Loxoprofen Sodium

Product Overview

Loxoprofen Sodium (development code CS-600) was developed by Sankyo (now Daiichi Sankyo) of Japan and marketed as Loxonin (Japan) and Lesong (China, Daiichi Sankyo). It is one of the few prodrugs among propionic acid-class NSAIDs.

Clinical significance of the prodrug design: Loxoprofen sodium itself has almost no pharmacological activity. After oral administration and gastrointestinal absorption, it is rapidly converted in the body (mainly via the liver) into the active metabolite—the trans-OH form (trans-alcohol metabolite)—which inhibits cyclooxygenase and blocks prostaglandin synthesis to exert its effect. This design brings two direct benefits:

1. Lower gastrointestinal irritation—before the drug is absorbed into the bloodstream and converted, it does not directly contact the gastric mucosa in its active form, so its direct gastrointestinal irritation is significantly lower than that of directly acting NSAIDs; literature data show an incidence of gastrointestinal symptoms of about 2.25%, lower than ibuprofen (about 16%) and diclofenac sodium (about 10%).
2. COX inhibition occurs in the systemic circulation, not locally.

Pharmacokinetic profile: Rapidly absorbed after oral administration; both loxoprofen (parent) and the trans-OH form (active metabolite) are present in blood. Time to peak—about 30 minutes for the parent and about 50 minutes for the trans-OH form; half-life of both is about 1 hour 15 minutes (other literature records 1.2 hours for the parent and 1.3 hours for the active metabolite). After absorption, it is excreted mainly in urine as glucuronide conjugates, with about 50% excreted within 8 hours of dosing. No accumulation was observed in healthy volunteers after repeated oral dosing (80 mg, three times daily, for 5 days).

Meaning of “this product alone carries JP”: Loxoprofen sodium is an originator product from Japan; the Japanese Pharmacopoeia (JP) contains a monograph for this product (the JP standard corresponds to its hydrate form), while in China it is included in the National Drug Standard (converted new drug standard, Volume 66, WS1-(X-157)-2005Z), with a molecular formula consistent with JP. This makes it one of the few NSAID APIs that can be supplied to both CHP and JP standards.

Technical Specifications

• Standards: CHP/JP (China National Drug Standard WS1-(X-157)-2005Z; the Japanese Pharmacopoeia includes a monograph for the hydrate of this product)

• Specification: 0.99 (purity ≥99.0%, HPLC); pharmacopoeial/pharmaceutical grade assay 98.5%–101.0% calculated on the anhydrous basis, water content 11.0%–13.0% (theoretical water content of the dihydrate 11.84%), pH 6.5–8.5, heavy metals ≤10 ppm, single impurity ≤0.05%, total impurities ≤0.50%

• CAS Numbers:

  • 80382-23-6—anhydrous form: PubChem CID 23663407, UNII NDC2M7399S, MDL MFCD00941425
  • 226721-96-6—dihydrate (the form used in pharmacopoeias and marketed formulations): PubChem CID 23674745
  • 68767-14-6—loxoprofen free acid (synthetic precursor): C₁₅H₁₈O₃, MW 246.30, melting point 108.5–111 ℃
  • Important note: “Loxoprofen sodium” in pharmacopoeias and marketed product labels refers to the dihydrate (C₁₅H₁₇NaO₃·2H₂O, MW 304.31); however, CAS 80382-23-6 corresponds to the anhydrous form (C₁₅H₁₇NaO₃, MW 268.28) in PubChem/CAS registrations. Many suppliers on the market list CAS 80382-23-6 alongside “dihydrate 304.32” (e.g., supply entries under CP2000/JP IV standards); always confirm the actual form and molecular weight before procurement and assay conversion

• Molecular Formula:

  • Anhydrous: C₁₅H₁₇NaO₃
  • Dihydrate: C₁₅H₁₇NaO₃·2H₂O (combined formula C₁₅H₂₁NaO₅)

• Molecular Weight:

  • Anhydrous: 268.28 (PubChem 268.28; ChemicalBook 268.2834; Guidechem 268.288); exact mass 268.1075
  • Dihydrate: 304.31 (Daiichi Sankyo label 304.31; National Drug Standard 304.32; ChemicalBook 304.314)
  • The tablet strength “60 mg” is calculated as anhydrous C₁₅H₁₇NaO₃

