EP2950796A1 - Composition pharmaceutique contenant du léflunomide - Google Patents

Composition pharmaceutique contenant du léflunomide

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Publication number
EP2950796A1
EP2950796A1 EP14700203.4A EP14700203A EP2950796A1 EP 2950796 A1 EP2950796 A1 EP 2950796A1 EP 14700203 A EP14700203 A EP 14700203A EP 2950796 A1 EP2950796 A1 EP 2950796A1
Authority
EP
European Patent Office
Prior art keywords
leflunomide
pharmaceutical composition
eur
treatment
composition according
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
EP14700203.4A
Other languages
German (de)
English (en)
Inventor
Jens Flemming
Harm Peters
Andreas Brandt
Heiner Will
Marguérite M. MENSONIDES-HARSEMA
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.)
Medac Gesellschaft fuer Klinische Spezialpraeparate mbH
Alfred E Tiefenbacher GmbH and Co KG
Original Assignee
Medac Gesellschaft fuer Klinische Spezialpraeparate mbH
Alfred E Tiefenbacher GmbH and Co KG
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
Priority claimed from DE201310001636 external-priority patent/DE102013001636A1/de
Priority claimed from DE102013007106.2A external-priority patent/DE102013007106A1/de
Application filed by Medac Gesellschaft fuer Klinische Spezialpraeparate mbH, Alfred E Tiefenbacher GmbH and Co KG filed Critical Medac Gesellschaft fuer Klinische Spezialpraeparate mbH
Publication of EP2950796A1 publication Critical patent/EP2950796A1/fr
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present invention relates to a pharmaceutical composition according to the invention with 14 to 17.5 mg leflunomide prepared as a single dose and their uses.
  • DMARDs disease-modifying antirheumatic drugs
  • leflunomide In addition to its use as an antirheumatic agent primarily for the treatment of rheumatoid arthritis and / or psoriatic arthritis, the action of leflunomide is currently also used in the treatment of other autoimmune diseases, in particular lupus nephritis, systemic lupus erythematosus, uveitis, myasthenia gravis and / or Granulomatosis with polyangitis (Wegener's disease); in the context of fixed organ transplants, in particular kidney and liver transplants; oncological diseases, in particular melanomas, sarcomas, gliomas, prostate carcinomas, brain and / or CNS tumors; and / or diseases with the Human Immunodeficiency Virus (HIV).
  • lupus nephritis systemic lupus erythematosus
  • uveitis myasthenia gravis
  • myasthenia gravis myasth
  • Leflunomide itself is a prodrug that after oral administration in the intestinal wall, but also in the liver by opening the Isoxazolrings to the active Malonnitrilamidmetabolites and
  • BEST ⁇ TfGUMGSKOPIE Drug teriflunomide (formula II, also called A77 1726) is metabolized, which has immunomodulating properties. Lefiunomide concentrations are detectable after oral administration in vivo only in very low concentrations. The mode of action of leflunomide is therefore based primarily on the in vivo action of the active metabolite teriflunomide, which on the one hand inhibits, on the one hand, the dihydroorotate dehydrogenase and, on the other hand, has antiproliferative and / or antiinflammatory effects.
  • the maximum concentration of teriflunomide in the blood can be measured approximately 6 to 12 hours after oral administration. Due to the relatively long half-life of teriflunomide (approximately 2 weeks), steady-state blood concentrations can be measured after approximately 2 months with 10 mg or 20 mg leflunomide once daily. Since a reliable statement about the individual effectiveness of leflunomide / teriflunomide and a possible dose increase or decrease can be made only after reaching the steady-state concentration, there were efforts to shorten the period until the onset of steady-state concentration.
  • Adverse reactions may be observed with the appropriate dosing regime, however, with frequent side effects such as: increased blood pressure, leukopenia, paresthesia, headache, dizziness, gastrointestinal complaints such as diarrhea, nausea, vomiting, oromucosal and / or abdominal pain, increased hair loss , Eczema, rash, pruritis, dry skin, tendonitis, creatinine kinase (CK) elevation, loss of appetite, weight loss, asthenia, mild allergic reactions and elevated liver enzymes (transaminases, gamma-GT, alkaline phosphatases, bilirubin). Due to one or more of these side effects, in particular with haematotoxic and / or hepatotoxic and / or gastrointestinal In particular, within 12 months after the start of therapy, the therapy may be discontinued or the therapeutic agent may change.
  • side effects such as: increased blood pressure, leukopenia, paresthesia, headache, dizziness, gastrointestinal complaints such as diarrhea, nausea, vomiting, oromucosal
  • RA rheumatoid arthritis
  • metabolizing enzymes, transporter proteins and / or plasma binding proteins which can be influenced by inflammatory reactions.
  • chronic inflammatory reactions the metabolic system of the liver may be overloaded and / or saturated by products of the inflammatory reactions, such that this may alter the metabolism of a drug and may result, for example, in a reduction in drug metabolism and in an increase in plasma drug level.
  • a comparable or improved efficacy in the prophylaxis and / or treatment of autoimmune diseases preferably rheumatoid arthritis, psoriatic arthritis, cystic fibrosis complication of cystic fibrosis, lupus nephritis, systemic lupus erythematosus, uveitis, myasthenia gravis and / or of granulomatosis with polyangitis (Wegener's disease); and / or in the context of organ transplantation prophylaxis and / or treatment, preferably kidney transplantation and / or liver transplantation; and / or in the prophylaxis and / or treatment of oncological diseases, preferably melanomas, sarcomas, gliomas, prostate carcinomas, brain and / or CNS tumors; and / or in the prophylaxis and / or treatment of human immunodeficiency virus (HIV) diseases and / or
  • a first subject of the invention relates to a pharmaceutical composition comprising leflunomide, characterized in that the composition is prepared as a single dose of 14 to 17.5 mg, preferably 15 to 17.5 mg, particularly preferably 15 mg leflunomide.
