WO2026029720A1 - Composition de comprimé de ticagrélor à libération immédiate stable - Google Patents

Composition de comprimé de ticagrélor à libération immédiate stable

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Publication number
WO2026029720A1
WO2026029720A1 PCT/TR2024/050893 TR2024050893W WO2026029720A1 WO 2026029720 A1 WO2026029720 A1 WO 2026029720A1 TR 2024050893 W TR2024050893 W TR 2024050893W WO 2026029720 A1 WO2026029720 A1 WO 2026029720A1
Authority
WO
WIPO (PCT)
Prior art keywords
ticagrelor
tablet composition
composition according
stable
stable tablet
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
PCT/TR2024/050893
Other languages
English (en)
Inventor
Hatice ONCEL
Onur Pinarbasli
Yagmur GULLU
Feristah BILGIN
Tolga OZBAY
Gulistan Pelin GURBETOGLU
Nurdan ATILGAN
Asuman AYBEY DOGANAY
Nagehan SARRACOGLU
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.)
Ilko Ilac Sanayi ve Ticaret AS
Original Assignee
Ilko Ilac Sanayi ve Ticaret AS
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 Ilko Ilac Sanayi ve Ticaret AS filed Critical Ilko Ilac Sanayi ve Ticaret AS
Priority to PCT/TR2024/050893 priority Critical patent/WO2026029720A1/fr
Publication of WO2026029720A1 publication Critical patent/WO2026029720A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • the present invention interests an oral solid dosage form featuring ticagrelor as the active pharmaceutical ingredient. It describes a method for manufacturing an immediate- release ticagrelor tablet that maintains a consistent and satisfactory in vitro dissolution profile over its shelf-life.
  • Ticagrelor is the most recent and most effective antiplatelet agent used to inhibit platelet aggregation via blocking the ADP receptors of the subtype P2Y12. It is a non- thienopyridine class drug. The drug was first discovered by Astra Zeneca and approved for use in 2011 by the FDA.
  • Ticagrelor is the drug of choice for the prevention and treatment of thromboembolism in adult patients with acute coronary syndrome.
  • Ticagrelor is a crystalline powder with low aqueous solubility of about 10 mg/L across the entire pH range. It is established that it has several polymorphs.
  • Ticagrelor was first described in WO 99/05143 and can be prepared according to the methods disclosed in this patent.
  • WO 01/92262 definitely states that ticagrelor exists in four different crystalline forms and an amorphous form.
  • Ticagrelor has four non-solvated polymorphs (Polymorph I, II, III and IV) and a number of solvated crystalline modifications, which can be distinguished by X-ray powder diffraction. It does not convert to any other form when stored.
  • Ticagrelor belongs to class IV compound according to the biopharmaceutical classification system (BCS), which means it has low solubility in water and low permeability.
  • BCS biopharmaceutical classification system
  • Its chemical name is 1S-[1 ⁇ ,2 ⁇ ,3 ⁇ (1S*,2R*),5 ⁇ ]-3-(7-[2-(3,4- difluorophenyl)cyclopropyl]amino-5-(propylthio) -3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)- 5-(2-hydroxyethoxy)cyclopentane-1,2-diol.
  • Its empirical formula is C 23 H 28 F 2 N 6 O 4 S, and its molecular weight is 522.57 Da.
  • Ticagrelor structural formula is as follows; Ticagrelor is an oral, direct-acting P2Y12 receptor antagonist. In vitro studies have definitely shown that ticagrelor binds reversibly and non-competitively to the P2Y12 receptor at a site distinct from that of the endogenous agonist adenosine diphosphate (ADP). This antiplatelet drug helps blood flow through the veins, reducing the likelihood of dangerous blood clots. Ticagrelor is used to prevent strokes, heart attacks and other events in people with acute coronary syndrome, which is a problem with the blood supply to the coronary arteries. It is marketed under the brand names Brilinta® in the US and Brilique® in the EU in 60 mg and 90 mg oral tablets.
  • compositions comprising ticagrelor are disclosed in WO 2008/024044 and WO 2008/024045.
