WO2007065713A2 - UTILISATION DE 8-α-ERGOLINES POUR LE TRAITEMENT DES TROUBLES CEREBRAUX - Google Patents

UTILISATION DE 8-α-ERGOLINES POUR LE TRAITEMENT DES TROUBLES CEREBRAUX Download PDF

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WO2007065713A2
WO2007065713A2 PCT/EP2006/011865 EP2006011865W WO2007065713A2 WO 2007065713 A2 WO2007065713 A2 WO 2007065713A2 EP 2006011865 W EP2006011865 W EP 2006011865W WO 2007065713 A2 WO2007065713 A2 WO 2007065713A2
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PCT/EP2006/011865
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WO2007065713B1 (fr
WO2007065713A3 (fr
WO2007065713A8 (fr
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Heinz Palla
Harald Mottl
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Axxonis Pharma Gmbh
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Publication of WO2007065713A8 publication Critical patent/WO2007065713A8/fr
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • 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
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • the present invention relates to 8- ⁇ -ergoline derived compounds especially to lisuride and terguride and salts, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, hydrates, solvates and racemates and/or pharmaceutically acceptable salts of these compounds for use in pharmaceutical compositions together with pharmaceutically acceptable carriers, excipients and/or diluents for the treatment and prophylaxis of brain disorders wherein the brain disorders are characterised by increased cranial pressure or epileptic seizures or neural edema.
  • Said ergoline derived compounds are useful for the preparation of pharmaceutical compositions for the treatment and/or prophylaxis of the above aspects of brain disorders.
  • this invention relates especially to methods and compositions for treatment and/or prophylaxis of the above aspects of brain disorders by administering to the patient lisuride or one of its derivatives.
  • Traumatic brain injury is one brain disorder which is characterised by increased cranial pressure or epileptic seizures or neural edema. Traumatic brain injury (TBI) refers to brain damage after trauma by external mechanical forces. Clinically, TBI presents itself heterogeneously including diffuse axonal damage, focal contusions, space occupying epidural and subdural hematomas, and open or closed head injuries.
  • Secondary brain injury following traumatic brain injury is a result of direct and delayed mechanisms.
  • a primary insult to the brain initiates metabolic and inflammatory processes which exacerbate the primary traumatic injury to neurons, leading to secondary brain injury.
  • Such secondary brain injury can include neural edema, neuroinflammation, and neurodegeneration, traumatic brain injury associated ischemia, the production of reactive oxygen species and epileptic seizures.
  • Acute traumatic brain injury is clinically graded as mild, moderate and severe based on the level of consciousness or the Glasgow Coma Scale (GCS) score after resuscitation. Severe TBI is characterized by coma or a GCS score lower than 9.
  • the acute phase of TBI begins immediately after the primary brain injury and has a duration of up to four weeks. Most of the mortality happens during the acute phase of TBI either as a direct consequence of the primary lesions or as a consequence of the secondary brain injuries that reinforce the primary lesion Proportions of mortality increase with age: 21 % of patients younger than 35 years and 52% of patients older than 55 years do not survive a severe case of TBI. If a patient has survived the first four weeks after a severe acute TBI incident, the prognosis for survival improves considerably.
  • ICP intracranial pressure
  • Lisuride is an ergot derived molecule, chemically related to dihydroergotamine, but it is not useful to treat acute migraine as are dihydroergotamine and sumatriptan. Lisuride is in fact useful to prevent the onset of migraine and would therefore not be expected to substitute for sumatriptan or dihydroergotamine in the volume targeted therapy based on what is known about its pharmacology. In addition lisuride is not associated with severe side effects and complications like dihydroergotamine.
  • 8- ⁇ -ergoline derived compounds have not been investigated for the treatment of the acute phase of traumatic brain injury in humans, where maintenance of haemodynamic stability and of ICP is of utmost importance to secure satisfactory cerebral perfusion.
  • Lisuride or other 8- ⁇ -ergolines are also useful for the therapy and prevention of epileptic seizures, which commonly occur during acute brain injury or in the rehabilitation phase after brain injury.
