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Kelly Limi Aida,1 Paula Fernanda Kreling,1 Karina Sampaio Caiaffa,2 Giovana Maria Fioramonti Calixto,3 Marlus Chorilli,3 Denise MP Spolidorio,4 Norival Alves Santos-Filho,5,6 Eduardo Maffud Cilli,5 Cristiane Duque1 1Department of Pediatric Dentistry and Public Health, Araçatuba Dental School, Sao Paulo State University (UNESP), Araçatuba, São Paulo, Brazil; 2Department of Endodontics, Araçatuba Dental School, Sao Paulo State University (UNESP), Araçatuba, São Paulo, Brazil; 3Department of Drugs and Medicines, School of Pharmaceutical Sciences, Sao Paulo State University (UNESP), Araraquara, São Paulo, Brazil; 4Department of Physiology and Pathology, Araraquara Dental School, Sao Paulo State University (UNESP), Araraquara, São Paulo, Brazil; 5Department of Biochemistry and Chemical Technology, Institute of Chemistry, Sao Paulo State University (UNESP), Araraquara, São Paulo, Brazil; 6Registro Experimental Campus, Sao Paulo State University (UNESP), Registro, São Paulo, Brazil Background: Anticaries agents must interfere with the adhesion of Streptococcus mutans and its proliferation in dental biofilm, without causing host toxicity and bacterial resistance. Natural substances, including cationic antimicrobial peptides (CAMPs) and their fragments, such as β-defensin-3 peptide fragment (D1–23), have been widely studied. However, the chemical and physical stability of CAMPs may be compromised by external factors, such as temperature and pH, reducing the period of antimicrobial activity. Methods: To overcome the aforementioned disadvantage, this study developed and characterized a drug delivery system and evaluated the cytotoxicity and effect against S. mutans biofilm of a D1–23-loaded bioadhesive liquid crystalline system (LCS). LCS was composed of oleic acid, polyoxypropylene-(5)-polyoxyethylene-(20)-cetyl alcohol, Carbopol® 974P and Carbopol® 971P. LCS was analyzed by polarized light microscopy (PLM), rheology (viscoelasticity and flow properties) and in vitro bioadhesion. The viability of epithelial cells was evaluated. Minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) against S. mutans were determined for D1–23 for further evaluation of the effect against S. mutans biofilm after 4 and 24h of exposure to treatments. Results: PLM, rheology, and in vitro bioadhesion tests showed that both viscosity and bioadhesion of LCS increased after it was diluted with artificial saliva. D1–23-loaded LCS system presented better activity against S. mutans biofilm after 24h when compared to 4h of treatment, showing a cumulative effect. Neither LCS nor D1–23-loaded LCS presented toxicity on human epithelial cells. Conclusion: D1–23-loaded LCS is a promising drug delivery system for the prevention of dental caries. Keywords: peptide fragments, drug delivery system, dental caries, biofilm, Streptococcus mutans

Formation of a dental biofilm by Streptococcus mutans can cause dental caries, and remains a costly health problem worldwide. Recently, there has been a growing interest in the use of peptidic drugs, such as peptide p1025, analogous to the fragments 1025-1044 of S. mutans cellular adhesin, responsible for the adhesion and formation of dental biofilm. However, peptides have physicochemical characteristics that may affect their biological action, limiting their clinical performance. Therefore, drug-delivery systems, such as a bioadhesive liquid-crystalline system (LCS), may be attractive strategies for peptide delivery. Potentiation of the action of LCS can be achieved with the use of bioadhesive polymers to prolong their residence on the teeth. In line with this, three formulations - polyoxypropylene-(5)-polyoxyethylene-(20)-cetyl alcohol, oleic acid, and Carbopol C974P in different combinations (F1C, F2C, and F3C) were developed to observe the influence of water in the LCS, with the aim of achieving in situ gelling in the oral environment. These formulations were assessed by polarized light microscopy, small-angle X-ray scattering, rheological analysis, and in vitro bioadhesion analysis. Then, p1025 and a control (chlorhexidine) were incorporated into the aqueous phase of the formulation (F + p1025 and F + chlorhexidine), to determine their antibiofilm effect and toxicity on epithelial cells. Polarized light microscopy and small-angle X-ray scattering showed that F1C and F2C were LCS, whereas F3C was a microemulsion. F1C and F2C showed pseudoplastic behavior and F3C Newtonian behavior. F1C showed the highest elastic and bioadhesive characteristics compared to other formulations. Antibiofilm effects were observed for F + p1025 when applied in the surface-bound salivary phase. The p1025-loaded nanostructured LCS presented limited cytotoxicity and effectively reduced S. mutans biofilm formation, and could be a promising p1025-delivery strategy to prevent the formation of S. mutans dental biofilm.