  • the compositions which may contain up to 50% by weight of the active ingredient, are suitable for oral administration and release substantially all of the active ingredient.
  • the compositions are prepared using a conventional wet granulation process.
  • Ticagrelor faces challenges as a pharmaceutically active compound due to its low solubility. This poor solubility presents significant problems in formulating effective pharmaceutical products. Ticagrelor has minimal solubility in neutral media such as water. Therefore, water is the preferred medium for assessing non-bioequivalence in dissolution studies.
  • the development of solid oral dosage forms containing ticagrelor will achieve formulations with high dissolution rates in water.
  • the objective of the present invention is to produce a stable solid oral pharmaceutical composition comprising therapeutically effective amount of ticagrelor and at least one excipient.
  • a stable pharmaceutical tablet composition comprising ticagrelor wherein said tablet composition comprises 4%-7% disintegrant by weight based on total weight of the composition which is present both in internal phase and in external phase.
  • a formulation for producing an immediate release tablet composition that ticagrelor is wet granulated with croscarmellose sodium or sodium starch glycolate as a disintegrant and at least one other excipient, wherein said tablet composition comprises 4%-7% disintegrant by weight based on total weight of the composition which is present both in the internal phase and in the external phase.
  • a formulation for producing an immediate release tablet composition that ticagrelor is wet granulated with croscarmellose sodium or sodium starch glycolate as a disintegrant and at least one other excipient, wherein said tablet composition comprises totally 4%-7% disintegrant by weight based on total weight of the composition and the disintegrant ratio in the internal phase and external phase is 1:1.
  • a formulation for producing an immediate release tablet composition with a ticagrelor active substance particle size of D90 between 5 ⁇ m and 50 ⁇ m.
  • a formulation for producing an immediate release tablet composition that ticagrelor is wet granulated with croscarmellose sodium or sodium starch glycolate as a disintegrant, hydroxypropyl cellulose as a binder and a mixture of mannitol and dibasic calcium phosphate as a filler/diluent to form the internal phase.
  • croscarmellose sodium or sodium starch glycolate as a disintegrant
  • hydroxypropyl cellulose as a binder
  • a mixture of mannitol and dibasic calcium phosphate as a filler/diluent
  • the present invention aims to exhibit good storage stability and fast dissolution.
  • the present invention produced a stable and solid oral pharmaceutical composition that contains ticagrelor.
  • This composition has an in-vitro dissolution profile that is comparable to that of Brilique® Tablets.
  • Pharmaceutical companies are committed to enhancing the quality of their products and accelerating drug development while simultaneously pursuing innovative strategies to reduce costs.
  • the method of preparation and choice of excipients are carefully selected to achieve the desired physical characteristics of the tablet formulation, allowing for efficient compression of the tablets.
  • the invention relates to a pharmaceutical composition prepared by wet granulation.
  • Granulation is the process by which primary particles (powders) are made to adhere and form larger, multiparticulate entities called granules.
  • Granulation normally commences after initial dry mixing of the powdered ingredients to ensure a uniform distribution of ingredients throughout the mix.
  • Granulation methods can be divided into two types: wet granulation methods that utilise a liquid to form the granules and dry methods that do not.
  • Wet granulation involves massing the primary powder particles using a granulating fluid.
  • the fluid contains a solvent that can be removed by drying and is non-toxic.
  • the granulating fluid can be used alone or more typically with a binding agent (binder) to ensure article adhesion in the dry state.
  • Binding agents can be added to the system in two ways: as a binder solution (as part of the granulating fluid) or as dry material mixed with the primary powder particles.
  • a binder solution as part of the granulating fluid
  • dry material mixed with the primary powder particles.
  • wet granulator There are three main types of wet granulator: shear granulators, high shear mixer granulators and fluid bed granualtors.
  • High shear wet granulation is a process that involves intensive dry mixing of primary powders and subsequent addition of granulating fluid, resulting in the formation of granules.
  • the granulating fluid contains a volatile solvent (usually water) and may also include a binder; which ensures particle adhesion. Binders may also be added dry as powders to the bulk of the formulation to be granulated.
