EP2672960A1 - Composition pharmaceutique comprenant du tadalafil et une cyclodextrine - Google Patents
Composition pharmaceutique comprenant du tadalafil et une cyclodextrineInfo
- Publication number
- EP2672960A1 EP2672960A1 EP12704054.1A EP12704054A EP2672960A1 EP 2672960 A1 EP2672960 A1 EP 2672960A1 EP 12704054 A EP12704054 A EP 12704054A EP 2672960 A1 EP2672960 A1 EP 2672960A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- tadalafil
- granulate
- cyclodextrin
- beta
- composition
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
Classifications
-
- 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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
Definitions
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a co- granulate of tadalafil and beta-cyclodextrin as the main components.
- CIALIS® is a known pharmaceutically active compound, which is marketed, e.g., under brand name CIALIS®, for treatment of erectile dysfunction and pulmonary arterial hypertension.
- the marketed product is a film-coated tablet for oral administration comprising 2.5, 5, 10 or 20 mg of the active substance.
- Inactive ingredients in CIALIS® are lactose monohydrate, croscarmellose sodium, hydroxypropylcellulose, microcrystalline cellulose, sodium laurylsulfate and magnesium stearate.
- Tadalafil and its pharmaceutical compositions have been disclosed, e.g., in
- tadalafil is in a certain aspect a follow-up product to the well known compound sildenafil (Viagra). Its main advantage is longer duration of action and minimized potential for side effects such as vision abnormalities.
- tadalafil is thereby finely dispersed in the carrier, which may result in improved dissolution due to the enhanced surface area of the drug substance.
- solid dispersions comprising tadalafil have been disclosed, e.g., in WO 96/38131.
- Molecular dispersions of tadalafil in a polymeric carrier have been disclosed, e.g., in WO 2009/000493.
- An adsorbate of tadalafil on the surface of silica has been disclosed in EP 2238979.
- Still another possibility of improving the dissolution rate of tadalafil from solid dosage forms is to formulate it into quickly disintegrating sublingual dosage forms.
- Examples of such compositions have been disclosed, e.g., in WO 00/20033, WO 01/41807,
- the present invention relates to pharmaceutical compositions comprising a co-granulate of tadalafil with a cyclodextrin as the pharmaceutically active component.
- the present invention provides a solid pharmaceutical composition
- a solid pharmaceutical composition comprising a co-granulate of tadalafil with beta-cyclodextrin, in a molar ratio higher than 1:1, typically a molar ratio of about 1:1.25, 1:1.3, 1:1.5, 1:2, 1:2.5, 1:3, and at least one pharmaceutically acceptable excipient.
- the tadalafil starting material comprises a population of tadalafil particles characterized by a particle size d(0.9) >40 microns.
- the invention provides a compressed dosage form, which typically is a tablet for oral administration of tadalafil, comprising the dose amount of the above defined composition.
- the tablet comprises from 1 to 50 mg of tadalafil.
- the dosage form exhibits a dissolution rate of at least about 75 wt% within about 15 min when tested by Ph.Eur. paddle method in 1000 ml of aqueous medium containing 0.35% of SLS with paddle rotating at a speed of 50 rpm.
- the invention provides a co-granulate of tadalafil with beta- cyclodextrin, in molar ratio higher than 1:1, typically a molar ratio of about 1:1.25, 1: 1.3, 1:1.5, 1:2, 1:2.5, 1:3, in a free flowing particulate form.
- the invention provides a process of making a co-granulate of tadalafil with beta-cyclodextrin in a free flowing particulate form comprising
- the above process steps are followed by the next step of formulating the produced co-granulate into a solid pharmaceutical composition and/or into a solid dosage form for oral administration, e.g. to compressed dosage form, which typically is a tablet.
- the formulation step into the tablet comprises direct compression.
- the invention relates to use of co-granulate of tadalafil with beta- cyclodextrin, in a molar ratio higher than 1:1, typically a molar ratio of about 1:1.25, 1:1.3, 1:1.5, 1:2, 1:2.5, 1:3, and preferably in a free flowing particulate form, in medicine, particularly in combination with a disintegrant.
