(19) TZZ_ _ZZZ_T (11) EP 1 210 090 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/724 (2006.01) A61K 31/194 (2006.01) 18.06.2014 Bulletin 2014/25 A61P 39/04 (2006.01) (21) Application number: 00964006.1 (86) International application number: PCT/EP2000/007694 (22) Date of filing: 07.08.2000 (87) International publication number: WO 2001/012202 (22.02.2001 Gazette 2001/08) (54) USE OF CHEMICAL CHELATORS AS REVERSAL AGENTS FOR DRUG- INDUCED NEUROMUSCULAR BLOCK VERWENDUNG VON CHEMISCHEN CHELATOREN ZUR UMKEHRUNG VON PHARMAKOLOGISCH-INDUZIERTER NEUROMUSKULÄRER BLOCKIERUNG UTILISATION D’AGENTS CHIMIQUES CHELATANTS COMME AGENTS DE NEUTRALISATION DU BLOCAGE NEUROMUSCULAIRE PROVOQUE PAR DES MEDICAMENTS (84) Designated Contracting States: (56) References cited: AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU AU-A- 3 662 895 MC NL PT SE • B DESIRE: "Inactivaton of sarin and soman by (30) Priority: 13.08.1999 EP 99306411 cyclodextrins in vitro" EXPERIENTIA, vol. 43, no. 4, 1987, pages 395-397, XP000907287 (43) Date of publication of application: • B. DESIRE: "Interaction of soman with beta- 05.06.2002 Bulletin 2002/23 cyclodextrin" FUNDAMENTAL AND APPLIED TOXICOLOGY, vol. 7, no. 4, 1986, pages 647-657, (73) Proprietor: Merck Sharp & Dohme B.V. XP000911170 2031 BN Haarlem (NL) • C. MAY: "Development of a toxin-binding agent as a treatment for tunicamycinuracil toxicity: (72) Inventors: protection against tunicamycin poisoning of • BOM, Antonius, Helena, Adolf sheep" AUSTRALIAN VETERINARY JOURNAL, Ratho, Midlothian EH28 8NY (GB) vol. 76, no. 11, 1998, pages 752-756, XP000913500 • MUIR, Alan, William • K. UEMA: "Effects of cyclodextrins on Ravenstruther, Lanark ML11 7SL (GB) chlorpromazine-induced haemolysis and • REES, David nervous systems responses" J. PHARM. S-412 68 Göthenburg (SE) PHARMACOL., vol. 33, no. 11, 1981, pages 707-710, XP000911185 (74) Representative: Hussain, Deeba et al • T. IRIE: "Protective mechanism of beta- Merck Sharp & Dohme Limited cyclodextrin for the hemolysis induced with Hertford Road phenothiazine neuroleptics in vitro" J. Hoddesdon PHARMACOBIO-DYNAMICS, vol. 6, no. 6, 1983, Hertfordshire EN11 9BU (GB) pages 408-414, XP000911177 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 210 090 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 210 090 B1 Description [0001] The invention relates to the use of chemical chelators for the preparation of a medicament for the reversal of drug-induced neuromuscular block, and to a kit for providing neuromuscular block and its reversal. 5 [0002] A neuromuscular blocking agent (NMBA, also called a muscle relaxant) is routinely used during the adminis- tration of anaesthesia to facilitate endotracheal intubation and to allow surgical access to body cavities, in particular the abdomen and thorax, without hindrance from voluntary or reflex muse movement. NMBAs are also used in the care of critically-ill patients undergoing intensive therapy, to facilitate compliance with mechanical ventilation when sedation and analgesia alone have proved inadequate. 10 [0003] Basedon their mechanisms ofaction, NMBAs are divided into two categories: depolarizing and non-depolarizing. Depolarizing neuromuscular blocking agents bind to nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction in a way similar to that of the endogenous neurotransmitter acetylcholine. They stimulate an initial opening of the ion channel, producing contractions known as fasciculations. However, since these drugs are broken down only relatively slowly by cholinesterase enzymes, compared to the very rapid hydrolysis of acetylcholine by acetylcholineste- 15 rases, they bind for a much longer period than acetylcholine, causing persistent depolarization of the end-plate and hence a neuromuscular block. Succinylcholine (suxamethonium) is the best known example of a depolarizing NMBA. [0004] Non-depolarizing neuromuscular blocking agents compete with acetylcholine for binding to muscle nAChRs, but unlike depolarizing NMBAs, they do not activate the channel. They block the activation of the channel by acetylcholine and hence prevent cell membrane depolarization, and as a result, the muscle will become flaccid. Most clinically-used 20 NMBAs belong to the non-depolarizing category. These include tubocurarine, atracurium, (cis)atracurium, mivacurium, pancuronium, vecuronium, rocuronium and rapacuronium (Org 9487). [0005] At the end of surgery or a period of intensive care, a reversal agent of NMBAs is often given to the patient to assist the recovery of muscle function. Most commonly