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WO2023118043A1 - Compositions pharmaceutiques comprenant l'aprémilast - Google Patents

Compositions pharmaceutiques comprenant l'aprémilast Download PDF

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Publication number
WO2023118043A1
WO2023118043A1 PCT/EP2022/086847 EP2022086847W WO2023118043A1 WO 2023118043 A1 WO2023118043 A1 WO 2023118043A1 EP 2022086847 W EP2022086847 W EP 2022086847W WO 2023118043 A1 WO2023118043 A1 WO 2023118043A1
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Prior art keywords
pharmaceutical composition
total amount
weight
respect
apremilast
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Inventor
José Vicente HERNÁNDEZ BALLESTER
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Biohorm SL
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Biohorm SL
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    • 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
    • A61K9/2009—Inorganic 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
    • A61K9/20—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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/2004—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • the present invention relates to pharmaceutical compositions comprising Apremilast or a pharmaceutically acceptable salt or solvate thereof and to processes for the manufacture of said pharmaceutical compositions.
  • W02007079182 discloses tablets, capsules, ampoules, ointment, paste and spray of Apremilast and processes for manufacturing Apremilast tablets by wet granulation.
  • WO2013101810 discloses Apremilast coated tablets.
  • WO2019073331 discloses Apremilast disintegrant free tablets.
  • the present invention in one aspect refers to a pharmaceutical composition
  • a pharmaceutical composition comprising Apremilast, at least one filler and at least one disintegrant, wherein the active ingredient has a particle size volume distribution with D90 between 10 and 50 pm when measured by laser diffraction analysis.
  • the pharmaceutical composition is lactose-free.
  • this invention refers to oral solid dosage forms obtained from said pharmaceutical composition.
  • this invention refers to a process of manufacturing the pharmaceutical composition.
  • this invention refers to the use of said pharmaceutical composition in treatments comprising, inter alia, psoriasis, psoriatic arthritis or Behget’s disease.
  • Figure 1 shows the PXRD of the crystalline anisaldehyde solvate of Apremilast
  • Figure 2. shows the PXRD of the crystalline 3-phenylpropanaldehyde solvate of Apremilast
  • Figure 3. shows the PXRD of the crystalline 3-methyl-2-cyclohexenone solvate of Apremilast
  • Figure 4. shows the PXRD of the crystalline 6-methyl-5-hepten-2-one solvate of Apremilast
  • the present invention provides pharmaceutical compositions of Apremilast as well as a manufacturing process thereof.
  • compositions of the present invention comprise Apremilast or a pharmaceutically acceptable salt or solvate thereof, at least one filler and at least one disintegrant, wherein the active ingredient has a particle size volume distribution with D90 between 10 and 50 pm when measured by laser diffraction analysis.
  • the pharmaceutical composition may also comprise a glidant, a lubricant, or any other pharmaceutically acceptable additives.
  • the pharmaceutical composition may be used to manufacture oral solid dosage forms, such as tablets.
  • the obtained tablets may be further coated with Opadry®-type coatings and then packaged in standard pharmaceutical packaging like bottles or blisters.
  • the manufacture of the pharmaceutical compositions comprises blending Apremilast or a pharmaceutically acceptable salt or solvate thereof with at least one filler and at least one disintegrant and then using direct compression to obtain oral solid dosage forms.
  • the pharmaceutical compositions of the invention allow for an easy and straightforward manufacturing process using the minimum of resources, while achieving excellent dissolution behaviour for therapeutic applications and resulting in oral solid dosage forms that are durable due to a very low friability.
  • the pharmaceutical composition of the first aspect may comprise between 7 and 15 % by weight of Apremilast or a pharmaceutically acceptable salt or solvate thereof, in respect of the total weight of the pharmaceutical composition.
  • the pharmaceutical composition of the first aspect comprises between 8.5 and 12.5 % by weight of Apremilast or pharmaceutically acceptable salts or solvate thereof, in respect of the total weight of the pharmaceutical composition.
  • the amount of Apremilast is used in such quantities to obtain oral dosage forms that may contain 10 mg, 20 mg or 30 mg of Apremilast.
