Enteric Capsules Research Articles

Development of a novel bi-coated combination capsule containing mosapride and probiotics for irritable bowel syndrome

The objective of this study was to develop a novel combination product containing mosapride and probiotics for the treatment of irritable bowel syndrome. Enteric-coated hard gelatin capsules containing probiotics were prepared to protect acid-labile probiotics from the stomach by spray coating with hydroxypropylmethylcellulose phthalate, and then coated with various hydrophilic polymer solutions containing mosapride. The influence of different hydrophilic polymers on the aqueous solubility and dissolution of sparingly soluble mosapride from the capsule was investigated to select the one which imparted highest solubility to mosapride in an aqueous solution. The physicochemical properties of the hydrophilic polymer coating were assessed using SEM and DSC. In addition, the bioavailability of the mosapride-coated capsule in beagle dog was evaluated and compared to that of conventional mosapride tablet (CMT). Based on DSC studies, the mosapride in polymer coating underwent amorphization or molecular dispersion. The enteric-capsule coated with mosapride/HPMC exhibited improved solubility of mosapride at acidic pH and showed significantly improved AUC (1.5-fold) and Cmax (1.6-fold) compared to the CMT. In conclusion, drug/polymer coated enteric gelatin capsule can be an alternative technique for co-delivery of sparingly water-soluble drug and acid-labile drug for enhanced solubility and bioavailability as well as for protection from acid degradation.

Characterization of a Surface Glycoprotein from Echinococcus multilocularis and Its Mucosal Vaccine Potential in Dogs

Alveolar echinococcosis is a refractory disease caused by the metacestode stage of Echinococcus multilocularis. The life cycle of this parasite is maintained primarily between foxes and many species of rodents; thus, dogs are thought to be a minor definitive host except in some endemic areas. However, dogs are highly susceptible to E. multilocularis infection. Because of the close contact between dogs and humans, infection of dogs with this parasite can be an important risk to human health. Therefore, new measures and tools to control and prevent parasite transmission required. Using 2-dimensional electrophoresis followed by western blot (2D-WB) analysis, a large glycoprotein component of protoscoleces was identified based on reactivity to intestinal IgA in dogs experimentally infected with E. multilocularis. This component, designated SRf1, was purified by gel filtration using a Superose 6 column. Glycosylation analysis and immunostaining revealed that SRf1 could be distinguished from Em2, a major mucin-type antigen of E. multilocularis. Dogs (n = 6) were immunized intranasally with 500 µg of SRf1 with cholera toxin subunit B by using a spray syringe, and a booster was given orally using an enteric capsule containing 15 mg of the same antigen. As a result, dogs immunized with this antigen showed an 87.6% reduction in worm numbers compared to control dogs (n = 5) who received only PBS administration. A weak serum antibody response was observed in SRf1-immunized dogs, but there was no correlation between antibody response and worm number. We demonstrated for the first time that mucosal immunization using SRf1, a glycoprotein component newly isolated from E. multilocularis protoscoleces, induced a protection response to E. multilocularis infection in dogs. Thus, our data indicated that mucosal immunization using surface antigens will be an important tool to facilitate the development of practical vaccines for definitive hosts.

Observation on the effect of eucalyptol limonene and pinene enteric soft capsules on elder community acquired pneumonia patients

Objective To observe the therapeutic effect of eucalyptol limonene and pinene enteric soft capsules on elder community acguired pneumonin (CAP) patients.Methods Use the retrospective cohort study methods,233 patients,above 65 year old,were breught into the study,101 patients were in the eucalyptol limonene and pinene enteric soft capsules group and 132 patients were in the control group.The clinical symptoms and length of stay in hospital were recorded.Results The improvement of clinical symptoms on the fifth day of the eucalyptol limonene and pinene enteric soft capsules group was better than that of control group (U =2.37,P ＜ 0.05).And the length of stay in hospital of the eucalyptol limonene and pinene entetic soft capsules group was shorter(U =3.06,P ＜ 0.05).Conclusion Eucalyptol limonene and pinene enteric soft capsules can quickly improve the elder CAP patients clinical symptoms and shorten the length of stay in hospital. Key words: Eucalyptol, limonene and pinene enteric soft capsules; Pneumonia; Aged

