WO2017055935A1 - Co-précipités amorphes de flibansérine - Google Patents

Co-précipités amorphes de flibansérine Download PDF

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Publication number
WO2017055935A1
WO2017055935A1 PCT/IB2016/050847 IB2016050847W WO2017055935A1 WO 2017055935 A1 WO2017055935 A1 WO 2017055935A1 IB 2016050847 W IB2016050847 W IB 2016050847W WO 2017055935 A1 WO2017055935 A1 WO 2017055935A1
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Prior art keywords
flibanserin
amorphous
precipitate
hypromellose
solvent
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PCT/IB2016/050847
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English (en)
Inventor
Dodda Mohan Rao
Vanga MALLA REDDY
Ambati Anna Reddy
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Symed Labs Limited
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Publication of WO2017055935A1 publication Critical patent/WO2017055935A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin

Definitions

  • the present invention relates to stable amorphous co-precipitates of Flibanserin with pharmaceutically acceptable excipients, methods for the preparation, pharmaceutical compositions, and method of treating thereof.
  • U.S. Patent No. 5,576,318 discloses pharmacologically active benzimidazolone derivatives and their salts, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds possess central serotonergic activity and are useful in the treatment of central nervous system (CNS) disorders.
  • CNS central nervous system
  • Flibanserin chemically named as l-[2-[4-[3-(trifluoromethyl)phenyl]-l- piperazinyl]ethyl]-2,3-dihydro- 1 H-benzimidazol-2-one, has agonist activity at 5-HTJA and antagonist activity at 5-HT 2 A- Flibanserin also has moderate antagonist activities at the 5-HT 2 B, 5-HT 2 C, and D 4 receptors.
  • Flibanserin is represented by the following structural formula I:
  • Flibanserin is sold by Sprout under the brand name ADDYI and it is orally administered as tablets containing 100 mg of Flibanserin.
  • ADDYI is indicated for the treatment of premenopausal women with acquired or generalized hypoactive sexual desire disorder (HSDD).
  • HSDD generalized hypoactive sexual desire disorder
  • Flibanserin is analogously prepared (as per the process exemplified in Example 1) by reacting l-(2- chloroethyl)-2,3-dihydro- 1 H-benzimidazol-2-one with 1 -(3-trifluoromethyl- phenyl)piperazine hydrochloride in the presence of potassium iodide and sodium carbonate in absolute ethanol at reflux temperature to produce a reaction mass.
  • This reaction mass is then subjected to usual work-up procedures, followed extraction into ethyl acetate and then subjected to removal of solvent under vacuum to produce a solid.
  • the resulting solid is then treated with diethylether, filtered and finally recrystallized from isopropanol to produce Flibanserin.
  • U.S. Patent No. 7,420,057 (hereinafter referred to as the '057 patent), assigned to Boehringer, discloses two crystalline forms (polymorph A and polymorph B) of Flibanserin, processes for their preparation, and characterizes the crystalline forms by powder X-ray diffraction (XRPD) peaks, and Differential Scanning Calorimetric thermogram (DSC).
  • XRPD powder X-ray diffraction
  • DSC Differential Scanning Calorimetric thermogram
  • polymorph A of Flibanserin is characterized by DSC having a melting point of about 161°C; and a powder X-ray diffraction spectrum having peaks expressed as 2-thcta angle positions at 5.19, 9.04, 9.33, 10.02, 10.59, 1 1.29, 13.22, 14.59, 15.46, 16.65, 17.08, 17.28, 17.42, 18.14, 18.65, 19.14, 19.82, 20.08, 20.38, 21.21, 21.89, 22.63, 23.21, 24.35, 24.61 , 24.99, 25.26, 26.57, 27.15, 27.31, 27.86, 28.21, 28.32, 28.65, 29.52, 30.25, 31.10 and 31.90 degrees.
  • Polymorph B is characterized by a DSC thermogram having a melting point of about 120°C. The ⁇ 57 patent also discloses that the polymorph B is less stable than polymorph A under the effects of mechanical stress produced by grinding.