  • Epileptic seizures occur in patients with idiopathic and symptomatic epilepsy. Symptomatic epilepsy also occurs as a result of an injury to the brain. Idiopathic seizures can also occur spontaneously without a known or suspected cause. In an acute mouse model of convulsions induced by hyperbaric oxygen, the dopamine agonists lisuride, apomorphine, (-)3-PPP and Quinpirole, but curiously also the dopamine antagonist haloperidol reduced the latency of convulsions, but did not prevent or inhibit the occurrence of convulsions (Criborn, CO et al. (1988) Aviat. Space
  • Hyperbaric oxygen therapy is based on the principle of saturating hemoglobin with oxygen. It is not obvious for those skilled in the art how an animal model based on this principle should be predictive for a physiological situation like brain injury that is characterized by insufficient brain perfusion with oxygen.
  • Apomorphine a dopamine agonist
  • traumatic brain injury refers also to epileptic seizures and symptomatic epilepsy, indications which are implicitly disclosed when referring to the term TBI.
  • Brain injury occurs when perfusion of the whole brain or a part of the brain with oxygenated blood is reduced below a minimum threshold. This can happen for example by direct lack of oxygen to the body as in CO poisoning, as a result of an external mechanical impact to the brain as in accidents and as a result of occlusion or rupture of blood vessels either intrinsically such as in ischemic stroke or hemorrhagic stroke or extrinsically as a consequence of a surgical procedure like brain or heart surgery.
  • the therapy of the brain injury incident happens in two distinct phases.
  • an acute phase the patient is normally admitted to an intensive care unit to treat the life- threatening symptoms. If the patient has survived this initial phase which is characterized by high mortality, treatment continues in a rehabilitation phase either in a specialized clinical setting or in an outpatient setting.
  • aspects of this invention are related to the use in the acute phase and/or the rehabilitation phase.
  • Object of the invention is to provide compounds useful for the treatment and/or prophylaxis of brain disorders wherein the brain disorder is characterized by increased cranial pressure, epileptic seizures, or neural edema
  • the object of the invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, and the examples of the present application.
  • the 8- ⁇ -ergoline derivatives of the invention and especially lisuride, terguride and proterguride are useful for the treatment and/or prophylaxis of brain disorders wherein the brain disorder is characterized by increased cranial pressure, epileptic seizures or neural edema.
  • the ergoline derived compounds of the invention reduce neural edema, intracranial pressure and frequency and magnitude of epileptic seizures in acute TBI or the rehabilitation phase after a brain injury event.
  • Seizures are common during the acute phase of brain injury and can occur unpredictably in the rehabilitation phase. Seizures during acute brain injury are typically treated with traditional anticonvulsants (phenytoin, carbamazepine, sodium valproate, ethosuximide, primidone, clonazepam, phenobarbital).
  • traditional anticonvulsants phenytoin, carbamazepine, sodium valproate, ethosuximide, primidone, clonazepam, phenobarbital.
  • Traumatic Injury (2000) does not recommend the use of phenytoine, carbamazepine, phenobarbital or valproate for preventing late posttraumatic seizures, occurring seven days after brain injury.
  • the present invention addresses the shortcomings of current therapies. Lisuride is not known to cause cognitive impairment and is safe when used over many years. The treatment with lisuride can therefore be applied in the rehabilitation phase when current anticonvulsants are not indicated and no cognitive changes are induced in patients.
  • the present invention relates to methods and compositions for treatment and prophylaxis of epileptic seizures which occur in the rehabilitation phase after a brain injury event by administering to the patient a pharmacologically effective amount of lisuride or one of its derivatives.
  • a specific brain injury event disclosed herein where lisuride was effective in preventing symptomatic seizures is stroke.
  • Symptomatic seizures are common in the rehabilitation phase after stroke, traumatic brain injury and other types of brain injury.
