Characteristics of Interpolyelectrolyte Complexes Based on Different Types of Pectin with Eudragit® EPO as Novel Carriers for Colon-Specific Drug Delivery.

Given that pectin is a well-known substance used for drug delivery, we aimed to obtain and further examine the efficacy of interpolyelectrolyte complexes based on citrus or apple pectin and the Eudragit® EPO for using these carriers in oral drug delivery. To characterize the physicochemical properties of these compounds, turbidity, gravimetry, viscosity, elementary analysis, FTIR spectroscopy, and DSC analysis were utilized. Diffusion transport characteristics were evaluated to assess the swelling ability of the matrices and the release of diclofenac sodium. To examine the release parameters, mathematical modeling was performed by using the Korsmayer-Peppas and Logistic equations as well. During the turbidity study, stoichiometry compositions were selected for the developed IPECs EPO/PecA and EPO/PecC at pH values = 4.0, 5.0, 6.0, and 7.0. The FTIR spectra of the complexes were characterized by an increase in the intensity of the bands at 1610 cm-1 and 1400 cm-1. According to the DSC analysis, IPEC has a certain Tg = 57.3 °C. The highest release rates were obtained for IPEC EPO/PecC_1 and EPO/PecC_4. The mechanism of drug transport from the matrices IPEC EPO/PecC, IPEC EPO/PecA_3, and EPO/PecA_4 can be characterized as Super Case II. Anomalous release (non-Fickian release) is typical for IPEC EPO/PecA_1 and EPO/PecA_2. Thus, the resulting systems can be further used for the effective delivery of the drugs to the colon.

Mucoadhesive and mucus-penetrating interpolyelectrolyte complexes for nose-to-brain drug delivery.

Nasal administration offers a possibility of delivering drugs to the brain. In the present work, nasal drug delivery systems were designed based on cationic Eudragit® EPO (EPO) and anionic Eudragit® L100-55 (L100-55) methacrylate copolymers. Two types of nanocarriers were prepared using interpolyelectrolyte complexation between these polymers. The first type of nanoparticles was prepared by forming interpolyelectrolyte complexes between unmodified EPO and L100-55. The second type of nanoparticles was formed through the complexation between PEGylated L100-55 and EPO. For this purpose, PEGylated L100-55 was synthesized by chemical conjugation of L100-55 with O-(2-aminoethyl)polyethylene glycol. The mucoadhesive properties of these nanoparticles were evaluated ex vivo using sheep nasal mucosa. Nanoparticles based on EPO and L100-55 exhibited mucoadhesive properties towards nasal mucosa, whereas PEGylated nanoparticles were non-mucoadhesive hence displayed mucus-penetrating properties. Both types of nanoparticles were used to formulate haloperidol and their ability to deliver the drug to the brain was evaluated in rats in vivo.

Conjugation of haloperidol to PEG allows peripheral localisation of haloperidol and eliminates CNS extrapyramidal effects.

We have previously reported the synthesis of a poly(ethylene glycol)-haloperidol (PEG-haloperidol) conjugate that retained affinity for its target D2 receptor and was stable in simulated physiological conditions. We hypothesised that this polymer-drug conjugate would localise haloperidol's activity either centrally or peripherally, dependent on the location of administration, due to the polymer preventing penetration through the blood-brain barrier (BBB). Herein, we validate this hypothesis using in vitro and in vivo studies. We first demonstrate, via a [35S]GTPγS-binding assay, that drug activity is retained after conjugation to the polymer, supportive of retention of effective therapeutic ability. Specifically, the PEG-haloperidol conjugate (at 10 and 100 nM) was able to significantly inhibit dopamine-induced G-protein activation via D2 receptors, albeit with a loss of potency compared to the free haloperidol (~18-fold at 10 nM). This loss of potency was further probed and rationalised using molecular docking experiments, which indicated that conjugated haloperidol can still bind to the D2 receptors, albeit with a flipped orientation in the binding pocket within the receptor, which may explain the reduced activity. Finally, rat catalepsy studies confirmed the restricted permeation of the conjugate through the BBB in vivo. Rats treated intravenously with free haloperidol became cataleptic, whereas normal behaviour was observed in rats that received the PEG-haloperidol conjugate, suggesting that conjugation can effectively prevent unwanted central effects. Taken together these results demonstrate that conjugating small molecules to polymers is effective at prohibiting penetration of the drug through the BBB and is a valid targeting strategy for drugs to facilitate peripheral (or central) effects without inducing side effects in other compartments.

