isopropanol), dimethyl sulfoxide (DMSO), acetone, butanol, ethyl acetate, heptane, pentanol, or mixtures thereof. Preference is given to water, in particular "Aqua purtficata” according to Ph.Eur. 6.0 used.
  • Suitable adhesives in this second embodiment are in particular modified celluloses such as HPMC, sugar alcohols such as isomalt and sorbitol and polyethylene glycol, in particular polyethylene glycol having a molecular weight of 2,000 to 10,000 g / mol.
  • the intermediate to be prepared additionally contains a crystallization inhibitor based on an inorganic salt or an organic acid or a highly viscous polymer, then this can likewise be added in step (a2).
  • a crystallization inhibitor based on an inorganic salt or an organic acid or a highly viscous polymer
  • step (b2) the solution from step (a2) is sprayed onto a carrier core.
  • Suitable carrier cores are particles consisting of pharmaceutically acceptable adjuvants, in particular so-called “neutral pellets”. To be favoured
  • Used pellets which are available under the trade name Cellets ® and a Mixture of lactose and microcrystalline cellulose contain or Sugarspheres, which represent a mixture of starch and sugar.
  • step (b2) takes place in a fluidized-bed dryer, for example in a Glatt GPCG 3 (Glatt GmbH, Germany). Preference is given to supply air temperatures of 60 0 C to 80 0 C, worked with product temperatures of 30 0 C to 40 0 C and with a spray pressure of 1 to 1, 5 bar.
  • the process conditions in this second embodiment are preferably selected such that the resulting intermediate particles have a volume-average particle diameter (D 50 ) of from 50 to 800 /, more preferably from 150 to 650 /, in particular from 250 to 480 /.
  • D 50 volume-average particle diameter
  • the invention relates to a spray-drying process for the preparation of the intermediate according to the invention, comprising the steps
  • Adhesion agent in a solvent or solvent mixture Adhesion agent in a solvent or solvent mixture
  • the third embodiment is particularly preferred among the six production methods described.
  • step (a3) dapoxetine, preferably crystalline dapoxetine and the above-described adhesive, dissolved in a solvent or solvent mixture, preferably completely dissolved.
  • Suitable solvents are e.g. Water, alcohol (e.g., methanol, ethanol, isopropanol), dimethyl sulfoxide (DMSO), acetone, butanol, ethyl acetate, heptane, pentanol, or mixtures thereof. Preference is given to water, in particular "Aqua purificata” according to Ph.Eur. 6.0 used.
  • Suitable adhesives in this embodiment are in particular modified celluloses such as HPMC, polyvinylpyrrolidone and copolymers thereof and sugar alcohols such as isomalt and sorbitol or mixtures thereof.
  • the intermediate to be prepared additionally contains a crystallization inhibitor based on an inorganic salt or an organic acid or a highly viscous polymer, this can likewise be added in step (a3) become.
  • a crystallization inhibitor based on an inorganic salt or an organic acid or a highly viscous polymer
  • the solution from step (a3) is spray-dried.
  • the spray-drying is usually carried out in a spray tower.
  • a Büchi B-191 is suitable (Büchi Labortechnik GmbH, Germany).
  • an inlet temperature of 10 0 C to 150 0 C, preferably 120 0 C to 140 0 C is selected.
  • the amount of air is for example 500 to 800 liters / hour and the aspirator preferably runs at 80 to 100%.
  • the process conditions in this third embodiment are preferably selected such that the resulting intermediate particles have a volume-average particle diameter (D 50 ) of from 1 to 250 ⁇ m, more preferably from 2 to 100 ⁇ m, particularly preferably from 3 to 45 ⁇ m, in particular from 4 to 20 ⁇ m exhibit.
  • D 50 volume-average particle diameter
  • the invention relates to a melt extrusion process, i. a process for the preparation of the intermediate according to the invention, comprising the steps
  • step (a4) dapoxetine, preferably crystalline dapoxetine with the
  • Adhesion agent preferably mixed in a mixer.
  • an adhesive in polymeric form is used.
  • Suitable polymeric adhesives in this fourth embodiment are in particular polyvinylpyrrolidone and vinylpyrrolidone-vinyl acetate copolymers and also polyvinyl alcohols, methacrylates and HPMC.
  • the intermediate to be prepared additionally contains a crystallization inhibitor based on an inorganic salt or an organic acid or a highly viscous polymer, this can likewise be added in step (a4).
  • a crystallization inhibitor based on an inorganic salt or an organic acid or a highly viscous polymer
  • step (b4) the mixture is extruded.
  • conventional melt extruders can be used.
  • a Leistritz Micro 18 is used.
  • the extrusion temperature depends on the type of polymeric adhesive. Usually it is between 40 0 C and 250 0 C, preferably between 80 0 C and 17O 0 C.
  • the cooled melt is usually comminuted by a rasp screen (e.g., Comil U5) and, consequently, subjected to a uniform grain size.
  • a rasp screen e.g., Comil U5
