Fluconazole-Loaded Ibuprofen In Situ Gel-Based Oral Spray for Oropharyngeal Candidiasis Treatment.

Oral candidiasis is a fungal infection affecting the oral mucous membrane, and this research specifically addresses on a localized treatment through fluconazole-loaded ibuprofen in situ gel-based oral spray. The low solubility of ibuprofen is advantageous for forming a gel when exposed to an aqueous phase. The 1% w/w fluconazole-loaded in situ gel oral sprays were developed utilizing various concentrations of ibuprofen in N-methyl pyrrolidone. The prepared solutions underwent evaluation for viscosity, surface tension, contact angle, water tolerance, gel formation, interface interaction, drug permeation, and antimicrobial studies. The higher amount of ibuprofen reduced the surface tension and retarded solvent exchange. The use of 50% ibuprofen as a gelling agent demonstrated prolonged drug permeation for up to 24 h. The incorporation of Cremophor EL in the formulations resulted in increased drug permeation and exhibited effective inhibition against Candida albicans, Candida krusei, Candida lusitaniae, and Candida tropicalis. While the Cremophor EL-loaded formulation did not exhibit enhanced antifungal effects on agar media, its ability to facilitate the permeation of fluconazole and ibuprofen suggested potential efficacy in countering Candida invasion in the oral mucosa. Moreover, these formulations demonstrated significant thermal inhibition of protein denaturation in egg albumin, indicating anti-inflammatory properties. Consequently, the fluconazole-loaded ibuprofen in situ gel-based oral spray presents itself as a promising dosage form for oropharyngeal candidiasis treatment.

Nitrocellulose for Prolonged Permeation of Levofloxacin HCl-Salicylic Acid In Situ Gel.

Currently, the application of solvent exchange-induced in situ gel is underway for drug delivery to the body target site. Nitrocellulose was attempted in this research as the matrix-forming agent in solvent exchange-induced in situ gel for acne and periodontitis treatments. The gel incorporated a combination of 1% w/w levofloxacin HCl and 2% w/w salicylic acid as the active compounds. In order to facilitate formulation development, the study explored the matrix-forming behavior of different concentrations of nitrocellulose in N-methyl pyrrolidone (NMP). Consequently, their physicochemical properties and matrix-forming behavior, as well as antimicrobial and anti-inflammatory activities, were evaluated using the agar cup diffusion method and thermal inhibition of protein denaturation in the egg albumin technique, respectively. All prepared formulations presented as clear solutions with Newtonian flow. Their contact angles on agarose gel were higher than on a glass slide due to matrix formation upon exposure to the aqueous phase of agarose, with an angle of less than 60° indicating good spreadability. Nitrocellulose concentrations exceeding 20% initiated stable opaque matrix formation upon contact with phosphate buffer pH 6.8. The high hardness and remaining force of the transformed gel indicated their robustness after solvent exchange. Fluorescence tracking using sodium fluorescein and Nile red confirmed the retardation of NMP and water diffusion by the nitrocellulose matrix. From the Franz cell permeation study, these drugs could permeate through neonate porcine skin and tissue of porcine buccal from the nitrocellulose in situ forming gel. Their accumulation in these tissues might enable the inhibition of the invading bacterial pathogens. The developed in situ gels effectively inhibited Staphylococcus aureus, Staphylococcus epidermidis, Propionibacterium acnes, and Porphyromonas gingivalis. Furthermore, the formulations demonstrated an anti-inflammatory effect. The low viscosity of LvSa25Nc makes it appropriate for injectable treatments targeting periodontitis, while the higher viscosity of LvSa40Nc renders it appropriate for topical applications in acne treatment. Therefore, the nitrocellulose in situ gel loaded with combined levofloxacin HCl and salicylic acid emerges as a promising dosage form for treating acne and periodontitis.

Numerical Mechanistic Modelling of Drug Release from Solvent-Removal Zein-Based In Situ Gel.

