WO2010070023A2 - Formulations - Google Patents

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Publication number
WO2010070023A2
WO2010070023A2 PCT/EP2009/067361 EP2009067361W WO2010070023A2 WO 2010070023 A2 WO2010070023 A2 WO 2010070023A2 EP 2009067361 W EP2009067361 W EP 2009067361W WO 2010070023 A2 WO2010070023 A2 WO 2010070023A2
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WO
WIPO (PCT)
Prior art keywords
oxo
hydroxy
tetrahydro
methyl
oxoethyl
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PCT/EP2009/067361
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French (fr)
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WO2010070023A3 (en
Inventor
Wolfram Eisenreich
Sebastian Haertter
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Boehringer Ingelheim International Gmbh
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Publication of WO2010070023A2 publication Critical patent/WO2010070023A2/en
Publication of WO2010070023A3 publication Critical patent/WO2010070023A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention is directed to orally deliverable dosage forms with a rapid release profile comprising 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodiazepin- 3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and a method for the production thereof.
  • the invention relates to orally deliverable dosage forms with a high drug load of 4-(1 ,2,4,5-tetrahydro-2-oxo-3H-1 ,3-benzodiazepin-3-yl)-(1 R)-1-[(4-hydroxy- 3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)-1 -piperidinyl]-2-oxoethyl- 1 -pipehdinecarboxylate (see formula (I)) and/or a pharmaceutically acceptable salt thereof exhibiting a rapid release profile of the active ingredient which is needed for a fast onset of pharmacological action.
  • CGRP-antagonists have already been described in International Patent Applications PCT/EP97/04862, PCT/EP03/11762, PCT/EP03/11763 and PCT/EP2005/003094.
  • Such CGRP-antagonists especially 4-(1 ,2,4,5-tetra- hydro-2-oxo-3H-1 ,3-benzodiazepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethyl- phenyl)methyl]-2-[4-(4-morpholinyl)-1 -piperidinyl]-2-oxoethyl-1 -piperidine- carboxylate and its pharmaceutically acceptable salts are promising therapeutic agents for the treatment of a variety of diseases, for instance acute and prophylactic treatment of headaches, particularly migraine and cluster headaches as well as tension headaches, for the treatment of non-insulin- dependent diabetes mellitus (NIDDM), cardiovascular diseases, morphine tolerance, diarrhea caused by Clostridium toxin, skin diseases, particularly thermal and radiation-induced damage including sunburn, lichen, pruritis, pruritic toxidermies and severe itching, inflammatory diseases, e.g.
  • NIDDM non-insulin- dependent diabetes
  • inflammatory diseases of the joints osteoarthritis, rheumatoid arthritis or neurogenic arthritis
  • generalised soft-tissue rheumatism fibromyalgia
  • neurogenic inflammation of the oral mucosa inflammatory lung diseases, allergic rhinitis, asthma and COPD
  • diseases accompanied by excessive vasodilatation and resultant reduced vascular blood flow e.g. shock and sepsis, chronic pain, such as e.g.
  • diabetic neuropathies neuropathies, neuropathies induced by chemotherapy, HIV-induced neuropathies, postherpetic neuropathies, neuropathies induced by tissue trauma, trigeminal neuralgias, temporomandibular dysfunctions, CRPS (complex regional pain syndrome), back pain, and for the treatment of visceral complaints, preferably irritable bowel syndrome (IBS) and inflammatory bowel syndrome, or for preventive or acute therapeutic treatment of the symptoms of menopausal hot flushes caused by vasodilatation and increased blood flow in oestrogen- deficient women and hormone-treated patients with prostate carcinoma and in castrated men.
  • IBS irritable bowel syndrome
  • inflammatory bowel syndrome or for preventive or acute therapeutic treatment of the symptoms of menopausal hot flushes caused by vasodilatation and increased blood flow in oestrogen- deficient women and hormone-treated patients with prostate carcinoma and in castrated men.
  • a pharmaceutical formulation has to comply with depending on the disease to be treated and the active ingredient used.
  • examples of such parameters are the stability of the active agent under various environmental conditions, its stability during production of the pharmaceutical formulation and the stability of the active agent in the final medicament compositions as well as the amount of active ingredient which can be formulated in one single dose.
  • a small dosage unit enhances patient compliance, especially, e.g. in case that patients suffer from nausea.
  • Further relevant parameters with regard to the pharmacological action or efficacy are the in-vitro dissolution profiles, time of maximal plasma concentration, (i.e. time from dosing to maximum measured concentration; (t max ), maximal plasma concentration (c ma ⁇ ) and the area under the time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity; (AUCo-oc).
  • the aim of the invention is thus to provide new orally deliverable formulations containing 4-(1 ,2 ,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodiazepin-3-yl)-(1 f?)-1 -[(4- hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)-1 -piperidinyl]-2-oxo- ethyl-1 -pipehdinecarboxylate and/or a pharmaceutically acceptable salt thereof which is adapted for the treatment of diseases where a rapid release of the active ingredient and a relatively high amount of active ingredient (more than 50 mg) in relatively small dosage units is desirable.
  • Such formulations are especially useful for the treatment of diseases where a quick onset of action is favourable and where patients may suffer from nausea.
  • the present invention provides for orally deliverable pharmaceutical formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetra- hydro-2-oxo-3H-1 ,3-benzodiazepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethyl- phenyl)methyl]-2-[4-(4-morpholinyl)-1 -piperidinyl]-2-oxoethyl-1 -piperidine- carboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, which exhibit an in-vitro rapid release - A -
  • a pharmaceutically orally deliverable dosage form comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodi- azepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -pipehdinecarboxylate and/or one or more of its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient, characterized in that said dosage forms exhibit an in-vitro release profile wherein more than 85% of the active ingredient are released within 15 min after placement of the composition in a standard dissolution test as described in the present invention.
  • It is a further object to provide orally deliverable formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3- benzodiazepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4- morpholinyl)-1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient providing an in-vivo release profile characterized in that the maximal plasma concentration t max (median) is reached after not more than at median 2 h after administration of a single dose to healthy volunteers in fasted state.
  • It is a further object to provide orally deliverable formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodi- azepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient exhibiting an average maximum plasma concentration C ma ⁇ (gMean) between about 50 and about 4000 nmol/L, and an AUCo-oc (gMean) between about 200 and about 14000 nmol x h/L after administration of a single dose to healthy volunteers in fasted state.
