Development and in vitro evaluation of a mucoadhesive vaginal delivery system for progesterone.

The purpose of the present study was to design a novel carrier system based on a mucoadhesive polymer exhibiting improved properties concerning drug delivery to the vaginal mucosa. This was reached by the covalent attachment of L-cysteine to commercially available polyacrylic acid (Carbopol 974P). Mediated by a carbodiimide, increasing amounts of L-cysteine were covalently linked to the polymer. The resulting thiolated polyacrylic acid conjugates (NaC974P-Cys) displayed between 24.8 and 45.8 micromol thiol groups per gram of polymer. Because of the formation of intra- and/or intermolecular disulfide bonds, the viscosity of an aqueous thiolated polymer gel (3%) increased about 50% at pH 7.0 within 1 h. In oscillatory rheological measurements, it was shown that this increase in viscosity is mainly due to the increase in elasticity. Tensile studies carried out on freshly excised cow vagina demonstrated a significant (P<0.05) increase in the total work of adhesion (TWA) compared to the unmodified polymer. An amount of 24.8 micromol thiol groups per gram of polymer resulted in a 1.45-fold increase in the TWA, whereas an amount of 45.8 micromol showed an even 2.28-fold increase. These improved mucoadhesive properties can be explained by the formation of disulfide bonds between the thiolated polymer and cysteine rich subdomaines of the mucus layer. The release rate of the model drug progesterone from tablets based on microcrystalline cellulose serving as the reference was approximately 1% per hour, whereas it was 0.58% per hour for the unmodified polymer (NaC974P) and 0.12% per hour for the thiolated polymer (NaC974P-Cys). Therefore, this thiolated polymer is a promising carrier for progesterone providing a prolonged residence time and a controlled drug release.     

Improvement in the mucoadhesive properties of alginate by the covalent attachment of cysteine.

The purpose of the present study was to improve the mucoadhesive properties of alginate by the covalent attachment of cysteine. Mediated by a carbodiimide, L-cysteine was covalently linked to the polymer. The resulting thiolated alginate displayed 340.4+/-74.9 micromol thiol groups per g conjugate (means+/-S.D.; n=4). Within 2 h the viscosity of an aqueous mucus/alginate-cysteine conjugate mixture pH 7.0 increased at 37 degrees C by more than 50% compared to a mucus/alginate mixture, indicating enlarged interactions between the mucus and the thiolated polymer. Tensile studies carried out on freshly excised porcine intestinal mucosa demonstrated a total work of adhesion (TWA) of 25.8+/-0.6 and 101.6+/-36.1 microJ for alginate and the alginate-cysteine conjugate, respectively (means+/-S.D.; n=5). The maximum detachment force (MDF) was thereby in good correlation with the TWA. Due to the immobilization of cysteine, the swelling velocity of the polymer was significantly accelerated (P<0.05). In aqueous media the alginate-cysteine conjugate was capable of forming inter- and/or intramolecular disulfide bonds. Because of this crosslinking process within the polymeric network, the cohesive properties of the conjugate were also improved. Tablets comprising the unmodified polymer disintegrated within 49+/-14.5 min, whereas tablets of thiolated alginate remained stable for 148.8+/-39.1 min (means+/-S.D.; n=3). These features should render thiolated alginate useful as excipient for various drug delivery systems providing an improved stability and a prolonged residence time on certain mucosal epithelia.     

Preparation and in vitro characterization of poly(acrylic acid)-cysteine microparticles.

The purpose of the present study was to prepare and characterize a novel mucoadhesive microparticulate drug delivery system. Microparticles were prepared by the solvent evaporation emulsion technique using a poly(acrylic acid)-cysteine conjugate of an average molecular mass of 450 kDa with an amount of 308 micromol thiol groups per gram polymer. The cross-linking of thiol groups via the formation of disulfide bonds during this preparation process was pH-controlled. The resulting microparticles were characterized with regard to the degree of cross-linking and the amount of remaining free thiol groups, shape, size distribution and stability. Furthermore, the drug release behaviour using bromelain as model drug and the mucoadhesive properties were evaluated.Results demonstrated that the higher the pH of the aqueous phase was during the preparation process, the higher was the degree of cross-linking within the particles. However, even at pH 9, 8.9+/-2.2% of free thiol groups remained on the microparticles. Particles were of spherical and partially porous structure and had a main size in the range of 20-60 microm with a center at 35 microm. Because of the formation of disulfide bonds within the particles, they did not disintegrate under physiological conditions within 48 h. In addition, a controlled drug release of bromelain was achieved. Due to the immobilization of thiol groups on poly(acrylic acid), the mucoadhesive properties of the corresponding microparticles were improved threefold.These features should render poly(acrylic acid)-cysteine conjugate microparticles useful as drug delivery system providing a prolonged residence time on mucosal epithelia.     

