WO2010066749A2 - Ulipristal acetate tablets - Google Patents
Ulipristal acetate tablets Download PDFInfo
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- WO2010066749A2 WO2010066749A2 PCT/EP2009/066652 EP2009066652W WO2010066749A2 WO 2010066749 A2 WO2010066749 A2 WO 2010066749A2 EP 2009066652 W EP2009066652 W EP 2009066652W WO 2010066749 A2 WO2010066749 A2 WO 2010066749A2
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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
- A61K9/20—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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- 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
- A61P15/18—Feminine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/36—Antigestagens
Definitions
- the present invention relates to a ulipristal acetate tablet for oral administration, as well as to the manufacture and uses thereof.
- Ulipristal acetate designates within the context of this application 17 ⁇ -acetoxy-l l ⁇ -[4-JV, ⁇ /-dimethylamino-phenyl)-19-norpregna- 4, 9- diene-3, 20-dione, represented by formula I:
- Ulipristal acetate and methods for its preparation, are described e.g., in US Patent Nos. 4,954,490 ; 5,073,548, and 5,929,262, as well as in international patent applications WO2004/065405 and WO2004/078709.
- Ulipristal acetate possesses antiprogestational and antiglucocorticoidal activity, and has been proposed for contraception, in particular for emergency contraception, and for the therapy of various hormonal diseases. Properties of this compound are further described in Blithe et al, Steroids. 2003 68(10-13): 1013-7. So far, clinical trials have been conducted using oral capsules of ulipristal acetate (Creinin et al, Obstetrics &
- the present invention relates to novel formulations of ulipristal acetate. More specifically, the invention relates to particular oral tablets of micronized ulipristal acetate.
- the inventors have now shown that the bioavailability, and hence the efficiency of ulipristal acetate, can be enhanced when formulating ulipristal acetate as a tablet under particular conditions. More specifically, the inventors have conducted many tests and discovered that the properties of ulipristal acetate can be improved when this compound is formulated as an oral tablet using particular types and amounts of excipients.
- the invention relates to a pharmaceutical tablet for oral administration, comprising ulipristal acetate in an amount of 1 to 18 wt%, together with the following excipients: a diluent in an amount of 50 to 98.5 wt%, a binding agent in an amount of 0 to 10 wt%, a disintegrating agent in an amount of 0.5 to 10 wt%, and a lubricant in an amount of 0 to 10 wt%.
- the invention relates to a pharmaceutical tablet for oral administration, comprising ulipristal acetate in an amount of 3 to 18 wt%, together with the following excipients: a diluent in an amount of 60 to 95 wt%, a binding agent in an amount of 0 to 10 wt%, a disintegrating agent in an amount of 1 to 10 wt%, and a lubricant in an amount of 0 to 5 wt%.
- the invention relates to a pharmaceutical tablet for oral administration, comprising ulipristal acetate in an amount of 3 to 18 wt%, together with the following excipients: a diluent in a total amount of 60 to 95 wt%, croscarmellose sodium in an amount of 1 to 10 wt%, and a lubricant in a total amount of0 to 5 wt%.
- the invention relates to a pharmaceutical tablet for oral administration, comprising ulipristal acetate in an amount of 3 to 18 wt%, together with the following excipients: a diluent in an amount of 60 to 95 wt%, a binding agent in an amount of 0 to 10 wt% (preferably 1 to 10 wt%), croscarmellose sodium in an amount of 1 to 10 wt%, and magnesium stearate in an amount of 0 to 5 wt%.
- a diluent in an amount of 60 to 95 wt%
- a binding agent in an amount of 0 to 10 wt% (preferably 1 to 10 wt%)
- croscarmellose sodium in an amount of 1 to 10 wt%
- magnesium stearate in an amount of 0 to 5 wt%.
- a micronized ulipristal acetate formulation according to the present invention exhibits not only very good pharmacotechnical characteristics (in particular hardness, friability, stability) for the manufacturing of the tablet, but also provides a substantially improved dissolution profile for ulipristal acetate.
- the formulation comprises 10%wt ulipristal acetate and is designed to contain from 5 to 50mg ulipristal acetate.
- a further object of this invention relates to a method of manufacturing a ulipristal acetate tablet, the method comprising mixing the above ingredients and ulipristal acetate and forming a tablet.
- a further object of this invention resides in a method of contraception comprising administering to a subject in need thereof an effective amount of a tablet of this invention.