  • C ma ⁇ average maximum plasma concentration
  • AUCo-oc gMean
  • the area under the curve (AUC) will be calculated using the linear up/log down algorithm. If an analyte concentration is equal to or higher than the preceding concentration, the linear trapezoidal method will be used. If the analyte concentration is smaller than the preceding concentration, the logarithmic method will be used.
  • AUC tl _ t2 0.5x(t 2 -t 1 )x(C tl + C t2 )
  • AUC 0 _ ⁇ AUC 0 _ tz + C>te ⁇ .
  • C' tz is the concentration predicted by the regression line for the time t z (time of last measurable concentration of the analyte in plasma).
  • the area under the concentration-time curve over the time interval from 0 to the last quantifiable plasma concentration (AUCo-tz) will be calculated by the linear up/log down method as described above.
  • It is a further object to provide orally deliverable formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodi- azepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient providing an in-vivo release profile characterized in that the maximal plasma concentration t max (median) is reached after not more than at median 2h, the average maximum plasma concentration C ma ⁇ (gMean) is between about 50 and about 4000 nmol/L, and an AUCo-oc (gMean) between about 200 and about 14000 nmol x h/L after administration of a single dose to healthy volunteers
  • Such formulations are especially useful for the treatment of diseases in which a fast onset of pharmacological action is desirable like the acute and prophylactic treatment of headaches, particularly migraine and cluster headaches as well as tension headaches, for the treatment of non-insulin-dependent diabetes mellitus (NIDDM), cardiovascular diseases, morphine tolerance, diarrhea caused by Clostridium toxin, skin diseases, particularly thermal and radiation-induced damage including sunburn, lichen, pruhtis, pruritic toxidermies and severe itching, inflammatory diseases, e.g.
  • NIDDM non-insulin-dependent diabetes mellitus
  • inflammatory diseases of the joints osteoarthritis, rheumatoid arthritis or neurogenic arthritis
  • generalised soft- tissue rheumatism fibromyalgia
  • neurogenic inflammation of the oral mucosa inflammatory lung diseases, allergic rhinitis, asthma and COPD
  • diseases accompanied by excessive vasodilatation and resultant reduced vascular blood flow e.g. shock and sepsis
  • chronic pain such as e.g. diabetic neuropathies, neuropathies induced by chemotherapy, HIV-induced neuropathies, postherpetic neuropathies, neuropathies induced by tissue trauma, trigeminal neuralgias, temporomandibular dysfunctions, CRPS
  • IBS irritable bowel syndrome
  • IBS irritable bowel syndrome
  • inflammatory bowel syndrome or for preventive or acute therapeutic treatment of the symptoms of menopausal hot flushes caused by vasodilatation and increased blood flow in oestrogen-deficient women and hormone-treated patients with prostate carcinoma and in castrated men, preferably for the treatment of headaches, particularly migraine and cluster headaches as well as tension headaches, irritable bowel syndrome (IBS) and for preventive or acute therapeutic treatment of the symptoms of menopausal hot flushes caused by vasodilatation and increased blood flow in oestrogen-deficient women.
  • headaches particularly migraine and cluster headaches as well as tension headaches
  • IBS irritable bowel syndrome
  • IBS preventive or acute therapeutic treatment of the symptoms of menopausal hot flushes caused by vasodilatation and increased blood flow in oestrogen-deficient women.
  • It is a further object to provide orally deliverable formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodi- azepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient providing an in-vivo release profile characterized in that the maximal plasma concentration t max (median) is reached after not more than at median 1.5 h, preferably after not more than at median 1.25 h after administration of a single dose to healthy volunteers in fasted state.
  • It is a further object to provide orally deliverable formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodi- azepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient providing an in-vivo release profile characterized in that the maximal plasma concentration t max (median) is reached after not more than at median 1.5 h, the average maximum plasma concentration C ma ⁇ (gMean) is between about 50 and about 4000 nmol/L, and an AUCo-oc (gMean) between about 200 and about 14000 nmol x h/L after administration of a single dose to healthy
  • It is a further object to provide orally deliverable formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodi- azepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient providing an in-vivo release profile characterized in that the maximal plasma concentration t max (median) is reached after not more than at median 1.25 h, the average maximum plasma concentration C ma ⁇ (gMean) is between about 50 and about 4000 nmol/L, and an AUCo-oc (gMean) between about 200 and about 14000 nmol x h/L after administration of a single dose to
  • It is a further object to provide orally deliverable formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodi- azepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient, exhibiting an average maximum plasma concentration C ma ⁇ (gMean) between about 500 and about 4000 nmol/L, and an AUCo-oc (gMean) between about 2000 and about 14000 nmolh/L after administration of a single dose to healthy volunteers in fasted state.
  • C ma ⁇ average maximum plasma concentration
  • AUCo-oc gMean
  • It is a further object to provide orally deliverable formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodi- azepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient providing an in-vivo release profile characterized in that the maximal plasma concentration t max (median) is reached after not more than at median 2 h, the average maximum plasma concentration C ma ⁇ (gMean) is between about 500 and about 4000 nmol/L, and an AUCo-oc (gMean) between about 2000 and about 14000 nmolh/L after administration of a single dose to healthy volunteers in fast
  • It is a further object to provide orally deliverable formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodi- azepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient providing an in-vivo release profile characterized in that the maximal plasma concentration t max (median) is reached after not more than at median 1.5 h, the average maximum plasma concentration C ma ⁇ (gMean) is about 500 and about 4000 nmol/L, and an AUCo-oc (gMean) between about 2000 and about 14000 nmolh/L after administration of a single dose to healthy volunteers in faste
  • It is a further object to provide orally deliverable formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodi- azepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient providing an in-vivo release profile characterized in that the maximal plasma concentration t max (median) is reached after not more than at median 1.25 h, the average maximum plasma concentration C ma ⁇ (gMean) is between about 500 and about 4000 nmol/L, and an AUCo-oc (gMean) between about 2000 and about 14000 nmolh/L after administration of a single dose to healthy volunteers in
  • pharmacokinetic data and dissolution profiles given above expressly include all the numerical values, both whole numbers and fractions, within the range specified.
  • PK studies in order to generate the parameters specified above for a composition according to the present invention are conducted according to a protocol that is generally accepted in the art.
  • at least 6, more preferably at least 8, most preferably more than 10 subjects are enrolled in such studies and receive the composition.
  • Study volunteers were healthy male Caucasian subjects. The medication was administered following an overnight fast of at least 10 hours. Subjects were not allowed to lie down during the 2 hours following drug administration.