  • a second subject of the invention relates to the use of leflunomide for the prophylaxis and / or treatment of autoimmune disease, preferably rheumatoid arthritis, psoriatic arthritis, cystic fibrosis complication of cystic fibrosis, lupus nephritis, systemic lupus erythematosus, uveitis, myasthenia gravis and / or of granulomatosis with polyangitis (Wegener's disease); and / or in the context of organ transplantation prophylaxis and / or treatment, preferably kidney transplantation and / or liver transplantation; and / or in the prophylaxis and / or treatment of oncological diseases, preferably melanomas, sarcomas, gliomas, prostate carcinomas, brain and / or CNS tumors; and / or in the prophylaxis and / or treatment of diseases with the human immunodeficiency virus (HIV)
  • a pharmaceutical composition according to the invention due to the single dosage of 14 to 17.5 mg, preferably 15 to 17.5 mg, more preferably 15 mg leflunomide per pharmaceutical formulation and once, twice, thrice or four times daily (simultaneous or sequential) administration in the prophylaxis and / or treatment of autoimmune diseases, preferably rheumatoid arthritis, psoriatic arthritis, cystic fibrosis complication of arthritis, lupus nephritis, systemic lupus erythematosus, uveitis, Myasthenia gravis and / or granulomatosis with polyangitis (Wegener's disease); and / or in the context of organ transplantation prophylaxis and / or treatment, preferably kidney transplantation and / or liver transplantation; and / or in the prophylaxis and / or treatment of oncological diseases, preferably melanomas, sarcoma
  • autoimmune diseases preferably rheum
  • the administration of the pharmaceutical composition according to the invention can thus also lead to improved patient compliance.
  • compositions according to the invention which contain 14 to 17.5 mg, preferably 15 to 17.5 mg, more preferably 15 mg leflunomide as a single dose and administered once a day, surprisingly show the same or improved activity, in particular in the prophylaxis and / or Treating autoimmune diseases, preferably rheumatoid arthritis, psoriatic arthritis, cystic fibrosis complication of cystic fibrosis, lupus nephritis, systemic lupus erythematosus, uveitis, myasthenia gravis and / or granulomatosis with polyangitis (Wegener's disease) over pharmaceutical compositions, containing 20 mg leflunomide as a single dose and administered once daily.
  • autoimmune diseases preferably rheumatoid arthritis, psoriatic arthritis, cystic fibrosis complication of cystic fibrosis, lupus nephritis, systemic lupus erythe
  • compositions according to the invention which contain 14 to 17.5 mg, preferably 15 to 17.5 mg, more preferably 15 mg leflunomide as a single dose and administered once, twice, three times or four times a day, depending on the severity of the disease, surprisingly show one same or improved efficacy compared to the currently known therapeutic proposals, in particular in the prophylaxis and / or treatment in the context of organ transplantation, preferably kidney transplantation or liver transplantation; and / or oncological diseases, preferably melanomas, sarcomas, gliomas, prostate carcinomas, brain and / or CNS tumors; and / or human immunodeficiency virus (HIV) diseases.
  • organ transplantation preferably kidney transplantation or liver transplantation
  • oncological diseases preferably melanomas, sarcomas, gliomas, prostate carcinomas, brain and / or CNS tumors
  • HAV human immunodeficiency virus
  • autoimmune diseases preferably rheumatoid arthritis, psoriatic arthritis, cystic fibrosis complication of arthritis, lupus nephritis, systemic lupus erythematosus, uveitis, myasthenia gravis and / or granulomatosis with polyangitis (Wegener's disease)
  • the number of side effects in particular hematotoxic and / or hepatotoxic and / or gastrointestinal side effects and / or the severity of the side effects by the single daily administration of a single pharmaceutical dosage of 14 to 17.5 according to the invention mg, preferably 15 to 17.5 mg, more preferably 15 mg leflunomide are reduced compared to a single dose of 20 mg or 10 mg leflunomide, whereby the number of treatment discontinuations or therapy changes can be reduced.
  • a pharmaceutical composition according to the invention containing 14 to 17.5 mg, preferably 15 to 17.5 mg, more preferably 15 mg leflunomide single dose in the prophylaxis and / or treatment of autoimmune diseases, preferably of rheumatoid arthritis Psoriatic arthritis, arthritis as a complication of cystic fibrosis, lupus nephritis, systemic lupus erythematosus, uveitis, myasthenia gravis and / or granulomatosis with polyangitis (Wegener's disease); and / or organ transplantation, preferably kidney transplantation and / or liver transplantation; and / or oncological diseases, preferably melanomas, sarcomas, gliomas, prostate carcinomas, brain and / or CNS tumors; and / or diseases with the Human Immunodeficiency Virus (HIV) compared to the single dose of 20 mg and / or HIV
  • HIV Human Immunodeficiency
  • a pharmaceutical composition according to the invention contain 14 to 17.5 mg, preferably 15 to 17.5 mg, more preferably 15 mg single-dose leflunomide can thus be an (improved) personalized therapy in the prophylaxis and / or treatment of autoimmune diseases, preferably of rheumatoid Arthritis, psoriatic arthritis, arthritis as a complication of cystic fibrosis, lupus nephritis, systemic lupus erythematosus, uveitis, myasthenia gravis, and / or granulomatosis with polyangitis (Wegener's disease); and / or in the context of organ transplantation, preferably kidney transplantation or liver transplantation; and / or oncological diseases, preferably melanomas, sarcomas, gliomas, prostate carcinomas, brain and / or CNS tumors; and / or diseases with the Human Immunodeficiency Virus (HIV).