  • Polymorphism is the ability of a solid material to exist in more than one form or crystal structure.
  • Amorphous solids consist of disordered arrangement of molecules and do not possess a distinguishable crystal lattice.
  • the amorphous form is generally more soluble than the crystalline form and thus contributes more in the bioavailability.
  • An important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid.
  • the rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered pharmaceutical compound may reach the patient's bloodstream.
  • the rate of dissolution is a consideration in formulating syrups, elixirs and other liquid medicaments.
  • the solid state form of a compound may also affect its behavior on compaction and its storage stability.
  • Amorphous co-precipitates alternatively named as solid dispersions, of
  • amorphous co-precipitates solid dispersions of Flibanserin free base with various pharmaceutically acceptable excipients, in different ratios, such as hypromellose (also called as hydroxypropyl methylcellulose or HPMC), lactose monohydrate, microcrystalline cellulose, polyvinylpyrrolidone (also called as povidone or PVP), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hypromellose phthalate (also called as hydroxypropyl methylcellulose phthalate or HPMCP), maltodextnn, cyclodextrin, copovidone, and the like. It has been found that the Flibanserin forms amorphous co-precipitates with few specific excipients like hypromellose, lactose monohydrate and microcrystalline cellulose when a specific solvent or a solvent medium is employed.
  • hypromellose also called as hydroxypropyl methylcellulose or HPMC
  • lactose monohydrate
  • amorphous co-precipitates of Flibanserin free base with a pharmaceutically acceptable excipient is selected from the group consisting of hypromellose, lactose monohydrate and microcrystalline cellulose.
  • the amorphous co-precipitates of Flibanserin disclosed herein have high purity, adequate stability and better solubility and dissolution properties.
  • the solubility of drugs in water and in buffer solutions with a pH of 6.8 and pH of 7.4 is fundamentally important for drug development and manufacturing.
  • Drugs administered orally as a solid or in suspension have to dissolve in the aqueous gastric fluid before they can be absorbed and transported via the systemic circulation to their site of action.
  • the rate and extent of dissolution of a drug is a major factor in controlling the absorption of that drug. This is because the concentration of the drug in the fluid in the gut lumen is one of the main factors governing the transfer of the drug through the membranes of the gastrointestinal tract (GIT).
  • GIT membranes of the gastrointestinal tract
  • the rate of dissolution depends on the surface of the solid, which is dependent on both the physical nature of the dosage form of the drug and the chemical structure of the drug. However, the extent of dissolution depends only on the drug's solubility.
  • the amorphous co-precipitate of Flibanserin with hypromellose of the present invention can be advantageously used for immediate release and extended release dosage forms as it shows better solubility in water as well as in the buffer solutions with a pH of 6.8 and pH of 7.4, and it is also having good solubility in 0.1N HC1, thereby having improved bioavailability when compared to the crystalline form of Flibanserin free base.
  • compositions comprising the amorphous co-precipitates of Flibanserin and one or more pharmaceutically acceptable excipients.
  • a process for preparing a pharmaceutical formulation comprising combining the amorphous co-precipitates of Flibanserin disclosed herein with one or more pharmaceutically acceptable excipients.
  • the amorphous co-precipitates of Flibanserin disclosed herein for use in the pharmaceutical compositions has a D90 particle size of less than or equal to about 400 microns, specifically about 1 micron to about 300 microns, and most specifically about 10 microns to about 150 microns.
  • Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of Amorphous Co-precipitate of Flibanserin with Hypromellose (5 : 3) obtained according to the example 1.
  • XRPD characteristic powder X-ray diffraction
  • Figure 2 is a characteristic powder X-ray diffraction (XRPD) pattern of Amorphous Co-precipitate of Flibanserin with Hypromellose (5 : 5) obtained according to the example 3.
  • XRPD characteristic powder X-ray diffraction
  • Figure 3 is a characteristic Infrared (IR) spectrum of Amorphous Co-precipitate of Flibanserin with Hypromellose (5 : 3) obtained according to example 1.