- the present invention relates to a discovery that a complex of tadalafil with beta- cyclodextrin may be prepared by a simple and reliable process and in a form, which is well suitable for formulation into solid pharmaceutical compositions and for making tablets for oral administration of tadalafil.
- Cyclodextrins are compounds made up of sugar molecules bound together in a ring and are composed of 5 or more a-D-glucopyranoside units linked l->4. Cyclodextrins are produced from starch by means of enzymatic conversion. Three naturally occurred cyclodextrins are known, one of these three, the so-called beta-cyclodextrin, has seven sugar molecules in the ring. As the natural beta-cyclodextrin exhibits relatively low aqueous solubility, various semi synthetic derivatives with enhanced aqueous solubility have been developed.
- 2-hydroxy-propyl-beta-cyclodextrin (2-HPCD), which is a partially substituted poly(2-hydroxpropyl) ether of beta-cyclodextrin. Its aqueous solubility is quite high, exceeding 600 mg/ml.
- Cyclodextrins may form stable complexes with various chemicals, in which the molecule of the chemical is encapsulated inside the cyclodextrin ring and forms a so called inclusion complex. Thereby, original properties of the chemical vis-a-vis the cyclodextrin- complexed chemical may be modified (For more details, see e.g., Arthur H. Kibbe (Ed.), Handbook of Pharmaceutical Excipients, Third Edition 2000, p. 165-168).
- the present invention provides a solid pharmaceutical composition
- a solid pharmaceutical composition comprising a co- granulate of tadalafil with beta-cyclodextrin, in a molar ratio higher than 1: 1, typically of molar ratio of about 1: 1.25, 1: 1.3, 1: 1.5, 1:2, 1: 2.5, 1 :3, and at least one pharmaceutically acceptable excipient.
- Formulation of the tadalafil and beta-cyclodextrin in a form of a co-granulate is advantageous as it avoids using complicated and expensive freeze-drying.
- the co-granulation assures a proper degree of complexation of tadalafil, which may be demonstrated by the fact that the co-granulate exhibits better dissolution rates than a plain physical mixture of both components.
- the co-granulate may be obtained as a free flowing particulate product, which is an advantageous form because it is well manageable in the process of formulating pharmaceutical compositions.
- composition of the present invention is a result of comparative study of the behaviour of tadalafil in solid granulated compositions comprising various cyclodextrins in the presence of pharmaceutically acceptable extragranular fillers, diluents and disintegrants, for instance in the presence of excipients found in Cialis. Contrary to the expectations predicted by Badr-Eldin et al., it was a co-granulate with natural beta-cyclodextrin, which provided the fastest dissolution of tadalafil when tested in an aqueous environment comprising 0.35% sodium lauryl sulfate (SLS), by a Ph.Eur. paddle method. Quite surprisingly, the high aqueous solubility of semi-synthetic cyclodextrins such as
- hydroxypropyl-beta-cyclodextrin is apparently not essential for making tadalafil-comprising solid pharmaceutical compositions with a good dissolution, e.g. with a dissolution comparable to Cialis tablets.
- the inventor speculates that the presence of certain excipients in the solid composition, apparently mainly disintegrants, also contributes to the overall dissolution rate; when combining this contribution with an effective complexation of the tadalafil by beta-cyclodextrin, a proper synergy is obtained.
- beta-cyclodextrin may be successfully used in this particular case.
- an optimal molar ratio is higher than 1:1, and preferably is about 1: 1.25, 1:1.3, 1: 1.5, 1:2, 1:2.5, 1:3.
- Compositions comprising the tadalafil-beta-cyclodextrin co-granulate of molar ratio lower that 1 : 1 exhibited an undesirably slow dissolution rate, probably due to less complexation.
- Higher absolute amounts of beta-cyclodextrin in final compositions e.g.
- the tadalafil-beta-cyclodextrin co-granulate is formulated into a tablet composition, due to a lack of flowability.
- the molar ratio between tadalafil and beta-cyclodextrin should not exceed 1:8, preferably not exceed 1:5.
- the total amount of beta- cyclodextrin in a single tablet made from the co-granulate does not exceed 150 mg, preferably does not exceed 75 mg.
