WO2021180862A1 - Compositions pharmaceutiques comprenant de l'élagolix sodique - Google Patents

Compositions pharmaceutiques comprenant de l'élagolix sodique Download PDF

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Publication number
WO2021180862A1
WO2021180862A1 PCT/EP2021/056219 EP2021056219W WO2021180862A1 WO 2021180862 A1 WO2021180862 A1 WO 2021180862A1 EP 2021056219 W EP2021056219 W EP 2021056219W WO 2021180862 A1 WO2021180862 A1 WO 2021180862A1
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WO
WIPO (PCT)
Prior art keywords
tablet
pharmaceutical composition
elagolix
alkalizer
super disintegrant
Prior art date
Application number
PCT/EP2021/056219
Other languages
English (en)
Inventor
Sonia GARCIA JIMENEZ
Lisardo Alvarez Fernandez
Rohit Kumar
Original Assignee
Synthon B.V.
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 B.V. filed Critical Synthon B.V.
Publication of WO2021180862A1 publication Critical patent/WO2021180862A1/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
    • A61K9/20—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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/2004—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

Definitions

  • Elagolix chemically 4-[2-[5-(2-Fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoro- methyl)benzyl]-4-methyl-2,6-dioxo-l,2,3,6-tetrahydro-l-pyrimidinyl]-l(R)-phenylethyl- amino]butyric acid is a gonadotropin-releasing hormone (GnRH) receptor antagonist. It was first disclosed in W02005007165 by Neurocrine Biosciences Inc. Sodium salt of elagolix is marketed by AbbVie under the brand name Orilissa for the management of moderate to severe pain associated with endometriosis. The product awaits registration in the U.S. for the management of heavy menstrual bleeding associated with uterine fibroids. Orilissa is supplied as immediate release film-coated tablets in two strengths: 150 and 200 mg.
  • Salts of weak acids convert to the less-soluble neutral forms during dissolution in the stomach. This in some cases causes gelling of the drug substance in the pharmaceutical formulation and in other cases the formation of a layer of free acid or neutral form on the surface of the dosage form. As a result, the release of the drug from the pharmaceutical composition is either retarded or completely hindered.
  • Sodium salt of elagolix has a tendency to form a gel, particularly when present in the composition at an amount greater than about 10% by weight.
  • the problem with gelation of GnRH antagonists was addressed in W02009137080 from Merrion.
  • the application discloses a composition comprising a GnRH antagonist and an anti-gelling agent, wherein the anti-gelling agents are medium chain fatty acid salt, or an ester, an ether, or a derivative of a medium chain fatty acid that has a carbon chain length of from about 4 to about 20 carbon atoms.
  • the anti-gelling agent can also be a surface active agent.
  • WO2019036712 from AbbVie, also addresses the tendency to form a gel by elagolix, but additionally identifies the second challenge to develop a pharmaceutical formulation comprising elagolix, which is a creation of a degradation product having a lactam moiety, namely (R)-5-(2-fluoro-3-methoxyphenyl)-l-(2-fluoro-6-(trifluoro- methyl)benzyl)-6-methyl-3-(2-(2-oxopyrrolidin-l-yl)-2-phenylethyl)pyrimidine-2,4(lH,3H)- dione.
  • the patent application relates to pharmaceutical compositions comprising Elagolix or pharmaceutically acceptable salt thereof, and at least one anti-gelling agent.
  • the anti-gelling agent can be a pH modifying agent such as buffer, an alkali metal salt, such as sodium carbonate, a base such as calcium hydroxide, guanidine, magnesium hydroxide, meglumine, piperidine, glucosamine, piperazine or TRIS (tris hydroxymethyl amino methane).
  • anti gelling disclosed in the application are basic amino acids (L-omithine, L-lysine or L- arginine), basic salts (sodium carbonate, potassium carbonate, trisodium phosphate, disodium hydrogen phosphate, trisodium citrate dehydrate, guanidine carbonate) and Eudragit EPO.
  • basic amino acids L-omithine, L-lysine or L- arginine
  • basic salts sodium carbonate, potassium carbonate, trisodium phosphate, disodium hydrogen phosphate, trisodium citrate dehydrate, guanidine carbonate
