Celecoxib Nanoformulations with Enhanced Solubility, Dissolution Rate, and Oral Bioavailability: Experimental Approaches over In Vitro/In Vivo Evaluation

Celecoxib (CXB) is a Biopharmaceutical Classification System (BCS) Class II molecule with high permeability that is practically insoluble in water. Because of the poor water solubility, there is a wide range of absorption and limited bioavailability following oral administration. These unfavorable properties can be improved using dry co-milling technology, which is an industrial applicable technology. The purpose of this study was to develop and optimize CXB nanoformulations prepared by dry co-milling technology, with a quality by design approach to maintain enhanced solubility, dissolution rate, and oral bioavailability.

The resulting co-milled CXB composition using povidone (PVP), mannitol (MAN) and sodium lauryl sulfate (SLS) showed the maximum solubility and dissolution rate in physiologically relevant media. Potential risk factors were determined with an Ishikawa diagram, important risk factors were selected with Plackett-Burman experimental design, and CXB compositions were optimized with Central Composite design (CCD) and Bayesian optimization (BO). Physical characterization, intrinsic dissolution rate, solubility, and stability experiments were used to evaluate the optimized co-milled CXB compositions.

Dissolution and permeability studies were carried out for the resulting CXB nanoformulation. Oral pharmacokinetic studies of the CXB nanoformulation and reference product were performed in rats. The results of in vitro and in vivo studies show that the CXB nanoformulations have enhanced solubility (over 4.8-fold (8.6 ± 1.06 µg/mL vs. 1.8 ± 0.33 µg/mL) in water when compared with celecoxib pure powder), and dissolution rate (at least 85% of celecoxib is dissolved in 20 min), and improved oral pharmacokinetic profile (the relative bioavailability was 145.2%, compared to that of Celebrex®, and faster tmax 3.80 ± 2.28 h vs. 6.00 ± 3.67 h, indicating a more rapid absorption rate).

2.1. Materials

CXB 4-(5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl) benzene sulfona mide (lot CE0311116) was purchased from Hetero Drugs Limited, Hyderabad, India. Povidone (PVP, Plasdone™ C-12, K-29/32, K-90), vinylpyrrolidone and vinyl acetate copolymer (PVP-VA, Plasdone™ S-630), and hydroxyethyl cellulose (Natrosol™ 250) were kindly donated by Ashland, İstanbul, Turkey. Sodium lauryl sulfate (SLS, Kolliphor® SLS) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus®) was donated by BASF, İstanbul, Turkey. Mannitol (Pearlitol® 100 SD), low-substituted hydroxypropyl cellulose (L-HPC LH-21), magnesium alumino metasilicate (Neusilin®), polyoxyl 40 stearate (Myrj™ S40) and lactose monohydrate (FlowLac® 90) were donated by Barentz Chemical (İstanbul, Turkey), Harke Pharma (İstanbul, Turkey), Fuji Chemical (Tokyo, Japan), Croda (Snaith, UK) and Meggle (Wasserburg am Inn, Germany), respectively. Croscarmellose sodium (Ac-Di-Sol®) and magnesium stearate (Ligamed® MF-2-V) were donated by IMCD, İstanbul, Turkey. Hard gelatin capsules were purchased from Lonza, New Jersey, USA. Celebrex® 200 mg Capsules (Pfizer Inc., New York, NY, USA, lot C080351) were purchased commercially from Turkey.

Biorelevant dissolution media powder (FaSSIF/FeSSIF/FaSSGF) was purchased from Biorelevant Ltd. (London, UK). Caco-2 cells (human colon carcinoma cell line) were purchased from American Type Culture Collection (Manassas, VI, USA). Thiazolyl blue tetrazolium bromide (MTT) was purchased from AppliChem GmBH (Darmstadt, Germany). Dulbecco’s Modified Eagle’s Medium (DMEM) and fetal bovine serum (FBS) were provided from BiochromAG (Berlin, Germany), and Penicillin-Streptomycin solution from Life Technologies, Inc., (Carlsbad, CA, USA). Thincerts™ cell culture inserts (transparent membrane, pore size: 0.4 µm, growth area: 1.13 cm2) were obtained from Grenier Bio-one (Frickenhausen, Germany). The water used in all experiments was ultra-purified water (Mili-Q, Millipore, Turkey). All analytical chemicals, buffer salts and reagents were all analytical grade and purchased from Merck KGaA (Darmstadt, Germany). Male Sprague-Dawley rats (8–10 weeks old, 280 ± 20 g) were purchased from Kobay Laboratory Animals Center (Ankara, Turkey). All experiments were performed according to the guidelines of the Declaration of Helsinki and Turkish Law for the Protection of Animals and animal experimentation was approved by the local ethics committee of Kobay Laboratory Animals Center (approval number: 439, date: 2 December 2020).

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Arslan, A.; Yet, B.; Nemutlu, E.; Akdağ Çaylı, Y.; Eroğlu, H.; Öner, L. Celecoxib Nanoformulations with Enhanced Solubility, Dissolution Rate, and Oral Bioavailability: Experimental Approaches over In Vitro/In Vivo Evaluation. Pharmaceutics 2023, 15, 363.

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