WO2012107092A1 - Composition pharmaceutique comportant du tadalafil et une cyclodextrine - Google Patents

Composition pharmaceutique comportant du tadalafil et une cyclodextrine Download PDF

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Publication number
WO2012107092A1
WO2012107092A1 PCT/EP2011/051969 EP2011051969W WO2012107092A1 WO 2012107092 A1 WO2012107092 A1 WO 2012107092A1 EP 2011051969 W EP2011051969 W EP 2011051969W WO 2012107092 A1 WO2012107092 A1 WO 2012107092A1
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WO
WIPO (PCT)
Prior art keywords
tadalafil
granulate
cyclodextrin
beta
composition
Prior art date
Application number
PCT/EP2011/051969
Other languages
English (en)
Inventor
Marta VIVANCOS MARTINEZ
Original Assignee
Synthon Bv
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Synthon Bv filed Critical Synthon Bv
Priority to PCT/EP2011/051969 priority Critical patent/WO2012107092A1/fr
Priority to EP12704054.1A priority patent/EP2672960A1/fr
Priority to PCT/EP2012/052266 priority patent/WO2012107541A1/fr
Priority to RU2013141446/15A priority patent/RU2013141446A/ru
Publication of WO2012107092A1 publication Critical patent/WO2012107092A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—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
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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 the 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 lauryl sulfate 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 One possibility of improving the dissolution rate of tadalafil from solid pharmaceutical compositions is to use the active ingredient with low average particle size.
  • the patent applications WO 01/08688 and WO 01/08686 disclose a population of tadalafil particles characterized by an average particle size (expressed as d(0.9)) less than 40 ⁇ . Such particulated form of tadalafil may exhibit better dissolution from pharmaceutical
  • tadalafil is thereby finely dispersed in the carrier, which may result in improved dissolution due to 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.
  • a pharmaceutical composition comprising a combination of tadalafil and starch has been disclosed in WO 2008/134557.
  • An adsorbate of tadalafil on the surface of silica has been disclosed in EP 2238979.
  • compositions have been disclosed, e.g., in WO 00/20033, WO 01/41807, WO 2007/002125 or WO 2008/005039.
  • 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 comprising a co-granulate of tadalafil with beta-cyclodextrin, in a molar ratio higher than 1 : 2, typically of molar ratio of about 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 ⁇ .
  • the invention provides a compressed dosage form, which typically is a tablet for oral administration of tadalafil, comprising a 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 an aqueous medium containing 0.35% of SLS with the paddle rotating at a speed of 50 rpm.
  • the invention provides a co-granulate of tadalafil with beta- cyclodextrin, in a molar ratio higher than 1 : 2, typically a molar ratio of about 1 : 3, in a free- flowing particulate form.
  • the invention provides a process for making a co-granulate of tadalafil with beta-cyclodextrin in a free-flowing particulate form comprising
  • beta-cyclodextrin with 5 to 30% of water (w/w)
  • the above process steps are followed by a next step of formulating the produced co-granulate into a solid pharmaceutical composition and/or to a solid dosage form for oral administration, e.g. to a compressed dosage form, which typically is a tablet
  • the formulation of the tablet comprises a direct compression.
  • the invention relates to the use of the co-granulate of tadalafil with beta-cyclodextrin, in a molar ratio higher than 1 : 2, typically a molar ratio of about 1 : 3, and preferably in a free-flowing particulate form, in medicine, particularly in combination with a disintegrant.
  • the present invention relates to a complex of tadalafil with beta-cyclodextrin 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 a family of compounds made up of sugar molecules bound together in a ring. Cyclodextrins 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 occurring cyclodextrins are known, whereby 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, the 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 : 2, typically a molar ratio of about 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, well manageable in the process of formulating pharmaceutical compositions.
  • composition of the present invention is a result of a comparative study of the behaviour of tadalafil in solid granulated compositions comprising various cyclodextrins in the presence of pharmaceutically acceptable extragranular fillers, diluents and dis integrants, for instance in the presence of excipients found in Cialis. Contrary to the expectations predicted by Bahr-Eldin et ah, 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. As a result, far cheaper, albeit less soluble, natural beta-cyclodextrin may be successfully used in this particular case.
  • an optimal molar ratio is higher than 1 : 2 and preferably is about 1 : 3.
  • Compositions comprising the tadalafil/beta-cyclodextrin co-granulate of a molar ratio lower that 1 : 2 exhibited an undesirably slow dissolution rate, probably due to less complexation.
  • Higher absolute amounts of beta-cyclodextrin in final compositions e.g. higher than 65% w/w, may also cause certain technological problems, particularly when the tadalafil/beta-cyclodextrin co-granulate is formulated to a tablet composition, due to a lack of flowability.
  • tadalafil/beta-cyclodextrin co-granulate is intended to be formulated into a tablet composition of higher tablet strengths, e.g. 10 to 20 mg, the molar ratio between tadalafil and beta- cyclodextrin should not exceed 1 : 8, preferably not exceed 1 : 5.
  • the upper limit of the molar ratio may be higher, e.g., up to 1 : 20.
  • the useful process for 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 contact with water is performed in a suitable mixer at ambient temperature, for about 15 to 30 minutes, typically for about 20 minutes. As a result a wet, but still solid, homogeneous mass is obtained.
  • 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 well as a homogenized mixture with a high degree of complexation must be provided. Therefore, mixing for at least 30 minutes is necessary and mixing for at least 2 hours is preferred.
  • the drying step is performed in fluid bed equipment, at a temperature of about 40°C to about 60°C, typically at 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- granular excipients, e.g. a suitable binder such as microcrystalline cellulose and/or a suitable disintegrant, e.g. crosscarmellose sodium.
  • auxiliary intra- granular excipients e.g. a suitable binder such as microcrystalline cellulose and/or a suitable disintegrant, e.g. crosscarmellose sodium.
  • the excipients may be incorporated into the granulate both in the wetting and in the homogenization step.
  • the co-granulate of the present invention may be formulated into well dissoluble solid pharmaceutical compositions without the 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 average particle size (when expressed by the d(0.9) value) of less than 40 ⁇ . 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 ⁇ , e.g. tadalafil directly produced by a chemical synthesis.
  • the "d(0.9)" in association with a number means that the size of 90% of the particles of a population were 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, with at least one extragranular pharmaceutical excipient.
  • the composition typically does not comprise any excipient serving as a release-controlling agent.
  • the extragranular excipients typically comprise
  • 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.
  • the preferred amount of the disintegrant is from 1 to 5 weight %, based on the total mass of the composition.
  • 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 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 lubricant are, without any limitation, lactose, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, dextrose, fructose, lactitol, maltitol, maltodextrins, maltose, calcium phosphate
  • 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 in the composition is typically from about 30 to about 70 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 about 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 or 20 mg of tadalafil.
  • the compressed dosage form preferably exhibits a dissolution rate which is
  • 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 co-granulate of tadalafil with beta-cyclodextrin in a molar ratio higher than 1 : 2, typically a molar ratio of about 1 : 3, as well as pharmaceutical compositions and dosage forms comprising such co-granulate, advantageously in combination with a disintegrant, are useful in medicine, specifically for the treatment of diseases and conditions known to be treated with tadalafil.
  • the present invention provides a method of treatment, particularly that of erectile dysfunction or pulmonary arterial hypertension, comprising orally administering to a patient in need thereof a solid
  • composition comprising a therapeutical amount of co-granulate of tadalafil with beta-cyclodextrin in molar ratio higher than 1 : 2, typically a molar ratio of about 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) co-granulate
  • the co-granulate of tadalafil and beta-cyclodextrin was prepared according to the process of Example 1. Extragranular excipients lactose monohydrate spray dried, microcrystalline cellulose, and croscarmellose sodium were mixed with the co-granulate in a free-fall blender. In a last step magnesium stearate was added and mixed with the rest of the excipients. The lubricated blend was compressed in an excentric press machine.
  • Example 3 Comparative tablet compositions
  • Comparative tablet compositions were made with a co-granulate of tadalafil/beta- cyclodextrin (1 : 3 molar ratio):
  • Active substance d(0.9) 62.2 ⁇ , 2 hours granulation
  • Active substance d(0.9) 62.2 ⁇ , 2 hours granulation
  • Active substance d(0.9) 40.6 ⁇ , 2 hours granulation
  • Active substance d(0.9) 48.9 ⁇ , 2 hours granulation
  • the granulates were formulated, by direct compression, into tablets of the composition identical to that of Example 2.
  • the tablet hardness was 75N in cases a), c) and d) and 100N in case b).