  • autoimmune diseases
  • a pharmaceutical composition according to the invention containing 14 to 17.5 mg, preferably 15 to 17.5 mg, more preferably 15 mg of single dose leflunomide according to the first subject of the invention may also be advantageous in certain patient populations compared to the commercial single doses of 20 mg leflunomide, if there is an individually unfavorable risk-benefit profile due to an adverse event or toxicity of leflunomide.
  • a corresponding unfavorable risk-benefit profile may preferably be based, for example, on the polymorphism of genes coding for proteins, in particular in the metabolism (metabolization), in the treatment of rheumatoid arthritis and in particular in a treatment regimen with one or more further autoimmune drugs ), preferably in the transport or uptake from the gastrointestinal tract, the distribution in the body (plasma level) or the excretion (for example, via the bile) of Leflunomide and / or its metabolites, preferably its active metabolite teriflunomide.
  • the composition according to the invention of the first article of the invention is administered to patients, preferably humans, which have a polymorphism of cytochrome P 450 2C19 (CYP2C19) enzyme and in particular represent poor to intermediate metabolizers (see Mead et al.: Polymorphisms in cytochromes P450 2C19 enzymes and cessation of leflunomide in patients with rheumatoid arthritis, Arthritis Research & Therapy 2012 14: R163). Poor CYP2C19 metabolizers are characterized by Wiese et al.
  • a composition according to the invention comprising 14 to 17.5 mg, preferably 15 to 17.5 mg, more preferably 15 mg single dose of leflunomide according to the first subject of the invention, in particular in the treatment of rheumatoid arthritis, can thus reduce the toxicity due to the reduced leflunomide content and thus lead to a reduction in the treatment discontinuation of leflunomide, especially in administration with other autoimmune drugs.
  • composition according to the invention of the first article according to the invention is administered to patients, preferably humans, having a polymorphism on the ATP binding cassette subfamily G member 2 (ATP binding cassette subfamily G member 2, ABCG2), also known as breast cancer resist protein BCRP) (See Wiese et al .: Polymorphisms in cytochrome P450 2C19 enzymes and cessation of leflunomide in patients with rheumatoid arthritis.) Arthritis Research & Therapy 2012 14: R163).
  • ATP binding cassette subfamily G member 2 ATP binding cassette subfamily G member 2, ABCG2
  • BCRP breast cancer resist protein
  • Patients with a corresponding ABCG2 genotype or BCRP genotype have a disadvantageous risk-benefit profile with regard to the side effect diarrhea and are more likely to break the leflunomide therapy, especially in the treatment of rheumatoid arthritis and especially in therapy from other drugs.
  • Administration of a composition according to the invention containing 14 to 17.5 mg, preferably 15 to 17.5 mg, more preferably 15 mg single-dose leflunomide according to the first subject of the invention, in particular in the treatment of rheumatoid arthritis can thus be reduced on account of the reduced lefluide content diarrhea and / or diarrhea and thus lead to a reduction in the treatment discontinuation of leflunomide, especially in the administration of leflunomide with other autoimmune drugs.
  • a pharmaceutical composition according to the invention containing 14 to 17.5 mg, preferably 15 to 17.5 mg, more preferably 15 mg of single dose leflunomide according to the first subject of the invention may also be advantageous over the commercial single doses of 20 mg leflunomide, if steady state level leflunomide and / or its metabolites, preferably teriflunomide.
  • a correspondingly advantageous risk-benefit profile can preferably be based on the treatment of rheumatoid arthritis and in particular in a treatment regimen with one or more further autoimmune active substances, for example on a saturation of transporter proteins, which in particular is absorbed from the gastrointestinal tract. Tract, the distribution in the body (plasma levels) and / or excretion (for example, via the bile) of leflunomide and / or its metabolites, preferably teriflunomide intervene.
  • the composition according to the invention of the first article according to the invention is preferably administered to patients, preferably humans, in the treatment of rheumatoid arthritis and in particular in a therapy regimen with one or more further autoimmune drugs.
  • Polymorphism of the ABCG2 / BCRP transporter For simplicity, reference will be made below to BCRP, which is used interchangeably with ABCG2 in the context of the present invention.
  • BCRP BCRP
  • Such transporter proteins play an important role in the absorption, distribution, metabolism and / or excretion of leflunomide and / or its metabolites, preferably teriflunomide.
  • BCRP is one of the most important efflux transporters of the cells of the endo- and epithelium. In vitro studies show that in particular leflunomide and its metabolite teriflunomide as substrates have a high binding affinity to the BCRP transporter [Bartlett, R.R., et al., Effects of leflunomide on immune responses and models of inflammation. Springer Semin Immunopathol, 1993. 14 (4): p. 381-94].
  • the saturation of the BCRP transporter thus plays an important role i) for the achievement of therapeutically effective plasma levels of leflunomide and / or its metabolites, preferably teriflunomide, especially with regard to the induction phase and ii) for the time necessary to reach the steady state level of Leflunomide and / or its metabolites, preferably teriflunomide, since leflunomide and / or its metabolites, preferably teriflunomide, are substrates for this BCRP transporter.
  • composition according to the invention comprising 14 to 17.5 mg, preferably 15 to 17.5 mg, more preferably 15 mg single dosage of leflunomide according to the first subject of the invention, may preferably be used in the treatment of rheumatoid arthritis and in particular in a therapy regimen with one or more further autoimmune drugs to a
  • Patients with the C.421CA genotype and a polymorphism of the BCRP transporter protein usually have higher plasma levels of leflunomide metabolites, preferably teriflunomide, than patients without this polymorphism, therefore this polymorphism results in inter-individual variability of plasma levels of leflunomide metabolites in the treatment of rheumatoid Arthritis, and particularly in a regimen of therapy with one or more other autoimmune drugs [Williams, JW, et al., Immunosuppressive effects of leflunomide in a cardiac allograft model. Transplant Proc, 1993. 25 (1 Pt 1): p. 745-6]. This circumstance is particularly relevant when one or more of the other autoimmune drugs in the combination therapy regimen itself and / or its metabolites also constitute substrates for this BCRP transporter protein.
