WO2012095151A1 - Formes pharmaceutiques solides comprenant du tadalafil et ses procédés de préparation - Google Patents

Formes pharmaceutiques solides comprenant du tadalafil et ses procédés de préparation Download PDF

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Publication number
WO2012095151A1
WO2012095151A1 PCT/EP2011/006544 EP2011006544W WO2012095151A1 WO 2012095151 A1 WO2012095151 A1 WO 2012095151A1 EP 2011006544 W EP2011006544 W EP 2011006544W WO 2012095151 A1 WO2012095151 A1 WO 2012095151A1
Authority
WO
WIPO (PCT)
Prior art keywords
tadalafil
granulation
water
ethylcellulose
process according
Prior art date
Application number
PCT/EP2011/006544
Other languages
English (en)
Inventor
Daniel Zakowiecki
Jaroslaw Mazgalski
Aleksandra Tukalska
Original Assignee
Zaklady Farmaceutyczne Polpharma Sa
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 Zaklady Farmaceutyczne Polpharma Sa filed Critical Zaklady Farmaceutyczne Polpharma Sa
Priority to DK11813321.4T priority Critical patent/DK2654723T3/en
Priority to PL11813321T priority patent/PL2654723T3/pl
Priority to ES11813321.4T priority patent/ES2533309T3/es
Priority to SI201130398T priority patent/SI2654723T1/sl
Priority to EP11813321.4A priority patent/EP2654723B1/fr
Publication of WO2012095151A1 publication Critical patent/WO2012095151A1/fr
Priority to HRP20150158TT priority patent/HRP20150158T1/hr

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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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—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

