Polycarbophil Research Articles

炭酸リチウム併用時におけるポリカルボフィルカルシウムの作用減弱について

Calcium polycarbophil has been found to be useful in the treatment of irritable bowel syndrome. It is activated through transformation to polycarbophil by decalcification under the acidic conditions in the stomach. Polycarbophil absorbs water in the small intestine, where conditions are neutral, causing it to swell and form a gel.We encountered a patient in whom calcium polycarbophil was effective when given alone but developed diarrhea when it was administered together with lithium carbonate. When these two agents were taken separately, the diarrhea was relieved. In order to ascertain how lithium carbonate affected calcium polycarbophil, we carried out an in vitro experiment whose results showed that lithium carbonate caused an increase in pH. This inhibited decalcification, and reduced the extent of swelling of polycarbophil. These results suggest that the efficacy of calcium polycarbophil would be reduced when administered together with lithium carbonate.

Systematic review: the role of different types of fibre in the treatment of irritable bowel syndrome.

Both high-fibre dietary advice and the prescription of fibre as a bulking agent are very common in primary and secondary care management of irritable bowel syndrome. Irritable bowel syndrome patients with constipation may have delayed intestinal transit. Therefore, fibres that accelerate intestinal transit may be beneficial in these patients. The uncertain benefits reported in several clinical studies, however, have led us to reappraise the value of fibre in irritable bowel syndrome management. To quantify the effect of different types of fibre on global and symptom relief from irritable bowel syndrome. Using a structured literature search in MEDLINE (1966-2002), we selected randomized controlled trials involving irritable bowel syndrome patients treated with fibre. Analyses were performed for the total group and for trials using soluble and insoluble fibre separately. Seventeen studies were included in the analysis. None investigated primary care irritable bowel syndrome patients. Fibre, in general, was effective in the relief of global irritable bowel syndrome symptoms [relative risk, 1.33; 95% confidence interval (CI), 1.19-1.50]. Irritable bowel syndrome patients with constipation may receive benefit from fibre treatment (relative risk, 1.56; 95% CI, 1.21-2.02), but there was no evidence that fibre was effective in the relief of abdominal pain in irritable bowel syndrome. Soluble and insoluble fibre, separately, had different effects on global irritable bowel syndrome symptoms. Soluble fibre (psyllium, ispaghula, calcium polycarbophil) showed significant improvement (relative risk, 1.55; 95% CI, 1.35-1.78), whereas insoluble fibre (corn, wheat bran), in some cases, worsened the clinical outcome, but there was no significant difference compared with placebo (relative risk, 0.89; 95% CI, 0.72-1.11). The benefits of fibre in the treatment of irritable bowel syndrome are marginal for global irritable bowel syndrome symptom improvement and irritable bowel syndrome-related constipation. Soluble and insoluble fibres have different effects on global irritable bowel syndrome symptoms. Indeed, in some cases, insoluble fibres may worsen the clinical outcome. Future clinical studies evaluating the effect and tolerability of fibre therapy are needed in primary care.

Mucoadhesive Delivery Systems. I. Evaluation of Mucoadhesive Polymers for Buccal Tablet Formulation

Different types of mucoadhesive polymers, intended for buccal tablet formulation, were investigated for their comparative mucoadhesive force, swelling behavior, residence time and surface pH. The selected polymers were carbopols (CP934, and CP940), polycarbophil (PC), sodium carboxymethyl cellulose (SCMC) and pectin representing the anionic type, while chitosan (Ch) as cationic polymer and hydroxypropylmethyl cellulose (HPMC) as a non‐ionic polymer. Results revealed that polyacrylic acid derivatives (PAA) showed the highest bioadhesion force, prolonged residence time and high surface acidity. SCMC and chitosan ensured promising bioadhesive characteristics, whilst HPMC and pectin exhibited weaker bioadhesion. Different polymer combinations as well as formulations were evaluated to improve the mucoadhesive performance of the tablets. Bioadhesive tablet formulations containing either 5% CP934, 65% HPMC and 30% spray‐dried lactose or 2% PC, 68% HPMC and 30% mannitol showed optimum mucoadhesion and suitable residence time. SCMC, when formulated individually, exhibited promising bioadhesion, acceptable swelling, convenient residence time and surface pH. In‐vivo trials of these formulations proved non‐irritative and prolonged residence of the mucoadhesive tablets on human buccal mucosa for 8 to 13 h.