  • Granules have significant advantages over powders in terms of improved flow properties, reduced risk of segregation and increased homogeneity.
  • active substance or “active pharmaceutical ingredient” refers to any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals.
  • the active substance is ticagrelor or its pharmaceutically acceptable salts thereof, particularly ticagrelor.
  • the active substance ticagrelor is present with a particle size of D90 between 5 ⁇ m and 50 ⁇ m.
  • the use of a small particle size raw material is essential to promote the release of the compound’s low aqueous solubility.
  • the most common approach to defining the distribution width is to cite three values on the x-axis as D10, D50 and D90.
  • the D50 also known as the median, is the diameter where 50 percent of the distribution lies below this value.
  • D90 is defined as 90 percent of the distribution lying below, with 10 percent of the population lying below the D10.
  • the term “therapeutically effective amount” refers to the amount of ticagrelor or its pharmaceutically acceptable salts, esters, and solvates thereof, that is sufficient to effect treatment when administered to a subject in need of such treatment, as defined herein.
  • the tablet composition of the present invention comprises 90 mg and 60 mg of ticagrelor.
  • immediate release refers to the release of the active ingredient immediately upon reaching the stomach.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and other complications commensurate with a reasonable benefit/risk ratio.
  • tablets contain a number of inert materials known as excipients, which are essential for their function.
  • excipients refers to any substance that is not itself a therapeutic agent.
  • a therapeutic agent e.g. to create a pharmaceutical composition
  • a therapeutic agent e.g. to create a pharmaceutical composition
  • It can also be used to permit or facilitate the formation of a dose unit of the composition.
  • Excipients include, by way of illustration and not limitation, binders, disintegrants, taste enhancers, solvents, thickening or gelling agents (and any neutralising agents, if necessary), penetration enhancers, solubilising agents, wetting agents, antioxidants, lubricants, emollients, emulsifying agents, surfactants, substances added to mask or counteract a disagreeable odour, fragrances or taste, and substances added to improve appearance or texture of the composition.
  • Such excipients can be used in any dosage forms, as set forth in the present disclosure. The foregoing classes of excipients are not exhaustive.
  • ticagrelor tablet comprises at least one binder, at least one filler (diluent), at least one disintegrant and at least one lubricant.
  • the excipients can be classified according to their role they play in the final tablet. Excipients are typically added to a formulation to impart good flow and compression characteristics to the material being compressed.
  • the lubricant is typically added to prevent the tableting materials from sticking to punches, minimise friction during tablet compression, and allow for removal of the compressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts of less than 1% by weight.
  • the composition comprises at least one lubricant selected from the group comprising magnesium stearate, stearic acid, palmitic acid, calcium stearate, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols and sodium stearyl fumarate or mixtures thereof.
  • magnesium stearate is selected.
  • the filler (diluents) is added to increase the bulk weight of the blend resulting in a practical size for compression. This is often necessary when the dose of the drug is relatively small.
  • the composition comprises at least one filler (diluent) selected from the group comprising microcrystalline cellulose, lactose, mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, inorganic phosphates, like dibasic calcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin , sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate polyols, dextrose, maltitol, or mixtures thereof.
  • filler selected from the group comprising microcrystalline cellulose, lactose, mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol,
  • the composition comprises at least one binder selected from the group comprising polyvinyl pyrrolidone, microcrystalline cellulose, cellulose ether, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, corn starch, maize starch, pregelatinised starch, polymethacrylate, or mixtures thereof.
  • hydroxypropyl cellulose is selected.
  • the disintegrants are included to decompose the tablet in the gastrointestinal fluid in order to ensure that the tablet has an acceptable rate of disintegration.
  • the composition comprises at least one disintegrant selected from the group comprising croscarmellose sodium, sodium carbonate, hydroxypropyl cellulose (HPC), cross-linked polyvinylpyrrolidone (crospovidone), copovidone, polycarbophil, low substituted poloxamer, sodium starch glycollate, starch, pregelatinised starch, alginic acid and alginates, ion exchange resins, magnesium aluminium silicate, sodium dodecyl sulfate, sodium carboxy methyl cellulose, carboxy methyl cellulose calcium, sodium docusate, guar gum, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, or mixtures thereof.