  • saturation and polymorphism of the BCRP transporter proteins play an important role, preferably in the treatment of rheumatoid arthritis and especially in a regimen of one or more other autoimmune drugs, because of the saturation or polymorphism of the BCRP transporter proteins, plasma levels and or the time necessary to achieve a steady state level of leflunomide and / or its metabolites, preferably teriflunomide, and / or the time to reach the therapeutic efficacy and / or toxicity level of leflunomide and / or its metabolites , preferably teriflunomide can be altered.
  • This circumstance is particularly relevant when one or more of the other autoimmune drugs in the combination therapy regimen itself and / or its metabolites also constitute substrates for this BCRP transporter protein.
  • composition according to the invention containing 14 to 17.5 mg, preferably 15 to 17.5 mg, more preferably 15 mg single dose of leflunomide according to the first subject of the invention, especially in the treatment of rheumatoid arthritis, may consequently be due to an altered ratio of plasma content of leflunomide its metabolites, preferably teriflunomide, to reduce toxicity and thus reduce tion of treatment discontinuation under leflunomide, especially in combination with one or more other autoimmune drugs.
  • the pharmaceutical composition comprising leflunomide, characterized in that the composition is prepared or prepared as a single dose of 14 to 17.5 mg, preferably 15 to 17.5 mg, more preferably 15 mg leflunomide.
  • the pharmaceutical compositions of the first article of the invention are preferably characterized in that the compositions are solid or liquid and suitable for oral administration.
  • Preferred solid pharmaceutical compositions for oral administration according to the invention are selected from the group consisting of powders, pellets, globules, granules, tablets and / or capsules, particularly preferably tablets, more preferably film-coated tablets.
  • Preferred liquid pharmaceutical compositions of the invention for oral administration are selected from the group consisting of elixirs, solutions, suspensions, emulsions, concoctions, syrups, juices and / or drops.
  • the pharmaceutical compositions of the first subject of the invention can be used as retarded or non-retarded formulation according to the invention.
  • auxiliaries customary for the respective pharmaceutical formulation can be used for the preparation of the pharmaceutical compositions according to the invention according to the first aspect of the invention.
  • compositions according to the first subject of the invention may be selected as pharmaceutically acceptable excipients depending on the type of tabletting (direct tableting, dry or wet granulation) each suitable excipients from the group consisting of i) fillers, preferably starch and Starch derivatives, particularly preferably potato, wheat and / or maize starch (derivatives), lactose, lactose monohydrate, mannitol, sorbitol, calcium carbonate, levulose, glucose, cellulose, microcrystalline cellulose, hydroxypropylcellulose, and / or calcium phosphates, particularly preferably Calcium phosphate, particularly preferred fillers are selected from the group consisting of lactose, lactose monohydrate, di-calcium phosphate and / or hydroxypropyl cellulose, preferably lactose monohydrate; ii) disintegrants, preferably starch or starch derivatives, particularly preferably potato, wheat and / or maize starch (derivatives), lactose, lacto
  • E1200 hypromellose, triacetin, macrogol, iron oxides (for example red and / or yellow), polyvinyl alcohol, titanium dioxide, talc, lecithin (preferably from soybeans), xanthan and / or suitable polyacrylic acid derivatives and / or (soluble) collidones.
  • the pharmaceutical compositions according to the invention additionally comprise a pH regulator, more preferably mono- or polybasic organic and / or inorganic acids as pharmaceutically acceptable excipients, wherein the inorganic Acids preferably selected from the group consisting of phosphoric acid and sulfuric acid, the acid-reacting salts such as dihydrogen phosphates and hydrogen sulfates and their condensates, such as polyphosphoric acid, and / or inorganic buffer systems which give a pH of less than 7 in aqueous solution, are selected ; and wherein the organic acids are preferably selected from the group consisting of carboxylic acids, preferably tartaric acid, malic acid, fumaric acid, citric acid, malonic acid, maleic acid and methane, ethane and / or p-toluenesulfonic acid, more preferably tartaric acid, malic acid, fumaric acid
  • compositions according to the invention are preferred because they additionally have the storage stability of leflunomide in the pharmaceutical composition compared to phar- can increase leflunomide without added acid, ie reduce the conversion of leflunomide to teriflunomide during storage.
  • the first subject of the invention comprises a tablet composition according to the invention in addition to the proportion of 14 to 17.5 mg, preferably 15 to 17.5 mg, more preferably 15 mg leflunomide the following auxiliaries in a suitable amount, namely a) lactose monohydrate , low-substituted hydroxypropyl cellulose, a pH regulator, preferably selected from organic acid, more preferably tartaric acid or citric acid, sodium lauryl sulfate and magnesium stearate or b) corn starch, povidone (E 1201), crospovidone (E1202), fumed silica, magnesium stearate (E470b) and lactose monohydrate.
  • the following auxiliaries in a suitable amount, namely a) lactose monohydrate , low-substituted hydroxypropyl cellulose, a pH regulator, preferably selected from organic acid, more preferably tartaric acid or citric acid, sodium lauryl sulfate and magnesium stearate or
  • film-coated tablets suitable amounts of the following film-coating auxiliaries are preferably used, namely a) polyvinyl alcohol, titanium dioxide, talc, lecithin and xanthan or b) talcum (E553b), hypromellose (E 464), titanium dioxide (E171), macrogol 8000 and optionally iron (III) hydroxide oxide (E 172).
  • film-coating auxiliaries namely a) polyvinyl alcohol, titanium dioxide, talc, lecithin and xanthan or b) talcum (E553b), hypromellose (E 464), titanium dioxide (E171), macrogol 8000 and optionally iron (III) hydroxide oxide (E 172).