The development of effective drug delivery systems remains a focus of extensive research to enhance therapeutic outcomes. Among these, in situ forming gels (ISG) have emerged as a promising avenue for controlled drug release. This research focuses on the mathematical modeling of levofloxacin HCl (Lv) release from zein-based ISG using the cup method, aiming to mimic the environment of a periodontal pocket. The drug release behavior of the ISGs was investigated through experimental observations and numerical simulations employing forward and central difference formula. Notably, the experimental data for drug release from the 20% w/w zein-based ISG formulations closely aligned with the simulations obtained from numerical mechanistic modeling. In summary, 20% w/w zein-based ISG formulations demonstrated nearly complete drug release with the maximum drug concentration at the edge of the matrix phase values consistently around 100-105%, while 25% w/w zein-based ISG formulations exhibited somewhat lower drug release extents, with values ranging from 70-90%. Additionally, the rate of drug transport from the polymer matrix to the external phase influenced initial release rates, resulting in a slower release. The utilization of glycerol formal as a solvent extended drug release further than dimethyl sulfoxide, thanks to denser matrices formed by high-loading polymers that acted as robust barriers to solvent removal and drug diffusion. Furthermore, UV-vis imaging was utilized to visualize the matrix formation process and solvent diffusion within the ISGs. The imaging results offered valuable insights into the matrix formation kinetics, controlled drug release mechanisms, and the influence of solvent properties on drug diffusion. The combination of mathematical modeling and experimental visualization provides a comprehensive understanding of drug release from zein-based ISGs and offers a foundation for tailored drug delivery strategies.

Injectable Gamboge-Based In Situ Gel for Sustained Delivery of Imatinib Mesylate.

The aim of this study was to prepare and characterize the imatinib mesylate (IM)-loaded gamboge-based ISG system for local administration of an anticancer agent against colorectal carcinoma. The ISG formulations were prepared in dimethyl sulfoxide (DMSO) and N-methyl-2-pyrrolidone (NMP). The physicochemical properties, drug release profile, and cytotoxicity of the developed formulations were assessed. The developed ISG demonstrated Newtonian flow behavior with acceptable rheological and mechanical properties. The viscosity of the developed ISG, measured at less than 80 cP, and the applied forces of less than 50 N·mm, indicated easy administration using clinical injection techniques. Upon contact with an aqueous phase, the ISG immediately formed a porous cross-sectional structure, enabling sustained release of IM over 14 days. The release profile of IM was fitted to the quasi-Fickian diffusion mechanism, and the release rate could be controlled by the types of solvent and the amount of IM content. The developed IM-loaded gamboge ISG effectively inhibited colorectal cancer cells, including HCT116 and HT29 cell lines, with less than 20% cell viability observed at a concentration of 1% w/w IM after 2 days of incubation. This suggests that the developed ISG may potentially serve as an injectable system for localized anticancer delivery against colorectal cells, potentially reducing the side effects of systemic chemotherapy and improving patient adherence.

Computational Insight of Phase Transformation and Drug Release Behaviour of Doxycycline-Loaded Ibuprofen-Based In-Situ Forming Gel.

This research investigates the gel formation behaviour and drug-controlling performance of doxycycline-loaded ibuprofen-based in-situ forming gels (DH-loaded IBU-based ISGs) for potential applications in periodontal treatment. The investigation begins by exploring the physical properties and gel formation behaviour of the ISGs, with a particular focus on determining their sustained release capabilities. To gain a deeper understanding of the molecular interactions and dynamics within the ISGs, molecular dynamic (MD) simulations are employed. The effects of adding IBU and DH on reducing surface tension and water tolerance properties, thus affecting molecular properties. The phase transformation phenomenon is observed around the interface, where droplets of ISGs move out to the water phase, leading to the precipitation of IBU around the interface. The optimization of drug release profiles ensures sustained local drug release over seven days, with a burst release observed on the first day. Interestingly, different organic solvents show varying abilities to control DH release, with dimethyl sulfoxide (DMSO) demonstrating superior control compared to N-Methyl-2-pyrrolidone (NMP). MD simulations using AMBER20 software provide valuable insights into the movement of individual molecules, as evidenced by root-mean-square deviation (RMSD) values. The addition of IBU to the system results in the retardation of IBU molecule movement, particularly evident in the DMSO series, with the diffusion constant value of DH reducing from 1.2452 to 0.3372 and in the NMP series from 0.3703 to 0.2245 after adding IBU. The RMSD values indicate a reduction in molecule fluctuation of DH, especially in the DMSO system, where it decreases from over 140 to 40 Å. Moreover, their radius of gyration is influenced by IBU, with the DMSO system showing lower values, suggesting an increase in molecular compactness. Notably, the DH-IBU configuration exhibits stable pairing through H-bonding, with a higher amount of H-bonding observed in the DMSO system, which is correlated with the drug retardation efficacy. These significant findings pave the way for the development of phase transformation mechanistic studies and offer new avenues for future design and optimization formulation in the ISG drug delivery systems field.

