EP4337210A2 - Stabile pharmazeutische zusammensetzung mit selexipag - Google Patents

Stabile pharmazeutische zusammensetzung mit selexipag

Info

Publication number
EP4337210A2
EP4337210A2 EP22807969.5A EP22807969A EP4337210A2 EP 4337210 A2 EP4337210 A2 EP 4337210A2 EP 22807969 A EP22807969 A EP 22807969A EP 4337210 A2 EP4337210 A2 EP 4337210A2
Authority
EP
European Patent Office
Prior art keywords
solid composition
selexipag
composition according
starch
composition
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
EP22807969.5A
Other languages
English (en)
French (fr)
Other versions
EP4337210A4 (de
Inventor
Volkan ESKI
Srinivasa Reddy Almareddy
Udaya Kumar DUDE
Ravindra Patil
Ayush Kumar
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.)
Abdi Ibrahim Ilac Sanayi Ve Ticaret AS
Original Assignee
Abdi Ibrahim 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 Abdi Ibrahim Ilac Sanayi Ve Ticaret AS filed Critical Abdi Ibrahim Ilac Sanayi Ve Ticaret AS
Priority claimed from PCT/TR2022/050408 external-priority patent/WO2022240379A2/en
Publication of EP4337210A2 publication Critical patent/EP4337210A2/de
Publication of EP4337210A4 publication Critical patent/EP4337210A4/de
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • 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

