Doxycycline and Monocaprin In Situ Hydrogel: Effect on Stability, Mucoadhesion and Texture Analysis and In Vitro Release

Publisher's version (útgefin grein).The aim of this study was to develop a stable aqueous formulation containing a combination of doxycycline and monocaprin in clinically relevant concentrations. Increase in expression of Matrix metalloproteinases (MMPs) and microbial role in oral diseases is well established and the combination of above active ingredients could be potentially beneficial in treatment of oral mucosal conditions. The hydrogels containing different concentrations of doxycycline and monocaprin in the presence and absence of stabilizing excipients were developed and their stabilities were studied at 4 ◦C for up to 1 year. The drug–drug interaction was evaluated using Fourier-transform infrared spectroscopy (FTIR). The addition of monocaprin on doxycycline in situ hydrogel’s mucoadhesiveness, texture properties and drug release mechanism was studied. The addition of monocaprin negatively affected the doxycycline stability and was concentration dependent, whereas monocaprin was stable up to 1 year. Doxycycline did not interfere with the anti-Candidal activity of monocaprin. Furthermore, the presence of monocaprin significantly affected the formulation hardness, compressibility and adhesiveness. Monocaprin and doxycycline release followed zero order kinetics and the release mechanism was, by anomalous (non-Fickian) diffusion. The addition of monocaprin increased the drug release time and altered the release mechanism. It is possible to stabilize doxycycline in the presence of monocaprin up to 1 year at 4 ◦C.This work was supported by a research fund from the University of Iceland (Rannsóknarsjóður Háskóla Íslands).Peer Reviewe

Effect of doxycycline microencapsulation on buccal films : Stability, mucoadhesion and in vitro drug release

Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This research was funded by Rannsóknarsjóður Háskóla Íslands (University of Iceland Research Grand).The aim of this work was to stabilize doxycycline in mucoadhesive buccal films at room temperature (25◦C). Since doxycycline is susceptible to degradation such as oxidation and epimerization, tablets are currently the only formulation that can keep the drug fully stable at room temperature, while liquid formulations are limited to refrigerated conditions (4◦C). In this study, the aim was to make formulations containing subclinical (antibiotic) doxycycline concentration that can act as matrix metalloproteinase inhibitors (MMPI) and can be stored at temperatures such as 25◦C. Here, doxycycline was complexed with excipients using three techniques and entrapped into microparticles that were stored at 4◦C, 25◦C and 40◦C. Effect of addition of precomplexed doxycycline microparticles on films: stability mucoadhesion capacity, tensile strength, swelling index and in vitro release was studied. The complexation efficiency between drug-excipients, microparticles and films was studied using Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). Two of the films were found to be stable at 4◦C but the film containing microparticle composed of precomplexed doxycycline with β-cyclodextrin, MgCl2, sodium thiosulfate, HPMC and Eudragit® RS 12.5 was found to be stable at 25◦C until 26 weeks. The addition of microparticles to the films was found to reduce the mucoadhesive capacity, peak detachment force, tensile strength and elasticity, but improved the stability at room temperature.Peer reviewe

Mucoadhesive drug delivery systems for the treatment of oral mucosal conditions

The oral mucosa is a convenient location where drug delivery systems could be employed to treat both local conditions as well as systemic delivery. It offers 4-4000 times more permeability relative to skin which makes it an ideal platform for delivering higher molecular weight compounds both for local as well as systemic delivery. The oral mucosa can be affected by some conditions that are local e.g., ulcerative conditions like aphthous ulcers, immunologically mediated conditions, hyperkeratosis and infections (bacterial, candida and virus (cold sores)). Some of these conditions require long-term clinical follow up which eventually could lead to drug resistance. There is a growing need to develop new treatments that are effective in reducing the inflammation and effectively treating the infections. Previous clinical trials and in vitro microbial tests proved that doxycycline is a promising alternative in downgrading the inflammation pathway and could be potentially useful in treatment of many oral conditions. Monocaprin is a lipid that is effective against various bacteria, yeast and viruses. It effectively healed cold sores in combination with doxycycline and treatment outcome was promising compared to the existing treatments. But the drawback was the stability of the compounds; doxycycline undergoes oxidation and epimerization while monocaprin undergoes hydrolysis and is also susceptible for acyl-migration in solutions and both the compounds need to be stabilized in formulations especially sensitive to aqueos formulations. So, the main aim of this project was focused on enhancing the stability of active components doxycycline and monocaprin and also stabilizing them in combination in a hydrogel formulation. The study also involved development of suitable HPLC/UPLC method for accurate chemical quantification of the active component. Further the physicochemical evaluation of the formulations was analyzed to optimize the formulations for the oral mucosal delivery. The formulations were also analyzed for mucoadhesion capacity and texture profile analysis to enhance the drug retention at application site and also to enhance the patient compliance. The doxycycline was successfully stabilized in aqueous formulation for a tested period of up to 5 years. A hydrogel containing combination of doxycycline and monocaprin was developed and both the active components were stabilized for a period up to 1 year at 4°C. The microparticles were further developed to enhance the doxycycline stability even at 25°C and films loaded with microparticles effectively stabilized doxycycline even at room temperature. Various buccal films with different polymeric blends and plasticizers were evaluated for their suitability for doxycycline stability and their effect on films, mechanical properties, swelling index, pH, mucoadhesive potential and in vitro release with varying release time profile ranging from immediate-intermediate-sustained films were developed and evaluated. Suitable polymers and plasticizers for doxycycline stability are reported. Selection of polymers based on film properties that can be tailored are discussed in this work. Overall, doxycycline formulation that is stable for 5 years was developed. A stable hydrogel containing combination of doxycycline and monocaprin was developed. An accurate HPLC method for monocaprin quantification was developed. Doxycycline was further stabilized in microparticles loaded buccal films even at room temperature. Effect of microparticles and their incorporation on doxycycline stability as well as film properties were evaluated. Suitable polymers and plasticizers for doxycycline, for buccal film development were studied and reported. This project successfully stabilized doxycycline in formulations, also in combination with monocaprin, that could deliver it for MMP inhibition for oral mucosa, were developed that could be commercially available

