EP3761965A1 - Ticagrelor-containing tablet formulation - Google Patents

Ticagrelor-containing tablet formulation

Info

Publication number
EP3761965A1
EP3761965A1 EP18711270.1A EP18711270A EP3761965A1 EP 3761965 A1 EP3761965 A1 EP 3761965A1 EP 18711270 A EP18711270 A EP 18711270A EP 3761965 A1 EP3761965 A1 EP 3761965A1
Authority
EP
European Patent Office
Prior art keywords
tablet
starch
ticagrelor
pregelatinized starch
weight
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.)
Pending
Application number
EP18711270.1A
Other languages
English (en)
French (fr)
Inventor
Panagiotis PANAGOPOULOS
Konstantinos-Emmanouil PANITSAS
Konstantinos KOMPOROZOS
Dimosthenis KANTAS
Sofia GEORGAKAKOU
Ioanna PARELI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmaceutical Oriented Services Ltd
Rontis Hellas SA
Original Assignee
Pharmaceutical Oriented Services Ltd
Rontis Hellas 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 Pharmaceutical Oriented Services Ltd, Rontis Hellas SA filed Critical Pharmaceutical Oriented Services Ltd
Publication of EP3761965A1 publication Critical patent/EP3761965A1/de
Pending legal-status Critical Current

Links

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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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