장용성 연질 캡슐 오메가3 지방산의 흡수율 평가

We investigate the changes of fatty acids in blood for an evaluation of the effects of soft and enteric coated capsules containing omega 3 fatty acids. Fish oil, which contained 62.87 g/100 g of sum of EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), was used as nutracueticals for omega 3 fatty acids. Lipid releasing amount in soft capsule was 70% in stomach condition. However, there was 10% of releasing amount of lipid observed in enteric coated capsule in stomach condition. In intestinal condition, 50% of lipid releasing amount in enteric coated capsule showed until 6 hr, but soft capsule until 90 min. EPA and DHA contents in soft capsule administration showed higher level than those in enteric coated capsule until 8 hr. However, the administration of enteric coated capsule showed higher level of EPA and DHA in blood after 8 hr. After 24 hr, mono-, poly-unsaturated and saturated fatty acids contents with enteric coated capsule showed higher level than those with soft capsule. The enteric coated capsule containing omega 3 fatty acids was expected to sustain omega 3 fatty acids.

Time–Action Profile of an Oral Enteric Insulin Formulation in Healthy Chinese Volunteers

BackgroundInsulin is an essential treatment for both type 1 and 2 diabetes. Among the available routes of insulin administration, oral delivery is the most appealing option. ObjectiveThe purpose of this study was to evaluate the pharmacodynamic and pharmacokinetic profiles of orally administered enteric insulin and compare the time–action of these oral insulin capsules with neutral protamine Hagedorn (NPH) insulin. MethodsThis was a single-center, randomized, 4-period, crossover study. Twelve healthy volunteers (3 per group) received 1 of 3 doses of oral enteric insulin (50, 100, or 200 U) or 1 subcutaneous injection of NPH insulin (6 U) on 4 separate days. After administration, glucose infusion rates and serum insulin concentrations were monitored for 10 hours. ResultsGlucose infusion rates increased after administration of either NPH or oral enteric insulin. The mean times for maximal metabolic effects for 50, 100, and 200 U of oral enteric insulin were 250 (118), 170 (58), and 236 (132) minutes, respectively, compared with 243 (79) minutes for NPH insulin. The onset of action was slower for oral enteric insulin at 50 U (38 [10] minutes), 100 U (41 [18] minutes), and 200 U (65 [58] minutes) compared with NPH insulin (35 [8] minutes). The maximum glucose infusion rates for oral enteric insulin treatment (1.66 [0.50], 1.61 [1.00], and 1.80 [0.60] mg/kg/min for 50, 100, and 200 U, respectively) were lower compared with NPH insulin (2.06 [0.82] mg/kg/min), although these differences were not statistically significant. ConclusionsOral enteric insulin capsules induced significant glucodynamic effects and exhibited a time–action profile similar to that of NPH insulin in these healthy volunteers. No detectable increases in serum insulin concentration were observed in any treatment group. Trial registry number: ChiCTR-TRC-12001872.

Colon-Targeted Cell-Permeable NFκB Inhibitory Peptide Is Orally Active against Experimental Colitis