In situ forming hydrogels for drug delivery to the oral mucosa

Background: Recurrent aphthous stomatitis (RAS) is a painful condition affecting 5-25 % of the general population. RAS may cause pain during eating, swallowing and talking, which in extreme cases can contribute to weight loss and thereby reducing the overall quality of life of patients. There are a few treatments available on the market today, of which Amlexanox 5 % is the most widely used treatment. A clinical trial showed that Amlexanox 5 % reduced the pain of ulcers by day 6 in majority of patients with minor RAS. Minor RAS can heal naturally in 7-14 days without leaving any scars. In an earlier clinical trial, which was based on treating the RAS by inhibiting the matrixmetalloproteinases (MMPs) with sub-antimicrobial dose of topical doxycycline containing gel, it was shown that ulcers healed completely by day 3 in majority of patients. This could be the novel treatment for treating RAS, as it has shown rapid healing time compared to Amlexanox. But the challenge here is that doxycycline is an unstable compound, it degrades rapidly in aqueous solutions and non-aqueous solvents. Aim: The main aim of this work was to formulate an in situ forming hydrogel containing a sub-antimicrobial dose of doxycycline that gels at physiological conditions with primary emphasis on increasing the stability of doxycycline in aqueous formulations. Also the in situ hydrogels should, upon instillation onto the oral cavity, adhere to the oral mucosa with sufficient strength. For this purpose suitable mucoadhesive polymers were added to the formulations after in vitro mucoadhesion analysis tests. The viscosities of the formulations were analysed and priority was given to maintaining low viscosities at room temperature. Additionally the formulation release behaviour was studied with polymer non-membrane method. Methods: A total of 40 in situ forming hydrogels were prepared and stability tests were carried out over 3 months, in some cases up to 23 months at 4 °C, 25 °C and 40 °C. The stability of doxycycline was analysed by HPLC. The mucoadhesive polymers were chosen after testing the mucoadhesive strengths of 14 different in situ hydrogels with varying concentrations and combinations of polymers using a Texture Analyser. The viscosity tests were carried out with a Brookfield DV-II cone and plate viscometer. The in vitro release studies were initially attempted using Franz diffusion cells and then replaced with a polymer non-membrane in vitro release method. Results: The exact mechanism of how the excipients were affecting the HPLC results was identified and the HPLC method was later replaced. In the stability studies at 4 °C, the majority of formulations were 100 % stable over a period of 3 months. Also at 25 °C and 40 °C, the highest stabilities were achieved. Selection of suitable polymers and adjusting the pH of hydrogels in a right region gave 99 % stability to doxycycline at 4 °C, over a tested period of 20 months. A combination of two different mucoadhesive polymers showed enhanced mucoadhesion capability with low viscosity values at room temperature and without affecting the gel strength and gelation temperature of the poloxamers. The results from non-membrane in vitro release studies showed sustained drug release behaviour from the polymer network over a period of 20 hours. Conclusions: The results indicate that the main aim of this project of formulating a stable doxycycline in situ formulation that is stable for at least 2 years was achieved. At 4 °C some of the formulations were 100 % stable after 15 months and 99 % stable after 20 months, at 25 °C one of the preferred formulation was 100 % stable for up to 1 month and 91 % stable by the end of 3 months. At 40 °C, one of the formulation was 71 % stable after 3 months. All the stabilities achieved at all the 3 temperatures are highest among all the previous studies