Definitions

  • the present invention relates to a tablet containing ticagrelor, wherein the tablet is prepared by wet-granulation.
  • Ticagrelor is marketed under the tradename Brilique ® in the form of film-coated tablets, which contain 60 mg or 90 mg ticagrelor.
  • Brilique ® is indicated for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS) or with a history of myocardial infarction (MI) and a high risk of developing an atherothrombotic event.
  • Brilique ® treatment should be initiated with a single 180 mg loading dose and then continued at 90 mg twice daily for twelve months in ACS-patients.
  • Brilique ® 60 mg twice daily is the recommended dose when an extended treatment is required for patients with a history of MI of at least one year and a high risk of an atherothrombotic event.
  • the tablets should be administered with a daily maintenance dose of acetylsalicylic acid of 75-100 mg.
  • Ticagrelor has a low and pH-independent solubility in aqueous media as well as a low permeability, so that the drug is classified as a class IV compound according to the Biopharmaceutics Classification System (BCS).
  • Ticagrelor may exist in various crystalline forms, including solvated forms.
  • WO 01/92262 describes the crystalline forms I-IV of ticagrelor as well as an amorphous form that may be prepared by freeze-drying or spray-drying of a solution containing the drug.
  • tablets are described containing ticagrelor, lactose, croscarmellose sodium, magnesium stearate, and maize starch paste or maize starch and polyvinylpyrrolidone (povidone).
  • the commercially available Brilique ® tablet contains, besides ticagrelor, mannitol and calcium hydrogen phosphate (dibasic calcium phosphate) as fillers, sodium starch glycolate as a disintegrant, hydroxypropylcellulose as a binder and magnesium stearate as a lubricant.
  • the tablet is prepared by wet-granulation and is further film- coated.
  • WO 2008/024044 and WO 2008/024045 describe the wet-granulation process used for the preparation of the Brilique ® tablets. It is stated in these applications that the drug release from the formulation and the stability of the formulation affects the bioavailability of ticagrelor, and that it is important that the formulation releases substantially all of the drug.
  • a tablet that releases substantially all of the drug and that has sufficiently high stability may be obtained if it contains, besides the drug, a water-soluble filler, e.g., mannitol, sorbitol, maltodextrin, maltose and dextrin, a water-insoluble filler, e.g., dibasic calcium phosphate (dihydrate or anhydrous), pregelatinized starch and tribasic calcium phosphate, a binder, e.g., hydroxypropylcellulose, alginic acid, carboxymethyl- cellulose sodium, a vinylpyrrolidone/vinyl acetate copolymer (copovidone) and methylcellulose, a superdisintegrant selected from sodium starch glycolate, croscarmellose sodium and crospovidone, as well as a lubricant.
  • a water-soluble filler e.g., mannitol, sorbitol, maltodextrin, mal
  • the tablet is prepared by wet-granulation using, e.g., a high-shear wet-granulator.
  • WO 2014/059955 discloses that a disintegrant is not necessary in order to release substantially all of the drug, if the main excipient of the tablet is a non-hygroscopic but water-soluble filler.
  • Preferred fillers are sugars and sugar alcohols such as lactose (monohydrate or anhydrous), xylitol, mannitol, isomaltose, maltose, maltitol and lactitol.
  • the tablet may be prepared by wet-granulation, dry-granulation or direct compression, wherein a non-hygroscopic binder should be present if wet-granulation is used.
  • suitable binders povidone, copovidone, microcrystalline cellulose, hydroxymethylcellulose, hydroxypropyl methylcellulose, starch, pregelatinized starch and polymethacrylates are mentioned.
  • the drug release may be further improved if the tablet contains only a low amount of ticagrelor, i.e. less than 20 % by weight based on the total weight of the tablet, and if the filler, which constitutes the major portion of the tablet composition, is not a water-insoluble filler.
  • the filler is preferably a sugar or sugar alcohol, e.g., mannitol, whereby the tablet is preferably prepared by wet-granulation using an aqueous povidone-containing granulation liquid.
  • the tablet may contain sodium starch glycolate as extragranular component.
  • WO 2011/076749 discloses that the formulations described in WO 2008/024044 and WO 2008/024045 may only contain up to 50 % by weight of ticagrelor, because otherwise, the unit dosage form may not release substantially all of the active ingredient.
  • WO 2011/076749 suggests as a solution to the problem of providing a tablet containing a high drug-load and releasing substantially all of drug, the co- grinding of ticagrelor and a hydrophilic polymer and/or an emulsifier, and the adjustment of the particle size of the ticagrelor particles.
  • the unit dosage form e.g., a tablet, which can be prepared by wet-granulation, melt-granulation or direct compression, should contain ticagrelor with a particle size distribution of D v 90 of 1 mm to 150 mm.
  • WO 2015/001489 suggests the use of ticagrelor in amorphous form, which includes a solid dispersion or solid solution (molecularly dispersed) of ticagrelor within a hydrophilic matrix, in order to provide a sufficiently high dissolution rate.
  • the tablet of the present invention is an immediate-release tablet, preferably a film- coated tablet.
  • This tablet is prepared by wet-granulation and contains starch as disintegrant, pregelatinized starch as binder, a filler and optionally further pharmaceutical excipients.
  • Starch e.g., maize starch
  • starch may be used as both a binder and disintegrant. If used as a binder, the starch needs to be converted to a paste. However, starch loses its disintegration properties when it gelatinizes in the preparation of the starch paste. Gelatinized starch contains amylose and amylopectin, which are set free in the preparation of starch paste. The free amylopectin is responsible for the binding.
  • the starch is not converted to starch paste, because otherwise, it cannot function as a disintegrant.
  • pregelatinized starch is used as a binder. Either fully or partially pregelatinized starch may be used.
  • a preferred partially pregelatinized starch is Starch 1500 ® .
  • pregelatinized starch contains 5 % of free amylose, 15 % of free amylopectin and 80 % unmodified starch.
  • the tablet of the present invention does not contain a disintegrant and a binder other than starch and pregelatinized starch.