  • compositions being in conformance with the above mentioned in-vitro dissolution profiles provide pharmacokinetic profiles according to the present invention.
  • rapid release should be understood as an in-vitro release rate of more than 85% of the active ingredient within 15 min determined under the standard dissolution test described in the USP 31 and European Pharmacopoeia 6.2: paddle test, 900 ml dissolution media at pH 4, 75 rpm.
  • compositions of the present invention are adapted primarily for peroral administration, i.e., for swallowing.
  • peroral administration i.e., for swallowing
  • the composition is in the form of a discrete solid article such as a tablet or capsule, it is typically swallowed whole or broken, with the aid of water or other drinkable fluid.
  • a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3H-1 ,3-benzo- diazepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpho- linyl)-1 -piperidinyl]-2-oxoethyl-1 -pipehdinecarboxylate and/or one or more of its pharmaceutically acceptable salts herein is a dosage amount that, when administered, provides therapeutic benefit in treatment of a condition or disorder for the above and below mentioned diseases and disorders.
  • Suitable amounts per dose are likely to be found in a range from about 10 to about 1000 mg, preferably about 25 to about 500 mg, more preferably about 50 to about 400 mg, more preferably about 50 to about 300 mg expressed as free base 4-(1 ,2,4,5-tetrahydro-2-oxo-3H-1 ,3-benzodiazepin-3-yl)-(1 R)- 1 -[(4- hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)-1 -piperidinyl]-2-oxo- ethyl-1 -pipehdinecarboxylate, for example a suitable amount per dose can be about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg or about 400 mg.
  • the pharmaceutically active substance which is contained in the pharmaceutical formulations according to the present invention is 4-(1 ,2,4,5- tetrahydro-2-oxo-3H-1 ,3-benzodiazepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethyl- phenyl)methyl]-2-[4-(4-morpholinyl)-1 -piperidinyl]-2-oxoethyl-1-piperidine- carboxylate. It can be used in form of the free base, or in form of any known pharmacologically acceptable derivative thereof such as its pharmaceutically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof.
  • Suitable acid addition salts include for example those of the acids selected from succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid and citric acid. Mixtures of the abovementioned acid addition salts may also be used.
  • the following salts are preferred:
  • pharmaceutical formulation should be understood in its broadest meaning comprising any type of formulation, preparation or pharmaceutical dosage form e.g. powder, powder for preparation of a solution, solution, suspension, syrup, pellet (derived either from pellet layering or extrusion), tablet, effervescent tablet, orally disintegrating tablet, sublingual tablet, multilayer tablet, mini tablet, hard or liquid filled capsule.
  • the system may be administered directly, e.g. in form of a tablet, or may be filled in another dosage form such as a capsule.
  • the pharmaceutical formulation according to the invention is a tablet.
  • the pharmaceutical formulation takes the form like a tablet, in addition to the requirement of rapid release and the pharmacokinetic profile a third requirement has to be fulfilled.
  • the formulation should be designed in such a manner that a high drug load, i.e. the ratio of active ingredient to the other ingredients is preferably at least 1 :3, more preferred is 1 :2, even more preferred is 1 :1.
  • composition which will be formulated to a tablet comprises the active ingredient, at least one diluent, a disintegrant, a glidant and at least one lubricant in a ratio as specified in the table below. Accordingly, in a further embodiment the present invention relates to a tablet comprising the following components:
  • a non-functional film-coat can be applied.
  • Suitable diluents according to the invention may be selected from, for example, lactose, in particular lactose monohydrate, starches and derivatives such as pregelatinized starch, corn starch, wheat starch, rice starch, potato starch, stehlizable maize, sodium chloride, calcium carbonate, calcium phosphate, particularly dibasic calcium phosphate, calcium sulphate, dicalcium or tricalcium phosphate, magnesium carbonate, magnesium oxide, cellulose and derivatives, such as powdered cellulose, microcrystalline or silicified microcrystalline cellulose, cellulose acetate, sugars and derivatives such as confectioner's sugar, fructose, sucrose, dextrates, dextrin, D-sorbitol sulfobutylether ⁇ -cyclodextrin, dextrose, polydextrose, trehalose, maltose, maltitol, mannitol, maltodextrin, sorbitol, inulin,
  • Suitable disintegrants according to the invention may be selected from, for example, powdered cellulose, crospovidone, croscarmellose sodium, docusate sodium, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, microcrystalline cellulose, polachlin potassium, sodium starch glycolate, starch, particularly pregelatinized starch, and corn starch.
  • sodium starch glycolate is a preferred disintegrant according to the invention.
  • Suitable lubricants according to the invention are stearic acid as well as salts thereof including sodium stearate, calcium stearate, zinc stearate, magnesium stearate, sodium stearyl fumarate, glyceryl monostearate, particularly magnesium stearate, polyethylene glycols (all types at different molecular weights of PEGs), fumaric acid, glycerides such as glyceryl behenate (Compritol ® 888), Dynasan ® 118 or Boeson ® VP, talc and kaolin.
  • the formulation is a tablet magnesium stearate, sodium stearyl fumarate and talc are preferred.
  • magnesium stearate slows down the in-vitro dissolution due to its hydrophobic properties. Accordingly, in case the formulation is a tablet, sodium stearyl fumarate is most preferred. In case of very high drug loads it is preferred to employ a combination of two lubricants. In this case, sodium stearyl fumarate and talc are most preferred. In this combination the two materials have slightly different functions: talc predominantly prevents the adhesion of the tabletting material to the surface of the dies and punches whereas sodium stearyl fumarate facilitates the ejection of the tablets form the die cavity by reducing the ejection forces.
  • Suitable glidants according to the invention are talc and colloidal silicon dioxide.
  • colloidal silicon dioxide is preferred.
  • the present invention relates to a tablet comprising the following components:
  • a non-functional film-coat can be applied.
  • the formulation according to the invention is a powder
  • the compositions of the formulations can be adopted accordingly.
  • the powders can be filled in capsules or in sachets.
  • the formulation is a powder for oral solution
  • the formulation contains mainly soluble fillers and flavoring agents.
  • the composition of the formulation could be changed that it contains soluble acids and a carbonate component.
  • acids could be citric acid, tartaric acid, ascorbic acid whereas sodium bicarbonate can be used to produce the carbon dioxide gas.
  • Figure 1 This figure shows the in-vitro release profile of a tablet according to the present invention.
  • the formulation (see example 2c) was prepared as described in Example 1 .