  • HPC hydroxypropyl cellulose
  • crospovidone cross-linked polyvinylpyrrolidone
  • copovidone polycarbophil
  • low substituted poloxamer sodium starch glycollate, starch, pregelatinised starch
  • sodium starch glycollate and croscarmellose sodium are selected for disintegrant.
  • Croscarmellose sodium and sodium starch glycolate are superdisintegrants that promote tablet disintegration by swelling and wicking mechanisms. When in contact with water, the omni-directional increase in the croscarmellose sodium particle size pushes the tablet apart. The wicking action draws water into the tablet, which effectively disrupts the intermolecular forces between particles in the tablet.
  • the disintegrant amount is set at 4 to 7% to ensure continuity of stability, given the moisture retention properties of the disintegrants.
  • the pharmaceutical dosage form according to the present invention comprising ticagrelor may be present in form of a tablet which is coated with one or more coating materials.
  • the coating materials are not limited and are known to the person skilled in the art. Finding suitable excipients for a particular active substance and determining the appropriate manufacturing process for the combination of excipient and active substance is a challenging task when designing a pharmaceutical product such as a tablet.
  • the excipients may be distributed partly in the internal (granular) phase and partly in the external phase, as seen in the described invention.
  • the disintegrant is distributed in the internal and external phase.
  • the binder and filler/ diluent are only part of the internal phase, whereas the lubricant is only part of the external phase.
  • the internal phase excipients e.g.
  • filler/diluent, binder and part of disintegrant, and the drug substance are mixed and granulated with an aqueous solution.
  • the granulate is then dried and sieved.
  • the external phase which contains, for example, part of the disintegrant and lubricant, is screened with the dried granulate and mixed.
  • the mixture is compressed into tablets.
  • the granulate phase is defined as the ‘internal phase’, the excipients added to the granulate are defined as the ‘external phase’ of the tabletting mixture. It is essential to develop a stable formulation that can withstand higher temperatures and relative humidity levels than those typically encountered when formulating a compound into a tablet or another solid dosage form.
  • the present invention provides a stable pharmaceutical dosage form for oral administration comprising ticagrelor and exhibiting an immediate drug release profile. Furthermore, the pharmaceutical composition shall be bioequivalent to reference product and meet the acceptance criteria for generic products and must be stable under different storage conditions.
  • Example 1
  • compositions prepared by wet granulation process comprises a method of preparing a pharmaceutical composition comprising a pharmaceutically effective amount of ticagrelor or pharmaceutically ieriquality Vietnamese salts thereof, a filler which is a mixture of mannitol and dibasic calcium phosphate dihydrate; a binder which is hydroxyl propyl cellulose; a lubricant which is magnesium stearate, and a disintegrant which is sodium starch glycollate or croscarmellose sodium.
  • internal phase was prepared with wet granulation of the required amounts of active ingredient ticagrelor, filler which is a mixture of mannitol and dibasic calcium phosphate dihydrate; binder which is hydroxyl propyl cellulose and part of disintegrant which is sodium starch glycollate or croscarmellose sodium.
  • the prepared granule was mixed with the external phase which comprised the rest of the disintegrant (sodium starch glycollate or croscarmellose sodium) and required amounts of lubricant (magnesium stearate). The final blends were compressed using a rotary tablet press.
  • Table 1 Unit formula for Ticagrelor Tablet % Component F -01 F-02 F-03 F-04 F-05 Internal phase Ticagrelor 30 30 30 30 30 Mannitol 41.5 40.5 39.5 38.5 41.5 Dibasic calcium phosphate 21 21 21 21 21 dihydrate Hydroxypropyl cellulose Sodium starch glycolate - - 3.0 3.5 4.0 Croscarmellose sodium 2.0 2.5 - - - External phase Sodium starch glycolate - - 3.0 3.5 - Croscarmellose sodium 2.0 2.5 - - - Magnesium stearate 1 1 1 1 1 Example 2.