For the purpose of development of orally active peptide therapeutics targeting NFκB for treatment of inflammatory bowel disease (IBD), two major barriers in oral delivery of therapeutic peptides, metabolic lability and tissue impermeability, were circumvented by introduction of a colon-targeted delivery system and cell permeable peptides (CPP) to NFκB inhibitory peptides (NIP). Suppression of NFκB activation was compared following treatment with various CPP conjugated NIPs (CPP-NIP). The most potent CPP-NIP was loaded in a capsule coated with a colon specific polymer, which was administered orally to colitic rats. The anti-inflammatory activity of the colon-targeted CPP-NIP was evaluated by measuring inflammatory indices in the inflamed colonic tissue. For confirmation of the local action of the CPP-NIP, the same experiment was done after rectal administration. Tissue permeability of the CPP-NIP was examined microscopically and spectrophotometrically using FITC-labeled CPP-NIP (CPP-NIP-FITC). NEMO binding domain peptide (NBD, TALDWSWLQTE) fused with a cell permeable peptide CTP (YGRRARRRARR), CTP-NBD, was most potent in inhibiting NFκB activity in cells. Colon-targeted CTP-NBD, but not colon-targeted NBD and CTP-NBD in an enteric capsule, ameliorated the colonic injury, which was in parallel with decrease in MPO activity and the levels of inflammatory mediators. Intracolonic treatment with CTP-NBD alleviated rat colitis and improved all the inflammatory indicators. CTP-NBD-FITC was detected at much greater level in the inflamed tissue than was NBD-FITC. Taken together, introduction of cell permeability and colon targetability to NIP may be a feasible strategy for an orally active peptide therapy for treatment of IBD.

HP55-coated capsule containing PLGA/RS nanoparticles for oral delivery of insulin

In this work, we designed and developed a two-stage delivery system composed of enteric capsule and cationic nanoparticles for oral delivery of insulin. The enteric capsule was coated with pH-sensitive hydroxypropyl methylcellulose phthalate (HP55), which could selectively release insulin from nanoparticles in the intestinal tract, instead of stomach. The biodegradable poly(lactic-co-glycolic acid) (PLGA) was selected as the matrix for loading insulin. Eurdragit® RS (RS) was also introduced to the nanoparticles for enhancing the penetration of insulin across the mucosal surface in the intestine. The nanoparticles were prepared with the multiple emulsions solvent evaporation method via ultrasonic emulsification. The optimized nanoparticles have a mean size of 285nm, a positive zeta potential of 42mV. The encapsulation efficiency was up to 73.9%. In vitro results revealed that the initial burst release of insulin from nanoparticles was markedly reduced at pH 1.2, which mimics the stomach environment. In vivo effects of the capsule containing insulin PLGA/RS nanoparticles were also investigated in diabetic rat models. The oral delivered capsules induced a prolonged reduction in blood glucose levels. The pharmacological availability was found to be approximately 9.2%. All the results indicated that the integration of HP55-coated capsule with cationic nanoparticles may be a promising platform for oral delivery of insulin with high bioavailability.

Bioavailability of omeprazole 20 mg capsules containing omeprazole 22.5% enteric coated pellets versus a reference product in healthy Bangladeshi male subjects: an open-label, single-dose, randomized-sequence, two-way crossover study