Interpolyelectrolyte complexes of Eudragit E PO with sodium alginate as potential carriers for colonic drug delivery: monitoring of structural transformation and composition changes during swellability and release evaluating.

BACKGROUND: With a view to the application in oral colon drug delivery systems, swelling and release behavior of synthesized interpolyelectrolyte complexes (IPEC) between sodium alginate and Eudragit EPO were investigated. METHOD: The microenvironmental changes in IPECs structure as a function of pH during swellability testing were investigated using FT-IR spectroscopy and elementary analysis. RESULTS: All samples of IPECs (Z = 0.66-1.25) during swelling were transformed to a similar structure with approximately the same composition. The release of the model drug diclofenac sodium was significantly delayed from matrices made up of the IPECs and independent from the composition of polycomplexes. CONCLUSION: According to the obtained results, these IPECs can be considered to have potential in colonic drug delivery as combined pH- and time-dependent systems.

Interpolymer complexes of carbopol® 971 and poly(2-ethyl-2-oxazoline): Physicochemical studies of complexation and formulations for oral drug delivery.

Carbopol® 971 and poly(2-ethyl-2-oxazoline) form hydrogen-bonded interpolymer complexes in aqueous solutions and their complexation is strongly dependent on solution pH. This work investigated the complexation between these polymers in aqueous solutions. The compositions of interpolymer complexes as well as the critical pH values of complexation were determined. The structure of these complexes was studied in solutions using transmission electron microscopy and in solid state using elemental analysis, FTIR spectroscopy and differential scanning calorimetry. Solid compacts were prepared based on interpolymer complexes and physical blends of these polymers and their swelling behaviour was studied in aqueous solutions mimicking the fluids present in the gastrointestinal tract. These materials were used to prepare oral formulations of mesalazine and its release from solid matrices was studied in vitro. It was demonstrated that the complexation between Carbopol® 971 and poly(2-ethyl-2-oxazoline) has a profound effect on the drug release from matrix tablets.

Acrylated Eudragit® E PO as a novel polymeric excipient with enhanced mucoadhesive properties for application in nasal drug delivery.

Eudragit® E PO (EPO) is a terpolymer based on N,N-dimethylaminoethyl methacrylate with methylmethacrylate and butylmethacrylate, produced by Evonik Industries AG as a pharmaceutical excipient. In this work, EPO was chemically modified through reaction with acryloyl chloride. The successful modification of EPO was confirmed by FTIR, NMR-spectroscopy, elemental and thermal analysis. The degree of acrylation was determined by permanganatometric titration. The slug mucosal irritation test was used to demonstrate non-irritant nature of EPO and its acrylated derivatives (AEPO). The mucoadhesive properties of EPO and AEPO were evaluated using freshly excised sheep nasal mucosa and it was demonstrated that acrylated polymers facilitated greater retention of sodium fluorescein on mucosal surfaces compared to solution mixture of this dye solution with EPO as well as free dye.

Comparative evaluation of interpolyelectrolyte complexes of chitosan with Eudragit L100 and Eudragit L100-55 as potential carriers for oral controlled drug delivery.

With a view to the application in oral controlled drug delivery systems, the formation of interpolyelectrolyte complexes (IPEC) between chitosan (CS) and Eudragit L100 (L100) or Eudragit L100-55 (L100-55) was investigated at pH 6.0, using elementary analysis. The interaction or binding ratio of a unit molecule of CS with Eudragit L copolymers depends on the molecular weight of CS, and changes from 1:0.85 to 1:1.22 (1.17

Polymer-lipid hybrid nanoparticles as enhanced indomethacin delivery systems.

