WO2005060957A1 - Preparation de nefopam et utilisation de cette preparation pour le traitement de la douleur - Google Patents

Preparation de nefopam et utilisation de cette preparation pour le traitement de la douleur Download PDF

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Publication number
WO2005060957A1
WO2005060957A1 PCT/GB2004/005408 GB2004005408W WO2005060957A1 WO 2005060957 A1 WO2005060957 A1 WO 2005060957A1 GB 2004005408 W GB2004005408 W GB 2004005408W WO 2005060957 A1 WO2005060957 A1 WO 2005060957A1
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WO
WIPO (PCT)
Prior art keywords
nefopam
pain
treatment
condition
product according
Prior art date
Application number
PCT/GB2004/005408
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English (en)
Inventor
Michael Harvey Lyne
Original Assignee
Arakis Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Arakis Ltd. filed Critical Arakis Ltd.
Publication of WO2005060957A1 publication Critical patent/WO2005060957A1/fr

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Classifications

    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61K31/5545—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having eight-membered rings not containing additional condensed or non-condensed nitrogen-containing 3-7 membered rings

Definitions

  • Nefopam is a centrally acting non-narcotic analgesic not structurally related to other analgesics. Nefopam has been shown to induce antinociception in animal models of pain and in humans (reviewed in Heel et al., Drugs 19(4): 249-67, 1980). However, nefopam is not active in the mouse tail-flick test, the hot plate test or the Randal l-Selitto pressure test in rats (Conway and Mitchell, Arch. Int.
  • (+)nefopam has more potent analgesic and dopamine-, norepinephrine- and serotonin- uptake inhibitory properties than (-)nefopam, with the order of potency given as (+)nefopam >( ⁇ )nefopam > (-)nefopam (Fasmer et al., J.Pharm. Pharmacol.42(6): 437- 8, 1987; Rosland and Hole, J. Pharm. Pharmacol. 42(6): 437-8, 1990; Mather et al., Chirality 12(3): 153-9, 2000). Mather etal.
  • Nefopam has also been shown to be opiate-sparing when given with morphine in trials of patient-controlled analgesia (Mimoz et al., Anaesthesia 56(6): 520-5, 2001). Conventional release preparations of nefopam have been commercially available for many years, for use in treating moderate to severe pain. However, the short elimination half-life of nefopam (four hours) means that it is difficult to maintain analgesic efficacy over the normal dosing period (three times daily).
  • nefopam Dose escalation of nefopam brings about an increase in the frequency of adverse drug reactions associated with the analgesic, and adverse effects on pulse and blood pressure have been observed following parenteral delivery of therapeutic doses of nefopam (Heel et al., 1980). Chronotropic and ionotropic effects on the heart are not present when nefopam is administered orally (Bhatt ef a/., Br. J. Clin. Pharmacol. 11(2): 209-11,
  • (+)-nefopam can be used to treat pain in a subject undergoing therapy for another condition, for example cancer.
  • the pain is associated with the condition, and may be acute, chronic or neuropathic.
  • the present invention has utility in the therapy of pain associated with cancer, surgery, arthritis, dental surgery, painful neuropathies, trauma, musculoskeletal injury or disease, visceral diseases, and migraine headache in mammals.
  • the (+) ⁇ nefopam may be formulated so that it avoids first-pass metabolism, e.g. in a form suitable for intranasal administration or another suitable route.
  • the (+)-nefopam may be administered in combination with another pain-relieving drug, in particular an opiate or other analgesic.
  • another pain-relieving drug in particular an opiate or other analgesic.
  • the present invention is partly based on the fact that (+)nefopam does not affect 2D6 metabolism and therefore has low drug-drug interaction potential. This is of particular utility since the use of (+)- nefopam in conjunction with an analgesic can give effective pain relief with reduced or minimal interaction.
  • (+)-nefopam can be used to treat cancer pain when the patient is receiving cancer treatment with chemotherapeutic agents, a situation where drug-drug interactions should be avoided.
  • the active agent may be in the form of the free base or any pharmaceutically acceptable salt, e.g. the hydrochloride, or in the form of a metabolite or prodrug.
  • suitable characteristics for formulation in a composition intended for intranasal administration It has a low molecular weight, is highly soluble and stable in solution across a wide pH range (4-7), including pH 5.5-6.5, which may be optimal for nasal absorption. Nefopam may thus be rapidly and completely absorbed from the nasal cavity and provide the rapid onset of action required to bring pain relief.
  • nefopam demonstrates no cytotoxicity, even at high concentrations (>5mM), against a nasal epithelial cell-line (RPMI 2650).
  • Nefopam should not irritate the nasal mucosa following nasal delivery in man.
  • a medicament may comprise components that are known for the purpose. Intranasal administration of nefopam avoids first-pass metabolism. Nasal delivery introduces significant concentrations of (+)- nefopam to the CNS, while reducing side-effects.
  • a typical daily dose is less than 60 mg, e.g. 1 to 50 mg, (+)nefopam.
  • a composition for intranasal delivery comprises, in addition to nefopam, one or more of a solubility enhancer such as propylene glycol, a humectant such as mannitol, a buffer and water. Mucoadhesive agents and penetration enhancers may also be used. Such agents and enhancers are known to those skilled in the art.
  • (+)-nefopam in combination with another drug used for pain therapy.
  • another drug may be an opiate or a non-opiate such as baclofen.
  • coadministration with gabapentin is preferred.
  • Other compounds that may be used include acetaminophen, a non-steroidal anti-inflammatory drug, a narcotic analgesic, a local anaesthetic, an NMDA antagonist, a neuroleptic agent, an anti-convulsant, an anti-spasmodic, an anti- depressant or a muscle relaxant.
  • Example 1 In the following composition, 1-10 mg nefopam is included in 100 ⁇ l of: Excipient: % w/w Benzalkonium chloride 0.02 preservative Sorbitol 15 humectant Hydroxyethylcellulose 0.25 mucoadhesive agent HNa 2 P0 4 (0.2M) 35.7 Citric Acid (0.1 M) 14.1 Deionised Water 34.9 Buffer to pH 6.5 The stability of nefopam with all the excipients individually has been demonstrated following 4 weeks incubation at both 25°C and 50°C.
  • Example 2 This invention is based in part on the surprising finding that there is essentially no drug-drug interaction, when using (+)-nefopam with a representative cytotoxic drug. Evidence for this assertion is now provided.
  • a cytochrome P450 2D6 inhibition assay was performed using a recombinant cytochrome P450 2D6 according to the method of Ono et al. (1996) Xenobiotica 26(11 ):681. Results are shown in the following table.
  • racemic nefopam would have limited or no use in combination with many common drugs, including those used in the treatment of pain. This applies to any drug that is metabolised by CYP2D6.
  • codeine is administered with a CYP2D6 inhibitor (e.g. tramadol or, to a lesser extent, racemic nefopam).
  • a common analgesic can be made ineffective by drug-drug interaction (DDI).
  • DAI drug-drug interaction
  • racemic and (-)-nefopam would be contraindicated for use with many common drugs used to treat pain. Such contraindication is unlikely in the case of (+)-nefopam, because of reduced or minimal DDIs.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de (+)-Néfopam pour le traitement de la douleur chez un sujet subissant un traitement pour une pathologie différente, par exemple un cancer. Cette pathologie peut être une pathologie associée à des douleurs.
PCT/GB2004/005408 2003-12-24 2004-12-24 Preparation de nefopam et utilisation de cette preparation pour le traitement de la douleur WO2005060957A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0330049.8A GB0330049D0 (en) 2003-12-24 2003-12-24 The treatment of neuropathic pain conditions
GB0330049.8 2003-12-24

