WO2011069608A1 - S-lénalidomide, ses formes polymorphes et mélange comprenant du s- et r-lénalidomide - Google Patents

S-lénalidomide, ses formes polymorphes et mélange comprenant du s- et r-lénalidomide Download PDF

Info

Publication number
WO2011069608A1
WO2011069608A1 PCT/EP2010/007228 EP2010007228W WO2011069608A1 WO 2011069608 A1 WO2011069608 A1 WO 2011069608A1 EP 2010007228 W EP2010007228 W EP 2010007228W WO 2011069608 A1 WO2011069608 A1 WO 2011069608A1
Authority
WO
WIPO (PCT)
Prior art keywords
lenalidomide
blend
xrpd
theta
characteristic peaks
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/EP2010/007228
Other languages
English (en)
Inventor
Hans-Guenter Striegel
Wolfgang Albrecht
Sandra Brueck
Konstantin Holfinger
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.)
Ratiopharm GmbH
Original Assignee
Ratiopharm GmbH
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 Ratiopharm GmbH filed Critical Ratiopharm GmbH
Publication of WO2011069608A1 publication Critical patent/WO2011069608A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention concerns a process for producing S-lenalidomide and polymorphic Forms A and B of S-lenalidomide obtainable by said process. Additionally, the present invention concerns a blend comprising S- lenalidomide and R-lenalidomide. Furthermore, the present invention relates to oral dosage forms comprising polymorphic Forms A and B of S-lenalidomide or a blend comprising S-lenalidomide and R-lenalidomide.
  • lenalidomide In vitro, lenalidomide induces tumour cell apoptosis directly and indirectly by inhibition of bone marrow stromal cell support, by anti-angiogenic and anti- osteoclastogenic effects, and by immunomodulatory activity. Thus, lenalidomide has a broad range of activities that can be exploited in order to treat many hematologic and solid cancers.
  • Racemic lenalidomide is marketed under the trade name Revlimid®.
  • racemic lenalidomide has some undesirable properties. For example, recrystallization and micronization is necessary in order to ensure blend and content uniformity in pharmaceutical dosage forms, see EMEA, Scientific Discussion of Revlimid ® , 2007.
  • micronization entails a number of drawbacks.
  • the micronization of a pharmaceutically active compound often results in a low flowability or pourability of the product formulation.
  • the enlargement of the outer surface area due to micronization increases the susceptibility of the substance towards oxidation. Therefore, a micronized agent is more likely to degrade over time.
  • lenalidomide in a form that provides a good flowability and pourability, a superior oxidation stability, as well as a superior storage stability and shelf-life.
  • the number and severity of the side effects, caused by the pharmaceutical dosage forms are reduced to a minimum, especially taking specific population intolerances towards any of the substances contained therein into account.
  • the dosage forms of the present invention should show a superior content uniformity.
  • the formulation should exhibit superior dissolution properties and good bioavailability (in particular before as well as after storage), especially with regard to bioequivalence to established formulations containing racemic lenalidomide on the market.
  • the formulation should release the active pharmaceutical ingredient completely.
  • the polymorphic forms of S-lenalidomide enable the preparation of dosage forms having advantageous properties. Moreover, the inventors unexpectedly have found that a blend of S-lenalidomide with R- lenalidomide has superior properties when compared to racemic lenalidomide known from prior art.
  • a first subject of the present invention is a process for producing S-lenalidomide according to formula I
  • step (iii) isolating S-lenalidomide, wherein preferably in step (ii) 55 to 95 % of the compound according to formula II are hydrogenated.
  • a further subject of the present invention is S-lenalidomide in
  • polymorphic Form B wherein an XRPD shows characteristic peaks at 8.03 °, 1 1.76 °, 17.46 ° and 18.84 0 2-Theta or
  • polymorphic Form A wherein an XRPD shows characteristic peaks at 1 1 .73 °, 15.76 °, 18.80 ° and 24.73 ° 2-Theta.
  • S-lenalidomide in polymorphic Forms A and/or B for producing a pharmaceutical dosage form and a pharmaceutical dosage form comprising said polymorphic forms of S- lenalidomide.
  • Still a further subject of the present invention is a blend comprising S- lenalidomide and R-lenalidomide.
  • a subject of the present invention is a blend comprising
  • polymorphic Form A wherein an XRPD shows characteristic peaks at 1 1 .73 °
  • Form B of S-lenalidomide is preferred.
  • R-lenalidomide in polymorphic Form B is R-lenalidomide in polymorphic Form B, wherein an XRPD shows characteristic peaks at 8.04°, 16. 16 °, 17.308 ° and 24.35 ° 2-Theta.
  • a further subject of the present invention is a process for producing S-lenalidomide comprising the steps (i) to (iii), wherein steps (i) to (iii) are explained in more detail below.
  • step (i) the compound according to formula II is provided. Said compound is known from prior art.
  • step (ii) the compound is hydrogenated, i.e. the nitro group is reduced to give an amino group.