Best Practice Dietary Management of Chronic Constipation

Objectives The objective of this review is to identify and present the best available evidence on dietetic treatment and management of constipation in children and adults. This will be achieved by reviewing the literature relevant to the management of constipation. Question To investigate effectiveness of dietary interventions in chronic constipation in achieving laxation. Criteria for Inclusion Types of Participants Participants will include children or adults, who are defined as constipated by the following definition: Having at least one of :- • < 3 bowel movements each week • hard or lumpy stools • anal blockage Patients with a constipation for a minimum of two weeks, whose constipation is treated for a minimum of one week. Patients from special populations, such as peripartum and tube-fed patients, will be excluded. Types of Interventions Interventions of interest will be those used for the purpose of treatment of constipation. Examples of specific interventions to be included in the review, but not be limited to, include: bulk, stimulant, osmotic and softening (surfactant) laxatives. Specific treatments previously identified include: psyllium, ispaghula, bran, prucara, lactulose, lactitol, propylethylene glycol, docusate sodium, docusate calcium, cisapride, senna, agiolax, lunelax, calcium polycarbophil, methylcellulose, magnesium hydroxide, laxamucil, sorbitol, dorbanex and sodium picosulphate. Results will be reported under the categories of: 1. Interventions provided by a dietary strategy solely. 2. Interventions provided by a dietary and laxative medication strategy. Types of Outcome measures Measures of outcome will include but not be limited to: • Frequency and/or consistency of bowel actions per week • Symptom improvement (including anal blockage). • Reduction in abdominal pain • Need for breakthrough laxatives • Cost.

Development of buccal drug delivery systems based on a thiolated polymer

The purpose of the present study was to investigate the benefit of thiolated polymers (thiomers) for the development of buccal drug delivery systems. l-Cysteine was thereby covalently attached to polycarbophil (PCP) mediated by a carbodiimide. The resulting conjugate displayed 140.5±8.4 μM thiol groups per gram polymer. Disintegration studies were carried out with tablets based on unmodified polymer and conjugated polymer, respectively. Due to the formation of disulfide bonds within the thiolated polymer, the stability of matrix-tablets based on this polymer was strongly improved. Additionally tensile studies were carried out, which were in good correlation with further results obtained by mucoadhesion studies, using the rotating cylinder method. These results showed that tablets based on thiolated PCP remained attached on freshly excised porcine mucosa 1.8 times longer than the corresponding control. Moreover, the enzyme inhibitory properties of polymers were evaluated as well. Thiolated PCP increased the stability of the synthetic substrate for aminopeptidase N-leu- p-nitroanilide ( N-leu- pNA) and the model drug leucin-enkephalin (leu-enkephalin) against enzymatic degradation on buccal mucosa. Due to the use of thiolated polymers also a controlled drug release for leu-enkephalin was guaranteed over a time period for more than 24 h. Results of the present studies suggest that thiolated polymers represent a very useful tool for buccal delivery of peptide drugs.

Development and in vivo evaluation of buccal tablets prepared using danazol–sulfobutylether 7 β‐cyclodextrin (SBE 7) complexes

The aim of the present work was to develop a mucoadhesive controlled‐release formulation of danazol–sulfobutylether 7 β‐cyclodextrin (SBE 7) complex and to evaluate the feasibility of improving the bioavailability of danazol via the buccal route. Different types of polymers, polycarbophil (PC) and hydroxypropylmethyl cellulose (HPMC) were mixed with danazol–SBE 7 complex and compressed into tablets. These tablets were evaluated for their dissolution and mucoadhesion properties and for drug absorption in female beagle dogs. Increased mucoadhesion was observed for PC‐containing tablets compared with HPMC tablets. As the concentration of polymer increased, drug release decreased, and PC‐containing tablets gave slower release compared to HPMC tablets. In vivo bioavailability performed in dogs showed that the perorally administered danazol–SBE 7 complex and the danazol–SBE 7 (in PC matrix) buccal tablets had absolute bioavailabilities of 64% and 25%, respectively, that are significantly greater than 1.8% observed for the commercial formulation Danocrine®. The increased bioavailability was attributed to the enhanced solubility consequent to complexation, and the possible avoidance of first‐pass metabolism upon buccal administration. © 2002 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:1659–1668, 2002

Prolonged antifungal effects of clotrimazole-containing mucoadhesive thermosensitive gels on vaginitis