  • Eudragit EPO Eudragit EPO
  • a tablet composition comprising elagolix sodium with good stability, that is suitable for production on commercial scale and bioequivalent to Orilissa.
  • the present invention relates to the pharmaceutical compositions, in the form of immediate release tablets, comprising elagolix sodium and pharmaceutically acceptable ingredients comprising a super disintegrant, wherein the super disintegrant is present in an amount of from 5% to 30%, more preferably 6.5 to 25%, even more preferably from 8 to 20% by weight based on the total weight of the composition.
  • the super disintegrant can be selected from crospovidone, low-substituted hydroxypropyl cellulose (L-HPC), carboxymethylcellulose calcium, calcium silicate or it can be a mixture thereof.
  • L-HPC low-substituted hydroxypropyl cellulose
  • carboxymethylcellulose calcium, calcium silicate or it can be a mixture thereof.
  • he present invention further relates to the pharmaceutical compositions, in the form of immediate release tablets, comprising elagolix sodium and pharmaceutically acceptable ingredients comprising a super disintegrant and an alkalizer.
  • the invention relates to the pharmaceutical compositions, in the form of immediate release tablets, comprising elagolix sodium and pharmaceutically acceptable ingredients comprising a super disintegrant and a non-ionic surfactant.
  • Tablets according to this invention have good stability and have appropriate size to help patient compliance and acceptability. They show faster dissolution in acidic media in comparison to tablet without the anti-gelling agent.
  • the tablets in accordance with the present invention are bioequivalent to the commercially available elagolix sodium tablets.
  • Said pharmaceutical compositions may be used as a medicament, particularly in the treatment of endometriosis, uterine fibroids, polycystic ovary syndrome, adenomyosis or the associated symptoms thereof.
  • Fig. 1 shows dissolution of the tablet comprising super disintegrant prepared according to example 1 compared with the tablet without any anti-gelling agent (comparative example 1) and reference product (Orilissa).
  • Fig. 2 shows dissolution of the tablet comprising super disintegrant and a non-ionic surfactant prepared according to example 2 compared with the tablet without any anti-gelling agent (comparative example 1) and reference product (Orilissa).
  • Fig. 3 shows dissolution of the tablet comprising super disintegrant and an alkalizer prepared according to example 3 compared with the tablet without any anti-gelling agent (comparative example 1)) and reference product (Orilissa).
  • Fig. 4 shows dissolution of the tablet comprising super disintegrant an alkalizer prepared according to example 4 compared with the tablet without any anti-gelling agent (comparative example 1) and reference product (Orilissa).
  • the present invention provides an immediate release tablet comprising elagolix sodium and pharmaceutically acceptable excipients comprising a super disintegrant, wherein the super disintegrant is present in an amount of from 5% to 30%, more preferably from 6.5% to 25%, even more preferably from 8% to 20% by weight based on the total weight of the composition.
  • the super disintegrants are super-absorbing materials with tailor-made swelling properties. They promote the breakup of the tablet/capsule into smaller fragments in an aqueous environment, thereby increasing the available surface area and promoting a more rapid release of the active pharmaceutical ingredient.
  • the super disintegrant can be selected from crospovidone, low-substituted hydroxypropyl cellulose (L-HPC), carboxymethylcellulose calcium, calcium silicate and mixtures of any of the foregoing.
  • the super disintegrants are preferably used in an amount of from 5 to 30%, more preferably from 6.5 to 25%, even more preferably from 8 to 20% by weight based on the total weight of the composition.
  • the super disintegrant is preferably present in both the intragranular and extragranular phase of the tablet composition.
  • the tablet comprising elagolix sodium and super disintegrant further comprises pharmaceutically acceptable excipients.
