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

Interpolymer complexes of Eudragit® copolymers as novel carriers for colon-specific drug delivery

Interpolymer complexes (IPC) based on Eudragit® EPO and Eudragit® S100 were investigated as potential carriers for oral controlled drug delivery to the colon. IPC samples were prepared by mixing copolymer solutions in organic solvents (ethanol, isopropanol:acetone mixture (60:40, % v/v) and tetrahydrofuran). According to the data of elemental analysis, FTIR-spectroscopy, X-ray photoelectron spectroscopy and thermal analysis these IPCs have excess of anionic copolymer (Eudragit® S100) in their structure; they are stabilized by hydrogen and ionic intermacromolecular bonds and do not include free copolymer domains. IPC have pH-independent swelling properties in the media mimicking gastrointestinal tract (GIT) conditions and provide colon-specific delivery of indomethacin in buffer solutions (pH 1.2; 5.8; 6.8; 7.4) and in biorelevant media (fasted state simulated gastric fluid, fasted state simulated intestinal fluid—version 2 and fasted stated simulated colonic fluid)

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

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 1560 cm−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 7 hours 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

Cataleptogenic effect of haloperidol formulated in water-soluble calixarene-based nanoparticles

In this study, a water-soluble form of haloperidol was obtained by coaggregation with calix[4]resorcinol bearing viologen groups on the upper rim and decyl chains on the lower rim to form vesicular nanoparticles. The formation of nanoparticles is achieved by the spontaneous loading of haloperidol into the hydrophobic domains of aggregates based on this macrocycle. The mucoadhesive and thermosensitive properties of calix[4]resorcinol–haloperidol nanoparticles were established by UV-, fluorescence and CD spectroscopy data. Pharmacological studies have revealed low in vivo toxicity of pure calix[4]resorcinol (LD50 is 540 ± 75 mg/kg for mice and 510 ± 63 mg/kg for rats) and the absence of its effect on the motor activity and psycho-emotional state of mice, which opens up a possibility for its use in the design of effective drug delivery systems. Haloperidol formulated with calix[4]resorcinol exhibits a cataleptogenic effect in rats both when administered intranasally and intraperitoneally. The effect of the intranasal administration of haloperidol with macrocycle in the first 120 min is comparable to the effect of commercial haloperidol, but the duration of catalepsy was shorter by 2.9 and 2.3 times (p < 0.05) at 180 and 240 min, respectively, than that of the control. There was a statistically significant reduction in the cataleptogenic activity at 10 and 30 min after the intraperitoneal injection of haloperidol with calix[4]resorcinol, then there was an increase in the activity by 1.8 times (p < 0.05) at 60 min, and after 120, 180 and 240 min the effect of this haloperidol formulation was at the level of the control sample

Hybrid Nanoparticles for Haloperidol Encapsulation: Quid Est Optimum?

The choice of drug delivery carrier is of paramount importance for the fate of a drug in a human body. In this study, we have prepared the hybrid nanoparticles composed of FDA-approved Eudragit L100-55 copolymer and polymeric surfactant Brij98 to load haloperidol-an antipsychotic hydrophobic drug used to treat schizophrenia and many other disorders. This platform shows good drug-loading efficiency and stability in comparison to the widely applied platforms of mesoporous silica (MSN) and a metal-organic framework (MOF). ZIF8, a biocompatible MOF, failed to encapsulate haloperidol, whereas MSN only showed limited encapsulation ability. Isothermal titration calorimetry showed that haloperidol has low binding with the surface of ZIF8 and MSN in comparison to Eudragit L100-55/Brij98, thus elucidating the striking difference in haloperidol loading. With further optimization, the haloperidol loading efficiency could reach up to 40% in the hybrid Eudragit L100-55/Brij98 nanoparticles with high stability over several months. Differential scanning calorimetry studies indicate that the encapsulated haloperidol stays in an amorphous state inside the Eudragit L100-55/Brij98 nanoparticles. Using a catalepsy and open field animal tests, we proved the prolongation of haloperidol release in vivo, resulting in later onset of action compared to the free drug

Crown ethers: novel permeability enhancers for ocular drug delivery?