Metronidazole-Loaded Camphor-Based In Situ Forming Matrix for Periodontitis Treatment.

Periodontitis is a widespread oral health problem caused by bacterial infections that lead to tooth loss and other systemic diseases. The aim of this study was to provide an alternative treatment for periodontitis by developing a metronidazole-loaded in situ forming matrix (ISM) using camphor as its matrix former. Five-percent w/w metronidazole dissolved in N-methyl pyrrolidone (NMP) with varying concentrations of camphor (30-50% w/w) and triacetin (0-25% w/w) were used. The physicochemical properties and antimicrobial activities of formulations were evaluated. Results showed that as the percentage of camphor increased, viscosity, density, contact angle, surface tension, and force of injection increased, while water tolerance decreased. The same trend was observed when increasing the triacetin concentration. The optimal metronidazole-loaded ISM was obtained at 40% w/w camphor and 5% w/w triacetin, which prolonged the release of metronidazole up to 6 days with Fickian diffusion release profile. The higher concentration of triacetin slowed down the phase inversion that led to an incomplete formation of the matrix and resulted in an inefficiently prolonged release of the metronidazole. Antimicrobial activities demonstrated that the developed formulation efficiently inhibited periodontitis-induced microorganisms including Porphyromonas gingivalis, Staphylococcus aureus, Escherichia coli, and Candida albicans. The metronidazole-loaded camphor-based ISM has potential as a new drug delivery system for periodontitis treatment.

Ways to Assess and Regulate the Performance of a Bi-Mechanism-Induced Borneol-Based In Situ Forming Matrix.

As an alternative to the traditional polymeric-based system, it is now possible to use an in situ forming system that is based on small molecules. Borneol was used as matrix formation in this study. While triacetin was incorporated into the formulation for prolonging the drug release. The objective of this study is to understand the initial period of the solvent exchange mechanism at the molecular level, which would provide a basis for explaining the matrix formation and drug release phenomena. The evaluation of basic physical properties, matrix formation, in vitro drug release, and molecular dynamics (MD) simulation of borneol-based in situ forming matrixes (ISM) was conducted in this study. The proportion of triacetin was found to determine the increase in density and viscosity. The density value was found to be related to viscosity which could be used for the purpose of prediction. Slow self-assembly of ISM upon the addition of triacetin was associated with higher viscosity and lower surface tension. This phenomenon enabled the regulation of solvent exchange and led to sustaining the drug release. In MD simulation using AMBER Tools, the free movement of the drug and the rapid approach to equilibrium of both solvent and water molecule in a solvent exchange mechanism in borneol-free ISM was observed, supporting that sustained release would not occur. Water infiltration was slowed down and NMP movement was restricted by the addition of borneol and triacetin. In addition, the increased proportion of triacetin promoted the diminished down of all substances' movement because of the viscosity. The diffusion constant of relevant molecules decreased with the addition of borneol and/or triacetin. Although the addition of triacetin tended to slow down the solvent exchange and molecular movement from computation modelling results, it may not guarantee to imply the best drug release control. The Low triacetin-incorporated (5%) borneol-based ISM showed the highest ability to sustain the drug release due to its self-assembly and has proper solvent exchange. MD simulation addressed the details of the mechanism at the beginning of the process. Therefore, both MD and classical methods contribute to a clearer understanding of solvent exchange from the molecular to macroscopic level and from the first nanosecond of the formulation contact with water to the 10-day of drug release. These would be beneficial for subsequent research and development efforts in small molecule-based in situ forming systems.

Phase Inversion-Based Doxycycline Hyclate-Incorporated Borneol In Situ Gel for Periodontitis Treatment.

Borneol has been successfully employed as a gelling agent for in situ forming gel (ISG). While 40% borneol can regulate drug release, there is interest in novel approaches to achieve extended drug release, particularly through the incorporation of hydrophobic substances. Herein, triacetin was selected as a hydrophobic additive solvent for doxycycline hyclate (Dox)-loaded 40% borneol-based ISGs in N-methyl-2-pyrrolidone (NMP) or dimethyl sulfoxide (DMSO), which were subsequently evaluated in terms of their physicochemical properties, gel formation morphology, water sensitivity, drug release, and antimicrobial activities. ISG density and viscosity gradually decreased with the triacetin proportion to a viscosity of <12 cPs and slightly influenced the surface tension (33.14-44.33 mN/m). The low expelled force values (1.59-2.39 N) indicated the convenience of injection. All of the prepared ISGs exhibited favorable wettability and plastic deformation. Higher gel firmness from ISG prepared using NMP as a solvent contributed to the ability of more efficient controlled drug release. High triacetin (25%)-loaded ISG retarded solvent diffusion and gel formation, but diminished gel firmness and water sensitivity. ISG containing 5% triacetin efficiently prolonged Dox release up to 10 days with Fickian diffusion and presented effective antimicrobial activities against periodontitis pathogens such as Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. Therefore, the Dox-loaded 40% borneol-based ISG with 5% triacetin is a potential effective local ISG for periodontitis treatment.