  • the process conditions in this fourth embodiment are preferably selected such that the resulting intermediate particles have a volume average particle diameter (D 50 ) of 150 to 1000 ⁇ m, more preferably a D 50 of 200 to 800 ⁇ m.
  • D 50 volume average particle diameter
  • the method according to the invention comprises the step
  • Examples are forms for tablets.
  • the invention relates to a milling process, i. a process for the preparation of the intermediate according to the invention, comprising the steps
  • step (b5) grinding the mixture from step (a5), wherein the milling conditions are preferably selected such that a transition from crystalline to amorphous dapoxetine occurs.
  • crystalline dapoxetine and adhesive are mixed in step (a5).
  • the mixture is ground in step (b5).
  • the mixing can be done before or during the milling, i. Steps (a5) and (b5) can be done simultaneously.
  • the intermediate to be prepared additionally contains a crystallization inhibitor based on an inorganic salt or an organic acid, it may also be added in step (a5) or (b5).
  • a crystallization inhibitor based on an inorganic salt or an organic acid
  • the milling conditions are preferably chosen such that a transition from crystalline to amorphous dapoxetine occurs.
  • the grinding is generally carried out in conventional grinding apparatus, preferably in a ball mill, for example in a Retsch ® PM 100th
  • the meal is usually 10 minutes to 5 hours, preferably 20 minutes to 3 hours, more preferably 30 minutes to 2 hours.
  • Suitable adhesives in this fifth embodiment are in particular polyvinylpyrrolidone, modified celluloses such as HPMC, sugar alcohols such as isomalt and sorbitol and polyethylene glycol, in particular polyethylene glycol having a weight-average molecular weight of 2,000 to 10,000 g / mol.
  • the process conditions in this fifth embodiment are preferably selected such that the resulting intermediate particles have a volume-average particle diameter (D 50 ) of 0.1 to 250 ⁇ m, more preferably 1 to 45 ⁇ m, in particular 2 to 20 ⁇ m.
  • D 50 volume-average particle diameter
  • the tablets according to the invention may contain crystalline or amorphous dapoxetine. Furthermore, the tablets according to the invention preferably contain the quantities of lubricant indicated above. The tablets according to the invention also contain the above-described adhesive. In addition, the tablets of the invention may contain further pharmaceutical excipients.
  • auxiliaries used are disintegrants, release agents, emulsifiers, pseudo-emulsifiers, fillers, additives to improve the powder flowability, wetting agents and / or gelling agents.
  • disintegrants are generally referred to substances that accelerate the disintegration of a dosage form, in particular a tablet, after being introduced into water.
  • Suitable disintegrants are e.g. organic disintegrants like
  • alkaline disintegrants can be used.
  • alkaline disintegrating agents disintegrating agents which when dissolved in water produce a pH of more than 7.0.
  • Suitable alkaline disintegrating agents are salts of alkali and alkaline earth metals. Preferred are sodium, potassium, magnesium and calcium.
  • As anions, carbonate, bicarbonate, phosphate, hydrogen phosphate and dihydrogen phosphate are preferred. Examples are sodium hydrogencarbonate, sodium hydrogenphosphate, calcium hydrogencarbonate and the like.
  • the disintegrating agents used are preferably croscarmellose and crospovidone.
  • Disintegrants are usually used in an amount of 0.1 to 15% by weight, preferably 1 to 12% by weight, more preferably 5 to 10% by weight, based on the total weight of the formulation (but without coating), used.
  • the formulation according to the invention optionally contains fillers.
  • Fillers are generally to be understood as meaning substances which serve to form the tablet body in the case of tablets with small amounts of active ingredient (for example less than 70% by weight). That is, fillers produce by "stretching" of the active ingredients sufficient Tablettiermasse. So fillers are usually used to obtain a suitable tablet size.
  • Examples of preferred fillers are starch, starch derivatives, treated starch, talc, calcium phosphate, sucrose, calcium carbonate, magnesium carbonate, magnesium oxide, maltodextrin, calcium sulfate, dextrates, dextrin, dextrose, hydrogenated vegetable oil, kaolin, sodium chloride, and / or potassium chloride. Also Prosolv® ® (Rettenmaier & Söhne, Germany) can be used.
  • Fillers are usually used in an amount of from 0 to 60% by weight, more preferably from 5 to 40% by weight, based on the total weight of the formulation (but without coating).
  • An example of an additive to improve the powder flowability is dispersed silica, such as known under the trade name Aerosil ®. Preference is given to using silicon dioxide having a specific surface area of from 50 to 400 m 2 / g, determined by gas adsorption in accordance with Ph. Eur., 6th edition of 2.9.26.
  • Additives for improving the powder flowability are usually used in an amount of 0.1 to 3% by weight, based on the total weight of the formulation.
