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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.

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.

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.

Polymeric material plays an important role as a matrix former in the modulation of drug release of antimicrobial-loaded in situ forming gel (ISG) for efficient periodontitis treatment. This study was conducted to compare three polymers, namely bleached shellac (BS), Ethocel (EC) and Eudragit RS (ERS), as matrix formers of doxycycline hyclate (DH)-loaded solvent exchange-induced ISG. All prepared ISGs, except 25% EC ISG, exhibited the Newtonian flow behaviour. Transformation from solution into matrix-like was achieved rapidly within 5 min. Increasing the amount of these polymers extended the release of DH. DH-loaded EC and ERS ISG systems exhibited high antimicrobial activity, and all ISGs were effective in inhibiting the growth of Staphylococcus aureus, Escherichia coli, Streptococcus mutans, Porphyromonas gingivalis and Candida albicans. By comparison, the DH-loaded ERS ISG, through the solvent exchange mechanism, was found to be ease in injection with low viscosity and sustained the release with higher concentration, meanwhile, it also exhibited interesting in vitro degradability and antimicrobial activities. Therefore, the DH-loaded ERS ISG exhibited a potential use for localized periodontal drug delivery system for the treatment periodontitis.

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.

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.