The use of thiolated polymers as carrier matrix in oral peptide delivery--proof of concept.

It was the aim of this study to develop an oral delivery system for the peptide drug antide. The stability of the therapeutic peptide towards gastrointestinal peptidases was evaluated. The therapeutic agent and the permeation mediator glutathione were embedded in the thiolated polymer chitosan-4-thio-butylamidine conjugate (chitosan-TBA conjugate) and compressed to tablets. Drug release studies were performed in the dissolution test apparatus according to the Pharmacopoeia Europea using the paddle method and demineralized water as release medium. In order to avoid mucoadhesion of these delivery systems already in the oral cavity and oesophagus tablets were coated with a triglyceride. These tablets were orally given to pigs (weight: 50+/-2 kg; Edelschwein Pietrain). Moreover, antide was administered intravenously, subcutaneously and orally in solution. Results showed stability of antide towards pepsin, trypsin and chymotrypsin. In contrast, antide was rapidly degraded by elastase. Consequently a stomach-targeted delivery system was designed. Drug release studies demonstrated an almost zero-order controlled release of antide over 8 h. In vivo studies demonstrated a relative bioavailability of 34.4% for the subcutaneous administration. Oral administration of antide in solution led to no detectable concentrations of the drug in plasma at all. In contrast, administering antide being incorporated in the thiolated polymer resulted in a significant uptake of the peptide. The absolute and relative bioavailability was determined to be 1.1% and 3.2%, respectively.     

Oral insulin delivery: the potential of thiolated chitosan-insulin tablets on non-diabetic rats.

It was the aim of this study to develop a delivery system providing an improved efficacy of orally administered insulin utilizing a thiolated polymer. 2-Iminothiolane was covalently linked to chitosan. The resulting chitosan-TBA (chitosan-4-thiobutylamidine) conjugate exhibited 453.5+/-64.1 micromol thiol groups per gram polymer. 3.1% of these thiol groups were oxidised. Additionally, the enzyme inhibitors BBI (Bowman-Birk-Inhibitor) and elastatinal were covalently linked to chitosan representing 3.5+/-0.1% and 0.5+/-0.03% of the total weight of the resulting polymer conjugate, respectively. Chitosan-TBA conjugate (5 mg), insulin (2.75 mg), the permeation mediator reduced glutathione (0.75 mg) and the two inhibitor conjugates (in each case 0.75 mg) were compressed to so-called chitosan-TBA-insulin tablets. Control tablets consisted of unmodified chitosan (7.25 mg) and insulin (2.75 mg). Chitosan-TBA-insulin tablets showed a controlled release of insulin over 8 h. In vitro mucoadhesion studies showed that the mucoadhesive/cohesive properties of chitosan were at least 60-fold improved by the immobilisation of thiol groups on the polymer. After oral administration of chitosan-TBA-insulin tablets to non-diabetic conscious rats, the blood glucose level decreased significantly for 24 h corresponding to a pharmacological efficacy of 1.69+/-0.42% (means+/-S.D.; n=6) versus s.c. injection. In contrast, neither control tablets nor insulin given in solution showed a comparable effect. According to these results the combination of chitosan-TBA, chitosan-enzyme-inhibitor conjugates and reduced glutathione seems to represent a promising strategy for the oral application of insulin.     

Comparative in vivo mucoadhesion studies of thiomer formulations using magnetic resonance imaging and fluorescence detection.