  • Suitable reducing agents might be NaBH 4 , LiBH 4 , KBH 4 , NaCNBH 3 , Na(AcO) 3 BH, L- Selectride ® , K-Selectride ® , N-Selectride ® , benzyltriethylammonium borohydri- de, lithium dimethylaminoborohydride, lithium morpholinoborohydride, lithium pyrrolidinoborohydride, lithium triethylborohydride, potassium triethylborohydride, potassium triphenylborohydride, sodium triethylborohydride, sodium trimethoxyborohydride, tetrabutylammonium borohydride, tetrabutylammonium cyanoborohydride, tetramethylammonium borohydride, or tetramethylammonium triacetoxyborohydride.
  • Hydrogenation with complex hydrides with hydrazine, ammonium formiate, or hydrocarbons as hydrogen donors are carried out in the presence of metals, especially noble metals from the platinum group (platinum, palladium, rhodium, ruthenium), transition metals of the iron group and/or titanium, tin, zinc and copper.
  • metals especially noble metals from the platinum group (platinum, palladium, rhodium, ruthenium), transition metals of the iron group and/or titanium, tin, zinc and copper.
  • Those metals can be used either pure (iron, cobalt and nickel), or alloyed (Raney nickel or nickel boride).
  • the hydrogenation is carried out by employing a palladium catalyst, preferably palladium on charcoal (Pd/C) in the presence of hydrogen gas.
  • a palladium catalyst preferably palladium on charcoal (Pd/C) in the presence of hydrogen gas.
  • the weight ratio of palladium: the compound according to formula (II) is 0.03 to 0. 15, more preferably from 0.05 to 0.010.
  • the term "palladium” refers in this context to the amount of palladium as such, not to the amount of palladium including the weight of the charcoal carrier.
  • Hydrogen can be applied with a pressure ranging from 1 to 10 bar, preferably from 2.5 to 4.0 bar.
  • the reaction of the compound according to formula (II) with the hydrogenating agent may be carried out in usual organic solvents and at usual temperatures. Usually the reaction is carried out at temperatures between - 50 °C and 50 °C, preferably between 10 °C and 35 °C.
  • the reaction time can range from 0.1 to 20 hours, preferably from 3 to 6 hours.
  • step (ii) the compound according to formula II is partially hydrogenated.
  • hydrogenation conditions are chosen such that 55 % to 99 % , more preferably 70 % to 95 % , particularly 75 % to 90 % of the compound according to formula II is hydrogenated.
  • "%" refers to "mol %”.
  • step (ii) the compound according to formula II is essentially completely hydrogenated. That means, preferably, hydrogenation conditions are chosen such that about 100 % of the compound according to formula II is hydrogenated.
  • the catalyst used in step (ii) can be recycled.
  • solvents suitable for the use in steps (i), (ii) and/or (iii) generally are polar organic solvents.
  • the permittivity of a substance is a characteristic, which describes how it affects any electric field set up in it. A high permittivity tends to reduce any electric field present.
  • the capacitance of a capacitor can be increased by increasing the permittivity of the dielectric material.
  • the permittivity of free space (or a vacuum), ⁇ 0 , has a value of 8.9 x 10 '12 F m '1 .
  • the permittivity of a material is usually given relative to that of free space, which is known as relative permittivity, ⁇ ⁇ .
  • suitable organic solvents might be selected from water, C2-C6 alcohol, C3-C6 ketone, C 1 -C4 carboxylic acids, C 1 -C6 carboxylic acid dialkylamides, C2-C6 sulfoxides and C2-C6 sulfons, C2-C4 nitriles, low polymerized liquid ethylene and propylene glycol ethers and mixtures thereof. Methanol is preferred.
  • Methanol is preferred.
  • S-lenalidomide can be obtained from the filtered reaction mixture by volume reduction through evaporation of volatile solvent amounts.
  • purification of S-lenalidomide obtainable by step (iii) can be performed by the use of solvent/ antisolvent systems.
  • Solvents suitable for the use as a "solvent" component are generally those described for step (iii).
  • Suitable organic solvents for the use as a "non solvent” component might be selected from a C5-C9 aliphatic or aromatic hydrocarbon, optionally substituted e.g. with halogen, a C3 -C6 ester, a C2-C6 ether, C2-C4 nitriles, and mixtures thereof. Ethyl acetate is preferred.
  • Solvents suitable for the use in step (iv) generally are non- or slight-polar organic solvents.
  • suitable organic solvents for the use in optional step (iv) might be selected from a C5 -C9 aliphatic or aromatic hydrocarbon, optionally substituted e.g. with halogen, a C3-C6 ester, a C2-C6 ether, C2 -C4 nitriles, and mixtures thereof. Ethyl acetate is preferred.
  • different forms of S-lenalidomide can be obtained.
  • S-lenalidomide in polymorphic Form B is obtained.
  • S-lenalidomide is produced by the process of the present invention, it can be obtained in amorphous or different crystallinic forms.
  • S-lenalidomide can be obtained in at least two polymorphic forms, namely polymorphic Form A and polymorphic Form B.
  • S-lenalidomide is obtained in polymorphic Form A, wherein Form A is characterized by an X-Ray powder diffraction (hereinafter referred to as XRPD) showing characteristic peaks at 1 1 .73 °, 15.76 °, 18.80 °, and 24.73 ° 2-Theta. Further characteristic peaks can be found at 19.38 °, 25.44 ° , 26.68 °, 27.91 ° and/ or 31 .90 ° 2-Theta. Generally, the XRPD measurements are carried out as outlined below in the experimental section. Generally, in all XRPD measurements the margin of error is approximately 0.2 °.