  • the in-vitro dissolution testing was performed as described in Example 3.
  • step (1 ) (3) reducing the ribbons obtained during step (1 ) to small granules by suitable milling or sieving steps;
  • step (3) optionally mixing the granules of step (3) with the remaining excipients in a mixer to obtain the final mixture; and (5) tabletting the granules of step (3) or the final mixture of step (4) by compressing it on a suitable tablet press to produce the rapid release tablet cores, (6) optionally film-coating of the tablet cores with a non-functional coat.
  • Example 2a (tablet)
  • Example 2b (tablet)
  • Example 2e (tablet)
  • Example 3a (effervescent tablet)
  • Dissolution testing was performed in apparatus 2 (paddle, USP 31 ).
  • Dissolution media was 900 ml of sodium acetate buffer pH 4 at 37°C.
  • Paddle speed was 75 rpm. Quantification of drug release is performed online using an UV-DAD spectrophotometer.

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Abstract

The present invention is directed to orally deliverable dosage forms with a rapid release profile comprising 4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin- 3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutical acceptable salt thereof and a method for the production thereof.

Description

FORMULATIONS
FIELD OF THE INVENTION
The present invention is directed to orally deliverable dosage forms with a rapid release profile comprising 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodiazepin- 3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and a method for the production thereof.
BACKGROUND OF THE INVENTION
The invention relates to orally deliverable dosage forms with a high drug load of 4-(1 ,2,4,5-tetrahydro-2-oxo-3H-1 ,3-benzodiazepin-3-yl)-(1 R)-1-[(4-hydroxy- 3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)-1 -piperidinyl]-2-oxoethyl- 1 -pipehdinecarboxylate (see formula (I)) and/or a pharmaceutically acceptable salt thereof exhibiting a rapid release profile of the active ingredient which is needed for a fast onset of pharmacological action.
Figure imgf000002_0001
CGRP-antagonists have already been described in International Patent Applications PCT/EP97/04862, PCT/EP03/11762, PCT/EP03/11763 and PCT/EP2005/003094. 4-(1 ,2,4,5-tetrahydro-2-oxo-3H-1 ,3-benzodiazepin-3-yl)- (1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)-1 -piperi- dinyl]-2-oxoethyl-1 -piperidinecarboxylate, its manufacture and pharmaceutically acceptable salts of this compound have been described in WO 2006/100026 and WO 2007/118819. Such CGRP-antagonists, especially 4-(1 ,2,4,5-tetra- hydro-2-oxo-3H-1 ,3-benzodiazepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethyl- phenyl)methyl]-2-[4-(4-morpholinyl)-1 -piperidinyl]-2-oxoethyl-1 -piperidine- carboxylate and its pharmaceutically acceptable salts are promising therapeutic agents for the treatment of a variety of diseases, for instance acute and prophylactic treatment of headaches, particularly migraine and cluster headaches as well as tension headaches, for the treatment of non-insulin- dependent diabetes mellitus (NIDDM), cardiovascular diseases, morphine tolerance, diarrhea caused by Clostridium toxin, skin diseases, particularly thermal and radiation-induced damage including sunburn, lichen, pruritis, pruritic toxidermies and severe itching, inflammatory diseases, e.g. inflammatory diseases of the joints (osteoarthritis, rheumatoid arthritis or neurogenic arthritis), generalised soft-tissue rheumatism (fibromyalgia), neurogenic inflammation of the oral mucosa, inflammatory lung diseases, allergic rhinitis, asthma and COPD, for the treatment of diseases accompanied by excessive vasodilatation and resultant reduced vascular blood flow, e.g. shock and sepsis, chronic pain, such as e.g. diabetic neuropathies, neuropathies induced by chemotherapy, HIV-induced neuropathies, postherpetic neuropathies, neuropathies induced by tissue trauma, trigeminal neuralgias, temporomandibular dysfunctions, CRPS (complex regional pain syndrome), back pain, and for the treatment of visceral complaints, preferably irritable bowel syndrome (IBS) and inflammatory bowel syndrome, or for preventive or acute therapeutic treatment of the symptoms of menopausal hot flushes caused by vasodilatation and increased blood flow in oestrogen- deficient women and hormone-treated patients with prostate carcinoma and in castrated men.
There are a variety of requirements and parameters a pharmaceutical formulation has to comply with depending on the disease to be treated and the active ingredient used. Without being restrictive, examples of such parameters are the stability of the active agent under various environmental conditions, its stability during production of the pharmaceutical formulation and the stability of the active agent in the final medicament compositions as well as the amount of active ingredient which can be formulated in one single dose. Because small dosage units are easier to swallow, a small dosage unit enhances patient compliance, especially, e.g. in case that patients suffer from nausea. Further relevant parameters with regard to the pharmacological action or efficacy are the in-vitro dissolution profiles, time of maximal plasma concentration, (i.e. time from dosing to maximum measured concentration; (tmax), maximal plasma concentration (cmaχ) and the area under the time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity; (AUCo-oc).
The aim of the invention is thus to provide new orally deliverable formulations containing 4-(1 ,2 ,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodiazepin-3-yl)-(1 f?)-1 -[(4- hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)-1 -piperidinyl]-2-oxo- ethyl-1 -pipehdinecarboxylate and/or a pharmaceutically acceptable salt thereof which is adapted for the treatment of diseases where a rapid release of the active ingredient and a relatively high amount of active ingredient (more than 50 mg) in relatively small dosage units is desirable. Such formulations are especially useful for the treatment of diseases where a quick onset of action is favourable and where patients may suffer from nausea.
Description of the invention
Accordingly, the present invention provides for orally deliverable pharmaceutical formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetra- hydro-2-oxo-3H-1 ,3-benzodiazepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethyl- phenyl)methyl]-2-[4-(4-morpholinyl)-1 -piperidinyl]-2-oxoethyl-1 -piperidine- carboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, which exhibit an in-vitro rapid release - A -
profile, i.e. a pharmaceutically orally deliverable dosage form, comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodi- azepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -pipehdinecarboxylate and/or one or more of its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient, characterized in that said dosage forms exhibit an in-vitro release profile wherein more than 85% of the active ingredient are released within 15 min after placement of the composition in a standard dissolution test as described in the present invention.
It is a further object to provide orally deliverable formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3- benzodiazepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4- morpholinyl)-1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient providing an in-vivo release profile characterized in that the maximal plasma concentration tmax (median) is reached after not more than at median 2 h after administration of a single dose to healthy volunteers in fasted state.
