Thiolated polymers: synthesis and in vitro evaluation of polymer-cysteamine conjugates.

The purpose of the present study was to synthesize and characterize novel thiolated polymers. Mediated by a carbodiimide cysteamine was covalently linked to sodium carboxymethylcellulose (CMC) and polycarbophil (PCP). The resulting CMC-cysteamine conjugates displayed 77.9+/-6.7 and 365.1+/-8.7 micromol thiol groups per gram of polymer, whereas the PCP-cysteamine conjugates showed 26.3+/-1.9 and 122.7+/-3.8 micromol thiol groups per gram of polymer (mean+/-S.D.; n=3). In aqueous solutions above pH 5.0 both modified polymers were capable of forming inter- and/or intra-molecular disulfide bonds. The reaction velocity of this oxidation process was accelerated with a decrease in the proton concentration. The oxidation proceeded more rapidly within thiolated CMC than within thiolated PCP. Permeation studies carried out in Ussing-type chambers with freshly excised intestinal mucosa from guinea pigs utilizing sodium fluorescein as model drug for the paracellular uptake revealed an enhancement ratio (R=P(app) (conjugate)/P(app) (control)) of 1.15 and 1.41 (mean+/-S.D.; n=3) for the higher thiolated CMC-cysteamine (0.5%; m/v) and PCP-cysteamine conjugate (1.0%; m/v), respectively. The decrease in the transepithelial electrical resistance values was in good correlation with the enhancement ratios. Due to a high crosslinking tendency by the formation of disulfide bonds stabilizing drug carrier systems based on thiolated polymers and a permeation enhancing effect, CMC- and PCP-cysteamine conjugates represent promising excipients for the development of novel drug delivery systems.

Direct compressible polymethacrylic acid-starch compositions for site-specific drug delivery.

The purpose of this study was to generate and characterize a direct compressible pH-sensitive excipient composition for controlled drug delivery. In acidic aqueous solutions, polymethacrylic acid (PMAA) forms complexes and precipitates with starch. As the extent of the interaction between PMAA and starch reaches a maximum at a weight ratio of 1:1.38 (PMAA/starch), this composition was used for the direct compression of tablets. These tablets (30 mg) showed no disintegration even after 2 days in a disintegration test apparatus according to the USP XXIII, in simulated gastric fluid at pH 1.2. In contrast, in 100 mM phosphate buffer pH 7.0 they disintegrated within 40.25+/-8.42 min (mean+/-S.D., n=3). Control tablets of starch disintegrated within the first minute at both pH values. Dissolution studies with the model peptide peroxidase demonstrated no release within 120 min at pH 1.2, whereas at pH 7.0, 100% of the peptide was released within 330 min. Similar release profiles were obtained with the model drugs amoxicillin and rifampicin. In addition, the use of a PMAA-starch composition as a carrier matrix for peroxidase and amoxicillin provided a protective effect towards pepsin and hydrolytic degradation at pH 1.2, respectively. According to these results, the PMAA-starch composition may be a useful tool to overcome the very harsh environment of the stomach for future delivery systems.

Thiolated polymers: development and evaluation of transdermal delivery systems for progesterone.

PURPOSE: To evaluate the possible use of polycarbophil-cysteine (PCP-Cys) as polymeric matrix for transdermal progesterone application. METHODS: Thiolated polycarbophil was synthesised by the covalent attachment of cysteine to the basis polymer. The adhesive properties of PCP-Cys in comparison to polyvinylpyrrolidone/hydroxypropylmethylcellulose (PVP/HPMC) and polyvinylpyrrolidone/polyvinylalcohol (PVP/PVA) were investigated by testing the total work of adhesion (TWA) on porcine skin. Release studies in Franz diffusion cells and standard in vitro permeation experiments with porcine skin were performed analysing the progesterone content by high-performance liquid chromatography. RESULTS: Films based on PCP-Cys displayed very high cohesive properties due to the formation of interchain disulfide bonds. The TWA of the thiolated polymer on porcine skin was significantly (P <0.05) the highest. In addition progesterone permeation was also the highest from PCP-Cys compared with PVP/HPMC and PVP/PVA within 24 hours. CONCLUSION: PCP-Cys--a partly thiolated polymer--might be a novel polymer matrix for transdermal progesterone delivery with excellent adhesiveness on porcine skin.