Definitions

  • the present invention relates to a stable solid composition
  • a stable solid composition comprising a) Selexipag, b) lactose monohydrate in an amount of 60% or less by weight based on the total weight of the solid composition.
  • the invention further relates to a process for the preparation of said pharmaceutical composition and use thereof as medicament in the treatment of pulmonary arterial hypertension.
  • Selexipag is a selective prostacyclin (PGI2) receptor (IP receptor) agonist, which is distinct from other prostacyclin and its analogues.
  • PKI2 prostacyclin
  • IP receptor IP receptor
  • Selexipag is hydrolyzed by carboxylesterases to yield its active metabolite, which is approximately 37-fold more potent than Selexipag.
  • Selexipag and the active metabolite are high-affinity IP receptor agonists with a high selectivity for the IP receptor versus other prostanoid receptors (EP1-EP4, DP, FP, and TP). Selectivity against EP1 , EP3, FP, and TP is important because these are well-described contractile receptors in the gastro-intestinal tract and blood vessels.
  • Uptravi ® contains 200-1600 pg Selexipag, whereby the therapy of PAH starts with 200 pg given twice daily, followed by an increase of the daily dose to the highest individually tolerated dose up to a maximum dose of 1600 p twice daily via increments of 200 pg twice daily, usually at weekly intervals.
  • Uptravi ® film-coated tablet is a standard immediate-release tablet that contains D- mannitol, maize starch, low substituted hydroxypropyl cellulose, hydroxypropyl cellulose and magnesium stearate in the tablet core; the film -coating contains hydroxypropyl methylcellulose (Hypromellose/ HPMC), propylene glycol, titanium dioxide, carnauba wax along with mixtures of iron oxides in order to protect the tablet core from light.
  • the tablet core is prepared by wet granulation (Ref: European Public Assessment Report (EPAR) for Selexipag, Apr-2016).
  • Uptravi ® contains very low load of active substance in the tablets (between 0.148 % and 1.185 % w/w of the core tablet), which poses a challenge to the manufacturing process particularly for achieving content uniformity of the blends used during the manufacture of the tablet and thus selection of excipient and assessment of its impact on content uniformity of the blends is very critical.
  • Selexipag is considered to be a BCS (Biopharmaceutics Classification System) Class II drug i.e. having high permeability and low solubility.
  • BCS Biopharmaceutics Classification System
  • particle size control seems a critical quality attribute in the manufacture of Selexipag composition.
  • WO 2010150865 A1 discloses crystalline form I, II & III of Selexipag, process for the preparation and pharmaceutical composition thereof. According to EPAR, marketed composition of Selexipag prepared by using the crystalline form I.
  • EP 3344607 B1 discloses a crystalline form of Selexipag designated as Form IV, processes for preparation thereof, and pharmaceutical compositions comprising the said crystalline form.
  • EP 3481807 A1 discloses a crystalline form of Selexipag designated as Form P, processes for preparation thereof, and pharmaceutical compositions comprising the said crystalline form.
  • EP 3384911 A1 discloses a solid preparation comprising Selexipag, and D-mannitol having a specific surface area of 1.0 m 2 /g or less. According to EP ‘911, when the specific surface area of D-mannitol used is 1.0 m 2 /g or less, the obtained compositions are stable as compared to the compositions prepared by using D-mannitol having specific surface are more than 1.0 m 2 /g.
  • WO 2019163822 A1 discloses a particulate composition comprising manufacturing method of the granular composition containing Selexipag. It also relates to a method for improving dissolution, which improves the dissolution of Selexipag in a granular composition containing Selexipag.
  • EP 2893922 A1 discloses formulation comprising polymeric nanoparticles encapsulated within crosslinked polymeric hydrogel microparticles, wherein the polymeric nanoparticles carry a therapeutic agent suitable for treatment of PAFI loaded within prostacyclin synthetic analogs, PPAR b agonists and NO donors.
  • WO 2020255157 A1 discloses stable solid dosage forms of Selexipag where the dosage form comprises of minor portion of active ingredient and major portion of inactive ingredient.
  • the composition characteristically uses ratio of intragranular and extragranular excipients for providing a faster dissolution and higher bioavailability profile for the dosage form. It also relates to a method for optimizing the best suitable release profile by using ratio of binder and disintegrant in the intragranular and extragranular portions of the dosage forms.
  • CN 112220770 discloses pharmaceutical composition and its preparation containing double-layer coating, wherein coating layer I comprises a film forming agent I and a plasticizer I; and coating layer 2 comprises a film forming agent II, a plasticizer II, an opacifier and a coloring agent.
  • CN 770 discloses, in preferred embodiment, the use of combination of Starch & mannitol for the preparation of pharmaceutical composition.
  • WO 2018015975 A1 discloses an amorphous solid dispersion comprising Selexipag and corn starch and process for preparation thereof.