  • compositions according to the invention for the prophylaxis and / or treatment of autoimmune diseases preferably selected from a group consisting of rheumatoid arthritis, psoriatic arthritis, cystic fibrosis complication, lupus nephritis, systemic lupus erythematosus , Uveitis, myasthenia gravis, granulomatosis with polyangitis (Wegener's disease); in the context of organ transplants, preferably selected from the group consisting of kidney transplantation and / or liver transplantation; of oncological diseases, preferably selected from the group consisting of melanomas, sarcomas, gliomas, prostate carcinomas, brain and / or CNS tumors; and / or diseases with the Human Immunodeficiency Virus (HIV), more preferably for the prophylaxis and / or treatment of rheumato
  • HIV Human Immunodeficiency Virus
  • the pharmaceutical composition according to the invention containing 14 to 17.5 mg, preferably 5 to 17.5 mg, more preferably 15 mg leflunomide once daily or depending on the nature and / or severity of the disease two, three or four times daily (simultaneous or sequentially) for the prophylaxis and / or treatment of the aforementioned diseases.
  • the "simultaneous" administration according to the first subject of the invention relates to the twice, three or four times daily administration of a pharmaceutical composition according to the invention containing leflunomide prepared as a single dose of 14 to 17.5 mg, preferably 15 to 17.5 mg, particularly preferably 15 mg leflunomide and means that the pharmaceutical composition according to the invention is taken simultaneously, ie in close time sequence, usually over a period of up to 10 minutes, preferably up to 5 minutes, more preferably up to 1 minute from the patient.
  • the "sequential" administration according to the first subject of the invention relates to the twice, three or four times daily administration of a pharmaceutical composition according to the invention containing leflunomide prepared as a single dose of 14 to 17.5 mg, preferably 15 to 17.5 mg, particularly preferably 15 mg leflunomide and means that the pharmaceutical composition according to the invention sequentially, ie offset in time, usually at intervals of about 12 hours, especially in a twice-daily administration, at a distance of about 8 hours, especially when administered three times daily and / or at a distance is taken by the patient of about 6 hours, especially in a four times daily administration.
  • the ingestion of the pharmaceutical compositions according to the first subject of the invention may usually be carried out at all times of day and night as well as before, during and after eating, preferably with a time interval before eating.
  • the pharmaceutical composition according to the invention comprising 14 to 17.5 mg, preferably 15 to 17.5 mg, particularly preferably 15 mg leflunomide prepared as a single dose usually once or twice daily (simultaneously or sequentially), more preferably administered once a day, in order to achieve the advantages according to the invention, in particular an optimized effect side-effect profile.
  • the pharmaceutical composition according to the invention containing 14 to 17.5 mg, preferably 15 to 17.5 mg, more preferably 15 mg leflunomide prepared as a single dose usually once, twice or administered three times (simultaneously or sequentially) daily, more preferably twice or three times daily (simultaneously or sequentially) in order to achieve the advantages according to the invention, in particular an optimized effect side-effect profile.
  • the pharmaceutical composition according to the invention containing 14 to 17.5 mg, preferably 15 up to 17.5 mg, more preferably 15 mg leflunomide, prepared as a single dose, usually once, twice, three times or four times daily (simultaneously or sequentially), more preferably twice, three times or four times daily (simultaneously or sequentially), more preferably administered once or four times daily (simultaneously or sequentially) in order to achieve the advantages according to the invention, in particular an optimized effect-side-effect profile.
  • the inventive pharmaceutical composition according to the first subject of the invention preferably to patients with an age of equal to or more than 45 years, more preferably equal to or more than 55 years, even more preferably equal to or more than 65 years more preferably equal to or administered for more than 70 years in order to achieve optimal results of the advantageous effects according to the invention, in particular with regard to the same or improved efficacy, the reduced side effects and the reduced discontinuation of therapy or change to other medicaments.
  • the second subject invention relates to the use of leflunomide for the prophylaxis and / or treatment of autoimmune disease, preferably rheumatoid arthritis, psoriatic arthritis, cystic fibrosis complication of cystic fibrosis, lupus nephritis, systemic lupus erythematosus, uveitis, myasthenia gravis and / or of granulomatosis with polyangitis (Wegener's disease); and / or in the context of organ transplantation prophylaxis and / or treatment, preferably kidney transplantation and / or liver transplantation; and / or in the prophylaxis and / or treatment of oncological diseases, preferably melanomas, sarcomas, gliomas, prostate carcinomas, brain and / or CNS tumors; and / or in the prophylaxis and / or treatment of diseases with the human immunodeficiency virus (HIV) characterized in
  • the expression "means that leflunomide is prepared as a single dose of a pharmaceutical composition with 14 to 17.5 mg, preferably 15 to 17.5 mg, more preferably 15 mg leflunomide", that the commercially available pharmaceutical composition according to the invention already in is present in such a form that one or more single dose formulations containing 14 to 17.5 mg, preferably 15 to 17.5 mg, more preferably 15 mg leflunomide are present.
  • the expression "that leflunomide can be prepared as a single dose of a pharmaceutical composition with 14 to 17.5 mg, preferably 15 to 17.5 mg, more preferably 15 mg leflunomide” means that the commercially available pharmaceutical composition according to the invention does not yet is present as a single dose formulation with 14 to 17.5 mg, preferably 15 to 17.5 mg, more preferably 15 mg leflunomide divided, but in particular In particular, it can be divided by the patient so that a pharmaceutical single-dose formulation according to the invention with 14 to 17.5 mg, preferably 15 to 17.5 mg, particularly preferably 15 mg leflunomide is prepared.
  • such a single dosage formulation can be prepared, for example, by measuring the liquid by means of a measuring cup or measuring spoon or by paying drops or by any other suitable method.
  • such a unit dosage formulation may be prepared, for example, by breaking a (film) tablet, preferably a scored (film) tablet, counting pellets, globules or granules, or any other suitable method.