  • Figure 4 is a characteristic Infrared (IR) spectrum of Amorphous Co-precipitate of Flibanserin with Hypromellose (5 : 5) obtained according to example 3.
  • the present invention provides amorphous co- precipitates (solid dispersions) comprising Flibanserin and a pharmaceutically acceptable excipient having improved physiochemical characteristics that assist in the effective bioavailability of Flibanserin.
  • the pharmaceutically acceptable excipient is selected from the group consisting of hypromellose (also called as hydroxypropyl methylcellulose or HPMC), lactose monohydrate and microcrystalline cellulose.
  • hypromellose also called as hydroxypropyl methylcellulose or HPMC
  • lactose monohydrate and microcrystalline cellulose.
  • compositions comprising the amorphous co-precipitates of Flibanserin disclosed herein, and one or more pharmaceutically acceptable excipients.
  • the amorphous co-precipitates of Flibanserin with a pharmaceutically acceptable carrier obtained by the processes disclosed herein may be characterized by one or more of their powder X-ray diffraction (XRD) pattern and Infrared absorption (IR) spectrum.
  • XRD powder X-ray diffraction
  • IR Infrared absorption
  • the amorphous co-precipitate of Flibanserin with hypromellose (5 : 3) is characterized by a powder XRD pattern substantially in accordance with Figure 1.
  • the X-ray powder diffraction patterns show a plain halo with no well-defined peaks, thus demonstrating the amorphous nature of the product.
  • the amorphous co-precipitate of Flibanserin with hypromellose is further characterized by an infrared (FT-IR) spectrum having main bands at about 3444, 3199, 3068, 2941 , 2832, 1719, 1697, 1649, 1624, 1588, 1491, 1450, 1359, 1237, 1 165, 1 120, 992, 946, 786, 754, 730 and 693 ⁇ 4 cm '1 substantially in accordance with Figure 3.
  • FT-IR infrared
  • the amorphous co-precipitate of Flibanserin with hypromellose (5 : 5) is characterized by a powder XRD pattern substantially in accordance with Figure 2.
  • the X-ray powder diffraction patterns show a plain halo with no well-defined peaks, thus demonstrating the amorphous nature of the product.
  • the amorphous co-precipitate of Flibanserin with hypromellose (5 : 5) is further characterized by an infra red (FT-IR) spectrum having main bands at about 3447, 3068, 2939, 2836, 1734, 1613, 1495, 1452, 1 122, 947, 789, 755, 732 and 694 ⁇ 4 cm "1 substantially in accordance with Figure 4.
  • FT-IR infra red
  • a process for preparing an amorphous co-precipitate of Flibanserin and a pharmaceutically acceptable excipient comprising:
  • the pharmaceutically acceptable excipient used in step-(a) is selected from the group consisting of hypromellose, lactose monohydrate and microcrystalline cellulose and mixtures thereof.
  • exemplary pharmaceutically acceptable excipients include, but are not limited to, polyvinylpyrrolidone (also called povidone), polyvinyl alcohol, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethylcellulose, polyvinyl acetate, maltodextrins, cyclodextrins, gelatins, hypromellose phthalate, sugars, and combinations comprising one or more of the foregoing hydrophilic carriers.
  • polyvinylpyrrolidone also called povidone
  • polyvinyl alcohol also called povidone
  • methyl cellulose carboxymethyl cellulose
  • sodium carboxymethyl cellulose sodium carboxymethyl cellulose
  • hydroxyethylcellulose polyvinyl acetate
  • maltodextrins cyclodextrins
  • gelatins hypromellose phthalate
  • sugars and combinations comprising one or more of the foregoing hydrophilic carriers.
  • the process can produce amorphous co-precipitates of Flibanserin with the pharmaceutically acceptable excipient in substantially pure form.
  • co-precipitate and solid dispersions as used in the present invention are synonymous and are intended to mean a dispersion of Flibanserin free base in an inert carrier or matrix in a solid state prepared by dissolving Flibanserin free base and one or more pharmaceutical excipients in a solvent or solvent mixture and removing the solvent or solvent mixture.
