WO2022045991A1 - Compositions pharmaceutiques comprenant du macitentan et des excipients appropriés - Google Patents

Compositions pharmaceutiques comprenant du macitentan et des excipients appropriés Download PDF

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Publication number
WO2022045991A1
WO2022045991A1 PCT/TR2020/050769 TR2020050769W WO2022045991A1 WO 2022045991 A1 WO2022045991 A1 WO 2022045991A1 TR 2020050769 W TR2020050769 W TR 2020050769W WO 2022045991 A1 WO2022045991 A1 WO 2022045991A1
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WO
WIPO (PCT)
Prior art keywords
bulk density
macitentan
tablet
pharmaceutical compositions
density
Prior art date
Application number
PCT/TR2020/050769
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English (en)
Inventor
Abdulhaluk SANCAK
Ayşe Figen ONUK GÖREN
Azmatullah ANSARİ
Hakan Gürpinar
Asiye SEZGİN
Onur ŞAHİN
Koray YILMAZ
Original Assignee
Pharmacti̇ve İlaç Sanayi̇ Ve Ti̇caret A.Ş.
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
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Application filed by Pharmacti̇ve İlaç Sanayi̇ Ve Ti̇caret A.Ş. filed Critical Pharmacti̇ve İlaç Sanayi̇ Ve Ti̇caret A.Ş.
Priority to PCT/TR2020/050769 priority Critical patent/WO2022045991A1/fr
Publication of WO2022045991A1 publication Critical patent/WO2022045991A1/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
    • A61K9/2022—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • 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
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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