Crown ethers are cyclic molecules consisting of a ring containing several ether groups. The most common and important members of this series are 12-crown-4 (12C4), 15-crown-5 (15C5), and 18-crown-6 (18C6). These container molecules have the ability to sequester metal ions and their complexes with drugs are able to traverse cell membranes. This study investigated 12C4, 15C5 and 18C6 for their ability to increase solubility of ocular drugs and enhance their penetration into the cornea. Phase solubility analysis determined crown ethers’ ability to enhance the solubility of riboflavin, a drug used for the therapy of keratoconus, and these solutions were investigated for ocular drug permeation enhancing properties. Atomic absorption spectroscopy demonstrated crown ether solutions ability to sequester Ca2+ from corneal epithelia and crown ether mediated adsorption of riboflavin into the stroma was investigated. Induced corneal opacity studies assessed potential toxicity of crown ethers. Crown ethers enhanced riboflavin’s aqueous solubility and its penetration into in vitro bovine corneas; the smaller sized crown ethers gave greatest enhancement. They were shown to sequester Ca2+ ions from corneal epithelia, doing so loosens cellular membrane tight junctions thus enhancing riboflavin penetration. Induced corneal opacity was similar to that afforded by benzalkonium chloride and less than is produced using polyaminocarboxylic acids. However, in vivo experiments performed in rats with 12C4 did not show any statistically significant permeability enhancement compared to enhancer-free formulation

Mucoadhesive Interpolyelectrolyte Complexes for the Buccal Delivery of Clobetasol

This work aimed to investigate the feasibility to design: (a) a mucoadhesive interpolyelectrolyte complex (IPEC) loaded with clobetasol propionate (CP) intended to treat oral lichen planus and (b) individuate an orodispersible dosage form suitable for its administration. IPECs were synthesized by mixing Eudragit® E PO (EPO) and different grades of cross-linked polyacrylate derivatives, in different molar ratios, namely 1:1, 1:2, and 2:1. All IPECs resulted at nanoscale independently of their composition (120–200 nm). Both zeta-potentials (ζ) and mucoadhesive performances were influenced by the ratio between polymers. On the bases of the preliminary data, IPECs made of Polycarbophil and EPO in the 1:2 ratio were loaded with CP. The encapsulation efficiency was up 88% independently of the CP-IPEC ratio. The drug encapsulation caused IPEC destabilization in water, as it was noticed by the increase of ζ values and the formation of aggregates. Oral lyophilisates were prepared by freeze-drying slurries made of placebo or CP loaded IPECs, maltodextrin with a dextrose equivalent 38 and Span®80. The optimized formulation permitted to obtain a fast disintegration upon contact with water reducing the tendency of IPECs to aggregate. Moreover, oral lyophilisates allowed improving the apparent solubility of CP throughout the in vitro release experiment

Design and production of hybrid nanoparticles with polymeric-lipid shell–core structures: conventional and next-generation approaches

An innovative, simil-microfluidic, nanoliposome-covering method operating continuously with massive production yield overcoming the disadvantages of conventional methods is proposed

Comparative Evaluation of Metformin and Metronidazole Release from Oral Lyophilisates with Different Methods

The aim of this study is to compare three different dissolution methods to assess the drug release from oral lyophilisates, based on interpolyelectrolyte complexes (IPECs). IPECs were prepared by mixing solutions of a linear polymer, Eudragit® EPO, with a polymer with a cross-linked structure, Noveon® AA-1 or Carbopol® 10 Ultrez (in ratios of 1:2 and 1:1, respectively). Metformin or metronidazole were used as model drugs to achieve a systemic or local effect. A comparative assessment of the drug release kinetics was carried out using artificial saliva and three different set-ups: a paddle stirrer (USP apparatus 2), a flow cell (USP apparatus 4) and a Franz diffusion cell. The results demonstrated that oral lyophilisates disintegrated within 1 min. In the case of metformin, the drug release was completed in about 90 min independently of the set-up. The static conditions in the Franz diffusion cell and USP apparatus 2 permitted the aggregation of the IPEC; therefore, the release profiles show a significant difference compared to the USP apparatus 4