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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/12—Antidiarrhoeals
• • 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
  • A61P25/06—Antimigraine agents
• • 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]

Definitions

• hydrochloride of the active ingredient base 1- [N 2 - [3 5 5-dibromo- / V - [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] - carbonyl ] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine in combination with sumatriptan for the treatment of migraines
• Migraine is one of the most common neurological disorders and includes periodic bouts of headache and nausea, as well as a variety of other symptoms. Although significant progress has been made in the past, the pathophysiology of migraines is still not understood. Several observations indicate involvement of the "calcitonin gene related peptide" (CGRP). Migraine headaches include activation of the trigeminal system and enlargement of the cranial vessels. CGRP is localized in neurons in trigeminal ganglia, and CGRP levels are elevated during a migraine attack. These elevated CGRP levels cause vasodilation and are believed to be responsible for the headache. Accordingly, it is conceivable that the inhibition of the enlargement of the cranial vessels caused by CGRP may allow a new treatment for migraine headaches.
• Medicaments which are widely used against migraines are the so-called “triptans”, for example almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan.
• triptans for example almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan.
• CGRP neuropeptide "calcitonin gene related peptide”
• the modified amino acids are therefore suitable for the acute and prophylactic treatment of headaches, in particular migraines and cluster headache.
• the international patent application PCT / EP 0208993 (published as WO 03/015787) generally discloses the use of the CGRP antagonist 1 - [N 2 - [3,5-dibromo- ⁇ / - [[4- (3,4-dihydro -2 (1 H) -oxoquinazolin-3-yl) -1-piperidinyl] -carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine in combination with other anti-migraine -I means to treat migraines.
• the present invention provides a method for the treatment or prevention of indications selected from the group consisting of headache, migraine and cluster headache, the method comprising the simultaneous or timed administration of a therapeutically effective amount of the hydrochloride the active ingredient base 1- [N 2 - [3,5-dibromo- / V- [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] - D-tyrosyl] -L-lysyl] - 4- (4-pyridinyl) -piperazine (A) and a therapeutically effective amount of the 5-HTi B / i D agonist sumatriptan or one of its physiologically tolerable salts to a person who has a such treatment requires.
• the dosage for the combined migraine drug sumatriptan or one of its physiologically acceptable salts is about 1/10 of the lowest normally recommended dose up to 1/1 of the normally recommended dose, preferably 1/3 to 1/1, on oral, nasal, inhalation , subcutaneous, rectal or intravenous route.
• the normally recommended dose for the combined migraine drug sumatriptan is the dose described in the 2003 Red List, Editio Cantor Verlag Aulendorf.
• the hydrochloride of the active ingredient base (A) can be administered intravenously or subcutaneously in a dosage of 0.0001 to 3 mg / kg body weight or in an oral, nasal, rectal or inhalative route in a dosage of 0.1 up to 10 mg / kg body weight is administered once, twice or three times a day, in combination with sumatriptan or a physiologically acceptable salt thereof, which
• the hydrochloride of the active ingredient base (A) can be administered intravenously or subcutaneously in a dosage of 0.0001 to 3 mg / kg body weight or by oral, nasal, rectal or inhalation route in a dosage of 0.1 to 10 mg / kg body weight once, twice or three times a day, in combination with sumatriptan or a physiologically acceptable salt thereof, which
• the present invention claims a pharmaceutical composition for the treatment or prevention of headache, migraine or cluster headache, which contains a therapeutically effective amount of the hydrochloride of the active ingredient base 1- [N 2 - [3,5-dibromo- ⁇ / - [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl ) -piperazine (A) and the migraine drug sumatriptan or one of its physiologically tolerable salts, as a combined preparation for simultaneous or timed administration.
• the hydrochloride of the active ingredient base 1- [N 2 - [3,5-dibromo- ⁇ / - [[4- (3,4-dihydro-2 (1H) -oxoquinazolin-3-yl) -1-piperidinyl] carbonyl]
• a pharmaceutical composition according to the invention can contain a single dosage unit from 0.1 to 10 mg of the hydrochloride of the active ingredient base (A) and a single dosage unit from 1 to 100 mg sumatriptan.