Definitions

  • the present invention relates to the preperation of pharmaceutical compositions comprising macitentan is indicated for the treatment of pulmonary arterial hypertension (PAH), having a specific ratio for binder to achieve optimum value for bulk density.
  • PAH pulmonary arterial hypertension
  • Macitentan is an endothelin receptor antagonist (ERA), administered orally as a tablet form.
  • ERA endothelin receptor antagonist
  • Macitentan has a chemical name as 5-(4-bromophenyl)-6-[2-(5-bromopyrimidin-2- yl)oxyethoxy]-N-(propylsulfamoyl)pyrimidin-4-amine and its chemical structure is shown in the Figure I. Macitentan has molecular weight of 588,3 g/mol, white or off-white Solid, crystalline powder.
  • Macitentan has been authorised as an orphan drug in the EU with the name of Opsumit in December 2013, is indicated for patients with pulmonary arterial hypertension, also in United States.
  • Pulmonary arterial hypertension is a rare, progressive disorder characterized by high blood pressure (hypertension) in the arteries of the lungs without any apparent reason.
  • the arteries of the lungs are the blood vessels that carry blood from the right side of the heart through the lungs.
  • Major symptom of PAH includes shortness of breath (dyspnea) especially during exercise.
  • the other symptoms include excessive fatigue, weakness, chest pain, dizzy spells, and fainting episodes.
  • Pulmonary arterial hypertension is a condition where there is high blood pressure in the arteries that supply the lungs. Pulmonary arterial hypertension (PAH) is also associated with a number of other medical diseases such as cirrhosis and connective tissue diseases like scleroderma. Subdivisions of Pulmonary Arterial Hypertension a) Heritable pulmonary arterial hypertension (HP AH) b) Idiopathic pulmonary arterial hypertension (IPAH) c) Associated pulmonary arterial hypertension (APAH)
  • Pulmonary Hypertension is a general term and it is used to describe high blood pressure in the lungs. There are five different groups of PH based on different causes according to World Health Organization classification. These groups are defined by the World Health Organization (WHO) and are referred to as PH WHO Groups.
  • WHO Groups WHO Group 1: Pulmonary Arterial Hypertension (PAH), WHO Group 2: Pulmonary Hypertension Due to Left Heart Disease, WHO Group 3: Pulmonary Hypertension Due to Lung Disease, WHO Group 4: Pulmonary Hypertension Due to Chronic Blood Clots in the Lungs, WHO Group 5: Pulmonary Hypertension Due to Unknown Causes.
  • PAH Pulmonary Arterial Hypertension
  • WHO Group 2 Pulmonary Hypertension Due to Left Heart Disease
  • WHO Group 3 Pulmonary Hypertension Due to Lung Disease
  • WHO Group 4 Pulmonary Hypertension Due to Chronic Blood Clots in the Lungs
  • WHO Group 5 Pulmonary Hypertension Due to Unknown Causes.
  • the oral administration route is prevalent comparison with the other administration routes of drug delivery such as injection, sublingual, buccal, rectal, topical, parenteral or transdermal.
  • the oral administration route has many advantages especially about patient compliance. Other advantages for oral administration route are ease of ingestion, pain avoidance, and versatility to accommodate various types of drugs.
  • solid oral delivery systems require basic conditions, not specific condition such as sterile condition and also cost-effective.
  • Tablet form has many advantages like cost-effective, lighter and compact, easiest and cheapest to package, can be masked by coating technique and greatest chemical and microbial stability over all oral dosage forms. Unlikely, tablet dosage form has some disadvantages such as difficulties for children and unconscious patients to swallow, troubles on BE/BA studies for drugs with poor wetting and slow dissolution properties.
  • Density is very important for developing a pharmaceutical product of oral administration route like tablets.
  • Density is used for pharmaceutical industry and four types of densities can be measured in pharmaceutical industry: true, tapped, appearent bulk and bulk density.
  • Appearent bulk density It is determined by pouring presieved bulk drug into a graduated cylinder via a large funnel and measuring the volume and weight (g/ml).
  • Tapped density The tapped density is obtained by mechanically tapping a graduated cylinder containing the sample until little further volume change is observed.
  • True density is calculated after exiting the pores and channels between the particles of powders. Experimentally, the true density is determined by suspending drug particles in solvents of various densities and in which the compound is insoluble.
  • Bulk density The density of a powder sample generally expressed as bulk density. The bulk density of a material is the ratio of the mass to the volume (including the interparticulate void volume) of an untapped powder sample.
  • Bulk density is a property of powders, granules, and other solids, especially used in reference to pharmaceutical ingredients also mineral components, chemical substances and similiar industries.
  • Bulk density of powders has always been one of the major factors to consider when material characterization of flowability, stacking and storage properties. Bulk density basically means that how a material will compact under various loads and can also be an indicator of flow.
  • the bulk density is the most common in-process powder attributes tested for pharmaceutical product development and manufacturing. Bulk density testing is also one of the simplest method to evaluate powder “flowability”.
  • the bulk density of a powder is the ratio of the mass of an untapped powder sample and its volume including the contribution of the interparticulate void volume.
  • the bulking properties of a powder are dependent upon the preparation, treatment and storage of the sample, i.e. how it was handled.
  • Density of a powder indicates its flow and compresibility. Bulk density is also affected by concentration of Binding agent in the formula.
  • binding agent Different concentration of binding agent produce granules of varying density which affects flow of blend, compresibility, hardness and release of product during dissolution.
  • powders having bulk density range from 0.4 - 0.7 have suitable flow property and compresibility to make tablets with enough hardness.
  • the present invention relates to the preparation of pharmaceutical compositions comprising macitentan, and one or more pharmaceutically acceptable excipients comprising binder, achieve optimum value for bulk density.
  • the present invention relates to the preperation of pharmaceutical compositions comprising macitentan is indicated for the treatment of pulmonary arterial hypertension (PAH), having a specific ratio for binder to achieve optimum value for bulk density.
  • PAH pulmonary arterial hypertension
  • the present invention relates to the preparation of pharmaceutical compositions comprising macitentan or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • the present invention relates to the preparation of pharmaceutical compositions comprising macitentan, and one or more pharmaceutically acceptable carriers or excipients, to optimum value for bulk density.
  • the present invention relates to the preperation of pharmaceutical compositions comprising macitentan is indicated for the treatment of pulmonary arterial hypertension (PAH), having a specific ratio for binder to achieve optimum value for bulk density.
  • PAH pulmonary arterial hypertension
  • a pharmaceutical composition comprising macitentan, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, wherein said binder is HPMC E5 at a concentration of from 1% to 3% (w/w), and wherein said composition is formulated for oral administration having bulk density between 0,4 to 0,7 gr/mL.
  • compositions comprising macitentan with the value of bulk density of the final blend is 0,4 to 0,7 gr/mL when the binder HPMC E5 used as a concentration of from 1% to 3% (w/w) in the weight of composition.
  • the present invention provides pharmaceutical compositions comprising macitentan formulated for use as tablet dosage form.
  • ⁇ Tablet should have elegant product without any cracks, discoloration or contamination.
  • ⁇ Tablet form should have predictable and reproducible manner for releasing the active ingredients.
  • the mechanical properties of a material has an important role in powder flow and compaction. These properties are critical properties that influence the true areas of contact between particles. Bulk & tapped density testing are the simplest methods to assess powder “flowability”. In preformulation studies for developing tablet dosage form, physicomechanical properties are determined such as particle size, tap density, crystalline form, compressibility, photomicrographs, melting point, taste, color, appearance, and bulk density.