- a useful process of making the co-granulate of tadalafil and beta-cyclodextrin in a free- flowing particulate form comprises the following steps:
- beta-cyclodextrin wetting, under stirring, beta-cyclodextrin with 5 to 30%, preferably with 10 to 25% and most preferably with about 20% of water (w/w).
- the mixing and homogenization is typically performed in the same equipment, at a speed of about 100 to 200 rpm.
- the time of mixing plays a certain role as a well
- the drying step is performed in fluid bed equipment, at a temperature of about 40°C to about 50°C.
- the dry co-granulate may be milled and/or sieved on a suitable equipment.
- the co-granulate may also comprise some auxiliary intra- granulate excipients.
- it may also comprise a suitable solubilizer.
- solubilizer may enhance the effect of cyclodextrin and/or may save the overall amount of the relatively expensive cyclodextrin.
- the examples of solubilizers are, without limitation, hydroxypropylmethyl cellulose, polyethylene glycol (PEG 4000, PEG 6000),
- the co-granulate may also comprise an intragranular disintegrant, e.g. a crosscarmellose sodium or crospovidone.
- the amount of a disintegrant in the co-granulate is advantageously less than 10%,
- the co-granulate may comprise a suitable binder/diluent such as microcrystalline cellulose or lactose.
- the auxiliary excipients may be incorporated into the granulate both in the wetting and in the mixing / homogenization step.
- the process of making the co-granulate comprises the following steps:
- beta-cyclodextrin wetting, under stirring, beta-cyclodextrin with 5 to 30%, preferably with 10 to 25% and most preferably with about 20% of water (w/w), wherein the water contains dissolved solubilizer, e.g. PEG 4000, optionally in the presence of binder/diluent and/ or disintegrant.
- solubilizer e.g. PEG 4000
- beta-cyclodextrin ration molar ratio higher than 1:1 typically of molar ratio of about 1:1.25, 1:1.3, 1:1.5, 1:2, 1:2.5, 1:3, and homogenizing the mixture by stirring for at least 30 minutes, typically from 2 to 5 hours.
- the dry co-granulate may be milled and/or sieved on a suitable equipment.
- the process comprises the following steps:
- beta-cyclodextrin wetting, under stirring, beta-cyclodextrin with 5 to 30%, preferably with 10 to 25% and most preferably with about 20% of water (w/w), wherein the water contains dissolved solubilizer, e.g. PEG 4000, optionally in the presence of binder/diluent.
- solubilizer e.g. PEG 4000
- the dry co-granulate may be milled and/or sieved on a suitable equipment.
- the co-granulate of the present invention may be formulated into well dissoluble solid pharmaceutical compositions without a requirement that the starting tadalafil must be of a small particle size. Specifically, it is not necessary to provide a population of tadalafil particles of an particles size (when expressed by the d(0.9) value) of less than 40 micrometers. Instead, it is possible and in certain aspects advantageous, to use batches of tadalafil having the average particle size d(0.9) higher than 40 micrometers, e.g. tadalafil directly produced by a chemical synthesis.
- the "d(0.9) " in an association with a number means that the size of 90% of particles of the population is less than or equal to the size expressed by that number when measured by a light scattering method.
- the co-granulate of the present invention may be formulated into solid pharmaceutical compositions, preferably to tablet compositions, by combining it, typically by dry mixing or by wet granulation/mixing, with at least one extragranular pharmaceutical excipient.
- the composition typically does not comprise any excipient serving as a release-controlling agent.
- the at least one extragranular excipient(s) may be selected from
- At least one disintegrant are, without any limitation, starches, modified celluloses or crosslinked polymers such as starch, modified starch, croscarmellose sodium, carboxymethylcellulose calcium, crospovidone, sodium starch glycolate, polacrilin potassium, sodium alginate, guar gum, etc.
- a preferred disintegrant is croscarmellose sodium.
- the extragranular disintegrant is an important excipient. As discussed above, it appears that the disintegrant potentiates the effect of the cyclodextrin and improves the overall release rate. Preferred amount of the disintegrant is from 1 to 5 weight %, based on the total mass of the composition. In some embodiments, the final composition may comprise both an extragranular disintegrant and an intragranular disintegrant, which may be the same or different.