• a pharmaceutical composition according to the invention can be a kit of parts for the treatment or prevention of headache, migraine or cluster headache, the kit comprising:
• a first enclosure containing a pharmaceutical composition comprising a therapeutically effective amount of the hydrochloride of the active ingredient base 1- [N 2 - [3,5-dibromo- / V - [[4- (3,4-dihydro-2 (1H) - oxoquinazolin-3-yl) -1-piperidinyl] carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyri- dinyl) piperazine (A) and one or more pharmaceutically acceptable diluents and / or carriers; and
• a third aspect of the present invention is the use of the hydrochloride of the active ingredient base 1- [N 2 - [3,5-dibromo- ⁇ / - [[4- (3,4-dihydro-2 (1 r) -oxoquinazoline-3 -yl) -1- piperidinyl] -carbonyl] -D-tyrosyl] -L-lysyl] -4- (4-pyridinyl) -piperazine (A) in combination with the migraine drug sumatriptan or a pharmaceutically acceptable salt thereof for the preparation a pharmaceutical composition or kit of parts for simultaneous or timed treatment or prevention of headache, migraine or cluster headache.
• migraine active ingredient sumatriptan is already on the market and is sold under the trade name Imigran®.
• the hydrochloride of the active ingredient base (A) can, for. B. using the pharmaceutical formulations disclosed in WO 98/11128 or using one of the following pharmaceutical formulations:
• inhalable solution for atomizers containing 1 mg to 50 mg of active substance
• propellant-driven MDI containing 1 mg to 50 mg of active substance
• Nasal spray containing 1 mg to 50 mg of active substance
• aqueous solution for nasal application containing 5 mg to 50 mg of active substance
• Suspension for nasal use containing 20 mg to 50 mg of active substance.
• Facial skin perfusion was measured using a modified procedure as described by Escott et al. (Escott, KJ, Beattie, DT, Connor, HE, Brain, SD (1995), Trigeminal ganglion stimulation increases facial skin blood flow in the rat: a major role for calcitonin gene-related peptide, Brain Research, 669 (1), 93-99) measured.
• Fasted male Wistar rats (strain CHbb: THOM, 280-320 g) were treated with sodium pentobarbitone (initially with 60 mg / kg ip and maintained during the experiment with an intraperitoneal infusion of 30 mg / kg / h through a 23 G - Anesthetized using a 10 mg / ml solution).
• Both sides of the buccal area of the facial skin were shaved and depilated with a commercially available depilatory cream (Pilca, Schwarzkopf & Henkel, 40551 Düsseldorf, Germany).
• the trachea was cannulated and the animals were artificially ventilated (80 beats / minute) with ambient air enriched with oxygen.
• the body temperature was kept at 37 ° C by an automatic heating pad.
• the left femoral artery and the left femoral vein were cannulated for the continuous measurement of arterial blood pressure and the intravenous administration of test compounds.
• Neuromuscular blockade was achieved by intravenous administration of pancuronium bromide (1 mg / kg / 0.5 ml, 5 minutes before each electrical stimulation).
• the heart rate was derived from the blood pressure signal. Blood pressure and heart rate were continuously monitored throughout the course of the experiment to assess the level of anesthesia and to monitor the cardiovascular effects of the drugs used in this study.
• the animals were placed in a stereotactic frame and a longitudinal incision was made in the scalp.
• a small hole was made in the skull (left or right), and a bipolar electrode (Rhodes SNEX-100, obtained from David Kopf Instruments, Tujunga, 91042 California, USA) was micromanipulated into the trigeminal ganglion (0.32 cm dorsal from the bregma, ⁇ 0.30 cm lateral from center line and 0.95 cm below the dural surface).