  • the characteristics of seizures that occur in the rehabilitation phase after stroke can not be distinguished medically or pharmacologically from the seizures that occur after traumatic brain injury. Therefore the use of lisuride and related compounds is claimed not only for the prophylaxis of seizures that occur in the rehabilitation phase after stroke but more generally for seizures that occur in the rehabilitation phase after a brain injury.
  • the pharmacological amount that was used was 150 ⁇ g lisuride hydrogen maleate per day, equivalent to about 2 ⁇ g/kg lisuride hydrogen maleate per day.
  • Lisuride has a bioavailability of only 25%.
  • the oral dose of lisuride of 2 ⁇ g/kg is therefore equivalent to a dose of 0.5 ⁇ g/kg when the drug is applied parenterally or transdermally.
  • lisuride Transdermal as well as subcutaneous applications of lisuride have been described and Parkinson patients tolerate subcutaneous daily infusions of 1000 - 2000 ⁇ g/kg without serious adverse side effects. Preferred are therefore doses of lisuride for treatment of symptomatic epilepsy ranging from 0.5 ⁇ g/kg per day up to 25 ⁇ g/kg day.
  • lisuride is a molecule with an established safety profile and patients have been under high dose parenteral therapy with lisuride for more than 10 years. Preferred is therefore a longterm chronic treatment of symptomatic epilepsy resulting from brain injury.
  • Such a method comprises administering to a patient in need of such treatment or such prophylaxis a pharmacologically effective amount of lisuride, terguride and proterguride or another 8- ⁇ -ergoline compound which is effective to treat and/or prevent epileptic seizures.
  • Another method comprises administering to a patient in need of such treatment a pharmacologically effective amount of lisuride, terguride and proterguride or another 8- ⁇ -ergoline compound which is effective to treat epilepsy, neural edema and traumatic brain injury associated ischemia.
  • the 8- ⁇ -ergoline derived compounds of the invention offer pharmacokinetic advantages over oral drugs as they can be administered as an intravenous or subcutaneous infusion or via a transdermal route, e.g. via a transdermal patch. This allows for stable and easily controllable plasma drug levels in a patient population that frequently has resorption and bioavailability problems.
  • R 1 and R 4 represent independently from each other -H, -CHO, -COCH 3 , -COC 2 H 5 , -COC 3 H 7 , -CO-cyclo-C 3 H 5 , -COCH(CH 3 ) 2 , -COC(CH 3 ) 3 , -COOH, -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 7 , -COO-cyclo-C 3 H 5 ,
  • R 2 and R 3 represent independently from each other -R 6 , -R 7 , a linear or branched, saturated or unsaturated alkyl residues with 1 - 10 carbon atoms, which can be substituted with one or more of the residues R 8 - R 43 ; a linear or branched, saturated or unsaturated -CO-alkyl residue with 1 - 10 carbon atoms, which can be substituted with one or more of the residues R 8 - R 43 ; a linear or branched, saturated or unsaturated -NH-CO-alkyl residue with 1 - 10 carbon atoms, which can be substituted with one or more of the residues R 8 - R 43 ; a linear or branched, saturated or unsaturated -NH-CO— NH-alkyl residue or -NH-CO— N(dialkyl residue) with alkyl residues with 1 - 10 carbon atoms, which can be substituted with one or more of the residues R 8 - R 43 ;
  • R 5 represents one of the residues -H, -F, -Cl 1 -Br, -I, -CN or -NO 2 ;
  • R 6 - R 45 represent independently from each other -H, -OH, -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -O-cyclo-C 3 H 5 , -OCH(CH 3 J 2 , -OC(CH 3 ) 3 , -OC 4 H 9 , -OPh, -OCH 2 -Ph, -OCPh 3 , -SH, -SCH 3 , -SC 2 H 5 , -SC 3 H 7 ,
  • X represents a single bond or a double bond
  • n an integer from 1 to 10; as well as
  • brain disorders wherein the brain disorder is characterized by increased cranial pressure, or epileptic seizures, or neural edema.