  • substantially pure amorphous co-precipitate of Flibanserin with the pharmaceutically acceptable excipient refers to the amorphous co-precipitate of Flibanserin having a purity greater than about 99%, specifically greater than about 99.5%, and more specifically greater than about 99.95% (measured by HPLC).
  • the total purity of the amorphous co-precipitate of Flibanserin obtained by the process disclosed herein can be about 99.5% to about 99.99% as measured by HPLC.
  • the amorphous co-precipitates of Flibanserin and hypromellose obtained by the process disclosed herein are stable, consistently reproducible and have good flow properties, and which are particularly suitable for bulk preparation and handling, and these solid dispersions are suitable for formulating Flibanserin free base.
  • the amorphous co-precipitate of Flibanserin with hypromellose as disclosed herein shows better solubility in water (107.14 ⁇ g/ml) than the prior art crystalline form of Flibanserin free base which shows comparatively very low solubility in water (8.25 ⁇ g/ml). This is a distinct advantage from a drug developing and manufacturing standpoint as the dissolution of a drug is directly related to its absorption when administered.
  • the amorphous co-precipitate of Flibanserin with hypromellose of the present invention also shows better solubility (16( ⁇ g/ml) in a buffer solution with a pH of 6.8 than the prior art crystalline form of Flibanserin free base which shows comparatively very low solubility (7.8 ⁇ 1).
  • the amorphous co-precipitate of Flibanserin with hypromellose of the present invention also shows better solubility (129.16 ⁇ / ⁇ ) in a buffer solution with a pH of 7.4 than the prior art crystalline form of Flibanserin free base which shows comparatively very low solubility (12.76 ⁇ / ⁇ 1).
  • the amorphous co-precipitate of Flibanserin with hypromellose of the present invention also shows good solubility (952 ⁇ 3 ⁇ 4/ ⁇ 1) in 0.1N HCl solution with a pH of 1.2 when compared with that of the prior art crystalline form of Flibanserin free base (126( g/ml).
  • the amorphous co-precipitate of Flibanserin with hypromellose as disclosed herein has better Partition Coefficient (log P) values in the solvent systems containing butanol/water and octanol/water 1.582 and 1.33 respectively when compared with that of the log P values (2.5 and 1.372 respectively) of crystalline Flibanserin free base.
  • partition coefficient value is between 1 and 2 the drug has good absorption throughout GIT.
  • the amorphous co-precipitate of Flibanserin with hypromellose disclosed herein has better bioavailability than that of the crystalline Flibanserin free base.
  • the amorphous co-precipitate of Flibanserin with hypromellose of the present invention remains stable and it is in the same amorphous form when stored at a temperature of about 40 ⁇ 2°C and at a relative humidity of about 75 ⁇ 5% for a period of more than 3 months.
  • the amorphous co-precipitate of Flibanserin with hypromellose of the present invention remains stable and it is in the same amorphous form when stored at a temperature of about 30 ⁇ 2°C and at a relative humidity of about 65 ⁇ 5% for a period of more than 3 months.
  • the amorphous co-precipitate of Flibanserin with hypromellose of the present invention remains stable and it is in the same amorphous form when stored at a temperature of about 25 ⁇ 2°C and at a relative humidity of about 60 ⁇ 5% for a period of more than 3 months.
  • the amorphous co-precipitates of Flibanserin disclosed herein are essentially free of crystalline forms, consistently reproducible, do not have the tendency to convert to crystalline forms, and are found to be more stable.
  • the amorphous co-precipitates of Flibanserin disclosed herein exhibit properties making them suitable for formulating Flibanserin. More particularly, disclosed herein are amorphous co-precipitates of Flibanserin with improved physiochemical characteristics which help in the effective bioavailability of Flibanserin.
  • Such pharmaceutical compositions may be administered easily to a mammalian patient in a dosage form with a high rate of bioavailability.
  • amorphous co-precipitates of Flibanserin essentially free of crystalline forms means that no crystalline forms of Flibanserin or the excipient can be detected within the limits of a powder X-ray diffractometer.
