Jongjan Mahadlek

Solvent exchange-induced in situ forming gel comprising ethyl cellulose-antimicrobial drugs.

Solvent-exchanged in situ forming gel is a drug delivery system which is in sol form before administration. When it contacts with the body fluid, then the water miscible organic solvent dissipates and water penetrates into the system, leading the polymer precipitation as in situ gel at the site of injection. The aim of this research was to study the parameters affecting the gel properties, drug release and antimicrobial activities of the in situ forming gels prepared from ethyl cellulose (EC) dissolved in N-methyl pyrrolidone (NMP) to deliver the antimicrobial agents (doxycycline hyclate, metronidazole and benzyl peroxide) for periodontitis treatment. The gel appearance, pH, viscosity, rheology, syringeability, gel formation, rate of water diffusion into the gels, in vitro degradation, drug release behavior and antimicrobial activities against Staphylococcus aureus, Escherichia coli, Candida albicans, Streptococcus mutans and Porphyrommonas gingivalis were determined. Increasing the amount of EC increased the viscosity of system while still exhibiting Newtonian flow and increased the work of syringeability whereas decreased the releasing of drug. The system transformed into the rigid gel formation after being injected into the simulated gingival crevicular fluid. The developed systems containing 5% w/w antimicrobial agent showed the antimicrobial activities against all test bacteria. Thus the developed solvent exchange-induced in situ forming gels comprising EC-antimicrobial drugs exhibited potential use for periodontitis treatment.

Characterization and antimicrobial activity of N-methyl-2-pyrrolidone-loaded ethylene oxide-propylene oxide block copolymer thermosensitive gel

The purpose of this study is to investigate the effects of N-methyl-2-pyrrolidone on the thermosensitive properties of aqueous ethylene oxide-propylene oxide block copolymer (Lutrol® F127) system. Due to the aqueous solubility enhancement and biocompatibility, N-methyl-2-pyrrolidone is an interesting solubilizer for the poorly water soluble drugs to be incorporated in the Lutrol® F127 system. Effect of N-methyl-2-pyrrolidone on physicochemical properties of Lutrol® F127 system was investigated using appearance, pH, gelation, gel melting temperature and rheology. The antimicrobial activity of the thermosensitive N-methyl-2-pyrrolidone gel was also tested. Lower N-methyl-2-pyrrolidone amount (≤30%w/w) could shift the sol-gel transition to a lower temperature but the gel-sol transition was shifted to a higher temperature. Higher N-methyl-2-pyrrolidone (≥40%w/w) could shift both sol-gel and gel-sol transitions of the system to a lower temperature. The amount of N-methyl-2-pyrrolidone >60% w/w could reverse the phase of the Lutrol® F127 system to non-newtonian flow at 4° and Newtonian flow at high temperature. Aqueous Lutrol® F127 system containing N-methyl-2-pyrrolidone exhibited antimicrobial activities against Staphylococcus aureus, Escherichia coli and Candida albicans with the N-methyl-2-pyrrolidone in a dose-dependent manner.

Characterization of indomethacin release from polyethylene glycol tablet fabricated with mold technique

The purpose of this study was to use polyethylene glycol as a carrier to improve the solubility of an aqueous insoluble drug by melting and molding method. The release of dissolved drug was designed to be subsequently sustained with an addition of xanthan gum. The release of indomethacin from the developed system into phosphate buffer pH 6.2 was conducted using the dissolution apparatus. This carrier system could effectively enhance the solubility of indomethacin and an addition of xanthan gum could sustain the drug release. Eudragit L100 film coating could protect the carrier not to be disturbed with HCl buffer pH 1.2 and could dissolve in phosphate buffer pH 6.2, therefore, the drug release from coated tablet was initially very low but subsequently gradually released and prolonged in phosphate buffer pH 6.2. Differential scanning calorimetry study indicated the amorphous state of drug in polyethylene glycol carrier. Scanning electron microscopy photomicrograph indicated the drug diffusion outward through the porous network of matrix tablets into the dissolution fluid and curve fitting signified that the drug release kinetic was Fickian diffusion.

Texture and topography analysis of doxycycline hyclate thermosensitive systems comprising zinc oxide.

