(19) TZZ Z¥_T (11) EP 2 446 903 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/085 (2006.01) A61K 31/165 (2006.01) 09.10.2019 Bulletin 2019/41 A61K 31/167 (2006.01) A61K 31/14 (2006.01) A61K 9/00 (2006.01) A61K 45/06 (2006.01) (2006.01) (2006.01) (21) Application number: 11007949.8 A61P 17/04 A61P 29/00 (22) Date of filing: 19.11.2007 (54) Compositions for treating itch Zusammensetzungen zur Behandlung von Juckreiz Compositions pour traiter les démangeaisons (84) Designated Contracting States: WO-A2-99/11252 US-A- 3 519 631 AT BE BG CH CY CZ DE DK EE ES FI FR GB GR US-A- 4 069 309 US-B1- 6 362 197 HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE US-B1- 6 413 961 SI SK TR • OMANA-ZAPATA I ET AL: "QX-314 inhibits (30) Priority: 20.11.2006 US 860124 P ectopic nerve activity associated with 06.07.2007 US 958594 P neuropathic pain.", BRAIN RESEARCH 17 OCT 03.10.2007 US 997510 P 1997,vol. 771, no. 2, 17 October 1997 (1997-10-17), pages 228-237, XP002486707, ISSN: 0006-8993 (43) Date of publication of application: • STRICHARTZ G R: "The inhibition of sodium 02.05.2012 Bulletin 2012/18 currents in myelinated nerve by quaternary derivatives of lidocaine.", THE JOURNAL OF (62) Document number(s) of the earlier application(s) in GENERAL PHYSIOLOGY JUL 1973, vol. 62, no. 1, accordance with Art. 76 EPC: July 1973 (1973-07), pages 37-57, XP002486708, 07862114.1 / 2 101 819 ISSN: 0022-1295 • CAHALAN M D ET AL: "Interactions between (73) Proprietors: quaternary lidocaine, the sodium channel gates, • President and Fellows of Harvard College andtetrodotoxin.", BIOPHYSICAL JOURNAL JUL Cambridge, MA 02138 (US) 1979, vol. 27, no. 1, July 1979 (1979-07), pages • The General Hospital Corporation 39-55, XP002486709, ISSN: 0006-3495 Boston, MA 02114 (US) • RICH T C ET AL: "Quaternary quinidine derivatives as a tool to study: Block of human (72) Inventors: potassium channels", BIOPHYSICAL JOURNAL, • Bean, Bruce P. vol. 66, no. 2 PART 2, 1994, page A143, Waban, MA 02468 (US) XP009102646, & THIRTY-EIGHTH ANNUAL • Woolf, Clifford J. MEETING OF THE BIOPHYSICAL SOCIETY; NEW Newton, MA 02458 (US) ORLEANS, LOUISIANA, USA; MARCH 6-10, 1994 ISSN: 0006-3495 (74) Representative: Lahrtz, Fritz et al • KIRKPATRICK W E ET AL: "Comparison of the Patentanwälte effects of procaine, chlorpromazine and their Isenbruck Bösl Hörschler PartG mbB quaternary derivatives on nerve action Prinzregentenstraße 68 potentials.", RESEARCH COMMUNICATIONS IN 81675 München (DE) CHEMICAL PATHOLOGY AND PHARMACOLOGY JAN 1970, vol. 1, no. 1, (56) References cited: January 1970 (1970-01), pages 149-155, WO-A-01/44218 WO-A1-98/24428 XP009102648, ISSN: 0034-5164 WO-A1-2006/010587 WO-A2-01/45678 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 2 446 903 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 446 903 B1 • NIELSEN A B ET AL: "Assessment of the • Scott M Fishman ET AL: "BRIEF CLINICAL combined approach of N-alkylation and salt OBSERVATIONS Intravenous Lidocaine for formation to enhance aqueous solubility of Treatment-resistant Pruritus", The American tertiary amines using bupivacaine as a model Journal of Medicine, vol. 102, 1 June 1997 drug", EUROPEAN JOURNAL OF (1997-06-01), pages 584-585, XP055479315, PHARMACEUTICAL SCIENCES, ELSEVIER, • Martin Steinhoff ET AL: "Neurophysiological, AMSTERDAM, NL, vol. 24, no. 1, 1 January 2005 Neuroimmunological,and Neuroendocrine Basis (2005-01-01), pages 85-93, XP027803616, ISSN: of Pruritus", Journal of Investigative 0928-0987 [retrieved on 2005-01-01] Dermatology, vol. 126, no. 8, 1 August 2006 • NIELSEN A B ET AL: "Bioreversible quaternary (2006-08-01), pages 1705-1718, XP055141873, N-acyloxymethyl derivatives of the tertiary ISSN: 0022-202X, DOI: 10.1038/sj.jid.5700231 amines bupivacaine and lidocaine-synthesis, aqueous solubility and stability in buffer, human plasma and simulated intestinal fluid", EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES,ELSEVIER, AMSTERDAM, NL, vol. 24, no. 5, 1 April 2005 (2005-04-01), pages 433-440, XP027803766, ISSN: 0928-0987 [retrieved on 2005-04-01] 2 EP 2 446 903 B1 Description Background of the Invention 5 [0001] The invention features uses in methods, compositions, and kits for selective inhibition of pain-and itch sensing neurons (nociceptors and pruriceptors) by drug molecules of small molecule weight, while minimizing effects on non- pain-sensing neurons or other types of cells. According to the invention, small, hydrophilic drug molecules gain access to the intracellular compartment of pain-sensing neurons via entry through receptors that are present in pain- and itch- sensing neurons but to a lesser extent or not at all in other types of neurons or in other types of tissue. 