PH Sensitive Hydrogels Modified With Amphiphilic PEG Macromonomer For Loading And Controlled Release Of Poorly Water Soluble Drugs

pH sensitive hydrogels such as poly acrylic acid(PAA) were considered as good candidates for the oral delivery system because they collapsed in the acidic gastric condition and swelled at high pH of intestinal environment, thus it can protect the drug from enzymatic degradation in the harsh environment of stomach and wash out effect in gastrointestinal (GI) tract. While poorly water-soluble drugs with low solubility in water always have lower bioavailability to limite their application. Therefore, the target of our research was to prepare pH sensitive hydrogels which remarkably improve the loading amount and release behavior of poorly water-soluble drugs. At the same time, the drug loading and release mechanism of these hydrogels was also studied. On this basis, we firstly synthesised a novel amphiphilic polyethyleneglycol (PEG) macromonomer, and used this macromonomer to modify the normal PAA hydrogels to prepare a novel pH sensitive hydrogels. Next, five poorly water-soluble drugs were chosen as model drug to study their loading and controlled release behavior. Moreover, their influence factors and the corresponding transport mechanism were comprehensively studied. The main contens and the results are as follows:1. For the fist time, a novel amphiphilic PEG macromonomer (PEGLA) was synthesized from ployoxyethylene lauryl alcohol (Brij 35) with acrylic acid (AA). The chemical structure of PEGLA was characterized with FT-IR and 1H-NMR. The critical micelle concentration (CMC) of PEGLA was 0.026 mmol/L determined with fluorescence excitation spectra of pyrene probe, which means the PEGLA could form micelle at lower concentration and then solubilize of poorly water-soluble drugs.2. The modified PAA hydrogels were synthesized by UV induced radical polymerization of amphiphilic PEG macromonomer PEGLA and PAA under water, designated as P(AA-co-PEGLA). In a typical procedure using ethylene glycol dimethacrylate (EGDMA) as crosslinker, the monomer mixture was diluted with pure water to 50 wt% and the photoinitiator 2-oxoglutaric acid was added of 1 wt% of the total monomers. The polymerization was induced by an UV light of 30 mW/cm2 for 15 min.3. Studied pH sensitive properties of hydrogels and swelling behavior in the poorly water-soluble drugs loading solvent. The results showed that when copolymerized with AA, the P(AA-co-PEGLA) hydrogel exhibits pH-sensitivity: collapse at low pH and swollen at high pH with a drastic volume change at pH about 5. Significantly, the swelling ratio of the P(AA-co-PEGLA) hydrogel is lower than 10 even at high pH. This seems due to the hydrophobic association formed by the hydrocarbon tail chains in PEGLA, which act as additional cross-linking in the P(AA-co-PEGLA) hydrogels. At low pH, the dipole attraction between the unionized carboxyl groups and hydrogen bonding between the carboxyl groups and ethylglycol groups in the PEGLA cause the P(AA-co-PEGLA) hydrogel to shrink to a lower q than that of the PEGLA homopolymer gel. At high pH, the hydrophobic association between the hydrocarbon tails in PEGLA restricts the swelling of the P(AA-co-PEGLA) hydrogel to a high degree. The hydrogen bonding is dissociated due to the ionization of the AA groups at high pH, but the hydrophobic association still exists in the hydrogels at high pH as physical cross-linking to decrease the hydrogel mesh sizeξ, which limited hydrogel swelling behavior. The swelling behavior of hydrogel in drugs loading solvents were also studied. In drug loading solvent acetone and ethanol/water=60:40(vol ratio), the equilibrium swelling ratio qs of hydrogels were increased by incorporating the amphiphilic PEG macromonomer. So the drug molecular could diffuse easier to the hydrogels and improved the loading amount of poorly water-soluble drugs.4. Using three poorly water-soluble drugs Naproxen, Ibuprofen and Diclofenac sodium with aryl acid group in their molecular as model drug. Researched on the drug loading and controlled release behavior from the P(AA-co-PEGLA) hydrogels. The results indicated that PEGLA content in the hydrogel were the key point to determine the drug loading and release behavior. Increasing the PEGLA content in the hydrogel improved the loading amount of these drugs. When there is no PEGLA in the hydrogel, the loading amount of Naproxen, Ibuprofen and Diclofenac sodium were 5.93 mg/g, 4.78 mg/g and 3.96 mg/g, respectively. While with 60 mol% PEGLA content in the hydrogel, the loading amount of drugs improved to 24.25 mg/g, 21.06 mg/g and 18.19 mg/g, respectively. In vitro release of these drugs indicated that P(AA-co-PEGLA) hydrogel could protect the encapsulated drug from the erosion in stomach and release the drug in intestinal environment. No burst release was observed during the drug delivery and the drug released rate was blocked by increasing the PEGLA content in the hydrogel. Therefore, the P(AA-co-PEGLA) hydrogel is a good candidate for the oral drug delivery system for Naproxen, Ibuprofen and Diclofenac sodium. In order to elucidate the drug release mechanism, Higuchi, Zero-order and Rigter-Peppas models were adopted to analysis the first 60% of drug release data. Experimental data were analyzed by nonlinear least-square fitting (NLSF) to determine the model parameters. The Akaike Information Criterion (AIC) was used to distinguish the fitting correlation of different models, which was independent of the parameter number used in each model. Rigter-Peppas model indicated the best fitting to the experimental data. The n value of Naproxen was between 0.61 and 0.80, the n value of Ibuprofen was between 0.57 and 0.76, while the n value of Diclofenac sodium was between 0.66 and 0.77, represents the drug release from hydrogels following the anomalous transportation mechanism, that is both the Fickian diffusion and polymer chain relaxation contribute to the drug release. The n value did not vary with the hydrogel composition regularly, indicating that the drug transportation mechanism from these P(AA-co-PEGLA) hydrogels was independent of PEGLA content.5. Another two poorly water-soluble drugs Piroxicam and Acyclovir without aryl acid structure were chosen as model drugs and studied their drug loading and controlled release behaviors. The results elucidated that PEGLA content in the hydrogel also dominated drug loading and release behavior. The loading amount of Piroxicam and Acyclovir were remarkably increased by adding PEGLA content in the hydrogels. The encapsulated drug was protected from gastric condition and released in intestinal environment. Drug release rate could be adjusted by changing the PEGLA content in the hydrogels. However, the release rate of Piroxicam and Acyclovir were faster than drugs with aryl acid structure in their molecular. When with 60mol% PEGLA in the hydrogel, the t1/2 of Piroxicam was 205 min, the t1/2 of Acyclovir was only 48min. Drug release mechanism was elucidated using Higuchi, Zero-order and Rigter-Peppas models were adopted to analysis the first 60% of drug release data. Moreover, Weibull model was also used to fit the 100% of drug release data. Compared with Rigter-Peppas model, Weibull model had smaller AIC value indicated the best fitting to the experiment data. The b value of Piroxicam was between 0.88 and 0.79, while the b value of Acyclovir was between 0.76 and 0.79, represents the drug release from hydrogels also following the anomalous transportation mechanism.