- At least one water soluble or water insoluble filler /binder At least one water soluble or water insoluble filler /binder.
- the examples are, without any limitation, lactose, lactose monohydrate, mannitol, sorbitol,
- microcrystalline cellulose methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, dextrose, fructose, lactitol, maltitol, maltodextrins, maltose, calcium phosphates, xylitol, starch, modified starch, polyvinylpyrrolidone, copovidone, sodium alginate, etc.
- At least one solubilizer At least one solubilizer.
- the examples are, without any limitation, hydroxypropyl methylcellulose, polyvinylpyrrolidone, nicotinamide, polyoxyethylene (20) sorbitan monooleate (Tween 80), polyethylene glycol (PEG 4000), sodium lauryl sulfate, etc.
- At least one lubricant At least one lubricant.
- the examples are, without any limitation, talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, palmitic acid, carnauba wax, mineral oil, sodium stearyl fumarate, polyethylene glycol, etc.
- the relative amount of the tadalafil/beta-cyclodextrin co-granulate, optionally comprising auxiliary excipients as described above, in the composition is typically from about 30 to about 80 weight %, preferably from about 40 to about 60 weight %, based on the total weight of the composition.
- the relative amount of the beta-cyclodextrin as such in the composition should not exceed 65%.
- the composition of the present invention is advantageously formulated into a compressed dosage form, which is typically a tablet, preferably by a process of direct compression.
- This process comprises adjusting the composition to portions - dose units - comprising dose amount of the active substance and compressing the doses of the composition to tablets on a suitable tablet press.
- the preferred hardness of tablets is higher than 50N, advantageously higher than 75N.
- the resulting compressed tablet for oral administration of tadalafil typically comprises a dose amount comprising from 1 to 50 mg of tadalafil, preferably 2.5, 5, 10, 20 or 40 mg of tadalafil.
- a tablet comprises in total less than 150 mg of beta-cyclodextrin, in some embodiments the amount of beta-cyclodextrin does not exceed 75 mg.
- the compressed dosage form preferably exhibits a dissolution rate which is characterized by a dissolution of more than 75 wt% and in some embodiments more than 80 wt% of tadalafil in 15 min when tested by a Ph.Eur. paddle method in 1000 ml of an aqueous medium containing 0.35% of SLS (sodium lauryl sulfate) with paddle rotating at a speed of 50 rpm.
- SLS sodium lauryl sulfate
- the tablets may be optionally further coated by a film-coat.
- the coating serves generally for cosmetic purposes.
- the coating material typically has no influence on the release rate, except of an inherent short initial delay in dissolution due to the time necessary to dissolve the coat.
- the coating may be selected from amongst one or more of those suitable coating materials known in the art. Coating may be performed by applying one or more film forming polymers, with or without other pharmaceutically inert excipients, as a solution/suspension. Coating is done using any conventional coating technique known in the art, such as spray coating in a conventional coating pan or fluidized bed processor; or dip coating.
- the co-granulate of tadalafil with beta-cyclodextrin of the present invention may be typically used in making solid pharmaceutical dosage forms, e.g., for oral administration of tadalafil.
- the present invention provides a method of treatment, particularly that of erectile dysfunction or pulmonary arterial hypertension, comprising orally administering to a patient of need thereof a solid pharmaceutical composition comprising a therapeutical amount of co-granulate of tadalafil with beta-cyclodextrin in a molar ratio higher than 1: 1, typically a molar ratio of about 1:1.25, 1: 1.3, 1: 1.5, 1:2, 1:2.5, 1:3, advantageously in combination with a disintegrant.
- Example 1 Co-granulate of tadalafil and beta-cyclodextrin
- a co-granulate of tadalafil with beta-cyclodextrin of a molar ratio of 1:3 was made by the following process:
- Example 2 Pharmaceutical tablet comprising tadalafil-beta-cyclodextrin (1:3 m/m) co-granulate
- the co-granulate of tadalafil and beta-cyclodextrin was prepared according to the process of example 1.