The aim of this study was to compare different oral delivery systems based on the thiolated polymer polycarbophil-cysteine (PCP-Cys) and to provide evidence for the validity of the hypothesis that unhydrated polymers provide better mucoadhesion in vivo. To achieve dry polymer application, a new, experimental dosage form named Eutex (made of Eudragit L100-55 and latex) capsule has been developed. Magnetic resonance imaging was used to localize the point of release of the thiolated polymer from the application forms via the positive magnetic resonance signal from a gadolinium complex (Gd-DTPA). In vivo mucoadhesion was determined by ascertaining the residence time of the fluorescence-tagged thiomer on intestinal mucosa after 3 h. Results showed that in comparison to conventional application forms the Eutex capsules led to 1.9-fold higher mucoadhesive properties of PCP-Cys when compared to application with a conventional enteric-coated capsule, and to 1.4-fold higher mucoadhesion when compared to administration with an enteric-coated tablet of the thiomer. The findings of this study should contribute to the understanding of mucoadhesion and mucoadhesion influencing parameters in vivo and should therefore be of considerable interest for the development of future mucoadhesive oral drug delivery dosage forms.     

Mucoadhesive ocular insert based on thiolated poly(acrylic acid): development and in vivo evaluation in humans.

The aim of the study was to develop a mucoadhesive ocular insert for the controlled delivery of ophthalmic drugs and to evaluate its efficacy in vivo. The inserts tested were based either on unmodified or thiolated poly(acrylic acid). Water uptake and swelling behavior of the inserts as well as the drug release rates of the model drugs fluorescein and two diclofenac salts with different solubility properties were evaluated in vitro. Fluorescein was used as fluorescent tracer to study the drug release from the insert in humans. The mean fluorescein concentration in the cornea/tearfilm compartment as a function of time was determined after application of aqueous eye drops and inserts composed of unmodified and of thiolated poly(acrylic acid). The acceptability of the inserts by the volunteers was also evaluated. Inserts based on thiolated poly(acrylic acid) were not soluble and had good cohesive properties. A controlled release was achieved for the incorporated model drugs. The in vivo study showed that inserts based on thiolated poly(acrylic acid) provide a fluorescein concentration on the eye surface for more than 8 h, whereas the fluorescein concentration rapidly decreased after application of aqueous eye drops or inserts based on unmodified poly(acrylic acid). Moreover, these inserts were well accepted by the volunteers. The present study indicates that ocular inserts based on thiolated poly(acrylic acid) are promising new solid devices for ocular drug delivery.     

Cross-linked amylose tablets containing alpha-amylase: an enzymatically-controlled drug release system.

An oral controlled release system based on direct compression of cross-linked amylose (CLA) and drug powders was previously introduced. For drugs with limited solubility or for some drugs for which solubility can be influenced by variation of gastro-intestinal pH, a system is required to accelerate drug release. This paper describes a novel enzymatically-controlled drug release (ECDR) system based on the addition of alpha-amylase to CLA tablets, which can modulate the release kinetics of drugs. The alpha-amylase within the tablets is able to hydrolyze alpha-1-4-glucosidic bonds present in the CLA semisynthetic substrate. Increasing amounts of alpha-amylase (5 to 25 EU) within the tablets induced a significant decrease in release time from 24 to 6 h. High amounts of external alpha-amylase (300-6000 EU/l) had a slight effect on the release rate. Drug release from the ECDR system seems to be controlled by two sequential mechanisms: (a) hydration and swelling of CLA tablets followed by (b) internal enzymatic hydrolysis of the hydrated gel phase.     

Disulfur-bridged polyethyleneglycol/DOX nanoparticles for the encapsulation of photosensitive drugs: a case of computational simulations on the redox-responsive chemo-photodynamic drug delivery system