  • the tablet composition further comprises an alkalizer.
  • the alkalizer helps to increase the solubility of the active substance.
  • the alkalizer can be selected from magnesium oxide, magnesium hydroxide and L-Arginine. Magnesium oxide is particularly preferred alkalizer.
  • An alkalizer is preferably used in an amount of from 3 to 20% by weight, more preferably from 4 to 12% by weight, even more preferably from 5 to 7% by weight based on the total weight of the composition.
  • the alkalizer is preferably present in the intragranular phase of the tablet composition.
  • the tablet composition further comprises a non-ionic surfactant.
  • Surfactants can have multiple roles in the pharmaceutical preparations. They modulate the solubility and bioavailability of APIs, increase the stability of active ingredients in the dosage forms, can also work as tablet binders, and disintegrants.
  • the tablet composition of this invention preferably comprises apoloxamer 188 as anon-ionic surfactant.
  • Anon-ionic surfactant is preferably used in an amount of from 4 to 12%, more preferably from 5 to 10%, even more preferably from 6 to 8% by weight based on the total weight of the composition.
  • the non-ionic surfactant is preferably present in the intragranular phase of the tablet composition.
  • excipients to be used in accordance with the present invention are well-known and are those excipients which are conventionally used by the person skilled in the art in pharmaceutical compositions.
  • the excipients are selected from one or more fillers, binders or lubricants.
  • Fillers are used to increase the bulk volume of a tablet or capsule. By combining a filler with the active pharmaceutical ingredient, the final product is given adequate weight and size to assist in production and handling.
  • Suitable examples of fillers to be used in accordance with the present invention include starch, pregelatinized starch, mannitol, microcrystalline cellulose, and calcium phosphate. High porosity microcrystalline cellulose is particularly preferred filler.
  • Fillers are preferably used in an amount of from 35 to 70%, most preferably 40 to 65%, even more preferably from 45 to 60% by weight based on the total weight of the composition.
  • the tablet composition of the invention may also contain a lubricant.
  • Lubricants are generally used in order to reduce sliding friction. In particular, to decrease friction at the interface between a tablet’s surface and the die wall during ejection, and reduce wear on punches and dies.
  • Suitable lubricants to be used in accordance with the present invention include magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, talk, hydrogenated vegetable oil, and glycerine fumarate.
  • Magnesium stearate is a particularly preferred lubricant.
  • Lubricant is preferably used in a total amount of from 0.05% to 5% by weight based on the total weight of the composition.
  • the pharmaceutically acceptable excipients to be used in accordance with the present invention can be used only intragranularly, only extragranularly, or both.
  • the pharmaceutical composition of the present invention contains the following ingredients, based on the total weight of the composition: a. A therapeutically effective dose of elagolix sodium in an amount of from 20% to 50% by weight; b. A super disintegrant in an amount of from 5% to 30% by weight; c. An alkalizer, preferably magnesium oxide, in an amount of from 3% to 20% by weight; d. A filler, preferably microcrystalline cellulose, in an amount of from 35% to 70% by weight; e. A lubricant, preferably magnesium stearate, in an amount of from 0.05% to 5%.
  • the tablets of the present invention can further be coated by a film-coat. The coating serves 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 coating. The coating may be selected from amongst one or more of those suitable coating materials known in the art.
  • the 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 tablets of the present invention are preferably prepared by a process comprising granulation, preferably dry granulation.