  • Apremilast may be used in any solid form.
  • amorphous or crystalline Apremilast may be employed in the composition.
  • crystalline Apremilast is used. Any solid crystalline form described in WO 2009120167 can be used here.
  • form B is used, wherein form B of Apremilast is characterized by XRPD peaks located at positions: 10.1 e , 12.4 e , 13.5 s , 15.7 s , 16.3 e , 18.1 s , 20.7 e , 22.5 e , 24.7 e , 26.2 e , 26.9 e , 29.1 s ⁇ 0.2 s 2-theta.
  • crystalline forms that can be used are the crystalline anisaldehyde solvate of Apremilast, the crystalline 3-phenylpropanaldehyde solvate of Apremilast, the crystalline 3- methyl-2-cyclohexenone solvate of Apremilast or the crystalline 6-methyl-5-hepten-2-one solvate of Apremilast.
  • the crystalline anisaldehyde solvate of Apremilast is characterised by an X-ray powder diffractogram comprising at least the peaks at diffraction 2-theta angle 7.40, 1 1.15 and 26.10° 20 ⁇ 0.2° 20.
  • the X-ray powder diffractogram comprises at least the peaks at diffraction 2-theta angle 7.40, 1 1.15, 26.10, 17.59 and 16.25° 20 ⁇ 0.2° 20.
  • the X-ray powder diffractogram comprises at least the peaks at diffraction 2- theta angles 7.40, 8.99, 9.58, 10.02, 1 1.15, 11.81 , 13.05, 13.62, 13.87, 15.15, 15.44, 16.25, 17.06, 17.59, 18.00, 19.00, 19.20, 20.09, 20.58, 21.21 , 21.82, 22.28, 22.58, 22.86, 23.25,
  • the crystalline 3-phenylpropanaldehyde solvate of Apremilast is characterised by an X-ray powder diffractogram comprising at least the peaks at diffraction 2-theta angle 7.31 , 11 .08, 25.96 and 11 .75° 20 ⁇ 0.2° 20.
  • X-ray powder diffractogram comprises at least the peaks at diffraction 2-theta angle 7.31 , 1 1.08, 25.96, 1 1.75, 16.14, 17.47 and 25.08° 20 ⁇ 0.2° 20.
  • the X-ray powder diffractogram comprises at least the peaks at diffraction 2-theta angles 7.31 , 8.91 , 9.49, 9.93, 11.08, 11.75, 12.96, 13.55, 13.76, 15.04, 15.33, 16.14, 17.47, 17.90, 18.92, 19.10, 19.96, 20.44, 21.10, 21.74, 22.14, 22.45, 22.78,
  • the crystalline 3-methyl-2-cyclohexenone solvate of Apremilast is characterised by an X- ray powder diffractogram comprising at least the peaks at diffraction 2-theta angle 7.41 , 1 1 .17, 26.16 and 17.61 ° 20 ⁇ 0.2° 20.
  • the X-ray powder diffractogram comprises at least the peaks at diffraction 2-theta angle 7.41 , 11.17, 26.16, 17.61 , 22.33, 24.60, 21.21 , 16.29, 25.29 and 23.30° 20 ⁇ 0.2° 20.
  • the X-ray powder diffractogram comprises at least the peaks at diffraction 2-theta angles 7.41 , 9.00, 9.60, 10.04, 1 1.16, 1 1.82, 13.07, 13.63, 13.90, 15.19, 15.47, 16.29, 17.61 , 18.02, 19.02, 19.24, 20.13, 20.62,
  • the crystalline 6-methyl-5-hepten-2-one solvate of Apremilast is characterised by an X-ray powder diffractogram comprising at least the peaks at diffraction 2-theta angle 11 .25, 7.40, 26.10, 17.61 and 17.80° 20 ⁇ 0.2° 20.
  • the X-ray powder diffractogram comprising at least the peaks at diffraction 2-theta angle 1 1.25, 7.40, 26.10, 11.99, 16.27, 17.61 and 17.80° 20 ⁇ 0.2° 20.
