WO2005060957A1 - Formulation of nefopam and its use in the treatment of pain - Google Patents
Formulation of nefopam and its use in the treatment of pain Download PDFInfo
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- 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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- nefopam
- pain
- treatment
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- product according
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- 208000002193 Pain Diseases 0.000 title claims abstract description 22
- 230000036407 pain Effects 0.000 title claims abstract description 21
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- RGPDEAGGEXEMMM-UHFFFAOYSA-N Nefopam Chemical compound C12=CC=CC=C2CN(C)CCOC1C1=CC=CC=C1 RGPDEAGGEXEMMM-UHFFFAOYSA-N 0.000 title description 27
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- 238000009472 formulation Methods 0.000 title description 3
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- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
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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.
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- 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
(+)-Nefopam can be used to treat pain in a subject undergoing therapy for another condition, for example cancer. The condition may be one which is associated with pain.
Description
FORMULATION OF NEFOPAM AND ITS USE IN THE TREATMENT OF PAIN Field of the Invention This invention relates to the use of (+)-nefopam, and to its use in the treatment of pain. Background of the Invention 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. Pharmacodyn. Ther. 226(1 ): 156- 71 , 1977), suggesting that its analgesic mechanism is not opiate-like or anti- inflammatory in nature. Nefopam's antinociception is not blocked by nalaxone, further suggesting that its analgesic action is not through opiate receptors. In vitro and in vivo studies with nefopam enantiomers have shown that (+)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. (2000) conclude that Athere is currently no compelling rationale to justify administering or monitoring individual enantiomers [of nefopam]". 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). 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,
1981).
Summary of the Invention According to the present invention, (+)-nefopam can be used to treat pain in a subject undergoing therapy for another condition, for example cancer. Typically, 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. Indeed, 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. Similarly, for example, (+)-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. Description of Preferred Embodiments 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. Such forms are known to those of ordinary skill in the art. Nefopam has 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.
In addition, it has been determined that 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. For use in the invention, 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. In this context, a typical daily dose is less than 60 mg, e.g. 1 to 50 mg, (+)nefopam. In particular, it is of benefit to administer nefopam in a manner that reduces peripheral exposure to vascular smooth muscle (minimise effect on vascular tone), while maximising the concentrations in the CNS (maximise analgesia). This may be done by nasal delivery, reducing systemic load, while maximising the concentration of drug in the CNS. By way of example only, 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. It may be advantageous to administer (+)-nefopam in combination with another drug used for pain therapy. Such another drug may be an opiate or a non-opiate such as baclofen. Especially for the treatment of neuropathic pain, 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. The following Example illustrates the invention. Example 1 In the following composition, 1-10 mg nefopam is included in 100 μl of: Excipient: % w/w Benzalkonium chloride 0.02 preservative Sorbitol 15 humectant
Hydroxyethylcellulose 0.25 mucoadhesive agent HNa2P04 (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.
These data show that 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. By way of analogy, many patients do not experience pain relief from codeine because they cannot metabolise it to the active metabolite, morphine. The same is true if codeine is administered with a CYP2D6 inhibitor (e.g. tramadol or, to a lesser extent, racemic nefopam). Thus, a common analgesic can be made ineffective by drug-drug
interaction (DDI). In summary, 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.
Claims
1. Use of (+)-nefopam for the manufacture of a medicament for use in the treatment of pain, wherein the subject of treatment is also undergoing treatment for a condition other than pain.
2. Use according to claim 1 , wherein the other condition is one with which pain is associated.
3. Use according to claim 1 or claim 2, wherein the other condition is cancer, arthritis, neuropathy, trauma, musculoskeletal injury or disease, a visceral disease, migraine headache or surgery.
4. A product comprising (+)-nefopam and an opiate or other analgesic, for simultaneous, sequential or separate use in the treatment of pain, wherein the subject of treatment is also undergoing treatment for a condition other than pain.
5. A product according to claim 4, wherein the (+)-nefopam is in a form that, on administration, avoids first-pass metabolism.
6. A product according to claim 4 or claim 5, wherein the opiate is in a form that, on administration, avoids first-pass metabolism.
7. A product according to any of claims 4 to 6, wherein the (+)-nefopam is in the form of a composition, suitable for intranasal administration.
8. A product according to claim 7, wherein the composition comprises one or more of a mucoadhesive agent, a solubility enhancer, a humectant, a buffer and water.
9. A product according to any of claims 4 to 8, wherein the other condition is as defined in claim 2 or claim 3.
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 (en) | 2005-07-07 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB2004/005408 WO2005060957A1 (en) | 2003-12-24 | 2004-12-24 | Formulation of nefopam and its use in the treatment of pain |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB0330049D0 (en) |
| WO (1) | WO2005060957A1 (en) |
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| FR2937553A1 (en) * | 2008-10-29 | 2010-04-30 | Biocodex | SYNERGISTIC COMBINATION OF ANALGESIC COMPOUNDS |
| WO2011072394A1 (en) | 2009-12-15 | 2011-06-23 | The Hospital For Sick Children | METHOD OF TREATING SCARS AND ß-CATENIN-MEDIATED DISORDERS USING NEFOPAM COMPOUNDS |
| US20110275626A1 (en) * | 2009-01-13 | 2011-11-10 | Philippe Perovitch | Formulation for oral transmucosal administration of analgesic and/or antispasmodic molecules |
| EP3679927A1 (en) * | 2019-01-14 | 2020-07-15 | APTYS Pharmaceuticals SAS | A method of manufacturing a pharmaceutical composition comprising nefopam and acetaminophen, and the pharmaceutical composition obtained thereby |
| 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 |
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| WO2002000195A2 (en) * | 2000-06-26 | 2002-01-03 | Epicept Corporation | Methods and compositions for treating pain of the mucous membrane |
| WO2003105833A1 (en) * | 2002-06-17 | 2003-12-24 | Arakis Ltd. | Formulation of nefopam and its use in the treatment of pain |
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2937553A1 (en) * | 2008-10-29 | 2010-04-30 | Biocodex | SYNERGISTIC COMBINATION OF ANALGESIC COMPOUNDS |
| EP2181709A1 (en) * | 2008-10-29 | 2010-05-05 | Biocodex | Synergic combination of analgesic compounds |
| 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 (en) | 2009-12-15 | 2011-06-23 | The Hospital For Sick Children | METHOD OF TREATING SCARS AND ß-CATENIN-MEDIATED DISORDERS USING NEFOPAM COMPOUNDS |
| 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 |
| US12226421B2 (en) | 2016-09-09 | 2025-02-18 | 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 |
| 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 |
| WO2020148219A1 (en) * | 2019-01-14 | 2020-07-23 | Aptys Pharmaceuticals Sas | A method of manufacturing a pharmaceutical composition comprising nefopam and acetaminophen, and the pharmaceutical composition obtained thereby |
| EP3679927A1 (en) * | 2019-01-14 | 2020-07-15 | APTYS Pharmaceuticals SAS | A method of manufacturing a pharmaceutical composition comprising nefopam and acetaminophen, and the pharmaceutical composition obtained thereby |
Also Published As
| Publication number | Publication date |
|---|---|
| GB0330049D0 (en) | 2004-02-04 |
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