To develop more effective treatment for vaginal candidasis, clotrimazole (CT) was formulated in mucoadhesive thermosensitive gels (MTG). Several MTG formulations composed of poloxamers (P) 407, 188, and polycarbophil (PC) were prepared. P188 and PC increased the mucoadhesiveness but reduced the syringebility of liquid forms of the gels. Based on the balance between the mucoadhesiveness and syringebility, MTG composed of P407/P188/PC (15/15/0.2 or 15/20/0.2) were further studied. Of the two MTG, the formulation with 15% of P188 gelled at higher temperature and revealed lower elastic modulus. In vitro, sustained release of CT from MTG was observed. In vivo antifungal activity of CT, tested against Candida albicans vaginitis in female rats, was significantly prolonged after vaginal delivery using MTG. At 10 days post-dose, the c.f.u. of C. albicans was more than 10 4-fold decreased in MTG-treated groups. Moreover, the vaginal delivery of CT in MTG enhanced the viability of epithelial cells without affecting the morphology of vaginal mucosa. These results indicate that CT-containing vaginal MTG might be further developed for safe, convenient, and effective treatment of vaginal candidasis with reduced dosing interval.

Assemblies for In Vitro Measurement of Bioadhesive Strength and Retention Characteristics in Simulated Vaginal Environment

ABSTRACTThe vaginal route of administration offers a promising option for local and systemic delivery of drugs. Conventional vaginal formulations are associated with limitations of poor retention, leakage, and messiness, thereby causing inconvenience to users. To overcome these limitations, formulations that adhere to the vaginal mucosa for a sufficient period of time need to be developed. Bioadhesion and retention are desirable characteristics of a vaginal formulation to achieve desired efficacy. These properties can be built in during formulation development by the use of bioadhesive polymers. In the present study, assemblies for in vitro measurement of bioadhesive strength and retention characteristics of vaginal formulations have been developed. A modified simulated vaginal fluid (SVFM) was used to simulate vaginal conditions for bioadhesion studies. Cellophane hydrated with SVFM and isolated sheep vaginal mucosa were used as model membranes. The bioadhesive potential of various polymers and their combinations was evaluated. Among the polymers evaluated, xanthan gum (XG), sodium alginate (SA), Polycarbophil (PC), and their combinations (XG + SA and XG + PC) were found to possess significant bioadhesive strength. In retention experiments, XG, SA, and combinations (XG + SA and XG + PC) were retained in isolated sheep vaginal tissue, while PC exhibited poor retention under experimental conditions. Based on the results of the study conducted, XG, SA, and combinations (XG + SA and XG + PC) have been proposed as potential candidates for developing bioadhesive vaginal drug delivery systems.

Effect of Bioadhesive Polymers, Sodium Salicylate, Polyoxyethylene-9-lauryl Ether, and Method of Preparation on the Relative Hypoglycemia Produced by Insulin Enteric-Coated Capsules in Diabetic Beagle Dogs

ABSTRACTThe hypoglycemic effect of oral insulin capsules coated with pH-dependent Eudragit® S100 and containing various absorption promoters was studied in hyperglycemic beagle dogs. The absorption enhancers used were bioadhesive polymers, sodium salicylate, and non-ionic surfactants. A comparative study of the bioadhesive polymers, polycarbophil (PC), hydroxypropyl methylcellulose (HPMC), and carbopol 934 in insulin-coated capsules revealed no significant difference between the insulin capsules containing these polymers, giving relative hypoglycemia (RH) values ranging from 4.3±2.3% to 6.5±5.1%. It was also found that the method of preparation of the mixture of the bioadhesive polymer with insulin either by physical mixing or freeze-drying did not affect the RH values obtained. Sodium salicylate, when used in insulin enteric-coated capsules (50 mg) mixed with insulin as a physical mixture, or prepared by wet granulation using 10% polyvinyl pyrollidone (PVP), or by freeze-drying, produced RH values ranging from 7.3±2.9% to 9.4±3.7%. When sodium salicylate (100 mg) was used with insulin in freeze-dried granules an RH value of 10±2.6% was produced. As the dose of insulin increased from 6 to 9 U/kg, the area under curve (AUC) of the enteric-coated capsules containing 50 mg sodium salicylate increased from 73.2±27.8% to 121.4±102.7% reduction, but the RH did not change significantly. Insulin capsules containing polyoxyethylene-9-lauryl ether (POELE) used in its optimum concentration (2%), found in these experiments, produced RH of 9.5±6.8% when prepared as granules by wetting with a few drops of absolute alcohol in the presence of PC (50 mg). Insulin capsules containing lower (1%) or higher (3%) concentrations of POELE and prepared with PC, 50 mg by wet granulation produced lower RH of about 6%. The enteric-coated oral insulin capsules containing insulin (6 or 9 U/kg) and sodium salicylate (50 mg) as an absorption promoter, together with the bioadhesive polymer polycarbophil (50 mg), and prepared either by wet granulation using ethanol or by freeze-drying, are the best formulations to be used. They achieved a reduction in plasma glucose levels of about 25–30% and RH of about 10%. Also insulin (9 U/kg) capsules containing 2% POELE produced a 28% reduction in plasma glucose levels and RH of 9.6±6.8%.