  • the tablet of the present invention does not contain a superdisintegrant as sodium starch glycolate, croscarmellose sodium or crospovidone. It was found that ticagrelor is not stable in a tablet prepared by wet-granulation that contains sodium starch glycolate as a disintegrant and povidone as a binder.
  • the release profile of ticagrelor may be adjusted by the weight ratio of starch to pregelatinized starch.
  • the weight ratio of starch to pregelatinized starch is 4 : 1 to 1 : 4, preferably 3 : 1 to 1 : 3, more preferred 2 : 1 to 1 : 2, and most preferably 1 : 1, If fully pregelatinized starch is used, more starch needs to be contained in the tablet in order to compensate the higher amount of binder.
  • the tablet or, if film-coated, the tablet core of the present invention contains ticagrelor in an amount of 20-40 % by weight, starch in an amount of 5-20 % by weight and pregelatinized starch in an amount of 5-20 % by weight.
  • the tablet or the tablet core consists of ticagrelor in an amount of 20-40 % by weight, starch in an amount of 5-20 % by weight, pregelatinized starch in an amount of 5-20 % by weight, a filler in an amount of 20-70 %, and further pharmaceutical excipients in an amount of 0-5 % by weight.
  • the further pharmaceutical excipient may be selected from a lubricant, a glidant and a surfactant.
  • the tablet of the present invention may be obtained by a process comprising the method steps: i) mixing ticagrelor, starch, at least a part of the pregelatinized starch, a filler, and optionally a first further pharmaceutical excipient,
  • step (i) subjecting the mixture obtained in step (i) to wet-granulation
  • step (iii) optionally mixing the granules obtained in step (ii) with a second further pharmaceutical excipient and with the remaining part of the pregelatinized starch, and
  • step (iv) subjecting the granules obtained in step (ii) or the mixture obtained in step (iii) to compression to obtain the tablet or the tablet core.
  • the tablet may contain a first further pharmaceutical excipient selected from a glidant and a surfactant.
  • the second further pharmaceutical excipient may be selected from a glidant and a lubricant. It is preferred that the tablet of the present invention does not contain a first further pharmaceutical excipient and, as a second further pharmaceutical excipient, only a lubricant.
  • fillers include microcrystalline cellulose, calcium hydrogen phosphate (anhydrous or dihydrate), lactose (anhydrous or monohydrate), calcium carbonate, magnesium carbonate, silicified microcrystalline cellulose, powder cellulose, mannitol, sorbitol, maltitol and lactitol. Mannitol, optionally in admixture with calcium hydrogen phosphate, is preferably used in the present invention.
  • glidants include silicon dioxide (silica) and magnesium silicate.
  • lubricants examples include magnesium stearate, calcium stearate, zinc stearate, talc, sodium stearyl iumarate and glyceryl dibehenate.
  • the tablet preferably contains talc and sodium stearyl fumarate.
  • surfactants include polyoxyethylene stearate, sodium lauryl sulfate, sorbitan fatty acid esters (e.g. sorbitan palmitate or sorbitan stearate) and polyoxyethylene sorbitan fatty acid esters (e.g. polysorbate 80).
  • the tablets of the present invention may optionally be coated with a film-coating.
  • Commercially available film-coating systems containing polyvinyl alcohol as coating polymer, which are marketed under the tradename Opadry ® may be used.
  • the drug contained in the tablet of the present invention is preferably crystalline ticagrelor, wherein the crystalline form II disclosed in WO 01/92262 is particularly suitable for the present invention.
  • the utilized ticagrelor has a particle size distribution D v 90 of 80 mm or below, preferably of 5-70 mm and more preferred of 10-60 mm (determined by using Mastersizer 2000).
  • the tablet of the present invention is suitable for preventing an atherothrombotic event in a patient, usually having acute coronary syndromes or being at risk of developing an atherothrombotic event.
  • the following examples are intended to further illustrate the present invention.
  • D v 90 corresponds to the particle size at 90 % of the cumulative volume distribution.
  • the dissolution tests were performed according to the FDA recommended dissolution method for ticagrelor tablets, i.e. in 900 ml purified water with 0.2 % (w/v) polysorbate 80, using USP apparatus II (paddle), speed: 75 rpm, temperature: 37 ⁇ 0.5°C.
  • Ticagrelor API The total amount of Ticagrelor API was introduced into a high shear mixer along with Mannitol, Calcium hydrogen phosphate dihydrate and part of Sodium Starch Glycolate and mixed for sufficient time.
  • step 2 The mixture of step 2 was granulated with water for sufficient time until granules are formed and was further dried in a fluid bed granulator. 4) Sizing step
  • step 3 The granules of step 3 were sized through an appropriate screen.
  • step 4 The granules of step 4 were added in a blender along with the remaining quantity of Sodium Starch Glycolate and were mixed for sufficient time.
  • Magnesium Stearate was added to the blender containing the mixture of step 5 and was mixed for sufficient time.
  • the tablets were further coated and tested for dissolution and compared to the reference product Brilique ® .
  • the tablet had acceptable physical characteristics comparable to the reference product and a similar dissolution.
  • the tablets were packed in PVC blisters and charged on stability study in the accelerated conditions.
  • Ticagrelor API The total amount of Ticagrelor API was introduced into a high shear mixer along with Mannitol, optionally Calcium hydrogen phosphate dihydrate, Maize Starch and part of Pregelatinized Starch and mixed for sufficient time.
  • step 2 The mixture of step 2 was granulated with water for sufficient time until granules are formed and was further dried in a fluid bed granulator. 4) Sizing step
  • step 3 The granules of step 3 were sized through an appropriate screen.
  • step 4 The granules of step 4 were added in a blender along with the remaining quantity of Pregelatinized Starch and Talc and were mixed for sufficient time.
  • the tablets were further coated and tested for dissolution in 900 mL purified water with 0.2%w/v Polysorbate 80 and compared to the reference product Brilique ® 90mg.
  • the comparative tables are presented below.
  • the tablets had acceptable tablet characteristics comparable to the reference product and similar dissolution profiles.
  • the related substances after one-month storage under accelerated conditions indicate that the formulations are stable and comparable to Brilique ® .