Tumor redox stimulus-responsive nanoparticulate drug delivery systems (nano-DDSs) have attracted considerable attention due to their thermodynamically stable microstructures and well-controlled drug release properties. However, drug-loading nanoparticle conformation and redox-triggered drug release mechanisms at the molecular level remain unclear. Herein, doxorubicin-conjugated polymers were constructed using disulfide bonds as linkages (PEG–SS–DOX), which loaded photosensitizer chlorin e6 (Ce6). We integrated multiple scale dynamic simulations (density functional theory (DFT) calculation, atomistic molecular dynamics (MD) simulation and dissipative particle dynamics (DPD) simulations) to elucidate the assembly/drug release dynamic processing. First, it was revealed that the emergence of the calculated bond flexible angle of disulfide bonds facilitated the assembly behavior and improved the stability of conformation. Sorted by the binding model, hydrogen bonding accounted for the major interactions between polymers and photosensitive drugs. DPD simulations were further delved into to acquire knowledge regarding the drug-free self-aggregation and Ce6-loaded assembly mechanism. The results show that nano-assembly conformation not only depended on the concentration of polymers, but also were associated with the polymer–drug ratio. Different from dicarbon bond-bridging polymers, disulfide bonds would contribute to the breakage of the polymer and the rapid release of DOX and Ce6. Our findings provide deep insights into the influence of redox-responsive chemical linkages and offer theoretical guidance to the rational design of specific stimulus-responsive nano-DDSs for cancer therapy.

Schematic of disulfide/dicarbide-bridged DOX polymer-encapsulated photosensitive drugs Ce6: a case of computational simulations on the redox-responsive chemo-photodynamic drug delivery system.     

Cross-linked amylose tablets containing α-amylase: an enzymatically-controlled drug release system

An oral controlled release system based on direct compression of cross-linked amylose (CLA) and drug powders was previously introduced. For drugs with limited solubility or for some drugs for which solubility can be influenced by variation of gastro–intestinal pH, a system is required to accelerate drug release. This paper describes a novel enzymatically-controlled drug release (ECDR) system based on the addition of α-amylase to CLA tablets, which can modulate the release kinetics of drugs. The α-amylase within the tablets is able to hydrolyze α-1-4-glucosidic bonds present in the CLA semisynthetic substrate. Increasing amounts of α-amylase (5 to 25 EU) within the tablets induced a significant decrease in release time from 24 to 6 h. High amounts of external α-amylase (300–6000 EU/l) had a slight effect on the release rate. Drug release from the ECDR system seems to be controlled by two sequential mechanisms: (a) hydration and swelling of CLA tablets followed by (b) internal enzymatic hydrolysis of the hydrated gel phase.     

Mucus-responsive functionalized emulsions: design,synthesis and study of novel branched polymers as functional emulsifiers

Mucus lines the moist cavities throughout the body, acting as barrier by protecting the underlying cells against the external environment, but it also hinders the permeation of drugs and drug delivery systems. As the rate of diffusion is low, the development of a system which could increase retention time at the mucosal surface would prove beneficial. Here, we have designed a range of branched copolymers to act as functional mucus-responsive oil-in-water emulsifiers comprising the hydrophilic monomer oligo(ethylene glycol) methacrylate and a hydrophobic dodecyl initiator. The study aimed to investigate the importance of chain end functionality on successful emulsion formation, by systematically replacing a fraction of the hydrophobic chain ends with a secondary poly(ethylene glycol) based hydrophilic initiator in a mixed-initiation strategy; a decrease of up to 75 mole percent of hydrophobic chain ends within the branched polymer emulsifiers was shown to maintain comparative emulsion stability. These redundant chain ends allowed for functionality to be incorporated into the polymers via a xanthate based initiator containing a masked thiol group; thiol groups are known to have mucoadhesive character, due to their ability to form disulfide bonds with the cysteine rich areas of mucus. The mucoadhesive nature of emulsions stabilised by thiol-containing branched copolymers was compared to non-functional emulsions in the presence of a biosimilar mucosal substrate and enhanced adherence to the mucosal surface was observed. Importantly, droplet rupture and mucus triggered release of dye-containing oil was seen from previously highly-stable thiol-functional emulsions; this observation was not mirrored by non-functional emulsions where droplet integrity was maintained even in the presence of mucus.

Mucoadhesion and mucus-sensitive materials have many applications. Redundant chain-ends within branched polymer emulsifiers have been functionalized with thiols, without compromising emulsion stability, to create mucus-interacting emulsions.     

Development of mucoadhesive patches for buccal administration of ibuprofen.