  • the unambiguous delimitation is therefore preferably fiction that a substance which is used as a specific excipient for the production of the tablet core, not at the same time as another pharmaceutical excipient for the production of the tablet core is used.
  • a substance which is used as a specific excipient for the production of the tablet core not at the same time as another pharmaceutical excipient for the production of the tablet core is used.
  • microcrystalline cellulose if used as in the amount indicated for adhesives, is not additionally used in the amount indicated for disintegrant (although microcrystalline cellulose exhibits some explosive activity).
  • the tablet according to the invention contains:
  • dapoxetine From 12 to 60% by weight, preferably from 20 to 40% by weight, of dapoxetine, in particular dapoxetine
  • adhesion agent From 20 to 80% by weight, preferably from 25 to 60% by weight, of adhesion agent;
  • the present invention will be illustrated by the following examples.
  • Dapoxetine hydrochloride was dissolved in water, polyvinylpyrrolidone was added and also dissolved. MCC was suspended in the solution. The solution was spray dried with a Büchi® B-191. Aspirator temperature [ 0 C] spray diaper
  • the substances 1-4 were Turbula mixed for 5 min ® and sieved over 0.5 mm and further mixed for 10 min.
  • Substance 5 was added to the mixture and mixed for 5 minutes.
  • the mixture was pressed on an eccentric press (EKO, 9 mm arched).
  • Comparative Example 1 Tabletting crystalline active ingredient according to the prior art
  • the substances 1-4 were Turbula mixed for 5 min ® and sieved over 0.5 mm and further mixed for 10 min.
  • Substance 5 was added to the mixture and mixed for 5 minutes. The mixture was pressed on the eccentric press (9 mm arched).
  • the resulting tablets had an average hardness of 69.8N.
  • Example 3 Tableting crystalline active ingredient with increased lubricant content
  • the substances 1-4 were Turbula mixed for 5 min ® and sieved over 0.5 mm and further mixed for 10 min. Substance 5 was added to the mixture and mixed for 5 minutes. The mixture was pressed on the eccentric press (9 mm arched).
  • Example 4 Tableting crystalline active ingredient with increased lubricant content and increased proportion of active ingredient
  • the substances 1-5 were mixed in the Turbula for 5 minutes and sieved over 0.5 mm, and then mixed for a further 10 minutes.
  • Substance 6 was added to the mixture and mixed for 5 minutes.
  • the mixture was pressed on the eccentric press (9 mm arched).
  • Dapoxetine hydrochloride is compacted together with microcrystalline cellulose and L-HPC at a pressure of 15 kN then through a 0.8 mm sieve granulated (Comü ® U5).
  • the granulated intermediate is mixed with corn starch, croscarmellose and Aerosil ® on a Turbula for 10 minutes. Subsequently, magnesium stearate is sieved through a 0.355 ⁇ m sieve and the final mixture is mixed again for 2 minutes and then compressed on the eccentric press (arched 9 mm).
  • the resulting tablets showed advantageous uniformity of content at a high level of active ingredient.
  • the tablets showed advantageous hardness and rapid disintegration time.
  • Ingredients 1-5 were mixed in a blender for 5 minutes at 15 rpm, then the mixture was poured over a 420 ⁇ va. Sieve sieved. The sieved mixture was mixed for 10 more minutes at 15 rpm, previously sieved magnesium stearate was added to the above mixture and mixed for 5 minutes at 15 rpm.
  • the tablet cores were coated with Opadry II 32k575000 gray.
  • the granulation was carried out with aqueous hydroxypropyl cellulose solution and water.
  • the granules were wet-milled in a Comil ®.
  • the milled granules were dried at 60 ° C. for 15 minutes.
  • LOD of the dried granules was 1.22% (15 minutes at 105 ° C.).
  • the dried granules were milled in a Comil ®.
  • the tablet cores were coated with Opadry II 32k575000 gray.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention porte sur des comprimés contenant de la dapoxétine ou un sel pharmaceutiquement compatible de cette dernière, ainsi que des substances auxiliaires pharmaceutiques, en particulier des agents d'adhésion, les comprimés présentant une uniformité de leur teneur de 85 à 115 %, ainsi que sur un procédé de fabrication à sec permettant de fabriquer ces comprimés. Les comprimés selon l'invention peuvent contenir de la dapoxétine sous forme cristalline ou amorphe. En conséquence, l'invention porte en outre sur un intermédiaire contenant de la dapoxétine sous forme amorphe, et sur un procédé pour sa préparation.
PCT/EP2010/002025 2009-03-31 2010-03-30 Comprimés contenant de la dapoxétine et procédé de traitement à sec pour leur préparation WO2010112203A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP10711165A EP2413910A1 (fr) 2009-03-31 2010-03-30 Comprimés contenant de la dapoxétine et procédé de traitement à sec pour leur préparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102009015702A DE102009015702A1 (de) 2009-03-31 2009-03-31 Tabletten enthaltend Dapoxetin und Trockenverarbeitungsverfahren zu deren Herstellung
DE102009015702.6 2009-03-31