To characterize the thermal behavior and texture analysis of doxycycline hyclate thermosensitive gels developed for periodontitis treatment containing zinc oxide prepared by using poloxamer (Lutrol® F127) as polymeric material and N-methyl pyrrolidone was used as cosolvent. The thermosensitive gel comprising doxycycline hyclate, Lutrol® F127, and N-methyl pyrrolidone were characterized for the thermal behavior and texture analysis. The topography of the system after the dissolution test was characterized with scanning electron microscope. Differential scanning calorimetric thermogram exhibited the endothermic peaks in the systems containing high amount of N-methyl pyrrolidone in solvent. The sol-gel transition temperature of the systems decreased as the zinc oxide amount was increased. The addition of doxycycline hyclate, zinc oxide, and N-methyl pyrrolidone affected the syringeability of systems. The addition of zinc oxide into the doxycycline hyclate-Lutrol® F127 systems decreased the diameter of inhibition zone against Staphylococcus aureus, Escherichia coli, and Candida albicans since zinc oxide decreased the diffusion and prolonged release of doxycycline hyclate. From scanning electron microscope analysis, the porous surface of 20% w/w Lutrol® F127 system was notably different from that of gel comprising doxycycline hyclate which had interconnected pores and smooth surfaces. The number of pores was decreased with increasing zinc oxide and the porous structure was smaller and more compact. Therefore, the addition of zinc oxide could increase the syringeability of doxycycline hyclate-Lutrol® F127 system with the temperature dependence. Zinc oxide decreased inhibition zone against test microbes because of prolongation of doxycycline hyclate release and reduced size of continuous cells. Furthermore, zinc oxide also increased the compactness of wall surfaces of Lutrol® F127.

Characterization of Antimicrobial Agent Loaded Eudragit RS Solvent Exchange-Induced In Situ Forming Gels for Periodontitis Treatment

Eudragit RS (ERS), a quaternary polyacrylate positively charged polymer, exhibits a very low permeability and swells in aqueous media independently of pH without dissolving. Owing to its high solubility in N-methyl pyrrolidone (NMP), it was interesting to apply as polymer matrix for solvent-exchanged in situ forming gel. The aim of this research was to prepare in situ forming gels from ERS to deliver the antimicrobial agents (doxycycline hyclate, metronidazole, and benzoyl peroxide) for periodontitis treatment. They were evaluated for viscosity and rheology, gel formation, syringeability, drug release, and antimicrobial activities. The solvent exchange between NMP and an external aqueous simulated gingival crevicular fluid stimulated the dissolved ERS transforming into the opaque rigid gel. Antimicrobial agent loaded ERS systems exhibited Newtonian flow with acceptable syringeability. The higher-loaded ERS promoted the more prolongation of drug release because of the retardation of water diffusion into the precipitated matrix. Antimicrobial activities against Staphylococcus aureus, Escherichia coli, Candida albicans, Streptococcus mutans, and Porphyromonas gingivalis depended on type of drugs and test microorganisms. Doxycycline hyclate loaded ERS systems showed these activities greater than the others; however, all of them could inhibit all test microorganisms. Thus, the solvent exchange-induced in situ forming gels comprising ERS-antimicrobial drugs exhibited potential use as localized delivery systems for periodontitis treatment.

Benzoyl Peroxide In Situ Forming Antimicrobial Gel for Periodontitis Treatment

Periodontitis is an inflammatory disease of the supporting structures of the tooth caused by bacterial infection which can result in tooth loss. The local intra-pocket drug delivery system was interesting and highly effective for periodontitis treatment. In situ forming gel system is the polymeric solution which could transform into gel for localizing and sustaining the drug release at desired site. This system has been recommended as one of suitable delivery system for this purpose. Benzoyl peroxide (BPO) in situ forming gels were developed using Eudragit RS as polymer dispersed in N-methyl-pyrrolidone (NMP). Peppermint oil and polyethylene glycol 1500 were also incorporated as the excipients. The prepared systems were evaluated for rheology, syringeability (using texture analyzers), in situ gel formation (after injection into PBS pH 6.8), antimicrobial activity (against Streptococcus mutans with agar diffusion) and drug release (with dialysis method in PBS pH 6.8 at 50 rpm, 37 °C). The viscosity and syringeability of the prepared systems was increased as the amount of BPO, peppermint oil or PEG 1500 was increased. All prepared gels showed the Newtonian flow which the viscosity was decreased as the temperature was increased. All prepared gels comprising peppermint oil and PEG 1500 could form in situ gel in used medium which the pH was close to the environment pH of periodontal pocket. The inhibition zone against Streptococcus mutans of the prepared system was significantly decreased when the peppermint oil and PEG 1500 was incorporated owing to the higher viscous environment and thereafter retardation of drug diffusion was evident. This effect could prolong the drug release. From drug release test, all prepared gels could sustain the BPO release for at least 96 hrs. Release kinetic obtained from curve fitting with various release equations using least square fit technique indicated that the release patterns were as Higuchi’s model therefore the release of BPO was performed with diffusion control. This developed BPO in situ forming gel presented its ability as the controlled drug delivery system for localized antimicrobial activity at periodontal pocket.