10 [0002] Local anesthetics such as lidocaine and articaine act by inhibiting voltage-dependent sodium channels in neurons. These anesthetics block sodium channels and thereby the excitability of all neurons, not just pain-sensing neurons (nociceptors). Thus, while the goal of topical or regional anesthesia is to block transmission of signals in nociceptors to prevent pain, administration of local anesthetics also produces unwanted or deletrious effects such as general numbness from block of low threshold pressure and touch receptors, motor deficits from block of motor axons 15 and other complications from block of autonomic fibers. Local anesthetics are relatively hydrophobic molecules that gain access to their blocking site on the sodium channel by diffusing into or through the cell membrane. Permanently-charged derivatives of these compounds (such as QX-314, a quaternary nitrogen derivative of lidocaine), which are not membrane- permeant, have no effect on neuronal sodium channels when applied to the external surface of the nerve membrane but can block sodium channels if somehow introduced inside the cell, for example by a micropipette used for whole-cell 20 electrophysiological recording from isolated neurons. Pain-sensing neurons differ from other types of neurons in ex- pressing (in most cases) the TRPV1 receptor/channel, activated by painful heat or by capsaicin, the pungent ingredient in chili pepper. Other types of receptors selectively expressed in various types of pain-sensing and itch-sensing (pruri- ceptor) neurons include but are not limited to TRPA1, TRPM8, and P2X(2/3) receptors. [0003] Neuropathic, inflammatory, and nociceptive pain differ in their etiology, pathophysiology, diagnosis, and treat- 25 ment. Nociceptive pain occurs in response to the activation of a specific subset of peripheral sensory neurons, the nociceptors by intense or noxious stimuli. It is generally acute, self-limiting and serves a protective biological function by acting as a warning of potential or on-going tissue damage. It is typically well-localized. Examples of nociceptive pain include but are not limited to traumatic or surgical pain, labor pain, sprains, bone fractures, burns, bumps, bruises, injections, dental procedures, skin biopsies, and obstructions. 30 [0004] Inflammatory pain is pain that occurs in the presence of tissue damage or inflammation including postoperative, post-traumatic pain, arthritic (rheumatoid or osteoarthritis) pain and pain associated with damage to joints, muscle, and tendons as in axial low back pain. [0005] Neuropathic pain is a common type of chronic, non-malignant pain, which is the result of an injury or malfunction in the peripheral or central nervous system and serves no protective biological function. It is estimated to affect more 35 than 1.6 million people in the U.S. population. Neuropathic pain has many different etiologies, and may occur, for example, due to trauma, surgery, herniation of an intervertebral disk, spinal cord injury, diabetes, infection with herpes zoster (shingles), HIV/AIDS, late-stage cancer, amputation (including mastectomy), carpal tunnel syndrome, chronic alcohol use, exposure to radiation, and as an unintended side-effect of neurotoxic treatment agents, such as certain anti-HIV and chemotherapeutic drugs. 40 [0006] In contrast to nociceptive pain, neuropathic pain is frequently described as "burning," "electric," "tingling," or "shooting" in nature. It is often characterized by chronic allodynia (defined as pain resulting from a stimulus that does not ordinarily elicit a painful response, such as light touch) and hyperalgesia (defined as an increased sensitivity to a normally painful stimulus), and may persist for months or years beyond the apparent healing of any damaged tissues. [0007] Pain may occur in patients with cancer, which may be due to multiple causes; inflammation, compression, 45 invasion, metastatic spread into bone or other tissues. [0008] There are some conditions where pain occurs in the absence of a noxious stimulus, tissue damage or a lesion to the nervous system, called dysfunctional pain and these include but are not limited to fibromyalgia, tension type headache, irritable bowel disorders and erythermalgia. [0009] Migraine is a headache associated with the activation of sensory fibers innervating the meninges of the brain. 50 [0010] Itch (pruritus) is a dermatological condition that may be localized and generalized and can be associated with skin lesions (rash, atopic eczema, wheals). Itch accompanies many conditions including but not limited to stress, anxiety, UV radiation from the sun, metabolic and endocrine disorders (e.g., liver or kidney disease, hyperthyroidism), cancers (e.g., lymphoma), reactions to drugs or food, parasitic and fungal infections, allergic reactions, diseases of the blood (e.g., polycythemia vera), and dermatological conditions.