| As we know, porous starch (PS) is a novel modified starch which has abundantmicro-sized pores from the surface of starch granules extending to the center. Porous starchhas a large relative surface areas. It has been widely used as an adsorbent in the field ofmedicine, food, agriculture and others due to its large specific surface area and adsorptioncapacity. Therefore, the microporous starch can be used as an excellent drug carrier toabsorb drugs. However, due to its poor mucoadhesive ability, natural porous starch could berapidly cleared by the respiratory system, resulting low bioavailability of drugs. Toovercome these shortcomings, modified porous starch has been developed to prolong theresidence time of the nasal drug. Previous research results have been shown that disulphidebonds between thiolated polymers and cysteine-rich subdomains of mucus glycoproteinscould enhance mucoadhesive properties of thiomers.In this study, to further improve its mucoadhesive characteristics, porous starch wasmodified through esterification using S-Acetyl mercapto succinic anhydride (SAMSA).The aim of our study was to synthesize and evaluate the new mucoadhesive materials ofS-Acetyl mercapto succinic porous starch (SAMSA-PS), to selecte propranolol(PRO) asmodel drug to prepare SAMSA-porous starch-PRO mucoadhesive microspheres, and tostudy its mucoadhesive properties, drug loading and release characteristics. Besides, theciliotoxicities was also evaluated.Methods1. Synthesis of S-Acetyl mercapto succinic porous starch (SAMSA-PS) and itscharacterizationSAMSA-porous starch was prepared by esterification of porous starch with S-Acetylmercapto succinic anhydride. By the orthogonal designs，the factors affecting the synthesisyields，such as the proportion of SAMSA, anhydrous sodium carbonate and water，were studied. Its morphology and structure was characterized by IR spectrum, specific surfacearea and pore size analysis, X-ray diffraction (XRD), scanning electron microscopy (SEM);the degrees of substitution (DS) and oil absorption rate were also measured.2. In vitro mucoadhesion test of SAMSA-PSThe adhesion of SAMSA-PS was determined with gastric mucin from porcine (PGM).3. In vivo ciliary ciliotoxicity and mucoadhesion test of SAMSA-PSThe lasting time of ciliary movement was recorded with in situ toad palate model toevaluate the ciliary ciliotoxicity of SAMSA-PS. To investigate its mucoadhesive properties,the mucociliary transport rate across a toad palate was recorded.4. Preparation of propranolol-carrying S-Acetyl mercapto succinic porous starchmicrosphere (SAMSA-PS-PRO) and its characterizationPRO-SAMSA porous starch microsphere was prepared by absorption and character-ized by IR spectrum, differential scanning calorimetry (DSC), X-ray diffraction (XRPD)and scanning electron microscopy (SEM).5. In vivo ciliary ciliotoxicity and mucoadhesion test of SAMSA-PS-PROThe lasting time of ciliary movement was recorded with in situ toad palate model toevaluate the ciliary ciliotoxicity of SAMSA-PS-PRO. To investigate its mucoadhesiveproperties, the mucociliary transport rate was recorded across a toad palate.6. In vitro release testsSAMSA-PS-PRO was placed into PBS which was simulated nasal condition. Thedrug release behaviours of SAMSA-PS-PRO in different medium were evaluated:1) PBS(pH6.5) of nasal environment.2) PBS (pH7.4) of intestinal juice environment.3) PBS(pH1.2) of gastric juice environment.4) aqueous solution. PRO concentration in releasebuffer were assayed by UV spectrometer at290nm.7. Pharmacokinetic studiesThe pharmacokinetic study was performed in rabbit. Compared with PRO table thatwere orally administered via gastric gavage, SAMSA-PS-PRO was administrated by nasalroute. Blood samples were collected at specific time points after drug administration.Plasma was obtained after15min of centrifugation at3000rpm. The PRO concentration atevery time pointin the plasmas was quantified by fluorescence spectrophotometer.Results 1. Optimum conditions for SAMSA-porous starch preparation were as follows:concentration of SAMSA8%, anhydrous sodium carbonate4%and water30%of dry basisof porous starch. The esterification of SAMSA-porous starch was confirmed by IRspectrum. The results of specific surface area and pore size analysis and SEM showed thatthe porous structurealmost remaind in the product. X-ray diffraction results indicated itsapparent surface change, but no crystalline change. Under these conditions, the DS ofproduct reached to1.24%, oil absorption rate was32.4%.2. The adhesion of SAMSA-PS was higher than porous starch in PBS (pH6.5) of nasalenvironment.3. Ciliotoxicity of SAMSA-PS is equivalent to porous starch, and its mucoadhesivecapability was considerably improved.4. The maximum drug-loading was13.91%when the PRO/carrier was1:2. IRspectrum, DSC, X-ray diffraction and SEM were performed to confirm the characteristicsof PRO-SAMSA porous starch microsphere. The PRO’s ciliotoxicity was reduced distinctlyand mucoadhesive capacity was simutaneously increased after the formation ofPRO-SAMSA porous starch microsphere.5. Fast release of SAMSA-PS-PRO and PRO was achieved in PBS of pH6.5. In vitrorelease tests in media simulating nasal conditions showed that sustained release ofSAMSA-PS-PRO. In addition, with the decrease of pH, the accumulative release ratetended to decrease. The results of pharmacokinetic study implied that the bioavailability ofSAMSA-PS-PRO which was used for intranasal administration was higher than PRO tablewhich was administrated orally. The area under the plasma concentration-time curve (AUC)of intranasal administration was higher than oral administration.Conclusions1. In this paper, the method of esterification was developed to prepare SAMSA-porousstarch. The modified starch not only remained porous structure of porous starch whichcould “hide” drug molecule completely to stabilize and slowly release drugs, but it alsohave high oil absorption. Moreover, ciliotoxicity of SAMSA-PS is equivalent to porousstarch, and its mucoadhesive capability was considerably improved2. PRO-SAMSA porous starch microsphere was prepared by absorption andcharacterized by IR spectrum, differential scanning calorimetry (DSC), X-ray diffraction (XRPD) and scanning electron microscopy (SEM). The maximum drug-loading was13.91%when the PRO/carrier was1:2. IR spectrum, DSC, X-ray diffraction and SEM wereperformed to confirm the characteristics of PRO-SAMSA porous starch microsphere. ThePRO’s ciliotoxicity was reduced distinctly and mucoadhesive capacity was simutaneouslyincreased after the formation of PRO-SAMSA porous starch microsphere.3. Compared to PRO which rapidly released in PBS of pH6.5, PRO in the SAMSA-PScan be slowly released. In vitro release test of SAMSA-PS-PRO indicated that the profilecurve of microspheres was fit for Weibull model. Pharmacokinetic study showed thatSAMSA-PS-PRO could obviously prolong residence time in administration area, so as toimprove drug bioavailability.4. In conclusion, SAMSA-PS could be used as a promising drug carrier formucoadhesive drug delivery systems because of its low toxicities and suitablemucoadhesion. It is expected to become a novel drug carrier materials in the field ofmucosa drug delivery system. |
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