  • WO 2021206159 A1 discloses solid preparation contains A) Selexipag, B) starch, and C) a granulated substance containing at least one type of binder selected from the group consisting of hydroxypropyl cellulose and hypromellose wherein the content ratio of component (B) per 100 parts by mass of the granulated substance is at least 20 parts by mass (but excluding 30.2-30.4 parts by mass), and the content ratio of component (C) per 100 parts by mass of the granulated substance is at most 4 parts by mass.
  • the inventors of the present invention have surprisingly found out that careful selection of process parameters and use of lactose monohydrate in amount of 60% or less by weight based on the total weight of the solid composition allow to obtain a stable composition with better dissolution profile.
  • the main object of the invention is to provide a stable solid composition of Selexipag.
  • Another object of the present invention is to provide a stable solid composition of Selexipag by using lactose monohydrate in amount of 60% or less by weight based on the total weight of the solid composition.
  • Another object of the present invention is to provide a stable solid composition of Selexipag, which overcomes the problems of the prior art.
  • Yet another object of the invention is to provide a commercially scalable, cost effective, environment friendly and robust process for the preparation of Selexipag composition.
  • the present invention discloses a stable solid composition
  • a stable solid composition comprising: a) Selexipag, b) Lactose monohydrate in an amount of 60% or less by weight based on the total weight of the solid composition.
  • the present invention discloses a stable solid composition
  • a stable solid composition comprising: a) Selexipag, b) Lactose monohydrate in an amount of 60% or less by weight based on the total weight of the solid composition, c) a starch in an amount of 30% to 40% by weight based on the total weight of the solid composition.
  • the present invention discloses a stable solid composition
  • a stable solid composition comprising: a) Selexipag, b) Lactose monohydrate in an amount of 60% or less by weight based on the total weight of the solid composition, c) a starch in an amount of 30% to 40% by weight based on the total weight of the solid composition, wherein starch is selected from, maize starch, potato starch, rice starch, pregelatinized starch, starch 1500 & starch 1500 LM.
  • present invention may further include one or more pharmaceutical acceptable excipients apart from lactose monohydrate and starch.
  • the present invention discloses a stable solid composition
  • a stable solid composition comprising: a) Selexipag, b) Lactose monohydrate in an amount of 60% or less by weight based on the total weight of the solid composition, wherein, the said composition comprises less than about 2% related substances when the composition is stored at about 40°C at about 75% relative humidity for at least 3 months, more preferably 6 months.
  • the present invention discloses a process to prepare said pharmaceutical composition in the form of a tablet by wet granulation.
  • the present invention discloses a process used to prepare said pharmaceutical composition is conventional process.
  • the present invention discloses a use of such pharmaceutical composition as medicament in the treatment of pulmonary arterial hypertension.
  • the details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description. DETAILED DESCRIPTION OF THE PRESENT INVENTION
  • solid composition means solid pharmaceutical composition includes, without limitation, capsules, tablets, caplets, powders, pellets, granules, liquid dispersions, beads, etc.
  • the term ' Selexipag ' as used in the present invention includes, but is not limited to, Selexipag per se, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof, and also its various crystalline and amorphous forms.
  • stable as used herein is intended to mean that a composition of a pharmaceutical product or a method of the present invention does not substantially decompose to form one or more degradation products when stored in a sealed package at 40° C at 75% relative humidity for at least 3 months. For example, there is not more than 2% degradation products e.g.
  • composition of the present invention is stored in a sealed package at about 40° C at about 75% relative humidity for at least 3 months, more preferably for 6 months.
  • similarity factor or f2 factor as used herein refers to one way of comparing dissolution profiles of two different products. (Multisource Pharmaceutical Products: Guidelines on Registration Requirements to establish Interchangeability, Quality Assurance and Safety: Medicines, Essential Drugs and Medicines Policy, World Health Organization, 1211 Geneva 27, Switzerland) This model independent mathematical approach compares the dissolution profile of the two products: test and reference (or two strengths, or pre- and post-approved products from the same manufacturer). Tests are recommended to be performed under the same test conditions.
  • the dissolution time points for both the profiles should be the same, for example for immediate release products e.g. 10, 15, 30, 45, 60 minutes and for extended release products, e.g., 1, 2, 3, 5 and 8 hours. Only one time point should be considered after 85% dissolution of the reference product.