Bioadhesiviness of polyacrylic acid polymers make them promising hydrogels to design topical drug delivery systems, allowing a close contact with biological substrate as well as an enhanced local concentration gradient, both factors that may improve the biological performance of the drugs.Texture and bioadhesive properties of hydrogels were assessed by using texture analyzer and they were correlated with their rheological behavior and performance as drug delivery systems.Aqueous dispersions of both polymers were prepared at 0.5%, 1.0% and 1.5% w/v. Hardness, compressibility, adhesiveness, cohesiveness, bioadhesion, continuous flow, oscillatory dynamic test and in vitro drug release were evaluated.Rheological and texture parameters were dependent on polymer concentration and C974P polymer built the strongest structures. Both 1.5% hydrogels presented high bioadhesion values. About 50% of the metronidazole (MTZ) was sustained released from hydrogels within 2 h with an initial burst release at early stage. After, the release rates were decreased and 10% of the MTZ was released in the next 10 h. The drug release process was driven by Fickian diffusion and complex mechanism for PP and C974P hydrogels, respectively.The set of results demonstrated that these hydrogels are promising to be used as topical controlled drug delivery system.

Liposomes containing hydrogenated soy phosphatidylcholine (PCH), with or without cholesterol (CHOL) and caffeine (CAF), were prepared by sonication and characterized for encapsulation efficiency and mean diameter. Dynamic light scattering assay showed that the incorporation of CHOL decreased significantly the size of the liposomes and led to a more heterogeneous distribution of size raising the CAF encapsulation efficiency. The in vitro drug release studies showed that the encapsulation of the CAF in liposomes produced a reduction in the release rate and the inclusion of CHOL in the liposome formulation delayed still further the release of the CAF.

Hydrogels are widely used for cutaneous formulations; thereby comparing the bioadhesive properties of polymers with a view to prolong the residence time of topical drugs on the skin would be very useful to design novel topical drug delivery systems.The objective of this study was to correlate data from rheological studies and texture profile analysis, with bioadhesion on the skin.Polyacrylic acid polymers used were carbomer homopolymer type A (C971) and type B (C974), and polycarbophil (PP) dispersed in water at various concentrations (0.1, 0.5, 1.0, 1.5, 2.0, 3.0, 5.0%, w/v). Rheological, texture, and bioadhesive properties were determined to compare the hydrogels.Rheological analysis showed that all samples exhibited pseudoplastic behavior with thixotropy. Texture profile analysis showed that compressibility, hardness, and adhesiveness of the hydrogels were dependent on the polymer concentration, and the cohesion values were high. Bioadhesion of C974 and PP at 0.5 and 2% was of the same magnitude, while all samples of C971 had lower values. The bioadhesion of 5% C974 was the highest, while that 5% PP was lower, possibly because PP showed the greatest hardness and this rigidity may decrease the interaction of the polymer with the skin.A comprehensive comparative rheological and textural analyses of several polymers for topical systems were undertaken in terms of their bioadhesion. Therefore, it is possible to conclude that these polymers can be used for optimization of drug delivery systems on the skin.