- a further object of this invention is a ulipristal acetate tablet as defined above as a contraceptive.
- a preferred object of this invention is a ulipristal acetate tablet as defined above, for emergency contraception.
- a further object of this invention resides in a method of treating a hormonal disease, such as uterine leiomyoma, comprising administering to a subject in need thereof an effective amount of a tablet of this invention.
- a further object of this invention is a ulipristal acetate tablet as defined above as a drug for treating a hormonal disease
- Figure 1 Mean ( ⁇ S. D) plasma concentration versus time profiles of ulipristal acetate on linear and log-linear scale. Comparison of the collected data from the tablet comprising 10 mg ulipristal acetate versus the capsule containing 10 mg ulipristal acetate in 120 mg microcristalline cellulose. X-axis: time in hours
- Y-axis Concentration of ulipristal acetate measured in the plasma in ng/mL. The concentration of ulipristal acetate was measured using liquid chromatography with tandem mass spectrometric detection LC-MS/MS, with a validated calibration range in between 0.100-20.0 ng/mL. The sample was later re-assayed using the non specific radioimmunoassay RIA Bioqual Inc.
- FIG. 1 Dissolution profile of a tablet comprising 30 mg ulipristal acetate, with the following excipients: lactose monohydrate 79 wt%, povidone 5 wt%, croscarmellose sodium 5 wt% and magnesium stearate 1 wt%.
- X-axis time in minutes
- Y-axis % dissolved composition
- the present invention relates to novel formulations of ulipristal acetate having improved properties.
- the invention relates to oral tablets comprising ulipristal acetate combined with particular types and amounts of excipients, namely:
- a diluent » means that one diluent or a mixture of several diluents may be used.
- a disintegrant » means that one disintegrant or a mixture of several disintegrants may be used.
- the term « a binding agent » means that one binding agent or a mixture of several binding agents may be used.
- the term “a lubricant” means that one lubricant or a mixture of several lubricants may be used.
- the term “a diluent in an amount of is therefore synonym to "at least one diluent in a total amount of.
- a disintegrant in an amount of is therefore synonym to "at least one disintegrant in a total amount of.
- the term "a binding agent in an amount of is therefore synonym to "at least one binding agents in a total amount of.
- the term "a lubricant in an amount of is therefore synonym to "at least one lubricant in a total amount of.
- the selected excipients allow obtaining of granules having good processing properties (compressibility, flowability) and tablets with improved pharmacotechnical properties: good hardness range, low friability and rapid disintegration.
- the tablets of this invention comprise:
- - ulipristal acetate in an amount of 3 to 18 wt%, preferably 5 to 15 wt%, even more preferably 8-12 wt%, together with the following excipients: - a diluent in an amount of 50 to 98.5 wt%, preferably 60 to 95 wt%, more preferably 65 to 92 wt%, yet even more preferably 70-85 wt%;
- a binding agent in an amount of 0 to 10 wt%, preferably 1 to 10 wt%, more preferably 1.5 to 8.5 wt%,
- a disintegrating agent such as e.g. croscarmellose sodium, in an amount of 0.5 to 10 wt %, preferably 1 to 10 wt%, more preferably 1.5 to 8.5 wt%, and
- a lubricant such as e.g. magnesium stearate, in an amount of 0 to 5 wt%, preferably 0.5 to 4 wt%.
- 'wt%' denotes an amount by weight, as a percentage of the total weight of the composition.
- the total percentage of the ingredients in a tablet adds up to 100.
- the composition comprises from 5-15 wt% of ulipristal acetate, even more preferably from 8-12 wt%, more preferably about 10 wt%.
- a preferred composition of this invention comprises:
- - ulipristal acetate in an amount of 5-15 wt% ; preferably 8-12 wt%, more preferably about 10% , - a diluent in an amount of 65 to 92 wt%,
- a binding agent in an amount of 0 to 10 wt%, preferably 1 to 10 wt%,
- ulipristal acetate is used in a dosage of 1 to 50 mg per tablet, preferably 5 to 30 mg, particularly 10 or 30 mg.
- the diluents may be selected from any pharmaceutically acceptable agents or combinations of agents that increase the bulk quantity of ulipristal acetate so that production of a compressed tablet of practical size is possible.
- the diluent(s) is(are) selected from the group consisting of appropriate salts, monosaccharides, disaccharides, derivative polyols of monosaccharides and hydrates thereof.