  • An f2 value of 50 or greater (50-100) ensures sameness or equivalence of the two curves, and thus the performance of the two products.
  • Uptravi tablets are packed in Alu/Alu blister with embedded desiccant.
  • the selected primary packaging is common for this dosage form and the included desiccant has been shown to be protective against degradation of active substance, in particular hydrolysis, as it has been confirmed in the stability studies.
  • a solid composition comprising a) Selexipag, b) lactose monohydrate in an amount of 60% or less by weight based on the total weight of the solid composition, overcome the problems faced in prior art. In addition to that, the obtained stable compositions are able to mimic the dissolution profile of the Uptravi ® tablets.
  • a composition of the present invention comprises active ingredient Selexipag in the ranges from 0.1 % to 2% by weight based on the total weight of the composition.
  • a solid composition of the present inventions comprises lactose monohydrate in the ranges of 60% or less, and more preferably from 60% to 50% by weight based on the total weight of the solid composition.
  • a solid composition of the present invention comprises a starch in an amount of 30% to 40% by weight based on the total weight of the solid composition. More preferably, the amount of starch by weight based on the total weight of the solid composition in the ranges of 35% to 40%.
  • the starch is selected from, maize starch, pregelatinized starch and starch 1500. More preferably, the starch is used maize starch.
  • a solid composition of the present invention further comprises one or more pharmaceutically acceptable excipients.
  • the 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. Depending on the dosage form chosen for the pharmaceutical composition, the person skilled in the art will be able to select suitable pharmaceutically acceptable excipients.
  • the pharmaceutical excipient apart from starch and lactose monohydrate can be selected from diluent, binder, disintegrant and lubricant.
  • Diluent includes, but are not limited to, mannitol, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, kaolin, magnesium carbonate, magnesium oxide, sugars such as sucrose; sugar alcohols such as sorbitol, erythritol; starch and mixtures thereof.
  • the amount of diluent apart from lactose monohydrate is preferably from 2% to 20%, more preferably from 2% to 15% by weight based on the total weight of the solid composition.
  • Disintegrant includes, but are not limited to, carmellose, carmellose calsium, carmellose sodium, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, a cation exchange resin, partially pregelatinized starch, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, sodium alginate, low substituted hydroxypropyl cellulose and mixtures thereof.
  • the amount of the disintegrant is preferably from 0.1 % to 10%, more preferably from 1 % to 8% by weight based on the total weight of the solid composition.
  • Binder includes, but are not limited to, carrageenan, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, carboxymethylcellulose sodium, dextrin, dextran, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, polyvinyl alcohol, pregelatinized sodium, sodium alginate, macrogol, pullulan, gums, synthetic resins and the like.
  • the amount of the binder is preferably from 0.1 % to 10%, more preferably from 1 % to 8%, furthermore preferably from 1 % to 5 % by weight based on the total weight of the solid composition.
  • Lubricant includes, but are not limited to, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, waxes, DL-leucine, sodium lauryl sulphate, magnesium lauryl sulphate, macrogol, light anhydrous silicic acid and mixtures thereof.
  • metallic stearates such as magnesium stearate, calcium stearate, zinc stearate
  • stearic acid hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate
  • polyethylene glycols corn starch
  • sodium stearyl fumarate sodium benzoate
  • mineral oil talc
  • waxes DL-le
  • the amount of the lubricant is preferably from 0.15 to 10%, more preferably from 0.2 to 5% by weight based on the total weight of the solid composition.
  • the solid composition of the present invention can be obtained by using known conventional methods i.e. granulation or direct compression.
  • the process to obtain granulate includes, but is not limited to, wet granulation, fluid bed granulation, spray drying, or dry granulation.
  • Suitable solvents used for wet granulation are selected from the group comprising methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof.
  • the solid composition of the present invention is intended for oral use, and can be in the form of tablets, capsules, minitablets, granules, or pellets, wherein the composition can be further film coated.
  • the solid composition is in the form of a tablet.
  • the tablet has immediate release.
  • the solid composition of the present invention may further be coated with a film forming polymer and one or more pharmaceutically acceptable excipients, using techniques well known in the art e.g., spray coating in a conventional coating pan, or a fluidized bed processor, or dip coating. Alternatively, coating can also be performed using a hot melt technique.