  • FIG. 1 An XRPD of Form A of S-lenalidomide according to the present invention is shown in Figure 1 .
  • S-lenalidomide is obtained in polymorphic Form B .
  • Form B of S-lenalidomide is characterized by an X-Ray powder diffraction showing characteristic peaks at 8.03 °, 1 1 .75 °, 1 7.46 ° and 18.84 ° 2-Theta. Further characteristic peaks can be found at 15.8 ° , 18.62 °, 19.25 °, 23.98 °, 24.30 °, 24.78 °, 25.32 ° and /or 26.82 ° 2-Theta.
  • S-lenalidomide according to the present invention is present in particulate form .
  • the D 50 -value of the particle size distribution of the particulate S-lenalidomide ranges from 0. 1 to 200 ⁇ , more preferably from 2.0 to 120 ⁇ , further more preferably from 15 to 75 ⁇ , most preferably from 15 to 75 ⁇ .
  • S-lenalidomide according to the present invention has a D 90 -value of the particle size distribution of 5 to 500 ⁇ , more preferably of 50 to 350 ⁇ , further more preferably of 80 to 250 /im, most preferably of 120 to 190 ⁇ .
  • S-lenalidomide according to the present invention has a D 10 -value of the particle size distribution of 0. 1 to 30 ⁇ , more preferably of 0.5 to 90 ⁇ , further more preferably of 1 .0 to 15 ⁇ , most preferably of 2.0 to 10 ⁇ .
  • the volume mean particle size (D 50 ) is determined by the light scattering method, using a Mastersizer 2000 apparatus made by Malvern Instruments (wet measurement, 2000 rpm, ultrasonic waves for 60 sec , data interpretation via Fraunhofer method).
  • the D 50 -value of the particle size distribution of a particulate compound is generally defined as the particle size, where 50 vol. -% of the particles have a smaller particle size than the particle size which corresponds to the D 50 -value.
  • the D 90 -value of the particle size distribution of a particulate compound generally is defined as the particle size, where 90 vol. -% of the particles have a smaller particle size than the particle size which corresponds to the D 90 -value.
  • the D 10 -value of the particle size distribution of a particulate compound is generally defined as the particle size, where 10 vol. -% of the particles have a smaller particle size than the particle size which corresponds to the D evalue.
  • a blend comprising S-lenalidomide according to the present invention (i.e. preferably S-lenalidomide in polymorphic Forms A and /or B) and R-lenalidomide.
  • R-lenalidomide can be prepared according to Example 16 of EP 0 925 294 B l , wherein (R)-3 -( 1 -oxo-4-nitroisoindolin-2-yl)piperidine-2 ,6-dione is used as precursor (which is obtainable by using t-butyl N-( l -oxo-4- nitroisoindolin-2-yl)-R-glutamine as corresponding starting material.
  • S and R-lenalidomide were prepared by preparative enantiomer separation using chiral chromatography, preferable as described in Example 5.
  • R-lenalidomide is produced as described below in Example 3.
  • R-lenalidomide is obtained in polymorphic Form B.
  • Form B of R-lenalidomide is characterized by an X-Ray powder diffraction showing characteristic peaks at 8.04°, 16.16 °, 17.308 0 and 24.35 ° 2-Theta. Further characteristic peaks can be found at 17.50°, 18.67 °, 19.29 °, 24.03 °, 25.36 ° and/or 26.96 ° 2-Theta. Further peaks can be found in Example 3.
  • An XRPD of Form B of R-lenalidomide according to the present invention is shown in Figure 4.
  • a subject of this second aspect of the present invention is a blend comprising
  • R-lenalidomide preferably R-lenalidomide, in crystalline form.
  • the term "blend” hereby refers to a physical mixture of S-lenalidomide and R- lenalidomide. Within this application said physical mixture is also designated as "RS-Blend” .
  • the RS-blend is a mixture of two type of crystals, namely a mixture of crystalline R-lenalidomide and crystalline S-lenalidomide. It has been unexpectedly found that the RS-Blend has superior dissolution properties when compared with lenalidomide in form of the racemic compound.
  • racemic compound refers to a homogenous composition comprising R-lenalidomide and S-lenalidomide in equal amounts and in form of a single crystalline compound.
  • the blend according to the second aspect of the invention comprises a weight ratio of S-lenalidomide to R-lenalidomide of 10 : 1 to 1 : 10, more preferably from 5 : 1 to 1 : 5, much more preferably from 3 : 1 to 1 : 3, still more preferably from 2 : 1 to 1 : 2, most preferably of about 1 : 1 .
  • the XRPD of the RS-blend according to the second aspect of the invention shows characteristic peaks at 8.03°, 16. 12°, 17.00° and 22.44° 2- Theta. Further characteristic peaks can be found at 17.47°, 18.25 °, 21 .96°, 24.08 °, 25.32 0 and/ or 38.26° 2-Theta. Further peaks can be found in Example 4.
  • An XRPD of the RS-Blend according to the present invention is shown in Figure 5.
  • the RS-Blend of Example 4 is also designated as Lenalidomide RS-Blend Form I.
  • the RS-Blend comprises S-lenalidomide, preferably S-lenalidomide in polymorphic B, and R-lenalidomide, preferably in polymorphic Form B in particulate form.
  • the D 50 -value of the particle size distribution of the RS-Blend is from 0.1 to 200 ⁇ , more preferably from 2.0 to 120 ⁇ , still more preferably of from 5.0 to 90 ⁇ , most preferably of from 15 to 75 ⁇ .
