Research Article Systematically Optimized Ketoprofen-Loaded Novel Proniosomal Formulation for Periodontitis: In Vitro Characterization and In Vivo Pharmacodynamic Evaluation N. K. Yadav, 1 Sanju Nanda, 1,3 Gajanand Sharma, 2 and O. P. Katare 2,3 Received 24 June 2016; accepted 4 November 2016 ABSTRACT. Various preclinical/clinical studies support the effectiveness of ketoprofen in periodontitis; however, the literature reveals that novel delivery systems have been less explored for the drug in periodontitis. The current investigation aims to explore the potential of a pro-vesicular approach-based proniosomal drug delivery of ketoprofen for its effectiveness and validation in experimental periodontal disease (EPD). Formulations were developed using I-optimal mixture design. Developed formulations were characterized for entrapment efficiency, vesicle size, and in vitro drug release. Selected proniosomal gels were evaluated for mucoadhesiveness, ex vivo drug permeation, and retention studies. Optimized proniosomal gel was evaluated for surface morphology, rheological behavior, texture studies, and pharmacodynamic activity in EPD. The results showed that ketoprofen-loaded proniosomal formulations formed a mucoadhesive hydrogel comprising spherical and flexible vesicles. Viscosity and texture studies showed good adhesion and smoothness, which are desired for enhanced permeation. The disease condition was improved with preserved bone resorption process, that too with intact cementum vis-à-vis marketed gel formulation, when evaluated in the EPD model. The results lead to the conclusion that proniosomes can act as a promising carrier and can be effectively used for improved ketoprofen delivery in periodontal pockets. KEY WORDS: I-optimal mixture design; ketoprofen; periodontitis; permeation studies; proniosomes. INTRODUCTION Periodontitis, a major cause of tooth loss in adults, is one of the most common inflammatory diseases. Periodontitis occurs due to the inflammation and infection of tissues around the teeth. The disease is characterized by gingival bleeding and localized bone resorption (1). However, pro- gression of disease leads to the loss of alveolar bone and, subsequently, also loss of teeth. Earlier, it was considered that microorganisms are the only agents which are responsible for the disease. But in the 1990s, it became clear that inflamma- tory responses from the host’s immune system also result in periodontal structure destruction (2). The principal factors and mediators responsible for inflammation progression in periodontitis include peptides of short chain (bradykinin) and long chain (interleukin-1), amines (histamine and 5- hydroxytryptamine), and cell products such as leukotrienes, platelets, and prostaglandins (3). The treatment strategy for periodontal disease includes management of chronic inflam- mation using non-steroidal anti-in flammatory drugs (NSAIDs). NSAIDs have been reported to offer therapeutic benefits in slowing down the rate of progression of the disease by effective inhibition of prostaglandin (PG) synthesis (4). To resolve the inflammatory process and clinical signs of the disease, topical NSAIDs have made their space in comple- ment periodontal therapy (5). Ketoprofen (Fig. 1) is one of the propionic acid derivatives and is a potent NSAID with high therapeutic value. Ketoprofen is observed to be of marked potency to other NSAIDs in blocking human periodontal PG E 2 synthesis (6). The in vitro anti-inflammatory effects of ketoprofen include anti-bradykinin activity, stabilization of lysosomal membranes, inhibition of leukotriene release from activated cells, and suppression of leukocyte migration (7). In a preclinical study on monkeys with periodontal disease, the application of 1.0% topical ketoprofen creams for 6 months resulted in significant reductions in crevicular PG E 2 and leukotriene B 4 and alveolar bone loss (8). Treatment of adult periodontitis human subjects with topical ketoprofen formu- lations was proven equipotent with comparatively higher 1 Department of Pharmaceutical Sciences, Maharshi Dayanand Uni- versity, Rohtak, 124001, India. 2 Division of Pharmaceutics, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University, Chandigarh, 160 014, India. 3 To whom correspondence should be addressed. (e-mail: sn_mdu@rediffmail.com; drkatare@yahoo.com.) AAPS PharmSciTech ( # 2016) DOI: 10.1208/s12249-016-0665-1 1530-9932/16/0000-0001/0 # 2016 American Association of Pharmaceutical Scientists