Omeprazole 20 mg enteric coated capsule formulation is generally prepared either with omeprazole 8.5% or omeprazole 7.5% enteric coated pellets to accommodate in capsule Shell 2, but the use of omeprazole 22.5% enteric coated pellets in capsule Shell 5 for the same amount of omeprazole is a new concept and for the first time in the Bangladesh market. This study was conducted to compare the relative bioavailability and pharmacokinetic properties of two omeprazole 20 mg capsule formulations namely Xeldrin®20 (ACI Ltd., Bangladesh) encapsulated with omeprazole 22.5% enteric coated pellets, as test product and Losec®20 (AstraZeneca, Wilmington, DE, USA) as reference product and to assess whether these formulations meet the FDA requirement for bioequivalence. 24 non-smoking healthy Bangladeshi male subjects participated in this open-label, randomized-sequence, single- dose, two-way crossover study. Subjects were randomly assigned to receive test formulation, followed by reference formulation or vice versa, as a single dose of 20 mg capsule after 12 h overnight fasting. A washout period of 1 week was maintained between the treatments. Blood samples were collected before study drug administration (baseline) and at 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 9.0, and 12.0 h after study drug administration. Serum omeprazole concentrations were determined using a validated HPLC method with UV detection. The pharmacokinetic parameters were determined by the non-compartmental method. The two formulations were to be considered bioequivalent if the 90% confidence intervals (CI) for the ln-transformed ratios of pharmacokinetic parameters were within the predetermined equivalence range of 80 - 125% according to the guidelines of the US Food and Drug Administration (FDA). Tolerability was assessed on the basis of adverse effects, monitoring vital signs, ECG and laboratory tests at baseline and after completion of the study with the assistance of registered physicians. All 24 subjects completed the study without any adverse effect reported. After administering a single dose of 20 mg of each omeprazole formulation, the obtained mean (SD) values for the test and reference products were 608.40 (116.37) and 588.56 (98.36) ng/ml for Cmax; 1.83 (0.25) and 2.00 (0.30) h for tmax; 1,635.77 (581.25) and 1,639.58 (652.54) h-ng/ml for AUC0-12; and 1,721.12 (572.07) and 1,805.58 (856.39) h-ng/ml for AUC(0-∞) respectively. The mean t(1/2) was 3.33 (1.61) and 3.57 (1.24) h for test and reference product respectively. From paired t-test, no significant differences were observed (p > 0.05) for any pharmacokinetic parameters. The point estimates (90% CI) for the test/reference ratios of the ln-transformed AUC(0-12), AUC(0-∞) and C(max) mean values were 100.73% (91.40 -111.01%), 98.29% (88.45 -109.24%) and 103.06% (99.05 - 07.24%) respectively, which fell within the predetermined FDA bioequivalence range of 80 - 125%. This single-dose study found that the test (Xeldrin®20) and reference (Losec®20) 20 mg capsule formulations of omeprazole in these fasting healthy male Bangladeshi subjects met the FDA regulatory criteria for bioequivalence.

Improving the oral bioavailability of sulpiride by sodium oleate in rabbits.

To improve the limited oral bioavailability of sulpiride, a dosage form containing sodium oleate as an absorption enhancer was developed and evaluated using gastric-emptying-controlled rabbits in a cross-over manner. In addition to the known properties of sodium oleate with respect to modifying the permeability of biomembranes, it was found to be capable of improving the physicochemical properties of sulpiride toward a higher lipophilicity (by ion-pair association) and a higher solubility (by micellar solubilization). Nonetheless, the incorporation of sodium oleate with sulpiride as a mixture filled in hard gelatin capsules failed to increase intestinal absorption, whereas the use of enteric capsules, instead of the hard gelatin capsules resulted in a significant increase (P < 0.05) in the oral bioavailability.

Polymer film formulations for the preparation of enteric pharmaceutical capsules

Standard pharmaceutical capsules are designed to dissolve in the acidic environment of the stomach releasing the encapsulated contents for absorption. When release is required further along the gastrointestinal tract capsules can be coated with acid insoluble polymers to enable passage through the stomach and dissolution in the intestine. This paper describes formulations that have the potential to be used to produce two-piece hard capsules for post-gastric delivery without the requirement of an exterior coat. The formulation uses three polysaccharides: sodium alginate, hypromellose and gellan gum to provide acid insolubility and the ability to form capsules using standard industrial equipment. The rheological profile, on cooling, of the base material, water content and thickness of the films were shown to be comparable with those of commercial capsules. The capsules remained intact for 2 h in 100 mm HCl at pH 1.2, and within 5 min of being removed from the acid and submerged in phosphate-buffered saline at pH 6.8 were ruptured. Selected formulations from this study have potential for use as delayed release capsules.