Lack of Interaction Between Cefdinir and Calcium Polycarbophil: In vitro and In vivo Studies

The effect of calcium polycarbophil on the absorption of cefdinir, cephalosporin derivative, was evaluated in both in vitro and in vivo studies. In the in vitro study, the release of cefdinir from a cellulose membrane in the presence or absence of metal cations was measured using the dissolution test procedure. In the in vivo study, volunteers and a randomized crossover design with two phases were used. In the first phase, the volunteers received 200 mg of cefdinir alone (Study 1); in the other phase, they received 200 mg of cefdinir and 1200 mg of fine calcium polycarbophil granules concomitantly (Study 2). The cefdinir concentrations in the samples or serum were measured by an UV-VIS spectrophotometer or high-performance liquid chromatography. Release in the presence of iron ions was slower than that in the absence of metal ions, however no difference was observed between release in the presence of calcium ions and that in the absence of metal ions. No difference was observed in AUC(0-10), C(max) and t(max) between Study 1 and Study 2. The absorption of cefdinir was not affected by co-administration of calcium polycarbophil. Moreover, the in vitro study on the release of drugs from a cellulose membrane may predict the absorption of a drug caused by the formation of chelate complexes between the drug and metal ions.

In situ gelling and mucoadhesive polymer vehicles for controlled intranasal delivery of plasmid DNA

Nasal administration of plasmid DNA is emerging as a new route of delivery for therapeutic genes and DNA vaccines. To improve the intranasal absorption of plasmid DNA, we designed delivery systems composed of in situ gelling and mucoadhesive polymers. Poloxamers (Pol) were used to provide in situ gelling property. Polycarbophil (PC) or polyethylene oxide (PEO) was used as mucoadhesive polymers. The gelation temperatures of the formulations slightly decreased by the mucoadhesive polymers, but not by plasmid DNA. The in vitro release of plasmid DNA from the gels followed Fickian diffusion. The absorption of plasmid DNA varied with the contents and type of mucoadhesive polymers. Of vehicles, Pol/PC 0.2% showed the highest absorption with an area under the curve value 11-fold higher than saline, the conventional vehicle. The nasal retention of plasmid DNA was highly prolonged by mucoadhesive polymers. At 3 h postdose, the nasal tissue levels of plasmid DNA given in Pol/PC and Pol/PEO 0.8% were 10- and 40-fold higher relative to saline. The histopathology of nasal tissues was not altered after repeated dosing over 2 weeks. The mRNA expression of plasmid DNA delivered by Pol or Pol/PEO 0.4% was observed in the nasal tissues. These results indicate that the nasal absorption of plasmid DNA can be effectively and safely enhanced by using in situ gelling and mucoadhesive polymer-based vehicles.

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 μmol thiol groups per gram of polymer, whereas the PCP–cysteamine conjugates showed 26.3±1.9 and 122.7±3.8 μmol 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.

Influence of the spacer on the inhibitory effect of different polycarbophil–protease inhibitor conjugates

Within the present study various polycarbophil (PCP)–serine protease inhibitor conjugates were synthesized and the influence of different spacers on their inhibitory efficacy was evaluated in vitro. Results demonstrated that 4.2±0.15 units ( n=3; ±SD) of α-chymotrypsin were inhibited by 50% utilizing 0.86% (w/v) of a PCP–tetramethylenediamine (TMDA)-chymostatin 20:1 conjugate. In contrast, only 0.6±0.05 units ( n=3; ±SD) of α-chymotrypsin were inhibited by a corresponding PCP–poly(ethylene glycol) (PEG)-chymostatin conjugate. Inhibitory effects of PCP–TMDA-antipain and -elastatinal conjugates towards trypsin and elastase, respectively, were also significantly higher ( P<0.05) than those of corresponding PCP–PEG-inhibitor conjugates. Hence, the great impact of the molecular size as well as the structure of the spacer on resulting polymer-inhibitor conjugates could be demonstrated. The small and rigid C4-spacer TMDA (molecular weight (MW) 161.1) was thereby shown to be highly advantageous over a long, hydrophilic and flexible PEG-diamine spacer (MW 3400). Results obtained should provide helpful basic knowledge for the development of mucoadhesive polymer–inhibitor conjugates used as auxiliary agents for the oral administration of peptide drugs.