A new formulation for topical administration of drugs in the oral cavity has been developed using several film-forming and mucoadhesive polymers. The films have been evaluated in terms of swelling, mucoadhesion and organoleptic characteristics. The best film, containing polyvinylpyrrolidone (PVP) as film-forming polymer and carboxymethylcellulose sodium salt (NaCMC) as mucoadhesive polymer, was loaded with ibuprofen as a model compound and in vitro and in vivo release studies were performed. Statistical investigation of in vitro release revealed that the diffusion process was the main drug release mechanism and the Higuchi's model provided the best fit. In vivo studies showed the presence of ibuprofen in saliva (range 70-210 microg/ml) for 5 h and no irritation was observed. These mucoadhesive formulations offer many advantages in comparison to traditional treatments and can be proposed as a new therapeutic tool against dental and buccal diseases and disturbs.     

Preparation and evaluation of verapamil hydrochloride microcapsules

Verapamil was encapsulated with ethylcellulose (EC) and cellulose acetate (CA) in various ratios of drug and polymer by the hot melt technique and the prepared microcapsules were evaluated for size range, drug content, drug release profiles, and kinetics of drug release. The microcapsules were compressed into tablets to study the variation of drug release between the 2 types of formulations (ie, microcapsules and tablets). The size analysis of prepared microcapsules was done by a standard sieving method and in vitro dissolution studies were carried out in USP XXI dissolution test apparatus in 0.1 N HCl as dissolution media to study the drug release profiles of the microcapsules. Scanning electron microscopy studies were carried out to investigate the surface characteristics of the microcapsules prepared from both type of polymers. Drug release profiles from the compressed non-disintegrating matrix tablets prepared from the microcapsules were also investigated. All the microcapsules were discrete, free flowing, and reproducible with respect to size distribution and drug content. Maximum percentage of the microcapsules belonged to the size range of 35/50. Drug release durations of VERCA1 (drug: CA 3:1), VERCA2 (drug: CA 2:1), and VERCA3 (drug: CA 1:1) microcapsules were extended up to 3, 5, and 6 hours, respectively, and those of VEREC1 (drug: EC 3:1), VEREC2 (drug: EC 2:1), and VEREC3 (drug: EC 1:1) microcapsules were extended up to 4, 5, and 7 hours, respectively. The microcapsules of both types having a drug:polymer ratio of 1:1 had the slowest release rate in their respective categories. The microcapsules were compressed into nondisintegrating matrix tablets. The hardness of the tablets was tested using the Monsanto Hardness Tester and was found to be 6-7 kg/cm. All the tablets contained the drug verapamil within 100% +/- 5%. The drug release data of both the microcapsules and tablets prepared were examined kinetically, and the ideal kinetic model was determined for the drug release. The tablets prepared by compressing the microcapsule formulations were more satisfactory in releasing the drug at a controlled and uniform rate following Higuchian kinetics and the formulations VCACRT3 and VECCRT3 were able to control release of drug up to 12 hours. Thus, it is possible to formulate a single-unit, controlled-release dosage form of verapamil for oral administration at least once every 12 hours using the polymers CA and EC.     

Lectin-mediated drug delivery: the second generation of bioadhesives.

This paper reviews some recent developments in the area of bioadhesive drug delivery systems. The area of bioadhesion in drug delivery had started some 20 years ago by using so-called mucoadhesive polymers. Many of these polymers were already used as excipients in pharmaceutical formulations. This has facilitated the development of the first bioadhesive drug products, which are now commercially available. A major disadvantage of the hitherto known mucoadhesives, however, is their non-specificity with respect to the substrate. In particular for gastro-intestinal applications, this may cause some premature inactivation and moreover limits the duration of mucoadhesive bonds to the relatively fast mucus turnover. Nevertheless, for some mucoadhesive polymers other interesting functionalities were discovered, such as their ability to modulate epithelial permeability and to inhibit proteolytic enzymes. In contrast to the mucoadhesive polymers, lectins and some other adhesion molecules specifically recognize receptor-like structures of the cell membrane and therefore bind directly to the epithelial cells themselves ("cytoadhesion") rather than to the mucus gel layer. Furthermore, when bioadhesion is receptor-mediated, it is not only restricted to mere binding, but may subsequently trigger the active transport of large molecules or nanoscalic drug carrier systems by vesicular transport processes (endo-/transcytosis). Rather than only acting as a platform for controlled release systems, the concept of lectin-mediated bioadhesion therefore bears the potential for the controlled delivery of macromolecular biopharmaceuticals at relevant biological barriers, such as the epithelia of the intestinal or respiratory tract.     

