Aceclofenac (1-30 μM; 72 hours) totally inhibits prostaglandin E2 synthesis by IL-1β or LPS-stimulated human chondrocytes and considerably lowers interleukin-6 production [1]. With an IC50 value more than 100 μM, aceclofenac suppresses COX-1; nevertheless, in whole blood testing, COX-2 activity was 50% lower at a dosage of 0.77 μM [1]. In human articular chondrocytes, aceclofenac reduces nitric oxide production and enhances the synthesis of interleukin-1 receptor antagonists [2].

Aceclofenac displays a Cmax of 4.59 μg/mL following oral treatment (rat 20 mg/kg) [3]. Because of its high plasma clearance (rat 1.10 L/h/kg) upon intravenous injection (rat 10 mg/kg), aceclofenac has a terminal elimination half-life (rat 3.24 hours) [3].

Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rats, body weight 32-340 g[3]
Doses: 10 mg/kg intravenously (iv) (iv)(iv), 20 mg/kg orally (pharmacokinetic/PK/PK analysis)
Route of Administration: oral and intravenous (iv) (iv)injection
Experimental Results:T1 /2 (3.24 hrs (hrs (hours)))), Cmax (orally 4.59 μg/mL).

Absorption, Distribution and Excretion
Following oral administration, Aceclofenac is rapidly and completely absorbed from the gastrointestinal tract and circulates primarily as the unchanged drug. Peak plasma concentrations are reached approximately 1.25 to 3 hours after administration. The drug can permeate into the synovial fluid, reaching concentrations up to 60% of the plasma concentration. Regular dosing does not lead to drug accumulation; the maximum plasma concentration (Cmax) and time to peak concentration (Tmax) are similar after single and multiple doses. The primary route of excretion is urine, accounting for 70-80% of drug clearance. Approximately two-thirds of the administered dose is excreted in the urine, primarily as glucuronidated and hydroxylated forms of Aceclofenac. Approximately 20% of the dose is excreted in the feces. The volume of distribution is approximately 25 liters. The mean clearance is approximately 5 liters per hour.

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Metabolism/Metabolites
4'-HydroxyAceclofenac is the major metabolite detected in plasma. Other minor metabolites include diclofenac, 5-hydroxyAceclofenac, 5-hydroxydiclofenac, and 4'-hydroxydiclofenac. The metabolism of Aceclofenac may be mediated by CYP2C9.
Known human metabolites of Aceclofenac include diclofenac, 5-hydroxyAceclofenac, and 4'-hydroxyAceclofenac.

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Biological Half-Life
The mean plasma elimination half-life is approximately 4 hours.

Protein Binding
It has been reported that its protein binding rate is very high (>99%).

[1]. In vitro effects of aceclofenac and its metabolites on the production by chondrocytes of inflammatory mediators. Inflamm Res. 2001 Aug;50(8):391-9.

[2]. Aceclofenac increases the synthesis of interleukin 1 receptor antagonist and decreases the production of nitric oxide in human articular chondrocytes. J Rheumatol. 2001 Dec;28(12):2692-9.

[3]. Absolute bioavailability and metabolism of aceclofenac in rats. Arch Pharm Res. 2015 Jan;38(1):68-72.

Aceclofenac is a monocarboxylic acid, the carboxymethyl ester of diclofenac. It is a nonsteroidal anti-inflammatory drug (NSAID) associated with diclofenac, used to treat osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis. It is a prostaglandin intraperoxidase (EC 1.14.99.1) inhibitor, and also an NSAID and non-narcotic analgesic. It is a monocarboxylic acid, carboxylic acid ester, secondary amino compound, amino acid, and dichlorobenzene. Its function is related to diclofenac. Aceclofenac is an oral NSAID with significant anti-inflammatory and analgesic effects, used to treat osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis. It has been reported that in double-blind studies, Aceclofenac had a stronger anti-inflammatory effect, or at least comparable to conventional NSAIDs. Aceclofenac effectively inhibits cyclooxygenase (COX), an enzyme involved in the synthesis of prostaglandins, which are inflammatory mediators causing pain, swelling, inflammation, and fever. Aceclofenac belongs to the BCS class II drugs due to its poor water solubility. It has high permeability, allowing it to penetrate into synovial joints. In patients with osteoarthritis and related diseases, the loss of articular cartilage leads to joint pain, tenderness, stiffness, crepitus, and local inflammation. Aceclofenac has also been reported to be effective for other painful conditions, such as dental and gynecological conditions. In 1991, Aceclofenac was developed through chemical modification as an analogue of a commonly used NSAID [DB00586] to improve gastrointestinal tolerability. It is a more commonly prescribed drug in Europe.

