WO2022240378A1 - A stable pharmaceutical composition comprising selexipag - Google Patents
A stable pharmaceutical composition comprising selexipag Download PDFInfo
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- WO2022240378A1 WO2022240378A1 PCT/TR2022/050407 TR2022050407W WO2022240378A1 WO 2022240378 A1 WO2022240378 A1 WO 2022240378A1 TR 2022050407 W TR2022050407 W TR 2022050407W WO 2022240378 A1 WO2022240378 A1 WO 2022240378A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- solid composition
- selexipag
- composition according
- starch
- sodium
- Prior art date
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- QXWZQTURMXZVHJ-UHFFFAOYSA-N selexipag Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCOCC(=O)NS(C)(=O)=O)C(C)C)=CN=C1C1=CC=CC=C1 QXWZQTURMXZVHJ-UHFFFAOYSA-N 0.000 title claims abstract description 61
- 229960003841 selexipag Drugs 0.000 title claims abstract description 50
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- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- VBMVTYDPPZVILR-UHFFFAOYSA-N iron(2+);oxygen(2-) Chemical class [O-2].[Fe+2] VBMVTYDPPZVILR-UHFFFAOYSA-N 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000008185 minitablet Substances 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000009516 primary packaging Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 108050007059 prostanoid receptors Proteins 0.000 description 1
- 102000017953 prostanoid receptors Human genes 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000275 quality assurance Methods 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 238000012776 robust process Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
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
-
- 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
Landscapes
- 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)
- Heart & Thoracic Surgery (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a stable solid pharmaceutical composition comprising a) Selexipag, b) D-mannitol having a specific surface area of 1.2 m2/g or more, and c) a starch in an amount of 50% to 80% by weight based on the total weight of the solid composition. The invention further relates to a process for the preparation of such pharmaceutical composition and use of said pharmaceutical composition as medicament in the treatment of pulmonary arterial hypertension.
Description
A STABLE PHARMACEUTICAL COMPOSITION COMPRISING SELEXIPAG
FIELD OF THE INVENTION The present invention relates to a stable solid composition comprising a) Selexipag, b) D-mannitol having a specific surface area of 1.2 m2/g or more, and c) a starch in an amount of 50% to 80% 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.
BACKGROUND OF THE INVENTION
Selexipag, is chemically named 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino] butyloxy}-N-(methylsulfonyl)acetamide of formula (I),
(I).
Selexipag is a selective prostacyclin (PGI2) receptor (IP receptor) agonist, which is distinct from other prostacyclin and its analogues. 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. Selectivity against EP2, EP4, and DP1 is important because these receptors mediate immune depressive effects. Stimulation of the IP receptor by Selexipag and the active metabolite leads to vasodilatory as well as anti-proliferative and anti-fibrotic effects (SmPC). l
Selexipag is marketed by Janssen-Cilag under the tradename Uptravi® in the form of a film-coated tablet for the treatment of pulmonary arterial hypertension (PAH). 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).
According to EPAR, 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. Thus, because of the poor solubility of the drug substance, particle size control seems a critical quality attribute in the manufacture of Selexipag composition.
Selexipag, process for the preparation, pharmaceutical composition and therapeutic use thereof are first time disclosed in the PCT application WO 2002088084.
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 m2/g or less. According to EP ‘911, when the specific surface area of D-mannitol used is 1.0 m2/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 m2/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.
From the discussion of above prior art, it is evident that obtaining a stable composition of Selexipag with desired parameters needs conscious efforts.
Despite different approaches discloses in the art, there still exist a need to develop a pharmaceutical composition of Selexipag that provides desired stability, content uniformity of blend, dissolution profile, bioavailability, bioequivalence, etc., because these all play important roles in determining a drug's market acceptance. In addition to this, it is desired to develop a process for the preparation of pharmaceutical composition of Selexipag, which is suitable for the production on commercial scale.