  • the X-ray powder diffractogram comprises at least the peaks at diffraction 2-theta angles 7.40, 9.04, 9.56, 10.02, 11.25, 1 1.99, 13.13, 13.85, 15.12, 16.27, 16.46, 17.61 , 17.80, 18.09, 19.15, 20.08, 20.55, 21.19, 21.35, 22.09, 22.27,
  • the solvent for forming the solvate selected from the group consisting of anisaldehyde, 3-phenylpropanaldehyde, 3-methyl-2-cyclohexenone or 6- methyl-5-hepten-2-one,
  • step (3) optionally, heating the mixture of step (2) at a temperature of from 50 to 85 e C, and
  • form B of Apremilast may be used in step 1 ).
  • Suitable solvents used in step 1 may be an organic solvent selected from a ketone solvent, an ester solvent, an ether solvent, a hydrocarbon solvent and/or water or mixtures thereof.
  • Suitable ketone solvent may be selected from acetone, methyl ethyl ketone or 2-butanone, methyl isobutyl ketone, cyclohexanone, cyclopentanone and 3-pentanone or mixtures thereof.
  • Suitable ester solvent may be selected from ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate and ethyl malonate or mixtures thereof.
  • Suitable ether solvent may be selected from diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran and 1 ,4-dioxane or mixtures thereof.
  • Suitable hydrocarbon solvent may be selected from n-pentane, n-hexane, n- heptane, n-octane, cyclohexane and methylcyclohexane or mixtures thereof.
  • the solvent used in step 1 ) is an organic solvent selected from a ketone solvent, a hydrocarbon solvent and/or water. More preferably, the solvent of step 1 ) is acetone, cyclohexane and/or water.
  • the amount of either anisaldehyde, 3-phenylpropanaldehyde, 3-methyl-2-cyclohexenone or 6-methyl-5-hepten-2-one used in step 2) may be of from 0.1 to 5.0 (v/v), preferably of from 0.1 to 4.0 (v/v), more preferably of from 0.1 to 3.0 (v/v), and even more preferably of from 0.1 to 2.0 (v/v) with respect to the solvent used in step 1 ).
  • the Apremilast is used with a specific particle size distribution (PSD), specifically D90 from about 10 to 50 pm.
  • PSD particle size distribution
  • the PSD may have influence in the dissolution of Apremilast and thus may be controlled.
  • the particle size distribution D90 ranges from about 10 to 40 pm, more preferably from about 12 to 35 pm, and even more preferably from 14 to 30 pm.
  • Apremilast has a PSD D90 of 15 pm.
  • Apremilast has a PSD D90 of 28 pm.
  • PSD D90 is lower than 10 pm, the release may be too fast, whereas when the PSD D90 is more than 50 pm, the release may be too slow.
  • particle size refers to the size of the particles measured in pm. The measurement was performed with an appropriate apparatus by conventional analytical techniques such as laser diffraction. In the present invention the particle size was measured by a Mastersizer 3000 particle size analyzer. Such apparatus uses a technique of laser diffraction to measure the size of particles. It operates by measuring the intensity of light scattered, as a laser beam passes through a dispersed particles sample. This data is then analyzed using the general-purpose model to calculate the size of the particles that created the scattering pattern, assuming a spherical particle shape.
  • particle size distribution or “PSD” have the same meaning and are used interchangeably. They refer to the percentage of the particles within a certain size range.
  • D90 refers to the value of particle size distribution where at least 90% of the particles have a size less or equal to the given value.
  • a particle size distribution D90 from about 10 to 50 pm means that 90% of the particles of Apremilast have a size less or equal to the given value within the range from about 10 to 50 pm.
  • the pharmaceutical composition as herein disclosed comprises at least one or more fillers.
  • the total amount of filler or fillers present in the pharmaceutical composition ranges from 60 % to 93 % by weight in respect of the total amount of the pharmaceutical composition. More preferably, the total amount of filler or fillers present in the pharmaceutical composition ranges from 70 % to 90 % by weight in respect of the total amount of the pharmaceutical composition. Even more preferably, the total amount of filler or fillers present in the pharmaceutical composition ranges from 80 % to 88 % by weight in respect of the total amount of the pharmaceutical composition.
