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Vinsamlegast notið þetta auðkenni þegar þið vitnið til verksins eða tengið í það: http://hdl.handle.net/1946/17393

Titill: 
  • Titill er á ensku In situ forming hydrogels for drug delivery to the oral mucosa
Námsstig: 
  • Meistara
Efnisorð: 
Útdráttur: 
  • Útdráttur er á ensku

    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.

Samþykkt: 
  • 24.2.2014
URI: 
  • http://hdl.handle.net/1946/17393


Skrár
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