Thiolated carboxymethylcellulose: in vitro evaluation of its permeation enhancing effect on peptide drugs.

The purpose of this study was to evaluate the effect of sodium carboxymethylcellulose (NaCMC) and carboxymethylcellulose-cysteine (CMC-Cys) conjugates on the intestinal permeation of sodium fluorescein (NaFlu) and model peptide drugs, bacitracin and insulin. Cysteine was covalently linked to carbodiimide activated NaCMC. Iodometric titration of the polymer conjugates was used to determine the extent of immobilised cysteine. Permeation studies were performed on guinea pig small intestinal mucosa mounted in Ussing-type chamber. Unmodified NaCMC (1% m/v) significantly improved the transport ratio (R= P(app) polymer/ P(app) control) of NaFlu to 1.3 and 1% (m/v) NaCMC conjugated with cysteine further enhanced the permeation. Cysteine conjugation at 3.6, 5.3 and 7.3% (m/m) resulted in R-values of 1.4, 1.7 and 1.8, respectively. Decreasing the concentration of CMC-Cys, exhibiting 7.3% (m/m) of immobilised cysteine (CMC-Cys7.3) from 1% (m/v) to 0.5% (m/v) decreased the R-value of NaFlu from 1.8 to 1.2. NaCMC at 1% (m/v) in the presence of free cysteine had no significant effect on the R-value of NaFlu compared to NaCMC alone. Formulation of fluorescence labelled bacitracin and insulin in unconjugated NaCMC (1% m/v) did not significantly improve the permeation, however in the presence of 1% (m/v) CMC-Cys7.3 a significantly improved permeation was observed (R= 1.3). Conjugation at NaCMC with cysteine moieties significantly improves the intestinal permeation of the hydrophilic molecule NaFlu and the model peptide drugs bacitracin and insulin in vitro, therefore this conjugated system maybe useful for peroral administration of peptide drugs in the future.

In vitro evaluation of the permeation-enhancing effect of thiolated polycarbophil.

The objective of this study was to investigate the permeation-enhancing effect of thiolated polycarbophil (PCP) on peptide drugs. Mediated by a carbodiimide, increasing amounts of cysteine (Cys) were covalently bound to sodium neutralized PCP (NaPCP). The extent of covalently attached Cys was determined by quantifying the share of thiol groups on the resulting polymer-Cys conjugates via iodometric titration. The permeation-enhancing effect of polymer-Cys conjugates was evaluated in Ussing-type chambers using intestinal mucosa from guinea pigs. Whereas the transport enhancement ratio (P(app) polymer/P(app) control) for 0.5% (m/v) NaPCP was 1.14 using sodium fluorescein as model drug, it was 1.63 for 0.5% (m/v) PCP-Cys displaying a share of 2.2% (m/m) Cys on the conjugate (PCP-Cys 2.2%). Moreover, the substitution of sodium fluorescein by bacitracin-fluorescein isothiocyanate (bacitracin-FITC) led to ratios of 1.03 and 1.36 and in the case of insulin-fluorescein isothiocyanate (insulin-FITC) to ratios of 1.07 and 1.33, respectively (means; n = 3). Additional permeation studies with 0.5% (m/v) PCP-Cys conjugates exhibiting a share of 1.8% up to 4.2% of cysteine showed enhancement ratios of 1.22 up to 1.47 for sodium fluorescein within 3 h. In contrast, the permeation-enhancing effect of PCP could not be improved by the addition of free unconjugated Cys. Because of their permeation-enhancing effect for the paracellular route of absorption, PCP-Cys conjugates probably represent a new tool for the peroral administration of peptide drugs.