  • the film coating may contain one or more film-forming polymers, and optionally one or more pharmaceutically acceptable excipients.
  • a suitable film-forming polymer is selected from the group comprising hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate trimellitate, methacrylic acid copolymers e.g., Eudragit®, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, or mixtures thereof.
  • a preferred film- forming polymer is hydroxypropyl methyl cellulose.
  • Other suitable film- forming polymers which are known in the art may also be used.
  • the film coating may also contain opacifiers like titanium dioxide, flow aids like talc and pigment like iron oxide yellow.
  • Biorelevant media aim to reproduce the conditions in the gastrointestinal (Gl) tract in vitro, so that the behavior of drugs and dosage forms in the Gl tract can be studied in the laboratory. Typically, they are used for in vitro solubility and dissolution studies but can also be applied to studies of decomposition under Gl conditions or for the determination of the permeability characteristics of the drug.
  • Biorelevant media typically comprise solutions of surfactants which are naturally occurring in the Gl tract and are adjusted to pH values representative of the local region to be simulated.
  • biorelevant media are designed to reflect the gastric and intestinal fluids in the fasted or the fed state.
  • the solid composition in accordance with the present invention exhibits a dissolution rate of at least 75% in 15 minutes and at least 85% in 45 minutes when tested in pH 6.8 phosphate buffer in a USP apparatus II at 50-100 rpm, 37°C.
  • the pharmaceutical composition of the present invention exhibits excellent accelerated stability.
  • the tablets of the present invention mimic the dissolution profile of the Uptravi ® tablets.
  • the solid composition in accordance with the present invention may be used as a medicament.
  • the pharmaceutical composition typically may be used in the treatment of pulmonary arterial hypertension.
  • the solid composition of the present invention is very suitable for production on commercial scale making use of equipment and techniques commonly used in industry.
  • Example 1 A Tablet composition comprising Selexipag & Lactose monohydrate
  • Example-2 Stability Testing of Example-1
  • Example - 1 The tablet prepared in Example - 1 was placed in a plastic bottle along with a desiccant and airtightly sealed, and then, stored for 3 months under conditions of 40°C/75% RH (accelerated test). 3 months stability results is presented at the below table-2.
  • the related substances of Compound (I) i.e. Selexipag in the tablet were measured before and after the storage using high-performance liquid chromatography, and the amount of related substances from the start of the test was evaluated. The results of performed stability testing is shown herein below table-2.
  • Example-1 Initial 40°C / 75% RH, 40°C/ 75% RH, air tightly sealed air tightly sealed
  • Example-3 A Tablet composition comprising Selexipag & Lactose monohydrate
  • Example-4 Stability Testing of Example-3
  • Example - 3 The tablet prepared in Example - 3 was placed in a plastic bottle along with a desiccant and airtightly sealed, and then, stored for 6 months under conditions of 40°C/75% RH (accelerated test). 6 months stability results are presented at the below table-4.
  • the related substances of Compound (I) i.e. Selexipag in the tablet were measured before and after the storage using high-performance liquid chromatography, and the amount of related substances from the start of the test was evaluated. The results of performed stability testing is shown herein below table-4.
  • Example-1 Initial 40°C/ 75% RH, 40°C/75% RH, 40°C/75% RH, air tightly air tightly air tightly sealed sealed sealed
  • the produced amount of the related substances is less than 2% in the tablets of Examples 3 when a Lactose used in an amount of 60% or less by weight based on the total weight of the solid composition.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Medicinal Preparation (AREA)
EP22807969.5A 2021-05-11 2022-05-10 Stabile pharmazeutische zusammensetzung mit selexipag Pending EP4337210A4 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR202108066 2021-05-11
PCT/TR2022/050408 WO2022240379A2 (en) 2021-05-11 2022-05-10 A stable pharmaceutical composition comprising selexipag

Publications (2)

Publication Number Publication Date
EP4337210A2 true EP4337210A2 (de) 2024-03-20
EP4337210A4 EP4337210A4 (de) 2025-03-19

Family

ID=89898821

Family Applications (1)

Application Number Title Priority Date Filing Date
EP22807969.5A Pending EP4337210A4 (de) 2021-05-11 2022-05-10 Stabile pharmazeutische zusammensetzung mit selexipag

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EP (1) EP4337210A4 (de)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111565720A (zh) * 2017-11-16 2020-08-21 日本新药株式会社 控释制剂
US20210069187A1 (en) * 2019-05-11 2021-03-11 RK Pharma Solutions LLC Stable pharmaceutical composition of Selexipag
TWI908789B (zh) * 2020-04-10 2025-12-21 日商日本新藥股份有限公司 固形製劑及其製造方法
TR2022005275A2 (tr) * 2022-04-05 2023-10-23 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Seleksi̇pag i̇çeren bi̇r fi̇lm kapli tablet ve bunun hazirlanma prosesi̇

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