The inventors of the present invention have surprisingly found out that careful selection of process parameters and use of starch in particular amount allow to obtain a composition with better dissolution profile and stability profile irrespective of specific surface area of Mannitol used.
OBJECT OF THE INVENTION
The main object of the invention is to provide a stable solid composition of Selexipag, which is devoid of the effect of specific surface area of D-Mannitol on its stability.
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.
SUMMARY OF THE INVENTION
In one aspect, the present invention discloses a stable solid composition comprising: a) Selexipag, b) D-mannitol having a specific surface area of 1 .2 m2/g or more, and c) a starch in an amount of 50% to 80% by weight based on the total weight of the solid composition.
In another aspect, the present invention discloses a stable solid composition comprising: a) Selexipag, b) D-mannitol having a specific surface area of 1 .2 m2/g or more, and c) a starch in an amount of 50% to 80% 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.
In another aspect, present invention may further include one or more pharmaceutical acceptable excipients apart from D-mannitol and starch.
In one aspect, the present invention discloses a stable solid composition comprising: a) Selexipag, b) D-mannitol having a specific surface area of 1 .2 m2/g or more, and c) a starch in an amount of 50% to 80% 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. In another aspect, the present invention discloses a process to prepare said pharmaceutical composition in the form of a tablet by wet granulation.
In another aspect, the present invention discloses a process used to prepare said pharmaceutical composition is conventional process.
In another aspect, 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 The present invention will now be more specifically illustrated as hereunder.
The term % used in this specification means the percentage by weight unless otherwise stipulated. The term "about" can indicate a difference of 10 percent of the value specified. Numerical ranges as used herein are meant to include every number and subset of numbers enclosed within that range, whether particularly disclosed or not. Further, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range.
The term “solid composition” as used in the present invention 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.
The term “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. related substances, more preferably less than 1.5% identified when the 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.
The term "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. The similarity factor f2 should be computed using the equation: f2 =50 log {[l+(l/n) t=1 n ( Rt - Tt )2 ]-0-5 100} where Rt and Tt are the cumulative percentage of the drug dissolved at each of the selected n time points of the comparator (reference) and (test) product respectively .
According to European Public Assessment Report (EPAR), while the development of Uptravi®, compatibility of the active substance with different excipients was studied, further studies were conducted which led to the selection of binder and disintegrant and diluents, and to the optimization of the composition.
Due to very low load of active substance in the marketed compositions (between 0.148 % and 1.185 % w/w of the core tablet), it poses a challenge to the manufacturing process. Considering this and the type of the dosage form it was deemed reasonable that the critical quality attributes are the uniformity of the blends during the manufacture, the content uniformity of the tablets (both coated and uncoated) and the comparison of the dissolution behavior of the tablets. The development history of the marketed composition of Selexipag i.e. Uptravi® indicates that selection of excipients for this product is a difficult task. According to European Public Assessment Report (EPAR), 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.
It was surprisingly found that a solid composition comprising a) Selexipag, b) D- mannitol having a specific surface area of 1.2 m2/g or more, and c) a starch in an amount of 50% to 80% 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.
In embodiments, 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.
In embodiments, a solid composition of the present inventions comprises the D- mannitol having a specific surface area of 1.2 m2/g or more in the ranges of 20% or more, and more preferably 40% or more by weight based on the total weight of the solid composition of the total weight of diluents. Any grade of D-mannitol having a
specific surface area of 1 .2 m2/g or more, known in the art, can be used in the present invention.
In embodiments, a solid composition of the present invention comprises a starch in an amount of 50% to 80% 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 50% to 65%. Preferably, the starch is selected from, maize starch, pregelatinized starch and starch 1500. More preferably, the starch is used maize starch.
In embodiments, 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 D-mannitol can be selected from diluent, binder, disintegrant and lubricant.
Diluent includes, but are not limited to, lactose, 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 D-mannitol having specific surface area 1 .2 m2/g or more 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 calcium, 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 starch, 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 sulfate, magnesium lauryl sulfate, macrogol, light anhydrous silicic acid and mixtures thereof.