Non-steroidal anti-inflammatory drugs (NSAIDs), i.e. indomethacin used for rheumatoid arthritis and non-rheumatoid inflammatory diseases, are known for their injurious actions on the gastrointestinal (GI) tract. Mucosal damage can be avoided by using nanoscale systems composed by a combination of liposomes and biodegradable natural polymer, i.e. chitosan, for enhancing drug activity. Aim of this study was to prepare chitosan-lipid hybrid delivery systems for indomethacin dosage through a novel continuous method based on microfluidic principles. The drop-wise conventional method was also applied in order to investigate the effect of the two polymeric coverage processes on the nanostructures features and their interactions with indomethacin. Thermal-physical properties, mucoadhesiveness, drug entrapment efficiency, in vitro release behavior in simulated GI fluids and stability in stocking conditions were assayed and compared, respectively, for the uncoated and chitosan-coated nanoliposomes prepared by the two introduced methods. The prepared chitosan-lipid hybrid structures, with nanometric size, have shown high indomethacin loading (about 10%) and drug encapsulation efficiency up to 99%. TEM investigation has highlighted that the developed novel simil-microfluidic method is able to put a polymeric layer, surrounding indomethacin loaded nanoliposomes, thicker and smoother than that achievable by the drop-wise method, improving their storage stability. Finally, double pH tests have confirmed that the chitosan-lipid hybrid nanostructures have a gastro retentive behavior in simulated gastric and intestinal fluids thus can be used as delivery systems for the oral-controlled release of indomethacin. Based on the present results, the simil-microfluidic method, working with large volumes, in a rapid manner, without the use of drastic conditions and with a precise control over the covering process, seems to be the most promising method for the production of suitable indomethacin delivery system, with a great potential in industrial manufacturing.

Hydrophilic drug encapsulation in shell-core microcarriers by two stage polyelectrolyte complexation method.

In this study a protocol exploiting the combination of the ultrasonic atomization and the complexation between polyelectrolytes was developed to efficiently encapsulate a hydrophilic chemotherapeutic agent essentially used in the treatment of colon cancer, 5-fluorouracil, in enteric shell-core alginate-based microcarriers. The atomization assisted by ultrasound allowed to obtain small droplets by supplying low energy and avoiding drug degradation. In particular microcarriers were produced in a home-made apparatus where both the core (composed of alginate, drug, and Pluronic F127) and shell (composed of only alginate) feed were separately sent to the coaxial ultrasonic atomizer where they were nebulized and placed in contact with the complexation bulk. With the aim to obtain microstructured particles of alginate encapsulating 5-fluorouracil, different formulations of the first complexation bulk were tested; at last an emulsion made of a calcium chloride aqueous solution and dichloromethane allowed to reach an encapsulation efficiency of about 50%. This result can be considered very interesting considering that in literature similar techniques gave 5-fluorouracil encapsulation efficiencies of about 10%. Since a single complexation stage was not able to assure microcarriers gastroresistance, the formulation of a second complexation bulk was evaluated. The solution of cationic and pH-insoluble Eudragit® RS 100 in dichloromethane was chosen as bulk of second-stage complexation obtaining good enteric properties of shell-core microcarriers, i.e. a 5-FU cumulative release at pH 1 (simulating gastric pH) lower than 35%. The formation of interpolyelectrolyte complex (IPEC) between countercharged polymers and the chemical stability of 5-FU in microcarriers were confirmed by FTIR analysis, the presence of an amorphous dispersion of 5-FU in prepared microparticles was also confirmed by DSC. Finally, shell-core enteric coated microcarriers encapsulating 5-fluorouracil were used to prepare tablets, which can be potentially used as oral administration dosage systems for their 5-fluorouracil slower release.

Indomethacin-containing interpolyelectrolyte complexes based on Eudragit® E PO/S 100 copolymers as a novel drug delivery system.

Potential applications of a novel system composed of two oppositely-charged (meth)acrylate copolymers, Eudragit® ЕРО (EPO) and Eudragit® S100 (S100), loaded with indomethacin (IND) in oral drug delivery were evaluated. The particles based on drug-interpolyelectrolyte complexes (DIPEC), (EPO-IND)/S100, were prepared by mixing aqueous solutions of both copolymers at fixed pH. Particles of drug-polyelectrolyte complex (DPC), (EPO-IND) have a positive zeta potential, pointing to the surface location of free EPO chains and IND bound to EPO sequences. The formation and composition of both DPC and DIPEC were established by gravimetry, UV-spectrophotometry, capillary viscosity and elemental analysis. The structure and solid state properties of the formulated DIPEC were investigated using FTIR/NIR, Raman spectroscopy, XRPD and modulated DSC. DIPEC is a chemically homogenous material, characterized by a single Tg. DIPEC have an IR absorption band at 1560cm-1, which can be assigned to the stretching vibration of the carboxylate groups (S100, IND) that form ionic bonds with the dimethylamino groups of EPO. XRPD, NIR and Raman-shifts confirm that during the preparation of this formulation, IND is converted into its amorphous form. The release of IND from DPC EPO/IND (3:1) and DIPEC EPO/L100/IND (4.5:1:1) is sustained and is completed within 7h under GIT mimicking conditions. However, S100 within DIPEC makes the release process slower making this system suitable for colon-specific delivery. Finally, DPC and DIPEC with indomethacin were used to prepare tablets, which can be potentially used as oral dosage forms for their slower indomethacin release in case of DIPEC which could be suitable for sustained delivery.