- the term 'derivative polyols of monosaccharides' stands for sugar alcohols such as mannitol, xylitol or sorbitol.
- the diluent(s) is(are) selected from the group consisting of calcium phosphate, sodium phosphate, calcium carbonate, sodium carbonate, cellulose, microcrystalline cellulose, lactose monohydrate and mannitol.
- the diluent(s) is(are) selected from the group consisting of calcium phosphate, sodium phosphate, calcium carbonate, sodium carbonate, cellulose, microcrystalline cellulose, lactose monohydrate and mannitol.
- studies were conducted by applicant to evaluate the effect of several distinct diluents on the tablet. Different batches were tested to assess the relative efficiency of the diluents. After addition of croscarmellose 5 wt% and magnesium stearate 1 wt%, compositions with lactose monohydrate or mannitol, 70 to 85 wt%, led to tablets with excellent appearance, compression and flowability properties.
- the diluent(s) is(are) selected from lactose monohydrate, microcrystalline cellulose, and mannitol.
- the diluent is lactose monohydrate is an amount of 65 to 92 wt%, more preferably 70-85 wt%.
- the ratio of diluents: other excipients ranges from about 5 to about 25, preferably from about 7 to about 18, yet preferably from about 7 to about 12.
- the ratio of diluents :ulipristal acetate ranges from about 5 to about 40.
- the ratio of diluents :binding agents preferably ranges from about 10 to about 20.
- the ratio of diluents: disintegrating agents ranges from about 10 to about 80
- the ratio of diluents: lubricants ranges from about 20 to about 90.
- the binding agents may be selected from any pharmaceutically acceptable agents (or combinations of agents) which impart cohesive qualities to powdered materials.
- the binding agents may be selected from starch, gelatin, sugars such as cellulose derivatives (including hydroxypropyl methyl cellulose), and natural and synthetic gums (e.g., alginates) may be used.
- a binding agent of the tablet according to the invention is selected from the group consisting of polymers.
- the binding agent may be a natural polymer material such as polysaccharide, or a synthetic polymer such as a plastic polymer.
- the binding agent is hydroxypropyl methyl cellulose and/or povidone.
- different tablets comprising 1 to 20 wt% of different binding agents (e.g., povidone, hydroxypropyl methyl cellulose or maize starch) were manufactured by wet granulation as described below. Based on these tests, a relative amount of 1-10 wt% binding agent was retained as certain granules obtained with other amounts could not stand the drying step (formation of powder) and/or had lower dissolution profiles.
- binding agents e.g., povidone, hydroxypropyl methyl cellulose or maize starch
- Povidone or hydroxypropyl methyl cellulose gave the best results in that they enabled to obtain granules whatever diluents used (lactose monohydrate or mannitol at 70 to
- Povidone is particularly preferred since very hard and homogeneous granules were obtained with povidone, which could easily stand the drying step.
- the binding agent is or comprises povidone, preferably 1.5% to 8.5 wt% of povidone, even more preferably between 3-7 wt%, most preferably about 5 wt% povidone.
- the ratio of binding agents:other excipients ranges from about 0.025 to about 0.075.
- the ratio of binding agents :ulipristal acetate ranges from about 0.25 to about 0.75.
- the ratio of binding agents: disintegrating agents ranges from about 0.5 to about 1.5.
- the ratio of binding agents: lubricants ranges from about 3 to about 7.
- the present tablets comprise at least one disintegrant which, e.g., facilitates break-up of the tablet.
- Disintegrating agents may be selected from maize starch, alginic acid and croscarmellose sodium.
- croscarmellose sodium may be used alone or in combination with other disintegrants, preferably alone.
- croscarmellose sodium when used in combination with the other ingredients of the present invention, allows to reduce the disintegration time and to keep good pharmacotechnical characteristics when present in an amount of 0.5 to 10 wt/%, preferably 1 to 10 wt/%, yet preferably 1.5 to 8.5 wt%, and more preferably 4.5 to 5.5 wt%, or even more preferably about 5 wt%.
- the ratio of disintegrating agents:other excipients ranges from about 0.005 to about 0.1.
- the ratio of disintegrating agents :ulipristal acetate ranges from about 0.25 to about 0.75.
- the ratio of disintegrating agents: lubricants ranges from about 0.5 to about 7.
- the present tablets comprise one or more lubricants.