Moxifloxacin HCl-Incorporated Aqueous-Induced Nitrocellulose-Based In Situ Gel for Periodontal Pocket Delivery.

A drug delivery system based on an aqueous-induced in situ forming gel (ISG) consists of solubilizing the drug within an organic solution of a polymer using a biocompatible organic solvent. Upon contact with an aqueous medium, the solvent diffuses out and the polymer, designed to be insoluble in water, solidifies and transforms into gel. Nitrocellulose (Nc), an aqueous insoluble nitrated ester of cellulose, should be a promising polymer for an ISG using water induction of its solution to gel state via phase inversion. The aim of this investigation was to develop and evaluate a moxifloxacin HCl (Mx)-incorporated aqueous-induced Nc-based ISG for periodontitis treatment. The effects of different solvents (N-methyl pyrrolidone (NMP), DMSO, 2-pyrrolidone (Py), and glycerol formal (Gf)) on the physicochemical and bioactivity properties of the ISGs were investigated. The viscosity and injection force of the ISGs varied depending on the solvent used, with Gf resulting in higher values of 4631.41 ± 52.81 cPs and 4.34 ± 0.42 N, respectively. All ISGs exhibited Newtonian flow and transformed into a gel state upon exposure to the aqueous phase. The Nc formulations in DMSO showed lower water tolerance (12.50 ± 0.72%). The developed ISGs were easily injectable and demonstrated water sensitivity of less than 15.44 ± 0.89%, forming a gel upon contact with aqueous phase. The transformed Nc gel effectively prolonged Mx release over two weeks via Fickian diffusion, with reduced initial burst release. Different solvent types influenced the sponge-like 3D structure of the dried Nc ISGs and affected mass loss during drug release. Incorporating Nc reduced both solvent and drug diffusion, resulting in a significantly narrower zone of bacterial growth inhibition (p < 0.05). The Mx-incorporated Nc-based ISGs exhibited efficient antibacterial activity against four strains of Staphylococcus aureu and against periodontitis pathogens including Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis. This study suggests that the developed Mx-incorporated Nc-based ISGs using DMSO and NMP as the solvents are the most promising formulations. They exhibited a low viscosity, ease of injection, and rapid transformation into a gel upon aqueous induction, and they enabled localized and prolonged drug release with effective antibacterial properties. Additionally, this study represents the first reported instance of utilizing Nc as the polymer for ISG. Further clinical experiments are necessary to evaluate the safety of this ISG formulation.

Levofloxacin HCl-Loaded Eudragit L-Based Solvent Exchange-Induced In Situ Forming Gel Using Monopropylene Glycol as a Solvent for Periodontitis Treatment.

Solvent exchange-induced in situ forming gel (ISG) is currently an appealing dosage form for periodontitis treatment via localized injection into the periodontal pocket. This study aims to apply Eudragit L and Eudragit S as matrix components of ISG by using monopropylene glycol as a solvent for loading levofloxacin HCl for periodontitis treatment. The influence of Eudragit concentration was investigated in terms of apparent viscosity, rheological behavior, injectability, gel-forming behavior, and mechanical properties. Eudragit L-based formulation presented less viscosity, was easier to inject, and could form more gel than Eudragit S-based ISG. Levofloxacin HCl-loading diminished the viscosity of Eudragit L-based formulation but did not significantly change the gel formation ability. Higher polymer loading increased viscosity, force-work of injectability, and hardness. SEM photographs and µCT images revealed their scaffold formation, which had a denser topographic structure and less porosity attained owing to higher polymer loading and less in vitro degradation. By tracking with fluorescence dyes, the interface interaction study revealed crucial information such as solvent movement ability and matrix formation of ISG. They prolonged the drug release for 14 days with fickian drug diffusion kinetics and increased the release amount above the MIC against test microbes. The 1% levofloxacin HCl and 15% Eudragit L dissolved in monopropylene glycol (LLM15) was a promising ISG because of its appropriate viscosity (3674.54 ± 188.03 cP) with Newtonian flow, acceptable gel formation and injectability (21.08 ± 1.38 N), hardness (33.81 ± 2.3 N) and prolonged drug release with efficient antimicrobial activities against S. aureus (ATCC 6538, 6532, and 25923), methicillin-resistant S. aureus (MRSA) (S. aureus ATCC 4430), E. coli ATCC 8739, C. albicans ATCC 10231, P. gingivalis ATCC 33277, and A. actinomycetemcomitans ATCC 29522; thus, it is the potential ISG formulation for periodontitis treatment by localized periodontal pocket injection.