  • the RS-Blend according to the present invention has a D 90 -value of the particle size distribution of 5 to 500 ⁇ , more preferably of 50 to 350 ⁇ , further more preferably of 80 to 250 ⁇ , most preferably of 120 to 190 ⁇ .
  • the RS-Blend according to the present invention has a D 10 -value of 0.1 to 30 ⁇ , more preferably of 0.5 to 20 ⁇ , further more preferably of 1.0 to 15 ⁇ , most preferably of 2.0 to 10 ⁇ .
  • the RS-Blend shows unexpected superior dissolution properties.
  • the RS-Blend shows a dissolution profile, wherein at least 95 wt. % of lenalidomide are dissolved within the first 10 minutes of a dissolution test according to USP Type II (paddle) at 37°C in 0.01 N HC1, pH 2.1 and 50 rpm.
  • the D 50 -value of the particle size distribution of the R-lenalidomide is from 0.1 to 200 ⁇ , more preferably from 2.0 to 120 ⁇ , further more preferably from 5.0 to 90 ⁇ , most preferably from 15 to 75 ⁇ .
  • R-lenalidomide Form B has a D 90 -value of the particle size distribution of 5 to 500 ⁇ , more preferably of 50 to 350 ⁇ , further more preferably of 80 to 250 ⁇ , most preferably of 120 to 190 ⁇ .
  • R-lenalidomide Form B has a D 10 -value of the particle size distribution of 0. 1 to 30 /im , more preferably of 0.5 to 20 /im , further more preferably of 1 .0 to 15 ⁇ , most preferably of 2.0 to 10 ⁇ ..
  • S-lenalidomide preferably in polymorphic Forms A and / or B
  • S-lenalidomide preferably in polymorphic Forms A and / or B
  • R-lenalidomide preferably in polymorphic Forms A and / or B
  • R-lenalidomide can be used for preparing a solid oral dosage form .
  • a further subject of the present invention is a pharmaceutical composition, preferably in form of a pharmaceutical dosage form.
  • Preferred dosage forms are tablets or capsules or sachets comprising the pharmaceutical composition in particulate form . Capsules are particularly preferred.
  • the present invention relates to a dosage form , preferably in form of a capsule , comprising
  • S-lenalidomide preferably in polymorphic Form A and / or B , or a blend comprising S-lenalidomide according to the present invention (i. e . preferably
  • fillers b) are used to top up the volume for an appropriate oral deliverable dose , when low concentrations of the active pharmaceutical ingredients (about 70 wt.% or lower) are present.
  • the active pharmaceutical ingredients about 70 wt.% or lower
  • Fillers are usually relatively chemically inert, but they can have an effect on the bioavailability of the active ingredient. They can influence the solubility of the active ingredient and enable a powder of an insoluble compound to break up more readily on capsule shell disintegration.
  • Typical state of the art formulations employ lactose as a filler.
  • Preferred fillers of the invention are calcium phosphate, saccharose , calcium carbonate, calcium silicate , magnesium carbonate , magnesium oxide , maltodextrin , calcium sulfate , dextran , dextrin , dextrose , hydrogenated vegetable oil and / or cellulose derivatives .
  • a pharmaceutical composition according to the invention may comprise an inorganic salt as a filler .
  • this inorganic salt is dicalcium phosphate , preferably in form of the dihydrate (dicafos).
  • Dicalcium phosphate dihydrate is insoluble in water, non-hygroscopic, but still hydrophilic. Surprisingly, this behavior contributes to a high storage stability of the composition. This is in contrast to e.g. lactose , which is readily soluble in water. Furthermore , lactose has the limitation that some people - about 75 % of the world population - have a more or less severe intolerance towards this compound and would therefore find drugs without this compound more agreeable on digestion. Therefore, a pharmaceutical composition comprising dicalcium phosphate dihydrate will not only enhance the storage stability of the resulting product, but will also offer an adequate treatment, which is suitable for lactose-intolerant people.
  • the pharmaceutical dosage form of the present invention is essentially free of lactose or derivatives thereof. This can be achieved by employing a filler, which does not comprise lactose or one of its derivatives.
  • the pharmaceutical composition further optionally comprises one or more solubilizers (c).
  • solubilizer means any organic excipient, which improves the solubility and dissolution of the active pharmaceutical ingredient.
  • the solubilizers are selected, for example, from the group of known inorganic or organic excipients.
  • the solubilizer is a hydrophilic polymer.
  • hydrophilic polymer encompasses polymers comprising polar groups.
  • the hydrophilic polymer usually has a weight average molecular weight ranging from 1 ,000 to 250,000 g/mol, preferably from 2,000 to 100,000 g/mol, particularly from 4,000 to 50,000 g/ mol. Furthermore, a 2 % w/w solution of the hydrophilic polymer in pure water preferably has a viscosity of from 2 to 8 mPas at 25 °C . The viscosity is determined according to the European Pharmacopoeia (hereinafter referred to as Ph. Eur. ), 6 th edition, chapter 2.2. 10.
  • the hydrophilic polymer used as solubilizer preferably has a glass transition temperature (T g ) or a melting point of 25 °C to 150 °C, more preferably of 40 °C to 100 °C .
  • T g glass transition temperature
