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Nicoboxil | CAS No: 13912-80-6 | GMP-certified suppliers
A medication that provides topical relief of musculoskeletal pain and stiffness in conditions like rheumatism, arthritis, sprains, strains, and acute low back pain through localized warming effects.
Therapeutic categories
Drugs that are Mainly Renally ExcretedPyridines
Generic name
Nicoboxil
Molecule type
small molecule
CAS number
13912-80-6
DrugBank ID
DB12911
Approval status
Approved drug, Investigational drug
Primary indications
- The primary therapeutic use for which nicoboxil is currently indicated for is as an active ingredient in combination with the capsaicinoid nonivamide compound as a topical analgesic for the temporary relief of the pain of rheumatism, arthritis, lumbago, muscular aches, sprains and strains, sporting injuries, and other conditions where local warmth is beneficial
- Nevertheless, most of the available studies regarding the use of nicoboxil and nonivamide topical analgesics focus specifically on their efficacy and safety in treating acute non-specific low back pain, typically finding the combination analgesic to be an effective, safe, and well-tolerated medication for such an indication [A32785, A32786]
Product Snapshot
- Nicoboxil is available as a topical ointment formulation and powder for solution intended for cutaneous application
- Its primary therapeutic use is as a topical analgesic in combination with nonivamide for temporary relief of musculoskeletal pain, including rheumatism, arthritis, lumbago, and related conditions
- Nicoboxil-containing products are approved for use in the Canadian market and are currently in investigational stages elsewhere
Clinical Overview
Nicoboxil (CAS Number 13912-80-6) is an organic compound classified within the pyridinecarboxylic acids, characterized by a pyridine ring with a carboxylic acid group. It is primarily employed as a topical analgesic agent in combination with nonivamide, a synthetic capsaicin analog. This fixed-dose combination is indicated for the temporary relief of pain associated with rheumatism, arthritis, lumbago, muscular aches, sprains, strains, and sports injuries, where localized warmth contributes to symptom alleviation.
Clinically, nicoboxil/nonivamide topical formulations have been extensively studied in the context of acute non-specific low back pain, demonstrating efficacy and an acceptable safety profile. Such products have been in use since the 1950s, with ongoing investigations supporting their role as alternative musculoskeletal pain therapies, particularly due to a lower incidence of systemic adverse effects compared to oral non-steroidal anti-inflammatory drugs and opioids.
Pharmacodynamically, nicoboxil acts as a rubefacient, eliciting vasodilation of cutaneous blood vessels through a mechanism proposed to involve prostaglandin-mediated pathways, thereby increasing local blood flow and producing a hyperemic response. The mechanism of action is considered a form of counter-irritation, where skin irritation and resultant warmth reduce the perception of musculoskeletal pain via sensory nerve modulation. In combination, nicoboxil’s vasodilatory effects complement nonivamide’s capsaicin-mediated depletion of Substance P in peripheral nociceptive fibers, exerting a synergistic analgesic effect.
Absorption, distribution, metabolism, and excretion (ADME) data specific to nicoboxil are limited, but it is categorized among drugs mainly eliminated via renal excretion pathways. Safety considerations primarily relate to local skin irritation and potential sensitization; systemic toxicity is minimal due to topical application and poor systemic absorption at therapeutic doses.
Nicoboxil/nonivamide topical products are approved in select regions including parts of Europe and Australia. Regulatory status in other jurisdictions may vary, underscoring the need for compliance with local regulatory frameworks.
For API procurement, sourcing nicoboxil requires attention to synthetic route consistency, impurity profiles, and compliance with pharmacopeial standards to ensure quality and batch-to-batch reproducibility. Given its use in combination topical analgesics, compatibility and stability with nonivamide must also be considered during formulation development.
Clinically, nicoboxil/nonivamide topical formulations have been extensively studied in the context of acute non-specific low back pain, demonstrating efficacy and an acceptable safety profile. Such products have been in use since the 1950s, with ongoing investigations supporting their role as alternative musculoskeletal pain therapies, particularly due to a lower incidence of systemic adverse effects compared to oral non-steroidal anti-inflammatory drugs and opioids.
Pharmacodynamically, nicoboxil acts as a rubefacient, eliciting vasodilation of cutaneous blood vessels through a mechanism proposed to involve prostaglandin-mediated pathways, thereby increasing local blood flow and producing a hyperemic response. The mechanism of action is considered a form of counter-irritation, where skin irritation and resultant warmth reduce the perception of musculoskeletal pain via sensory nerve modulation. In combination, nicoboxil’s vasodilatory effects complement nonivamide’s capsaicin-mediated depletion of Substance P in peripheral nociceptive fibers, exerting a synergistic analgesic effect.
Absorption, distribution, metabolism, and excretion (ADME) data specific to nicoboxil are limited, but it is categorized among drugs mainly eliminated via renal excretion pathways. Safety considerations primarily relate to local skin irritation and potential sensitization; systemic toxicity is minimal due to topical application and poor systemic absorption at therapeutic doses.