- Lubricants may be selected from stearic acid, talc and magnesium stearate.
- the tablets of the present invention contain at least magnesium stearate, and optionally talc. Indeed, the inventors have shown that magnesium stearate is the most adapted lubricant to prevent adhesion to the tablet material to surfaces in the manufacturing process and to improve the flow characteristics of the powder material during manufacture of ulipristal acetate tablets.
- Magnesium stearate may be used in combination with other lubricants or alone, in an amount comprised between 0.5 and 4 wt%.
- the ratio of lubricants: other excipients ranges from about 0.01 to about 0.06.
- the ratio of lubricants :ulipristal acetate ranges from about 0.1 to about 2
- the ratio of croscarmellose sodium:magnesium stearate ranges from about 0.75 to about 5, preferably about 5, or from about 1 to about 2, more preferably about 1.5 or 1.7.
- the tablet according to the present invention comprises lactose monohydrate as a diluent and povidone as a binding agent.
- the tablet according to the present invention comprises mannitol and cellulose (such as microcrystalline cellulose) as diluents and does not contain any binding agent.
- the tablet comprises: ulipristal acetate 5 to 15 wt%, lactose monohydrate 71 to 87 wt%, povidone 4.5 to 5.5 wt%, croscarmellose sodium 4.5 to 5.5 wt% and magnesium stearate 1 to 4 wt%, where the total percentage adds up to 100.
- the tablet comprises: ulipristal acetate 10%, lactose monohydrate 79 wt%, povidone 5 wt%, croscarmellose sodium 5 wt% and magnesium stearate 1 wt%.
- the tablet comprises: ulipristal acetate about 10 mg (6.7 wt%), microcrystalline cellulose about 91 mg (61 wt%), mannitol about 41 mg (27 wt%), croscarmellose sodium about 2.5 mg (1.7 wt%), talc about 4 mg (2.6 wt%) and magnesium stearate about 1.5 mg (1 wt%), where the total percentage adds up to 100.
- the tablets can be prepared at a dosage of e.g., 5, 10, 15, 20 or 30mg ulipristal acetate.
- Tablets of the present invention may be prepared according to techniques known per se in the art. Suitable methods include direct compression ("dry blending"), dry granulation followed by compression, and wet granulation followed by drying and compression. Several methods include the use of compacting roller technology such as a chilsonator or drop roller, or molding, casting, or extrusion technologies. All of these methods are known per se in the art, and are described in detail in, for example, Lachman, et al., "The Theory and Practice of Industrial Pharmacy," Chapter 11, (3.sup.rd Ed. 1986), which is incorporated by reference herein.
- the tablet according to the invention can be coated or not, and/or engraved or not.
- a preferred method for producing tablets of this invention is a wet granulation process. Indeed, the inventors have shown that such a method improves the qualities of the powder before compression and reduces the size of the tablet. More particularly, the wet granulation process led to better pharmacotechnical results on blends, an improvement of compressibility characteristics and a decrease of the final tablet mass.
- An object of the present invention therefore resides in a method of manufacturing an ulipristal acetate tablet, the method comprising mixing the above ingredients and ulipristal acetate and forming a tablet.
- the tablet is formed by wet granulation, especially when 10 to 30mg ulipristal acetate tablets, more preferably 30mg ulipristal acetate tablets are prepared.
- the ingredients may be all mixed together simultaneously, or sequentially.
- the diluent e.g., lactose monohydrate
- ulipristal acetate and the binding agent e.g., povidone
- a drying step e.g., in an oven at about 40 0 C, or on a fluidized air bed, or in a one-pot granulator.
- a calibration step is then carried out, e.g., with a sieve comprised between about 600 and 850 ⁇ m, such as a 800 ⁇ m sieve or a 710 ⁇ m Frewitt sieve.
- Croscarmellose sodium and magnesium stearate are then added for the lubrication.
- the obtained formulation is then compressed to get the tablet (compression step).
- croscarmellose which is added after the granulation step
- diluents and binding agents may be used, such as Avicel® (microcristalline cellulose), Starlac® (lactose monohydrate 85 % with maize starch 15%) or, Ludipress® (lactose monohydrate 93 % with Povidone 7%).
- the tablet is formed by direct compression, especially when 5 or 1 Omg ulipristal acetate tablets are prepared.
- direct compression especially when 5 or 1 Omg ulipristal acetate tablets are prepared.