• Appearance: White to pale yellowish-white (white or off-white) crystal or crystalline powder; the dihydrate is hygroscopic

• Purity (HPLC): ≥ 99.0%

• Melting Point: 194–198 ℃, melting with decomposition (value recorded in the National Drug Standard WS1-(X-157)-2005Z, corresponding to the dihydrate; recommended). Other sources differ: dihydrate about 198 ℃ (decomposition) (ChemicalBook, InvivoChem, consistent with the pharmacopoeia); anhydrous about 215–217 ℃ (Baidu Baike) or 195–202 ℃ (Guidechem, Yinuo Chemical, though the latter entry actually refers to the dihydrate)—differences among sources arise from the form (anhydrous/dihydrate) and measurement method; when citing, state the form and source

• Specific Rotation: Optically inactive—the National Drug Standard specifies that an aqueous solution of this product (1→20) shows no optical activity. This product is a racemate (±); the molecule contains 2 undefined stereocenters (the α-position of the propionic acid and the 2-position of the cyclopentanone); PubChem records “Defined Atom Stereocenter Count 0, Undefined 2”; therefore the pharmacopoeia sets no specific rotation test

• Chemical Name: Sodium 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propanoate dihydrate; IUPAC: sodium 2-[4-[(2-oxocyclopentyl)methyl]phenyl]propanoate

• Stereochemistry: Racemate (±), no defined stereocenters

• Solubility (National Drug Standard): Very soluble in water or methanol, freely soluble in ethanol, practically insoluble in diethyl ether. Other sources record: freely soluble in hot water, insoluble in chloroform and benzene; water solubility about 53 mg/mL; reagent grade soluble in DMSO (slightly soluble, sonication required)

  • Note: Some sources claim “insoluble in DMSO and ethanol,” which contradicts the pharmacopoeial “freely soluble in ethanol”—this is a source discrepancy; for release and formulation purposes, the pharmacopoeial record prevails

• Calculated Physicochemical Parameters (anhydrous): Boiling point about 417.9 ℃ (760 mmHg); flash point about 220.7 ℃; vapor pressure about 9.92×10⁻⁸ mmHg (25 ℃); LogP about 1.45 (dihydrate recorded as 1.32); topological polar surface area about 57.2 Ų (dihydrate recorded as 75.66); H-bond donors 0 / acceptors 3; rotatable bonds 4; heavy atom count 19

• Marketed Formulation Strengths: Tablets 60 mg, dispersible tablets 60 mg, capsules 60 mg (all calculated as C₁₅H₁₇NaO₃); patches 50 mg, 100 mg; oral solution

• Storage: Protect from light, seal tightly, store in a dry place below 25 ℃ (the dihydrate is hygroscopic and must be protected from moisture); shelf life 3 years (as stated by some suppliers)

Applications

• Anti-inflammatory analgesia for chronic joint and soft-tissue diseases: Rheumatoid arthritis, osteoarthritis, low back pain, periarthritis of the shoulder, cervico-omo-brachial syndrome, toothache. The usual adult dose is 60 mg of loxoprofen sodium (calculated as anhydrous) orally, three times daily; at symptom onset, 60–120 mg as a single dose, adjusted by age and symptoms; avoid taking on an empty stomach

• Analgesia and anti-inflammation after surgery, trauma, and tooth extraction: Dosage as above

• Antipyresis and analgesia in acute upper respiratory tract inflammation: Including acute upper respiratory tract inflammation accompanied by acute bronchitis. The usual adult dose is 60 mg as a single dose at symptom onset, in principle twice daily, up to a maximum of 180 mg per day; avoid taking on an empty stomach

• Topical formulations (patches): Once daily, applied to the affected area (50 mg / 100 mg strengths)

• Clinical features: Rapid onset (parent compound peaks at about 30 minutes), strong analgesic effect, short half-life (about 1 hour 15 minutes) with no accumulation on repeated dosing; as a prodrug, its incidence of gastrointestinal adverse reactions is among the lower levels of NSAIDs in its class, and it is well tolerated in elderly patients (in an 8-week open multicenter trial of 4,024 elderly patients, the incidence of adverse events was about 2.2%, mostly mild gastrointestinal reactions)