It is a further object to provide orally deliverable formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodi- azepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient exhibiting an average maximum plasma concentration Cmaχ (gMean) between about 50 and about 4000 nmol/L, and an AUCo-oc (gMean) between about 200 and about 14000 nmol x h/L after administration of a single dose to healthy volunteers in fasted state. The area under the curve (AUC) will be calculated using the linear up/log down algorithm. If an analyte concentration is equal to or higher than the preceding concentration, the linear trapezoidal method will be used. If the analyte concentration is smaller than the preceding concentration, the logarithmic method will be used.
Linear trapezoidal rule (t2 > U and Ct2 ≥ Qi):
The area of the trapezoid between the two data points (ti, Cn) and (t2, Ct2) will be computed by: AUCtl_t2 = 0.5x(t2 -t1)x(Ctl + Ct2)
Logarithmic trapezoid rule (t2 > ti and Ct2 < Cn):
The area of the trapezoid between the two data points (ti, Cn) and (t2, Ct2) will be computed by:
Figure imgf000006_0001
The area under the plasma concentration-time curve over the time interval from 0 extrapolated to infinity (AUCo-∞) will be calculated according to the following equation
AUC0_∞ = AUC0_tz + C>te λ.
where C'tz is the concentration predicted by the regression line for the time tz (time of last measurable concentration of the analyte in plasma). The area under the concentration-time curve over the time interval from 0 to the last quantifiable plasma concentration (AUCo-tz) will be calculated by the linear up/log down method as described above.
The percentage of the AUCo-∞ will be obtained by extrapolation according to the following equation: AUCn -AUC
% AUC -O-' 0-tz X lOO
AUC o-«
It is a further object to provide orally deliverable formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodi- azepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient providing an in-vivo release profile characterized in that the maximal plasma concentration tmax (median) is reached after not more than at median 2h, the average maximum plasma concentration Cmaχ (gMean) is between about 50 and about 4000 nmol/L, and an AUCo-oc (gMean) between about 200 and about 14000 nmol x h/L after administration of a single dose to healthy volunteers in fasted state.
Such formulations are especially useful for the treatment of diseases in which a fast onset of pharmacological action is desirable like the acute and prophylactic treatment of headaches, particularly migraine and cluster headaches as well as tension headaches, for the treatment of non-insulin-dependent diabetes mellitus (NIDDM), cardiovascular diseases, morphine tolerance, diarrhea caused by Clostridium toxin, skin diseases, particularly thermal and radiation-induced damage including sunburn, lichen, pruhtis, pruritic toxidermies and severe itching, inflammatory diseases, e.g. inflammatory diseases of the joints (osteoarthritis, rheumatoid arthritis or neurogenic arthritis), generalised soft- tissue rheumatism (fibromyalgia), neurogenic inflammation of the oral mucosa, inflammatory lung diseases, allergic rhinitis, asthma and COPD, for the treatment of diseases accompanied by excessive vasodilatation and resultant reduced vascular blood flow, e.g. shock and sepsis, chronic pain, such as e.g. diabetic neuropathies, neuropathies induced by chemotherapy, HIV-induced neuropathies, postherpetic neuropathies, neuropathies induced by tissue trauma, trigeminal neuralgias, temporomandibular dysfunctions, CRPS
(complex regional pain syndrome), back pain, and for the treatment of visceral complaints, preferably irritable bowel syndrome (IBS) and inflammatory bowel syndrome, or for preventive or acute therapeutic treatment of the symptoms of menopausal hot flushes caused by vasodilatation and increased blood flow in oestrogen-deficient women and hormone-treated patients with prostate carcinoma and in castrated men, preferably for the treatment of headaches, particularly migraine and cluster headaches as well as tension headaches, irritable bowel syndrome (IBS) and for preventive or acute therapeutic treatment of the symptoms of menopausal hot flushes caused by vasodilatation and increased blood flow in oestrogen-deficient women.
Accordingly, there is still further provided the use of the pharmaceutical oral deliverable dosage forms according to the present invention for the manufacture of a medicament for the treatment of such conditions or disorders for which a fast onset of action is desirable and 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodi- azepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate or a pharmaceutically acceptable salt thereof is indicated.
It is a further object to provide orally deliverable formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodi- azepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient providing an in-vivo release profile characterized in that the maximal plasma concentration tmax (median) is reached after not more than at median 1.5 h, preferably after not more than at median 1.25 h after administration of a single dose to healthy volunteers in fasted state.
It is a further object to provide orally deliverable formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodi- azepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient providing an in-vivo release profile characterized in that the maximal plasma concentration tmax (median) is reached after not more than at median 1.5 h, the average maximum plasma concentration Cmaχ (gMean) is between about 50 and about 4000 nmol/L, and an AUCo-oc (gMean) between about 200 and about 14000 nmol x h/L after administration of a single dose to healthy volunteers in fasted state.
It is a further object to provide orally deliverable formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodi- azepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient providing an in-vivo release profile characterized in that the maximal plasma concentration tmax (median) is reached after not more than at median 1.25 h, the average maximum plasma concentration Cmaχ (gMean) is between about 50 and about 4000 nmol/L, and an AUCo-oc (gMean) between about 200 and about 14000 nmol x h/L after administration of a single dose to healthy volunteers in fasted state.
It is a further object to provide orally deliverable formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodi- azepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient, exhibiting an average maximum plasma concentration Cmaχ (gMean) between about 500 and about 4000 nmol/L, and an AUCo-oc (gMean) between about 2000 and about 14000 nmolh/L after administration of a single dose to healthy volunteers in fasted state.
It is a further object to provide orally deliverable formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodi- azepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient providing an in-vivo release profile characterized in that the maximal plasma concentration tmax (median) is reached after not more than at median 2 h, the average maximum plasma concentration Cmaχ (gMean) is between about 500 and about 4000 nmol/L, and an AUCo-oc (gMean) between about 2000 and about 14000 nmolh/L after administration of a single dose to healthy volunteers in fasted state.
It is a further object to provide orally deliverable formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodi- azepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient providing an in-vivo release profile characterized in that the maximal plasma concentration tmax (median) is reached after not more than at median 1.5 h, the average maximum plasma concentration Cmaχ (gMean) is about 500 and about 4000 nmol/L, and an AUCo-oc (gMean) between about 2000 and about 14000 nmolh/L after administration of a single dose to healthy volunteers in fasted state.