- the extragranular excipients spray-dried lactose, microcrystalline cellulose, and croscarmellose sodium were mixed with the co-granulate in a free fall blender, subsequently magnesium stearate was added and mixed with the rest of excipients.
- the lubricated blend was compressed in an excentric press machine.
- Comparative tablets compositions were made with a co-granulate of tadalafil/beta- cyclodextrin (1:3 molar) made of:
- the tablet hardness was 75N in cases a], c] and d] and 100N in the case b]
- composition comprising tadalafil-beta-cyclodextrin (1:2.5 m/m) co-granulate with an intragranular solubilizer.
- HPMC HPMC was dissolved in water (20% w/w of the amount of cyclodextrin). This solution was mixed with cyclodextrin in a granulator for 20 minutes. Drug substance was added to the formed paste and blended for 4 h. After that, the wet mass was removed from the granulator, sieved through a conical sieve (BTS, 2.5 mm) and dried in a fluid bed at 50°C until getting a LOD ⁇ 14%. The granulate was sieved through 0.5 mm mesh (BTS) and was mixed with lactose monohydrate, microcrystalline cellulose and Na croscarmellose for 30 minutes. Magnesium stearate was added to the blend and mixed for 5 additional minutes. Finally, the lubricated blend was compressed in a rotary tablet press.
- BTS conical sieve
- Magnesium stearate Magnesium stearate was added to the blend and mixed for 5 additional minutes.
- composition comprising tadalafil-beta-cyclodextrin (1:2.5 m/m) co-granulate with an extragranular solubilizer.
- Cyclodextrin and water (20% w/w of the amount of cyclodextrin) were mixed in a high shear mixer/granulator for 20 minutes.
- Tadalafil was added to the CD: water paste and blended for 4 h.
- the granulate was sieved through conical sieve (BTS, 2.5 mm) and dried in fluid bed at 50°C until getting a LOD ⁇ 14%.
- Granulate was sieved through 0.5 mm mesh (BTS).
- TDI -CD granulate was granulated with lactose monohydrate, half of microcrystalline cellulose and 40% of the sodium croscarmellose, using water (25% w/w of granulated mass) as the granulation liquid. Nicotinamide was partially dissolved in the granulation liquid and partially added as powder in the high shear mixer. The granulated product was dried in Glatt GPCG-1. The dried granulate was blended with the remaining microcrystalline cellulose and sodium croscarmellose for 30 minutes. Finally, magnesium stearate was added and the mixture was blended for 5 minutes. The lubricated blend was compressed in a rotative press machine to get 20, 10, 5 and 2.5 mg tablets.
- composition comprising tadalafil-beta-cyclodextrin (1:2.5 m m) co-granulate with an extragranular solubilizer.
- Cyclodextrin and water (20% w/w of the amount of cyclodextrin) were mixed in a Mimipro high shear mixer/granulator for 20 minutes. Tadalafil was added to the
- the tadalafil: ⁇ -CD granulate was granulated with lactose monohydrate, half of microcrystalline cellulose and 40% of the sodium croscarmellose in Mimipro. Tween was dissolved in the granulation liquid and added in the high shear mixer. The granulated product was dried in fluid bed equipment. The dried granulate was blended with the remaining microcrystalline cellulose and sodium croscarmellose for 10 minutes. Finally, magnesium stearate was added and blended for 5 minutes. The lubricated blend was compressed in a excentric press machine to get 20 mg tablets (mass 480 mg, hardness 150 N).
- composition comprising tadalafil-beta-cyclodextrin (1:1.3 m/m) co-granulate with an intragranular solubilizer, binder and disintegrant.
- Cyclodextrin, lactose, half of the sodium croscarmellose was mixed with an aqueous solution of PEG 4000 (amount of water is 20% w/w of the total weight of the composition) a VMA 10 high shear mixer/granulator for 20 min Tadalafil was added to the wet paste and blended for 3 hours. After blending, the granulate was dried in a fluid bed at 50°C. The dried granulate was sieved through 1.0 mm sieve.
- the dried granulate was blended with the microcrystalline cellulose and the rest of sodium croscarmellose for 10 minutes. Finally, magnesium stearate was added and blended. The lubricated blend was compressed to get 20 mg tablets.