  • filler refers to pharmaceutically acceptable excipients which are added to the bulk volume of the active agent making up the solid composition.
  • said pharmaceutical composition comprises at least one filler wherein said filler may be selected from the group comprising or consisting of microcrystalline cellulose, lactose, powdered cellulose, dibasic calcium phosphate, tribasic calcium phosphate, starch, pregelatinized starch, dextrose, mannitol, sucrose and sorbitol or any combination thereof.
  • the lactose may be lactose monohydrate, anhydrous lactose and combinations thereof.
  • anhydrous lactose is used.
  • the filler is a combination of microcrystalline cellulose and lactose. In another preferred embodiment, the filler is microcrystalline cellulose. In a more preferred embodiment, the filler does not comprise any lactose and is thus lactose-free. Lactose-free formulations avoid possible gastrointestinal disorders resulting from lactose intolerance. These alterations are becoming more common among the population and avoiding this excipient prevents any intolerance issues and allows its use for any kind of patients.
  • lubricant means a substance that reduces friction between the composition of the present invention and the surfaces of the apparatus used to compact the composition into a compressed form.
  • said pharmaceutical composition comprises at least one lubricant.
  • the total amount of lubricant or lubricants present in the pharmaceutical composition ranges from 0.1 to 2 % by weight in respect of the total amount of the pharmaceutical composition. More preferably, the total amount of lubricant or lubricants present in the pharmaceutical composition ranges from 0.5 to 1 .5 % by weight in respect of the total amount of the pharmaceutical composition.
  • the total amount of lubricant or lubricants present in the pharmaceutical composition ranges from 0.5 to 1 % by weight in respect of the total amount of the pharmaceutical composition.
  • said pharmaceutical composition comprises at least one lubricant selected from stearic acid, magnesium stearate, polyethylene glycol, sodium stearyl fumarate, sodium benzoate and mixtures thereof.
  • the pharmaceutical composition comprises at least one lubricant selected from magnesium stearate, stearic acid, sodium stearyl fumarate or mixtures thereof, more preferably the pharmaceutical composition comprises magnesium stearate.
  • disintegrant means a substance or a mixture of substances added to a tablet to facilitate its breakup or disintegration after administration.
  • the pharmaceutical composition as herein disclosed comprises at least one disintegrant.
  • the total amount of disintegrant or disintegrants present in the pharmaceutical composition ranges from 1 to 10 % by weight in respect of the total amount of the pharmaceutical composition. More preferably, the total amount of disintegrant or disintegrants present in the pharmaceutical composition ranges from 2 to 7 % by weight in respect of the total amount of the pharmaceutical composition. Even more preferably, the total amount of disintegrant or disintegrants present in the pharmaceutical composition ranges from 3 to 5 % by weight in respect of the total amount of the pharmaceutical composition.
  • the use of a disintegrant in a formulation helps to the proper dissolution of the tablet, making the Apremilast more easily available for the absorption in the gastrointestinal tract.
  • said pharmaceutical composition comprises at least one disintegrant selected from water- soluble disintegrants, such as starch, pregelatinized starch, sodium carboxymethyl cellulose, croscarmellose sodium, crosslinked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose and mixtures thereof.
  • the pharmaceutical composition comprises croscarmellose sodium.
  • glidant means a substance which improves the flow characteristics of powder mixtures in the dry state.
  • said pharmaceutical composition comprises at least one glidant.
  • the total amount of glidant or glidants present in the pharmaceutical composition ranges from 0.1 to 2.0 % by weight in respect of the total amount of the pharmaceutical composition. More preferably, the total amount of glidant or glidants present in the pharmaceutical composition ranges from 0.2 to 1 .0 % by weight in respect of the total amount of the pharmaceutical composition. Even more preferably, the total amount of glidant or glidants present in the pharmaceutical composition ranges from 0.3 to 0.8 % by weight in respect of the total amount of the pharmaceutical composition.
  • said pharmaceutical composition comprises at least one glidant selected from the group consisting of colloidal silicon dioxide, talc, starch, starch derivatives, and mixtures thereof.