  • compositions according to the invention which are tabular in the following, comprising leflunomide, in particular as film tablets according to the invention:
  • Lactose monohydrate (Ph. Eur.) 50,000 - 45,000 215,000 106,500
  • Microcrystalline Cellulose (Ph. Eur.) 45,000 25,000 85,000 55,000 35,000
  • Croscarmellosis (Ph. Eur.) - 15,000 5,500 - 8,500
  • Polysorbate 80 (Ph. Eur.) 0.500 - - - -
  • Weight Tablet Core (mg) 130,000 154,000 172,500 293,000 194,000
  • Hypromellose (Ph. Eur.) 1, 461 1, 461 5,200 0.250
  • Titanium dioxide (Ph. Eur.) 1, 250 1, 250 2,110
  • Weight Film-coated tablet (mg) 134,000 158,000 N / A 301, 000 197,050 Ingredients (in mg / tablet) F6 F7 F8 F9 F10
  • Lactose monohydrate (Ph. Eur.) 80,000 120,000 36,500
  • Croscarmellosis (Ph. Eur.) 10,000 12,000
  • Weight Film-coated tablet (mg) 149,000 154,500 134,500 N / A 144,250 Ingredients (in mg / tablet) F11 F12 F13 F14
  • Lactose monohydrate (Ph. Eur.) 80,000 105,000 118,000 100,000
  • Corn starch (Ph. Eur.) 18,000 6,300 25,000
  • Carboxamethyl starch Na (Ph. Eur.) 12,000 5,000
  • Citric acid anhydrous (Ph. Eur.)
  • Weight Film-coated tablet (mg) 119,00 164,000 163,500 220,500
  • the individual features of the above exemplary embodiments of pharmaceutical compositions according to the invention can be combined separately in each case also in combination with features of the further embodiments or the general description of the invention.
  • a pharmaceutical composition according to the invention containing 14 to 17.5 mg, preferably 15 to 17.5 mg, more preferably 15 mg Leflunomid- single dose according to the first subject of the invention and their use according to the second subject invention preferably in the treatment of rheumatoid arthritis and in particular in a treatment regimen with one or more other autoimmune active ingredients compared to the commercial single doses of 10 mg and 20 mg leflunomide can be detected in animal models.
  • animal models allow the study of autoimmune diseases, in particular of chronic diseases such as rheumatoid arthritis (RA).
  • Such animal models include, but are not limited to, the collagen-induced-arthritis (CIA) animal model, the adjuvant-induced arthritis (AIA) animal model and the experimental allergy-encephalomyelitis (EAE) animal model, as well as animal models for graft versus Host disease or for graft rejection reactions.
  • animal models for the study of other autoimmune diseases such as psoriatic arthritis, arthritis as a complication of cystic fibrosis, lupus nephritis, systemic lupus erythematosus, uveitis, myasthenia gravis, and / or granulomatosis with polyangitis (Morbus Wegner) may also be used.
  • animal models of chronic autoimmune diseases in particular animal models of rheumatoid arthritis, it may be similar to the treatment of patients with autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, cystic fibrosis complication, lupus nephritis, systemic lupus erythematosus, uveitis, myasthenia gravis, and / or granulomatosis Polyangitis (Wegener's disease) to an altered metabolism and / or pharmacokinetics and / or pharmacodynamics of the active ingredients.
  • autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, cystic fibrosis complication, lupus nephritis, systemic lupus erythematosus, uveitis, myasthenia gravis, and / or granulomatosis Polyangitis (Wegener's disease) to an altered metabolism and
  • the abovementioned animal models are suitable for studying the risk-benefit ratio of corresponding active ingredients, preferably leflunomide and / or its metabolites, such as teriflunomide. So far, safety studies in which na ⁇ ve, untreated animals have been treated with leflunomide have been published. The aforementioned animal models can represent the patient situation and allow conclusions to be drawn on the risk-benefit ratio without compromising the safety of humans.
  • a pharmaceutical composition according to the invention due to the single dose of 14 to 17.5 mg, preferably 15 to 17.5 mg, more preferably 15 mg leflunomide per pharmaceutical formulation according to the first subject of the invention and their use according to the second subject of the invention in one or more animal models of these diseases, such as, but not limited to, the collagen-induced arthritis (CIA) RA animal model
  • CIA collagen-induced arthritis
  • a comparable or improved efficacy in the prophylaxis and / or treatment of autoimmune diseases preferably rheumatoid arthritis, psoriatic arthritis, cystic fibrosis complication of cystic fibrosis, lupus nephritis, systemic lupus erythematosus, uveitis, myasthenia gravis and / or of granulomatosis with polyangitis (Wegener's disease); and / or in the context of organ transplantation prophylaxis and / or treatment, preferably kidney transplantation and / or liver transplantation; and / or in the prophylaxis and / or treatment of oncological diseases, preferably melanomas, sarcomas, gliomas, prostate carcinomas, brain and / or CNS tumors; and / or in the prophylaxis and / or treatment of diseases with the Human Immunodeficiency Virus (HIV) compared to the standard therapy with 20 mg
  • the film-coated tablets according to the invention can be prepared in accordance with conventional preparation processes (direct tabletting, dry or wet granulation). According to a preferred embodiment, all or part of the ingredients of the tablet core can be compressed to a tablet core in accordance with wet granulation methods. In a suitable apparatus, the tabs lettenkerne then coated with the ingredients of the film coating and optionally then dried.
  • RA Rheumatoid arthritis
  • CIA collagen type II-induced arthritis
  • PIA pristan (2, 6, 10, 14-tetramethylpentadecane) -induced arthritis
  • adjuvant-induced arthritis Oil-induced arthritis, avidin-induced arthritis, collagen type XI-induced arthritis and oligomeric matrix protein-induced arthritis of the cartilage.
