Chemical apparatus and process disinfecting – deodorizing – preser – Analyzer – structured indicator – or manipulative laboratory... – Sample mechanical transport means in or for automated...
Reexamination Certificate
2001-11-16
2003-08-12
Gerstl, Robert (Department: 1626)
Chemical apparatus and process disinfecting, deodorizing, preser
Analyzer, structured indicator, or manipulative laboratory...
Sample mechanical transport means in or for automated...
C424S009362, C435S004000, C514S373000, C548S210000
Reexamination Certificate
active
06605255
ABSTRACT:
The invention relates to a kit comprising a pharmaceutical composition containing repinotan or a physiologically acceptable salt of repinotan, and a means for the determination of the concentration of repinotan or its metabolites in body fluids, and also new pharmaceutical compositions containing repinotan or a physiologically acceptable salt of repinotan, and processes for their preparation.
For the acute treatment of neurodegenerative diseases such as stroke and cranio-cerebral trauma, which frequently lead to neurological and functional long-term deficits in these patients, up to now no treatment principle has yet been accepted worldwide as effective. Apart from the use of thrombolytics (for example t-PA) in the first 3 hours after an ischaemic stroke or the use of nimodipine in patients having a traumatic subarachnoid haemorrhage, there are still no medicinal approaches which adequately take into account the pathophysiological cascade.
EP-A-0 352 613 discloses 2-[4-({[(2R)-chroman-2-yl]methyl}amino)butyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (generic name: repinotan) und repinotan salts for the treatment of diseases of the central nervous system, in particular stroke.
In DE-A-195 43 476, the suitability of repinotan and its salts for the treatment of craniocerebral trauma is described.
In a number of clinical studies, repinotan has shown its good tolerability in healthy subjects and patients after a stroke or craniocerebral trauma. Moreover, the existing clinical data indicate the fact that it was possible to improve the neurological and functional deficits (after 3 and 6 months respectively depending on indication). In particular in the case of patients who reached blood plasma concentrations in the range of about 5-20 &mgr;g/l, the result of treatment was markedly better than in the patients who had received placebo.
A particularly good result of treatment can be obtained using the kit according to the invention, which comprises a pharmaceutical composition containing repinotan or a physiologically acceptable salt of repinotan and a means for the determination of the concentration of repinotan or its metabolites in body fluids.
The use of the kit according to the invention allows a medicament which, as active compound, contains repinotan in the form of the free base or of an acid addition salt to be administered and within a short time for the actual concentrations of repinotan or its metabolites to be determined in body fluids of the treated patient. Thus it is possible without a time delay and with a small outlay in terms of personnel and apparatus to perform the dose adjustments optionally necessary for an optimal therapy. The kit according to the invention therefore represents a significant advance in the acute therapy of neurodegenerative diseases, in particular of stroke and craniocerebral trauma.
The pharmaceutical compositions comprised by the kit according to the invention can be present, for example, as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions, solutions or lyophilizates which can be reconstituted to give a solution. As active compound, the pharmaceutical compositions contain repinotan or a physiologically acceptable salt of repinotan. The active compound should be present here in a concentration of approximately 0.05 to 95% by weight, preferably of approximately 0.5 to 90% by weight, of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated. In addition to the active compound, the pharmaceutical compositions additionally contain inert, non-toxic, pharmaceutically suitable excipients.
Repinotan has the following structural formula:
Physiologically acceptable salts of repinotan can be salts of repinotan with mineral acids, carboxylic acids or sulphonic acids. Preferred salts of repinotan are those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid. Repinotan hydrochloride is particularly preferred.
The choice of the excipients is dependent on the manner of formulation. Excipients which may be mentioned, for example, are water, non-toxic organic solvents, such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut/sesame oil), alcohols (e.g. ethyl alcohol, glycerol), carriers, such as, for example, ground natural minerals (e.g. kaolins, argillaceous earths, talc, chalk), ground synthetic minerals (e.g. highly disperse silicic acid, silicates), sugars (e.g. sucrose, lactose and dextrose), emulsifying agents (e.g. polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers), dispersing agents (e.g. lignin sulphite waste liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium sulphate).
The kit according to the invention preferably comprises as pharmaceutical composition an infusion solution containing the active compound or a solid pharmaceutical composition from which this infusion solution can be prepared by addition of water or isotonic electrolyte solution.
A preferred solid pharmaceutical formulation is the lyophilizate, which can be reconstituted by addition of water or of an isotonic electrolyte solution to, for example, an infusion solution. In the lyophilizate, the active compound has an increased storage stability, and, from the lyophilizate, it is easily and rapidly possible under sterile conditions to prepare a particle-free solution which is directly suitable for use in the patient, for example as an infusion solution. In addition to the active compound, the lyophilizate advantageously contains further pharmaceutically suitable excipients, in particular matrix-forming agents.
Matrix-forming agents within the meaning of the invention are amino acids such as glycine, alanine or aspartic acid, peptides such as gelatin, collagen or albumin, monosaccharides such as glucose or lactose, disaccharides such as maltose, sucrose or trehalose, oligosacharides such as cyclodextrins or maltodextrins, polysaccharides such as starch and starch derivatives or cellulose and cellulose derivatives, polymeric matrix-forming agents such as polyvinylpyrrolidone or polyethylene glycol, salts with sodium chloride or calcium carbonate, sugar alcohols such as mannitol, sorbitol or xylitol. Mannitol, sodium chloride, glycine, sucrose, maltose and lactose are preferred. Mannitol is very particularly preferred.
If the lyophilizate is reconstituted to give an infusion solution, this is advantageously isotonic. This can be achieved by the lyophilizate already containing adequate amounts of electrolytes, such as, for example, sodium chloride, mannitol or glucose, or by an isotonic electrolyte solution being used for the reconstitution and dilution of the solution.
Isotonic electrolyte solutions are, for example, aqueous 0.9% by weight sodium chloride solutions or 5% by weight glucose solutions.
The amount of active compound in the infusion solution should be approximately 0.1 &mgr;g/ml to 1 mg/ml, preferably approximately 0.5 to 5 &mgr;g/ml.
The preparation of repinotan and repinotan salts is described in EP-A-0 352 613. Repinotan hydrochloride corresponds to Example 92H therein.
The salts according to the invention can additionally be obtained by reacting the free base repinotan in suitable solvents with stoichiometric or superstoichiometric amounts of the acid on which the salt is based in a temperature range from 0° C. up to the boiling point of the solvent. Suitable solvents are, for example, water, aliphatic alcohols such as methanol, ethanol or 2-propanol, aliphatic open-chain or cyclic ethers such as diethyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran or aliphatic ketones such as 2-propanone, 2-butanone, and also mixtures thereof. The salts are obtained directly from this mixture as a solid,
Kroll Werner
Rodriguez Maria-Luisa
Rombout Ferdinand
Schohe-Loop Rudolf
Sennhenn Bernd
Bayer Aktiengesellschaft
Pellegrino Susan M.
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