WO2011050962A1 - Sels d'addition d'acide du lénalidomide - Google Patents

Sels d'addition d'acide du lénalidomide Download PDF

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WO2011050962A1
WO2011050962A1 PCT/EP2010/006595 EP2010006595W WO2011050962A1 WO 2011050962 A1 WO2011050962 A1 WO 2011050962A1 EP 2010006595 W EP2010006595 W EP 2010006595W WO 2011050962 A1 WO2011050962 A1 WO 2011050962A1
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Prior art keywords
lenalidomide
acid
addition salt
acid addition
pomalidomide
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PCT/EP2010/006595
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English (en)
Inventor
Hans-Huenter^ Dr. Stiegel
Wolfgang Dr. Albrecht
Sandra Brueck
Jana Paetz
Dominique Meergans
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Ratiopharm Gmbh
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Publication of WO2011050962A1 publication Critical patent/WO2011050962A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the invention relates to acid addition salts of lenalidomide and/or pomalidomide as well as to desirable polymorphic forms of lenalidomide hydrogen sulfate. Furthermore, the invention provides a process for producing acid addition salts of lenalidomide and/or pomalidomide, which optionally can comprise a further step producing lenalidomide in form of the free base. Moreover, the application refers to desirable acid addition salts of pomalidomide and blends of lenalidomide and pomalidomide. Finally, the present invention relates to oral dosage forms comprising acid addition salts of lenalidomide and/or pomalidomide.
  • lenalidomide refers within this application either to the racemic mixture of the S- and the R-enantiomer or to the S-enan- tiomer or to the R-enantiomer.
  • the racemic mixture is preferred.
  • 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.
  • 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 ® .
  • WO2006 / 028964 A l discloses processes for producing substituted 2-(2 ,6-dioxopiperidin-3-yl) l -oxoisoindolines.
  • racemic lenalidomide it has to be noted that the suggested preparation process seems to be not sufficiently enabled.
  • racemic lenalidomide has some undesirable properties. For example, recrystallisation and micronisation is necessary in order to ensure blend and content uniformity in pharmaceutical dosage forms, see EMEA, Scientific Discussion of Revlimid ® , 2007.
  • micronisation entails a number of drawbacks.
  • the micronisation 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 micronisation increases the susceptibility of the substance towards oxidation. Therefore, a micronised agent is more likely to degrade over time. It is therefore desired to develop lenalidomide in a form that provides a good flowability and pourability, a superiour oxidation stability, as well as a superior storage stability and shelf-life.
  • the inventors of the present invention unexpectedly have found that the above drawbacks can be overcome by providing lenalidomide in form of pharmaceutically acceptable acid addition salts as defined in claim 1 .
  • the acid addition salts enable the preparation of dosage forms having advantageous properties.
  • the addition salts enable an advantageous process for the production of racemic lenalidomide in form of the free base.
  • HX is an acid having a pK a value in water at 25 °C from - 10 to +4.
  • HX is not selected from hydrochloric acid, nitric acid, hydrobromic acid, alkylsulfonic acids, arylsulfonic acids, in particular methanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid and phosphoric acid.
  • HX is sulfuric acid
  • the resulting acid addition salts preferably are present in a salt form comprising the hydrogen sulfate salt, more preferably as a mixture of sulfate and hydrogen sulfate or as hydrogen sulfate.
  • a further subject of the present invention is a process for producing acid addition salts of lenalidomide, comprising the steps of
  • HX is an acid having a pK a value in water at 25 °C from - 10 to +4, preferably a pK a value from -9.5 to +3, more preferably a pK a value from -9.0 to + 1 or from -9.0 to -2.
  • the "pK a value" is the logarithmic measure to the basis 10 of the acid dissociation constant. In case of acids having more than one dissociable hydrogen atom, the above pK a values refer to the dissociation constant of the dissociation of the first proton.