Lincomycin HCl-Loaded Borneol-Based In Situ Gel for Periodontitis Treatment.

Solvent exchange-induced in situ forming gel (ISG) has emerged as a versatile drug delivery system, particularly for periodontal pocket applications. In this study, we developed lincomycin HCl-loaded ISGs using a 40% borneol-based matrix and N-methyl pyrrolidone (NMP) as a solvent. The physicochemical properties and antimicrobial activities of the ISGs were evaluated. The prepared ISGs exhibited low viscosity and reduced surface tension, allowing for easy injection and spreadability. Gel formation increased the contact angle on agarose gel, while higher lincomycin HCl content decreased water tolerance and facilitated phase separation. The drug-loading influenced solvent exchange and matrix formation, resulting in thinner and inhomogeneous borneol matrices with slower gel formation and lower gel hardness. The lincomycin HCl-loaded borneol-based ISGs demonstrated sustained drug release above the minimum inhibitory concentration (MIC) for 8 days, following Fickian diffusion and fitting well with Higuchi's equation. These formulations exhibited dose-dependent inhibition of Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 8739, and Prophyromonas gingivalis ATCC 33277, and the release of NMP effectively inhibited Candida albicans ATCC 10231. Overall, the 7.5% lincomycin HCl-loaded 40% borneol-based ISGs hold promise as localized drug delivery systems for periodontitis treatment.

Clotrimazole-Loaded Borneol-Based In Situ Forming Gel as Oral Sprays for Oropharyngeal Candidiasis Therapy.

Oral candidiasis encompasses fungal infections of the tongue and other oral mucosal sites with fungal overgrowth and its invasion of superficial oral tissues. Borneol was assessed in this research as the matrix-forming agent of clotrimazole-loaded in situ forming gel (ISG) comprising clove oil as the co-active agent and N-methyl pyrrolidone (NMP) as a solvent. Their physicochemical properties, including pH, density, viscosity, surface tension, contact angle, water tolerance, gel formation, and drug release/permeation, were determined. Their antimicrobial activities were tested using agar cup diffusion. The pH values of clotrimazole-loaded borneol-based ISGs were in the range of 5.59-6.61, which are close to the pH of 6.8 of saliva. Increasing the borneol content in the formulation slightly decreased the density, surface tension, water tolerance, and spray angle but increased the viscosity and gel formation. The borneol matrix formation from NMP removal promoted a significantly (p < 0.05) higher contact angle of the borneol-loaded ISGs on agarose gel and porcine buccal mucosa than those of all borneol-free solutions. Clotrimazole-loaded ISG containing 40% borneol demonstrated appropriate physicochemical properties and rapid gel formation at microscopic and macroscopic levels. In addition, it prolonged drug release with a maximum flux of 370 µg·cm-2 at 2 days. The borneol matrix generated from this ISG obsentively controlled the drug penetration through the porcine buccal membrane. Most clotrimazole amounts still remained in formulation at the donor part and then the buccal membrane and receiving medium, repectively. Therefore, the borneol matrix extended the drug release and penetration through the buccal membrane efficiently. Some accumulated clotrimazole in tissue should exhibit its potential antifugal activity against microbes invading the host tissue. The other predominant drug release into the saliva of the oral cavity should influence the pathogen of oropharyngeal candidiasis. Clotrimazole-loaded ISG demonstrated efficacious inhibition of growth against S. aureus, E. coli, C. albicans, C. krusei, C. Lusitaniae, and C. tropicalis. Consequently, the clotrimazole-loaded ISG exhibited great potential as a drug delivery system for oropharyngeal candidiasis treatment by localized spraying.

