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WO2014141298A2 - Composition pharmaceutique stable de fingolimod - Google Patents

Composition pharmaceutique stable de fingolimod Download PDF

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Publication number
WO2014141298A2
WO2014141298A2 PCT/IN2014/000153 IN2014000153W WO2014141298A2 WO 2014141298 A2 WO2014141298 A2 WO 2014141298A2 IN 2014000153 W IN2014000153 W IN 2014000153W WO 2014141298 A2 WO2014141298 A2 WO 2014141298A2
Authority
WO
WIPO (PCT)
Prior art keywords
fingolimod
pharmaceutically acceptable
pharmaceutical composition
stable pharmaceutical
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.)
Ceased
Application number
PCT/IN2014/000153
Other languages
English (en)
Other versions
WO2014141298A3 (fr
Inventor
Kapil AGNIHOTRI
Balvir SINGH
Ashish Sehgal
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.)
Astron Research Ltd
Original Assignee
Astron Research Ltd
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 Astron Research Ltd filed Critical Astron Research Ltd
Publication of WO2014141298A2 publication Critical patent/WO2014141298A2/fr
Publication of WO2014141298A3 publication Critical patent/WO2014141298A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • This present invention relates to stable phannaceutical composition of fingolimod or its pharmaceutically acceptable salts thereof and process for preparation of the same.
  • the pharmaceutical compositions as disclosed ill the present invention can be dispensed as an oral dosage form, which are bioequivalent to the marketed Fingolimod product.
  • Fingolimod is a sphingosine-1 phosphate (SIP) agonist, having immunosuppressive activity. Chemically, fingolimod is 2-amino-2-[2-(4-octylphenyl)ethyl]pi pan-l ,3- diol hydrochloride. Us structure is shown: ⁇
  • Fingolimod hydrochloride is a white to practically white powder that is freely soluble in water and alcohol and soluble in propylene glycol. It has a molecular weight of 343.93.
  • WO2004/089341 discloses the solid pharmaceutical composition suitable for oral administration comprising mannitol and 2-amino-2-[2-(4-octylphenyl)ethyl]propane- 1,3-diol or a pharmaceutically acceptable salts thereof.
  • US20110105620 also discloses the solid pharmaceutical composition suitable for oral administration, comprising: (a) a SIP receptor agonist; and (b) a sugar alcohol.
  • the sugar alcohol can be, e.g. mannitol, maltitol, inositol, xylitol or lactitol.
  • US20100040678 discloses rapidly disintegrating dosage forms of SIP agonists including FTY720 (fingolimod).
  • the compositions comprise a coating, wherein the coating comprises one or more polymer resins and one or more metal oxides.
  • WO2009/048993 discloses dosage forms containing SIP modulators and one or more excipients selected from fillers, binders, disintegrants, lubricants, flow regulators, matrix formers, plasticizers, flavouring agents and sweeteners.
  • fingolimod.- possess properties that can cause several processing problems like content uniformity as fingolimod particles have strong tendency to stick surfaces and each othe . ' urther fingolimod can react with certain excipients to produce degradation products in- the final composition. Moreover, the applicant has found that there are significant problems in pharmaceutical composition containing fingolimod.
  • the present invention addresses the need to provide stable composition of fingolimod to overcome the above mentioned problems.
  • the inventors of the present invention have found a stable pharmaceutical composition of fingolimod or its pharmaceutically, acceptable salts.
  • the object of the present invention is to provide a stable composition comprising fingolimod or its pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a stable composition comprising fingolimod or its pharmaceutically acceptable salt thereof, vvhich can be dispensed as an oral dosage form.
  • Another object of the present invention is to ⁇ ⁇ provide a stable composition comprising fingolimod or its pharmaceutically acceptable salt thereof, maltodextrin, and optionally at least one pharmaceutically acceptable excipient.
  • Another object of the present invention is to provide a stable composition comprising fingolimod or its pharmaceutically acceptable salt thereof, pullulan, and optionally at least one pharmaceutically acceptable excipient.
  • Another object of the present invention is to provide a: stable composition comprising fingolimod or its pharmaceutically acceptable salt thereof, prege latinized starch, and optionally at least one pharmaceutically acceptable excipient.