  • the acid dissociation constant, Ka (also known in the art as acidity constant, or acid ionization constant), is a quantitative measure of the strength of an acid in solution, preferably in water, more preferably in pure water. It is the equilibrium constant for a chemical reaction known as dissociation in the context of acid-base reactions. The equilibrium can be written symbolically as: HX H + + X- where HX Is an acid which dissociates by splitting into X " , known as the conjugate base of the acid, and the hydrogen ion or proton, H + , which, in the case of aqueous solutions, exists as a solvated hydronium ion.
  • the dissociation constant is usually written as a quotient of the equilibrium concentrations, denoted by [HX], [X " ] and [H + ]:
  • pK a which is equal to -log 10 K a , may also be referred to as an acid dissociation constant:
  • HBr HC1, H 2 S0 4 , HN0 3 , para toluene sulfonic acid, benzenesulfonic acid, (+)- ( l S)-Camphor- l O-sulfonic acid, d-glucuronic acid, lactobionic acid, glucoheptonic acid, d-gluconic acid, lactic acid, Naphtalene- 1 ,5-disulfonic acid, salicylic acid, gentisic acid, embonic acid, oxalic acid, maleic acid, malonic acid, salicylic acid, (+)-L-tartaric acid, alginic acid, (- )-L-malic acid and citric acid.
  • HC1 (hydrochloric acid) and H 2 S0 4 (sulfuric acid) are used. Hydrochloric acid is particularly preferred.
  • a subject of the present invention is an acid addition salt of lenalidomide according to formula (I), wherein HX is selected from the above- mentioned acids, except from hydrochloric acid, nitric acid, hydrobromic acid, alkylsulfonic acids, arylsulfonic acids, in particular methanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid and phosphoric acid.
  • HX is sulfuric acid
  • the resulting acid addition salts preferably are present in a salt form comprising the hydrogen sulfate salt, more preferably as a mixture of sulfate and hydrogen sulfate or as hydrogen sulfate.
  • the acid addition salts of lenalidomide according to the present invention may comprise anions, which still do contain remaining dissociable protons, and/ or anions, which do not contain remaining dissociable protons.
  • the resulting acid addition salts of lenalidomide according to the present invention may comprise lenalidomide in form of the sulfate, lenalidomide in form of the hydrogen sulfate , or mixtures thereof.
  • preferred subjects of the present inventions are crystalline lenalidomide salts and / or crystalline mixtures of pomalidomide salts and lenalidomide salts, wherein the lenalidomide salts can be illustrated by the following formulae:
  • a further subject of the present invention is a process for producing acid addition salts of lenalidomide, comprising the steps of i) providing a compound according to formula (II)
  • step (i) the compound according to formula (II) (racemic) is provided.
  • Said compound is known from prior art.
  • the compound according to formula (II) (racemic) is obtainable as described below in Precursor-Example 1 .
  • 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, 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 0.001 to 0.02 , more preferably from 0.005 to 0.015.
  • 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.
  • step (ii) Preferably alcohols or alcohol/water mixtures are used as suitable solvents. Particularly, methanol is used.
  • 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.
  • the product resulting in step (ii) can be used in step (iii) with or without an intermittent work-up step. Contrary to the teaching of WO 2009 / 1 14601 it has been found that the hydrogenation step should not be carried out in the presence of acids, in particular not in the presence of methanesulfonic acid. The presence of acids in step (ii) leads to undesired corrosion.
  • step (iii) an acid (HX) is added to the product resulting from step (ii).
  • the acids are added in form of an aqueous solution.
  • Reaction step (iii) may be carried out in usual organic solvents at usual temperatures.
  • alcohols or alcohol/water mixtures are used.
  • organic acids, having a pK a higher than 4 may be used, in particular, acetic acid.
  • the reaction is carried out at temperatures between 0 °C and 100 °C, preferably between 20 °C and 80 °C.
  • the reaction time can range from 0.01 to 5 hours, preferably from 0. 1 to 2 hours.