  • the glass transition temperature, T g is the temperature at which the hydrophilic polymer becomes brittle on cooling and soft on heating. That means, above the T g , the hydrophilic polymers become soft and capable of plastic deformation without fracture.
  • the glass transition temperature or the melting point are determined with a Mettler-Toledo ® DSC 1 , wherein a heating rate of 10 °C per minute and a cooling rate of 15 °C per minute is applied.
  • hydrophilic polymers useful as solubilizer are derivatives of cellulose, hydrophilic derivatives of cellulose (microcrystalline cellulose, hydroxyproplymethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), preferably sodium or calcium salts thereof, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), polyvinylpyrrolidone, preferably having an average molecular weight of 10,000 to 60,000 g/mol, copolymers of polyvinylpyrrolidones, preferably copolymers comprising vinylpyrrolidone and vinylacetate units (e.g.
  • Povidon ® VA 64; BASF preferably having a weight average molecular weight of 40,000 to 70,000 g/mol, polyoxyethylene alkylethers, polyethylene glycol, co- blockpolymers of ethylene oxide and propylene oxide (Poloxamer, Pluronic ® ), derivates of methacrylates, polyvinyl alcohol and / or polyethylene glycols or derivatives thereof.
  • the weight average molecular weight is preferably determined by gel permeation chromatography.
  • sugar alcohols like isomalt, sorbitol, xylitol or mannitol can be used as solubilizers.
  • microcrystalline cellulose is used as solubilizer, more preferably microcrystalline cellulose having a moisture content of 3 to 5 % and a bulk density from 0.25 to 0.32 g/ cm 3 .
  • the pharmaceutical composition of this invention optionally further comprises a disintegrant (d), or a combination of more than one disintegrant compound.
  • a disintegrant is generally a compound that accelerates the disintegration of the orally deliverable dose unit - preferably a capsule or tablet - on contact with water.
  • Suitable disintegrants are polacrilin potassium, corn starch, microcrystalline cellulose, starch, pre-agglutinated starch, sodium carboxymethyl starch, sodium carboxymethyl cellulose, croscarmellose sodium and / or cross-linked polyvinylpyrrolidone (crospovidone).
  • so-called "superdisintegrants” are used. These include croscarmellose and more preferably crospovidone. Superdisintegrants either swell many-fold on absorbing water or act as wicks, thereby attracting water into the powder plug so as to disrupt the latter from the inside.
  • the disintegrant is an intragranular crospovidone such as Polyplasdone ® XL 10 or croscarmellose sodium (e.g. Ac-Di-Sol ® ).
  • the pharmaceutical composition preferably the pharmaceutical dosage form, may comprise one or more additional excipients as for example lubricant, glidant and / or anti-sticking agent.
  • a lubricant may be used.
  • Lubricants are generally employed to reduce dynamic friction.
  • the lubricant preferably is a stearate, talcum powder or fatty acid, more preferably, hexanedioic acid or an earth alkali metal stearate, such as magnesium stearate .
  • the lubricant is suitably present in an amount of 0. 1 to 3 wt.% , preferably about 0.5 to 1 .5 wt.% of the total weight of the composition.
  • the lubricant is applied in a final lubrication step during the powder preparation.
  • the lubricant generally increases the powder flowability.
  • the active ingredient (a) can be present in an amount of 0. 1 to 50 wt.% , preferably 0.5 to 20 wt.% , more preferably 2 to 15 wt.% , and particularly preferred between 3 and 10 wt.% , based on the total weight of the dosage form.
  • the dosage forms of the present invention may contain dosage amounts of 0. 1 - 50 mg, preferably 0.5 - 25 mg, more preferable 5 - 25 mg, e.g. 5 mg, 10 mg, 15 mg or 25 mg of the active pharmaceutical ingredient, based on the weight of lenalidomide in form of the free base.
  • the filler (b) can be present in an amount of 0 to 90 wt.% , preferably 10 to 85 wt.% , more preferably 15 to 80 wt.% , based on the total weight of the composition.
  • the solubilizer (c) can be present in an amount of 0 to 90 wt.% , preferably 10 to 85 wt.% , more preferably 15 to 80 wt.% , based on the total weight of the composition.
  • components (b) and (c) together are present in an amount of 50 to 99 wt.% , more preferably of 60 to 95 wt.% , still more preferably of 70 to 95 wt.% .
  • the disintegrant (d) is suitably present in an amount of 0 to 20 wt.% , more preferably at about 1 to 15 wt.% of the total weight of the composition.
  • the lubricant is suitably present in an amount of 0 to 2 wt.% , preferably about 0.5 to 1 .5 wt.% of the total weight of the composition.
  • the glidant agent is present in an amount of 0 to 8 wt.% , more preferably at 0. 1 to 3 wt.% of the total weight of the composition.
  • the anti-sticking agent may be present in amounts of 0 to 5 wt.% , more preferably in an amount of 0.5 to 3 wt.% of the total weight of the composition.
  • the total weight of the pharmaceutical composition or the pharmaceutical dosage form is the combined weight of the components present in the dosage form excluding, if applicable, the weight of any coating, capsule shell or sachet.
  • the pharmaceutical dosage form generally is produced by blending the above- mentioned ingredients and subsequently transferring the blend into the desired dosage form, e.g. by filling into capsules or sachets or by compressing into tablets.