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.
Preferably, the solid composition is in the form of a tablet. Most preferably, 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.
As it is evident that solubility and dissolution of drug in the stomach and small intestine are often critical to the bioavailability after oral administration. So it is desirable to test solubility and dissolution of BCS Class 2 and 4 drugs in media simulating these regions to assess the extent their oral absorption will be limited by poor solubility/dissolution. In the pharmaceutical industry it is common practice to test for solubility in biorelevant media. 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. Typically, biorelevant media are designed to reflect the gastric and intestinal fluids in the fasted or the fed state.
Apart from that 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.
Moreover, 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.
The following examples are intended to illustrate the scope of the present invention but not to limit it thereto.
Examples:
Example 1 : A Tablet composition comprising Selexipag & Pearlitol 100 SD Table-1
Process For The Preparation:
1. The Selexipag, D-Mannitol having specific surface area 1.56 m2/g, maize starch, Low-Substituted Hydroxypropyl Cellulose, Hydroxyl propyl cellulose, Magnesium stearate were sieved through a suitable mesh sieve for deagglomeration and mixed in a suitable tumbling mixer. 2. Purified water and HPC were added under continuous stirring using an overhead stirrer, till clear solution is formed. Using binder solution, wet granulation process was performed.
3. After drying process and milling, Magnesium stearate adding to the granules and blend.
4. The powder in step-3 was loading to tablet compression machine.
Example-2: Stability Testing of 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 6 months under conditions of 40°C/75% RH (accelerated test). 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.
Table-2
Amount of Related Substances (%)
Example-1 initial 40°C/ 75% RH, 40°C/ 75% RH, 40°C/ 75% RH, air tightly air tightly air tightly sealed sealed sealed
1 month 3 Months 6 Months
Related
0.055 0.075 0.401 0.671
Substance It can be seen from the above table that the produced amount of the related substances is less than 2% in the tablets of Examples 1 even though the specific surface area of D-mannitol used in Examples 1 was higher than 1.0 m2/g.
Example-3: A Tablet composition comprising Selexipag & Pearlitol 100 SD
Table-3
Process For The Preparation:
1. The Selexipag, D-Mannitol having specific surface area 1.56 m2/g, maize starch, Low-Substituted Hydroxypropyl Cellulose, Hydroxyl propyl cellulose, Magnesium stearate were sieved through a suitable mesh sieve for deagglomeration.
2. Purified water and HPC were added under continuous stirring using an overhead stirrer, till clear solution is formed. Using binder solution, wet granulation process was performed.
3. After drying process and milling, D-Mannitol having specific surface area 1.56 m2/g, low substituted hydroxypropyl cellulose is added and mixed.
4. Magnesium stearate adding to mixture at step-3 and blend.
5. The powder in step-4 was loading to tablet compression machine.
Example-4: Stability Testing of 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). 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.
Table-4
Amount of Related Substances (%)
Example-3 Initial 40°C/ 75% RH, air 40°C/75% RH, air tightly sealed tightly sealed
3 Months 6 Months
Related Substance
0.067 0.403 0.711
It can be seen from the above table that the produced amount of the related substances is less than 2% in the tablets of Examples 3 even though the specific surface area of D-mannitol used in Examples 3 was higher than 1.0 m2/g.
Example-5: Comparative Dissolution Studies of Example-3 with RLD in FeSSIF
Dissolution of test product (of Example-3) and reference product Uptravi® were preformed using standard USP apparatus II, paddles, at 50 RPM in 500 ml at pH = 5.8. The drug release was determined by using an HPLC method. From the above tabulated dissolution data, it can be said that higher F2 value of test product i.e. more than 50 establishes sameness or equivalence both the products i.e. test and reference product in terms of its dissolution and performance.