  • the molar ratio of lenalidomide (obtained by hydrogenating the compound according to formula (II)) to dissociable hydrogen atoms of the added acid ranges from 0.5 to 5 , preferably from 0.8 to 2.
  • HC1 hydrochloric acid
  • H 2 S0 4 sulfuric acid
  • the addition of the acid results in the formation of an acid addition salt of lenalidomide.
  • the resulting acid addition salt preferably is isolated.
  • solvent and temperature are chosen such that the resulting acid addition salt can be isolated by crystallisation and subsequent filtration.
  • the resulting acid addition salt can be recrystallized. Suitable solvents are water, ethanol, acetic acid and mixtures of water and ethanol, water and acetic acid.
  • the catalyst used in step (ii) can be recycled.
  • a hydrogenation is usually carried out in solutions of the starting material in a suitable solvent, which has to be resistant against hydrogenation conditions, and inert against the starting material or product.
  • a suitable solvent which has to be resistant against hydrogenation conditions, and inert against the starting material or product.
  • Hydrogenation catalysts are usually introduced as solids bound onto carriers with a large surface like charcoal (heterogeneous catalysis).
  • products with a low solubility in the chosen hydrogenation medium often are precipitated onto the surface of the catalyst carrier, and the catalyst becomes inactivated. Thus, conversion will be incomplete.
  • lenalidomide in form of the hydrochloride i.e. in formula (I) HX is HC1
  • lenalidomide hydrochloride is produced by the process of the present invention it can be obtained in crystalline form.
  • lenalidomide hydrochloride is obtained in crystalline form A, wherein form A is characterized by an X-Ray powder diffraction (hereinafter referred to as XRPD) showing characteristic peaks at 12. 1 1 °, 24.35°, 24.73° and 26.12° 2-Theta. Further characteristic peaks can be found at 13.29°, 17.1 1 °, 21.67°, 26.77° and/or 31.17° 2-Theta.
  • XRPD X-Ray powder diffraction
  • lenalidomide in form of the sulfate is produced. If lenalidomide sulfate is produced by the process of the present invention it can be obtained in crystalline form.
  • lenalidomide sulfate can be obtained in at least two polymorphic forms, namely polymorphic form A and polymorphic form B.
  • Form A of lenalidomide sulfate is characterized by an X-Ray powder diffraction showing characteristic peaks at 16.69°, 18.85°, 19.68° and 26.25° 2-Theta. Further characteristic peaks can be found at 21.02°, 22.49°, 25.56 and/ or 26.92° 2-Theta.
  • Form A preferably is obtained by dissolving the product resulting from step (ii) in acetic acid and adding in step (iii) sulfuric acid.
  • Form B of lenalidomide sulfate is characterized by an X-Ray powder diffraction showing characteristic peaks at 16.96°, 17.28°, 18.90° and 25.72° 2-Theta. Further characteristic peaks can be found at 14.32°, 21 .54°, 27.48°, 28.09° and / or 30.3 1 ° 2-Theta.
  • Form B can be obtained from lenalidomide sulfate, in the Form how it will be obtained by recrystallisation of lenalidomide with half molar equivalent H 2 S0 4 per base in acetic acid, by vapor sorption, wherein preferably during sorption the lenalidomide sulfate is contacted with air having a relative humidity of about 75% to 95 % more preferably at 85 % at 25 °C.
  • lenalidomide in form of the hydrogen sulfate or mixtures of hydrogen sulfate and sulfate salts of lenalidomide are produced.
  • a mixture of lenalidomide sulfate/ hydrogen sulfate is preferably characterized by an X-Ray powder diffraction showing characteristic peaks at 18.88°, 2 1 . 10°, and 25.62° 2-Theta. Further characteristic peaks can be found at 16.96° , 1 7.26°, 2 1 .50°, 26.5 1 and / or 28.09° 2-Theta.