- An example of a direct compression method includes a blanketing step (e.g., with mannitol), then a premix step by adding ulipristal, followed by sieving, and mixing once microcrystalline cellulose and croscarmellose sodium have been added. Then comes a lubricating step by adding the other excipients (e.g., talc and magnesium stearate) before tableting.
- a blanketing step e.g., with mannitol
- a premix step by adding ulipristal, followed by sieving, and mixing once microcrystalline cellulose and croscarmellose sodium have been added.
- a lubricating step by adding the other excipients (e.g., talc and magnesium stearate) before tableting.
- talc and magnesium stearate e.g., talc and magnesium stearate
- the ulipristal acetate tablets of the invention are useful in a number of therapeutic indications, including contraception, including emergency contraception.
- the tablets of the invention are useful in other indications including, but being not limited to, endometriosis, dysmenorrhea, uterine leiomyoma (leiomyomata), uterine fibroid, excessive uterine bleeding (menorrhagia), either idiopathic or resulting from spontaneous or iatrogenic coagulation disorders, meningioma, hormonal diseases, such as hormone-responsive cancers, endocrine hormone-dependent tumors, breast cancer and inhibition of uterine endometrial proliferation.
- Example 1 30 mg ulipristal acetate tablet produced by wet granulation
- a 30mg ulipristal acetate tablet was prepared, containing the following ingredients:
- Lactose monohydrate 79 wt%, ulipristal acetate 10 wt% and povidone 5 wt% were mixed and purified water was added. This granulation step was immediately followed by a drying step in an oven at 40 0 C. Then, a calibration step with a Frewitt 630 ⁇ m sieve was carried out. Croscarmellose sodium 5 wt% and magnesium stearate 1 wt% were added for the lubrication step. The obtained formulation is compressed to get the tablet.
- Example 2 Other ulipristal acetate tablets produced by wet granulation Further compositions of this invention contain the following ingredients: Table 2:
- Example 3 10 mg ulipristal acetate tablet produced by direct compression
- a lOmg ulipristal acetate tablet was prepared containing the following ingredients:
- This tablet was produced by mixing mannitol and ulipristal acetate, then sieving, e.g. with a 315 ⁇ m mesh size, and adding microcrystalline cellulose and croscarmellose sodium. Talc and magnesium stearate were then added to the mixture as lubricants, and homogeneized. Tabletting was achieved by direct compression of the mixture.
- Quantities of excipients may be adapted (for example halved or doubled) while remaining in the same proportions in wt%.
- Tablets with a total weight of 75, 150, 300 mg, containing lOmg ulipristal acetate, and the same excipients as recited in Table 3 can be prepared accordingly
- a comparative bioavailability study of a 10 mg tablet (as prepared according to example 3) vs different ulipristal acetate capsule formulations and a study characterizing the pharmacokinetic profile have been performed.
- Various assay methods have been employed in the measurement of ulipristal acetate in plasma or serum, including radioimmunoassay (RIA) and liquid chromatography with tandem mass spectrometry (LC-MS/MS). Because of the presence of cross-reacting metabolites, the RIA fails to distinguish the parent ulipristal acetate from potential cross-reactive metabolites present in the circulation, and results reported using this method hence represents the sum of ulipristal acetate and its cross-reactive metabolites.
- RIA radioimmunoassay
- LC-MS/MS liquid chromatography with tandem mass spectrometry
- the LC-MS/MS has been developed for use in menopausal and non menopausal human plasma and serum, and permits separation and determination of both ulipristal acetate and its pharmacologically active metabolite, 17 ⁇ -acetoxy-l l ⁇ - [4- ⁇ /-methylamino-phenyl)- 19-norpregna-4,9-diene-3 ,20-dione.
- the comparative bioavailability study also included a re-assay of samples using the non-selective RIA, thereby providing a point of reference to which results from other studies could be compared irrespective of the analytical method employed.
- Comparative bioavailability studies were performed as a pharmacokinetic bridging study between different formulations of ulipristal acetate.
- the formulations tested included a 10 mg capsule with micronized ulipristal acetate in 120 mg microcrystalline cellulose, and a 10 mg ulipristal acetate tablet. The experiments were carried out to compare the bioavailability and the bioequivalence of ulipristal acetate, or of its metabolites, between these two formulations.
- 'C max ' stands for a peak of ulipristal acetate concentration in the plasma.