  • Said brain disorders are selected from acute traumatic brain injury, severe acute traumatic brain injury, epileptic seizures, symptomatic epilepsy and neural edema.
  • the indication epileptic seizures and symptomatic epilepsy and especially preferred is the use of the 8- ⁇ -ergoline compounds and first of all lisuride for the treatment and prophylaxis of epileptic seizures which occur as a consequence of a brain injury event as well as epileptic seizures which occur during the acute phase or during rehabilitation phase after traumatic brain injury or after stroke.
  • the use of the 8- ⁇ -ergoline compounds for the treatment of a brain injury event associated with increased cranial pressure occurring during the acute phase of the brain injury is especially preferred.
  • Still especially preferred is the use of the 8- ⁇ - ergoline compounds for the treatment of a brain injury event associated with a brain edema occurring during the acute phase of a brain injury event.
  • lisuride terguride and proterguride as well as salts and combinations of these compounds.
  • the compounds of the general formula (I) are basic and acidic addition-salts can be obtained by addition of organic or inorganic acids.
  • acids which build an acidic addition-salt of the compound of formula (I) 1 the following can be mentioned: sulfuric acid, sulfonic acid, phosphoric acid, nitric acid, nitrous acid, perchloric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, succinic acid, oxalic acid, gluconic acid (glyconic acid, dextronic acid), lactic acid, malic acid, tartaric acid, tartronic acid (hydroxymalonic acid, hydroxypropionic diacid), fumaric acid, citric acid, ascorbic acid, maleic acid, malonic acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, (o-, m-, p-) toluylic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, salicylic acid, p-aminosalicylic acid, methanesulfonic acid
  • alkaline metal-salts such as the sodium salt, the potassium salt, the lithium salt or the magnesium salt, the calcium salt, alkylamino salts or amino acid salts, such as with basic amino acids, e.g. lysine, can be formed.
  • the general formula (I) also comprises stereoisomers, enantiomers, mixtures of enantiomers, diastereomers and mixtures of diastereomers, wherein chiral compounds of the following formulas (II) - (NE) are preferred, for example:
  • R 3 represents hydrogen. Moreover, it is preferred in all of the formulas disclosed herein, if R 3 has the configuration shown in formula (II), (HA) and (HB) 1 i.e. protrudes out of the plane and accordingly R 2 lies behind the plane. Thus, the 8- ⁇ - ergolines are preferred. In the case, that X represents a single bond, the trans position of the two hydrogen atoms at C-5 and C-10 is preferred, as shown in the general formulas (IH) - (IIIE).
  • R 1 and/or R 4 preferably represent hydrogen or an alkyl residue with 1 to 8 carbon atoms.
  • R 3 preferably represents a carbonyl group, to which a mono-, bi- or tricyclic heterocyclus is bound.
  • R 2 represents a residue -NH-CO-NH 2 , -NH-CO-NHCH 3 , -NH-CO-NHC 2 H 5 , -NH-CO-NHC 3 H 7 , -NH-CO-NH-CyCIo-C 3 H 5 , - NH-CO-NH[CH(CH 3 ) 2 ], -NH-CO-NH[C(CH 3 ) 3 ], -NH-CO-N(CH 3 ) 2 ,
  • R * represents one of the residues R 6 - R 45 , which may be bound to a nitrogen atom.
  • R * especially represents a linear or branched, saturated or unsaturated acyl group with 1 to 20 carbon atoms, which can also comprise carboncycles, heterocycles or aromatic rings in the carbon chain, and the carbon chain of which can be further substituted with one or more of the residues R 6 - R 45 .
  • R ** represents in the formulas (ME) and (HIE) one of the residues R 6 - R 45 and preferably an amino group, alkylamino group or dialkylamino group, wherein the alkyl group or the alkyl groups comprise 1 to 20 carbon atoms, wherein the alkyl groups can comprise or contain also carboncycles, heterocycles and aromatic systems and the alkyl groups can be branched or linear as well as saturated or unsaturated and can be substituted with one or more of the residues R 6 - R 45 .