  • a lenalidomide hydrogen sulfate salt preferably is characterized by an X-Ray powder diffraction showing characteristic peaks at 18.92°, 21 . 10° and 25.63° 2-Theta. Further characteristic peaks can be found at 16.71 °, 26.52°, 28.07 and / or 28.55° 2-Theta.
  • a further aspect of the present invention is the use of the acid addition salts of lenalidomide for producing lenalidomide in form of the free base.
  • acid addition salts of lenalidomide according to formula (I) as defined above are used.
  • a further subject of the present invention is a process for producing lenalidomide in form of the free base, comprising the steps of i) providing a compound according to formula (II)
  • a basic compound is added.
  • a basic compound is capable of producing a pH of greater than 7 when brought into contact with water.
  • suitable basic compounds are NaHC0 3 , Na 2 C0 3 , NaOH, KHC0 3 , K 2 C0 3 , KOH, NH 4 OH , sodium acetate, potassium acetate.
  • sodium hydrogen carbonate (NaHC0 3 ) is used.
  • the molar ratio of acid addition salt to basic compound usually ranges from 1 .0 to 10, preferably from 1 .2 to 5.
  • a pH of above 4.0 and below 9.0 might be adjusted, as lenalidomide is a weak base, too.
  • Reaction step (v) may be carried out in usual organic solvents and / or water at usual temperatures.
  • water or alcohol /water mixtures are used.
  • organic acids, having a pK a higher than 4 may be used, in particular, acetic acid.
  • the reaction is carried out at temperatures between 0 °C and 100 °C, preferably between 40 °C and 80 °C.
  • the reaction time can range from 0.01 to 5 hours, preferably from 0. 1 to 2 hours.
  • lenalidomide resulting from step (v) is recrystallized. Depending on the crystallisation conditions, lenalidomide (free base) can be obtained in crystalline form A or crystalline form B or, alternatively, crystalline Form E, which are known from WO 2005 / 023192.
  • a subject of the present invention is a process for producing polymorphic form A of lenalidomide in form of the free base, wherein acetic acid is used as solvent.
  • a subject of the present invention is a process for producing polymorphic form B of lenalidomide in form of the free base, wherein
  • a further aspect of the present invention relates to the separation of enantiomers. It has been found that racemic lenalidomide salts of the present invention can be separated, e.g. by chiral HPLC, as illustrated in the examples.
  • a subject of the present invention is an acid addition salt of lenalidomide according to the present invention, essentially comprising S- lenalidomide or essentially comprising R-lenalidomide.
  • the term "essentially comprising” indicates that the enantiomeric excess (ee) is preferably more than 90 % , more preferably more than 95 % , in particular more than 99 % .
  • a further aspect of the present invention relates to a pharmaceutical composition comprising a mixture of lenalidomide and pomalidomide.
  • a composition shows superior properties.
  • mixtures of lenalidomide and pomalidomide can be produced by the process of the present invention.
  • a subject of the present invention is a pharmaceutical composition comprising a) lenalidomide,
  • Pomalidomide brand name: Actimid ®
  • the chemical structure (III) is as follows:
  • pomalidomide refers within this application either to the racemic mixture of the S- and the R-enantiomer or to the S-enantiomer or to the R-enantiomer.
  • the racemic mixture is preferred.
  • Pomalidomide can be present in form of the free base or in form of a pharmaceutically acceptable salt. The same applies, as mentioned above, to lenalidomide.
  • lenalidomide (a) is present in form of an acid addition salt according to the invention, i.e. an acid addition salt, wherein an acid having a pK a value in water at 25 °C from - 10 to +4, is used.
  • pomalidomide ( ⁇ ) is present in form of an acid addition salt according to the invention, i.e. an acid addition salt, wherein an acid having a pK a value in water at 25 °C from - 10 to +4, is used.
  • an acid addition salt i.e. an acid addition salt, wherein an acid having a pK a value in water at 25 °C from - 10 to +4, is used.
  • the composition comprises:
  • 0.1 to 90 wt.% preferably 0.1 to 50 wt.% , more preferably 0.5 to 10 wt.% , in particular 0.6 to 3.0 wt.% pomalidomide, based on the total weight of the composition.