  • the blending can be carried out in conventional blenders. Suitable examples are tumble blenders such as Turbula TC 10 B.
  • the inventive capsules display a high content uniformity.
  • these parameters indicate the relative deviation in the amount of content of the capsules.
  • the content uniformity is determined according to Ph. Eur. 6.0, chapter 2.9.40 and provided in terms of the acceptance value.
  • the latter parameter is calculated according to table 2.9.40. -2 , Ph. Eur. 6.0, and pages 328 and 329.
  • the maximum allowed acceptance value is 15.0 (Ph. Eur. 6.0).
  • the present invention provides acceptance values of 7.0 or lower, more preferably of 5.0 or lower, in particular, of 3.0 or lower.
  • compositions and formulations display a high storage stability, which is preferably higher than for previous formulations.
  • the storage stability is ascertained for at least 12 months at 40 °C and 75% humidity.
  • the incurred deterioration and / or impurities after this timespan are less than 2.5 wt.% .
  • the pharmaceutical dosage forms of the present invention comprise formulations showing "immediate release".
  • immediate release formulations having a Q value of not less than 75 % , preferably having a Q value from 80 % to 100 % , more preferably a Q value from 90 % to 100 % .
  • the Q value is determined as described in USP 32- NF 27 method II (paddle, chapter ⁇ 71 1 >). In case of tablets, these values refer to the uncoated tablet.
  • IR-spectrum V [cm 1 ] (intensity): 1661,9 (0,600), 1702,8 (0,513), 1195,3 (0,430), 1624,8 (0,335), 1322,3 (0,287), 1605,0 (0,275), 753,6 (0,277), 1175,0 (0,265), 3367,6 (0,260), 1265,3 (0,256), 1463,7 (0,231), 1353,8 (0,209), 1297,5 (0,202), 1425,3 (0,185), 3079,7 (0,184), 1494,6 (0,174), 810,0 (0,161), 3475,5 (0,138), 870,0 (0,133).
  • IR-spectrum v [cm 1 ] (intensity): 1662,3 (0,405), 1703,2 (0,360), 1195,6 (0,288), 1624,8 (0,235), 1605,1 (0,206), 1322,4 (0,199), 3367,5 (0,194), 753,7 (0,189), 1175,1 (0,187), 1265,4 (0,180), 1463,7 (0,165), 1353,8 (0,155), 1297,5 (0,148), 3078,1 (0,141), 1494,2 (0,137), 1425,1 (0,135), 810,1 (0,114), 3475,3 (0,112), 870,0 (0,0953) ST09030601-2 (09031602-3. dif)
  • reaction medium in the reactor was kept for a whole of 23 h under hydrogenation conditions. After that time a second IPC showed no more starting material and an amount of 80 %-87 % of product in the supernatant.
  • the reaction was stopped the reactor inertized and the reaction mixture was released from the reactor. This was filtered through filter paper covered with diatomaceous earth (40 g) on a Buchner funnel to remove catalyst. The clear, colorless filtrate was concentrated in vacuo (on a Rotavapor). On evaporation of the volatiles no crystal solid was separated.
  • the crystalline solid When analyzed by DSC the crystalline solid could be characterized with melting endotherm peak at 232.95 °C, with onset and offset temperatures at 220.77 °C and 238.91 °C, respectively (norm. 77. 17 J/g).
  • the XRPD from this solid was recorded, showing reflections of a crystalline solid different to that from Example 1 (Form A). Differences to these samples were observed in IR spectra, too.
  • IR-spectrum V [cm 1 ] (intensity): 1671 ,0 (0,730), 1623,6 (0,625), 1 199,4 (0,443), 1359, 1 (0,363), 739,0 (0,331 ), 1492,5 (0,320), 1236,4 (0,319), 3213, 1 (0,290), 1324,8 (0,286), 3368,5 (0,282), 1441 ,3 (0,248), 1735,7 (0,235), 3471 ,2 (0,232), 1 148,9 (0,230), 1297,8 (0,222), 1462,6 (0,201 ), 1264,5 (0, 192), 800,6 (0, 180), 937,0 (0, 129), 1047,5 (0, 128) XRPD: (°2theta/rel. Int.%): 8.029 (72.5), 9.377 (27.8), 1 1.751 ( 100), 15.8
  • S-lenalidomide in polymorphic Form B or a blend comprising S- lenalidomide according to the present invention (i.e. preferably S-lenalidomide in polymorphic Forms A and/or B) and R-lenalidomide can be used as active pharmaceutical ingredient in formulation Example 1 , 2 , 3 or 4.
  • Formulation Example 5 was repeated, wherein instead of the RS-Blend a lenalidomide racemate in polymorphic Form B as disclosed in WO 2005 / 023192 was used.
  • Dissolution Test The dissolution profile of Formulation Example 5 and comparative Formulation Example 6 was tested (according to USP Type II (paddle) at 37 °C in 0.01 N HCl, pH 2. 1 and 50 rpm for the first 60 minutes, 100 rpm after 60 minutes). The results (average value of 6 samples each) are shown in Figure 6. It was unexpectedly found that the dissolution properties of the RS-Blend are superior to the racemate known from the prior art.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de fabrication de S-lénalidomide et les formes polymorphes A et B de S-lénalidomide pouvant être obtenues par ledit procédé. Par ailleurs, la présente invention concerne un mélange comprenant du S-lénalidomide et du R-lénalidomide. Par ailleurs, la présente invention concerne des formes pharmaceutiques orales comprenant des formes polymorphes A et B du S-lénalidomide ou un mélange comprenant du S-lénalidomide et du R-lénalidomide.
PCT/EP2010/007228 2009-12-09 2010-11-29 S-lénalidomide, ses formes polymorphes et mélange comprenant du s- et r-lénalidomide Ceased WO2011069608A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP09015254 2009-12-09
EP09015254.7 2009-12-09