Nicoboxil/nonivamide topical products are approved in select regions including parts of Europe and Australia. Regulatory status in other jurisdictions may vary, underscoring the need for compliance with local regulatory frameworks.
For API procurement, sourcing nicoboxil requires attention to synthetic route consistency, impurity profiles, and compliance with pharmacopeial standards to ensure quality and batch-to-batch reproducibility. Given its use in combination topical analgesics, compatibility and stability with nonivamide must also be considered during formulation development.
Identification & chemistry
| Generic name | Nicoboxil |
|---|---|
| Molecule type | Small molecule |
| CAS | 13912-80-6 |
| UNII | GSD5B9US0W |
| DrugBank ID | DB12911 |
Pharmacology
| Summary | Nicoboxil is a topical rubefacient that induces vasodilation and skin hyperemia through irritation of sensory nerve endings, producing a counter-irritant effect that may alleviate musculoskeletal pain. Its vasodilatory activity is mediated in part by prostaglandin mechanisms and nerve conduction pathways. Nicoboxil is primarily formulated in combination with nonivamide, a synthetic capsaicin analog that depletes Substance P in peripheral nociceptive fibers, together providing complementary actions that enhance local blood flow and analgesic efficacy in conditions such as rheumatism and muscular pain. |
|---|---|
| Mechanism of action | In particular, nicoboxil is considered a rubefacient [F11, A32785]. However, the specific mechanism of action by which rubefacients like nicoboxil elicit pharmacologic effects has not yet been formally elucidated [A32798, A32799]. Nevertheless, it is generally proposed that rubefacients cause irritation of the skin when applied topically, and are believed to alleviate pain in muscles, joints, tendons, and other musculoskeletal pains in the extremities by counter-irritation . This specific term, 'counter-irritant', derives from the fact that rubefacients can cause a reddening of the skin by causing the blood vessels of the skin to dilate, which gives a soothing feeling of warmth . In essence, the term largely refers to the notion that irritation of the sensory nerve endings alters or offsets pain in the underlying muscle or joints that are innervated by the same nerves . In fact, the vasodilation effect of rubefacients like nicoboxil has been considered the result of nerve conduction mechanisms as early as the late 1950s when certain studies demonstrated that the concomitant application of xylocaine could counteract or prevent the vasolidator response to rubefacients in 50% of such related experiments . |
| Pharmacodynamics | Topical applications consisting of the individual active ingredients of nicoboxil and nonivamide at doses considered to be therapeutic are generally not considered readily available commercially . Subsequently, the pharmacodynamics of nicoboxil are considered useful in commercially available combination products largely because they combine with those of nonivamide to offer a synergistic effect from the unique complementary actions of these two agents . Subsequently, nonivamide is a synthetic capsaicin analog with analgesic properties which are assumed to result from the depletion of Substance P in the peripheral nociceptive C-fibres and A-delta nerve fibers upon repetitive topical application . Resultant stimulation of afferent nerve endings in the skin evidently causes a dilatory effect on the surrounding blood vessels accompanied by an intense, long-lasting sensation of warmth associated with the nonivamide use . Given the proposed effect of nonivamide, it is believed that nicoboxil is a vitamin of the B complex that possesses vasodilating properties facilitated by prostaglandin . The observed hyperaemic increased blood flow effect of nicoboxil occurs earlier and is described as being more intense than the nonivamide hyperaemic effect . Nicoboxil and nonivamide are consequently generally indicated as a combination product because the pharmacodynamics of nicoboxil are considered useful as a complement to those of nonivamide, and vice versa [F11, A32785]. In essence, both compounds induce vasodilation by different effects and therefore have complementary abilities inducing increased blood flow, thus hastening the hyperaemic skin reaction . |
ADME / PK
| Absorption | Specific investigations on absorption of dermally applied nicoboxil in laboratory animals or target species were not available . Published data for nicotinate esters related to nicoboxil indicated however, that members of this class of compounds are in principle able to penetrate skin [12]. Regardless, there is interest in the studies that demonstrate nicoboxil and nonivamide combination topical applications as effective and safe analgesic products precisely because such topical formulations are expected to have much lower systemic absorption - and thus less exposure to systemic side effects (ie. like gastrointestinal upset, drowsiness, etc.) - than the oral non-steroidal anti-inflammatory drugs, opioids, muscle relaxants, and steroids that may be more commonly prescribed over a rubefacient like nicoboxil [A32785, A32786]. Nevertheless, despite the fact that topical nicoboxil and nonivamide products been available to use in some parts of Europe since the 1950s to treat discomfort of the muscuoskeletal system, the effects of nicoboxil and nonivamide have not been investigated in detail and a lack of detailed studies on nicoboxil pharmacodynamics and pharmacokinetics remains ongoing . |
|---|---|
| Half-life | The half-life of ester hydrolysis was found to be very short in the presence of human serum albumin - less than 15 minutes, 50uM . |
| Protein binding | Despite the fact that topical nicoboxil and nonivamide products been available to use in some parts of Europe since the 1950s to treat discomfort of the muscuoskeletal system, the effects of nicoboxil and nonivamide have not been investigated in detail and a lack of detailed studies on nicoboxil pharmacodynamics and pharmacokinetics remains ongoing . Readily accessible data regarding the protein binding of nicoboxil is subsequently not available. |