  • the two most important properties are bulk density and improvement in flow that determine the ease with which pharmaceutical powders can be handled, stored and processed, is done through surface modification.
  • the bulk density and tapped density are among the most common in-process powder attributes tested for pharmaceutical product development and manufacturing.
  • Bulk density parameter is very critical for drugs of low potency, which may constitute the bulk of the final granulation of the tablet.
  • the density of solids affects flow properties. Segredation can be occurred because of significant difference in the densities, in the case of physical mixture of powders.
  • excipients that is used in tablet dosage form are diluent, binder, disintegrants, lubricant, glidant, colouring agent, flavoring agent, sweetening agent and solvent except active ingredient.
  • HPMC E5 is used as a binder.
  • the ratio of HPMC E5 used to the total weight is between l%-3%.
  • the composition comprises HPMC E5 at the concentration of 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8 and 3.0% (w/w). The most preferred amount in this range is 2.0%.
  • optimum bulk density value of pharmaceutical composition are between 0.4 to 0.7 g/mL, preferably 0.40 to 0.65 g/mL, most preferably 0,4 to 0,6 gr/mL.
  • manufacturing process generally consists of four stages: a) Sieving and mixing, b) Granulation, c) Mixing granule with external excipients, d) Tablet compression and Film Coating.
  • the pharmaceutical composition preferably is a tablet.
  • the tablet may comprise a film coating material.
  • the formulations preferably contain active ingredient, filler, disintegrant, binder, surfactant, lubricant and solvent.
  • the present invention provides a pharmaceutical composition for the treatment of pulmonary arterial hypertension (PAH).
  • PAH pulmonary arterial hypertension
  • compositions of the invention are particularly suited for the oral administration.
  • the present invention provides pharmaceutical composition comprising macitentan and relevant excipients, characterized by i) A simple and exclusive manufacturing process ii) Stable formulation
  • Tablet dosage form is simple, cost-effective, easy and convenient to use, so it has high patient compliance.
  • compositions of the invention are advantageously in the form of unit dose.
  • each unit dose according to the invention comprises 1 to 100 mg, e.g. 5 to 50 mg, advantageously 8 to 20 mg, e.g. about 10 mg according to the invention, advantageously in combination with standard excipients and additives well known to one skilled in the field.
  • treatment means any treatment of a disease or condition in a subject, such as a mammal, including: 1) preventing or protecting against the disease or condition, that is, causing the clinical symptoms not to develop; 2) inhibiting the disease or condition, that is, arresting or suppressing the development of clinical symptoms; and/or 3) relieving the disease or condition that is, causing the regression of clinical symptoms.
  • pulmonary hypertension will be understood to include “a condition where there is high blood pressure in the arteries that supply the lungs”, including Subdivisions of Pulmonary Arterial Hypertension and World Health Organization classifications for Pulmonary Hypertension (PH).
  • Granulation refers to the act or process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules.
  • Granules may for example be formed collecting particles together by creating mechanical bonds between them, e.g. by compression or by using a binder. Granulation is extensively used in the manufacturing of tablets.
  • oral solid dosage form denotes solid preparations (e.g. tablets) for oral administration each containing a single dose of one or more active substances.
  • optimum value for bulk density denotes the value of bulk density of the final blend is between 0.4 g/mL to 0.7 g/mL.
  • composition of the present inventions may comprise one or more pharmaceutically acceptable excipient(s).
  • Pharmaceutically acceptable excipients comprise, but are not limited to, filler, disintegrant, binder, surfactant, lubricant, solvent and the mixtures thereof, to facilitate the physical formulation of various dosage forms for oral administration like tablets.
  • “pharmaceutically acceptable salt” refers to a salt of a compound that does not abrogate the biological activity and properties ofthe compound.
  • Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base.
  • Suitable disintegrants according to the present invention include, but are not limited to, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose (crosslinked carboxymethylcellulose) sodium, cross-linked polyvinylpyrrolidone, crospovidone (cross-linked povidone, a synthetic cross-linked homopolymer of N-vinyl-2- pyrrolidone), alginic acid, microcrystalline cellulose (such as refined wood pulp derived from alpha cellulose), hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, polacrillin potassium, sodium alginate, sodium starch glycolate, partially hydrolysed starch, sodium carboxymethyl starch, and starch.
  • the preferred disintegrants is sodium starch glycolate.
  • Suitable binders according to the present invention include, but are not limited to, hydroxypropyl cellulose, hypromellose (hydroxypropyl methylcellulose, HPMC), HPMC E5, microcrystalline cellulose, acacia, alginic acid, carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, polyvinyl alcohol, polyacrylates, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, polyvinyl pyrrolidone and pregelatinized starch.
  • the preferred binder is HPMC E5.
  • Suitable lubricants according to the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, fumaric acid, sodium stearylfumarate, zinc stearate and polyethylene glycol.
  • the preferred lubricant is magnesium stearate.
  • Suitable fillers according to the present invention include, but are not limited to, dibasic calcium phosphate, kaolin, microcrystalline cellulose, silicated microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, lactose such as example the anhydrous form or the hydrate form such as the monohydrate form, sugars such as dextrose, maltose, saccharose, glucose, fructose or maltodextrine, sugar alcohols such as mannitol, maltitol, sorbitol, xylitol, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate and starch. Fillers which are slightly hygroscopic or non- hygroscopic are preferred, with non-hygroscopic fillers being particularly preferred, in particular when the dosage form is to be used for tropical countries.
  • the preferred fillers is microcrystalline cellulose.
  • Suitable surfactants and wetting agents include, but are not limited to, heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, polyoxyethylene stearate, polyoxyethylen sorbitan monolaurate, benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbates, for example polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80, sorbitan monopalmitate, sodium salts of fatty alcoholsulfates such as sodium lauryl sulfate, sodium dodecylsulfate, sodium salts of sulfosuccinates such as sodium dioctylsulfosuccinate, partially esters of fatty acids with alcohols such as glycerine monostearate, partially esters of fatty acids with sorbitans such as sorbitan monolaurate,
  • Suitable film-forming agents and coating materials according to the present invention include, but are not limited to, liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose, HPMC), methylcellulose, ethylcellulose, cellulose acetate phthalate, shellac, polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinylacetate such as Kollidon® VA64 BASF, copolymers of acrylic and/or methacrylic acid esters with trimethylammoniummethylacrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylic acid esters, polymers of methacrylic acid or methacrylic acid esters, copolymers of acrylic acid ethylester and methacrylic acid methyl ester, and copolymers of acrylic acid and acrylic acid methylester.
  • liquid glucose hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl
  • Solvents can be selected from the group, but not limited to, ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, purified water and other materials known to one of ordinary skill in the art and mixtures thereof.
  • the preferred solvent is purified water.
  • Example 1 Macitentan lOmg film coated tablet unit formula