Landscapes

  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
EP18711270.1A 2018-03-08 2018-03-08 Ticagrelor-containing tablet formulation Pending EP3761965A1 (de)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2018/055824 WO2019170244A1 (en) 2018-03-08 2018-03-08 Ticagrelor—containing tablet formulation

Publications (1)

Publication Number Publication Date
EP3761965A1 true EP3761965A1 (de) 2021-01-13

Family

ID=61655746

Family Applications (1)

Application Number Title Priority Date Filing Date
EP18711270.1A Pending EP3761965A1 (de) 2018-03-08 2018-03-08 Ticagrelor-containing tablet formulation

Country Status (2)

Country Link
EP (1) EP3761965A1 (de)
WO (1) WO2019170244A1 (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021080529A1 (en) * 2019-10-26 2021-04-29 Santa Farma İlaç Sanayi̇ A.Ş. Solid pharmaceutical formulations comprising ticagrelor

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0013407D0 (en) 2000-06-02 2000-07-26 Astrazeneca Ab Forms of a chemical compound
WO2008024044A1 (en) 2006-08-21 2008-02-28 Astrazeneca Ab Compositions, suitable for oral administration, comprising a triazolo [4, 5] pyrimidin derivate
TWI482772B (zh) 2006-08-21 2015-05-01 Astrazeneca Ab 適合口服且包含三唑并[4,5-d]嘧啶衍生物之組合物
EP2515871B1 (de) 2009-12-23 2015-09-23 ratiopharm GmbH Feste pharmazeutische dosierungsform von ticagrelor
CZ2012705A3 (cs) 2012-10-16 2014-04-23 Zentiva, K.S. Pevná orální farmaceutická formulace obsahující ticagrelor
WO2015001489A1 (en) 2013-07-01 2015-01-08 Ranbaxy Laboratories Limited Pharmaceutical compositions of ticagrelor
CN103735552B (zh) * 2014-01-11 2015-11-25 福州乾正药业有限公司 替格瑞洛和西洛他唑的药物组合物及其制备方法和应用
WO2015110952A1 (en) 2014-01-21 2015-07-30 Wockhardt Limited Solid oral pharmaceutical compositions comprising ticagrelor or salt thereof
CN106727378A (zh) * 2016-12-28 2017-05-31 江苏飞马药业有限公司 一种含有替格瑞洛主药的片剂组合物及其制备方法

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