Size Controlled Fabrication of Starch Acetate Nanoparticles and Assessment of their Potential Applications as Hydrophobic Drug Carriers
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Date
2019-03
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Addis Abeba University
Abstract
Size Controlled Fabrication of Starch Acetate Nanoparticles and Assessment of their
Potential Applications as Hydrophobic Drug Carriers
Getahun Paulos,
Addis Ababa University, 2019
Over the past few decades, there has been considerable interest in developing biodegradable
polymer-based nanoparticles (NPs) to effectively deliver a drug to a target site. Polymeric
materials used for preparing NPs for drug delivery must be biocompatible and preferably
biodegradable. Starch has been a focus of increasing attention in recent years for the design and
engineering of novel nanoparticulate drug delivery systems due to its desirable attributes
including plentiful availability, renewability, biocompatibility, biodegradability, nontoxicity and
ease of modification. The objectives of this study were to fabricate NPs from acetylated starches
having particle size less than 200 nm with minimum polydispersity index (PDI); to investigate if
the origin of starch has effect on the particle size and PDI of starch acetate (SA) NPs; to
investigate the potential applications of SA as nano drug carrier with respect to drug loading
(DL) capacity, encapsulation efficiency (EE) and release profile; and to determine the influence
of solubility and partition coefficient of different drugs on the characterstics of starch-based NPs.
To meet these objectives, acetylated starch was first synthesized by reacting native (cassava,
dioscorea, enset and maize) starches with acetic anhydride (AA) in the presence of sodium
hydroxide as a catalyst. Starch acetate nanoparticles (SANPs) were then fabricated via
spontaneous emulsification solvent evaporation method (using, chloroform, dichloromethane or
ethyl acetate; surfactants - Pluronic® F68, Pluronic® F127, Polyvinyl Alcohol (PVA) or
Tween® 80) and nanoprecipitation method (using Pluronic® F127). A systematic investigation
of independent variables revealed that solvent type, surfactant type and concentration, and
homogenization speed and time have significant influence on the size and PDI of SANPs. Hence,
response surface methodology (RSM) based on central composite design (CCD) was employed
to fabricate the desired SANPs (particle size less than 200 nm and PDI < 0.2) under optimized
condition. 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,
respectively, whereas, the experimentally determined responses were found to be 96.37 nm
1.208 nm and 0.131 0.021, respectively using emulsification solvent evaporation method. The
predicted optimum responses and experimentally determined responses obtained under optimal
fabrication conditions of independent variables (consisting of ethyl acetate, 1.51% of Pluronic®
F127, homogenization speed of~15,000 rpm and homogenization time of ~16 min) were
therefore found to be in reasonable agreement. Hence, judicious selection of solvent system and
surfactant as well as optimizing formulation and process variables is crucial in order to fabricate
the desired NPs. Based on the optimized conditions for fabrication of NPs, comparative study
was conducted to determine if the origin of starch has effect on particle size and PDI of SANPs.
The size and PDI of SANPs fabricated by emulsification solvent evaporation method were found
to be 94.48 nm 1.622, 0.107 0.024 (cassava), 90.27 nm 4.257, 0.133 0.031 (dioscorea),
98.74 nm 2.975, 0.176 0.011 (enset) and 104.61nm 2.766, 0.076 0.001 (maize),
respectively. SANPs fabricated by nanoprecipitation method were found to be 211.52 nm 7.42,
0.356 0.016 (cassava), 201.74 nm 9.53, 0.243 0.051 (dioscorea), 207.63 nm 5.75, 0.283
0.035 (enset) and 216.691nm 6.80, 0.203 0.027 (maize), respectively. The size and PDI of
cassava SANPs fabricated either by emulsification solvent evaporation or by nanoprecipitation
methods were significantly different from those NPs obtained from dioscorea, enset or maize
SAs (p ˂ 0.05). Similar differences were also observed among the NPs of dioscorea, enset and
maize SAs, indicating the origin of starch has significant effect on fabrication of SANPs. Based
on ICH guideline, SANPs stored for 3 months at different storage conditions (5°C ± 3°C, 25°C ±
2°C/60% ± 5% RH and 40°C ± 2°C/75% ± 5% RH) remained stable. SANPs prepared from
various SAs with different degrees of substitution (DS) were loaded with ibuprofen or oat
ceramides (CERs) and their properties, namely, size, PDI, DL, EE, release profiles were studied.
Like unloaded SANPs, ibuprofen or oat CERs loaded SANPs were also fabricated with desired
particle size (< 200 nm) and PDI (< 0.2). The DL and EE of SANPs increased with an increase in
the DS. The average DL of ibuprofen and oat CERs loaded SANPs increased from 9.3 to 26.6%
and 8.8 to 21.2%, respectively as DS of SAs increased from low (0.91) to high (2.74). Similarly
EEs of ibuprofen and oat CERs increased from 44.7 to 78.3% and 2.2 to 85.2%, respectively. In
vitro drug release of ibuprofen was sustained over 8 h of study period. Drug release profile of
SANPs followed Higuchi Model. In vitro a comparative artificial membrane penetration study,
the release and penetration of oat CERs from microemulsion (ME) was higher than from SANPs.
Over 90% of oat CERs incorporated in ME, and 59-63% oat CERs in the SANPs were released
and penetrated into multilayer membrane system after 60 min. Thus, compared to ME, SANPs
retarded the release of oat CERs into the artificial membrane. Hence, this study provides insight
into the potential applications of SANPs as sustained release nano drug carrier. Finally, the
effects of solubility and partition coefficient of different model drugs based on Biopharmaceutics
Classification System (BCS) Class II (ibuprofen), BCS Class III (acyclovir) and BCS Class IV
(furosemide) on DL, EE and release profile of SANPs were investigated. The results showed that
the DL and EE of ibuprofen and furosemide-loaded SANPs increased consistently with an
increase in the DS of SA. On the contrary, DL and EE of acyclovir-loaded NPs decreased as DS
of SA increased. Due to their poor solubility and high partition coefficient, the EEs of ibuprofen
(77.9%) and furosemide (80.5%) in SANPs fabricated from SA with high DS were much greater
than that of acyclovir (50.9%). Furthermore, as DS of SA increased, the cumulative release of
ibuprofen from SANPs was retarded whereas the release of acyclovir was enhanced. On the other
hand, furosemide, the most lipophilic drug of all, exhibited the lowest extent of release over the
study period. Hence, along with the hydrophobic nature of SA, the DL, EE and drug release
profile from SANPs were dependent on the solubility and partition coefficient of the
incorporated drug molecule. In conclusion, the favourable particle size, PDI, DL and EE with
sustained drug release profile suggest that SANPs could be regarded as promising carriers in
nano drug delivery systems.
Description
Keywords
Acetylated starch, Central composite design, Drug loading capacity, Emulsification solvent evaporation, Encapsulation efficiency, Nanoprecipitation, Particle size, Polydispersity index, Release profile, Response surface methodology, Starch acetate nanoparticles