Physicochemical characterization and drug release properties of Eudragit E PO/Eudragit L 100-55 interpolyelectrolyte complexes.

The formation of interpolyelectrolyte complexes (IPEC) between Eudragit E PO (EE) and Eudragit L 100-55 (EL) was investigated, using turbidimetry, apparent viscosity measurements, elementary analysis and MT-DSC. The structure of the synthesized IPEC was investigated using FT-IR spectroscopy. The binding ratio of a unit molecule of EL with EE was found to be approximately 1:1 at pH 5.5. Based on the results of elementary analysis and FT-IR, the binding ratio of each component in the solid complexes was very close to that observed in turbidity and apparent viscosity measurements and indicate that the synthesized products can be considered as IPEC. As a result of electrostatic interaction between the polymer chains, the glass transition temperature of the IPEC increased significantly. Due to the structure of the IPEC, two maxima were observed in the swelling behavior as a function of pH. The release of the model drug ibuprofen (IBF) was significantly retarded from tablets made up of the IPEC as compared with individual copolymers, its physical mixture and Eudragit RL PO (RL), RS PO (RS).

Drug release modification by interpolymer interaction between countercharged types of Eudragit® RL 30D and FS 30D in double-layer films.

Interpolymer interactions between the countercharged methacrylate copolymers Eudragit(®) RL 30D (polycation) and Eudragit(®) FS 30D (polyanion), were investigated in conditions mimicking the gastrointestinal environment. The formation of inter-macromolecular ionic bonds between Eudragit(®) RL 30D and Eudragit(®) FS 30D was investigated using FT-IR spectroscopy and modulated DSC. The FT-IR spectra of the tested polymeric matrices are characterized by visible changes in the observed IR region indicating the interaction between chains of two oppositely charged copolymers. A new band at 1570 cm(-1) appeared which was assigned to the absorption of the carboxylate groups that form the ionic bonds with the quaternary ammonium groups. Moreover, while increasing the pH values from pH 5.8 to 7.4, a decrease of the intensity of the band at 960 cm(-1) (quaternary ammonium group vibration) was observed. All binary mixtures were characterized by the presence of only one and narrow Tg, pointing to sample homogeneity, because of the compatibility of components. As a result of electrostatic interaction between the copolymer chains during swelling, the resulting Tg is decreased significantly and was dependent on the quantity of copolymers present in the structure of polycomplexes formed. Overall, the interaction between countercharged copolymers during passage in gastrointestinal tract can strongly modify the release profile of the model drug diclofenac sodium.

Structural transformations during swelling of polycomplex matrices based on countercharged (meth)acrylate copolymers (Eudragit EPO/Eudragit L 100-55).

With a view to the application in oral controlled drug delivery systems (DDS), the design of new interpolyelectrolyte complexes (IPECs) between countercharged types of Eudragit EPO (EPO) and Eudragit L 100-55 (L100-55) was investigated. The formation and composition of four new IPECs between EPO and L100-55 were established by elementary analysis. The structure of the synthesized IPEC was investigated using FTIR spectroscopy and modulated-temperature differential scanning calorimetry. The binding ratio of a unit molecule of EPO with L100-55 was found to range between 1:2.75 (Z = 0.36) and 1:0.55 (Z = 1.81) while increasing the pH value from 5.5 to 7.0. As a result of electrostatic interaction between the copolymer chains, the glass transition temperature of the IPEC increased significantly. A large pH-sensitive swelling behavior was observed for different structures of the IPECs. The outcome of swelling and diclofenac sodium release from the polycomplex matrices confirm that they have great potential to be used as a controlled DDS in specified regions of gastrointestinal tract.