It is a further object to provide orally deliverable formulations comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodi- azepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)- 1 -piperidinyl]-2-oxoethyl-1 -piperidinecarboxylate and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient providing an in-vivo release profile characterized in that the maximal plasma concentration tmax (median) is reached after not more than at median 1.25 h, the average maximum plasma concentration Cmaχ (gMean) is between about 500 and about 4000 nmol/L, and an AUCo-oc (gMean) between about 2000 and about 14000 nmolh/L after administration of a single dose to healthy volunteers in fasted state.
The pharmacokinetic data and dissolution profiles given above expressly include all the numerical values, both whole numbers and fractions, within the range specified.
Preferably PK studies in order to generate the parameters specified above for a composition according to the present invention are conducted according to a protocol that is generally accepted in the art. Preferably at least 6, more preferably at least 8, most preferably more than 10 subjects are enrolled in such studies and receive the composition. Study volunteers were healthy male Caucasian subjects. The medication was administered following an overnight fast of at least 10 hours. Subjects were not allowed to lie down during the 2 hours following drug administration.
Pharmaceutical formulations being in conformance with the above mentioned in-vitro dissolution profiles provide pharmacokinetic profiles according to the present invention.
In the context of the present invention the term "rapid release" should be understood as an in-vitro release rate of more than 85% of the active ingredient within 15 min determined under the standard dissolution test described in the USP 31 and European Pharmacopoeia 6.2: paddle test, 900 ml dissolution media at pH 4, 75 rpm.
The term "orally deliverable" herein means suitable for oral, including peroral and intra-oral (e.g., sublingual or buccal) administration, but compositions of the present invention are adapted primarily for peroral administration, i.e., for swallowing. Where the composition is in the form of a discrete solid article such as a tablet or capsule, it is typically swallowed whole or broken, with the aid of water or other drinkable fluid.
The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about' is used herein to modify a numerical value above and below the stated value by a variance of 20%.
A therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3H-1 ,3-benzo- diazepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpho- linyl)-1 -piperidinyl]-2-oxoethyl-1 -pipehdinecarboxylate and/or one or more of its pharmaceutically acceptable salts herein is a dosage amount that, when administered, provides therapeutic benefit in treatment of a condition or disorder for the above and below mentioned diseases and disorders.
Suitable amounts per dose are likely to be found in a range from about 10 to about 1000 mg, preferably about 25 to about 500 mg, more preferably about 50 to about 400 mg, more preferably about 50 to about 300 mg expressed as free base 4-(1 ,2,4,5-tetrahydro-2-oxo-3H-1 ,3-benzodiazepin-3-yl)-(1 R)- 1 -[(4- hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)-1 -piperidinyl]-2-oxo- ethyl-1 -pipehdinecarboxylate, for example a suitable amount per dose can be about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg or about 400 mg.
The pharmaceutically active substance which is contained in the pharmaceutical formulations according to the present invention is 4-(1 ,2,4,5- tetrahydro-2-oxo-3H-1 ,3-benzodiazepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethyl- phenyl)methyl]-2-[4-(4-morpholinyl)-1 -piperidinyl]-2-oxoethyl-1-piperidine- carboxylate. It can be used in form of the free base, or in form of any known pharmacologically acceptable derivative thereof such as its pharmaceutically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof. In addition the present invention shall be understood to embrace all polymorphs of the active ingredient, of its salts, hydrates and solvates. Suitable acid addition salts include for example those of the acids selected from succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid and citric acid. Mixtures of the abovementioned acid addition salts may also be used. The following salts are preferred:
4-(1 ,2,4,5-tetrahydro-2-oxo-3H-1 ,3-benzodiazepin-3-yl)-(1 R)-1 -[(4-hydroxy- 3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)-1 -piperidinyl]-2-oxoethyl 1 -pipehdinecarboxylate hydrobromide,
4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodiazepin-3-yl)-(1 R)-1-[(4-hydroxy- 3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)-1 -piperidinyl]-2-oxoethyl 1 -pipehdinecarboxylate hydrochloride,
4-(1 ,2,4,5-tetrahydro-2-oxo-3H-1 ,3-benzodiazepin-3-yl)-(1 R)-1 -[(4-hydroxy- 3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)-1 -piperidinyl]-2-oxoethyl 1 -pipehdinecarboxylate phosphate,
4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodiazepin-3-yl)-(1 R)- 1 -[(4-hydroxy- 3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)-1 -piperidinyl]-2-oxoethyl 1 -pipehdinecarboxylate (2R,3R)-2,3-dihydroxybutanedioate,
4-(1 ,2,4,5-tetrahydro-2-oxo-3H-1 ,3-benzodiazepin-3-yl)-(1 R)-1 -[(4-hydroxy- 3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)-1 -piperidinyl]-2-oxoethyl 1 -pipehdinecarboxylate (2S,3S)-2,3-dihydroxybutanedioate. The particular formulation selected for the active ingredient is not critical as long as it achieves a release and/or pharmacokinetic profile as defined herein and is orally deliverable. Accordingly the term "pharmaceutical formulation" according to the present invention should be understood in its broadest meaning comprising any type of formulation, preparation or pharmaceutical dosage form e.g. powder, powder for preparation of a solution, solution, suspension, syrup, pellet (derived either from pellet layering or extrusion), tablet, effervescent tablet, orally disintegrating tablet, sublingual tablet, multilayer tablet, mini tablet, hard or liquid filled capsule. The system may be administered directly, e.g. in form of a tablet, or may be filled in another dosage form such as a capsule. However, in a preferred embodiment the pharmaceutical formulation according to the invention is a tablet.
In case the pharmaceutical formulation takes the form like a tablet, in addition to the requirement of rapid release and the pharmacokinetic profile a third requirement has to be fulfilled. As a relatively high amount of active ingredient is needed, the formulation should be designed in such a manner that a high drug load, i.e. the ratio of active ingredient to the other ingredients is preferably at least 1 :3, more preferred is 1 :2, even more preferred is 1 :1.
It has been found that all these above mentioned requirements are met if the composition which will be formulated to a tablet comprises the active ingredient, at least one diluent, a disintegrant, a glidant and at least one lubricant in a ratio as specified in the table below. Accordingly, in a further embodiment the present invention relates to a tablet comprising the following components:
Compound Amount (% by weight)
4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodiazepin-3-yl)-(1 R)-1 - 25 - 65 [(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4-morpholinyl)-1 -
Figure imgf000015_0001
In a further embodiment the present invention relates to a tablet comprising the following components:
Figure imgf000015_0002
In a further embodiment the present invention relates to a tablet comprising the following components:
Compound Amount (% by weight)
Figure imgf000016_0001
In a further embodiment the present invention relates to a tablet comprising the following components:
Figure imgf000016_0002
In a further embodiment the present invention relates to a tablet comprising the following components:
Figure imgf000017_0001
In a further embodiment the present invention relates to a tablet comprising the following components:
Figure imgf000017_0002
Optionally, a non-functional film-coat can be applied.