  • a further subject of the present invention is a process for producing acid addition salts of pomalidomide, comprising the steps of i) providing a compound according to formula (IV)
  • the pharmaceutical composition comprising components (a) and ( ⁇ ) shows superior pharmacologic properties.
  • the combination of components (a) and ( ⁇ ) shows an unexpected additive or even synergistic effect.
  • the combination of components (a) and ( ⁇ ) shows an unexpected superior effect in the treatment of cancer, immune disorders and / or transplantation therapy.
  • cancers and immune disorders include, but are not limited to, advanced malignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforme, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblasts leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymph
  • Lenalidomide and pomalidomide can occur simultaneously or sequentially by the same or different routes of administration.
  • the compounds can be administered orally, intravenously, subcutaneously and/ or intramuscularly.
  • a preferred route of administration for lenalidomide and pomalidomide is orally.
  • lenalidomide and pomalidomide are administered simultaneously, more preferably in a single dosage form, still more preferably in a single solid oral dosage form, e.g. a tablet or a capsule, whereas a tablet is preferred.
  • lenalidomide can be administered daily in an amount of from about 0. 1 to about 150 mg, preferably from about 1 to about 50 mg, more preferably from about 2 to about 25 mg and most preferably in an amount of 5 mg, 10 mg, 15 mg or 20 mg; whereas pomalidomide can be administered daily in an amount of from about 0.01 to about 150 mg, preferably from about 0. 1 to about 50 mg, more preferably from about 0.5 to about 25 mg and most preferably in an amount of 1 mg, 2 mg, 5 mg or 10 mg.
  • lenalidomide and / or pomalidomide may be administered in a single daily dose or in divided doses two to six times a day.
  • lenalidomide and/ or pomalidomide may be administered less frequent then once daily, e.g. every second, third, or fourth day.
  • lenalidomide and/ or pomalidomide are cyclically administered to a patient. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and / or improves the efficacy of the treatment.
  • lenalidomide and / or pomalidomide are administered daily in a single or divided doses in a three to six week cycle with a rest period of about a week or two weeks, preferably in a three week cycle with a rest period of one week.
  • the invention further allows the frequency, number, and length of dosing cycles to be increased.
  • another specific embodiment of the invention encompasses the administration of lenalidomide and/ or pomalidomide for more cycles than are typical when it is administered alone.
  • lenalidomide and / or pomalidomide are administered daily and continuously for three or four weeks at a dose of from about 0. 1 to about 150 mg/ d, followed by a break of one or two weeks.
  • Lenalidomide is preferably administered daily and continuously at an initial dose of 0. 1 to 5 mg/ d with dose escalation (every week) by 1 to 10 mg/ d to a maximum dose of 50 mg/ d for as long as therapy is tolerated.
  • lenalidomide is administered in an amount of about 5 mg, 10 mg, 15 mg or 25 mg/ day, preferably in an amount of about 25 mg/ day for three to four weeks, followed by one week or two weeks of rest in a four or six week cycle .
  • Pomalidomide is preferably administered daily and continuously at an initial dose of 0. 1 to 5 mg/ d with dose escalation (every week) by 1 to 10 mg/ d to a maximum dose of 50 mg/ d for as long as therapy is tolerated.
  • pomalidomide is administered in an amount of about 1 mg, 2 mg, 5 mg or 10 mg/ day, preferably in an amount of about 2 mg/ day for three to four weeks, followed by one week or two weeks of rest in a four or six week cycle.
  • another embodiment of the invention is a combination of pomalidomide and / or lenalidomide with a glucocorticoid.
  • Dexamethasone and prednisone are the preferred glucocorticoids.
  • a further subject of the present invention is a pharmaceutical composition or a pharmaceutical set comprising
  • Another subject of the present invention is a pharmaceutical composition or a pharmaceutical set comprising
  • lenalidomide preferably in form of an acid addition salt
  • the glucocorticoid can be administered orally, intravenously, subcutaneously and/ or intramuscularly.