Increased bioavailability of propranolol in rats by retaining thermally gelling liquid suppositories in the rectum.

Mucoadhesive liquid suppositories were prepared by adding mucoadhesive polymers (0.6%) to a formulation of thermally gelling suppositories that contained poloxamer 407 (15%), poloxamer 188 (15%) and propranolol HCl (2%). Hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), carbopol, polycarbophil and sodium alginate were examined as mucoadhesive polymers. The characteristics of the suppositories differed depending on the choice of mucoadhesive polymer. For example, the gelation temperature was between 30 and 36 degrees C, the mucoadhesive force was between 430 and 5800 dyne/cm2, the apparent first-order release rate constant in phosphate buffer, pH 6.8, was between 0.399 and 0.271 h-1, the migration distance of the suppository in the rectum 4 h after administration was between 1 and 5 cm, and the bioavailability of propranolol was between 60.9 and 84.7%. Rectal bioavailability increased as the mucoadhesive force increased (r=0.984, p<0.0005), and the migration distance decreased (r=-0.951, p<0.005). No relationship was found between the bioavailability and the gelation temperature, drug release or irritation of the rectal mucosal membrane by the suppository. Therefore, retaining propranolol at the dosed site in the rectum by the addition of appropriate mucoadhesives to the formulation of liquid suppositories appears to be a very important factor in avoiding first-pass hepatic elimination and thereby increasing the bioavailability of the drug. Among the mucoadhesive polymers examined, sodium alginate and polycarbophil exhibited the largest mucoadhesive force and the smallest intrarectal migration resulting in the largest bioavailability of propranolol (84.7 and 82.3%, respectively). In contrast to other polymers, sodium alginate alone caused no irritation of the rectal mucosal membrane. Thus, poloxamer liquid suppositories containing sodium alginate appears to be a preferred formulation for drugs that are sensitive to extensive first-pass metabolism.     

Mucoadhesive drug carrier based on interpolymer complex of poly(vinyl pyrrolidone) and poly(acrylic acid) prepared by template polymerization.

To develop a new mucoadhesive drug carrier, poly(vinyl pyrrolidone) (PVP)/poly(acrylic acid) (PAA) interpolymer complexes were prepared by the template polymerization of acrylic acid using PVP as a template polymer. Fourier transform infrared results showed that the interpolymer complexes were formed by hydrogen bonds between the carboxyl groups of PAA and the carbonyl groups of PVP. The adhesive forces of the PVP/PAA interpolymer complexes were higher than that of commercial Carbopol 971. Moreover, the adhesive force and the release rate can be controlled by changing the mole ratios of PVP and PAA. The release rates of ketoprofen from the PVP/PAA interpolymer complexes showed pH-dependency, and were slower at lower pH. The release rate of ketoprofen from the complex seemed to be mainly controlled by the dissolution rate of the complex above a pK(a) of PAA (4.75) and by the diffusion rate below the pK(a). The prepared complex appears to be an adequate carrier for the mucoadhesive drug delivery system.     

Mucoadhesive drug carriers based on complexes of poly(acrylic acid) and PEGylated drugs having hydrolysable PEG-anhydride-drug linkages.

We have designed a new mucoadhesive drug delivery formulation based on H-bonded complexes of poly(acrylic acid) (PAA) or poly(methacrylic acid) (PMAA) with the poly(ethylene glycol) (PEG), of a (PEG)-drug conjugate. The PEGylated prodrugs are synthesized with degradable PEG-anhydride-drug bonds for eventual delivery of free drug from the formulation. In this work we have used indomethacin as the model drug which is PEGylated via anhydride bonds to the PEG. The complexes are designed first to dissociate as the formulation swells in contact with mucosal surfaces at pH 7.4, releasing PEG-indomethacin, which then hydrolyses to release free drug and free PEG. We found that as MW of PAA increases, the dissociation rate of the complex decreases, which results in decreased rate of release of the drug. On the other hand, the drug release from PEG-indomethacin alone and from solid mixture of PEG-indomethacin+PAA was much faster than that from the H-bonded complexes. Due to the differences in the thermal stability, PMAA complex exhibited slightly faster drug release than that of the PAA complex of comparable MW. These H-bonded complexes of degradable PEGylated drugs with bioadhesive polymers should be useful for mucosal drug delivery.     

