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.

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.

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.

Borneol-based antisolvent-induced in situ forming matrix for crevicular pocket delivery of vancomycin hydrochloride.

Given its safety and apparent low aqueous solubility, borneol may serve as a matrix forming component of anti-solvent based in situ forming matrixes (ISMs) for crevicular pocket targeting. Drug-free and vancomycin hydrochloride-loaded borneol ISMs were evaluated for pH, density, viscosity, contact angle, surface tension, matrix formation, drug release behavior, in vitro degradability and antimicrobial activities. Density and pH values of borneol-based ISMs decreased with increasing borneol concentration. Given their markedly low viscosity could facilitate better injectability. The contact angles of the drug-free and vancomycin HCl-loaded borneol ISMs increased after being in contact with the agarose gel or the bulge tissue of porcine due to phase inversion. A dense borneol crystal matrix formed after using the highly concentrated ISM corresponded to fast matrix formation. The borneol-based ISM exhibited a sustainable drug release longer than 14 days with a diffusion-controlled release mechanism. Moreover, the developed ISM exhibited strong antimicrobial activities against various microbes. Thus, the vancomycin HCl-loaded borneol-based ISM is a potentially effective local anti-solvent-based ISM for periodontitis treatment via crevicular pocket injection.

Physicochemical properties of ß-cyclodextrin solutions and precipitates prepared from injectable vehicles.

ß-Cyclodextrin (ß-CyD) is cyclic oligosaccharide of a glucopyranose, containing a relatively hydrophobic central cavity and hydrophilic outer surface. However, the usefulness of ß-CyD is limited owing to its low aqueous solubility whereas we found that its apparent high solubility was evident in some injectable solvents including 2-pyrrolidone (PYR), N-methyl pyrrolidone (NMP) and dimethyl sulfoxide (DMSO). Therefore, in the present study, the physicochemical properties of the 30-60% w/w ß-CyD in PYR, NMP and DMSO were investigated such as viscosity, water resistant, matrix formation rate and syringeability. The higher the concentration of ß-CyD resulted in the increased viscosity and the higher force and energy of syringeability. ß-CyD in PYR gave the highest viscosity which contributed to the lowest syringeability while ß-CyD in DMSO exhibited the highest syringeability. The ß-CyD in DMSO and NMP exhibited the higher rate of matrix formation. ß-CyD in PYR showed the highest water resistant for phase separation while ß-CyD in NMP gave the faster de-mixing rate compared to that from PYR. The difference in physicochemical properties of ß-CyD dried ppts studied by scanning electron microscope (SEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR) and thermogravimetric analysis (TGA) revealed that there was partial complexation of ß-CyD with respective solvents. Both solution and precipitate characteristic properties will be useful for using ß-CyD in further investigation as matrix material dissolved in the injectable vehicles as the in situ forming gel for periodontitis treatment.