  • the pharmaceutical composition comprises colloidal silicon dioxide.
  • Another aspect of the invention refers to a process for the preparation of the compositions of the invention in the form of tablets.
  • the process for the preparation of the tablets of the present invention comprises: a) preparing a pre-mixture comprising Apremilast or a pharmaceutically acceptable salt or solvate thereof, a first part of the filler, disintegrant, and glidant; b) mixing the pre-mixture obtained in step a) with the remaining part of the filler; c) adding the lubricant to the mixture obtained in step b); d) compressing the mixture obtained in step c) to form tablets; and e) optionally, coating the tablets obtained in step d).
  • the addition of the filler in step a) is done in two steps, meaning that first about of 10-20% of the total amount of the filler is added first, then Apremilast, disintegrant and glidant are added and finally about another 10-20% of the total amount of the filler is added and then altogether is homogenized to obtain the pre-mixture.
  • step b) is carried out by adding a third part of the filler first, then mixing this with the obtained pre-mixture of step a) and then adding a fourth part of the filler. The so obtained blend is then homogenized.
  • the pre-mixture obtained in step a) as well as the third and fourth parts of the filler needed in step b) may each be sieved using a sieve having a sieve diameter from 750 to 1250 pm.
  • the lubricant before adding it to the manufacturing process may be sieved using a sieve having a sieve diameter from 225 to 275 pm.
  • the filler in this process is added in different portions as explained above, in order to ensure the homogenization of the mixtures during pre-blending and blending steps. Otherwise, a loss of uniformity may be observed.
  • the first filler is added in form of the first part and the second part while the second filler is added as the third part and the fourth part.
  • the second filler is added as the third part and the fourth part.
  • the composition mentioned herein is other than a combination of Apremilast and anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica and gelatin.
  • polyvinylpyrrolidone is not desired, since it is known to undergo degradation more easily due to the high content of peroxides and this will affect eventually the oral solid dosage forms with respect to purity, dissolution behaviour and other aspects.
  • the pharmaceutical composition of the present invention may be used to manufacture oral solid dosage forms such as tablets. The resulting tablets may then be stored in bulk or packaged into standard containers in the pharmaceutical industry, such as bottles, sachets or blisters.
  • Known blisters comprise materials such as Alu/Alu (aluminium/aluminium), PVC/Alu (Polyvinylchloride/aluminium), PVC/PCTFE/Alu (Polyvinylchloride/ Polychlorotrifluoroethylene/aluminium), Polyamide/Alu/PVC-Alu (Polyamide/Aluminium/Polyvinyl chloride-aluminium) or PVC/PVDC/Alu (Polyvinylchloride/ Polyvinylidene chloride/aluminium).
  • Bottles may be made, without limitations, from glass, or plastic material, for example HDPE (High-density polyethylene), LDPE (Low-density polyethylene), or PET (Polyethylene terephthalate).
  • Composition comprising 30 mg Apremilast and tablet preparation.
  • the tablets were film-coated using Opadry.
  • the resulting tablets were submitted to a dissolution test according to the USP II dissolution test (paddle) at pH 6.8 with 0.15% of a lauryl sulfate solution and at rotation speed of 60 rpm. Testing 4 samples, the following average dissolution values, in percentage, at defined time points were obtained and compared to the dissolution profile of the reference product Otezla®. These results show an excellent dissolution profile compared to the innovator product.
  • Composition comprising 30 mg Apremilast and tablet preparation.
  • Example 2 was prepared following the procedure applied in example 1 , the differences being the particle size of Apremilast, and the quantity of disintegrant, in this example 1% more, compensated with 1% less of the diluent.
  • the resulting tablets were submitted to a dissolution test according to the USP II dissolution test (paddle) at pH 6.8 with 0.15% of a lauryl sulfate solution and at rotation speed of 60 rpm. Testing 4 samples, the following average dissolution values, in percentage, at defined time points were obtained and compared to the dissolution profile of the reference product Otezla®
  • Composition comprising 30 mg Apremilast and tablet preparation.