  • the solvent used in step-(a) is selected from the group consisting of an alcohol, a ketone, a nitrile, an ester, and mixtures thereof.
  • the solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, acetone, dichloromethane, acetonitrile, tetrahydrofuran, N,N- dimethylformamide, dimethoxyethane, and mixtures thereof.
  • the solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetone, dichloromethane and mixtures thereof.
  • Step-(a) of providing a solution includes dissolving Flibanserin in the solvent, or such a solution may be obtained directly from a reaction in which Flibanserin is formed, and then combining the solution with a pharmaceutically acceptable excipient.
  • the pharmaceutical excipient can be dissolved in a solution containing Flibanserin, or, Flibanserin can be dissolved in a solution containing a pharmaceutical excipient.
  • the solution in step-(a) is prepared by treating an acid addition salt of Flibanserin with a base to liberate Flibanserin free base, followed by extracting or dissolving Flibanserin free base in the solvent and then combining the solution with a pharmaceutically acceptable excipient.
  • the base used herein can be selected from the group consisting of inorganic and organic bases.
  • Exemplary bases include, but are not limited to, methylamine, trimethylarnine, tributylamine, triethyl amine, diisopropylethylamine; and hydroxides, alkoxides, bicarbonates and carbonates of alkali or alkaline earth metals.
  • Specific bases are collidine, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide.
  • Acid addition salts of Flibanserin may be derived from organic and inorganic acids.
  • the acid addition salts are derived from a therapeutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, phosphoric acid, succinic acid, maleic acid, fumaric acid, citric acid, glutaric acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, malic acid, ascorbic acid, and the like.
  • a therapeutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, phosphoric acid, succinic acid, maleic acid, fumaric acid, citric acid, glutaric acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, malic acid, ascorbic
  • Exemplary acid addition salts include, but are not limited to, hydrochloride, hydrobromide, sulphate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, tartrate, and the like.
  • a most specific acid addition salt of Flibanserin is hydrochloride salt.
  • a solution containing Flibanserin can be combined with a solution containing a pharmaceutically acceptable excipient, and the solvents used for preparing the different solutions need not be the same as long as the solvents have mutual solubility and form a single phase.
  • Flibanserin should be completely soluble in the solvents used and should provide a clear solution. The presence of insoluble crystals could lead to the formation of a material that is not completely amorphous.
  • the dissolution is carried out at a temperature of about 20°C to about 100°C, specifically at about 25°C to about 80°C, and more specifically at about 25°C to about 65°C.
  • the solution obtained in step-(a) is optionally be subjected to carbon treatment or silica gel treatment.
  • the carbon treatment or silica gel treatment may be carried out by methods known in the art, for example by stirring the solution with finely powdered carbon or silica gel at a temperature of below about 70°C for at least 5 minutes, specifically at a temperature of about 40°C to about 70°C for at least 30 minutes; and filtering the resulting mixture through hyflo bed to obtain a filtrate containing Flibanserin by removing charcoal or silica gel.
  • a finely powdered carbon is an active carbon.
  • a specific mesh size of silica gel is 40-500 mesh, and more specifically 60-120 mesh.
  • step-(a) The solution obtained in step-(a) is stirred at a temperature of about 20°C to the reflux temperature of the solvent used for at least 10 minutes, and specifically at a temperature of about 20°C to about 60°C for about 20 minutes to about 2 hours.
  • Removal of solvent in step-(c) is accomplished, for example, by substantially complete evaporation of the solvent, concentrating the solution, or distillation of solvent, under inert atmosphere to obtain amorphous co-precipitate comprising Flibanserin and the pharmaceutically acceptable excipient.
  • the removal of solvent in step-(c) is carried out by distillation.
  • the distillation process can be performed at atmospheric pressure or at reduced pressure.
  • the distillation process is performed at reduced pressure.
  • the solvent is removed at a pressure of about 760 mm Hg or less, specifically at about 400 mm Hg or less, more specifically at about 80 mm Hg or less, and most specifically from about 30 to about 80 mm Hg.