  • Especially preferred for R ** are -CH 2 F, -CH 2 -CH 2 F, -CH 2 -CHF 2 , -CH 2 -CF 3 , -CH 2 -CH 2 CI 1
  • the pharmaceutical composition comprising the 8- ⁇ -ergoline derived compounds of the present invention is suitable for the treatment and/or prophylaxis of aspects of acute phase traumatic brain injury.
  • the acute phase of traumatic brain injury begins immediately after the primary brain injury and has a duration of up to four weeks.
  • Particularly preferred is the treatment and/or prophylaxis of epileptic seizures in the acute phase of traumatic brain injury.
  • the ergoline derived compounds of the invention offer pharmacokinetic advantages over oral formulations as they can be administered as an intravenous or subcutaneous infusion or via a transdermal route, e.g. via a transdermal patch. This allows for stable and easily controllable plasma drug levels in a patient population that frequently has resorption and bioavailability problems.
  • the possibility to administer lisuride via the intravenous or subcutaneous route is especially advantageous and preferred if the patient is hospitalized in an intensive care unit.
  • the ergoline derived compounds and especially lisuride, terguride and proterguride are useful for treatment and prophylaxis of epileptic seizures. Especially lisuride can be used to prevent seizures during acute brain injury or in the rehabilitation phase.
  • Example 1 The particular invention described here demonstrates (Example 1 ) the use of lisuride 6 months after a brain injury has occurred. To those skilled in the art there is no reason to not use lisuride earlier in the rehabilitation phase after a brain injury, since the molecule has an established and well understood safety profile.
  • the preferred pharmaceutical composition for administration is subcutaneous or intravenous application.
  • Controlled drug delivery systems provide maintenance of drug plasma levels within a desired range for an extended period of time.
  • Parenteral administration can be achieved by means of continuous infusion by a perfusor system or a programmable minipump. Infusion pumps or perfusors are used to infuse pharmaceutical compositions into the circulatory system at the required dosage rate.
  • the pharmaceutical composition can be continuously infused intravenously or subcutaneously.
  • Transdermal administration can be achieved by means of transdermal patch, such as a matrix plaster or a membrane plaster.
  • Transdermal patch delivery systems control the rate and duration of drug input and are used to continuously infuse pharmaceutical compositions into the circulatory system.
  • a pharmaceutical composition suitable for oral, low dose intravenous, subcutaneous or intramuscular injection, continuous intravenous infusion or continuous subcutaneous infusion, and transdermal administration is particularly preferred.
  • a pharmaceutical composition suitable for continuous intravenous infusion or continuous subcutaneous infusion administered by a perfusor system or a programmable minipump is particularly preferred.
  • a pharmaceutical composition suitable for administration via a transdermal patch is particularly preferred.
  • composition suitable for oral administration is particularly preferred.
  • the pharmaceutical composition comprising the ergoline derived compounds of the present invention is administered in a dosage corresponding to an effective concentration in the range of 0.5 - 25 microgram/kg body weight. Particularly preferred is that the dosage is infused continuously over a period of 24 hours to several years.
  • Another aspect of the invention is directed to pharmaceutical compositions comprising the 8- ⁇ -ergoline derived compounds as active ingredient prepared in a conventional liquid carrier or diluent and a conventional pharmaceutically-made adjuvant at suitable dosage level in a known way.
  • the preferred pharmaceutical composition is suitable for parenteral administration or transdermal administration.
  • the preferred pharmaceutical composition is suitable for controlled administration via parenteral administration or transdermal administration.
  • Controlled drug delivery systems provide maintenance of drug plasma levels within a desired range for an extended period of time. Depending on the formulation and the application this time may be, for example, anywhere from 24 hours to 4 weeks or without a predefined limit as a longterm chronic therapy.
  • Parenteral administration can be achieved by means of continuous infusion by a perfusor system or a programmable minipump. Infusion pumps or perfusors are used to infuse pharmaceutical compositions into the circulatory system at the required dosage rate.