  • CIA is one of the most commonly used models of RA, and can be easily induced by intradermal injection of autologous or heterologous collagen type II (Cll) with incomplete Freund's adjuvant in susceptible rats and mice.
  • Another commonly used model of RA is PIA, which is induced by a single subcutaneous injection of pristane.
  • PIA is induced by a single subcutaneous injection of pristane.
  • disease progression is followed for 28 days, with symptoms occurring regularly 14 days after pristane injection.
  • the peak of the disease symptoms is usually about 21 days after disease induction.
  • the disease symptoms in the CIA model usually begin 18 days after Cll administration, with the peak of the disease symptoms being about 28 days after disease induction.
  • DA rats from Taconic Europa (DK) can be used as animals for the aforementioned models, preferably keeping the animals in a specific pathogen-free state and a 12-hour light-dark cycle.
  • CM is usually produced from the dorsal root cartilage of the DA rat by the pepsin digestion method (see LU et al: Immunization of rats with homologous type XI collagen leads to chronic and recurrent arthritis, with different genetics and joint pathology, as arthritis induced with homologous type II collagen J Autoimmun 2002; 18: 199-211).
  • the mixture is usually extracted with buffer (1.0 M NaCl / 50 mM Tris / pH 7.5). Subsequently, 0.9 M NaCl can be used to precipitate C II.
  • the collagen is usually lyophilized, weighed, and then dissolved and stored in 0.1 M acetic acid until use. The purity of Cll can be detected by Coomasssie blue staining after SDS-PAGE analysis.
  • rats are usually immunized by a single intradermal injection of 150 ⁇ emulsion containing 150pg C II dissolved in 75 ⁇ _ 0.1mol / l acetic acid and 75 ⁇ incomplete Freund's adjuvant (Sigma-Aldrich, USA), i. induces the disease.
  • rats are usually injected subcutaneously at the base of the tail with 150 ⁇ _pristane (Acros Organics, Belgium) to induce the disease.
  • Control rats are usually injected subcutaneously with 150 ⁇ _ phosphate buffered saline.
  • a macroscopic scoring system is used to monitor the development of arthritis in all four extremities. Within this rating system is usually
  • the maximum score for each paw is 15.
  • the rats are usually considered 3 times a week after disease induction.
  • the left hind paws of the rats are usually removed and fixed, then descaled in 12.5% EDTA (ethylenediaminetetraacetic acid) solution for 4 weeks. During this time, the solution is usually changed every 2 days.
  • EDTA ethylenediaminetetraacetic acid
  • the decalcified samples are then paraffin embedded and cut into 6 ⁇ m sections of tissue which are then stained with hematoxylin and eosin (H & E).
  • a pathological rating system is commonly used to assess the severity of arthritis. Synovitis is evaluated by the number of synovial cell layer areas, areas of the pannus coating articular surface, infiltration of synovial inflammatory cells and formation of new vessels. Each index is given points from 0 to 3. Articular destruction due to cartilage degradation, bone erosion, synarthrophysis and joint structure are rated 0 to 3 points. A repair of damage from the formation of new cartilage and bone is rated 0 to 3 points.
  • the gastrointestinal tract, kidney, liver, inguinal lymph nodes and popliteric lymph nodes of the rat can be removed and weighed after removal. After paraformaldehyde fixation and H & E staining, the pathological changes in the harvested tissues of both the control and PIA animals can be identified and evaluated.
  • the level of cytochrome P450 can be measured using rat specific, commercially available ELISA kits.
  • ABCG2 ATP-binding cassette subfamily G member 2
  • BCRP breast cancer resistance protein
  • the DHODH level can be measured using a rat-specific commercially available ELISA kit.
  • a cine scan can, as in Fabian, M.A. et al. (A small molecule kinase interaction map for clinical kinase inhibitors, Nat. Biotechnol., 23, 329-336, 2005) and Wodicka, L.M. et al. (Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry, Chem. Biol. 17, 1241-1249, 2010).
  • Kinases as fusions with T7 phage are produced in an E. coli host, which is usually produced from strain BL21. E. coli is usually cultured up to the log phase and infected with T7 phages and incubated with shaking at 32 ° C until lysis. The lysates are centrifuged and filtered to remove cell debris. The remaining kinases are expressed as fusions with NF- ⁇ B in HEK-293 cells. The constructs are then labeled with DNA for PCR detection.
  • Streptavidin-coated magnetic beads can be treated with biotinylated small molecule ligands for 30 minutes at room temperature to produce affinity resins for kinase assays.
  • the ligated beads are usually blocked with excess biotin and washed with blocking buffer (Seablock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligands and avoid non-specific binding.
  • freshly-isolated tissue is usually washed with ice-cold homogenization buffer and homogenized.
  • Lysed tissue is usually incubated with commercially available primary antibodies that are specific for the corresponding kinases. These are activated by leflunomide and / or teriflunomide. The presence of phosphorylated and total kinases is measured using cell-based ELISA according to the manufacturer's instructions.
  • kinase phosphorylation can be studied in situ.
  • Monoclonal antibodies to kinases activated by leflunomide and / or teriflunomide (kinoscan) are commonly used to localize kinase activity at the cellular source.
  • Binding reactions can be performed by the combination of kinases and ligand affinity beads for leflunomide and its active metabolite A77 1726 (teriflunomide).
  • the kinase concentration in the eluates is usually measured by quantitative PCR.
  • Heparinized whole blood, buffy coat or leukocyte fraction is used by healthy volunteers (human) for the isolation of human peripheral blood mononuclear cells. Heparinized whole blood or spleen is taken from female or male DA rats (Taconic Europa, DK).
  • PBMCs Human peripheral blood mononuclear cells
  • PBMCs Human peripheral blood mononuclear cells
  • the white cells are collected from the Ficoll plasma intermediate phase and washed twice with fresh phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • Cell pellet erythrocytes are lysed with distilled H 2 O and the reaction is stopped by adding the same volume of 1.8% NaCl to restore isotonicity.