| Metabolism | Any systemically absorbed nicoboxil is expected to be hydrolyzed to nicotinic acid and 2-butoxyethanol in blood plasma . In vitro it is reported that such hydrolysis reactions are catalyzed by esterase-like activity of serum albumin and by plasma esterases . The nicotinic acid metabolite is also capable of vascular dilatation . In humans, the urinary elimination of 2-butoxyethanol's metabolite, 2-butoxyacetic acid was also reported . The metabolism of nicoboxil is considered to be rapid . |
| Route of elimination | Following ester cleavage, the nicotinic acid metabolite is expected to enter the endogenous metabolic pool as a part of the vitamin B complex . The 2-butoxyethanol metabolite is believed to be mainly excreted primarily in the urine and to a certain extent, in exhaled air . In humans, the urinary elimination of 2-butoxyethanol's metabolite, 2-butoxyacetic acid was also reported . |
| Volume of distribution | Despite the fact that topical nicoboxil and nonivamide products been available to use in some parts of Europe since the 1950s to treat discomfort of the muscuoskeletal system, the effects of nicoboxil and nonivamide have not been investigated in detail and a lack of detailed studies on nicoboxil pharmacodynamics and pharmacokinetics remains ongoing . Readily accessible data regarding the volume of distribution of nicoboxil is subsequently not available. |
| Clearance | The elimination of nicoboxil is considered to be rapid . Despite the fact that topical nicoboxil and nonivamide products been available to use in some parts of Europe since the 1950s to treat discomfort of the muscuoskeletal system, the effects of nicoboxil and nonivamide have not been investigated in detail and a lack of detailed studies on nicoboxil pharmacodynamics and pharmacokinetics remains ongoing . Readily accessible data regarding the clearance of nicoboxil is subsequently not available. |
Formulation & handling
- Nicoboxil is a small molecule intended for topical and cutaneous application, not suitable for oral or injectable formulations.
- Its moderate water solubility and LogP indicate balanced hydrophilic-lipophilic properties beneficial for skin absorption.
- Formulations may be prepared as powders or ointments; handling should consider its stability in topical vehicles.
Regulatory status
| Lifecycle | The API is currently marketed in Canada with patent protection set to expire within the next 1-2 years, indicating an impending transition towards increased generic competition and market maturity. |
|---|
| Markets | Canada |
|---|
Supply Chain
| Supply chain summary | The manufacturing and supply landscape for Nicoboxil includes originator companies producing branded products primarily in Canada, such as Actinac Pwr and Actinac Pws. These branded products have a limited global presence, focused mainly on the Canadian market, with no significant activity reported in the US or EU regions. Patent expiry status is not specified, suggesting that any generic competition may be currently limited or emerging depending on regional patent protections. |
|---|
Safety
| Toxicity | Nicoboxil is of low acute toxicity . No adverse side effects were reported in humans after therapeutic use of the combination of nicoboxil/nonivamide . In a study using dermal application of nicoboxil/nonivamide in over 1000 patients, no allergic reactions were observed . |
|---|
High Level Warnings:
- Nicoboxil demonstrates low acute toxicity based on available toxicological data
- Combined dermal application of nicoboxil/nonivamide shows no reported allergic reactions in clinical use involving over 1000 subjects
- No significant adverse effects have been documented in human studies following therapeutic topical application of the nicoboxil/nonivamide combination
Nicoboxil is a type of Analgesics
Analgesics are a category of pharmaceutical Active Pharmaceutical Ingredients (APIs) that are commonly used to relieve pain. They are designed to alleviate discomfort by targeting the body's pain receptors or by reducing inflammation. Analgesics are widely utilized in the medical field to manage various types of pain, ranging from mild to severe.
One of the primary classes of analgesics is nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs work by inhibiting the production of prostaglandins, substances that contribute to pain and inflammation. This class includes well-known drugs like ibuprofen and naproxen. Another class of analgesics is opioids, which are derived from opium or synthetic compounds that mimic the effects of opium. Opioids act on the central nervous system to reduce pain perception and provide potent pain relief. Examples of opioids include morphine, codeine, and oxycodone.
Analgesics are available in various forms, such as tablets, capsules, creams, and injections, allowing for different routes of administration based on the patient's needs. They are commonly used to manage pain associated with conditions like arthritis, headaches, dental procedures, and post-operative recovery.
It is important to note that analgesics should be used under medical supervision, as improper use or overuse can lead to adverse effects, including gastrointestinal complications, addiction, and respiratory depression in the case of opioids. Therefore, it is crucial for healthcare professionals to assess each patient's individual needs and prescribe the appropriate analgesic and dosage.
In summary, analgesics are a vital category of pharmaceutical APIs used to alleviate pain by targeting pain receptors or reducing inflammation. With various classes and forms available, they provide valuable options for pain management when used responsibly and under medical guidance.