Definitions

  • Solid pharmaceutical dosage forms comprising tadalafil and methods of
  • the present invention relates to a process for preparing solid pharmaceutical composition containing tadalafil as active pharmaceutical ingredient.
  • the invention furthermore relates to the pharmaceutical compositions containing tadalafil on the surface of a water-insoluble polymer. Background of the invention
  • Tadalafil is a drug used to treat male penile erectile dysfunction (impotence) and pulmonary arterial hypertension (ATC code: G04BE08).
  • the drug works by selective inhibiting phosphodiesterase type 5 (PDE5) enzyme what cause relaxing muscles and increasing blood flow to particular areas of the organism.
  • PDE5 phosphodiesterase type 5
  • Tadalafil is currently marketed under brand name Cialis by the Eli Lilly ICOS joint venture, and is used to treat erectile dysfunction in a men, although can also be used for other purposes. Cialis is available in different strengths, i.e. 5 mg, 10 mg, and 20 mg in the form of film-coated tablets for oral administration.
  • Tadalafil is ⁇ -carboline derivative, chemically described as ⁇ 6R-trans)-6-( ⁇ ,3- benzodioxol-5-yl)- 2,3,6,7,12, 12a-hexahydro-2-methyl-pyrazino [ ⁇ , 2':1,6] pyrido[3,4- b] indole- 1,4-dione (CAS No. 171596-29-5). Its empirical molecular formula is C 22 Hi 9 N 3 0 4 , and its structural formula is given in Figure 1. Its molecular weight is 389.4 g/mol.
  • Tadalafil is a solid and is characterized as a BCS class IV compound because of its low solubility and low permeability. Its experimental water solubility is about 2 ⁇ g/mL at 37°C. Additionally it is characterized by low permeability which is a further limiting factor for pharmaceutical and biological availability of the drug.
  • a pharmaceutical composition comprising the free drug particulate form of tadalafil and pharmaceutically acceptable salts and solvates thereof are disclosed.
  • Said particles of the compound are characterized by particle size distribution, where at least 90% of particles have dimensions less than about 40 ⁇ .
  • solid solutions comprising tadalafil and at least one carrier are disclosed, which are suitable for preparing pharmaceutical finished dosage forms.
  • the active pharmaceutical ingredient and the carrier are "intimately associated" i.e. tadalafil is absorbed in the excipient forming a solid solution after the evaporation of the solvent, although no proof was disclosed to prove the existence of any interactions on molecular level.
  • the present invention provides an orally administered tadalafil drug formulation and the method of preparation thereof, which has improved pharmaceutical properties and biological availability.
  • the present invention provides a process comprising the steps: a) preparing a solution of tadalafil in organic solvent; b) carrying up tadalafil onto a water- insoluble polymer mixed with a diluent by fluid bed granulation; c) mixing the granulation with one or more further excipients.
  • the organic solvent can be a lower aliphatic alcohol like methanol, ethanol, isopropanol; or can be a keton like aceton or can be a mixture thereof.
  • the solvent isopropanol or aceton, more preferably the mixture of aceton and isopropanol.
  • API active pharmaceutical ingredient
  • crystalline or amorphous form can cause several problems during the technological process.
  • Such a problems can be a unwanted change in physical properties like conversions between different polymorphic forms or a change in particle size, shape, surface properties.
  • Using a solution of the API allows to avoid such limitations.
  • the possibility of eliminating such processes as water and other solvent adsorption and absorption by API, which translates to the creation of hydrates and solvates plays a significant role, together with the changes in melting temperature, solubility, hygroscopic parameters, mechanical properties of the substance and other parameters. Even minor changes in physical properties of the API can influence its bioavailability. Therefore according to the present invention API-in- solution is used as a starting material.
  • the granulation method also can play an important role in the formulation process and can have a significant influence on the properties of the composition.
  • fluid-bed granulation method preferably fluid-bed hot-melt granulation method is used at 50-150 °C.
  • This method results a granulation of tadalafil having very advantageous properties for preparing solid pharmaceutical formulations.
  • the formulation prepared from the obtained granulation does not show these advantageous properties.
  • the dissolution rate is significantly better in the case of the formulation which was prepared by using the granulation obtained by the fluid-bed granulation method (Example 2, Figure 8.)
  • the other important factor is the polymer.
  • the polymer used in the granulation step can be a water-insoluble polymer, preferably it can be a water-insoluble polymer which can soften under high temperature used during this step. More preferably the polymer can be selected from the group of ethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carbomers, Kollicoat SR, Eudragit and glycerin monostearate, most preferably it is ethylcelllulose.
  • the preferred polymers are physiologically inert, tasteless and odorless hydrophobic polymers, mainly used to control or reduce the release rate of a soluble drug substance.
  • compositions according to the present invention provide an improvement of dissolution rate of poorly soluble tadalafil, as is presented in the Figure 6.
  • the present invention is illustrated by the following examples which limit in no way its scope.
  • Example 1 A Glatt GPCG3 (Binzen, Germany) fluid bed apparatus was used for the granulation.
  • Example 1 A Glatt GPCG3 (Binzen, Germany) fluid bed apparatus was used for the granulation.
  • API-in-solution Starting material, which is tadalafil in the mixture of acetone and isopropanol (API-in- solution) is combined with carrier (excipients) in the process of fluid hot melt granulation. Obtained blend is mixed with other excipients and finally with lubricant, then compressed to form tablets.
  • API in solution :
  • FIG. 3 Comparison of XRPD patterns of tadalafil 10 mg tablets prepared according to composition No. 1 and flow chart presented in Figure 2 (II) and crystalline tadalafil drug substance (I) XRPD pattern of tadalafil 10 mg tablets prepared according to composition No. 1 (Table 2) and flow chart presented in Figure 2, shows lack of the most intensive peaks characteristic to crystalline tadalafil (marked with arrows). Moreover it is characterized by improved solubility of tadalafil, what is illustrated by means of dissolution profile presented in Figure 8.
  • FIG. 7 Comparison of XRPD patterns of tadalafil 10 mg tablets prepared according to composition No. 2 and flow chart presented in Figure 6 (II) and crystalline tadalafil drug substance (I) XRPD pattern of tadalafil 10 mg tablets prepared according to composition No. 2 (Table 3) and flow chart presented in Figure 6, shows lack of the most intensive peaks characteristic to crystalline tadalafil (marked with arrows). Moreover it is characterized by improved solubility of tadalafil, in similar way as is presented in example 1.