Levofloxacin HCl-Incorporated Zein-Based Solvent Removal Phase Inversion In Situ Forming Gel for Periodontitis Treatment.

Zein is composed of nonpolar amino acids and is a water-insoluble protein used as the matrix-forming agent of localized in situ forming gel (ISG). Therefore, this study prepared solvent removal phase inversion zein-based ISG formulations to load levofloxacin HCl (Lv) for periodontitis treatment using dimethyl sulfoxide (DMSO) and glycerol formal (GF) as the solvents. Their physicochemical properties were determined, including viscosity, injectability, gel formation, and drug release. The topography of dried remnants after drug release was revealed using a scanning electron microscope and X-ray computed microtomography (µCT) to investigate their 3D structure and % porosity. The antimicrobial activities were tested against Staphylococcus aureus (ATCC 6538), Escherichia coli ATCC 8739, Candida albicans ATCC 10231, and Porphyromonas gingivalis ATCC 33277 with agar cup diffusion. Increasing zein concentration or using GF as the solvent notably enhanced the apparent viscosity and injection force of the zein ISG. However, its gel formation slowed due to the dense zein matrix barrier's solvent exchange: the higher loaded zein or utilization of GF as an ISG solvent prolonged Lv release. The SEM and µCT images revealed the scaffold of dried ISG in that their % porosity corresponded with their phase transformation and drug release behavior. In addition, the sustainability of drug diffusion promoted a smaller antimicrobial inhibition clear zone. Drug release from all formulations was attained with minimum inhibitory concentrations against pathogen microbes and exhibited a controlled release over 7 days. Lv-loaded 20% zein ISG using GF as a solvent exhibited appropriate viscosity, Newtonian flow, acceptable gel formation and injectability, and prolonged Lv release over 7 days with efficient antimicrobial activities against various test microbes; thus, it is the potential ISG formulation for periodontitis treatment. Consequently, the Lv-loaded solvent removal zein-based ISGs proposed in this investigation offer promising potential as an efficacious drug delivery system for periodontitis treatment by local injection.

Physicochemical and Bioactivity Characteristics of Doxycycline Hyclate-Loaded Solvent Removal-Induced Ibuprofen-Based In Situ Forming Gel.

Modulation with the suppression of infection and inflammation is essential to the successful treatment of periodontitis. An aqueous insoluble hydrophobic anti-inflammatory compound, i.e., ibuprofen (IBU), was investigated in this study as the matrix-forming agent of a doxycycline hyclate (DH)-loaded solvent removal-induced in situ forming gel (ISG) using dimethyl sulfoxide (DMSO) and N-methyl pyrrolidone (NMP) as the solvents. Their physicochemical properties, including pH, density, viscosity, surface tension, contact angle, water tolerance, injectability, mechanical properties, gel formation, and drug release, were determined. Their antimicrobial activities were tested using agar cup diffusion, and their anti-inflammatory activity was assessed using thermal inhibition of protein denaturation of egg albumin. Increasing the IBU content decreased the density, pH, surface tension, and contact angle but increased the viscosity, force and work of injection, and gel formation of IBU-based ISG solution. Although their water tolerance values decreased with the increase in IBU content, the addition of DH and the use of NMP led to high water tolerance. The characterization of the dried gel remnants of ISGs presented no change in IBU crystallinity and thermal properties and confirmed no chemical interaction among the components of ISGs. The obtained transformed IBU matrix prolonged the release of DH and IBU from ISGs over 7 days from its tortuously packed IBU matrix with small pores, and conformed well with Fickian diffusion mechanism. The developed DH-loaded solvent removal-induced IBU-based ISGs exhibited efficient antimicrobial activities against Staphylococcus aureus, methicillin-resistant S. aureus, Escherichia coli, Candida albicans, Porphyromonas gingivalis, and Aggregatibacter actinomycetemcomitans. IBU in formulation promoted the antimicrobial activity of ISGs, whereas DH and NMP promoted the anti-inflammatory activity of ISGs. Consequently, the DH-loaded solvent removal-induced IBU-based ISGs proposed in this study show great potential as an effective bioactive drug delivery system for periodontitis treatment by localized periodontal pocket injection.

Natural rubber blends for floating theophylline beads.