  • Dissolution testing is sometimes used as a surrogate for the direct evaluation of drug bioavailability (Source Emmanuel et al., Pharmaceutics (2010), 2:351-363). Dissolution testing measures the percentage of the active substance released from the drug product (i.e., tablet or capsule) and dissolved in the dissolution medium under controlled testing conditions over a defined period of time. To maintain sink conditions, the saturation solubility of the drug in the dissolution media should be at least three times the drug concentration. For low solubility compounds, dissolution may sometimes be determined under non-sink conditions.
  • Dissolution is affected by the properties of the active substance (e.g., particle size, crystal form, bulk density), the composition of the drug product (e.g., drug loading, excipients), the manufacturing process (e.g., compression forces) and the stability under storage conditions (e.g., temperature, humidity).
  • the tablets were tested in a USP 2 apparatus with paddles spinning at 75 rpm, in 900 mL of 0.2% w/v Polysorbate 80 in water at a temperature of 37°C ⁇ 0.5 o C (FDA Dissolution Methods Database, 25.06.2015).
  • the dissolution profiles were compared and evaluated using the similarity factor (f 2 ) (Helmy & Bedaiwy, 2013). An f 2 value between 50 and 100 indicates that the all- dissolution profiles are similar (EMEA Guideline on the Investigation of Bioequivalence, 2010).
  • the similarity factor (f 2 ) values of the test products (Formulations F-01 to F-05) and the reference product (Brilique® Tablet) for the different pH media are found between 50 and 100.
  • Example 3 Stability Studies It is crucial to ensure that the stability of a drug substance in order to manufacture safe and effective pharmaceutical products. Any applicant seeking approval for a new pharmaceutical product must submit stability studies. The rules in force (e.g.
  • compositions must be chemically stable. Degradation by oxidation, hydrolysis, isomerisation, photolysis, polymerisation or any other method of degradation, either as a result of mixing with excipients or by any other method, will lead to a reduction in bioavailability. Chemical stability can be determined by a suitable, stability indicating chromatographic method for determining degradation products. It is well-established that many drugs exhibit poor or modest shelf stability. The presence of degradation products of these drugs can give rise to efficacy or toxicity issues. Even if they do not, the diminution of the concentration of a drug as a result of its degradation is inherently undesirable. It makes therapy with the drug less certain.
  • Bioequivalence study As per USFDA guideline titled “Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations” Bioequivalence is defined as: "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.”
  • the tablets produced with the present invention (F-04) are bioequivalent to the reference product Brilique® with the bioequivalence study conducted in normal, healthy, adult, female subjects under fasting conditions.
  • FIGURES Figure 1 Comparison of in vitro dissolution profile for Test product (F-04) and Reference product (BriliqueTablet)

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne une forme posologique solide orale comprenant du ticagrélor en tant que principe pharmaceutiquement actif et au moins un excipient. En particulier, la présente invention concerne un procédé de production d'une composition de comprimé de ticagrélor à libération immédiate qui est granulée par voie humide, comportant du croscarmellose sodique ou du glycolate d'amidon sodique en tant que désintégrant afin de produire un profil de dissolution in vitro stable pendant toute la durée de conservation.
PCT/TR2024/050893 2024-07-30 2024-07-30 Composition de comprimé de ticagrélor à libération immédiate stable Pending WO2026029720A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/TR2024/050893 WO2026029720A1 (fr) 2024-07-30 2024-07-30 Composition de comprimé de ticagrélor à libération immédiate stable

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/TR2024/050893 WO2026029720A1 (fr) 2024-07-30 2024-07-30 Composition de comprimé de ticagrélor à libération immédiate stable

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WO2026029720A1 true WO2026029720A1 (fr) 2026-02-05

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PCT/TR2024/050893 Pending WO2026029720A1 (fr) 2024-07-30 2024-07-30 Composition de comprimé de ticagrélor à libération immédiate stable

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WO (1) WO2026029720A1 (fr)

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