Matheus Aparecido dos Santos Ramos,1 Giovana Calixto,2 Luciani Gaspar de Toledo,3 Bruna Vidal Bonifácio,1 Lourdes Campaner dos Santos,4 Margarete Teresa Gottardo de Almeida,3 Marlus Chorilli,2 Taís Maria Bauab1 1Department of Biological Sciences, School of Pharmaceutical Sciences, 2Department of Drugs and Medicine, School of Pharmaceutical Sciences, São Paulo State University, Araraquara, 3Department of Infectious Diseases, Faculty of Medicine of São José do Rio Preto, São José do Rio Preto, 4Department of Organic Chemistry, Chemistry Institute, São Paulo State University, Araraquara, São Paulo, Brazil Abstract: Vaginal infections caused by Candida krusei are a problem of extreme complexity due to the intrinsic resistance to azole drugs. The species Syngonanthus nitens (Bong.) Ruhland is a plant of the Eriocaulaceae family that has demonstrated promising antifungal activity. In phyto-formulation research, liquid crystal precursor mucoadhesive systems (LCPM) stand out as drug delivery systems for vaginal administration because they increase the activity and overcome the problems associated with plant-based medicines. Therefore, the objective of this study was to evaluate the potential of the methanolic extract of scapes of S. nitens (S. nitens extract [SNE]) and an SNE-loaded LCPM against C. krusei as prophylaxis for vulvovaginal candidiasis. LCPM formulation developed consisted of oleic acid as the oil phase (50% w/w), polyoxypropylene (5) polyoxyethylene (20) cetyl alcohol (40% w/w) as the surfactant and a polymeric dispersion containing 2.5% Carbopol® 974P and 2.5% polycarbophil (10% w/w) as the aqueous phase. LCPM formulation developed was characterized using polarized light microscopy, rheological analysis, and in vitro mucoadhesive studies. Different strains of C. krusei, including one standard strain (American Type Culture Collection 6258) and three clinically isolated strains from the vaginal region (CKV1, 2, and 3), were used to determine the minimum inhibitory concentration, inhibition of biofilms, and time kill. The in vivo prophylaxis assay was performed using the standard strain (American Type Culture Collection 6258). The analyses of F by polarized light microscopy and rheology showed isotropy; however, the addition of 100% artificial vaginal mucus (F100) made it more viscous and anisotropic. Moreover, the mucoadhesive strength was modified, which makes F an excellent formulation for vaginal applications. SNE was active against all strains studied, with minimum inhibitory concentration values ranging from 125 to 62.5 µg/mL; after incorporating SNE into F (FE), these values decreased to 62.5 to 31.2 µg/mL, demonstrating that incorporation into the formulation potentiated the action of SNE. Additionally, the time kill assays showed that both forms of SNE were capable of controlling growth, thereby suggesting a possible fungistatic mechanism. Unloaded SNE was not active against C. krusei biofilms, but FE was active against a clinical strain (CKV2). In vivo analysis showed that FE was able to prevent the development of infection following 10 days of administration. We concluded that the formulation developed in this study was an important vehicle for the delivery of SNE based on the improved antifungal activity in all in vitro and in vivo analyses. Furthermore, the extract incorporated into the system may serve as an important prophylactic agent against vaginal infections caused by C. krusei. Keywords: precursor system of mucoadhesive liquid crystal, nanostructured system, ­prophylaxis, Candida krusei

Made available in DSpace on 2015-12-07T15:34:41Z (GMT). No. of bitstreams: 0 Previous issue date: 2015. Added 1 bitstream(s) on 2015-12-07T15:54:19Z : No. of bitstreams: 1 PMC4525803.pdf: 1159237 bytes, checksum: 5d62bb3d5bc2b343d38c60e292cb8188 (MD5) Women often develop vaginal infections that are caused primarily by organisms of the genus Candida. The current treatments of vaginal candidiasis usually involve azole-based antifungals, though fungal resistance to these compounds has become prevalent. Therefore, much attention has been given to molecules with antifungal properties from natural sources, such as curcumin (CUR). However, CUR has poor solubility in aqueous solvents and poor oral bioavailability. This study attempted to overcome this problem by developing, characterizing, and evaluating the in vitro antifungal action of a CUR-loaded liquid crystal precursor mucoadhesive system (LCPM) for vaginal administration. A low-viscosity LCPM (F) consisting of 40% wt/wt polyoxpropylene-(5)-polyoxyethylene-(20)-cetyl alcohol, 50% wt/wt oleic acid, and 10% wt/wt chitosan dispersion at 0.5% with the addition of 16% poloxamer 407 was developed to take advantage of the lyotropic phase behavior of this formulation. Notably, F could transform into liquid crystal systems when diluted with artificial vaginal mucus at ratios of 1:3 and 1:1 (wt/wt), resulting in the formation of F30 and F100, respectively. Polarized light microscopy and rheological studies revealed that F behaved like an isotropic formulation, whereas F30 and F100 behaved like an anisotropic liquid crystalline system (LCS). Moreover, F30 and F100 presented higher mucoadhesion to porcine vaginal mucosa than F. The analysis of the in vitro activity against Candida albicans revealed that CUR-loaded F was more potent against standard and clinical strains compared with a CUR solution. Therefore, the vaginal administration of CUR-loaded LCPMs represents a promising platform for the treatment of vaginal candidiasis. School of Pharmaceutical Sciences, UNESP - Sao Paulo State University, Campus Araraquara, Department of Drugs and Medicines, Araraquara, Sao Paulo, Brazil. School of Pharmaceutical Sciences, UNESP - Sao Paulo State University, Campus Araraquara, Department of Drugs and Medicines, Araraquara, Sao Paulo, Brazil.