Enhanced therapeutic effect of LK-423 in treating experimentally induced colitis in rats when administered in colon delivery microcapsules

LK-423 is a phthalimido-desmuramyl-dipeptide derivative with immunomodulating activity. In the present study the therapeutic efficacy of a colon-specific drug delivery system–LK-423 microcapsules–was examined in the 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced ulcerative colitis model in rats. The colon-specific delivery of the drug using microcapsules relies on the combination of pH (outer gastroresistant coating), time (inner retard coating of Eudragit® RS and RL) and enzyme (pectin core) controlled drug release mechanisms. The optimal in vitro dissolution profile for LK-423 delivery to the colon of rats was obtained after coating newly developed LK-423 loaded pectin cores with 20% w/w of retard coating with a Eudragit® RS/RL ratio of 8.5/1.5 and 30% w/w of enteric coating. Orally administered LK-423 microcapsules were therapeutically more beneficial in treating TNBS-induced ulcerative colitis in rats than orally or rectally administered LK-423 in the form of suspension. Clinical activity scores and colon weight to length ratio were insignificantly lower and the macroscopically estimated degree of healing was significantly greater. On the histological level, the administration of LK-423 microcapsules resulted in most physiological regeneration of intestinal mucosa, indicated by regular architecture of all mucosal tissue components, what is probably related to local drug delivery near the site of inflammation achieved using microcapsules. These results demonstrate that LK-23 colon delivery microcapsules enhance the therapeutic efficacy of the drug and therefore appear to be a useful approach for treating various inflammatory diseases in the large intestine.     

Characterization of structure and diffusion behaviour of Ca-alginate beads prepared with external or internal calcium sources

Ca-alginate beads were prepared with either external or internal calcium sources. The structures of both beads were investigated with the aid of scanning electron microscopy (SEM) and confocal microscopy. It was shown that the beads with internal calcium source had a looser structure and bigger pore size than those with external calcium source. The attempts to interpret the difference were carried out by determining the Ca content within the beads at various times, which indicated that it was the different gelation mechanisms that caused the difference of structures of both beads. Furthermore, it was also found that the diffusion rate of haemoglobin (Hb) within the beads with an internal calcium source was faster than that of the beads with an external one, which was consistent with the observation of their structures.     

混合交联剂制备海藻酸盐微囊及其性能研究

目的以氯化钙和氯化钡混合盐溶液为交联剂,制备海藻酸盐微囊并考察其性能。方法采用高压静电法制备胶珠,以几丁聚糖为膜材制备微胶囊,考察了海藻酸盐胶珠和微囊的形态、粒径分布、膨胀率、振荡破损率及膜蛋白渗透性。结果以［Ba2＋］∶［Ca2＋］为7∶3作为混合交联剂制备的微囊粒径最小为309μm,膨胀率最小为147%,振荡破损率为26%。各组微囊膜厚度均小于20μm。两种蛋白渗透曲线表明,胰蛋白酶能渗透进入各组微囊膜,而牛血清清蛋白则不能进入微囊。结论混合交联剂制备的微囊粒径分布较均一,膜强度较高,可广泛应用于各种生物活性物质如蛋白、细胞等的包埋。     

铁叶绿酸钠微囊的制备及释放度测定

目的:制备铁叶绿酸钠微囊,并考察其体外释放情况。方法:采用优化的溶剂挥发法制备铁叶绿酸钠微囊,以正交试验确定制备工艺。结果:铁叶绿酸钠微囊的最佳制备工艺为EC与内相铁叶绿酸钠比为2:1、以1%PVA为分散剂、EC浓度为3%、搅拌速度为700 r·min^-1。结论:铁叶绿酸钠微囊制备方法简单,微囊具有明显的缓释作用。     

Microencapsulation enhances the anti-ulcerogenic properties of Entada africana leaf extract

Ethnopharmacological relevance

The antiulcer potentials of most plants still remain largely unexplored, despite their prospects evidenced by their use as ethnomedicine. Entada africana (Mimosaceae) has been widely used in Africa for the treatment of skin infections, wounds, tonic for stomach troubles and against diphtheria-like throat complaints. The aim of the present study was to evaluate the anti-ulcer properties of Entada africana (EA) ethanol leaf extract and to obtain a novel multiparticulate pharmaceutical formulation (ACE) with it.

Materials and methods

Ethanol or Indomethacin was administered to rats after oral administration of EA (200, 400 and 800 mg extract/kg b.w), ACE (400 and 800 mg/kg bw), cimetidine (100 mg/kg bw), misoprostol (40 μg/kg bw) or distilled water/saline (vehicle). Anti ulcer property was evaluated by examining and scoring stomach lesions.

Results

The extract exhibited significant (P < 0.01) cytoprotective effect against ethanol and indomethacin induced gastro ulceration. The microcapsules showed enhanced cytoprotective effect against ethanol and indomethacin induced gastro ulceration. Histopathologically, the effects of EA and ACE on mucus epithelia were mild with reduced neutrophil, eosinophil and lymphocytic infiltration in stomach tissues of rats ulcerated with ethanol.

Conclusions

Our current findings show that EA and its multiparticulate formulation may be a useful preparation in peptic ulcer disease.     