  • the pharmaceutical composition can be continuously infused intravenously or subcutaneously.
  • Transdermal administration can be achieved by means of transdermal patch, such as a matrix plaster or a membrane plaster.
  • Transdermal patch delivery systems control the rate and duration of drug input and are used to continuously infuse pharmaceutical compositions into the circulatory system.
  • Particularly preferred is a pharmaceutical composition suitable for continuous intravenous infusion or continuous subcutaneous infusion administered by a perfusor system or a programmable minipump.
  • Particularly preferred is a pharmaceutical composition suitable for administration via a transdermal patch.
  • the pharmaceutical composition comprising the 8- ⁇ -ergoline derived compounds of the present invention is administered in a dosage corresponding to an effective concentration in the range of 0.5 - 25 ⁇ g/kg body weight.
  • Another aspect of the present invention is directed to a method of treatment and/or prophylaxis of aspects of traumatic brain injury comprising administering an effective amount of a compound according to general formula (I) to a patient in need thereof.
  • the 8- ⁇ -ergoline derived compounds of the present invention are also suitable for a method of treatment and/or prophylaxis of aspects of acute phase traumatic brain injury.
  • Particularly preferred is a method of treatment and/or prophylaxis of aspects of acute phase traumatic brain injury.
  • Another aspect of the present invention is directed to a method of treatment and/or prophylaxis of aspects of traumatic brain injury, wherein the compound according to general formula (I) is administered parenterally or transdermal ⁇ to a patient in need thereof.
  • administration by low dose intravenous, subcutaneous or intramuscular injection, continuous intravenous infusion or continuous subcutaneous infusion and transdermal administration.
  • Particularly preferred is administration of the continuous intravenous infusion or continuous subcutaneous infusion by a perfusor system or a programmable minipump.
  • Another aspect of the present invention is directed to a method of treatment and/or prophylaxis of aspects of traumatic brain injury, wherein the compound of the general formula (I) is administered in a dosage corresponding to an effective concentration in the range of 0.5 - 50 ⁇ g/kg preferably 5 - 25 ⁇ g/kg body weight.
  • a method of treatment and/or prophylaxis wherein the dosage is infused continuously over a period of from 24 hours to 4 weeks.
  • Figure 1 Diagram showing the intracranial pressure (ICP) measured at different time-points before and after trauma. Bolus administration of 0.3 mg/kg at 30 minutes following CCII. Mean values and standard error.
  • ICP intracranial pressure
  • SCAG Sandoz Clinical Assessment Geriatric Rating Scale
  • the tolerability of the treatment was assessed by means of a retrospective evaluation of side effects (or accompanying symptoms) recorded during the various follow-up examinations. To this purpose it is to be noted that many symptoms recorded during the study had to be reinterpreted after the opening of randomization key as accompanying symptoms probably related to the lack of a protective action against their appearance.
  • the tolerability was also evaluated by repeating after 12 weeks of treatment the physical examination including the determination of blood pressure and various hematochemical tests (hemoglobin, hematocrit, RBC, WBC with formula, platelets, glucose, BUN, creatinine, electrolytes, bilirubin, alkaline phosphatase, SGOT, SGPT, gamma-GT, serum protein levels) and urinalysis.
  • Lisuride group In half of them these fits prompted the doctor to stop treatment (Table 5). These differences between groups are significant.
  • Table 6 reports the total adverse events that occurred during the trial and the total number of cases with adverse events (each patient is counted only once). A significant difference (p ⁇ 0.01 ) was found between the two therapeutic groups. In the Lisuride group fewer side effects occurred, patients under Lisuride therapy developed also fewer newly diagnosed conditions.
  • the obtained colorless to light yellow solution has a pH value between 4.5 and 5.4.
  • This solution is pre-filtered over a membrane filter and then sterile filtered over another membrane filter (0.2 urn) under aseptic conditions.
  • Each 1.0 g of the obtained sterile solution is transferred into sterilized vials with an inner volume of 6 ml, provided with a rubber plug suitable for the subsequent lyophilization and cooled to -40 to -50 0 C in a lyophilizator. Then it is dried and post-dried, respectively, under vacuum obtaining a dry substance bulk.