Reduction-responsive molecularly imprinted nanogels for drug delivery applications

Degradable molecularly imprinted polymers (MIPs) with affinity for S-propranolol were prepared by the copolymerization of methacrylic acid as functional monomer and a disulfide-containing cross-linker, bis(2-methacryloyloxyethyl)disulfide (DSDMA), using bulk polymerization or high dilution polymerization for nanogels synthesis. The specificity and the selectivity of DSDMA-based molecularly imprinted polymers toward S-propranolol were studied in batch binding experiments, and their binding properties were compared to a traditional ethylene glycol dimethacrylate (EDMA)-based MIP. Nanosized MIPs prepared with DSDMA as crosslinker could be degraded into lower molecular weight linear polymers by cleaving the disulfide bonds and thus reversing cross-linking using different reducing agents (NaBH₄, DTT, GSH). Turbidity, viscosity, polymer size and IR-spectra were measured to study the polymer degradation. The loss of specific recognition and binding capacity of S-propranolol was also observed after MIP degradation. This phenomenon was applied to modulate the release properties of the MIP. In presence of GSH at its intracellular concentration, the S-propranolol release was higher, showing that these materials could potentially be applied as intracellular controlled drug delivery system.

Degradable molecularly imprinted polymers were prepared using redox sensitive cross-linkers and applied as intracellular drug delivery system to address the biocompatibility and cytotoxicity issues encountered with these synthetic polymers.     

Pharmacokinetic evaluation of guar gum-based colon-targeted drug delivery systems of mebendazole in healthy volunteers.

The pharmacokinetic evaluation of guar gum-based colon-targeted tablets of mebendazole against an immediate release tablet was carried out in human volunteers. Six healthy volunteers participated in the study and a crossover design was followed. Mebendazole was administered at a dose of 50 mg both in immediate release tablet and colon-targeted tablets. On oral administration of colon-targeted tablets, mebendazole started appearing in the plasma at 5 h, and reached the peak concentration (C(max) of 25.7+/-2.6 ng/ml) at 9.4+/-1.7 h (T(max)) whereas the immediate release tablets produced peak plasma concentration (C(max) of 37.2+/-6.8 ng/ml) at 3.4+/-0.9 h (T(max)). Colon-targeted tablets showed delayed t(max) and absorption time, and decreased C(max) and absorption rate constant when compared to the immediate release tablets. The results of the study indicated that the guar gum-based colon-targeted tablets of mebendazole did not release the drug in stomach and small intestine, but delivered the drug to the colon resulting in a slow absorption of the drug and making the drug available for local action in the colon.     

Thiolated chitosans: development and in vitro evaluation of a mucoadhesive, permeation enhancing oral drug delivery system.

It was the aim of this study to develop a mucoadhesive, permeation enhancing delivery system for orally administered poorly absorbed drugs. Chitosan was modified by the immobilisation of thiol groups utilising 2-iminothiolane (Traut's reagent). The permeation enhancing effect of the resulting chitosan-4-thio-butylamidine conjugate (chitosan-TBA conjugate) in combination with the permeation mediator glutathione (GSH) was evaluated in Ussing chambers on freshly excised small intestinal mucosa from guinea pigs using rhodamine 123 as marker for passive drug uptake. The mucoadhesive properties of the chitosan-TBA conjugate adjusted to pH 3, 5 and 7 were evaluated via the rotating cylinder method and via tensile studies. Release studies were performed with tablets comprising 10% cefadroxil used as model drug, 10% GSH and 80% chitosan-TBA conjugate pH 3 in 100 mM phosphate buffer pH 6.8 at 37 degrees C. Results showed a 3-fold higher permeation enhancing effect of the chitosan-TBA conjugate/GSH system in comparison to unmodified chitosan. Mucoadhesion studies revealed that the lower the pH of the thiolated chitosan is, the higher are its mucoadhesive properties. Release studies showed a sustained release of both cefadroxil and GSH over several hours. This delivery system might represent a promising novel tool in order to improve the therapeutic efficacy of various drugs which are poorly absorbed from the gastrointestinal tract.