Because of the patient compliance and the therapeutic efficacy, oral delivery of hydrophobic drug, anticancer drug and biomolecule has drawn lots attention recently, especially colon targeted delivery due to the neutral condition, high microorganisam concentration and long transition time though the colon. Stimuli-responsive hydrogel and nanoparticles show great potential for oral drug delivery owing to the pH and microorganism population changing along the gastrointestinal tract. Polymerization of microemulsions is a reliable, conveniently one-pot, economic, eco-friendly, easy to scale up in industry method to prepare nanostructured hydrogels or particles. And polymerization of hydrogels from bicontinuous microemulsions has heretofore rarely been studied.
In this research, a series of nanoporous, pH-responsive and microorganism-responsive hydrogels were polymerized from bicontinuous microemulsion made of drugs, acrylic acid (AA), 2-hydroxyethyl methacrylate (HEMA), and methyl methacrylate (MMA), polymer surfactant and polysaccharide coemulsifier aqueous solution. The surfactants were choosen from Pluronic® poly(ethylene glycol)-poly(propylene glycol)-poly(ethylene glycol) (PEO-PPO-PEO) or synthesized poly(¿-caprolactone)-block-poly(acrylic acid) (PCL-PAA). It was studied the polymerization of microemulsions with additional coemulsifier of natural sodium alginate, pectin and gum Arabic. All the components of the hydrogel are FDA approved for oral drug delivery. After
polymerization, the monomers in oil phase were turned into a PHEMA-PAA-PMMA hydrogel network and the drugs were encapsulated in polymer surfactant micelles distributed in the matrix of hydrogel. Guided by ternary phase diagrams, conductivity and viscosity tests, microemulsion precursors containing 80wt.% to 90wt.% of surfactant solutions with up to 2wt.% polysaccharide emulsifier and 10wt.% to 20wt.% of acrylate monomers were identified as bicontinuous microemulsions. Hydrogels were polymerized from the bicontinuous microemulsions with pore size distribution from up to 40 nm deduced from the freezing point depression of water encapsulated tested by differential scanning calorimetry. Then PAA-PMMA nanoparticles were polymerized from O/W microemulsions with more than 90wt.% surfactant solution. Due to droplet coalescence during polymerization, these particles had larger size about 35nm to 80nm than O/W droplet size up to 10 nm measured by dynamic light scattering.
Generally drug loading capability was determined by drug’s solubility in microemulsion. The in situ drug loading in precursor was reliable, and higher and more uniform than the post drug loading. This in-situ loading process can fabricate ideal hydrogel for long time, slow drug release without burst release. Moreover, ß- galactosidase with higher activity was released from the polymerized microemulsion initiated by visible light, compared with the enzyme released from the thermal-polymerized hydrogel at 55ºC. Due to the protonation and deprotonation of carboxylic acid moieties polymer chain, the PAA-PHEMA-PMMA hydrogel contracted at pH 2.2 and swelled at pH >4.5 to as high as 5 fold of original weight. Rhodamine B released at pH >4.5 was up to 10 times of the drug released at pH<4.5 in the simulated GI tract. Moreover, the on/off switch swelling behavior provides the hydrogel with the potential to control drug delivery.
The ternary phase diagram of microemulsion precursors, the pore size distribution and the swelling property of the hydrogels, the drug loading capability and the drug release profiles were influenced by AA/HEMA/MMA monomer composition, fraction of aqurous phase, polymer surfactant, polysaccharide emulsifier, and crosslinker fraction in the precursor. PEO-PPO-PEO surfactant with larger molecular weight and higher hydrophilic-lipophilic balance (HLB), polysaccharide with smaller molecular weight and higher emulsification ability, and higher percentage of oil phase in precursor were helpful to form hydrogels with larger hydrophobic drug loading capability and smaller pores for slower release of drugs. The optimum monomer composition AA/HEMA/MMA 1.5/1.5/1, and larger fraction of aqueous phase (90wt.%) lead to the formation of hydrogels with higher swelling ratio at pH>4.5.
Based on Peppas’ power law equation, the hydrogels followed the diffusion-controlled mechanism for the release of citric acid, ß-galactosidase and fluorouracil (5-FU) from the PAA-PHEMA-PMMA hydrogel polymerized from bicontinuous microemulsions. However, the Rhodamine B release from the same hydrogel presented a Case-II (zero order) transport (swelling-control). The release mechanism was determined by drug-hydrogel interaction, drug solubility and drug molecular volume in hydrogel. Moreover, polymerized microemulsion with 11wt.% pectin and 26wt.% PEO-PPO-PEO revealed a complete degradation of pectin and diffusion of surfactant out of the hydrogel in simulated GI tract with 2 U/ml pectinase at pH 7.4.
In summery, this research verified that polymerized microemulsion with polysaccharide emulsifier can be an effective pH- and microorganism-responsive vehicle with large loading capability and controllable drug release for colon targeted oral drug delivery, .especially for hydrophibic, anticancer and bioactive drugs.