  • a preferred route of administration for the glucocorticoid is oral.
  • the glucocorticoid is combined with the lenalidomide salt and / or pomalidomide salt of the present invention within a tablet (hereinafter referred to as combination tablet).
  • a further subject of the present invention is a tablet comprising a glucocorticoid and a pharmaceutical acceptable salt of lenalidomide.
  • Another subject of the present invention is a tablet comprising a glucocorticoid and a pharmaceutical acceptable salt of pomalidomide.
  • Still another subject of the present invention is a tablet comprising a glucocorticoid, a pharmaceutical acceptable salt of lenalidomide salt and a pharmaceutical acceptable salt of pomalidomide.
  • dexamethasone or prednisone is used as glucocorticoid.
  • lenalidomide hydrochloride or hydrogensulfate is used.
  • the combination tablet comprises the above described active ingredients and pharmaceutical excipients, preferably the below described pharmaceutical expients, e.g. b) a filler, preferably a lactose-free filler, and/ or c) a solubilizer, and/ or d) a disintegrant.
  • pharmaceutical excipients e.g. b) a filler, preferably a lactose-free filler, and/ or c) a solubilizer, and/ or d) a disintegrant.
  • the combination tablet is prepared by a direct compression process.
  • the combination tablet can be prepared by a granulation process (wet or dry, wherein wet is preferred).
  • the lenalidomide salt and / or pomalidomide salt is present in the intragranular phase, whereas the glucocorticoid is present in the extragranular phase.
  • the lenalidomide salt and/ or pomalidomide salt is present in the extragranular phase, whereas the glucocorticoid is present in the intragranular phase.
  • the combination tablet can be prepared by a pellet layering process or by a melt granulation process.
  • the combination tablet preferably comprises
  • dexamethasone can be administered daily in an amount of from about 0. 1 to about 150 mg, preferably from about 1 to about 50 mg, more preferably in an amount of 20 mg or 40 mg; whereas prednisone can be administered daily in an amount of from about 0.01 to about 150 mg, preferably from about 0. 1 to about 50 mg, more preferably in an amount of 20 mg, 30 mg or 40 mg.
  • patients with relapsed or refractory multiple myeloma are treated by the administration of from about 5 to about 25 mg/ day of lenalidomide and / or from about 0.01 to about 5 mg/ day of pomalidomide accompanied by the administration of 40 mg/ day of dexamethasone.
  • the pharmaceutical composition comprising pomalidomide (preferably in form of the above described acid addition salt) and optionally lenalidomide (preferably in form of the above described acid addition salt) and optionally a glucocorticosteroid is unexpectedly superior for the treatment of cancer, immune disorders and /or transplantation therapy, wherein patients are treated, who do not sufficiently respond to a thalidomide treatment.
  • a further aspect of the present invention is the use of an acid addition salt of lenalidomide and/or pomalidomide according to the present invention for producing a pharmaceutical 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
  • an acid addition salt or a combination of acid addition salts according to the present invention preferably lenalidomide hydrogen sulfate,
  • a filler preferably a lactose-free filler, and/ or
  • the active ingredient (a) (lenalidomide acid addition salt and/ or pomalidomide acid addition salt) is employed in particulate form. More preferably, the active ingredient (a) of the pharmaceutical composition of the present invention has a volume mean particle size (D 50 ) of 0. 1 to 100 ⁇ ., more preferably of 0.3 to 50 ⁇ , further more preferably of 1 to 20 ⁇ , most preferably of 2 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).
  • 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, dextrate, 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 behaviour 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 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. Examples for polar groups are hydroxy, amino, carboxy, carbonyl, ether, ester and sulfonate. Hydroxy groups are particularly preferred.
  • 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 is the temperature at which the hydrophilic polymer becomes brittle on cooling and soft on heating. That means, above 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), polyvinyl - pyrrolidone, 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 carboxy- methyl 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 ® ).