• Pharmacology and mechanism research: Used for COX (prostaglandin endoperoxide synthase, EC 1.14.99.1) inhibitory activity evaluation, in vivo prodrug conversion (trans-OH form) kinetics, prostaglandin synthesis inhibition, comparative NSAID gastrointestinal tolerability studies, and other in vitro and animal research

• Formulation and manufacturing: Used for formulation development of tablets (60 mg), dispersible tablets, capsules, patches, and oral solutions; the API is very soluble in water and methanol, and formulations must address pH 6.5–8.5 and moisture control due to hygroscopicity; key manufacturing control points include assay (98.5%–101.0% calculated on the anhydrous basis), water content (11.0%–13.0%), related substances (single ≤0.05%, total ≤0.50%), heavy metals (≤10 ppm), and residual solvents (toluene, DMF, DMSO); suitable for analytical method development and validation, stability studies, impurity reference standards, and GMP scale-up and CMO/CDMO contract manufacturing

Safety Notice: This product is a pharmaceutical active ingredient (API) intended solely for compliant industrial, research, and pharmaceutical manufacturing use; it is not intended for end clinical use or self-medication guidance. The finished product is a prescription drug and should be used under physician guidance, following the principle of “using the lowest effective dose for the shortest treatment duration.” Contraindications: ① Patients with known hypersensitivity to this product; ② patients in whom aspirin or other NSAIDs have induced asthma, urticaria, or allergic reactions; ③ perioperative pain in coronary artery bypass graft (CABG) surgery; ④ patients who have experienced gastrointestinal bleeding or perforation with NSAID use; ⑤ active peptic ulcer/bleeding, or a history of recurrent ulcer/bleeding; ⑥ severe heart failure; ⑦ severe hematological abnormalities; ⑧ severe hepatic impairment; ⑨ severe renal impairment; ⑩ pregnant and lactating women. Key warnings (boxed-warning-level risks common to the NSAID class): ① Gastrointestinal bleeding, ulceration, and perforation may occur at any time during treatment—potentially fatal and without warning symptoms; elderly patients are at greater risk; ② may increase the risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal; risk is greater in patients with cardiovascular disease or risk factors; ③ may cause new-onset hypertension or worsen existing hypertension, and may attenuate the efficacy of thiazide/loop diuretics—blood pressure should be monitored throughout treatment; ④ may cause fatal serious cutaneous adverse reactions (exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis)—discontinue at the first appearance of rash. Other major adverse reactions: shock and anaphylaxis, agranulocytosis/leukopenia/hemolytic anemia/aplastic anemia/thrombocytopenia, mucocutaneous ocular syndrome, acute renal injury/nephrotic syndrome/interstitial nephritis (may be accompanied by hyperkalemia), congestive heart failure, interstitial pneumonia, peptic ulcer and gastrointestinal bleeding/perforation, small or large intestinal stenosis/obstruction, fulminant hepatitis/hepatic dysfunction/jaundice, asthma attacks, aseptic meningitis, rhabdomyolysis. Common adverse reactions: abdominal pain, stomach discomfort, nausea, vomiting, loss of appetite, constipation, heartburn, as well as edema, rash/urticaria, and somnolence (in a 13,486-case survey, the incidence of adverse reactions was 3.03%, dominated by gastrointestinal symptoms at 2.25%). Drug interactions: coumarin anticoagulants (warfarin—dose reduction required), new quinolone antibacterials (enoxacin—convulsions may occasionally occur), sulfonylurea hypoglycemics (tolbutamide—enhanced hypoglycemic effect), thiazide diuretics (hydrochlorothiazide—attenuated diuretic/antihypertensive effect), lithium preparations (lithium carbonate—may raise serum lithium levels causing lithium toxicity). Avoid concomitant use with other NSAIDs (including selective COX-2 inhibitors). The API is GHS-classified as Skin Irritation Category 2, Serious Eye Irritation Category 2, and Specific Target Organ Toxicity (single exposure, respiratory irritation) Category 3 (H315/H319/H335); wear protective gloves, protective clothing, and respiratory and eye/face protection during handling, and avoid dust inhalation.

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