Suitable diluents according to the invention may be selected from, for example, lactose, in particular lactose monohydrate, starches and derivatives such as pregelatinized starch, corn starch, wheat starch, rice starch, potato starch, stehlizable maize, sodium chloride, calcium carbonate, calcium phosphate, particularly dibasic calcium phosphate, calcium sulphate, dicalcium or tricalcium phosphate, magnesium carbonate, magnesium oxide, cellulose and derivatives, such as powdered cellulose, microcrystalline or silicified microcrystalline cellulose, cellulose acetate, sugars and derivatives such as confectioner's sugar, fructose, sucrose, dextrates, dextrin, D-sorbitol sulfobutylether β-cyclodextrin, dextrose, polydextrose, trehalose, maltose, maltitol, mannitol, maltodextrin, sorbitol, inulin, xylitol, erythritol, isomalt, kaolin and lactitol. In case the formulation is a tablet, lactose monohydrate and microcrystalline cellulose are the preferred diluents according to the invention.
Suitable disintegrants according to the invention may be selected from, for example, powdered cellulose, crospovidone, croscarmellose sodium, docusate sodium, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, microcrystalline cellulose, polachlin potassium, sodium starch glycolate, starch, particularly pregelatinized starch, and corn starch. In case the formulation is a tablet, sodium starch glycolate is a preferred disintegrant according to the invention.
Suitable lubricants according to the invention are stearic acid as well as salts thereof including sodium stearate, calcium stearate, zinc stearate, magnesium stearate, sodium stearyl fumarate, glyceryl monostearate, particularly magnesium stearate, polyethylene glycols (all types at different molecular weights of PEGs), fumaric acid, glycerides such as glyceryl behenate (Compritol® 888), Dynasan® 118 or Boeson® VP, talc and kaolin. In case the formulation is a tablet magnesium stearate, sodium stearyl fumarate and talc are preferred. However, the use of magnesium stearate slows down the in-vitro dissolution due to its hydrophobic properties. Accordingly, in case the formulation is a tablet, sodium stearyl fumarate is most preferred. In case of very high drug loads it is preferred to employ a combination of two lubricants. In this case, sodium stearyl fumarate and talc are most preferred. In this combination the two materials have slightly different functions: talc predominantly prevents the adhesion of the tabletting material to the surface of the dies and punches whereas sodium stearyl fumarate facilitates the ejection of the tablets form the die cavity by reducing the ejection forces.
Suitable glidants according to the invention are talc and colloidal silicon dioxide. In case the formulation is a tablet, colloidal silicon dioxide is preferred.
Accordingly, in a further embodiment the present invention relates to a tablet comprising the following components:
Figure imgf000019_0001
In a further embodiment the present invention relates to a tablet comprising the following components:
Compound Amount (% by weight)
4-(1 ,2,4,5-tetrahydro-2-oxo-3H-1 ,3-benzodiazepin-3-yl)-(1 R)-1 - 45.5
Figure imgf000020_0001
In a further embodiment the present invention relates to a tablet comprising the following components:
Figure imgf000020_0002
In a further embodiment the present invention relates to a tablet comprising the following components:
Figure imgf000021_0001
In a further embodiment the present invention relates to a tablet comprising the following components:
Figure imgf000021_0002
In a further embodiment the present invention relates to a tablet comprising the following components:
Figure imgf000022_0001
Optionally, a non-functional film-coat can be applied.
In case the formulation according to the invention is a powder the compositions of the formulations can be adopted accordingly. The powders can be filled in capsules or in sachets.
In case the formulation is a powder for oral solution the formulation contains mainly soluble fillers and flavoring agents.
In case the formulation according to the invention is an effervescent tablet the composition of the formulation could be changed that it contains soluble acids and a carbonate component. Examples for acids could be citric acid, tartaric acid, ascorbic acid whereas sodium bicarbonate can be used to produce the carbon dioxide gas. BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 : This figure shows the in-vitro release profile of a tablet according to the present invention. The formulation (see example 2c) was prepared as described in Example 1 . The in-vitro dissolution testing was performed as described in Example 3.
The invention described will now be illustrated by the following Examples. However, it is expressly pointed out that the Examples and description are intended solely as an illustration and should not be regarded as restricting the invention.
Example 1
In the following a preferably process to manufacture a tablet according to the invention is exemplarily described. However, the process steps are not intended to be of limitative character at all.
(1 ) mixing the active ingredient or a pharmaceutically acceptable salt thereof with either all or a portion of the excipients in a mixer, (2) compaction of the mixture of step (1 ) on a suitable roller compactor;
(3) reducing the ribbons obtained during step (1 ) to small granules by suitable milling or sieving steps;
(4) optionally mixing the granules of step (3) with the remaining excipients in a mixer to obtain the final mixture; and (5) tabletting the granules of step (3) or the final mixture of step (4) by compressing it on a suitable tablet press to produce the rapid release tablet cores, (6) optionally film-coating of the tablet cores with a non-functional coat.
The following formulations have been prepared according to the method described above. Example 2a (tablet)
Figure imgf000024_0001
Example 2b (tablet)
Figure imgf000024_0002
Example 2c (tablet)
Figure imgf000024_0003
Figure imgf000025_0001
Example 2d (capsule)
Figure imgf000025_0002
Example 2e (tablet)
Figure imgf000025_0003
Example 3a (effervescent tablet)
Figure imgf000026_0001
Example 3b (effervescent tablet)
Figure imgf000026_0002
Example 3c (powder for oral solution)
Figure imgf000026_0003
Figure imgf000027_0001
Example 4
Dissolution testing was performed in apparatus 2 (paddle, USP 31 ). Dissolution media was 900 ml of sodium acetate buffer pH 4 at 37°C. Paddle speed was 75 rpm. Quantification of drug release is performed online using an UV-DAD spectrophotometer.