• the position of the electrodes in the trigeminal ganglia was checked visually at the end of each experiment after brain removal.
• the trigeminal ganglion was stimulated at 10 Hz, 1 mA, 1 msec for 30 seconds using a stimulator obtained from Hugo Sachs Elektronik (79232 March-Hugstetten, Germany).
• Microvascular blood flow changes in the facial skin were measured by laser Doppler flow measurement with a Periflux laser Doppler system (PeriFLUX 4001, wavelength: 780 nm; time constant: 3 s; Perimed AB, Järimplla, S-17526, Sweden) measured.
• Standard laser Doppler probes PROBE 408 were placed on each side of the face approximately 0.5 cm below the center of the eye in an area innervated by the maxillary branch (V2) of the trigeminal nerve. Circulation changes were measured as the flow rate in arbitrary units and as the area under the flow curve (mm2) according to Escott et al. (1995).
• mice were subjected to three periods of electrical stimulation, separated by an interval of 30 minutes.
• the first stimulation was used as a control for the subsequent stimulations.
• Saline, single compound and the combination were administered intravenously 5 minutes before the second stimulation.
• Table 1 The results are shown in Table 1 below. They show that the improved efficacy of the combination of the 5-HT- ⁇ B / iD agonist sumatriptan with the hydrochloride of the CGRP antagonist (A) should allow a higher efficacy and a lower dosage, which leads to a similar efficacy with less Side effects should result, and that the addition of two mechanisms may result in less headache recurrence.
• Table 1 Effect of the hydrochloride of the active ingredient base (A) in combination with the migraine active ingredient sumatriptan against migraine headache on the facial skin vasodilation, which is induced in the rat by electrical ganglion stimulation.
• Composition 1 capsule for powder inhalation contains: active substance 1.0 mg
• the active substance is ground to a particle size required for inhalation.
• the milled active substance is mixed homogeneously with the lactose and the mixture is packed in hard gelatin capsules.
• Composition 1 spray contains: active substance 1.0 mg
• the active substance and benzalkonium chloride are dissolved in water and filled in Respimat® cartridges.
• 1 vial contains: active substance 0.1 g Sodium chloride 0.18 g
• Active substance sodium chloride and benzalkonium chloride are dissolved in water.
• Composition 1 spray contains: active substance 1.0 mg lecithin 0.1%
• micronized active substance is homogeneously suspended in the mixture of lecithin and propellant.
• the suspension is transferred to a pressurized container with a metering valve.
• 1 spray contains: active substance 1.0 mg
• the active substance and additives are dissolved in water and transferred to a suitable container.
• composition active substance in the form of 5 mg hydrochloride
• Glycofuroi and glucose are dissolved in water for injections (Wfl). Human serum albumin is added and the active substance is dissolved with heating. The specified volume is filled with Wfl and transferred into ampoules under a nitrogen gas atmosphere.
• composition active substance 5 mg
• Polysorbate 80 Tween 80 2 mg Water for injections ad 1 ml
• Glucose and polysorbate are dissolved in water for injections.
• the active substance is dissolved using heating or using ultrasound. It is filled up to the specified volume with Wfl and transferred into ampoules under inert gas.
• composition active substance 100 mg
• Polysorbate 80 sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate are dissolved in water for injections (Wfl). Human serum albumin is added. The active substance is dissolved with heating. It is filled to the specified volume with Wfl and transferred to ampoules.
• Lyophilisate containing 10 mg active substance Composition active substance in the form of 10 mg
• Mannitol is dissolved in water for injections (Wfl) and the active substance is added with heating. It is filled to the specified volume with Wfl, transferred into vials and freeze-dried.
• Polysorbate 80 Tween 80 20 mg
• composition active substance 5 mg polar or non-polar solvent (which can be removed by freeze-drying) to 1 ml
• the active substance is dissolved in a suitable solvent, in vials transferred and freeze-dried.
• Polysorbate 80 Tween 80 5 mg mannitol 100 mg
• Polysorbate 80 and mannitol are dissolved in water for injections (Wfl) and transferred into ampoules.