  • Isolated cells are resuspended in sterile complete medium R10 (RPMI 1640 with HEPES buffer 25 mM, Glutamax I, 10% fetal bovine serum and penicillin-streptomycin (5 ml penicillin 5000IU / ml + streptomycin 5000pg / ml)
  • the cells are usually plated on 96w plates seeded at a density of 1 x 10 6 cells / ml and incubated for 1 hour with A771726 (concentrations of 1 x 10 9 - 1 x 10 -4 M).
  • the cells are then usually stimulated either with anti-CD3 (10 ng / ml), PHA (1 pg / ml) or ConA (10 g / ml) and incubated at 37 ° C, 5% C0 2 , 90% relative humidity ( relative humidity, RH) for 24, 48 or 72 hours.
  • the cells are usually pulsed with BrdU (30 ⁇ ) one hour before harvest (to measure proliferative capacity).
  • the supernatants are usually collected and stored at -80 ° C for further analysis.
  • the cells are usually stained with surface markers to identify the relevant populations of leukocytes and T cells with anti-CD3, anti-CD4, anti-CD8, B cells with anti-CD19 and monocytes and neutrophils with anti-CD14 / antiCD16 ,
  • the cells are then usually fixed, permeabilized and stained for presence on nuclear BrdU. Subsequently, the cells are usually analyzed using a FACS-Calibur. And% BrdU-positive cells, and recorded within the various leukocyte populations as an indication of proliferative capacity.
  • the cells incubated with teriflunomide and then stimulated with mitogen are also commonly analyzed for DHODH and selected tyrosine kinase activity to study the concentration-effect relationship.
  • Rat white blood cells are isolated from spleens of control rats and pristane-treated rats and gently homogenized to produce a single cell suspension.
  • the spleen cells are usually recovered at the peak of inflammation and placed on Ficoll-Paque.
  • spleen cells can be processed as described for human PBMC, but using rat specific antibody for leukocyte subpopulation.
  • the cells incubated with teriflunomide and then stimulated with mitogen, as mentioned, can also be analyzed for DHODH and selected tyrosine kinase activity to study the concentration-response relationship.
  • D In vivo studies with leflunomide
  • dosage groups for example, 5 different dosages.
  • blood samples are usually taken at 7 to 10 times after administration to measure plasma concentrations of active leflunomide metabolite (A77 1726) teriflunomide. In the animals with inflammation, the dosage and blood collection takes place at the peak of the inflammation.
  • Each group preferably contains a subgroup that is not treated.
  • liver drug clearance e.g. B. expression / activity of the cytochrome P450 (CYP) and of inflow / outflow transporters to confirm, and are sacrificed at the peak of inflammation.
  • the livers are taken from the animals. Part of the liver is prepared for immunohistochemical analysis and used to study expression levels of transporter proteins. The remaining liver tissue is homogenized and microsomes are isolated by differential centrifugation.
  • the total CYP expression in microsomes can be measured (carbon monoxide difference spectrum) and activities of CYP isoforms can be determined by the quantified metabolization of testosterone.
  • Example 4 Effect of inflammation on efficacy and toxicity Dose-response relationship of leflunomide
  • Male DA rats aged 8 to 12 weeks are randomly divided into 2 groups, a PIA group and a control group.
  • leflunomide for example 4 different dosages or vehicle
  • blood samples are usually taken at 7 to 10 times on Day 1 and on the day of peak disease in animals with inflammation to measure plasma concentrations of active leflunomide metabolite (A77 1726) teriflunomide.
  • Blood samples taken at the peak of the disease may be further used for clinical chemistry, hematology and plasma markers, e.g. As cytokines are analyzed.
  • efficacy parameters disease score
  • general health parameters Weight, behavior
  • Tissue samples taken for ex vivo measurement in Example 4 can be used to establish DHODH activity ex vivo.
  • Tissue samples taken for ex vivo measurement in Example 4 can be used to establish kinase activity ex vivo.
  • the phosphorylation status / activity of selected kinases identified in the kinome scan can be quantified using an ELISA-based assay in homogenized tissue and their cellular source located in the tissues using immunohistochemistry.

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Abstract

La présente invention concerne une composition pharmaceutique contenant 14 à 17,5 mg de léflunomide, préparée sous forme de dose unitaire, ainsi que ses utilisations.
EP14700203.4A 2013-01-31 2014-01-06 Composition pharmaceutique contenant du léflunomide Ceased EP2950796A1 (fr)

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DE201310001636 DE102013001636A1 (de) 2013-01-31 2013-01-31 Pharmazeutische Zusammensetzung umfassend Leflunomid
DE102013007106.2A DE102013007106A1 (de) 2013-04-25 2013-04-25 Pharmazeutische Zusammensetzung umfassend Leflunomid
PCT/EP2014/000006 WO2014096464A1 (fr) 2013-01-31 2014-01-06 Composition pharmaceutique contenant du léflunomide

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Title
ANONYMOUS: "Assessment report Leflunomide medac", 30 May 2013 (2013-05-30), pages 1 - 26, XP055507770, Retrieved from the Internet <URL:http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/001227/WC500151737.pdf> [retrieved on 20180918] *
See also references of WO2014096464A1 *
SMOLEN JOSEF S ET AL: "The efficacy of leflunomide monotherapy in rheumatoid arthritis: towards the goals of disease modifying antirheumatic drug therapy", JOURNAL OF RHEUMATOLOGY, JOURNAL OF RHEUMATOLOGY PUBLISHING CO. LTD, CA, vol. 71, no. SUPPLEMENT, 31 May 2004 (2004-05-31), pages 13 - 20, XP009501839, ISSN: 0380-0903 *

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