Effects of Changjishu soft elastic capsule in treatment of diarrhea-predominant irritable bowel patients with liver-qi stagnation and spleen deficiency syndrome: a randomized double-blinded controlled trial

To evaluate the efficacy and safety of Changjishu soft elastic capsule, a new Chinese herbal medicine for smoothing liver, invigorating spleen and regulating qi activity, on diarrhea-predominant irritable bowel syndrome (D-IBS) patients with liver-qi stagnation and spleen deficiency syndrome. A randomized, double-blinded, and positive control method was adopted. One hundred and four cases of D-IBS conforming to the inclusive criteria were randomly divided into treatment group (78 cases) and control group (26 cases). Patients in the treatment group were treated with Changjishu soft elastic capsule, four capsules once daily and three times a day. Patients in the control group were treated with glutamine compound enteric capsule, three capsules once daily and three times a day. After 21-day treatment, the efficacy of Changjishu soft elastic capsule was evaluated by the changes of single symptom such as abdominal pain or discomfort, defecation frequency, and stool characteristics. The safety of Changjishu elastic capsule was assessed by laboratory data and adverse events. Abdominal pain or discomfort scores at days 7, 14, 21 and the declined score at day 21 in the treatment group significantly decreased as compared with the control group (P < 0.05). Defecation frequency score at day 14 and the declined score at day 21 in the treatment group significantly decreased as compared with the control group (P < 0.05). Stool characteristics score and the declined score at day 21 in the treatment group significantly decreased as compared with those of the control group (P < 0.05). Rugitus scores and the declined scores at days 14 and 21 significantly decreased as compared with the control group (P < 0.05). The total response rates in the treatment and control groups were 71.62% and 40.91%, and the recovery rates were 20.27% and 13.64%, respectively. There existed significant differences between the two groups in therapeutic effect (P < 0.01). The therapeutic effect of Changjishu elastic capsule was better than that of glutamine compound enteric capsule. Side effects and adverse events were not found in the two groups. Changjishu soft elastic capsule is effective and safe for treatment of D-IBS patients with liver-qi stagnation and spleen deficiency syndrome.

Preparation of esomeprazole zinc solid dispersion and study on its pharmacokinetics

Esomeprazole zinc (EZ) is a poorly water-soluble substance. In order to increase its dissolution rate and bioavailability, solid dispersions of esomeprazole zinc (SDEZ) in polyethylene glycol 4000 (PEG4000) with different EZ to PEG4000 ratios were prepared by solvent method. Our studies showed that dissolution rate of EZ were distinctively increased in the solid dispersion system compared to that in pure EZ or physical mixtures. The increase of dissolution rate was obviously related to the ratio of EZ to PEG4000. The solid dispersion system (EZ/PEG4000 = 1/8, w/w) gave the highest dissolution rate: about 14.7-fold higher than that of the pure EZ. EZ was proved to be in amorphous state in this solid dispersion by using differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) techniques. In vivo administration studies, SDEZ in enteric capsule (SDEZ-EC) has a lower C max and a longer T max than that of esomeprazole magnesium enteric-coated tablet (Nexium), and the differences of C max and T max between SDEZ-EC and Nexium are significant. This result suggests SDEZ-EC has a lower absorption rate than Nexium and corresponds with the in vitro dissolution.

Bioequivalence study of two enteric coated capsule formulations of omeprazole in healthy volunteers

Medical profession has realized the problem of wide variations in the therapeutic effectiveness of various brands of oral formulations containing the same active ingredient in equal amounts. The study was conducted as an open label, balanced, randomized, two-treatment, two-period, two-sequence single-dose crossover study to determine the bioequivalence of Lomac 20-mg and Protoloc 20-mg enteric coated capsules under fasting conditions. A group of 12 healthy, adult, male human subjects participated in the study. The bioavailability was compared using pharmacokinetic parameters Cmax, Tmax, AUC0-t, and AUC0-&#8734;. Moreover, the 90% confidence interval (CI) for the ratio of logarithmic transformed Cmax, AUC0-t and AUC0-&#8734; was also used to determine bioequivalence. A washout period of seven days was kept between each study period. Serial blood samples were collected at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12 h post dose during each study. The samples were analyzed using high performance liquid chromatography (HPLC) by liquid-liquid extraction method using lansoprazole as a reference standard. The 90% CI for the log transformed data for Cmax, AUC0-t, and AUC0-&#8734; for the test product were 72.13-152.7, 58.49-144.28 and 61.77-136, respectively. The T/R (test/reference) ratio of the product was quite close to the prescribed limits of bioequivalence i.e., 94% (95-105%). There was no period, sequence, formulation effect as indicated by the p values. The test product of omeprazole i.e., Lomac was not bioequivalent to the reference product i.e. Protoloc but bioavailability of the test product was quite satisfactory i.e. 94%. Keywords: bioequivalence, omeprazole, pharmacokinetics, bioavailability, healthy volunteers Ethiopian Pharmaceutical Journal Vol. 23 2005: 45-52