- 'AUCo-t' denotes the area under the concentration time profile from 0 to time t.
- 'SD' refers to standard deviation.
- the lipids or surfactants that are present in the capsule composition are expected to help to achieve an immediate dissolution of the compound, and to make it easier to be absorbed in both the stomach and intestine, with a preference for the intestine, i.e. the lower GIT (Gastro-Intestinal Tract).
- GIT Gastro-Intestinal Tract
- the results obtained by the inventors show that, in comparison with the capsule formulation, the tablet formulation was absorbed faster, had a higher plasma concentration peak, and had a greater overall bioavailability as measured by the AUC measured in the study and extrapolated to infinity for the parent compound and metabolite.
- Example 5 Dissolution profile for the tablet according to Example 1 Dissolution studies were carried out using various tablets, including the tablet of example 1. The dissolution tests were conducted according to the general monograph of the European Pharmacopoeia ⁇ 2.9.3: - Paddle apparatus
- Dissolution medium HCl 0.1N Rotation speed: 50 rpm - Temperature: 37°C ⁇ 0.5 0 C
- Table 5 presents the comparative dissolution profiles of the tablets of examples 1 and 3, which contain different ratios of ingredients. The results unexpectedly show that the tablet of Example 1 has a much better dissolution profile than the tablet of example 3, illustrating the importance of the specific excipients and ratiosfor ulipristal acetate formulations. Table 5. Comparative dissolution profiles: ulipristal acetate dissolved (%) versus time (minutes)
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Priority Applications (24)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
UAA201108556A UA101863C2 (en) | 2008-12-08 | 2009-08-12 | Ulipristal acetate tablets |
DK09764855.4T DK2365800T3 (en) | 2008-12-08 | 2009-12-08 | Ulipristal acetate tablets |
EP09764855.4A EP2365800B1 (en) | 2008-12-08 | 2009-12-08 | Ulipristal acetate tablets |
JP2011540058A JP5784502B2 (en) | 2008-12-08 | 2009-12-08 | Ulipristal acetate ester tablets |
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CN2009801493094A CN102245173A (en) | 2008-12-08 | 2009-12-08 | Ulipristal acetate tablets |
RU2011127989/15A RU2492853C2 (en) | 2008-12-08 | 2009-12-08 | Tablets of ulipristal acetate |
CA2745084A CA2745084C (en) | 2008-12-08 | 2009-12-08 | Ulipristal acetate tablets |
NZ593498A NZ593498A (en) | 2008-12-08 | 2009-12-08 | Ulipristal acetate tablets |
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US13/140,219 US8735380B2 (en) | 2008-12-08 | 2009-12-08 | Ulipristal acetate tablets |
AU2009326084A AU2009326084B2 (en) | 2008-12-08 | 2009-12-08 | Ulipristal acetate tablets |
RS20160834A RS55209B1 (en) | 2008-12-08 | 2009-12-08 | Ulipristal acetate tablets |
LTEP09764855.4T LT2365800T (en) | 2008-12-08 | 2009-12-08 | Ulipristal acetate tablets |
BRPI0922796A BRPI0922796A2 (en) | 2008-12-08 | 2009-12-08 | PHARMACEUTICAL TABLET FOR ORAL ADMINISTRATION AND MANUFACTURING METHOD |
SI200931534A SI2365800T1 (en) | 2008-12-08 | 2009-12-08 | Ulipristal acetate tablets |
KR1020117015784A KR101733533B1 (en) | 2008-12-08 | 2009-12-08 | Ulipristal acetate tablets |
IL213247A IL213247A (en) | 2008-12-08 | 2011-05-31 | Ulipristal acetate tablets |
ZA2011/04137A ZA201104137B (en) | 2008-12-08 | 2011-06-03 | Ulipristal acetate tablets |
US14/255,426 US20140228335A1 (en) | 2008-12-08 | 2014-04-17 | Ulipristal Acetate Tablets |
US15/185,508 US9844510B2 (en) | 2008-12-08 | 2016-06-17 | Ulipristal acetate tablets |
HRP20161262TT HRP20161262T1 (en) | 2008-12-08 | 2016-10-03 | Ulipristal acetate tablets |
CY20161101034T CY1118099T1 (en) | 2008-12-08 | 2016-10-17 | ACETIC OLYPRISTAL TABLES |
US15/808,420 US20180064651A1 (en) | 2008-12-08 | 2017-11-09 | Ulipristal acetate tablets |