  • the distillation process is performed under reduced pressure and at a temperature of about 50°C to about 120°C, and most specifically at a temperature of about 60°C to about 90°C.
  • the solvent is removed by evaporation. Evaporation can be achieved at sub-zero temperatures by lyophilisation or freeze-drying techniques.
  • the solution may also be completely evaporated in, for example, a pilot plant Rota vapor, a Vacuum Paddle Dryer or in a conventional reactor under vacuum above about 720 mm Hg by flash evaporation techniques by using an agitated thin film dryer ("ATFD").
  • ATFD agitated thin film dryer
  • the removal of solvent in step-(c) may also be accomplished by spray-drying.
  • the air inlet temperature to the spray drier used may range from * about 50°C to about 150°C, specifically from about 60°C to about 120°C and most specifically from about 70°C to about 100°C; and the outlet air temperature used may range from about 30°C to about 90°C.
  • the dried product obtained by the process disclosed herein above can optionally be milled to get desired particle sizes. Milling or micronization can be performed prior to drying, or after the completion of drying of the product.
  • the milling operation reduces the size of particles and increases surface area of particles. Drying is more efficient when the particle size of the material is smaller and the surface area is higher, hence milling will frequently be performed prior to the drying operation.
  • Flibanserin as used herein as starting materials can be obtained by the processes described in the prior art, for example, the processes described in the U.S. Patent No. 5,576,318. Milling can be done suitably using jet milling equipment like an air jet mill, or using other conventional milling equipment.
  • the resulting amorphous powder compositions disclosed herein have improved solubility properties and hence also have improved bioavailability.
  • the amorphous co-precipitates of Flibanserin with the pharmaceutically acceptable excipients obtained by the process disclosed herein are a random distribution of the Flibanserin and the pharmaceutically acceptable excipient in a particle matrix.
  • the co-precipitates have the characteristics of solid dispersions at a molecular level, being in the nature of solid solutions.
  • the solid solutions, or molecular dispersions provide homogeneous particles in which substantially no discrete areas of only amorphous Flibanserin and/or only pharmaceutically acceptable excipient can be observed.
  • amorphous co-precipitates of Flibanserin and the pharmaceutically acceptable excipients for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.
  • a specific pharmaceutical composition of the amorphous co-precipitates of Flibanserin is selected from a solid dosage form and an oral suspension.
  • the amorphous co-precipitate of Flibanserin and the pharmaceutically acceptable excipient has a D90 particle size of less than or equal to about 400 microns, specifically about 1 micron to about 300 microns, and most specifically about 10 microns to about 150 microns.
  • the amorphous co-precipitate of Flibanserin and the pharmaceutically acceptable excipient, disclosed herein for use in the pharmaceutical compositions has a D90 particle size of less than or equal to about 400 microns, specifically about 1 micron to about 300 microns, and most specifically about 10 microns to about 150 microns.
  • the particle sizes of the amorphous co-precipitate of Flibanserin and the pharmaceutically acceptable excipient can be achieved by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.
  • a method for treating a premenopausal women with acquired or generalized hypoactive sexual desire disorder comprising administering a therapeutically effective amount of the amorphous co-precipitate of Flibanserin, or a pharmaceutical composition that comprises a therapeutically effective amount of amorphous co-precipitate of Flibanserin along with pharmaceutical ly acceptable excipients.
  • HSDD generalized hypoactive sexual desire disorder
  • compositions comprising amorphous co-precipitate of Flibanserin prepared according to the processes disclosed herein and one or more pharmaceutically acceptable excipients.
  • a process for preparing a pharmaceutical formulation comprising combining amorphous co-precipitate of Flibanserin prepared according to the process disclosed herein, with one or more pharmaceutically acceptable excipients.
  • the pharmaceutical compositions comprise at least a therapeutically effective amount of the amorphous co-precipitate of Flibanserin.
  • Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, elixir, aerosol, syrups, injectable solution, etc.
  • Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes or any other acceptable route of administration.
  • Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, troches, sachets, suspensions, powders, lozenges, elixirs and the like.
  • compositions further contain one or more pharmaceutically acceptable excipients.
  • suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinafter.
  • capsule dosage forms contain the amorphous co-precipitate of Flibanserin within a capsule which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. Suitable enteric coating agents include phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxy methyl ethyl cellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, the coating agents may be employed with suitable plasticizers and/or extending agents.
  • a coated capsule or tablet may have a coating on the surface thereof or may be a capsule or tablet comprising a powder or granules with an enteric-coating.
  • compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors.
  • the compositions described herein may contain diluents such as cellulose-derived materials like powdered lactose monohydrate, cellulose, microcrystalline cellulose, micro fine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art.
  • Suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols such as mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
  • excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.
  • binders such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes
  • disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others
  • lubricants like magnesium and calcium stearate and sodium stearyl fumarate
  • flavorings sweeteners
  • preservatives pharmaceutical
  • the X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X-ray powder diffractometer equipped with a Cu-anode (copper- ⁇ radiation). Approximately 1 gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees 2-theta, at 0.03 degrees to theta per step and a step time of 38.4 seconds. The sample was simply placed on the sample holder. The sample was applied with a voltage of 40 KV and current of 35 mA.
  • FT-IR spectroscopy was carried out with a Bruker vertex 70 spectrometer.
  • a Bruker vertex 70 spectrometer For the production of the KBr compacts approximately 5 mg of sample was powdered with 200 mg of KBr. The spectra were recorded in transmission mode ranging from 3800 cm “ to 650 cm “1 .
  • Flibanserin (5 g) and hydroxypropyl methylcellulose (3 g) were added to methanol (240 ml), followed by heating the mixture at 60-65 °C to form a clear solution. The resulting solution was stirred for 10-15 minutes at the same temperature, followed by removal of the solvent by distillation under reduced pressure at 50-60°C to produce 7.8 g of amorphous co-precipitate of Flibanserin with hydroxypropyl methylcellulose (5 : 3) as a white colored powder.
  • the resulting amorphous co-precipitate of Flibanserin with hydroxypropyl methylcellulose (5 : 3) is characterized by an X-ray powder diffraction pattern, showing a plain halo with no peaks, as shown in Figure 1.
  • Flibanserin (5 g) and hydroxypropyl methylcellulose (5 g) were added to methanol (270 ml), followed by heating the mixture at 60-65°C to form a clear solution. The resulting solution was stirred for 10-15 minutes at the same temperature, followed by removal of the solvent by distillation under reduced pressure at 50-60°C to produce 9.7 g of amorphous co-precipitate of Flibanserin with hydroxypropyl methylcellulose (5 ; 5) as a white colored powder.
  • the resulting amorphous co-precipitate of Flibanserin with hydroxypropyl methylcellulose (5 : 5) is characterized by an X-ray powder diffraction pattern, showing a plain halo with no peaks, as shown in Figure 2.
  • Flibanserin (5 g) and microcrystalline cellulose (3 g) were added to methanol (270 ml), followed by heating the mixture at 60-65 °C to form a clear solution. The resulting solution was stirred for 10-15 minutes at the same temperature, followed by removal of the solvent by distillation under reduced pressure at 50-60°C to produce 7.5 g of amorphous co-precipitate of Flibanserin with microcrystalline cellulose (5 : 3) as a white colored powder.
  • micronization means a process or method by which the size of a population of particles is reduced.
  • micron or " ⁇ ” both are equivalent and refer to “micrometer” which is 1 x 10 "6 meter.
  • P.S.D particle Size Distribution
  • the important characteristics of the PSD are the (D90), which is the size, in microns, below which 90% of the particles by volume are found, and the (D 50 ), which is the size, in microns, below which 50% of the particles by volume are found.
  • D90 or d(0.9) of less than 300 microns means that 90 volume-percent of the particles in a composition have a diameter less than 300 microns.
  • pharmaceutically acceptable means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and includes that which is acceptable for human pharmaceutical use.
  • composition is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.