  • 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: a lubricant, a glidant and/ or an 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 glidant can for example be colloidal silicone dioxide (e.g. Aerosil ® ⁇ .
  • 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 silicone dioxide has a specific surface area of 50 to 400 m 2 / g, measured according to Ph. Eur. , 6th edition, chapter 2.9.26.
  • the anti-sticking agent is for example talcum and may be present in amounts of 0.05 to 5 wt.% , more preferably in an amount of 0.5 to 3 wt.% of the total weight of the composition.
  • the active ingredient (a) (lenalidomide acid addition salt and/or pomalidomide acid addition salt) can be present in an amount of 0.
  • 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. Where it is referred to the total weight of the pharmaceutical composition or the pharmaceutical dosage form, the total weight 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.
  • the invention is hereinafter illustrated by the following examples. EXAMPLES A) Equipment
  • Dibenzoylperoxide (0.2 g) was added and reflux continued for 72h. Within this time, conversion reached about 80 % . Additional NBS (2.2 g) was added and the reflux continued. After 93 h a conversion of 86 % was reached.
  • the reaction mixture was cooled to room temperature and filtered. The residual from the filter was discarded and the filtrate was transferred to a separatory funnel, washed with water (2 x 120 ml), with brine ( 120 ml) and finally dried over anhydrous MgS0 4 . After filtration the solvent was removed in vacuo to give a honey yellow colored, partially crystallizing oil (24.2 1 g).
  • the reflux condenser was replaced by a distillation bridge and THF was distilled from the mixture until about 4.5 L distillate were collected. The residue was allowed to come to 30-40 °C , and then treated with 2 L of cold water ( 10°C). The slurry was stirred overnight at RT ( 15 h). The crystalline mass was filtered and sucked to dryness on a Buchner filter funnel under vacuum.
  • DIPEA diisopropyl-ethyl-amine
  • the light yellow colored filtrate was concentrated on a Rotavapor ( 1000 ml) flask to a residual volume of 150 ml.
  • a light beige colored, crystalline solid with a melting point of 265 °C was obtained (7.6 g, 29% ), which turned to light grey color on standing.
  • the inner temperature raised within the first 5 hours continuously from 2 1 °C to 35 °C , while hydrogen was continuously charged to maintain the preset pressure. After 2 h the speed of the stirrer was set to 600 rpm and the reaction was terminated after 18 h.
  • the reaction mixture was released from the reactor and equipment rinsed with additional MeOH (793.9 g/ 1 1).
  • the combined suspension was filtered under vacuum on a pre-weighed Buchner Funnel equipped with a filter paper. 245.6 g wet solid was collected on the filter paper and after air drying for 16 h at RT, 214g were obtained.
  • This mass was transferred into hot aqueous hydrochloric acid (prepared from 600 g water and 86 ml 32% HCl), immediately transferred onto a pre-weighed Buchner funnel, equipped with filter paper and filtered under vacuum. A light yellow colored filtrate was obtained, from which a light solid started to crystallize immediately.
  • the crystal suspension was chilled in an ice bath for 60 min, the obtained crystals were collected by vacuum filtration through a Buchner funnel on filter paper. The cake of crystals was rinsed with 100 ml of cold MeOH sucked to dryness on the filter, and dried on air overnight. 216.5 g dry lenalidomide hydrochloride was collected (83.5% from theory 258.8g).
  • Lenalidomide hydrochloride (345 g, 1 . 1 7 mol), obtained according to Example 2 , was charged to a 3 1 beaker and suspended in water ( 1500 ml). With stirring by a magnetic stirring bar, the suspension was heated to about 85°C. When most of the solid had dissolved, charcoal ( 10 g) was added in portions and stirring continued for 30 min at 80°C. The black suspension was filtered through a Buchner funnel into a preheated round bottom flask (3 1) under vacuum. The clear solution was kept at 70°C and 350 ml of a saturated NaHC0 3 sol. was added dropwise until pH 8. The measured inner temperature was 65°C .
