RESUMEN
In-situ forming implants receive great attention for repairing serious bone injuries. The aim of the present study was to prepare novel chitosan in-situ forming implants (CIFI) loaded with bioactive glass nanoparticles and/or raloxifene hydrochloride (RLX). Incorporating raloxifene hydrochloride (RLX) as a selective estrogen receptor modulator was essential to make use of its anti-resorptive properties. The prepared formulae were tested for their in-vitro gelation time, drug release, injectability, rheological properties, erosion rate and morphological properties. Results revealed that the formulation composed of 1% (w/v) chitosan with 2% (w/v) NaHCO3 and 1% (w/v) bioactive glass nanoparticles (CIFI-BG) possessed the most sustained drug release profile which extended over four months with low burst release effect compared to the same formulation lacking bioactive glass nanoparticles (CIFI). Selected formulations were tested for their ability to enhance bone regeneration in induced puncture in rate tibia. Results declared that these formulations were able to enhance bone regeneration after 12 weeks in comparison to the untreated tibial punctures and that containing bioactive glass could be considered as novel approach for treatment of serious bone injuries which require long term treatment and internal mechanical bone support during healing.
Asunto(s)
Conservadores de la Densidad Ósea/síntesis química , Quitosano/síntesis química , Composición de Medicamentos/métodos , Nanopartículas/química , Clorhidrato de Raloxifeno/síntesis química , Tibia/efectos de los fármacos , Animales , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/metabolismo , Regeneración Ósea/efectos de los fármacos , Regeneración Ósea/fisiología , Quitosano/administración & dosificación , Quitosano/metabolismo , Modelos Animales de Enfermedad , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Implantes de Medicamentos/administración & dosificación , Implantes de Medicamentos/síntesis química , Implantes de Medicamentos/metabolismo , Vidrio/química , Masculino , Nanopartículas/administración & dosificación , Nanopartículas/metabolismo , Clorhidrato de Raloxifeno/administración & dosificación , Clorhidrato de Raloxifeno/metabolismo , Ratas , Ratas Sprague-Dawley , Tibia/lesiones , Tibia/metabolismo , Resultado del TratamientoRESUMEN
Bone injury is very serious in elder people or osteoporotic patients. In-situ forming implants (IFI) for bone rebuilding are usually poly-lactic-co-glycolic acid (PLGA)-based, which have a burst release effect. This study aimed to prepare novel liquid lipid-based PLGA-IFI loaded with raloxifene hydrochloride for prolonged non-surgical treatment of bone injuries by applying solvent-induced phase inversion technique. Labrasol® and Maisine® were added to the selected IFI forming long lasting lipid-based IFI (LLL-IFI). The formulations were characterized by analysing their in-vitro drug release, solidification time, injectability, rheological properties, and DSC in addition to their morphological properties. Results revealed that the LLL-IFI composed of 10%w/v PLGA with a lactide to glycolide ratio of 75:25 with ester terminal and 10% Maisine® possessed the most sustained drug release and lowest burst effect, as well as delayed pore formation compared to its counterpart lacking Maisine®. The selected LLL-IFI and PLGA-IFI formulations were tested for their capability to enhance bone regeneration in bone injuries induced in rats. Both formulations succeeded in healing the bones completely with the superiority of LLL-IFI in the formation of well-organized bone structures lacking fibrous tissues. The results suggest that LLL-IFI and PLGA-IFI are innovative approaches for treating critical and non-critical sized bone injuries.
Asunto(s)
Conservadores de la Densidad Ósea/administración & dosificación , Portadores de Fármacos/química , Implantes de Medicamentos/administración & dosificación , Fracturas Osteoporóticas/tratamiento farmacológico , Clorhidrato de Raloxifeno/administración & dosificación , Animales , Conservadores de la Densidad Ósea/farmacocinética , Huesos/efectos de los fármacos , Huesos/lesiones , Química Farmacéutica , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Implantes de Medicamentos/farmacocinética , Liberación de Fármacos , Humanos , Inyecciones Intralesiones , Masculino , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Porosidad , Clorhidrato de Raloxifeno/farmacocinética , Ratas , Propiedades de SuperficieRESUMEN
Two groups of fluconazole mucoadhesive buccal discs were prepared: (a) Fluconazole buccal discs prepared by direct compression containing bioadhesive polymers, namely, Carbopol 974p (Cp), sodium carboxymethyl cellulose (SCMC), or sodium alginate (SALG) in combination with hydroxypropyl methylcellulose (HPMC) or hydroxyethyl cellulose (HEC). (b) Fluconazole buccal discs prepared by freeze drying containing different polymer combinations (SCMC/HPMC, Cp/HPMC, SALG/HPMC, and chitosan/SALG). The prepared discs were evaluated by investigating their release pattern, swelling capacity, mucoadhesion properties, and in vitro adhesion time. In vivo evaluation of the buccal disc and in vivo residence times were also performed. Fluconazole salivary concentration after application of fluconazole buccal systems to four healthy volunteers was determined using microbiological assay and high-performance liquid chromatography. SCMC/HPMC buccal disc prepared by direct compression could be considered comparatively superior mucoadhesive disc regarding its in vitro adhesion time, in vivo residence time, and in vitro/in vivo release rates of the drug. Determination of the amount of drug released in saliva after application of the selected fluconazole disc confirmed the ability of the disc to deliver the drug over a period of approximately 5 h and to reduce side effects and possibility of drug interaction encountered during systemic therapy of fluconazole, which would be beneficial in the case of oral candidiasis.