Jovanka M. Filipović

Hydrogels of N-isopropylacrylamide copolymers with controlled release of a model protein

Temperature- and pH-sensitive hydrogels, based on N-isopropylacrylamide (NiPAAm) and itaconic acid (IA), were synthesized by free radical crosslinking copolymerization in the presence of lipase from Candida rugosa. The samples were characterized for their sensitivity to the changes of external conditions and the ability to control the release of a hydrophilic model protein, lipase. These hydrogels were highly responsive to temperature and pH, at constant ionic strength. Parameters, such as the crosslinking degree and non-ionic/ionic (NiPAAm/IA) ratio, were found to impact the hydrogel structure, mechanical properties, morphology and swelling kinetics at different pH and temperatures. The hydrogels demonstrated protein loading efficiency as high as 95 wt%. Release studies of a hydrophilic model protein at a physiological temperature of 37 degrees C were performed at different pH values. High dependence of lipase release kinetics on hydrogel structure and the environmental pH was found, showing generally low release rates, lower in acidic media (pH 2.20) and higher at higher pHs (6.80). Lipase activity was retained even after treatment conditions that would provoke denaturation of the enzyme if it was not protected in the gel. The obtained hydrogels were found suitable for releasing therapeutic proteins in a controlled manner at specific sites in gastrointestinal tract.

Sorption of zinc by novel pH-sensitive hydrogels based on chitosan, itaconic acid and methacrylic acid

Novel pH-sensitive hydrogels based on chitosan, itaconic acid and methacrylic acid were applied as adsorbents for the removal of Zn(2+) ions from aqueous solution. In batch tests, the influence of solution pH, contact time, initial metal ion concentration and temperature was examined. The sorption was found pH dependent, pH 5.5 being the optimum value. The adsorption process was well described by the pseudo-second order kinetic. The hydrogels were characterized by spectral (Fourier transform infrared-FTIR) and structural (SEM/EDX and atomic force microscopy-AFM) analyses. The surface topography changes were observed by atomic force microscopy, while the changes in surface composition were detected using phase imaging AFM. The negative values of free energy and enthalpy indicated that the adsorption is spontaneous and exothermic one. The best fitting isotherms were Langmuir and Redlich-Peterson and it was found that both linear and nonlinear methods were appropriate for obtaining the isotherm parameters. However, the increase of temperature leads to higher adsorption capacity, since swelling degree increased with temperature.

An Investigation into the Influence of Hydrogel Composition on Swelling Behavior and Drug Release from Poly(Acrylamide-co-Itaconic Acid) Hydrogels in Various Media

The hydrogels prepared by free radical copolymerization of acrylamide and itaconic acid were investigated with regard to their composition and crosslinking degree to find materials with satisfactory swelling and drug release properties. Samples were characterized by measuring the swelling behavior and in vitro release of paracetamol as a model drug in aqueous media with different pH values. The two-factor, three-level experimental design and response surface methodology were applied to statistically evaluate the influence of investigated factors.

The synthesis and characterization of poly(itaconic) acid

SummaryPoly(itaconic acid) (PIA) was obtained indirectly, by the hydrolysis of PIA esters and directly by the polymerization of itaconic acid in water or methanol at 30°C. The first method was not satisfactory but the second gave better results. The elemental composition of the synthetized samples deviated very little from the calculated values. Several crude polymers were fractionated in methanol/isopropanol and the fractions characterized by viscosity and light scattering. The statistically calculated LVN/MW relation, valid for the undissociated polymer, was treated according to the method of Stockmayer and Kurata, to calculate the unperturbed dimensions and to compare them with those of other polymers.

The polymerisation kinetics of lower dialkyl itaconates

SUMMARY: The free radical polymerisation kinetics of diethyl- (DEI), dipropyl- (DnPI), dibutyl- (DnBI), and dihexyl itaconate (DHI) in the bulk were studied in the temperature range from 50 to 70 C. The concentration of the initiator, 2,2 -azoisobutyronitrile (AIBN), was varied between 0.02 and 0.085 mol/dm 3 . The rate of polymerisation (Rp), degree of polymerisation (DP), overall polymerization rate constant (K), the ratio of the propagation and termination rate constants (kp/kt 1/2 ), as well as the chain transfer constant to monomer (CM) were determined. The values of Rp, K, and kp/kt 1/2 of the investigated monomers all increase with increasing size of the alkyl group in the ester substituent, whereas CM decreases when going from the dimethyl to the dihexyl ester. The values of CM are larger than the corresponding values for the alkyl esters of methacrylic acid.