  • Example 3 was prepared following the procedure applied in example 1 , the differences being the particle size of Apremilast, and the quantity of disintegrant, in this example 1% more, compensated with 1% less of the diluent.
  • Composition comprising 30 mg Apremilast and tablet preparation.
  • Example 4 was prepared like example 1 , adding the two fillers microcrystalline cellulose and anhydrous lactose in 4 parts.
  • Example 5 was prepared like example 4. The obtained mixture was then compressed with 3 rounded punches resulting in tablets having a friability under 0.5% showing that there is a very low tendency of the obtained tablets to break under duress or contact. The resulting tablets were submitted to a dissolution test according to the USP II dissolution test (paddle) at pH 6.8 with 0.15% of a lauryl sulfate solution and at rotation speed of 60 rpm. Testing 4 samples, the following average dissolution values, in percentage, at defined time points were obtained and compared to the dissolution profile of the reference product Otezla®
  • the product was characterized by PXRD as it can be seen in figure 1 .
  • the product was characterized by PXRD as it can be seen in figure 4.
  • Example 10 Preparation of a 3-phenylpropanaldehyde solvate of Apremilast in acetone
  • Apremilast (5 g, 10.86 mmol) and acetone (10 mL) were charged into a 50 mL round-bottom flask, and the resulting mixture was stirred at room temperature for 1 hour.
  • 3- phenylpropanaldehyde (3 mL) was added and the resulting mixture was stirred at reflux temperature for 3 hours, cooled down to room temperature for 24 hours and then to 0-5 e C and stirred for 2 hours at 0-5 e C.
  • the solid obtained was filtered off, washed with acetone and dried under vacuum at 45-50°C until constant weight. Yield: 63%.
  • Particle Type Non-spherical
  • Sample preparation the powder samples were sandwiched between films of polyester of 3.6 microns of thickness.
  • Powder diffraction pattern were acquired on a Broker D8 Advance Series 2Theta/Theta powder diffraction system using CuKal -radiation in transmission geometry.
  • the system is equipped with a VANTEC-1 single photon counting PSD, a Germanium monochromator, a ninety positions auto-changer sample stage, fixed divergence slits and a radial soller.
  • the samples were measured in a range from 4 to 40 e in 20 in a 1 hour measurement using an angular step of 0.026 e and a time per step of 300 s.

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  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Inorganic Chemistry (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une composition pharmaceutique comprenant l'aprémilast ou des sels pharmaceutiquement acceptables de celui-ci, au moins une charge et au moins un délitant, le principe actif ayant une distribution dimensionnelle en volume des tailles de particules de diamètre D90 comprise entre 10 et 50 µm. L'invention concerne également un procédé de fabrication d'une composition pharmaceutique selon l'une quelconque des revendications précédentes, comprenant les étapes suivantes consistant à : a) préparer un prémélange comprenant l'aprémilast ou un sel pharmaceutiquement acceptable de celui-ci, une première partie de la charge, un délitant et un glissant ; b) mélanger le prémélange obtenu à l'étape (a) avec la partie restante de la charge ; c) ajouter le lubrifiant au mélange obtenu à l'étape (b) ; d) comprimer le mélange obtenu à l'étape (c) pour former des comprimés ; et e) facultativement, enrober les comprimés obtenus à l'étape (d). Ladite composition est destinée à être utilisée dans le traitement du psoriasis, de l'arthrite psoriasique ou des aphtes buccaux associés à la maladie de Behçet.
