WO2019116386A1 - Compositions pharmaceutiques orales d'aprémilast amorphe et ses procédés de préparation - Google Patents

Compositions pharmaceutiques orales d'aprémilast amorphe et ses procédés de préparation Download PDF

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Publication number
WO2019116386A1
WO2019116386A1 PCT/IN2018/050828 IN2018050828W WO2019116386A1 WO 2019116386 A1 WO2019116386 A1 WO 2019116386A1 IN 2018050828 W IN2018050828 W IN 2018050828W WO 2019116386 A1 WO2019116386 A1 WO 2019116386A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
apremilast
composition
core
sodium
Prior art date
Application number
PCT/IN2018/050828
Other languages
English (en)
Inventor
Arun Kumar Pandey
Umadoss POTHUVAN
Chandan Sharma
Binayak SADANGI
Original Assignee
Alkem Laboratories 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 Alkem Laboratories Ltd. filed Critical Alkem Laboratories Ltd.
Publication of WO2019116386A1 publication Critical patent/WO2019116386A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone

Definitions

  • the invention relates to an oral pharmaceutical compositions of Amorphous Apremilast and processes for preparing thereof
  • Apremilast is a phosphodiesterase 4 (PDE4) inhibitor.
  • PDE4 phosphodiesterase 4
  • Apremilast is known chemically as N-[2- [(lS)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH- isoindol-4-yl]acetamide. Its empirical formula is C22H24N207S and the molecular weight is 460.5.
  • Apremilast is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels. The specific mechanism(s) by which apremilast exerts its therapeutic action in psoriatic arthritis patients is not well defined.
  • PDE4 phosphodiesterase 4
  • cAMP cyclic adenosine monophosphate
  • apremilast is a major circulating component (45%) followed by inactive metabolite M12 (39%), a glucuronide conjugate of O-demethylated apremilast. It is extensively metabolized in humans with up to 23 metabolites identified in plasma, urine and feces. Apremilast is metabolized by both cytochrome (CYP) oxidative metabolism with subsequent glucuronidation and non-CYP mediated hydrolysis. In vitro, CYP metabolism of apremilast is primarily mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2A6.
  • CYP cytochrome
  • the plasma clearance of apremilast is about 10 L/hr in healthy subjects, with a terminal elimination half-life of approximately 6-9 hours.
  • apremilast Following oral administration of radio-labeled apremilast, about 58% and 39% of the radioactivity is recovered in urine and feces, respectively, with about 3% and 7% of the radioactive dose recovered as apremilast in urine and feces, respectively.
  • Apremilast is available in the United States of America as OTEZLA® (apremilast) oral tablets and indicated for the treatment of adult patients with active psoriatic arthritis. It is available in various strengths i.e. 10, 20, and 30 mg strengths for oral administration
  • US 6,020,358 discloses substituted phenethylsulfones, including apremilast, and methods of use thereof for reducing TNFa levels.
  • WO 2003/080048 and WO 2003/080049 disclose the use of the (-) and (+) enantiomers of apremilast, respectively, in the treatment or prevention of diseases or disorders by the inhibiting TNF-a production or PDE4.
  • U.S. Pat. No. 7,427,638 discloses stereomerically pure (+)-2-[l-(3-ethoxy-4-methoxyphenyl)-2- methylsulfonylethyl]-4-acetylaminoisoindoline-l,3-dione, substantially free of its (-) isomer, or a pharmaceutically acceptable metabolite, salt, solvate or hydrate, thereof and its pharmaceutical composition.
  • (+)-2-[l-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyl- ethyl]-4-acetylaminoisoindoline-l,3-dione is the (+)-isomer of racemic 2-[l-(3-ethoxy-4- methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl]acetamide
  • WO 2009/120167 and U.S. Pat. No. 7,893,101 disclose various solid forms comprising apremilast include single-component and multiple-component forms, including crystal forms and amorphous forms and their mixture comprising one or more of the Forms A, B, C, D, E, F, G and an amorphous solid form and provides representative XRPD patterns, DSC plots, TGA plots and DVS plots for each of Forms A, B, C, D, E, F and G.
  • WO 2009/120167 also generally mentions an amorphous form of apremilast but does not teach that a single amorphous form was actually obtained or characterized.
  • US20130164376A1 disclose formulations and dosage forms of apremilast, i.e., (+)-2-[l-(3- ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-l,3-dione. or a pharmaceutically acceptable salt thereof; a filler; a disintegrant; and a lubricant. Methods of using the formulations and dosage forms are also provided herein.
  • WO 2014/072259 discloses pharmaceutical composition of amorphous apremilast with at least one excipients prepared by melt extrusion technique.
  • US9351957 discloses the pharmaceutical composition comprising an amorphous solid dispersion of apremilast and one or more of pharmaceutically acceptable carriers, excipients or diluents used for the treatment of active psoriatic arthritis.
  • polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e.g., tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more stable crystalline form) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity).
  • chemical reactivity e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph
  • mechanical changes e.g., tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more stable crystalline form
  • both e.g., tablets of one polymorph are more susceptible to breakdown at high humidity.
  • An amorphous form generally provides better solubility and bioavailability than the crystalline form and may be useful for formulations which can have better stability, solubility and compressibility etc. which are important for formulation and product manufacturing.
  • amorphous form of drug with high purity to meet the needs of regulatory agencies and highly reproducible processes for its preparation.
  • the amorphous form provided herein is stable under ordinary stability conditions with respect to purity and storage.
  • composition for oral administration comprising:
  • a core composition wherein the core composition comprises:
  • a core composition wherein the core composition comprises:
  • the said pharmaceutical composition about 90 to 95% of Apremilast is released in about 1 hour in an aqueous buffer solution of about pH 6.8 with a paddle speed of 75 RPM.
  • the present invention relates to an oral pharmaceutical compositions of Amorphous Apremilast and processes for preparing thereof.
  • a pharmaceutical composition for oral administration comprising:
  • the said pharmaceutical composition about 90 to 95% of Apremilast is released in about 1 hour in an aqueous buffer solution of about pH 6.8 with a paddle speed of 75 RPM.
  • a process to prepare a pharmaceutical composition for oral administration comprising:
  • a core composition wherein the core composition comprises:
  • stable refers to chemical stability of amorphous form of Apremilast in solid dosage forms wherein there is no change in assay values and dissolution and/or the total impurity remains less than 1%, when the dosage form is kept at 40°C/75% RH for 6 months.
  • composition as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amounts, if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant that the diluent, excipient or carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof
  • polymorph refers to polymorph form of Apremilast which, when present as a solid, exists as different crystalline forms.
  • polymorph includes solid forms of a compound such as crystals, microcrystals, foams, and powders, among others.
  • Polymorphs typically differ in their physical properties due to the order of the molecules in the lattice of the polymorph.
  • the physical properties of the polymorph can differ due to the presence of solvates or other molecules incorporated into the lattice of the polymorph.
  • polymorphs are readily distinguished using techniques such as melting point, rate of dissolution, Infrared (IR) and Raman spectroscopy, and X-ray diffraction such as crystal and powder techniques.
  • amorphous refers to a compound having no definite crystal structure or form.
  • amorphous refers to amorphous Apremilast that can be present in the amorphous form as a solid or in a solution.
  • the dosage form can be formulated as oral formulation by any suitable granulation process, dry or wet in the form of tablet, coated tablet or multiparticulate formulation known to those skilled in the art.
  • the dosage form can be formulated as oral tablets formulation and dissolution of formulated oral tablets is evaluated by Drug Dissolution Apparatus II USP (Paddle), known to those skilled in the art.
  • the pharmaceutical composition of the present invention may further comprise conventional pharmaceutically acceptable excipients.
  • Conventional pharmaceutical excipients include those which function in a dosage form, for example, as fillers or diluents, binders, disintegrants, lubricants, glidants, and film forming material.
  • Fillers or diluents for use in the formulations of the present invention include fillers or diluents typically used in the formulation of pharmaceuticals.
  • Examples of fillers or diluents for use in accordance with the present invention include but are not limited to Starlac(mixture of Lactose monohydrate and corn starch), sugars such as lactose, dextrose, glucose, sucrose, cellulose, starches and carbohydrate derivatives, polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cycludextrins, calcium carbonates, magnesium carbonates, microcrystalline cellulose, combinations thereof, and the like.
  • lactose selected from the group consisting of anhydrous lactose, lactose monohydrate, lactose fast flow directly compressible anhydrous lactose, and modified lactose monohydrate.
  • Binders for use in the formulations of the present invention include binders commonly used in the formulation of pharmaceuticals.
  • binders for use in accordance with the present invention include but are not limited to an Ammonio methacrylate copolymer dispersion (Eudragit Type A and Type B) or Acrylic derivatives.
  • Disintegrants include, but are not limited to, carboxymethcellulose(e.g.,croscarmellose sodium, such as AC -DI-SOL®).
  • the disintegrant is carboxymethyl cellulose.
  • the disintegrant is croscarmellose sodium.
  • the disintegrant is AC-DI-SOL®.
  • Lubricants for use in the formulations of the present invention include lubricants commonly used in the formulation of pharmaceuticals.
  • examples of lubricants for use in accordance with the present invention include but are not limited to magnesium carbonate, magnesium laurylsulphate, calcium silicate, talc, fumed silicon dioxide, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulphate, magnesium lauryl sulphate, sodium benzoate, colloidal silicon dioxide, magnesium oxide, microcrystalline cellulose, starches, mineral oil, waxes, glyceryl behenate, polyethylene glycol, sodium acetate, sodium chloride, combinations thereof.
  • Coats include, but are not limited to, Opadry (e.g., Opadry). In one embodiment, the coat is Opadry. In another embodiment, the coat is Opadry II.
  • compositions of the present invention may be prepared by the conventional processes such as wet granulation, dry granulation or direct compression as known to those skilled in the art.
  • composition of the present invention was prepared as given in table 1.
  • composition of the present invention was prepared as given in table 2.
  • Dissolution Profile study The comparative dissolution study between the Apremilast Tablets 30 mg of Otezla ® Oral tablets as reference product and Example 1 and Example 2 of the present invention as Test product and showed about 90 to 95% of Apremilast is released in about 1 hour in an aqueous buffer solution of about pH 6.8 with a paddle speed of 75 RPM wherein the an aqueous buffer solution is 0.30% sodium lauryl sulphate in 25 mM Sodium Phosphate Buffer in Dissolution Apparatus II ETSP (Paddle). The results are as shown in tables 3 and 4.
  • Bioequivalence Study The comparative study between the Apremilast Tablets 30 mg of Otezla ® Oral tablets as reference product and Example 1 of the present invention as Test product showed that the two formulations were bioequivalent. (Within 90% confidence interval for the ratios). The results are as shown in tables 5 and 6.
  • AUC ( o-inf ) Area under the plasma concentration time curve from time 0 to inf