Publications (1)

Publication Number Publication Date
WO2005060957A1 true WO2005060957A1 (fr) 2005-07-07

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ID=31503197

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2004/005408 WO2005060957A1 (fr) 2003-12-24 2004-12-24 Preparation de nefopam et utilisation de cette preparation pour le traitement de la douleur

Country Status (2)

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GB (1) GB0330049D0 (fr)
WO (1) WO2005060957A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2937553A1 (fr) * 2008-10-29 2010-04-30 Biocodex Combinaison synergique de composes analgesiques
WO2011072394A1 (fr) 2009-12-15 2011-06-23 The Hospital For Sick Children Procédé de traitement de cicatrices et de troubles à médiation par la β-caténine à l'aide de composés du néfopam
US20110275626A1 (en) * 2009-01-13 2011-11-10 Philippe Perovitch Formulation for oral transmucosal administration of analgesic and/or antispasmodic molecules
EP3679927A1 (fr) * 2019-01-14 2020-07-15 APTYS Pharmaceuticals SAS Procédé de fabrication d'une composition pharmaceutique comprenant du néfopam et de l'acétaminophène et composition pharmaceutique ainsi obtenue
US10736905B1 (en) 2016-09-09 2020-08-11 Shahin Fatholahi Nefopam dosage forms and methods of treatment
US10736874B1 (en) 2017-09-08 2020-08-11 Shahin Fatholahi Methods for treating pain associated with sickle cell disease
US11446311B2 (en) 2017-09-08 2022-09-20 Shahin Fatholahi Methods for treating pain associated with sickle cell disease

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002000195A2 (fr) * 2000-06-26 2002-01-03 Epicept Corporation Procedes et compositions pour traiter les douleurs de la membrane mueuqueuse
WO2003105833A1 (fr) * 2002-06-17 2003-12-24 Arakis Ltd. Formulation de nefopam et utilisation de celle-ci dans le traitement de la douleur

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002000195A2 (fr) * 2000-06-26 2002-01-03 Epicept Corporation Procedes et compositions pour traiter les douleurs de la membrane mueuqueuse
WO2003105833A1 (fr) * 2002-06-17 2003-12-24 Arakis Ltd. Formulation de nefopam et utilisation de celle-ci dans le traitement de la douleur