- proportional tablets of 10 mg, 5 mg and 2.5 mg tadalafil were also prepared.
- composition comprising tadalafil-beta-cyclodextrin (1:1.3 m/m) co-granulate with an intragranular solubilizer, binder and disintegrant.
- composition comprising tadalafil-beta-cyclodextrin (1:1.3 m/m) co-granulate with an intragranular solubilizer, binder and disintegrant.
- Cyclodextrin, lactose and half of the croscarmellose was mixed with an aqueous solution of PEG 4000 (amount of water is 20% w/w of the mass) in a VMA 10 high shear mixer/granulator for 20 minutes.
- Tadalafil was added to the wet paste and blended for 3 hours.
- the granulate was sieved and dried in a fluid bed at 50°C. The dried granulate was sieved through a 1.0 mm sieve.
- the dried granulate was blended with the microcrystalline cellulose and the rest of sodium croscarmellose for 10 minutes. Finally, magnesium stearate was added and the mixture was blended. The lubricated blend was compressed in a rotative compression machine to get 20 mg. 10 mg. 5 mg and 2.5 mg tablets.
- Cyclodextrin, lactose and half of the crospovidone was mixed with an aqueous solution of PEG 4000 (amount of water is 20% w/w of the mass) in a VMA 10 high shear mixer/granulator for 20 minutes.
- Tadalafil was added to the wet paste and blended for 3 hours.
- the granulate was sieved and dried in a fluid bed at 50°C.
- the dried granulate was sieved through 1.0 mm sieve.
- the dried granulate was blended with the microcrystalline cellulose and the rest of sodium crospovidone for 10 minutes.
- magnesium stearate was added and blended.
- the lubricated blend was compressed in a rotative compression machine to get 20 mg. 10 mg. 5 mg and 2.5 mg tablets.
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- Pharmacology & Pharmacy (AREA)
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- Life Sciences & Earth Sciences (AREA)
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Abstract
L'invention porte sur un produit de co-granulation de tadalafil avec de la bêta-cyclodextrine sous forme particulaire coulante, sur un procédé de fabrication de celui-ci, sur des compositions pharmaceutiques et des formes pharmaceutiques comprenant de tel produit de co-granulation et sur l'utilisation de celles-ci en médecine.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP12704054.1A EP2672960A1 (fr) | 2011-02-10 | 2012-02-10 | Composition pharmaceutique comprenant du tadalafil et une cyclodextrine |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/EP2011/051969 WO2012107092A1 (fr) | 2011-02-10 | 2011-02-10 | Composition pharmaceutique comportant du tadalafil et une cyclodextrine |
EP2011066730 | 2011-09-27 | ||
EP12704054.1A EP2672960A1 (fr) | 2011-02-10 | 2012-02-10 | Composition pharmaceutique comprenant du tadalafil et une cyclodextrine |
PCT/EP2012/052266 WO2012107541A1 (fr) | 2011-02-10 | 2012-02-10 | Composition pharmaceutique comprenant du tadalafil et une cyclodextrine |
Publications (1)
Publication Number | Publication Date |
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EP2672960A1 true EP2672960A1 (fr) | 2013-12-18 |
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ID=45660939
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP12704054.1A Withdrawn EP2672960A1 (fr) | 2011-02-10 | 2012-02-10 | Composition pharmaceutique comprenant du tadalafil et une cyclodextrine |
Country Status (1)
Country | Link |
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EP (1) | EP2672960A1 (fr) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2238979A1 (fr) * | 2009-04-06 | 2010-10-13 | LEK Pharmaceuticals d.d. | Ingrédient pharmaceutique actif absorbé sur un support solide |
-
2012
- 2012-02-10 EP EP12704054.1A patent/EP2672960A1/fr not_active Withdrawn
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2238979A1 (fr) * | 2009-04-06 | 2010-10-13 | LEK Pharmaceuticals d.d. | Ingrédient pharmaceutique actif absorbé sur un support solide |
Non-Patent Citations (1)
Title |
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See also references of WO2012107541A1 * |
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