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US12/329,865 US8512745B2 (en) | 2008-12-08 | 2008-12-08 | Ulipristal acetate tablets |
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US13/140,219 A-371-Of-International US8735380B2 (en) | 2008-12-08 | 2009-12-08 | Ulipristal acetate tablets |
US14/255,426 Continuation US20140228335A1 (en) | 2008-12-08 | 2014-04-17 | Ulipristal Acetate Tablets |
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JP (2) | JP5784502B2 (en) |
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CN (2) | CN102245173A (en) |
AU (1) | AU2009326084B2 (en) |
BR (1) | BRPI0922796A2 (en) |
CA (1) | CA2745084C (en) |
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DK (1) | DK2365800T3 (en) |
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HK (1) | HK1232134A1 (en) |
HR (1) | HRP20161262T1 (en) |
HU (1) | HUE030762T2 (en) |
IL (1) | IL213247A (en) |
LT (1) | LT2365800T (en) |
MX (1) | MX343358B (en) |
NZ (1) | NZ593498A (en) |
PL (1) | PL2365800T3 (en) |
PT (1) | PT2365800T (en) |
RS (1) | RS55209B1 (en) |
RU (1) | RU2492853C2 (en) |
SI (1) | SI2365800T1 (en) |
SM (1) | SMT201600372B (en) |
UA (1) | UA101863C2 (en) |
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WO2010119029A1 (en) * | 2009-04-14 | 2010-10-21 | Laboratoire Hra-Pharma | Method for on-demand contraception |
CN102727457A (en) * | 2011-04-08 | 2012-10-17 | 北京紫竹药业有限公司 | A stable ulipristal preparation |
WO2013128134A1 (en) | 2012-02-28 | 2013-09-06 | Laboratoire Hra-Pharma | Combination of selective progesterone-receptor modulators and nonsteroidal anti-inflammatory drugs |
CN103313715A (en) * | 2010-12-30 | 2013-09-18 | 普雷格莱姆股份有限公司 | Treatment of pain associated with dislocation of basal endometrium |
WO2013175009A1 (en) | 2012-05-25 | 2013-11-28 | Laboratoire Hra-Pharma | Ulipristal acetate for prevention and treatment of breast tumors |
WO2014072646A1 (en) | 2012-11-08 | 2014-05-15 | Laboratoire Hra-Pharma | Co-micronisation product comprising ulipristal acetate |
WO2014072647A1 (en) | 2012-11-08 | 2014-05-15 | Laboratoire Hra-Pharma | Co-micronisation product comprising a selective progesterone-receptor modulator |
WO2014087106A1 (en) | 2012-12-06 | 2014-06-12 | Laboratoire Hra-Pharma | Solid dispersion of a selective modulator of the progesterone receptor |
WO2018115743A1 (en) | 2016-12-20 | 2018-06-28 | Laboratoire Hra-Pharma | Coated tablet comprising ulipristal acetate or one of the metabolites thereof |
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WO2017216637A2 (en) | 2017-08-04 | 2017-12-21 | Alvogen Malta Operations (Row) Ltd | Tablet form including ulipristal acetate and the methods for its preparation |
CN107982230A (en) * | 2017-12-25 | 2018-05-04 | 郑州泰丰制药有限公司 | A kind of uliprista acetate dispersible tablet and preparation method thereof |
CN114137115B (en) * | 2021-11-26 | 2023-08-04 | 四川尚锐分析检测有限公司 | Method for detecting ulipristal acetate and metabolite thereof in blood plasma by adopting LC-MS method |
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2008
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2009
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- 2009-12-08 KR KR1020117015784A patent/KR101733533B1/en active IP Right Grant
- 2009-12-08 HU HUE09764855A patent/HUE030762T2/en unknown
- 2009-12-08 PT PT97648554T patent/PT2365800T/en unknown
- 2009-12-08 EP EP09764855.4A patent/EP2365800B1/en not_active Revoked
- 2009-12-08 MX MX2011006106A patent/MX343358B/en active IP Right Grant
- 2009-12-08 LT LTEP09764855.4T patent/LT2365800T/en unknown
- 2009-12-08 WO PCT/EP2009/066652 patent/WO2010066749A2/en active Application Filing
- 2009-12-08 CA CA2745084A patent/CA2745084C/en active Active
- 2009-12-08 EP EP16180011.5A patent/EP3103445A1/en not_active Withdrawn