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Abstract

La présente invention concerne la préparation de compositions pharmaceutiques comprenant du macitentan qui est indiquée pour le traitement de l'hypertension artérielle pulmonaire (HTAP), ayant un rapport spécifique pour que le liant atteigne une valeur optimale de masse volumique apparente.
PCT/TR2020/050769 2020-08-26 2020-08-26 Compositions pharmaceutiques comprenant du macitentan et des excipients appropriés WO2022045991A1 (fr)

Priority Applications (1)

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PCT/TR2020/050769 WO2022045991A1 (fr) 2020-08-26 2020-08-26 Compositions pharmaceutiques comprenant du macitentan et des excipients appropriés

Applications Claiming Priority (1)

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PCT/TR2020/050769 WO2022045991A1 (fr) 2020-08-26 2020-08-26 Compositions pharmaceutiques comprenant du macitentan et des excipients appropriés

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180008603A1 (en) * 2013-04-22 2018-01-11 Sandoz Ag Pharmaceutical composition containing crystalline macitentan
WO2018153925A1 (fr) * 2017-02-22 2018-08-30 Amneal Pharmaceuticals Company Gmbh Compositions pharmaceutiques stables comprenant du macitentan

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180008603A1 (en) * 2013-04-22 2018-01-11 Sandoz Ag Pharmaceutical composition containing crystalline macitentan
WO2018153925A1 (fr) * 2017-02-22 2018-08-30 Amneal Pharmaceuticals Company Gmbh Compositions pharmaceutiques stables comprenant du macitentan

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ANJANEYULU V., GNANAPRAKASH K, CHANDRASEKHAR K: "DEVELOPMENT AND EVALUATION OF BOSENTAN PULSINCAP FORMULATION FOR CONTROLLED RELEASE", INTERNATIONAL JOURNAL OF PHARMACEUTICALS AND HEALTH CARE RESEARCH, 1 January 2014 (2014-01-01), pages 119 - 114, XP055970825, ISSN: 2306-6091 *
METHOCEL: "Premium Cellulose Ethers (Low Viscosity) Product Information", METHOCEL, pages 1 - 5, XP055970804, Retrieved from the Internet <URL:https://www.colorcon.com/products-formulation/all-products/excipients/tablets/methocel-low-viscosity> [retrieved on 20221013] *
MORKHADE DINESH M.: "Comparative impact of different binder addition methods, binders and diluents on resulting granule and tablet attributes via high shear wet granulation", POWDER TECHNOLOGY, vol. 320, 15 July 2017 (2017-07-15), Basel (CH) , pages 114 - 124, XP085169056, ISSN: 0032-5910, DOI: 10.1016/j.powtec.2017.07.038 *

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