  • therapeutically effective amount means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
  • delivering means providing a therapeutically effective amount of an active ingredient to a particular location within a host causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host.
  • buffering agent as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali.
  • Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate and other such materials known to those of ordinary skill in the art.
  • sweetening agent as used herein is intended to mean a compound used to impart sweetness to a formulation.
  • Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.
  • binder as used herein is intended to mean substances used to cause adhesion of powder particles in granulations.
  • Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethy 1 cellulose sodium, polyvinylpyrrolidone, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch, starch, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers, collagen, albumin, celluloses in non-aqueous solvents, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, microcrystalline cellulose, combinations thereof and other material known to those of ordinary skill in the art.
  • fillers or “filler” as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage formulations.
  • Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.
  • glidant as used herein is intended to mean agents used in solid dosage formulations to improve flow-properties during tablet compression and to produce an anti-caking effect.
  • Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
  • lubricant as used herein is intended to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage.
  • Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.
  • disintegrant as used herein is intended to mean a compound used in solid dosage formulations to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved.
  • exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pregelatinized, sweeteners, clays, such as bentonite, microcrystalline cellulose, carsium, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.
  • wetting agent as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids.
  • exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxylpropylcellulose, hydroxyprop

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Abstract

La présente invention concerne des co-précipités amorphes stables de flibansérine et un excipient pharmaceutiquement acceptable, des procédés de préparation, des compositions pharmaceutiques, et un procédé de traitement de ceux-ci. D'importants efforts de recherche et d'expérimentation ont été mis en œuvre pour préparer des co-précipités amorphes (dispersions solides) d'une base exempte de flibansérine avec divers excipients pharmaceutiquement acceptables, dans des rapports différents, tels que l'hypromellose (également appelée hydroxypropylméthylcellulose ou HPMC), du lactose monohydraté, de la cellulose macrocristalline, de la polyvinylpyrrolidone (également appelée povidone ou PVP), de l'hydroxypropylcellulose (HPC), de l'hydroxypropylméthylcellulose (HPMC), du phtalate d'hypromellose (également appelé phtalate d'hydroxypropylméthylcellulose ou HPMCP), de la maltodextrine, de la cyclodextrine, de la copovidone, et analogues. Il s'est avéré que la flibansérine forme des co-précipités amorphes avec peu d'excipients spécifiques tels que l'hypromellose, le lactose monohydraté et la cellulose microcristalline lorsqu'un solvant spécifique ou qu'un milieu servant de solvant spécifique est utilisé.
PCT/IB2016/050847 2015-09-30 2016-02-17 Co-précipités amorphes de flibansérine WO2017055935A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010146595A2 (fr) * 2009-06-16 2010-12-23 Symed Labs Limited Nouveaux polymorphes d'hydrochlorure de flibansérine
US20130209519A1 (en) * 2008-02-13 2013-08-15 Sprout Pharmaceuticals Inc. Formulations of flibanserin
US20140154313A1 (en) * 2011-06-08 2014-06-05 Sti Pharma, Llc Controlled Absorption Water-Soluble Pharmaceutically Active Organic Compound Formulation for Once-Daily Administration
US20140329827A1 (en) * 2005-11-08 2014-11-06 Sprout Pharmaceuticals, Inc. Use of flibanserin for the treatment of pre-menopausal sexual desire disorders

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140329827A1 (en) * 2005-11-08 2014-11-06 Sprout Pharmaceuticals, Inc. Use of flibanserin for the treatment of pre-menopausal sexual desire disorders
US20130209519A1 (en) * 2008-02-13 2013-08-15 Sprout Pharmaceuticals Inc. Formulations of flibanserin
WO2010146595A2 (fr) * 2009-06-16 2010-12-23 Symed Labs Limited Nouveaux polymorphes d'hydrochlorure de flibansérine
US20140154313A1 (en) * 2011-06-08 2014-06-05 Sti Pharma, Llc Controlled Absorption Water-Soluble Pharmaceutically Active Organic Compound Formulation for Once-Daily Administration

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