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
BLASCHKE G ET AL: "[Nefopam-enantiomers: isolation and antinociceptive action]", ARCHIV DER PHARMAZIE. APR 1987, vol. 320, no. 4, April 1987 (1987-04-01), pages 341 - 347, XP008046821, ISSN: 0365-6233 *
CHAWLA JYOTI ET AL: "Effect of route of administration on the pharmacokinetic behavior of enantiomers of nefopam and desmethylnefopam.", THERAPEUTIC DRUG MONITORING. APR 2003, vol. 25, no. 2, April 2003 (2003-04-01), pages 203 - 210, XP008046826, ISSN: 0163-4356 *
DATABASE EMBASE [online] ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL; 2001, LEONARD B E: "An introduction to enantiomers in psychopharmacology", XP002328153, Database accession no. EMB-2002017881 *
FASMER O B ET AL: "ANTINOCICEPTIVE EFFECTS OF (PLUS OR MINUS)-, (+)- AND (-)-NEFOPAM IN MICE", JOURNAL OF PHARMACY AND PHARMACOLOGY, LONDON, GB, vol. 39, no. 7, 1987, pages 508 - 511, XP009036262, ISSN: 0022-3573 *
HUMAN PSYCHOPHARMACOLOGY 2001 UNITED KINGDOM, vol. 16, no. SUPPL. 2, 2001, pages S79 - S84, ISSN: 0885-6222 *
ISAKSSON R ET AL: "Enantiomer resolution of nefopam hydrochloride, a novel analgesic: a study by liquid chromatography and circular dichroism spectroscopy.", THE JOURNAL OF PHARMACY AND PHARMACOLOGY. JAN 1988, vol. 40, no. 1, January 1988 (1988-01-01), pages 48 - 50, XP008046820, ISSN: 0022-3573 *
MATHER G G ET AL: "NEFOPAM ENANTIOMERS: PRECLINICAL PHARMACOLOGY/TOXICOLOGY AND PHARMACOKINETIC CHARACTERISTICS IN HEALTHY SUBJECTS AFTER INTRAVENOUS ADMINISTRATION", CHIRALITY, WILEY-LISS, NEW YORK, US, vol. 12, no. 3, March 2000 (2000-03-01), pages 153 - 159, XP009036271, ISSN: 0899-0042 *
MIMOZ O ET AL: "Analgesic efficacy and safety of nefopam vs. propacetamol following hepatic resection.", ANAESTHESIA. JUN 2001, vol. 56, no. 6, June 2001 (2001-06-01), pages 520 - 525, XP009017735, ISSN: 0003-2409 *
MOFFAT A C ET AL: "Postoperative nefopam and diclofenac. Evaluation of their morphine-sparing effect after upper abdominal surgery.", ANAESTHESIA. APR 1990, vol. 45, no. 4, April 1990 (1990-04-01), pages 302 - 305, XP009017736, ISSN: 0003-2409 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2937553A1 (fr) * 2008-10-29 2010-04-30 Biocodex Combinaison synergique de composes analgesiques
EP2181709A1 (fr) * 2008-10-29 2010-05-05 Biocodex Combinaison synergique de composés analgésiques
US20110275626A1 (en) * 2009-01-13 2011-11-10 Philippe Perovitch Formulation for oral transmucosal administration of analgesic and/or antispasmodic molecules
US9532947B2 (en) * 2009-01-13 2017-01-03 Philippe Perovitch Formulation for oral transmucosal administration of analgesic and/or antispasmodic molecules
WO2011072394A1 (fr) 2009-12-15 2011-06-23 The Hospital For Sick Children Procédé de traitement de cicatrices et de troubles à médiation par la β-caténine à l'aide de composés du néfopam
US8957107B2 (en) 2009-12-15 2015-02-17 The Hospital For Sick Children Method of treating scars and β-catenin-mediated disorders using Nefopam compounds
US10736905B1 (en) 2016-09-09 2020-08-11 Shahin Fatholahi Nefopam dosage forms and methods of treatment
US11013747B2 (en) 2016-09-09 2021-05-25 Shahin Fatholahi Nefopam dosage forms and methods of treatment
US10736874B1 (en) 2017-09-08 2020-08-11 Shahin Fatholahi Methods for treating pain associated with sickle cell disease
US11446311B2 (en) 2017-09-08 2022-09-20 Shahin Fatholahi Methods for treating pain associated with sickle cell disease
EP3679927A1 (fr) * 2019-01-14 2020-07-15 APTYS Pharmaceuticals SAS Procédé de fabrication d'une composition pharmaceutique comprenant du néfopam et de l'acétaminophène et composition pharmaceutique ainsi obtenue
WO2020148219A1 (fr) * 2019-01-14 2020-07-23 Aptys Pharmaceuticals Sas Procédé de fabrication de composition pharmaceutique comprenant du néfopam et de l'acétaminophène, et composition pharmaceutique ainsi obtenue

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