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

Abstract

La présente invention concerne une composition pharmaceutique orale d'Aprémilast Amorphe et des procédés de préparation de celle-ci, la composition de cœur comprenant : une forme amorphe d'Aprémilast, en tant que principe actif; une dispersion de copolymère d'Ammonio méthacrylate en tant qu'agent de liaison; un mélange de Lactose monohydraté et d'amidon de maïs en tant que diluant; au moins un Délitant, au moins un lubrifiant et le cœur est revêtu d'un agent filmogène à base d'acétate de Polyvinyle; ladite composition pharmaceutique d'environ 90 à 95 % d'Aprémilast étant libérée en environ 1 heure dans une solution tampon aqueuse à un pH d'environ 6,8 avec une vitesse de pale de 75 RP.
PCT/IN2018/050828 2017-12-12 2018-12-11 Compositions pharmaceutiques orales d'aprémilast amorphe et ses procédés de préparation WO2019116386A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201721042447 2017-12-12
IN201721042447 2017-12-12

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WO2019116386A1 true WO2019116386A1 (fr) 2019-06-20

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4183389A1 (fr) 2021-11-18 2023-05-24 KRKA, d.d., Novo mesto Composition pharmaceutique comprenant de l'aprémilast
WO2023120466A1 (fr) * 2021-12-23 2023-06-29 沢井製薬株式会社 Préparation médicinale contenant un hydrate d'aprémilast

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014204825A1 (fr) * 2013-06-17 2014-12-24 Celgene Corporation Formulations de comprime de (+)-2-[1 -(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione
US9351957B2 (en) * 2014-04-04 2016-05-31 Cadila Healthcare Limited Amorphous form of apremilast
CA3008471A1 (fr) * 2015-12-24 2017-06-29 Jiangsu Hengrui Medicine Co., Ltd. Preparation a liberation prolongee d'apremilast

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014204825A1 (fr) * 2013-06-17 2014-12-24 Celgene Corporation Formulations de comprime de (+)-2-[1 -(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione
US9351957B2 (en) * 2014-04-04 2016-05-31 Cadila Healthcare Limited Amorphous form of apremilast
CA3008471A1 (fr) * 2015-12-24 2017-06-29 Jiangsu Hengrui Medicine Co., Ltd. Preparation a liberation prolongee d'apremilast

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4183389A1 (fr) 2021-11-18 2023-05-24 KRKA, d.d., Novo mesto Composition pharmaceutique comprenant de l'aprémilast
WO2023089101A1 (fr) 2021-11-18 2023-05-25 Krka, D.D., Novo Mesto Composition pharmaceutique comprenant de l'aprémilast
WO2023120466A1 (fr) * 2021-12-23 2023-06-29 沢井製薬株式会社 Préparation médicinale contenant un hydrate d'aprémilast

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