  • the hot suspension was vacuum-filtered into a preheated flask.
  • the flask was allowed to come to RT overnight.
  • the crystal suspension was filtered under vacuum and the crystals collected were sucked on the filter to dryness.
  • the filter cake was dried in a vacuum drying cabinet at 100 mbar/ 40°C overnight. After drying, 39.60 g of coarse lenalidomide hemihydrate with high purity (99.7 % purity, 76.48 % from 5 1 .78 g, theoretical yield) were obtained in the first crop. This material was used for seeding in example 5.
  • aqueous EtOH mother liquor was evaporated on a rotavapor to a residual volume of about 0.5 1 and chilled in the refrigerator overnight. After filtration and drying, a second crop could be obtained (3.2 g, 6. 18% ).
  • Lenalidomide sulfate obtained according to example 7 (0.25 g) was exactly weighed into a tared weighing bottle and this was placed into a hygrostat chamber over saturated C1 solution for equilibration (85% r.H. at 20°C) within 4 weeks. Within the first 16 hours the mass of the sample had grown by about 6-7 % (hygroscopicity) but during further exposure the mass of the substance was lowered again below 99 % from starting value (desolvation). DSC and XRPD had changed completely after this time.
  • Example 9 Preparation of Lenalidomide sulfate /Hydrogen Sulfate
  • THF (30 ml) was added and the crystal suspension, which had been formed, was decanted from the supernatant, slurried with two aliquots of THF ( 10 ml each) for 10 min.
  • the washed solid was collected on a filter by vacuum filtration and dried at 40 °C in vacuum drying cabinet at 100 mbar.
  • the solids had a weight of 1 . 10 g ( 100 % yield).
  • Example 10 Preparation of Lenalidomide Hydrogen Sulfate
  • a round bottom flask 3-( 1 -oxo-4-amino-isoindoline-2-yl)piperidine-2 ,6-dione ( 1 .0 g, 98.8 % pure) was placed.
  • Water 10.07 ml was added and the mixture was heated to 50 °C while stirring.
  • Sulfuric acid H 2 S0 4 , 0.24 ml, 96% was added and a clear solution was obtained.
  • the aqueous phase was concentrated to leave a viscous oil. THF (30 ml) was added and stirred for 15 min. , but no solid was obtained.
  • the supernatant was decanted and slurried with three additional aliquots of THF ( 10 ml each) for 15 min.
  • the washed oil was treated with MeOH (20 ml) and stirred for 10 min. when it became a suspension of crystals.
  • the solid formed was collected on a filter by vacuum filtration and dried at 40 °C in vacuum drying cabinet at 100 mbar. The solids had a weight of 0.68 g (49.3 % yield).

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Abstract

L'invention porte sur des sels d'addition d'acide du lénalidomide ainsi que sur des formes polymorphes recherchées d'hydrogénosulfate de lénalidomide. En outre, l'invention porte sur un procédé pour la production de sels d'addition d'acide du lénalidomide, qui peut éventuellement comprendre une étape supplémentaire produisant du lénalidomide sous la forme de la base libre.
PCT/EP2010/006595 2009-10-29 2010-10-28 Sels d'addition d'acide du lénalidomide WO2011050962A1 (fr)

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WO2014170909A3 (fr) * 2013-04-01 2015-04-02 Hetero Research Foundation Procédé de préparation de pomalidomide
WO2015057043A1 (fr) 2013-10-14 2015-04-23 Latvian Institute Of Organic Synthesis Procédé de préparation de lénalidomide
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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
ITUB20169994A1 (it) * 2016-01-14 2017-07-14 Phf Sa Nuove forme cristalline di farmaci immunomodulatori
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WO2019227968A1 (fr) 2018-06-01 2019-12-05 上海博志研新药物技术有限公司 Procédé de préparation de lénalidomide
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