Development of a new method for small bowel transit study

Currently, most studies combine the small bowel transit examination with gastric emptying time examination. There are significant drawbacks to this method. The radiotracer does not enter the small intestine in a bolus and the starting time for transit in the duodenum is difficult to define. This makes the result unreliable. In this study, we used a commercial enteric capsule containing radioactive charcoal to solve these problems. Activated charcoal powder was mixed with Tc-99m pertechnetate and loaded to the enteric capsule which can resist gastric acid and dissolve only in the small intestine. In-vitro stability experiment was performed by immersing these capsules in a colorless phosphate buffer of variable pH which mimicked the condition in stomach and small intestine. In addition, ten healthy Chinese volunteers were included for in-vivo experiment. Anterior and posterior views of abdomen were obtained at regular 30-minute intervals until the eighth hour after administration of the radioactive enteric capsule. Small bowel transit time was calculated. The enteric capsule remained intact for at least 480 minutes in the solution mimicking gastric content (pH = 3.0) and disrupted at a mean duration of 227.2 minutes at a pH of 6.8 and at a mean duration of 212.4 minutes at a pH of 7.4 in the solution mimicking pancreaticobiliary secretions. In nine of ten volunteers, the small bowel transit time was between 30 to 270 minutes with a mean transit time of 140 min. In one volunteer, we failed to detect the exact time of small bowel transit because the capsule remained in the stomach throughout the study for up to 8 hours. We consider activated charcoal labeled with Tc-99m pertechnetate using an enteric capsule as the carrier to be a potential radioactive marker for small bowel transit study.

Colon-specific drug delivery: Influence of solution reticulation properties upon pectin beads performance

In this study, pectinate gel beads were produced by ionotropic gelation method with different solutions of cross-linking agents and ketoprofen was entrapped as model drug. The influence of these formulation parameters was investigated upon bead properties and upon their performance to target the colon. Zinc pectinate beads obtained with 10% of counter-ions solution at pH 1.6 exhibited the strongest gel network due to “egg-box” dimmer formation helped by hydrogen bonding. Furthermore the gel network formed at low pH was arranged in a compact three-fold conformation. Thus, this matrix structure in enteric capsules induced the lowest drug release in the upper gastro-intestinal tract (pH 1.2 following by pH 7.4). However ketoprofen release occurred specifically in the colon thanks to the presence of pectinolytic enzymes and the release rate can be modulated by the counter-ion concentration during the reticulation process. Therefore this approach using pectinate beads is very promising as efficient carrier for specific delivery of drug into the colon, after oral administration.

Preparation and evaluation of oral solid heparin using emulsifier and adsorbent for in vitro and in vivo studies

