Studies On Microemulsion-based Gels And Their Applications As Drug Delivery Systems

Recently,the stability and bioavailability of the drug delivery and the controlled drug release have attracted more and more attention.Microemulsion-based gels (MBGs)not only have the characteristics of microemulsion but also the characteristics of gel.MBGs could improve the stability and the bioavailability of the drug and could also control the release of some drugs due to the higher viscosity.In the present study,MBGs are characterized by several techniques including rheological measurements and electron microscope.The formation conditions of MBGs,viscoelastic properties and microstructures of the systems are systematically investigated.Moreover.the phase behaviors of Pluronic copolymer in ionic liquid (bmimBF₄)are investigated.Three main experimental researches are included.In the first part.gelatin-containing microemulsion-based organogels(MBGs) systems composed of isopropyl myristate(IPM)/AOT/Tween85/H₂O.both with and without a model drug(Butenafine hydrochloride),are investigated by rheological measurements and environmental scanning electron microscope(ESEM).Then the effects of gelatin and butenafine hydrochloride on the rheological properties and microstructures of the MBGs are investigated generally.It is revealed that there exits an optimal gelation concentration of gelatin,homogeneous and compact MBGs can be formed when the concentration of gelatin in the selected W/O microemulsion sample is in the range of 7.0 to 12.0 wt%.Moreover.the rheological properties such as the yield stresses(σ_y).storage and loss moduli(G′.G″)of the samples increase with increasing the concentration of gelatin.Accordingly.the ESEM photographs also reveal that the network structures of MBGs are formed when the concentration of gelatin is between 7.0 and 12.0 wt%.and the network structures become more compact as the concentration of gelatin is increased.At the concentration of gelatin lower than 7.0 wt%,the systems are sols.At the concentration of gelatin higher than 12.0 wt%.the systems are two-phases containing jelly-like phase and solid particles of gelatin.The addition of butenafine hydrochloride to the MBGs could weaken the interconnected network structures of the system at a certain extent.Namely,when the concentration of butenafine hydrochloride is lower than 0.5 wt%,the network structures of MBGs could be maintained perfectly.Consequently,the systems are potentially transdermal drug delivery vehicles.At the higher butenafine hydrochloride concentration(1.0 wt%),the effect of butenafine hydrochloride on the weaken network structures of MBGs is obvious,but the networks have not been destroyed completely.In the second part,temperature-sensitive microemulsion-based gels(MBGs)of three copolymers of different composition,F127(EO₉₉PO₆₇EO₉₉),F68(EO₇₉PO₃₀EO₇₉) and L64(EO₁₃PO₃₀EO₁₃),are formed in microemulsion systems composed of isopropyl myristate(IPM)/Span20/Tween20/H₂O,and the phase behaviors of the systems are investigated.For the same polymer,the gelation concentration of copolymer is much lower in MBGs than in hydrogels which indicates that there are hydrophobic interactions between copolymer and surfactant molecules,so the micelles easily pack and turn into gels.Temperature sweep measurements indicate that the type of microemulsion is important for the formation of MBG.The gelation can not form in B.C.microemulsion,but can form in O/W microemulsion and water. this suggests that the enough amount water is very important for forming copolymer micelles and the micelles are formed in the water phase of the O/W microemulsion. The gelation mechanism of MBGs is similar to that of hydrogels,both based on the micellization and aggregation of micelles.The melting temperatures of MBGs increase with increasing F127 or F68 concentration,while the MBGs formed by L64 are opposite.Moreover,when the concentration of L64 is more than 48 wt%,the systems are liquid at any temperature. In F127 and F68 systems,the results of fluorescent experiments suggest that pyrene is located in the core of the microemulsion droplet,and the major structure of the microemulsion is retained after formation MBGs,which is further proved by FF-TEM photographs.In L64 systems,some pyrene is located in the core of the microemulsion droplet,some is located in micelles of L64.and the structure of the microemulsion is destroyed at a considerable extent.There are very different phase behaviors between L64 with F127 or F68 systems,which is because that the hydrogen bonds between EO and H₂O are much less due to the shorter EO chains of L64,so hydrogen bonds force is weak.Moreover,the entanglement of EO chains is weakened due to the shorter EO chains.Therefore,the network structure is much looser.Furthermore,there are many free L64 macromolecules in the network structure,so there are some necklace-like structures formed by L64 macromolecules and the surfactants(Span20.Tween20). When the concentration of L64 reaches a certain level(＞48 wt%),L64 macromolecules and water molecules are miscible,and L64 exists as monomer.so the MBGs are not formed at any temperature.Chloramphenicol has little effect on the rheological properties of the MBGs formed by F127 and F68,and the network structures of MBGs are still retained. While the network structures of MBGs formed by L64 are destroyed at a certain extent after the addition of chloramphenicol into the systems.The continued existence of microemulsion droplets plays an important role in enhancing the solubility and stability of oil-soluble drugs.The results of controlled release experiments suggest that MBG shows sustained release properties.Moreover.due to its temperature-sensitivity.MBG is superior to other drug carriers,e.g.multiple administrations are much easier to achieve at room temperature.Furthermore.in these systems,the formulations have low toxicity and are approved for pharmaceutical use. so the MBG systems have potential as drug delivery systems.In the last part,lyotropic liquid crystalline(LLC)made of nonionic block copolymer L64 and ionic liquid(ILs)bmimBF₄(1-n-butyl-3-methyl imidazolium tetrafluoroborate)is constructed and characterized by POM and SAXS measurements. with comparison of component and temperature effects.Moreover.the formation mechanism is discussed.POM and SAXS measurements indicate that lamellar phase can be obtained with increasing L64 concentration at a certain temperature range.The various interactions between PEO-bmimBF₄(hydrogen bonding)and PPO-bmimBF₄(hydrophobic interaction)play the key role in LLC formation.The results of SAXS suggest that the lattice spacing(d)decrease with increasing L64 concentration.The effect of temperature on the lamellar phase is investigated.The lattice spacing increases with increasing temperature.This change can be attributed to swelling of polar and apolar microdomains.At certain temperature range,the lamellar region shifts to lower polymer concentrations and the lamellar phase becomes more ordered with increasing temperature.However,the birefringent phenomenon of the lamellar phase disappears when the temperature reaches a certain level,which is attributed to the breakage of hydrogen bonds between bmimBF₄ and EO chains.So the long-range order of LLC is decreased.The effect of different polarity molecules on the lamellar phase is also investigated.With addition water,water molecules insert into the polar microdomains of LLC,and form hydrogen bonds with the oxygen atom of EO groups.The static actions which occur between the cation moiety(-N⁺)of IL and the lone pairs on oxygen atom of EO groups are the key driving force for the formation of LLC.The addition of water molecules makes the static actions weaken and the long-range order of LLC decrease.However,after addition a little apolar molecules,apolar molecules insert into hydrophobic microdomains(PPO chains),which makes PPO chains extend at certain degree,and the order of LLC increases.Therefore,the systems will supply favorable conditions for enhancing the solubility of oil-soluble molecules,which further expands application prospects of the systems.