Formulation and In Vitro Evaluation of Matrix Tablets Containing Ketoprofen–Beta Cyclodextrin Complex for Enhanced Rheumatoid Arthritis Therapy: Experimental and Computational Insights

Abstract

Background: Rheumatoid arthritis is a chronic autoimmune disease that leads to severe disability and requires improved therapeutic strategies to optimize anti-inflammatory treatment. This study aimed to address this challenge by developing and characterizing an extended-release polymer matrix tablet containing ketoprofen and a ketoprofen–β-cyclodextrin complex with enhanced therapeutic properties. The objective was to improve inflammation management and therapeutic outcomes using a novel delivery system based on the inclusion of the active substance in cyclodextrin complexes.

Methods: Tablets were formulated using ketoprofen and ketoprofen–β-cyclodextrin complexes combined with hydrophilic polymers such as Carbopol^® 971P NF, Kollidon^® VA 64, and Methocel^TM K4M. The complexes were obtained via the coprecipitation method to improve bioavailability. The kinetics of the release of ketoprofen, ketoprofen–β-cyclodextrin complex (2:1), and ketoprofen–β-cyclodextrin complex (1:1) from the tablets were investigated in vitro in artificial gastric and intestinal fluids, and drug release profiles were established. Advanced mathematical models were used to describe the nonlinear behavior of the drug–polymer systems.

Results: The inclusion of ketoprofen in the β-cyclodextrin complexes was confirmed, revealing distinct release profiles. Tablets (K-3 F-3) containing the 1:1 complex showed rapid release (96.2% in 4–7 h), while tablets (K-1 F-4) containing free ketoprofen released 76% over 9–11 h. Higher polymer concentrations slowed the release due to gel barrier formation. Pharmacotechnical and stability tests supported their suitability as extended-release forms. A multifractal modeling approach described the release dynamics, treating the polymer–drug matrix as a complex system, with release curves characterized by variations in the fractal dimension and resolution.

Conclusions: Specific hydrophilic polymer combinations effectively prolonged ketoprofen release. The developed matrix tablets, which were evaluated via in vitro studies and mathematical modeling, show promise for improving therapeutic outcomes and patient compliance during rheumatoid arthritis treatment.

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Chemicals and reagents

Ketoprofen, or 2-(3-benzoylphenyl)propionic acid (K, ≥98% purity), and β-cyclodextrin (β-CD, ≥97% purity) were obtained from Sigma Aldrich Chemie GmbH (Steinheim, Germany). Potassium dihydrogen phosphate (KH2PO4, ≥99.5%; Mr = 136.01 g/mol), potassium chloride (KCl, ≥99%; Mr = 74.5 g/mol), and concentrated hydrochloric acid (HCl, ≥37%; Mr = 36.46 g/mol) were obtained from Chimreactiv SRL (Bucharest, Romania). Sodium hydroxide (NaOH, 98.5%; Mr = 40.00 g/mol) and ethanol (CH3 CH2 OH, ≥96.0%; Mr = 46.07 g/mol) were purchased from Chemical Company S.A. (Iasi, Romania). Distilled water was obtained using a GFL type 2004 distillation unit (Burgweld, Germany). All reagents met the quality requirements, according to national and European standards, and were used without any purification operations. Carbopol® 971P NF (carbomer resin) was obtained from The Lubrizol Corporation (Wickliffe, OH, USA). Kollidon® VA 64 (copolyvidone) was obtained from Sigma Aldrich Chemie GmbH (Steinheim, Germany). Magnesium stearate (C36H70MgO4, magnesium content: 4.0–5.0%, Mr = 591.24 g/mol) was obtained from Union Derivan S.A (Barcelona, Spain). Methocel ™ K4M (C56H108O30, Mr = 1261.4 g/mol) was an excipient obtained from Funahai (Zhejiang, China), and Croscarmellose (C8H16NaO8, Mr = 263.2 g/mol) was obtained from Sigma Aldrich Chemie GmbH (Steinheim, Germany). Matrix tablets (K-β-CD) were based on the sustained-release polymers Carbopol® 971P NF, Kollidon® VA 64, MethocelTM K4M, and Croscarmellose.

Stamate Cretan, M.; Ochiuz, L.; Ghizdovat, V.; Molcalut, M.; Agop, M.; Gafițanu, C.A.; Barsan, A.; Sha’at, M.; Stamate, C. Formulation and In Vitro Evaluation of Matrix Tablets Containing Ketoprofen–Beta Cyclodextrin Complex for Enhanced Rheumatoid Arthritis Therapy: Experimental and Computational Insights. Pharmaceutics 2025, 17, 474. https://doi.org/10.3390/pharmaceutics17040474