Metrodidazole In Situ Forming Eudragit RS Gel Comprising Different Solvents

In situ forming gel with solvent exchange mechanism is one of drug delivery systems for periodontitis treatment. The system is injected into the desired site then transforms into a gel state when the solvent diffuses out and aqueous diffuses in. The in situ forming Eudragit RSgels loading 1, 5 and 10%w/w metronidazole (MT) were developed in this study using N-methyl pyrrolidone (NMP), 2-pyrrolidone and dimethyl sulfoxide (DMSO) as solvent. The viscosity of the gel systems in all solvents were increased as drug or polymer amount was increased with Newtonian flow behavior. Transformation into gel was evident after initiated the systems in phosphate buffer pH 6.8. NMP systems exhibited the lowest work of syringeability through 18 G syringe. Drug release from dialysis tube of DMSO systems was slower than that of NMP and 2-pyrrolidone systems, respectively. Antimicrobial activity against Staphylococcus aureus of the systems comprising MT using NMP as solvent was greater than that using 2-pyrrolidone and DMSO, respectively, which the antimicrobial activity was increased as the drug amount was increased. Therefore, the solvent type affected the viscosity, gel formation, syringeability, drug release and antimicrobial activity of Eudragit RS systems. These developed systems sustained the drug release and inhibited the bacterial growth hence they were interesting systems for periodontitis treatment.

Combination Effects of the Antimicrobial Agents and Cinnamon Oil

The use of antimicrobial combination may be interesting because it can decrease doses and side effects of antimicrobial agents. The cinnamon essential oil was examined with respect to antimicrobial modifying activity. The combination effect of antimicrobial agents (doxycycline hyclate, ciprofloxacin HCl and metronidazole) and cinnamon oil was evaluated by checkerboard method to obtain a fractional inhibitory concentration (FIC) index. The effect of metronidazole+doxycycline hyclate and metronidazole+ciprofloxacin hydrochloride combinations were additive against Staphylococcus aureus. The indifference FIC index was observed only with the doxycycline hyclate+ciprofloxacin HCl combination. Combinations of cinnamon oil and all antimicrobial agents showed the additive effects against S. aureus. These results indicated that the antimicrobial activity of cinnamon oil was generally additive to all test antimicrobial agents.

Role of Zinc Oxide on Rheology of Thermosensitive Gel Developed for Periodontitis Treatment

Periodontal disease is a major cause of tooth loss, therefore a more recent approach such as thermosensitive gel is loaded with antimicrobial drugs to be delivered locally to the periodontal pocket. The effect of ZnO on thermosensitive gel properties including gelation-gel melting temperature, rheology, syringeability, and the release behavior of antimicrobial drug such as doxycycline hyclate were investigated. The increased amount of ZnO apparently decreased the gelation temperature of the Lutrol® F127 system. Syringeability of the doxycycline hyclate-Lutrol® F127 systems were increased with the increased amount of ZnO. System comprising zinc oxide could prolong the release of doxycycline hyclate from Lutrol F127 systems and could be delivered from a syringe through a needle for utilizing in periodontitis therapy at the periodontal pocket.

Peppermint oil/doxycycline hyclate-loaded Eudragit RS in situ forming gel for periodontitis treatment

Antibiotic-loaded in situ forming gels are particularly attractive for periodontitis treatment. They are in a sol form and gradually alter to a solid-like depot after administration into a periodontal pocket to deliver and maintain the effective high level of drug in the gingival crevicular fluid. Solvent-inducing in situ forming gel mostly exhibits the burst drug release owing to rapid diffusion of solvent. This study incorporated peppermint oil to modulate the drug release and the gel characteristics of doxycycline hyclate-loaded Eudragit RS in situ forming gel systems. Peppermint oil increased the viscosity and syringeability of the Eudragit RS solution comprising NMP as solvent and retarded the water penetration. Therefore the diminishment of burst liberation and the prolongation of drug release with an addition of peppermint oil were attained with concentration dependence mainly following Fickian diffusion mechanism. The drug release from the membrane-less diffusion method was apparently slower than that from the dialysis method because the rapid phase separation into solid-like matrix through a direct contact with dissolution medium generated a hard surrounding shell. These solvent exchange-inducing in situ forming gels comprising peppermint oil effectively inhibited Staphylococcus aureus, Escherichia coli, Streptococcus mutans and Porphyrommonas gingivalis; therefore, they exhibited the potential use as localized delivery systems for periodontitis treatment.Graphical Abstract