  • the granulation process applied is simple and cost effective and includes processes known as slugging and/or roller compaction.
  • the present invention further relates to a tablet composition as described hereinabove, prepared by a dry-granulation process, which process comprises:
  • step (iii) Compressing the mixture obtained in step (iii) into a tablet; and optionally
  • Example 1 Tablet comprising super disintegrant
  • the tablet comprising elagolix sodium and carboxymethylcellulose calcium as a super disintegrant has the composition as given in table 1.
  • Elagolix sodium and part of the microcrystalline cellulose, carboxymethylcellulose calcium and magnesium stearate were sieved and mixed together employing a suitable mixer.
  • the resulting mixture was compacted and the resulting ribbons/“slugs” were milled.
  • the milled granulation was mixed with the remaining microcrystalline cellulose, carboxymethylcellulose calcium and magnesium stearate.
  • the resulting homogeneous mixture was then compressed into tablets containing 200 mg elagolix.
  • the tablets dissolution was assessed using USP apparatus II, in 900 mL of 0.1 N HCL at 37°C and paddle speed 75 rpm and compared with the formulation.
  • Example 2 Tablet comprising super disintegrant and non-ionic surfactant
  • the tablet comprising elagolix sodium, crospovidone as a super disintegrant and poloxamer as a non-ionic surfactant has the composition as given in table 2.
  • Elagolix sodium, the poloxamer and part of the microcrystalline cellulose, crospovidone and magnesium stearate were sieved and mixed together employing a suitable mixer.
  • the resulting mixture was compacted and the resulting ribbons/“slugs” were milled.
  • the milled granulation was mixed with the remaining microcrystalline cellulose, crospovidone and magnesium stearate.
  • the resulting homogeneous mixture was then compressed into tablets containing 200 mg elagolix.
  • Example 3 Tablet comprising super disintegrant and alkalizer
  • the tablet comprising elagolix sodium, carboxymethylcellulose calcium as a super disintegrant and magnesium oxide as an alkalizer has the composition as given in table 3.
  • Elagolix sodium, magnesium oxide and part of the microcrystalline cellulose, carboxymethylcellulose calcium and magnesium stearate were sieved and mixed together employing a suitable mixer.
  • the resulting mixture was compacted and the resulting ribbons/ ’’slugs” were milled.
  • the milled granulation was mixed with the remaining microcrystalline cellulose, carboxymethylcellulose calcium and magnesium stearate.
  • the resulting homogeneous mixture was then compressed into tablets containing 200 mg elagolix.
  • a suspension of Opadry II 85F240222 pink in water (15%) was prepared and sprayed over the core tablets using a pan coating.
  • Example 4 Tablet comprising super disintegrant and alkalizer
  • the tablet comprising elagolix sodium, crospovidone as a super disintegrant and magnesium oxide as an alkalizer has the composition as given in table 4.
  • Elagolix sodium, magnesium oxide and part of the microcrystalline cellulose, crospovidone and magnesium stearate were sieved and mixed together employing a suitable mixer.
  • the resulting mixture was compacted and the resulting ribbons/”slugs” were milled.
  • the milled granulation was mixed with the remaining microcrystalline cellulose, crospovidone and magnesium stearate.
  • the resulting homogeneous mixture was then compressed into tablets containing 200 mg elagolix.
  • a suspension of Opadry II 85F240222 pink in water (15%) was prepared and sprayed over the core tablets using a pan coating. Stability studies were carried out with by storing the coated tablets in
  • Comparative example 1 Tablets without any anti-gelling agent
  • the tablet comprising elagolix sodium has the composition as given in table 5.
  • Elagolix sodium, mannitol, povidone and part of the magnesium stearate were sieved and mixed together employing a suitable mixer.
  • the resulting mixture was compacted and the resulting ribbons/”slugs” were milled.
  • the milled granulation was mixed with starch and the remaining magnesium stearate.
  • the resulting homogeneous mixture was then compressed into tablets containing 200 mg elagolix.