  • Another object of the present invention is to.' provide a stable composition of fingolimod comprising: (a) a core; (b) dry coating on the said core, wherein the drug coating comprises of fingolimod or its pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable excipient.
  • Another object of the present invention is to provide a method for the preparation of a stable composition of fingolimod comprising fingol imod or its pharmaceutical ly acceptable salt thereof, polysaccharide and optional ly at least one pharmaceutically acceptable excipient. , .
  • Another object of the present invention is to provide a stable composition comprising fingol imod or its pharmaceutical ly acceptable salt thereof for the treatment of multiple sclerosis, preferably relapsing-rem itting multiple sclerosis SUMMARY OF THE INVENTION
  • This present invention relates to stable pharmaceutical composition of fingol imod or its pharmaceutical ly acceptable salts thereof, polysaccharide and/or its derivatives and optionally at least one pharmaceutical ly acceptable excipient.
  • Said composition can be dispensed as an oral dosage form to overcome the several processing problem associated with the fingol imod composition.
  • the present invention provides a method for the preparation of said fingolimod' composition which is bioequivalent to the marketed Fingolimod product.
  • the polysaccharide and/or its derivatives are selected form maltodextrin, pul lulan or pregelatinized starch. DETAILED DESCRIPTION
  • This present invention relates to stable pharmaceutical composition
  • fingolimod or its pharmaceutically acceptable salts thereof, polysaccharide and/or its derivatives and optionally at least one pharmaceutically acceptable excipient.
  • Fingolimod is marketed by Novartis under the brand name Gilenya® for the treatment of multiple sclerosis
  • Gilenya® is presented as immediate-release hard gelatin capsules containing 0.56 mg of fingolimod hydrochloride as the active substance corresponding to 0.5 mg of fingolimod base.
  • the proportion of the active agent in the total weight of the formulation in the case of formulations for oral administration is typically in the range of only a few per cent by weight, such as 0.25 to 4 % by weight.
  • the present invention is based on the findings that pharmaceutical compositions and dosage forms comprising fingolimod having improved stability and/or content uniformity by using the excipients like polysaccharide and/or its derivatives, chosen based on compatibility studies and experience from development of similar formulations.
  • the present invention provides a stable composition
  • fingolimod or its pharmaceutically acceptable salt thereof polysaccharide and/or its derivatives, and optionally at least one pharmaceutically acceptable excipient.
  • the polysaccharide and/or its derivatives are selected from maltodextrin, pullulan, pregelatinized starch or mixtures thereof.
  • the composition of the present invention preferably contains 0.01 to 20% by weight of fingolimod or its pharmaceutically acceptable salts, more preferably 0.1 to 10%, e.g.0.5 to 5% by weight, based on the total weight of the composition.
  • the 90% by volume or more of the particles (d90) of fmgolimod or its pharmaceutical ly acceptable salts have not more than 30 ⁇ particle size, more preferably not more than 20 ⁇ .
  • the average particle size (d50) of fmgolimod or its pharmaceutically acceptable salt is not more than 1 0 ⁇ .
  • the present invention provides a stable composition
  • maltodextrin is a nonsweet nutritive saccharide m ixture of polymer that consists of D-glucose unit, with a dextrose equivalent (DE) o f less than 20.
  • the composition may comprise at least one pharmaceutical ly acceptable excipients selected form binders, di luents, lubricants.
  • the composition preferably comprises a lubricant.
  • Suitable lubricants selected from magnesium stearate, talc, stearic acid, zinc stearte, calcium stearate, sodium stearyl fumarate, hydrogenated vegetable oil such as hydrogenated castor oil or a mixture of any of the above.
  • the lubricant is magnesium stearate.
  • the composition consists of fingolimod or its pharmaceutically acceptable salts thereof, maltodextrin and magnesium stearate.
  • the present invention provides a stable composition comprising fingolimod or its pharmaceutically acceptable salt thereof, pullulan, and optionally at least one pharmaceutically acceptable excipient.
  • Pullulan is a polysaccharide produced by yeast like fungus Aureobasidium pullulans.
  • Pullulan is an essentially linear glucan consisting mainly of 1,6-linked maltotriose and some interspersed maltotetraose units.
  • the composition preferably comprises a lubricant, more preferably lubricant is magnesium stearate.