Claims

Claims
1. Pharmaceutical orally deliverable dosage form, comprising a therapeutically effective amount of 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3- benzodiazepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4- morpholinyl)-1 -piperidinyl]-2-oxoethyl-1 -pipehdinecarboxylate and/or one or more of its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient, characterized in that said dosage forms exhibit an in-vitro release profile wherein more than 85% of the active ingredient are released within 15 min after placement of the composition in a standard dissolution test.
2. Pharmaceutical formulation according to claim 1 characterized in that it exhibits an in-vivo release profile characterized in that the maximal plasma concentration tmax (median) is reached after not more than at median 2 h after administration of a single dose to healthy volunteers in fasted state.
3. Pharmaceutical formulation according to claim 1 characterized in that it exhibits an in-vivo release profile characterized in that the maximal plasma concentration tmax (median) is reached after not more than at median 1.5 h after administration of a single dose to healthy volunteers in fasted state.
4. Pharmaceutical formulation according to claim 1 characterized in that it exhibits an in-vivo release profile characterized in that the maximal plasma concentration tmax (median) is reached after not more than at median 1.25 h after administration of a single dose to healthy volunteers in fasted state.
5. Pharmaceutical formulation according to one or more of claims 1 to 4 characterized in that it exhibits an average maximum plasma concentration
Cmax (gMean) between about 50 and about 4000 nmol/L, and an AUCo-oc (gMean) between about 200 and about 14000 nmolh/L after administration of a single dose to healthy volunteers in fasted state.
6. Pharmaceutical formulation according to one or more of claims 1 to 4 characterized in that it exhibits an average maximum plasma concentration
Cmax (gMean) between about 500 and about 4000 nmol/L, and an AUCo-oc (gMean) between about 2000 and about 14000 nmolh/L after administration of a single dose to healthy volunteers in fasted state.
7. Pharmaceutical formulation according to one or more of claims 1 to 4 characterized in that it is a tablet.
8. Tablet according to claim 7, characterized in that the tablet consists of
Figure imgf000029_0001
9. Pharmaceutical formulation according to one or more of claims 1 to 8 characterized in that the pharmaceutically acceptable salts of 4-(1 ,2,4,5- tetrahydro-2-oxo-3H-1 ,3-benzodiazepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5- dimethylphenyl)methyl]-2-[4-(4-morpholinyl)-1-piperidinyl]-2-oxoethyl-1 - piperidinecarboxylate are selected from 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3- benzodiazepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4- morpholinyl)-1 -piperidinyl]-2-oxoethyl 1 -piperidinecarboxylate hydrobromide, 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3-benzodiazepin-3-yl)-(1 R)A -[(4-hydroxy- 3,5-dimethylphenyl)methyl]-2-[4-(4-nnorpholinyl)-1 -piperidinyl]-2-oxoethyl 1 - piperidinecarboxylate hydrochloride, 4-(1 ,2,4,5-tetrahydro-2-oxo-3/-/-1 ,3- benzodiazepin-3-yl)-(1 R)-1 -[(4-hydroxy-3,5-dimethylphenyl)methyl]-2-[4-(4- morpholinyl)-1-piperidinyl]-2-oxoethyl 1 -piperidinecarboxylate phosphate, A- (1 ,2,4,5-tetrahydro-2-oxo-3H-1 ,3-benzodiazepin-3-yl)-(1 R)A -[(4-hydroxy- 3,5-dimethylphenyl)methyl]-2-[4-(4-nnorpholinyl)-1 -pipendinyl]-2-oxoethyl 1- piperidinecarboxylate (2R,3R)-2,3-dihydroxybutanedioate, 4-(1 ,2,4,5- tetrahydro-2-oxo-3H-1 ,3-benzodiazepin-3-yl)-(1 R)A -[(4-hydroxy-3,5- dimethylphenyl)methyl]-2-[4-(4-morpholinyl)-1 -piperidinyl]-2-oxoethyl 1 - piperidinecarboxylate (2S,3S)-2,3-dihydroxybutane-dioate.
PCT/EP2009/067361 2008-12-19 2009-12-17 Formulations WO2010070023A2 (en)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
FR2531866A1 (en) * 1982-08-20 1984-02-24 Narcisse Guy Rapidly disintegrating tablets comprising benzodiazepine type compounds
EP1770086A1 (en) * 2005-09-29 2007-04-04 Boehringer Ingelheim Pharma GmbH & Co. KG Selected CGRP antagonists, process for their preparation as well as their use as medicaments
WO2007141285A1 (en) * 2006-06-08 2007-12-13 Boehringer Ingelheim International Gmbh Treatment of gastrointestinal disorders with cgrp-antagonists

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
FR2531866A1 (en) * 1982-08-20 1984-02-24 Narcisse Guy Rapidly disintegrating tablets comprising benzodiazepine type compounds
EP1770086A1 (en) * 2005-09-29 2007-04-04 Boehringer Ingelheim Pharma GmbH & Co. KG Selected CGRP antagonists, process for their preparation as well as their use as medicaments
WO2007141285A1 (en) * 2006-06-08 2007-12-13 Boehringer Ingelheim International Gmbh Treatment of gastrointestinal disorders with cgrp-antagonists

Non-Patent Citations (3)

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Title
LAKE O A ET AL: "In vitro/in vivo correlations of dissolution data of carbamazepine immediate release tablets with pharmacokinetic data obtained in healthy volunteers", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, ELSEVIER SCIENCE PUBLISHERS B.V., AMSTERDAM, NL, vol. 48, no. 1, 1 July 1999 (1999-07-01), pages 13-19, XP004257085, ISSN: 0939-6411, DOI: DOI:10.1016/S0939-6411(99)00016-8 *
MOHAMMAD HOSSAIN ET AL: "Nonlinear Mixed Effects Modeling of Single Dose and Multiple Dose Data for an Immediate Release (IR) and a Controlled Release (CR) Dosage Form of Alprazolam", PHARMACEUTICAL RESEARCH, KLUWER ACADEMIC PUBLISHERS-PLENUM PUBLISHERS, NL, vol. 14, no. 3, 1 March 1997 (1997-03-01), pages 309-315, XP019370609, ISSN: 1573-904X, DOI: DOI:10.1023/A:1012041920119 *
VUCICEVIC K ET AL: "population pharmacokinetic model of carbamazepine derived from routine therapeutic drug monitoring data", THERAPEUTIC DRUG MONITORING, LIPPINCOTT WILLIAMS AND WILKINS, NEW YORK, NY, US, vol. 29, no. 6, 1 December 2007 (2007-12-01), pages 781-788, XP008135424, ISSN: 0163-4356 *

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