Natural rubber (NR)'s value has become increasingly important for human applications. This study prepared NR beads as floating drug delivery system by dripping NR latex into hardening solution to obtain spherical beads. Theophylline was loaded as a model drug. NR latex formed into harden beads suddenly after dripping droplets in acidic medium. These NR beads floated instantly and buoyant in HCl buffer for over 8 h with prolonged theophylline release. Their morphologies, crystallinity and thermal properties were observed using microscope, X-ray diffractometer, and thermogravimetry, respectively. Addition of 100 phr sodium bicarbonate increased drug release owing to liberation of carbon dioxide promoting porous NR matrix. Composite of 50 and 200 phr shellac in NR beads floated in HCl buffer for over 12 h. Moreover, 200 phr shellac efficiently retarded release of theophylline from NR composite beads (lower than 10 % in 8 h), whereby promoting theophylline release in phosphate buffer (pH 6.8) (approximately 80 % in 8 h). NR-shellac beads had greater water sorption (2.5 times) and erosion (4.9 times) in phosphate buffer than in HCl buffer. Thus, NR beads exhibited desirable attributes as floating drug delivery system. Both sodium bicarbonate and shellac modified matrix properties and drug release of NR beads.

New Insight into the Impact of Effervescence on Gel Layer Microstructure and Drug Release of Effervescent Matrices Using Combined Mechanical and Imaging Characterisation Techniques.

Gel layer characteristics play a crucial role in hydrophilic hydroxypropyl methylcellulose (HPMC) matrix development. Effervescent agents have the potential to affect the gel layer microstructures. This study aimed to investigate the influence of effervescence on the microstructure of the gel layer around HPMC matrices using a combination of texture analysis and imaging techniques. The relationship with drug release profile and release mechanisms were also examined. The high amounts of effervescent agents promoted a rapid carbonation reaction, resulting in a high gel layer formation with a low gel strength through texture analysis. This finding was ascribed to the enhanced surface roughness and porosity observed under digital microscopy and microporous structure of the gel layer under scanning electron microscopy. The reconstructed three-dimensional images from synchrotron radiation X-ray tomographic microscopy notably exhibited the interconnected pores of various sizes from the carbonation reaction of effervescent and microporous networks, indicating the gel layer on the tablet surface. Notably, effervescence promoted the increase in interconnected porosities, which directly influenced the strength of the gel layer microstructure, drug release patterns and release mechanism of the effervescent matrix tablet. Therefore, combined mechanical characterisation and imaging techniques can provide new insights into the role of effervescent agents on the gel layer microstructure, and describe the relationship of drug release patterns and release mechanism of matrix tablets.

Thermoresponsive Azithromycin-Loaded Niosome Gel Based on Poloxamer 407 and Hyaluronic Interactions for Periodontitis Treatment.

Azithromycin (AZM) is a potential antimicrobial drug for periodontitis treatment. However, a potential sustained-release system is needed for intra-periodontal pocket delivery. This study focused on the development and evaluation of a thermoresponsive azithromycin-loaded niosome gel (AZG) to search for a desirable formulation for periodontitis treatment. AZG was further developed from an AZM-loaded niosomal formulation by exploiting the advantages of poloxamer 407 (P407) and hyaluronic acid (HA) interactions. The results showed that the addition of HA decreased the gelation temperature and gelation time of AZG. HA was found to increase the viscosity as well as mucoadhesive and tooth-root surface adhesive properties. The AZG solution state was injectable and exhibited pseudoplastic shear-thinning behavior. P407-HA interactions in AZG could contribute to gel strength. AZG showed 72 h of continuous drug release following the Korsmeyer-Peppas model and potentially enhanced drug permeation. The formulations apparently presented more efficient antibacterial activity against major periodontal pathogens than the standard AZM solution. AZM intra-periodontal pocket formulation and the remarkable properties of niosomes exhibited potential characteristics, including ease of administration, bioadhesion to the anatomical structure of the periodontal pocket, and sustained drug release with competent antimicrobial activity, which could be beneficial for periodontitis treatment.

Imatinib Mesylate-Loaded Rosin/Cinnamon Oil-Based In Situ Forming Gel against Colorectal Cancer Cells.

