Size Controlled Fabrication Of Starch Acetate Nanoparticles And Assessment Of Their Potential Applications As Hydrophobic Drug Carriers

Size Controlled Fabrication of Starch Acetate Nanoparticles and Assessment of theirrnPotential Applications as Hydrophobic Drug CarriersrnGetahun Paulos,rnAddis Ababa University, 2019rnrnOver the past few decades, there has been considerable interest in developing biodegradablernpolymer-based nanoparticles (NPs) to effectively deliver a drug to a target site. Polymericrnmaterials used for preparing NPs for drug delivery must be biocompatible and preferablyrnbiodegradable. Starch has been a focus of increasing attention in recent years for the design andrnengineering of novel nanoparticulate drug delivery systems due to its desirable attributesrnincluding plentiful availability, renewability, biocompatibility, biodegradability, nontoxicity andrnease of modification. The objectives of this study were to fabricate NPs from acetylated starchesrnhaving particle size less than 200 nm with minimum polydispersity index (PDI); to investigate ifrnthe origin of starch has effect on the particle size and PDI of starch acetate (SA) NPs; torninvestigate the potential applications of SA as nano drug carrier with respect to drug loadingrn(DL) capacity, encapsulation efficiency (EE) and release profile; and to determine the influencernof solubility and partition coefficient of different drugs on the characterstics of starch-based NPs.rnTo meet these objectives, acetylated starch was first synthesized by reacting native (cassava,rndioscorea, enset and maize) starches with acetic anhydride (AA) in the presence of sodiumrnhydroxide as a catalyst. Starch acetate nanoparticles (SANPs) were then fabricated viarnspontaneous emulsification solvent evaporation method (using, chloroform, dichloromethane orrnethyl acetate; surfactants - Pluronic® F68, Pluronic® F127, Polyvinyl Alcohol (PVA) orrnTween® 80) and nanoprecipitation method (using Pluronic® F127). A systematic investigationrnof independent variables revealed that solvent type, surfactant type and concentration, andrnhomogenization speed and time have significant influence on the size and PDI of SANPs. Hence,rnresponse surface methodology (RSM) based on central composite design (CCD) was employedrnto fabricate the desired SANPs (particle size less than 200 nm and PDI < 0.2) under optimizedrncondition. According to RSM based on CCD, the predicted optimum responses (particle size and PDI) of SANPs of cassava starch were found to be 94.48  1.622 nm and 0.107  0.024,rnrespectively, whereas, the experimentally determined responses were found to be 96.37 nm rn1.208 nm and 0.131  0.021, respectively using emulsification solvent evaporation method. The rnpredicted optimum responses and experimentally determined responses obtained under optimalrnfabrication conditions of independent variables (consisting of ethyl acetate, 1.51% of Pluronic®rnF127, homogenization speed of~15,000 rpm and homogenization time of ~16 min) wererntherefore found to be in reasonable agreement. Hence, judicious selection of solvent system andrnsurfactant as well as optimizing formulation and process variables is crucial in order to fabricaternthe desired NPs. Based on the optimized conditions for fabrication of NPs, comparative studyrnwas conducted to determine if the origin of starch has effect on particle size and PDI of SANPs.rnThe size and PDI of SANPs fabricated by emulsification solvent evaporation method were found rnto be 94.48 nm  1.622, 0.107  0.024 (cassava), 90.27 nm  4.257, 0.133  0.031 (dioscorea),rn98.74 nm  2.975, 0.176  0.011 (enset) and 104.61nm  2.766, 0.076  0.001 (maize),rnrespectively. SANPs fabricated by nanoprecipitation method were found to be 211.52 nm  7.42,rn0.356  0.016 (cassava), 201.74 nm  9.53, 0.243  0.051 (dioscorea), 207.63 nm  5.75, 0.283 rn0.035 (enset) and 216.691nm  6.80, 0.203  0.027 (maize), respectively. The size and PDI of rncassava SANPs fabricated either by emulsification solvent evaporation or by nanoprecipitationrnmethods were significantly different from those NPs obtained from dioscorea, enset or maizernSAs (p ˂ 0.05). Similar differences were also observed among the NPs of dioscorea, enset andrnmaize SAs, indicating the origin of starch has significant effect on fabrication of SANPs. Basedrnon ICH guideline, SANPs stored for 3 months at different storage conditions (5°C ± 3°C, 25°C ±rn2°C/60% ± 5% RH and 40°C ± 2°C/75% ± 5% RH) remained stable. SANPs prepared fromrnvarious SAs with different degrees of substitution (DS) were loaded with ibuprofen or oatrnceramides (CERs) and their properties, namely, size, PDI, DL, EE, release profiles were studied.rnLike unloaded SANPs, ibuprofen or oat CERs loaded SANPs were also fabricated with desiredrnparticle size (< 200 nm) and PDI (< 0.2). The DL and EE of SANPs increased with an increase inrnthe DS. The average DL of ibuprofen and oat CERs loaded SANPs increased from 9.3 to 26.6%rnand 8.8 to 21.2%, respectively as DS of SAs increased from low (0.91) to high (2.74). SimilarlyrnEEs of ibuprofen and oat CERs increased from 44.7 to 78.3% and 2.2 to 85.2%, respectively. Inrnvitro drug release of ibuprofen was sustained over 8 h of study period. Drug release profile ofrnSANPs followed Higuchi Model. In vitro a comparative artificial membrane penetration study, rnthe release and penetration of oat CERs from microemulsion (ME) was higher than from SANPs.rnOver 90% of oat CERs incorporated in ME, and 59-63% oat CERs in the SANPs were releasedrnand penetrated into multilayer membrane system after 60 min. Thus, compared to ME, SANPsrnretarded the release of oat CERs into the artificial membrane. Hence, this study provides insightrninto the potential applications of SANPs as sustained release nano drug carrier. Finally, therneffects of solubility and partition coefficient of different model drugs based on BiopharmaceuticsrnClassification System (BCS) Class II (ibuprofen), BCS Class III (acyclovir) and BCS Class IVrn(furosemide) on DL, EE and release profile of SANPs were investigated. The results showed thatrnthe DL and EE of ibuprofen and furosemide-loaded SANPs increased consistently with anrnincrease in the DS of SA. On the contrary, DL and EE of acyclovir-loaded NPs decreased as DSrnof SA increased. Due to their poor solubility and high partition coefficient, the EEs of ibuprofenrn(77.9%) and furosemide (80.5%) in SANPs fabricated from SA with high DS were much greaterrnthan that of acyclovir (50.9%). Furthermore, as DS of SA increased, the cumulative release ofrnibuprofen from SANPs was retarded whereas the release of acyclovir was enhanced. On the otherrnhand, furosemide, the most lipophilic drug of all, exhibited the lowest extent of release over thernstudy period. Hence, along with the hydrophobic nature of SA, the DL, EE and drug releasernprofile from SANPs were dependent on the solubility and partition coefficient of thernincorporated drug molecule. In conclusion, the favourable particle size, PDI, DL and EE withrnsustained drug release profile suggest that SANPs could be regarded as promising carriers inrnnano drug delivery systems.

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