- 2009-12-08 US US13/140,219 patent/US8735380B2/en active Active
- 2009-12-08 CN CN2009801493094A patent/CN102245173A/en active Pending
- 2009-12-08 ES ES09764855.4T patent/ES2596554T3/en active Active
- 2009-12-08 RU RU2011127989/15A patent/RU2492853C2/en active
- 2009-12-08 PL PL09764855T patent/PL2365800T3/en unknown
- 2009-12-08 SI SI200931534A patent/SI2365800T1/en unknown
- 2009-12-08 BR BRPI0922796A patent/BRPI0922796A2/en not_active Application Discontinuation
- 2009-12-08 JP JP2011540058A patent/JP5784502B2/en active Active
- 2009-12-08 AU AU2009326084A patent/AU2009326084B2/en active Active
- 2009-12-08 CN CN201510648506.8A patent/CN105267168A/en active Pending
- 2009-12-08 DK DK09764855.4T patent/DK2365800T3/en active
- 2009-12-08 RS RS20160834A patent/RS55209B1/en unknown
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2011
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2014
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2015
- 2015-01-15 JP JP2015006168A patent/JP6151727B2/en active Active
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2016
- 2016-06-17 US US15/185,508 patent/US9844510B2/en active Active
- 2016-10-03 HR HRP20161262TT patent/HRP20161262T1/en unknown
- 2016-10-13 SM SM201600372T patent/SMT201600372B/en unknown
- 2016-10-17 CY CY20161101034T patent/CY1118099T1/en unknown
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2017
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- 2017-11-09 US US15/808,420 patent/US20180064651A1/en not_active Abandoned
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Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
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US9283233B2 (en) | 2009-04-14 | 2016-03-15 | Laboratoire Hra-Pharma | Method for on-demand contraception |
WO2010119029A1 (en) * | 2009-04-14 | 2010-10-21 | Laboratoire Hra-Pharma | Method for on-demand contraception |
US9616073B2 (en) | 2009-04-14 | 2017-04-11 | Laboratoire Hra-Pharma | Method for on-demand contraception |
CN103313715A (en) * | 2010-12-30 | 2013-09-18 | 普雷格莱姆股份有限公司 | Treatment of pain associated with dislocation of basal endometrium |
US10441593B2 (en) | 2010-12-30 | 2019-10-15 | Preglem S.A. | Treatment of pain associated with dislocation of endometrium |
CN102727457A (en) * | 2011-04-08 | 2012-10-17 | 北京紫竹药业有限公司 | A stable ulipristal preparation |
WO2013128134A1 (en) | 2012-02-28 | 2013-09-06 | Laboratoire Hra-Pharma | Combination of selective progesterone-receptor modulators and nonsteroidal anti-inflammatory drugs |
WO2013175009A1 (en) | 2012-05-25 | 2013-11-28 | Laboratoire Hra-Pharma | Ulipristal acetate for prevention and treatment of breast tumors |
US9814732B2 (en) * | 2012-05-25 | 2017-11-14 | Laboratoire Hra-Pharma | Ulipristal acetate for prevention and treatment of breast tumors |
US9610293B2 (en) | 2012-11-08 | 2017-04-04 | Laboratoire Hra-Pharma | Co-micronization product comprising ulipristal acetate |
WO2014072647A1 (en) | 2012-11-08 | 2014-05-15 | Laboratoire Hra-Pharma | Co-micronisation product comprising a selective progesterone-receptor modulator |
MD4546B1 (en) * | 2012-11-08 | 2018-01-31 | Laboratoire Hra-Pharma | Co-micronisation product comprising a selective progesterone-receptor modulator |
MD4563B1 (en) * | 2012-11-08 | 2018-05-31 | Laboratoire Hra-Pharma | Co-micronisation product comprising ulipristal acetate |
WO2014072646A1 (en) | 2012-11-08 | 2014-05-15 | Laboratoire Hra-Pharma | Co-micronisation product comprising ulipristal acetate |
WO2014087106A1 (en) | 2012-12-06 | 2014-06-12 | Laboratoire Hra-Pharma | Solid dispersion of a selective modulator of the progesterone receptor |
WO2018115743A1 (en) | 2016-12-20 | 2018-06-28 | Laboratoire Hra-Pharma | Coated tablet comprising ulipristal acetate or one of the metabolites thereof |
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