Oral anticoagulant therapy with heparin has been challenged by formulating heparin in oral solid preparation. As heparin, low molecular weight heparin (LMWH) was used. LMWH was dispersed with a surfactant used for the self-microemulsifying drug delivery system (SMEDDS), PEG-8 caprylic/capric glycerides (Labrasol), and the mixture was solidified with three kinds of adsorbents, microporous calcium silicate (Florite™ RE), magnesium alminometa silicate (Neusilin™ US 2) and silicon dioxide (Sylysia™ 320). The in vitro release study showed that the T50%s were 3.2 ± 0.1 min for Sylysia 320, 4.6 ± 0.2 min for Florite RE, 13.7 ± 0.1 min for Neusilin US 2. The in vivo rat absorption study showed that Florite RE system had the highest C max, 0.42 ± 0.01 IU/mL and AUC, 0.59 ± 0.06 IU h/mL, where plasma LMWH levels were measured as anti-Xa activity. Other preparations had the C max and AUC, 0.12 ± 0.01 IU/mL and 0.15 ± 0.02 IU h/mL for Neusilin US 2 and 0.25 ± 0.02 IU/mL and 0.40 ± 0.03 IU h/mL for Sylysia 320, respectively. The bioavailability (BA) of LMWH from the microporous calcium silicate preparation, Florite RE, was 18.8% in rats by comparing the AUC obtained after i.v. injection of LMWH, 40 IU/kg to another group of rats. Florite RE system was evaluated in dogs after oral administration in an enteric capsule made of Eudragit S100 at the LMWH dose of 200 IU/kg. High plasma anti-Xa activity levels were obtained, i.e., the C max was 0.48 ± 0.11 IU/mL and AUC was 1.64 ± 0.32 IU h/mL. These results suggest that adsorbent system is useful as an oral solid delivery system of poorly absorbable drugs such as LMWH.

Colonic Drug Delivery: Influence of Cross-linking Agent on Pectin Beads Properties and Role of the Shell Capsule type

ABSTRACTFor colonic delivery, pectin beads obtained by ionotropic gelation method have been already reported as an interesting approach. This study investigated the influence of the cross-linking agent (calcium or zinc) and the type of shell capsule used (classical or enteric capsules) on pectin beads properties and on their performance to target the colon (in vitro dissolution studies with subsequent pH change to mimic overall gastro-intestinal tract). Zinc pectinate beads seemed to be relatively similar to calcium's ones in morphological point, except on the surface aspect. When beads were introduced in classical hard capsules, ketoprofen release was not significantly different between CPG and ZPG beads, and it was too premature and too quick due to a chemical erosion of the pectinate matrix (acid + basic attacks). However, zinc pectinate beads showed slower ketoprofen release compared with calcium pectinate beads when enteric hard capsules were used. This interesting finding could be due to the strength of the network formed during the process between the zinc cations and the LM-pectin following the “egg-box” model. This network was stronger and induced a reduction of swelling and hydration when contact with dissolution medium, then subsequently a decrease of drug release. Thus, the zinc pectinate beads could protect sufficiently drug entrapped from the upper gastro-intestinal conditions and drug release will be controlled by pectin degradation with colonic microflora. Finally, these zinc pectinate beads in enteric hard capsules are promising as a carrier for specific colonic delivery of drugs after oral administration.

A Nexus of Progression of Chronic Kidney Disease: Charcoal, Tryptophan and Profibrotic Cytokines

Fibrosis plays a role in the pathogenesis of progressive chronic kidney disease (CKD). The inhibition of the renin-angiotensin system, which promotes fibrosis, has become the standard of care in the treatment of patients with CKD. A novel charcoal compound, AST-120, has been used for over a decade in Japan to prevent progression of CKD. It is thought that the oral administration of AST-120 blocks the intestinal absorption of tryptophan-derived indole. This prevents the hepatic conversion of indole to indoxyl sulfate (IS). IS has been shown to stimulate the production of profibrotic cytokines such as transforming growth factor-beta. AST-120 lowers IS in a dose dependent fashion and does not change the creatinine appearance rate in the urine. Enteric capsules containing Bifidobacterium longum have been shown to prevent progression of CKD in a preliminary study. These findings suggest that prospective clinical trials be undertaken to determine if these other potential methods of inhibiting fibrosis are useful in slowing progressive CKD.