Publications (1)

Publication Number Publication Date
WO2010112203A1 true WO2010112203A1 (fr) 2010-10-07

Family

ID=42136260

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2010/002025 WO2010112203A1 (fr) 2009-03-31 2010-03-30 Comprimés contenant de la dapoxétine et procédé de traitement à sec pour leur préparation

Country Status (3)

Country Link
EP (1) EP2413910A1 (fr)
DE (1) DE102009015702A1 (fr)
WO (1) WO2010112203A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103130661A (zh) * 2011-11-25 2013-06-05 厦门福满药业有限公司 盐酸达泊西汀的晶体、无定形物及其制备方法
WO2013082003A1 (fr) * 2011-11-29 2013-06-06 Gilead Pharmasset Llc Compositions et méthodes pour traiter le virus de l'hépatite c
US8889159B2 (en) 2011-11-29 2014-11-18 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
US9393256B2 (en) 2011-09-16 2016-07-19 Gilead Pharmasset Llc Methods for treating HCV
US9814679B2 (en) 2009-06-05 2017-11-14 Euro-Celtique S.A. Tamper resistant dosage form comprising a matrix and melt-extruded particulates comprising a drug
US10039779B2 (en) 2013-01-31 2018-08-07 Gilead Pharmasset Llc Combination formulation of two antiviral compounds
CN113181127A (zh) * 2021-05-07 2021-07-30 苏州康恒研新药物技术有限公司 一种盐酸达泊西汀微丸片的制备方法

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102009058321A1 (de) * 2009-12-15 2011-06-16 Ratiopharm Gmbh Schmelztablette, enthaltend Dapoxetin
WO2013180675A1 (fr) * 2012-05-28 2013-12-05 Mahmut Bilgic Formulation en comprimés comprenant de la dapoxétine
WO2014140159A1 (fr) * 2013-03-13 2014-09-18 Ratiopharm Gmbh Forme dosifiée comprenant du crizotinib

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0288188A1 (fr) 1987-04-09 1988-10-26 Eli Lilly And Company 1-Phényl-3-naphtalényloxy-propénamines
EP1225881B1 (fr) 1999-09-03 2006-02-22 APBI Holdings, LLC Utilisation de dapoxetine, un inhibiteur selectif de recaptage de serotonine a action rapide, pour traiter un dysfonctionnement sexuel
WO2008035358A2 (fr) * 2006-06-05 2008-03-27 Cadila Healthcare Limited Procédé de préparation de la dapoxetine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0288188A1 (fr) 1987-04-09 1988-10-26 Eli Lilly And Company 1-Phényl-3-naphtalényloxy-propénamines
EP1225881B1 (fr) 1999-09-03 2006-02-22 APBI Holdings, LLC Utilisation de dapoxetine, un inhibiteur selectif de recaptage de serotonine a action rapide, pour traiter un dysfonctionnement sexuel
WO2008035358A2 (fr) * 2006-06-05 2008-03-27 Cadila Healthcare Limited Procédé de préparation de la dapoxetine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SORBERA L A ET AL: "Dapoxetine Hydrochloride", DRUGS OF THE FUTURE, PROUS SCIENCE, ES LNKD- DOI:10.1358/DOF.2004.029.12.865936, vol. 29, no. 12, 1 January 2004 (2004-01-01), pages 1201 - 1205, XP002472308, ISSN: 0377-8282 *
STRICKLAND ET AL., J. AM. PHARM. ASS., SCI. ED., vol. 45, 1956, pages 51