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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
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Abstract

La présente invention concerne des compositions pharmaceutiques comprenant une dose thérapeutiquement efficace d'élagolix sodique et des excipients pharmaceutiquement acceptables comprenant un super-désintégrant. Lesdites compositions peuvent en outre comprendre un alcaliseur et/ou un tensioactif non ionique.
PCT/EP2021/056219 2020-03-12 2021-03-11 Compositions pharmaceutiques comprenant de l'élagolix sodique WO2021180862A1 (fr)

Applications Claiming Priority (2)

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EP20162743 2020-03-12
EP20162743.7 2020-03-12

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WO2021180862A1 true WO2021180862A1 (fr) 2021-09-16

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114948889A (zh) * 2022-06-17 2022-08-30 哈药集团技术中心 一种噁拉戈利片的制备方法及其制备的噁拉戈利片
CN115177595A (zh) * 2022-07-06 2022-10-14 金陵药业股份有限公司 一种噁拉戈利钠片剂及其制备方法
WO2022222886A1 (fr) * 2021-04-21 2022-10-27 上海启晟合研医药科技有限公司 Composition d'élagolix sodique
AU2022202500A1 (en) * 2021-04-15 2022-11-03 Sandoz Ag Elagolix formulation
CN115804774A (zh) * 2022-08-26 2023-03-17 济川(上海)医学科技有限公司 一种噁拉戈利的药物组合物，包含其的药物制剂，及其应用
WO2023126973A1 (fr) * 2022-01-03 2023-07-06 Alkem Laboratories Limited Composition pharmaceutique stable d'elagolix
EP4279075A1 (fr) 2022-05-12 2023-11-22 Zaklady Farmaceutyczne Polpharma S.A. Composition pharmaceutique contenant de l'elagolix

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005007165A1 (fr) 2003-07-07 2005-01-27 Neurocrine Biosciences, Inc. Derives de pyrimidine-2, 4-dione utilises comme antagonistes du recepteur d'hormone liberant de la gonadotrophine
WO2009137080A1 (fr) 2008-05-07 2009-11-12 Merrion Research Iii Limited Compositions de composés apparentés à la gnrh et leurs procédés de préparation
US20190054027A1 (en) * 2017-08-18 2019-02-21 Abbvie Inc. Solid Pharmaceutical Formulations for Treating Endometriosis, Uterine Fibroids, Polycystic Ovary Syndrome or Adenomyosis
WO2019036712A1 (fr) 2017-08-18 2019-02-21 Abbvie Inc. Formulations pharmaceutiques pour le traitement de l'endométriose, de fibromes utérins, du syndrome des ovaires polykystiques ou de l'adénomyose
WO2020020999A1 (fr) * 2018-07-27 2020-01-30 Sandoz Ag Procédé de préparation de comprimés à dissolution rapide ou très rapide, comprenant un api librement soluble

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005007165A1 (fr) 2003-07-07 2005-01-27 Neurocrine Biosciences, Inc. Derives de pyrimidine-2, 4-dione utilises comme antagonistes du recepteur d'hormone liberant de la gonadotrophine
WO2009137080A1 (fr) 2008-05-07 2009-11-12 Merrion Research Iii Limited Compositions de composés apparentés à la gnrh et leurs procédés de préparation
US20190054027A1 (en) * 2017-08-18 2019-02-21 Abbvie Inc. Solid Pharmaceutical Formulations for Treating Endometriosis, Uterine Fibroids, Polycystic Ovary Syndrome or Adenomyosis
WO2019036712A1 (fr) 2017-08-18 2019-02-21 Abbvie Inc. Formulations pharmaceutiques pour le traitement de l'endométriose, de fibromes utérins, du syndrome des ovaires polykystiques ou de l'adénomyose
WO2020020999A1 (fr) * 2018-07-27 2020-01-30 Sandoz Ag Procédé de préparation de comprimés à dissolution rapide ou très rapide, comprenant un api librement soluble

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2022202500A1 (en) * 2021-04-15 2022-11-03 Sandoz Ag Elagolix formulation
AU2022202500B2 (en) * 2021-04-15 2022-12-01 Sandoz Ag Elagolix formulation
WO2022222886A1 (fr) * 2021-04-21 2022-10-27 上海启晟合研医药科技有限公司 Composition d'élagolix sodique
WO2023126973A1 (fr) * 2022-01-03 2023-07-06 Alkem Laboratories Limited Composition pharmaceutique stable d'elagolix
EP4279075A1 (fr) 2022-05-12 2023-11-22 Zaklady Farmaceutyczne Polpharma S.A. Composition pharmaceutique contenant de l'elagolix
CN114948889A (zh) * 2022-06-17 2022-08-30 哈药集团技术中心 一种噁拉戈利片的制备方法及其制备的噁拉戈利片
CN115177595A (zh) * 2022-07-06 2022-10-14 金陵药业股份有限公司 一种噁拉戈利钠片剂及其制备方法
CN115804774A (zh) * 2022-08-26 2023-03-17 济川(上海)医学科技有限公司 一种噁拉戈利的药物组合物，包含其的药物制剂，及其应用

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