The study of drug release from microspheres adhered on pig vesical mucosa

The object of our work is the preparation of a mucoadhesive drug delivery system intended for intravesical application. In the present work, microspheres with Eudragit RS matrix polymer and different mucoadhesive polymers, i.e. chitosan hydrochloride (Ch), sodium salt of carboxymethyl cellulose (CMC) and polycarbophil (PC) were prepared to evaluate their influence on the mucoadhesive properties of microspheres. Different parameters were determined and their influence on pipemidic acid release from microspheres adhered on intact and damaged pig vesical mucosa was evaluated: swelling of polymers, mucoadhesion strength of polymeric films and drug dissolution according to USP XXIV method. The dissolution rate from microspheres containing different mucoadhesive polymers decreases as follows: PC>Ch>CMC. PC swelled to the largest volume among all polymers and as a result the fastest release of the drug from PC microspheres was obtained. The release rate of pipemidic acid from microspheres adhered on intact mucosa followed the order PC>CMC>Ch. These results show that both drug dissolution and mucoadhesion strength strongly influence drug release from adhered microspheres. The slowest release from Ch microspheres could be interpreted by the largest mucoadhesion strength of Ch polymeric films. The release rate of pipemidic acid from microspheres adhered on damaged mucosa followed the order PC=Ch>CMC. The results obtained on pathologically changed mucosa model support the indication of the role of glycosaminoglycans and polymer charge in the mucoadhesion process on vesical mucosa. Analysis of release data shows that the drug dissolution profiles follow the Higuchi kinetics better than the release profiles from adhered microspheres and different kinetics might be a consequence of different release mechanisms.

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 (Papp polymer/Papp 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. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 1253–1261, 2000

Development of controlled drug release systems based on thiolated polymers

The purpose of the present study was to generate mucoadhesive matrix-tablets based on thiolated polymers. Mediated by a carbodiimide, l-cysteine was thereby covalently linked to polycarbophil (PCP) and sodium carboxymethylcellulose (CMC). The resulting thiolated polymers displayed 100±8 and 1280±84 μmol thiol groups per gram, respectively (means±S.D.; n=6–8). In aqueous solutions these modified polymers were capable of forming inter- and/or intramolecular disulfide bonds. The velocity of this process augmented with increase of the polymer- and decrease of the proton-concentration. The oxidation proceeded more rapidly within thiolated PCP than within thiolated CMC. Due to the formation of disulfide bonds within thiol-containing polymers, the stability of matrix-tablets based on such polymers could be strongly improved. Whereas tablets based on the corresponding unmodified polymer disintegrated within 2 h, the swollen carrier matrix of thiolated CMC and PCP remained stable for 6.2 h (mean, n=4) and more than 48 h, respectively. Release studies of the model drug rifampicin demonstrated that a controlled release can be provided by thiolated polymer tablets. The combination of high stability, controlled drug release and mucoadhesive properties renders matrix-tablets based on thiolated polymers useful as novel drug delivery systems.

Calcium polycarbophil, a water absorbing polymer, increases bowel movement and prevents sennoside-induced diarrhea in dogs.

The effects of calcium polycarbophil (CP), a water-absorbing polymer, on bowel movement were examined in comparison with known laxatives and anti-diarrheal agents in dogs, a species that resembles humans for stool output. CP increased stool frequency, fecal water content and fecal weight in a dose-dependent manner, but did not induce diarrhea. Sennoside and carboxymethylcellulose sodium (CMC-Na) increased fecal water content and induced diarrhea at lower doses than that which enhanced stool frequency. Trimebutine decreased stool frequency, fecal weight and fecal water content, resulting in inhibition rather than stimulation of defecation. In sennoside-induced diarrhea, loperamide and CP improved stool consistency and this was accompanied by reduced fecal moisture and frequency of diarrhea. In contrast, CMC-Na aggravated stool consistency with increased fecal water content and frequency of diarrhea, and trimebutine had little noticeable effect apart from reducing fecal weight. Our results show that CP has both laxative and anti-diarrheal effects in dogs and differed from conventional laxatives and anti-diarrheal agents. CP may be a suitable agent for treatment of idiopathic constipation, secretory diarrhea and irritable bowel syndrome with alternating constipation and diarrhea and with either predominating in terms of less side effects such as diarrhea or constipation.