Biocompatibility and function of microencapsulated pancreatic islets

Encapsulation of pancreatic islets in alginate is used to protect against xenogenic rejection in different animal models. In this study, several factors, including differences in alginate composition, the presence or absence of xenogenic islet tissue and a transient immunosuppression, were investigated in a model of bovine islet transplantation in rats. A pure alginate with predominantly guluronic acid (Manugel) and an ultrapure low viscosity guluronic acid alginate (UP-LVG) were used. When microcapsules of Manugel or UP-LVG containing 16,000 bovine islet equivalents were transplanted in diabetic rats, we observed normoglycemia for 8.3+/-0.7 (range 6-12 days) and 7.5+/-0.2 days (range 7-8 days) on average, respectively. To ameliorate immunoprotection of alginate microcapsules we repeated the same experiments using transient immunosuppressive therapy. Low doses of cyclosporin A (CyA) administered for 18 days after implantation increased the time in normoglycemia, which averaged 27+/-3 days (range 8-55 days) in Manugel capsules while in UP-LVG capsules it averaged 18+/-8 days (range 3-39 days). The surface of recovered capsules showed less capsules free of overgrowth in Manugel with respect to UP-LVG alginate. These data were comparable with those observed in empty microcapsules similarly implanted, indicating that the capsular overgrowth was not promoted by the presence of xenogenic islet tissue. In recovered Manugel capsules the percentage of capsules without fibrotic overgrowth was higher than that observed without CyA. The same observation was made in empty capsules. These observations indicate that a combination of a highly purified alginate and short-term immunosuppression prolong islet function in a model of xenotransplantation.     

萘普生微囊的制备及其质量考察

目的:制备萘普生微囊并考察其制剂质量。方法:以明胶和阿拉伯胶为囊材,采用复凝聚法将萘普生制成微囊;以阿拉伯胶浓度(A)、萘普生与阿拉伯胶的质量比例(B)和成囊温度(C)为考察因素,包封率为指标设计正交试验优化成囊的最佳制备工艺,并对优化工艺所制得微囊的粒径、包封率、载药量、体外释放性进行考察。结果:最佳工艺条件为A2%、B1:1、C50℃;所制微囊的平均囊径48.92μm,包封率(77.03±1.43)%,载药量(35.31±1.02)%,微囊在48h时体外累积溶出百分率达到91.32%。结论:所制萘普生微囊工艺重现性好、稳定,并具有良好的缓释作用。     

Sustained release and biological availability of dalarelin from the biodegradable coacervate microcapsules

A complex coacervation method was used to prepare microcapsules containing 74.8 +/- 1.5% of the 125I labelled dalarelin incorporated in the gelatine-algin coating. Microcapsules (62 +/- 1.7%) formed, did not exceed a size of 108 microm. The high content of the small size allowed this formulation to be administered by intramuscular injection to rats. It was found that the 125I labelled dalarelin in the form of microcapsules had better bioavailability and was active longer in the rat when compared with the 125I labelled dalarelin solution injections. Dalarelin administered in the microcapsular form was characterised by a higher biological availability. The degree of relative biological availability was calculated as 123% for the dalarelin in the microcapsular form.     

Preparation of alginate/chitosan microcapsules and enteric coated granules of mistletoe lectin

The aqueous extract of European mistletoe (Viscum album, L.) has been used in cancer therapy. The purified mistletoe lectins, main components of mistletoe, have demonstrated cytotoxic and immune-system-stimulating activities. Korean mistletoe (Viscum album L. coloratum), a subspecies of European mistletoe, has also been reported to possess anticancer and immunological activities. A galactose- and N-acetyl-D-galactosamine-specific lectin (Viscum album L. coloratum agglutinin, VCA) with Mr 60 kDa was isolated from Korean mistletoe. Mistletoe preparations have been given subcutaneously due to the low stability of lectin in the gastrointestinal (GI) tract. In the present study, we investigated the possibility of alginate/chitosan microcapsules as a tool for oral delivery of mistletoe lectin. In addition, our strategy has been to develop a system composed of stabilizing cores (granules), which contain mistletoe lectin, extract or powder, coated by a biodegradable polymer wall. Our results indicated that successful incorporation of VCA into alginate/chitosan microcapsules has been achieved and that the alginate/chitosan microcapsule protected the VCA from degradation at acidic pH values. And coating the VCA with polyacrylic polymers, Eudragit, produced outstanding results with ideal release profiles and only minimal losses of cytotoxicity after manufacturing step. The granules prepared with extract or whole plant produced the best results due to the stability in the extract or whole plant during manufacturing process.     

Effect of different ratios of high and low molecular weight PLGA blend on the characteristics of pentamidine microcapsules

Two different PLGA samples (Resomer 502 and Resomer 506), either alone or in combinations, were used to prepare microcapsules. Microcapsules were prepared using a double emulsion solvent evaporation technique. The efficiency of encapsulation increased significantly when a mixture of 1 part Resomer 506 and 7 parts Resomer 502 was used to prepare the microcapsules. The efficiency of encapsulation of this batch was 23.7%, whereas the efficiency of encapsulations was only 13.9 and 9.8%, respectively, when the microcapsules were prepared with 100% Resomer 502 or 100% Resomer 506. In contrast, irrespective of the relative ratio of Resomer 502/Resomer 506, the median particle size of the microcapsules showed similar distribution pattern with the median size lies between 49 and 83 μm. The glass transition temperature (T_g) decreased significantly (44.6–25.5 °C) as the amount of Resomer 502 was increased in the formulation. The presence of Resomer 502 at lower concentration, along with Resomer 506, initially reduced the “burst effect.” However, incorporation of a higher amount of Resomer 502 increased the “burst effect.” Drug release from these microcapsules continued over 80 days. In conclusion, efficiency of encapsulation increased significantly when Resomer 506 was mixed with Resomer 502 at a ratio of 1:7. Blending of Resomer 502 with Resomer 506 reduced the glass transition temperature, which resulted in higher amount of drug release throughout the dissolution study.