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9814679B2 (en) 2009-06-05 2017-11-14 Euro-Celtique S.A. Tamper resistant dosage form comprising a matrix and melt-extruded particulates comprising a drug
US10456414B2 (en) 2011-09-16 2019-10-29 Gilead Pharmasset Llc Methods for treating HCV
US9393256B2 (en) 2011-09-16 2016-07-19 Gilead Pharmasset Llc Methods for treating HCV
CN103130661A (zh) * 2011-11-25 2013-06-05 厦门福满药业有限公司 盐酸达泊西汀的晶体、无定形物及其制备方法
CN103130661B (zh) * 2011-11-25 2014-09-17 厦门福满药业有限公司 盐酸达泊西汀的晶体、无定形物及其制备方法
MD4430C1 (ro) * 2011-11-29 2017-03-31 Gilead Pharmasset Llc Compoziţii şi metode de tratament al hepatitei virale C
US9549941B2 (en) 2011-11-29 2017-01-24 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
EA027296B1 (ru) * 2011-11-29 2017-07-31 Джилид Фармассет Ллс Композиции и способы лечения вирусного гепатита c
US8889159B2 (en) 2011-11-29 2014-11-18 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
WO2013082003A1 (fr) * 2011-11-29 2013-06-06 Gilead Pharmasset Llc Compositions et méthodes pour traiter le virus de l'hépatite c
EP3777867A1 (fr) * 2011-11-29 2021-02-17 Gilead Pharmasset LLC Composition et procédés pour le traitement du virus de l'hépatite c
US10039779B2 (en) 2013-01-31 2018-08-07 Gilead Pharmasset Llc Combination formulation of two antiviral compounds
CN113181127A (zh) * 2021-05-07 2021-07-30 苏州康恒研新药物技术有限公司 一种盐酸达泊西汀微丸片的制备方法

Also Published As

Publication number Publication date
EP2413910A1 (fr) 2012-02-08
DE102009015702A1 (de) 2010-10-07

Similar Documents

Publication Publication Date Title
EP2413910A1 (fr) Comprimés contenant de la dapoxétine et procédé de traitement à sec pour leur préparation
EP2355802A1 (fr) Produits intermédiaires et formes galéniques orales contenant de la lénalidomide
EP2364141B1 (fr) Moxifloxacine compactée
EP2408431A1 (fr) Rétigabine solide sous forme non cristalline
EP2415460A1 (fr) Formulations pour l'administration orale de prégabaline
WO2012010669A2 (fr) Médicament d'administration orale contenant un mélange de silodosine et d'un copolymère basique
EP2309995A1 (fr) Formulation pharmaceutique pour la réduction de la pression artérielle pulmonaire
EP2334284A2 (fr) Cinacalcet compacté
EP2309996A2 (fr) Ambrisentan amorphe
WO2008148731A1 (fr) Préparation pharmaceutique pour produire des comprimés à délitement rapide
EP2560621A1 (fr) Fingolimod sous la forme de solution solide
EP2490674A2 (fr) Cinacalcet granulé par fusion
DE102008057284A1 (de) Tabletten enthaltend Lenalidomid und Adhäsionsverstärker
EP2408424A2 (fr) Transformation à sec de rétigabine
EP2379058A1 (fr) Comprimés de rétigabine, de préférence à libération modifiée
WO2011138037A2 (fr) Tapentadol solide sous forme non cristalline
DE202021003994U1 (de) Dosierungsform mit verlängerter Freisetzung von Tapentadol-Phosphorsäuresalz
EP2445484A1 (fr) Aprépitant sous forme de solution solide
EP3995135B1 (fr) Formes pharmaceutiques avec libération prolongée d'un sel de tapentadol avec l - (+) - acide tartrique
WO2022101247A1 (fr) Formes posologiques à libération prolongée d'un sel de tapentadol avec de l'acide l-(+)-tartrique
DE102008057285A1 (de) 3-(4-Amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidindion in Form einer festen Lösung
DE202020005470U1 (de) Darreichungsformen mit verlängerter Freisetzung eines Salzes von Tapentadol mit L-(+)-Weinsäure
EP2382967A1 (fr) Aliskiren sous forme d'une dispersion solide
DE102008057335A1 (de) Amorphes Lenalidomid

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: 10711165

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2010711165

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载