Localized delivery systems have been typically designed to enhance drug concentration at a target site and minimize systemic drug toxicity. A rosin/cinnamon oil (CO) in situ forming gel (ISG) was developed for the sustainable delivery of imatinib mesylate (IM) against colorectal cancer cells. CO has been claimed to express a potent anticancer effect against various cancer cells, as well as a synergistic effect with IM on colorectal cancer cells; however, poor aqueous solubility limits its application. The effect of rosin with the adding CO was assessed on physicochemical properties and in vitro drug release from developed IM-loaded rosin/CO-based ISG. Moreover, in vitro cytotoxicity tests were conducted against two colorectal cancer cells. All formulations exhibited Newtonian flow behavior with viscosity less than 266.9 cP with easier injectability. The adding of CO decreased the hardness and increased the adhesive force of the obtained rosin gel. The gel formation increased over time under microscopic observation. CO-added ISG had a particle-like gel appearance, and it promoted a higher release of IM over a period of 28 days. All tested ISG formulations revealed cytotoxicity against HCT-116 and HT-29 cell lines at different incubation times. Thus, CO-loaded rosin-based ISG can act as a potentially sustainable IM delivery system for chemotherapy against colorectal cancer cells.

Stereomicroscope with Imaging Analysis: A Versatile Tool for Wetting, Gel Formation and Erosion Rate Determinations of Eutectic Effervescent Tablet.

Wettability, gel formation and erosion behaviors could influence the drug release pattern of solid dosage forms. Typically, these parameters are evaluated using a variety of techniques. Nonetheless, there has been no previous research on versatile tool development for evaluating several tablet characteristics with a single tool. The aim of this study was to develop the versatile tool for measuring various physical properties of eutectic effervescent tablets and also investigate the relationship between these parameters with parameters from drug dissolution. Ibuprofen (IBU)-poloxamer 407 (P407) eutectic effervescent tablets were fabricated with a direct compression method. Their wetting properties, gel formation and erosion behaviors were investigated using a stereomicroscope with imaging analysis in terms of the liquid penetration distance, gel thickness and erosion boundary diameter, respectively. In addition, the dissolution rate (k) and disintegration time of eutectic effervescent tablets in 0.1 N HCl buffer pH 1.2 were also determined. Incorporation of P407 into the IBU tablet improved the tablet wetting properties with increasing liquid penetration distance under stereoscope. CO2 liberation from effervescent agents promoted tablet surface roughness from matrix erosion. The relationship between observed physical properties and disintegration and dissolution parameters suggested that the combination of erosion by effervescent agents and gel formation by P407 had a potential influence on dissolution enhancement of the formulation. Therefore, a developed stereomicroscope with an imaging analysis technique was exhibited as an alternative versatile tool for determining the wetting properties, gel formation and erosion behaviors of pharmaceutical solid dosage forms.

Design and Comparative Evaluation of Vancomycin HCl-Loaded Rosin-Based In Situ Forming Gel and Microparticles.

Vancomycin hydrochloride (HCl) is a glycopeptide antibiotic used to treat serious or life-threatening infections, and it reduces plaque scores and gingivitis in periodontal patients. In this study, vancomycin HCl was incorporated into rosin in situ forming gel (ISG) and rosin in situ forming microparticles (ISM) to generate a local drug delivery system to treat periodontal disease. The physical properties of the ISG and ISM were measured, including pH, viscosity, injectability, adhesion properties, in-vitro transformation, and drug release. Moreover, the effectiveness of antimicrobial activity was tested using the agar-cup diffusion method against Staphylococcus aureus, Streptococcus mutans, Porphyromonas gingivalis, and Escherichia coli. Vancomycin HCl-loaded rosin-based ISG and ISM had a pH value in the range of 5.02−6.48 and exhibited the ease of injection with an injection force of less than 20 N. Additionally, the lubricity effect of the external oil phase of ISM promoted less work of injection than ISG and 40−60% rosin-based ISM showed good emulsion stability. The droplet size of emulsions containing 40%, 50%, and 60% rosin was 98.48 ± 16.11, 125.55 ± 4.75, and 137.80 ± 16.8 µm, respectively. Their obtained microparticles were significantly smaller in diameter, 78.63 ± 12.97, 93.81 ± 10.53, and 118.32 ± 15.61 µm, respectively, because the particles shrank due to the solvent loss from solvent exchange. Moreover, increasing the concentration of rosin increased the size of microparticles. After phase transformation, all formulations had better plasticity properties than elasticity; therefore, they could easily adapt to the specific shape of a patient's gum cavity. Both developed ISG and ISM presented inhibition zones against S. mutans and P. gingivalis, with ISG presenting significantly more effectively against these two microbes (p < 0.05). The vancomycin HCl-loaded rosin ISG and ISM delayed drug release for 7 days with efficient antimicrobial activities; thus, they exhibit potential as the drug delivery systems for periodontitis treatment.