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  • Pharmacology & Pharmacy (AREA)
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Abstract

La présente invention concerne un cogranulé de tadalafil avec une bétâ-cyclodextrine sous une forme particulaire fluide, son procédé de fabrication, des compositions pharmaceutiques et des formes pharmaceutiques comportant un tel cogranulé et son utilisation dans le domaine médical.
PCT/EP2011/051969 2011-02-10 2011-02-10 Composition pharmaceutique comportant du tadalafil et une cyclodextrine WO2012107092A1 (fr)

Priority Applications (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
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
RU2013141446/15A RU2013141446A (ru) 2011-02-10 2012-02-10 Фармацевтическая композиция, содержащая тадалафил и циклодекстрин

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PCT/EP2011/051969 WO2012107092A1 (fr) 2011-02-10 2011-02-10 Composition pharmaceutique comportant du tadalafil et une cyclodextrine

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015000853A1 (fr) * 2013-07-05 2015-01-08 Synthon B.V. Composition pharmaceutique comprenant une dispersion solide de tadalafil
CN105213333A (zh) * 2014-06-30 2016-01-06 深圳海王药业有限公司 一种他达拉非药物组合物及其制备方法
EP3466951A1 (fr) 2014-07-23 2019-04-10 KRKA, d.d., Novo mesto Procédé de préparation d'inhibiteur de cgmp-phosphodiestérase et formulation pharmaceutique orale comprenant des co-précipités de tadalafil

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CN105213333A (zh) * 2014-06-30 2016-01-06 深圳海王药业有限公司 一种他达拉非药物组合物及其制备方法
EP3466951A1 (fr) 2014-07-23 2019-04-10 KRKA, d.d., Novo mesto Procédé de préparation d'inhibiteur de cgmp-phosphodiestérase et formulation pharmaceutique orale comprenant des co-précipités de tadalafil

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