Oral solid gentamicin preparation using emulsifier and adsorbent

Oral gentamicin (GM) therapy has been challenged by formulating GM in oral solid preparation. GM was dispersed with a surfactant used for the self-microemulsifying drug delivery system (SMEDDS), PEG-8 caprylic/capric glycerides (Labrasol), and the mixture was solidified with several kinds of adsorbents. The used adsorbents were microporous calcium silicate (Florite™ RE), magnesium alminometa silicate (Neusilin™ US 2), and silicon dioxide (Sylysia™ 320). In vitro release study showed that the percentage released of GM from each preparation per 2 h was 99.8 ± 0.06% for Florite RE 10 mg, 96.7 ± 1.16% for Florite RE 20 mg, 98.3 ± 0.32% for Neusilin US 2, and 94.4 ± 0.23% for Sylysia 320. The T 50% values were 0.35 ± 0.05 h for Florite RE 10 mg, 0.34 ± 0.03 h for Florite RE 20 mg, 0.26 ± 0.03 h for Neusilin US 2, and 0.15 ± 0.01 h for Sylysia 320. The in vivo rat absorption study showed that Florite RE 10 mg preparation had the highest C max (2.14 ± 0.67 μg/ml) and AUC (4.74 ± 1.21 μg h/ml). Other preparations had C max and AUC of 0.69 ± 0.10 μg/ml and 1.56 ± 0.43 μg h/ml for Florite RE 20 mg, 1.07 ± 0.31 μg/ml and 1.80 ± 0.33 μg h/ml for Neusilin US 2, and 0.99 ± 0.21 μg/ml and 1.77 ± 0.50 μg h/ml for Sylysia 320, respectively. The bioavailability (BA) of GM from the microporous calcium silicate preparation, Florite RE 10 mg, was 14.1% in rats, derived by comparing the AUC obtained after intravenous injection of GM, 1.0 mg/kg, to another group of rats. The microporous calcium silicate preparation using Florite RE 10 mg was evaluated in dogs after oral administration in an enteric capsule, Eudragit S100 (50 mg/dog). High plasma GM levels were obtained (i.e., the C max was 1.26 ± 0.20 μg/ml and the AUC was 2.59 ± 0.33 μg h/ml). These results suggest that an adsorbent system is useful as an oral solid delivery system of poorly absorbable drugs such as GM.

Effect of adsorbents on the absorption of lansoprazole with surfactant

Lansoprazole (LPZ) is a representative drug that shows a high inter-subject variation of bioavailability (BA). Solid preparation composed of surfactant, adsorbent and LPZ were prepared to improve the dissolution and absorption of LPZ, and the BA of LPZ was measured in rats and dogs. As surfactant, Tween 80, polyoxy 60 hydrogenated caster oil derivative (HCO-60) and PEG-8 caprylic/capric glycerides (Labrasol) were used. As adsorbant, porous silicon dioxide (Sylysia 550, 320), magnesium aluminometa silicate (Neusilin S 2, NS 2N, US 2,) and porous calcium silicate (Florite RE) were used. After small intestinal administration of LPZ, 5.0 mg/kg, solution with HCO-60 showed the highest plasma LPZ concentration versus time curve of which C max and AUC was 0.46 ± 0.01 μg/mL and 0.73 ± 0.03 μg h/mL. By comparing to that after i.v. injection of LPZ solution, 2.0 mg/kg, the BA of LPZ from HCO-60 solution was 39.0%, which was about seven times higher than that of LPZ powder. To solidify the LPZ solution with HCO-60, adsorbents were used and the obtained solid preparations were used for in vitro release experiment. Sylysia 320, Neusilin S 2 and Neusilin NS 2 showed the T50% of about 1 h. To evaluate the BA of these solid preparations, absorption study was performed in rats. Sylysia 550 system showed the higher AUC than other systems, showing the BA of 28.1%. Sylysia 550 system was filled in an enteric capsule and was orally administered to dogs and BA was compared with enteric tablet. The AUC of Sylysia 550 system was 2.16 ± 0.26 μg h/mL and was greater than enteric tablet and the BA of 71.7% was obtained. Solid system composed of LPZ, surfactant and adsorbent has suggested the possibility as a good tool to improve the BA of LPZ.