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Drug Indications
Aceclofenac is indicated for the relief of pain and inflammation in osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis.

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Mechanism of Action
Aceclofenac inhibits COX-2, downregulating various inflammatory mediators produced through the arachidonic acid (AA) pathway, including prostaglandin E2 (PGE2), IL-1β, and TNF. IL-6 inhibition is thought to be mediated by diclofenac, a derivative of Aceclofenac. The activity of inflammatory cytokines is suppressed, thereby reducing the production of reactive oxygen species. Studies have shown that Aceclofenac can reduce nitric oxide production in human articular chondrocytes. Furthermore, Aceclofenac interferes with neutrophil-endothelial cell adhesion by reducing the expression of the cell adhesion molecule L-selectin (CD62L) expressed on the surface of lymphocytes. Aceclofenac is thought to stimulate the synthesis of glycosaminoglycans in human osteoarthritic cartilage, possibly through its inhibitory effect on IL-1 production and activity. Chondroprotective effects are produced by 4'-hydroxyAceclofenac, which inhibits IL-1-mediated production of matrix metalloproteinase-1 and matrix metalloproteinase-3 and interferes with the release of proteoglycans from chondrocytes.

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Pharmacodynamics
Aceclofenac is a nonsteroidal anti-inflammatory drug that inhibits two isoenzymes of cyclooxygenase (COX), a key enzyme in the inflammatory cascade.
COX-1 is a constitutive enzyme involved in the production of prostacyclin and the protective function of the gastric mucosa; while COX-2 is an inducible enzyme involved in the production of inflammatory mediators under inflammatory stimulation. Aceclofenac exhibits higher selectivity for COX-2 (IC50 0.77 μM) than COX-1 (IC50 > 100 μM), making it more tolerable in the stomach than other nonsteroidal anti-inflammatory drugs (NSAIDs). Its main metabolite, 4'-hydroxyAceclofenac, also has a weak inhibitory effect on COX-2, with an IC50 of 36 μM. Although the mechanism of action of Aceclofenac is believed to primarily stem from the inhibition of prostaglandin (PGE2) synthesis, it also inhibits the production of inflammatory cytokines, interleukins (IL-1β, IL-6), and tumor necrosis factor (TNF). Aceclofenac has also been reported to affect neutrophil cell adhesion molecules. Furthermore, Aceclofenac targets the synthesis of glycosaminoglycans and exerts a chondroprotective effect.

C16H13CL2NO4

354.183

353.022

89796-99-6

Aceclofenac-d4

71771

White to off-white solid powder

1.5±0.1 g/cm3

486.0±45.0 °C at 760 mmHg

149-153°C

247.8±28.7 °C

0.0±1.3 mmHg at 25°C

1.639

4.16

2

5

7

23

411

0

MNIPYSSQXLZQLJ-UHFFFAOYSA-N

InChI=1S/C16H13Cl2NO4/c17-11-5-3-6-12(18)16(11)19-13-7-2-1-4-10(13)8-15(22)23-9-14(20)21/h1-7,19H,8-9H2,(H,20,21)

2-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)acetic acid

Aceclofenac Airtal BeofenacYT-919 YT919YT 919

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~282.34 mM)
H2O : ~0.1 mg/mL (~0.28 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.06 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.06 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.06 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)