Publications (1)

Publication Number Publication Date
WO2011069608A1 true WO2011069608A1 (fr) 2011-06-16

Family

ID=42167615

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2010/007228 Ceased WO2011069608A1 (fr) 2009-12-09 2010-11-29 S-lénalidomide, ses formes polymorphes et mélange comprenant du s- et r-lénalidomide

Country Status (1)

Country Link
WO (1) WO2011069608A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015057043A1 (fr) 2013-10-14 2015-04-23 Latvian Institute Of Organic Synthesis Procédé de préparation de lénalidomide
US9045453B2 (en) 2008-11-14 2015-06-02 Concert Pharmaceuticals, Inc. Substituted dioxopiperidinyl phthalimide derivatives
US9353080B2 (en) 2003-09-04 2016-05-31 Celgene Corporation Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione
US9643950B2 (en) 2012-10-22 2017-05-09 Concert Pharmaceuticals, Inc. Solid forms of {s-3-(4-amino-1-oxo-isoindolin-2-yl)(piperidine-3,4,4,5,5-d5)-2,6-dione}
EP3147282A4 (fr) * 2014-05-22 2017-11-29 Shiseido Company, Ltd. Procédé de résolution optique du lénalidomide
WO2019081749A1 (fr) * 2017-10-26 2019-05-02 Synbias Pharma Ag Formulations à libération immédiate de lénalidomide
WO2019199136A1 (fr) * 2018-04-13 2019-10-17 주식회사 삼양바이오팜 Composition de comprimé oral de lénalidomide permettant une désintégration améliorée
EP3744318A1 (fr) * 2015-08-27 2020-12-02 Grindeks, A Joint Stock Company Composition pharmaceutique pouvant incorporer la lénalidomine sous diverses variantes cristallines

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998003502A1 (fr) * 1996-07-24 1998-01-29 Celgene Corporation 2-(2,6- DIOXOPIPERIDINE-3-YL)-PHTALIMIDES ET -1-OXO-ISO-INDOLINES SUBSTITUES ET METHODES POUR REDUIRE LES TAUX DE TNF-alpha
WO2005023192A2 (fr) 2003-09-04 2005-03-17 Celgene Corporation Formes polymorphes de 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
WO2006028964A1 (fr) * 2004-09-03 2006-03-16 Celgene Corporation Procedes de preparation de 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines substituees
WO2006081251A2 (fr) * 2005-01-25 2006-08-03 Celgene Corporation Methodes et compositions utilisant 4-amino-2-(3-methyl-2,6-dioxopiperidin-3-yl)-isoindole-1-3-dione
WO2009114601A2 (fr) * 2008-03-11 2009-09-17 Dr. Reddy's Laboratories Ltd. Préparation de lénalidomide

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998003502A1 (fr) * 1996-07-24 1998-01-29 Celgene Corporation 2-(2,6- DIOXOPIPERIDINE-3-YL)-PHTALIMIDES ET -1-OXO-ISO-INDOLINES SUBSTITUES ET METHODES POUR REDUIRE LES TAUX DE TNF-alpha
EP0925294A1 (fr) 1996-07-24 1999-06-30 Celgene Corporation 2-(2,6- DIOXOPIPERIDINE-3-YL)-PHTALIMIDES ET -1-OXO-ISO-INDOLINES SUBSTITUES ET METHODES POUR REDUIRE LES TAUX DE TNF-alpha
EP0925294B1 (fr) 1996-07-24 2002-12-11 Celgene Corporation 2-(2,6- DIOXOPIPERIDINE-3-YL)-PHTALIMIDES ET -1-OXO-ISO-INDOLINES SUBSTITUES ET METHODES POUR REDUIRE LES TAUX DE TNF-alpha
WO2005023192A2 (fr) 2003-09-04 2005-03-17 Celgene Corporation Formes polymorphes de 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
WO2006028964A1 (fr) * 2004-09-03 2006-03-16 Celgene Corporation Procedes de preparation de 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines substituees
WO2006081251A2 (fr) * 2005-01-25 2006-08-03 Celgene Corporation Methodes et compositions utilisant 4-amino-2-(3-methyl-2,6-dioxopiperidin-3-yl)-isoindole-1-3-dione
WO2009114601A2 (fr) * 2008-03-11 2009-09-17 Dr. Reddy's Laboratories Ltd. Préparation de lénalidomide

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
"European Pharmacopoeia"
CONTINO-PEPIN C ET AL: "Preliminary biological evaluations of new thalidomide analogues for multiple sclerosis application", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB LNKD- DOI:10.1016/J.BMCL.2008.11.118, vol. 19, no. 3, 1 February 2009 (2009-02-01), pages 878 - 881, XP025925843, ISSN: 0960-894X, [retrieved on 20081207] *
HON-WAH MAN ET AL.: "alpha-Fluoro-Substituted Thalidomide Analogues", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 13, no. 20, 20 October 2003 (2003-10-20), pages 3415 - 3417, XP002583299, ISSN: 0960-894X *
MULLER ET AL., BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 9, 1999, pages 1625 - 1630
MULLER G W ET AL: "Amino-substituted thalidomide analogs: potent inhibitors of TNF-alpha production", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB LNKD- DOI:10.1016/S0960-894X(99)00250-4, vol. 9, no. 11, 7 June 1999 (1999-06-07), pages 1625 - 1630, XP004169632, ISSN: 0960-894X *
RICHARD C. LAROCK: "Comprehensive Organic Transformations: A Guide to Functional Group Preparation", 1989, VCH, pages: 411 - 415