PCT/EP2022/086847 2021-12-22 2022-12-20 Compositions pharmaceutiques comprenant l'aprémilast Ceased WO2023118043A1 (fr)

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EP21383189 2021-12-22
EP21383189.4 2021-12-22

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Citations (10)

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WO2007079182A1 (fr) 2005-12-29 2007-07-12 Celgene Corporation Procede pour le traitement de lupus cutane mettant en oeuvre des composes a base d'aminoisoindoline
WO2009120167A1 (fr) 2008-03-27 2009-10-01 Celgene Corporation Formes solides comprenant de la (+)-2-[1-(3-éthoxy-4-méthoxyphényl)-2-méthylsulfonyléthyl]-4-acétylaminoisoindoline-1,3-dione, leurs compositions, et utilisations associées
WO2013101810A1 (fr) 2011-12-27 2013-07-04 Celgene Corporation Formulations de (+)-2-[1-(3-éthoxy-4-méthoxy-phényl)-2-méthanesulfonyl-éthyl]-4-acétylaminoisoindoline-1,3-dione
WO2013119607A2 (fr) * 2012-02-08 2013-08-15 Celgene Corporation Formulations à libération modifiée à base de (+)-2-[1-(3-éthoxy-4-méthoxy-phényl)-2-méthanesulfonyl-éthyl]-4-acétyl aminoisoindoline-1,3-dione
CN104892486A (zh) * 2015-06-25 2015-09-09 济南纽华医药科技有限公司 阿普斯特的新晶型及其制备方法
WO2017118447A1 (fr) * 2016-01-06 2017-07-13 Zentiva, K.S. Procédé de préparation d'aprémilast amorphe
AU2015385707A1 (en) * 2014-11-24 2017-08-24 Junzhi Luo Stable apremilast crystal form II free of solvates, and preparation method therefor
WO2019073477A1 (fr) * 2017-10-10 2019-04-18 Mankind Pharma Ltd. Composition pharmaceutique d'aprémilast à libération prolongée
WO2019073331A2 (fr) 2017-10-13 2019-04-18 Unichem Laboratories Ltd Compositions pharmaceutiques d'aprémilast
EP2651400B1 (fr) * 2010-12-16 2019-08-07 Celgene Corporation Formes posologiques pour des médicaments peu solubles administrés par voie orale à libération contrôlée et leurs utilisations

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007079182A1 (fr) 2005-12-29 2007-07-12 Celgene Corporation Procede pour le traitement de lupus cutane mettant en oeuvre des composes a base d'aminoisoindoline
WO2009120167A1 (fr) 2008-03-27 2009-10-01 Celgene Corporation Formes solides comprenant de la (+)-2-[1-(3-éthoxy-4-méthoxyphényl)-2-méthylsulfonyléthyl]-4-acétylaminoisoindoline-1,3-dione, leurs compositions, et utilisations associées
EP2695616A1 (fr) * 2008-03-27 2014-02-12 Celgene Corporation Formes solides comprenant de la (+)-2-[1-(3-éthoxy-4-méthoxyphényl)-2-méthylsulfonyléthyl]-4-acétylaminoisoindoline-1,3-dione, leurs compositions, et utilisations associées
EP2651400B1 (fr) * 2010-12-16 2019-08-07 Celgene Corporation Formes posologiques pour des médicaments peu solubles administrés par voie orale à libération contrôlée et leurs utilisations
WO2013101810A1 (fr) 2011-12-27 2013-07-04 Celgene Corporation Formulations de (+)-2-[1-(3-éthoxy-4-méthoxy-phényl)-2-méthanesulfonyl-éthyl]-4-acétylaminoisoindoline-1,3-dione
WO2013119607A2 (fr) * 2012-02-08 2013-08-15 Celgene Corporation Formulations à libération modifiée à base de (+)-2-[1-(3-éthoxy-4-méthoxy-phényl)-2-méthanesulfonyl-éthyl]-4-acétyl aminoisoindoline-1,3-dione
AU2015385707A1 (en) * 2014-11-24 2017-08-24 Junzhi Luo Stable apremilast crystal form II free of solvates, and preparation method therefor
CN104892486A (zh) * 2015-06-25 2015-09-09 济南纽华医药科技有限公司 阿普斯特的新晶型及其制备方法
WO2017118447A1 (fr) * 2016-01-06 2017-07-13 Zentiva, K.S. Procédé de préparation d'aprémilast amorphe
WO2019073477A1 (fr) * 2017-10-10 2019-04-18 Mankind Pharma Ltd. Composition pharmaceutique d'aprémilast à libération prolongée
WO2019073331A2 (fr) 2017-10-13 2019-04-18 Unichem Laboratories Ltd Compositions pharmaceutiques d'aprémilast

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