  • lubricant is magnesium stearate.
  • the composition consists of fingolimod or its pharmaceutically acceptable salts thereof, pullulan and magnesium stearate.
  • the present invention provides a stable composition
  • fingolimod or its pharmaceutically acceptable salt thereof pregelatinized starch, and optionally at least one pharmaceutically acceptable excipient.
  • pregelatinized starch is a pharmaceutical grade of partially pregelatinized maize starch.
  • Pregelatinized starch also called modified starch or starch derivatives that has been chemically and/or mechanically processed to rupture all or part of the native starch and so render the starch flow able and directly compressible.
  • Further starch is a polysaccharides consisting of large number of glucose units joined by glycosidic bonds.
  • Pregelatinized starch is a unique pharmaceutical excipient combining several properties in a single product: binder, disintegrant, filler and flow-aid while having lubricant properties.
  • pregelatinized starch used in the present invention is commercially available Starch 1500® Partially Pregelatinized Maize Starch by Colorcon. More preferably, the pregelatinized starch is Starch 1500® LM of Colorcon.
  • pregelatinized starch works is used in the range of 5% to 75% by weight based on the total weight of the composition, more preferably 10% to 70%, most preferably 20% to 60% by weight based on the total weight of the composition.
  • the composition preferably comprises a lubricant, more preferably lubricant is magnesium stearate.
  • the composition consists of fingolimod or its pharmaceutically acceptable salts thereof, pregelatinized starch and magnesium stearate.
  • the present invention provides a stable composition
  • a stable composition comprising: (a) a core; (b) drug coating on the said core, wherein the said drug layer comprising fingolimod or its pharmaceutically acceptable salts and optionally at least one pharmaceutically acceptable excipient.
  • a core is inert microcrystalline cellulose core unit.
  • the microcrystalline cellulose core unit of the beads is any core or seed that contains microcrystalline cellulose and is typically a commercially available microcrystalline cellulose sphere such as Cellets® or Celpheres®.
  • the drug coating consists essentially of fingolimod or its pharmaceutically acceptable salts, preferably fingolimod HCl. together with a pharmaceutically acceptable binder.
  • drug layer comprises a binder which is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose polyvinylpyrrolidone, starch or a combination thereof, more preferable the binder is a low viscosity of hydroxypropyl methylcellulose.
  • the drug layer solution comprises the fingolimod HCI, a binder and a suitable solvent, most preferably purified water.
  • the drug layer solution is applied on to the MCC core by any method known in the art.
  • the present invention provides a method for the preparation of a stable composition comprising fingolimod or its pharmaceutically acceptable salt thereof, polysaccharide and optionally at least one pharmaceutically acceptable excipient
  • the composition according to the present invention can be dispensed as a dosage form for oral administration.
  • the compositions of the present invention are well ⁇ adapted for encapsulation into an orally administrate capsule shelf, particularly a hard gelatin shell. Alternatively the compositions may be compacted into tablets. The tablets may optionally be coated.
  • compositions of the present invention may be produced by standard processes, for instance by mixing, granulating, sugar-coating, dissolving or lyophilizing processes.
  • the present invention provides a method for the preparation of a stable composition comprising mixing the fingolimod or its pharmaceutically acceptable slats thereof, with polysaccharide and/or its derivatives and sifted through mesh screen. Further the above sifted mixture is blended with suitable blender. Then lubricated the above mixture with magnesium stearate and blended to produce a product composition showing a substantially uniform distribution of fingolimod throughout the blend. The product composition is then filled into size 3 hard gelatin capsule shell. :
  • a wet granulation process is employed.
  • the fingolimod is dissolved in purified water followed by wet granulation with polysaccharide and/or its derivatives.
  • composition according to present invention optionally comprises one or more ingredients selected from fillers, diluents, binders, disintegrants, lubricants, glidants, surfactants, stabilizers and other suitable excipients or mixture thereof.