used reversal agents are inhibitors of acetylcholinesterase (AChE), such as neostigmine, edrophonium and pyridostigmine. Because the mechanism of action of these drugs is to 25 increase the level of acetylcholine at the neuromuscular junction by inhibiting the breakdown of acetylcholine, they are not suitable for reversal of depolarizing NMBAs such as succinylcholine. The use of AChE inhibitors as reversal agents leads to problems with selectivity, since neurotransmission to all synapses (both somatic and autonomic) involving the neurotransmitter acetylcholine is potentiated by these agents. This non-selectivity may lead to many side-effects due to the non-selective activation of muscarinic and nicotinic acetylcholine receptors, including bradycardia, hypotension, 30 increased salivation, nausea, vomiting, abdominal cramps, diarrhoea and bronchoconstriction. Therefore in practice, these agents can be used only after or together with the administration of atropine (or glycopyrrolate) to antagonize the muscarinic effects of acetylcholine at the muscarinic receptors in the autonomic parasympathetic neuro-effector junctions (e.g. the heart).The use of a muscarinic acetylcholine receptor (mAChR) antagonist such as atropine causes a number of side-effects, e.g., tachycardia, dry mouth, blurred vision, and furthermore may affect cardiac conduction. 35 [0006] A further problem with anticholinesterase agents is that residual neuromuscular activity must be present (>10 % twitch activity) to allow the rapid recovery of neuromuscular function. Occasionally, either due to hypersensitivity of the patient or accidental overdose, administration of NMBAs can cause complete blockade of neuromuscular function ("deep block"). At present, there is no reliable treatment to reverse such a ’deep block’. Attempts to overcome a ’deep block’ with high doses of AChE inhibitors has the risk of inducing a "cholinergic crisis", resulting in a broad range of 40 symptoms related to enhanced stimulation of nicotinic and muscarinic receptors. [0007] There is thus a need for an alternative method for reversing the action of NMBAs, i.e. to restore the muscular contractions. [0008] Described herein is the use of chemical chelators (or sequestrants) as reversal agents, in particular the use of a chemical chelator capable of forming a guest-host complex for the manufacture of a medicament for the reversal of 45 drug-induced neuromuscular block. [0009] Specifically, the invention provides the use of a particular water-soluble chemical chelator for the manufacture of a medicament for the reversal of neuromuscular block by a particular neuromuscular blocking agent, as specified in the claims hereinafter. [0010] The use of chemical chelators as reversal agents for NMBAs has the advantage that they are effective in 50 reversing the action of both depolarizing and non-depolarizing NMBAs, since chemical chelators do not compete with the NMBA for binding to nAChRs. Their use does not increase the level of acetylcholine and therefore they produce fewer side effects than AChE-based reversal agents. In addition, there is no need for the combined use of a AChE inhibitor and a mach antagonist (e.g., atropine). The chemical chelators of the invention may further be safely employed for the reversal of ’deep block’. 55 [0011] The term chemical chelator (or sequestrant), as used herein, means an organic compound which can engage in host-guest complex formation with a neuromuscular blocking agent. The chemical chelator acts as the host molecule, the neuromuscular blocking agent being the guest molecule. The specific molecular complex, the guest-host complex, is defined as an organised chemical entity resulting from the association of two or more components held together by 2 EP 1 210 090 B1 noncovalent intermolecular forces. [0012] The chemical chelators (or sequestrants), according to the invention, are host molecules selected from various classes of cyclic organic compounds which are known for their ability to form inclusion complexes with various organic compounds in aqueous solution, e Formation of inclusion complexes (also called encapsulation, or chemical chelation) 5 is part of the well-known area of ’supramolecular chemistry’ or ’host-guest chemistry’. Many cyclic organic compounds are known to be capable of forming an inclusion complex with another molecule, organic or inorganic. The structures and chemistry of these compounds are well documented (Comprehensive Supramolecular Chemistry, Volumes 1-11, Atwood J.L., Davies J.E.D., MacNicol D.D., Vogtle F., eds;