Calcium Polycarbophil, a Water Absorbing Polymer, Increases Bowel Movement and Prevents Sennoside-Induced Diarrhea in Dogs

The effects of calcium polycarbophil (CP), a water-absorbing polymer, on bowel movement were examined in comparison with known laxatives and anti-diarrheal agents in dogs, a species that resembles humans for stool output. CP increased stool frequency, fecal water content and fecal weight in a dose-dependent manner, but did not induce diarrhea. Sennoside and carboxymethylcellulose sodium (CMC-Na) increased fecal water content and induced diarrhea at lower doses than that which enhanced stool frequency. Trimebutine decreased stool frequency, fecal weight and fecal water content, resulting in inhibition rather than stimulation of defecation. In sennoside-induced diarrhea, loperamide and CP improved stool consistency and this was accompanied by reduced fecal moisture and frequency of diarrhea. In contrast, CMC-Na aggravated stool consistency with increased fecal water content and frequency of diarrhea, and trimebutine had little noticeable effect apart from reducing fecal weight. Our results show that CP has both laxative and anti-diarrheal effects in dogs and differed from conventional laxatives and anti-diarrheal agents. CP may be a suitable agent for treatment of idiopathic constipation, secretory diarrhea and irritable bowel syndrome with alternating constipation and diarrhea and with either predominating in terms of less side effects such as diarrhea or constipation.

Synthesis and characterisation of mucoadhesive thiolated polymers

This study examined various factors influencing the mucoadhesive properties of thiolated polymers (thiomers), which are capable of forming covalent bonds with thiol sub-structures of the mucus glycoprotein. Mediated by a carbodiimide, l-cysteine was therefore covalently bound to polycarbophil (PCP) and to carboxymethylcellulose (CMC). The resulting polymer conjugates displayed 12.3 and 22.3 μmol thiol groups per gram, respectively. Whereas the swelling behaviour of tablets based on CMC was not markedly influenced by the immobilisation of cysteine, it was improved significantly ( P<0.05) in case of PCP. Tensile studies carried out with the unmodified and thiolated polymers of pH 3, 5 and 7, respectively, revealed that only if the polymer displays a pH-value of 5, the total work of adhesion can be improved significantly due to the covalent attachment of thiol groups. These results were in good agreement with a new mucoadhesion test system described here taking also the cohesiveness of the delivery system into account. The results represent helpful basic information in order to improve the mucoadhesive properties of thiolated polymers.

Polymers with thiol groups: a new generation of mucoadhesive polymers?

To improve the mucoadhesive properties of polycarbophil by the introduction of sulfhydryl groups. Mediated by a carbodiimide, cysteine was covalently bound to polycarbophil (PCP) forming amide bonds between the primary amino group of the amino acid and the carboxylic acid moieties of the polymer. The amount of covalently attached cysteine and the formation of disulfide bonds within the modified polymer were determined by quantifying the share of thiol groups on the polymer conjugates with Ellman's reagent. The adhesive properties of polycarbophil-cysteine conjugates were evaluated in vitro on excised porcine intestinal mucosa by determining the total work of adhesion (TWA). Depending on the weight-ratio of polycarbophil to cysteine at the coupling reaction, e.g., 16:1 and 2:1, 0.6+/-0.7 micromole and 5.3+/-2.4 micromole cysteine, respectively, were covalently bound per g polymer. The modified polymer displayed improved internal cohesive properties due to the formation of interchain disulfide bonds within the polymer in aqueous solutions at pH-values above 5. Adhesion studies revealed strongly improved adhesive properties. Whereas the TWA was determined to be 104+/-21 microJ for the unmodified polymer, it was 191+/-47 microJ for the polymer-cysteine conjugate 16:1 and 280+/-67 microJ for the polymer-cysteine conjugate 2:1. Polymers with thiol groups might represent a new generation of mucoadhesive polymers displaying comparatively stronger adhesive properties.