Abstract

La présente invention concerne une forme pharmaceutique solide stable, comprenant du tadalafil combiné à un polymère insoluble dans l'eau, et son procédé de préparation.
PCT/EP2011/006544 2010-12-23 2011-12-23 Formes pharmaceutiques solides comprenant du tadalafil et ses procédés de préparation WO2012095151A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
DK11813321.4T DK2654723T3 (en) 2010-12-23 2011-12-23 Solid pharmaceutical dosage forms comprising tadalafil and processes for their preparation
PL11813321T PL2654723T3 (pl) 2010-12-23 2011-12-23 Stałe postacie leku zawierające tadalafil i sposoby ich otrzymywania
ES11813321.4T ES2533309T3 (es) 2010-12-23 2011-12-23 Formas farmacéuticas sólidas que contienen taladafil y métodos de preparación de las mismas
SI201130398T SI2654723T1 (sl) 2010-12-23 2011-12-23 Trdne farmacevtske dozirna oblike, ki obsegajo tadalafil in metode za njihovo pripravo
EP11813321.4A EP2654723B1 (fr) 2010-12-23 2011-12-23 Formes pharmaceutiques solides comprenant du tadalafil et ses procédés de préparation
HRP20150158TT HRP20150158T1 (hr) 2010-12-23 2015-02-09 Äśvrsti farmaceutski dozirani oblici koji sadrže tadalafil i postupci njihove pripreme

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EPEP10460052 2010-12-23
EP10460052 2010-12-23

Publications (1)

Publication Number Publication Date
WO2012095151A1 true WO2012095151A1 (fr) 2012-07-19

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2011/006544 WO2012095151A1 (fr) 2010-12-23 2011-12-23 Formes pharmaceutiques solides comprenant du tadalafil et ses procédés de préparation

Country Status (1)

Country Link
WO (1) WO2012095151A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014167579A2 (fr) * 2013-03-28 2014-10-16 Astron Research Limited Compositions pharmaceutiques stables de tadalafil
CN110664766A (zh) * 2019-10-10 2020-01-10 甘肃普安制药股份有限公司 一种他达拉非片剂及其制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996038131A1 (fr) * 1995-06-02 1996-12-05 Glaxo Group Limited Procede de production d'une dispersion solide d'un medicament faiblement hydrosoluble
WO2001008688A2 (fr) 1999-08-03 2001-02-08 Lilly Icos Llc PRODUITS DE MEDICAMENTS A BASE DE β-CARBOLINE
US6841167B1 (en) 1999-08-03 2005-01-11 Lilly Icos Llc. β-carboline pharmaceutical compositions
EP1985310A1 (fr) * 2007-04-25 2008-10-29 Teva Pharmaceutical Industries Ltd. Formes de dosage solide
US20100099687A1 (en) 2006-07-07 2010-04-22 Teva Pharmaceutical Industries Ltd. Tadalafil solid composites

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996038131A1 (fr) * 1995-06-02 1996-12-05 Glaxo Group Limited Procede de production d'une dispersion solide d'un medicament faiblement hydrosoluble
US5985326A (en) 1995-06-02 1999-11-16 Icos Corporation Method of producing a solid dispersion of a poorly water soluble drug
WO2001008688A2 (fr) 1999-08-03 2001-02-08 Lilly Icos Llc PRODUITS DE MEDICAMENTS A BASE DE β-CARBOLINE
US6841167B1 (en) 1999-08-03 2005-01-11 Lilly Icos Llc. β-carboline pharmaceutical compositions
US20100099687A1 (en) 2006-07-07 2010-04-22 Teva Pharmaceutical Industries Ltd. Tadalafil solid composites
EP1985310A1 (fr) * 2007-04-25 2008-10-29 Teva Pharmaceutical Industries Ltd. Formes de dosage solide

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014167579A2 (fr) * 2013-03-28 2014-10-16 Astron Research Limited Compositions pharmaceutiques stables de tadalafil
WO2014167579A3 (fr) * 2013-03-28 2014-12-24 Astron Research Limited Compositions pharmaceutiques stables de tadalafil
CN110664766A (zh) * 2019-10-10 2020-01-10 甘肃普安制药股份有限公司 一种他达拉非片剂及其制备方法

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