The thermal degradation of some alkali metal salts of poly(itaconic acid)

The Li-, Na- and K salts of poly(itaconic acid) (PIA) were prepared by treating the polyacid with the corresponding aqueous hydroxide.The resulting polysalts were analyzed by elemental analysis, FTIR spectroscopy and thermogravimetry. The results indicate that the polysalts are thermally more stable than the parent PIA, they all degrade in a similar manner and somewhat more complexly than the poly(methacrylic acid) salts.

Controlled release of lipase from Candida rugosa loaded into hydrogels of N-isopropylacrylamide and itaconic acid

The series of poly(N-isopropylacrylamide-co-itaconic acid) hydrogels, with lipase from Candida rugosa as a model protein, were synthesized by free radical copolymerization. The composition of hydrogels was varied by monomers ratio, crosslinking agent concentration and amounts of lipase, which was loaded by in situ polymerization. All samples were characterized regarding morphology. The investigation of hydrogel swelling properties revealed their pH and temperature sensitive character. Protein loading efficiency, release profiles and the specific activity yield of the released lipase were also investigated as a function of hydrogel composition, protein content and pH, at the physiological temperature of 37 °C. Copolymers of N-isopropylacrylamide and itaconic acid presented high lipase loading efficiency. Another very important feature of these copolymers was that the protein release kinetic strongly depended on the pH value of the medium. The diffusion exponents values around 1 denoted that these hydrogel compositions could be adjusted to follow near zero-order kinetics. Namely, hydrogel formulations released low amounts of lipase at pH 2.20, but much higher released protein quantities were observed at pH 6.80 enabling these copolymers to be attractive candidates as site specific protein oral drug delivery systems.

Dilute solution properties of styrene/di-n-alkyl itaconate copolymers

SummarySolution properties of styrene/di-n-butyl itaconate (SDBI), styrene/di-n-hexyl (SDHI) and styrene/di-n-octyl itaconate (SDOI) copolymers from the entire range of copolymer compositions were investigated on series of fractions of uniform composition. Kuhn-Mark-Houwink-Sakurada (KMHS) constants were extrapolated to K⊖ and all results combined with those of styrene/dimethyl itaconate (SDMI) from a previous publication. The σ-parameters describing short range interactions deviate increasingly from the linear summation of parent homopolymer contributions.The excess unperturbed dimensions are correlated with parent homopolymer solubility parameters and discussed in terms of hetero-contacts in the copolymer chain.

pH-sensitive hydrogels based on (meth)acrylates and itaconic acid

Novel hydrogels based on 2-hydroxyethyl methacrylate (HEMA), itaconic acid (IA) and different poly (alkylene glycol) (meth)acrylates (PAGM) (P(HEMA/IA/PAGM)) were synthesized. We investigated the influence of different PAGM components, with acrylic or methacrylic acid residues in the main chain and ethylene glycol (EG) and/or propylene glycol (PG) units in pendant chains of varying length, on the nature and inherent properties of P(HEMA/IA/PAGM) copolymeric hydrogels. Swelling studies revealed pH sensitive behavior of P(HEMA/IA/PAGM) samples. Hydrogel structure and morphology were characterized by Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM), which confirmed their chemical structure and differences in pore size. The shear modulus values for P(HEMA/IA/PAGM) hydrogels were close to that of PHEMA, but slightly lower than the value for P(HEMA/IA). Cephalexin (CEX) drug release profiles from P(HEMA/IA/PAGM) samples showed a marked dependence on the PAGM component. The presence of IA also influenced the release rate of CEX, leading to a faster release when IA was combined with the more hydrophilic PAGM component. An in vitro assay of P(HEMA/IA/PAGM) cytotoxicity showed good cell viability. The results obtained indicate that P(HEMA/IA/PAGM) hydrogel properties were significantly dependent on the PAGM component, meaning that the type of side chains can be used to tune the characteristics of such biomaterials. These properties make P(HEMA/IA/PAGM) copolymeric hydrogels applicable in biomedical and biotechnological fields and controlled drug delivery.

The Thermal Degradation of Poly(dimethyl Itaconate-co-4-vinylpyridine)

Copolymers of dimethyl itaconate (DMI) and 4-vinylpyridine (4VP) were synthetized in toluene at 60°C with0.26 mol% of AIBN as initiator. Their compositions were determined by differential refractometry and by differential scanning calorimetry. The 4VP contents of the copolymer samples ranged between 7 and 75 mol%. The reactivity ratios calculated via the Fineman-Ross method were r1=0.24 (DMI) and r2=0.57 (4VP).The thermal degradations of these copolymers were studied. The results of thermogravimetric measurements indicated that the copolymers degrade at lower temperatures than those of their parent homopolymers. A possible explanation of this anomalous behaviour is the formation of thermally unstable structures during the copolymerisation.