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11655232B2 (en) 2003-09-04 2023-05-23 Celgene Corporation Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione
US9353080B2 (en) 2003-09-04 2016-05-31 Celgene Corporation Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione
US9365538B2 (en) 2003-09-04 2016-06-14 Celgene Corporation Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione
US9371309B2 (en) 2003-09-04 2016-06-21 Celgene Corporation Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione
US11136306B2 (en) 2003-09-04 2021-10-05 Celgene Corporation Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-peridine-2,6-dione
US10590104B2 (en) 2003-09-04 2020-03-17 Celgene Corporation Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione
US9045453B2 (en) 2008-11-14 2015-06-02 Concert Pharmaceuticals, Inc. Substituted dioxopiperidinyl phthalimide derivatives
US9643950B2 (en) 2012-10-22 2017-05-09 Concert Pharmaceuticals, Inc. Solid forms of {s-3-(4-amino-1-oxo-isoindolin-2-yl)(piperidine-3,4,4,5,5-d5)-2,6-dione}
WO2015057043A1 (fr) 2013-10-14 2015-04-23 Latvian Institute Of Organic Synthesis Procédé de préparation de lénalidomide
EP3147282A4 (fr) * 2014-05-22 2017-11-29 Shiseido Company, Ltd. Procédé de résolution optique du lénalidomide
TWI659009B (zh) * 2014-05-22 2019-05-11 日商資生堂股份有限公司 來那度胺（Ｌｅｎａｌｉｄｏｍｉｄｅ）之光學分割方法
US10047068B2 (en) 2014-05-22 2018-08-14 Shiseido Company, Ltd. Optical resolution method of lenalidomide
EP3744318A1 (fr) * 2015-08-27 2020-12-02 Grindeks, A Joint Stock Company Composition pharmaceutique pouvant incorporer la lénalidomine sous diverses variantes cristallines
WO2019081749A1 (fr) * 2017-10-26 2019-05-02 Synbias Pharma Ag Formulations à libération immédiate de lénalidomide
CN111278432A (zh) * 2017-10-26 2020-06-12 赛比亚斯药业股份公司 来那度胺速释制剂
WO2019199136A1 (fr) * 2018-04-13 2019-10-17 주식회사 삼양바이오팜 Composition de comprimé oral de lénalidomide permettant une désintégration améliorée

Similar Documents

Publication Publication Date Title
WO2011069608A1 (fr) S-lénalidomide, ses formes polymorphes et mélange comprenant du s- et r-lénalidomide
WO2011050962A1 (fr) Sels d'addition d'acide du lénalidomide
JP3750023B2 (ja) アリピプラゾール無水物結晶、それらの製造方法及びそれらを含む製剤
KR100405116B1 (ko) 피페리디노알칸올화합물에대한약제학적조성물
AU2012331395B2 (en) Ivabradine hydrochloride form IV
EP2579858B1 (fr) Composition pharmaceutique contenant de l'ivabradine
EP2783688A1 (fr) Comprimés pharmaceutiques de fore cristalline d'aripiprazole II
AU2011307608B2 (en) Crystalline naloxol-PEG conjugate
JP2013209419A (ja) 酢酸バゼドキシフェン製剤
EP3978474A1 (fr) Formes cristallines d'un composé pharmaceutique
EP2927226A1 (fr) Cristal monohydrate de sel de potassium de fimasartan, son procédé de préparation, et composition pharmaceutique le comprenant
EP2572703A1 (fr) Forme pharmaceutique orale compressée pour maléate d'asénapine
US20030195249A1 (en) Venlafaxine besylate
EP3453384B1 (fr) Comprime pharmaceutique comprenant du bilastine
WO2008071966A2 (fr) Composition pharmaceutique de zolpidem
CN110882249B (zh) 含苯磺酸左氨氯地平水合物的组合物及其制备方法
EP2914599A1 (fr) Forme de sel solide d'alpha-6-mpeg6-o-hydroxycodone utilisée en tant qu'agoniste opioïde et ses utilisations
EP4613266A1 (fr) Dispersion solide de dérivé de curcumine, procédé pour sa préparation et utilisation correspondante
WO2013013114A1 (fr) Compositions biodisponibles de composés pipéridinyliques amorphes
EP2054372A2 (fr) Tartrate de toltérodine cristallin et composition pharmaceutique le contenant
EP3073996A1 (fr) Composition pharmaceutique comprenant de l'ivabradine amorphe
US20040198794A1 (en) Ondansetron forms and processes of making the same
KR20060034636A (ko) 결정 형태의 시부트라민 프리 베이스 및 그의 약학적 용도
EP3782989A1 (fr) Monohydrate d'hydrochlorure de detomidine
EP2945948A1 (fr) Forme cristalline de type ii de monohydrate d'anagrélide hydrochloride

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10782562

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10782562

Country of ref document: EP

Kind code of ref document: A1