Claims
1. A solid composition comprising: a) Selexipag, b) D-mannitol having a specific surface area of 1.2 m2/g or more, and c) a starch in an amount of 50% to 80% by weight based on the total weight of the solid composition.
2. The solid composition according to claim 1 , wherein the Selexipag is in crystalline state.
3. The solid composition according to claim 1 , wherein the Selexipag is present in an amount from 0.1 % to 2% by weight based on the total weight of the solid composition.
4. The solid composition according to claim 1 , wherein the D-mannitol is present in an amount from 10% to 50% by weight based on the total weight of the solid composition.
5. The solid composition according to claim 1 , further comprising a binder, disintegrant and lubricant.
6. The solid composition according to claim 5, wherein the binder is selected from gelatin, pullulan, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, macrogol, gum Arabic, dextran, polyvinyl alcohol, pregelatinized starch, and hypromellose.
7. The solid composition according to claim 5, wherein the disintegrant is selected from carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, sodium starch glycolate, crospovidone, a cation exchange resin, partially pregelatinized starch, and low-substituted hydroxypropyl cellulose.
8. The solid composition according to claim 5, wherein the lubricant is selected from stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, waxes, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate, macrogol, and light anhydrous silicic acid.
9. The solid composition according to any one of claims 1 to 8, which is used for treating pulmonary arterial hypertension.
10. The solid composition according to any one of claims 1 to 9, wherein the composition is in the form of a tablet.
11 . The solid composition according to any one of the claims 1 to 10, 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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2021008065 | 2021-05-11 | ||
| TR2021/008065 TR2021008065A2 (en) | 2021-05-11 | A stable pharmaceutical composition containing selexipag. |
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| Publication Number | Publication Date |
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| WO2022240378A1 true WO2022240378A1 (en) | 2022-11-17 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/TR2022/050407 WO2022240378A1 (en) | 2021-05-11 | 2022-05-10 | A stable pharmaceutical composition comprising selexipag |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH1036291A (en) * | 1996-04-16 | 1998-02-10 | Takeda Chem Ind Ltd | D-mannitol and its production |
| US20010001106A1 (en) * | 1996-04-16 | 2001-05-10 | Tomohiro Yoshinari | D-mannitol and its preparation |
| EP3384911A1 (en) * | 2015-12-02 | 2018-10-10 | Nippon Shinyaku Co., Ltd. | Pharmaceutical composition containing 2-{4-[n-(5,6- diphenylpyrazin-2-yl)-n-isopropylamino]butyloxy}-n- (methylsulfonyl)acetamide |
| CN112220770A (en) * | 2020-12-17 | 2021-01-15 | 上海翰森生物医药科技有限公司 | Pharmaceutical composition of selepag and preparation method thereof |
| CN112472675A (en) * | 2020-12-17 | 2021-03-12 | 江苏豪森药业集团有限公司 | Sparapage tablet and preparation method thereof |
-
2022
- 2022-05-10 WO PCT/TR2022/050407 patent/WO2022240378A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH1036291A (en) * | 1996-04-16 | 1998-02-10 | Takeda Chem Ind Ltd | D-mannitol and its production |
| US20010001106A1 (en) * | 1996-04-16 | 2001-05-10 | Tomohiro Yoshinari | D-mannitol and its preparation |
| EP3384911A1 (en) * | 2015-12-02 | 2018-10-10 | Nippon Shinyaku Co., Ltd. | Pharmaceutical composition containing 2-{4-[n-(5,6- diphenylpyrazin-2-yl)-n-isopropylamino]butyloxy}-n- (methylsulfonyl)acetamide |
| CN112220770A (en) * | 2020-12-17 | 2021-01-15 | 上海翰森生物医药科技有限公司 | Pharmaceutical composition of selepag and preparation method thereof |
| CN112472675A (en) * | 2020-12-17 | 2021-03-12 | 江苏豪森药业集团有限公司 | Sparapage tablet and preparation method thereof |
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