• composition active substance 20 mg
• the active substance, lactose and corn starch are mixed homogeneously, and granulated with an aqueous solution of Povidone, mixed with magnesium stearate and pressed in a tablet press. Tablet weight: 200 mg.
• composition active substance 20 mg Corn starch 80 mg highly disperse silicon dioxide 5 mg
• the active substance, corn starch and silicon dioxide are mixed homogeneously and mixed with magnesium stearate.
• the mixture is transferred into 8 size 3 gelatin capsules in a capsule filling machine.
• composition active substance 50 mg
• the hard fat is melted at around 38 ° C.
• the ground active substance is homogeneously dispersed in the molten hard fat and, after cooling to about 35 ° C., poured into cooled molds.
• Aqueous solution for nasal administration containing 10 mg of active substance l
• composition active substance in the form of 10.0 mg hydrochloride
• the active substance is dissolved in purified water and methyl and propyl PHB are added.
• the solution is made up to the specified volume with purified water, sterile filtered and transferred to a suitable container.
• composition active substance 5 mg
• the active substance is dissolved in 1,2-propanediol.
• a hydroxyethyl cellulose solution in purified water containing sorbic acid is prepared and added to the solution of the active substance.
• the solution is sterile filtered and transferred to a suitable container.
• Aqueous solution for intravenous administration containing 5 mg of active substance
• composition active substance 5 mg
• the active substance is dissolved in 1,2-propanediol and the solution is made up to approximately the volume indicated with Wfl.
• the mannitol is added and it is made up to approximately the specified volume with Wfl.
• the solution is sterile filtered, transferred to individual containers and autoclaved.
• Liposomal formulation for intravenous injection containing 7.5 mg active substance
• composition active substance 7.5 mg
• the active substance is dissolved in a mixture of lecithin and cholesterol.
• the solution is added to a mixture of glycerol and Wfl and homogenized by high pressure homogenization or by the microfluidizer technique.
• the liposomal formulation obtained is transferred to a suitable container under aseptic conditions.
• composition active substance 20.0 mg
• Carboxymethyl cellulose 20.0 mg Sodium monohydrogen phosphate / sodium dihydrogen phosphate buffer pH 6.8 qs
• the active substance is suspended in an aqueous CMC solution; the other ingredients are added to the suspension one after the other, and the suspension is made up with the stated volume of purified water.
• composition active substance 10.0 mg
• the active substance is dissolved in the phosphate buffer solution and, after adding the table salt, the solution is made up to the specified volume with water.
• the solution is sterile filtered, transferred to a suitable container and autoclaved.
• the active substance is suspended in the polysorbate 80 solution and crushed to a particle size of about 1 micron using a suitable dispersing technique (e.g. wet milling, high pressure homogenization, microfluidization and the like).
• a suitable dispersing technique e.g. wet milling, high pressure homogenization, microfluidization and the like.
• the suspension is transferred to an appropriate container under aseptic conditions.

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• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Citations (2)

• 2003
  • 2003-04-01 DE DE10314617A patent/DE10314617A1/de not_active Withdrawn
• 2004
  • 2004-03-26 CA CA002520930A patent/CA2520930A1/en not_active Abandoned
  • 2004-03-26 JP JP2006504871A patent/JP2006522044A/ja active Pending
  • 2004-03-26 WO PCT/EP2004/003210 patent/WO2004087134A1/de not_active Application Discontinuation
  • 2004-03-26 EP EP04723571A patent/EP1631282A1/de not_active Withdrawn
  • 2004-03-30 CL CL200400686A patent/CL2004000686A1/es unknown
  • 2004-03-30 TW TW093108719A patent/TW200501956A/zh unknown
  • 2004-03-31 AR ARP040101065A patent/AR043793A1/es unknown
  • 2004-03-31 UY UY28251A patent/UY28251A1/es not_active Application Discontinuation

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