  • the present invention provides a stable composition comprising fingolimod or its pharmaceutical ly acceptable salt thereof for the treatment of multiple sclerosis, preferably relapsing-rem itting multiple sclerosis EXAMPLES
  • fingol imod 0.56 mg is mixed with 46.48 mg of maltodextrin and then screened through 30 mesh screen. Magnesium stearate separately screened and blended with the fingolimod/maltodextrin m ixture. The above lubricated m ixture further screen through 40 mesh screen and blended to produce a product composition showing a substantial ly uniform distribution of fingolimod throughout the maltodextrin in the blend. The product composition is then fi lled into size 3 hard gelatin capsu le shel l .
  • fingol imod 0.56 mg is m ixed with 46.48 mg of pul lu lan and then screened through 30 mesh screen. Magnesium stearate separately screened and blended vvith the fingolimod/pullulan m ixture. The above lubricated m ixture further screen through 40 mesh screen and blended to produce a product composition showing a substantially uni form distribution of fingol imod throughout the pul lulan in the blend. The product composition is then filled into size 3 hard gelatin capsule shel l .
  • Example 3 Example 3:
  • a drug layer solution by dissolving the fingol imod HCI & HPMC in purified water. Coat the MCC sphere with above prepared drug layer solution in FBD or suitable granulator and then lubricated the above drug coated core with talc. The above lubricated drug coated core further screen through 40 mesh screen and blended to produce a drug pel lets. The drug pel lets is then fi l led into size 3 hard gelatin capsule shell .
  • fingol imod 0.56 mg is m ixed with 46.48 mg of starch 1 500 and then screened through 1 00 mesh screen. Magnesium stearate separately screened and blended with the fingolimod/starch 1500 mixture. The above lubricated m ixture further screen through 40 mesh screen and blended to produce a product composition showing a substantially uniform distribution of fingol imod throughout the starch 1 500 in the blend. The product composition is then fil led into size 3 hard gelatin capsule shel l .
  • Table 1 Stability data under different time interval at stress condition of 40°C / 75 % RH
  • the above data shows a total impurity of 1 .3% in the formulation indicative of stability of flngolimod HC1 in the drug product.
  • Total impurity describes herein the degradation product of fingol imod produce during the manufacturing process of pharmaceutical composition.
  • Table 2 Stability data under 6 month time interval at condition of 25°C / 60% RH
  • the above data shows a total impurity of 0.2% in the formu lation indicative of stability of fingolimod HCI in the drug product.
  • composition of the present invention overcomes the problem associated vvith the content uniformity related with fingolimod composition.
  • Dissolution study of the example 4 were carried with USP dissolution apparatus I at 100 rpm using 1 000 ml in 0.1 N HCI with 0.2% SLS.
  • Table 3 Dissolution profile in (U N HCI with 0.2% SLS, USP d issolution apparatus I at 100 rpm using 1000 ml at 40°C/75%RH.
  • Table 4 Dissolution profile in 0.1N HCI with 0.2% SLS, USP dissolution apparatus I at 100 rpm using 1000 ml at 25°C/60% RH.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une composition pharmaceutique stable de fingolimod ou ses sels pharmaceutiquement acceptables, et son procédé de préparation. Les compositions pharmaceutiques de la présente invention peuvent être dispensées sous forme dosifiée orale, et constituent des bioéquivalents du produit commercialisé Fingolimod.
PCT/IN2014/000153 2013-03-11 2014-03-10 Composition pharmaceutique stable de fingolimod Ceased WO2014141298A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN725/MUM/2013 2013-03-11
IN725MU2013 2013-03-11

Publications (2)

Publication Number Publication Date
WO2014141298A2 true WO2014141298A2 (fr) 2014-09-18
WO2014141298A3 WO2014141298A3 (fr) 2014-12-24

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PCT/IN2014/000153 Ceased WO2014141298A2 (fr) 2013-03-11 2014-03-10 Composition pharmaceutique stable de fingolimod

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Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2769713A1 (fr) * 2003-04-08 2014-08-27 Novartis AG Composition orale solide comprenant un agoniste de récepteur S1P et alcool de sucre
RU2487703C2 (ru) * 2006-09-26 2013-07-20 Новартис Аг Фармацевтические композиции, включающие модулятор s1р
WO2009048993A2 (fr) * 2007-10-12 2009-04-16 Novartis Ag Compositions comprenant des modulateurs du récepteur de sphingosine 1-phosphate (s1p)
AR085749A1 (es) * 2011-04-01 2013-10-23 Novartis Ag Formulaciones

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