  • the vials are sealed and crimped under aseptic conditions.
  • 2.5 g of lisuride are mixed with 2.13 g of acetone and 51.54 g of a solution of basic butylmethacrylate copolymer (eudragit 100 solution).
  • an antioxidant e.g. butylhydroxyanisol
  • the obtained coating solution is continuously spread, under appropriate process conditions in a coater, onto a polymer film of polyethylene and then dried to an area weight of 50 mg/10 cm2 ( ⁇ 5%) of coated area.
  • the obtained sticky matrix is laminated with a polymer film which is siliconised on one side and in a further step stamped into plasters of a a size for the therapeutic utilisation (e.g. 20 cm 2 ) and packaged in bags.
  • the prepared Lisuride plaster continuously releases the active agent at a rate of between 0,1 to 0,5 ⁇ g/ cm 2 /h over several days into the systemic circulation. The dosage can be adjusted through the use of different plaster sizes.
  • a membrane of microporous polyethylene (Solupor® 10P05A) is coated as a control membrane (or alternatively of ethylenevinylacetate copolymer (EVA, Cotran® 3M 9728)) with a skin-acceptable silicon adhesive (BioPSA®7-4202) (alternatively polyisobutylene adhesive, Oppanol®) and dried with an area weight of about 10 to 25 mg/cm2 and then laminated with a liner (polyethylene) which is siliconized on one side.
  • a skin-acceptable silicon adhesive (BioPSA®7-4202) (alternatively polyisobutylene adhesive, Oppanol®)
  • the obtained laminate is annularly sealed in a suitable sealing apparatus with heat sealable polyethylene except for a small opening and stamped.
  • a suitable sealing apparatus with heat sealable polyethylene except for a small opening and stamped.
  • CCII Controlled Cortical Impact Injury
  • Fifty male Sprague-Dawly rats (350-40Og) were anesthetized with isofluoran gas/N2O.
  • a cortical controlled impact injury was performed as followed: A trauma was applied directly on the intact meninx through a pneumatically driven 5 mm bolt with convex end. Rate (7 m/s) Penetration depth (1.5 mm), contact time (300 ms) and localization (stereotactic fastener, impedance controlled positioning) are controlled, so that always the same deflection of the meninx takes place, resulting in a focal, mechanical cortex injury.
  • MAP mean arterial pressure
  • heart rate heart rate
  • ICP intracranial pressure
  • CCPP cerebral perfusion pressure
  • Electroencephalography ECG
  • Brain water content of traumatized hemispheres increased to 80.2 ⁇ 1.2% in control animals as opposed to the contralateral, non-traumatized side (78.7 ⁇ 0.5%). Brain water content was reduced in animals treated with lisuride (79.0 ⁇ 0.9 and 78.5 ⁇ 0.5%) resulting in a decrease of brain edema from 12 ⁇ 3% to 8 ⁇ 4%.

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Abstract

La présente invention concerne des composés dérivés de la 8-α-ergoline et les sels, les énantiomères, les mélanges d'énantiomères, les diastéréomères, les mélanges de diastéréomères, les hydrates, les solvates et racémates et/ou les sels pharmaceutiquement acceptables de ces composés utilisables dans des compositions pharmaceutiques avec des supports, des excipients et/ou des diluants pharmaceutiquement acceptables. Lesdits composés dérivés de la 8-α-ergoline sont utilisables pour la préparation de compositions pharmaceutiques destinées au traitement et/ou à la prophylaxie des crises d'épilepsie, de la pression crânienne accrue et de l'œdème cérébral dans la phase aiguë ou de réhabilitation d'une lésion cérébrale.
PCT/EP2006/011865 2005-12-08 2006-12-08 UTILISATION DE 8-α-ERGOLINES POUR LE TRAITEMENT DES TROUBLES CEREBRAUX WO2007065713A2 (fr)

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