Eudragit S100 coated iron oxide-chitosan nanocomposites for colon targeting of 5-aminosalicylic acid ameliorate ulcerative colitis by improving intestinal barrier function and inhibiting NLRP3 inflammasome.

The therapeutic effect of 5-amino salicylic acid (5-ASA), a first-line therapeutic agent for the treatment of ulcerative colitis (UC), is limited by the modest bioavailability afforded by its oral administration. In this study, a 5-ASA oral delivery system was developed using Eudragit S100-coated iron oxide-chitosan nanocomposites (ES-IOCS/5-ASA) to address this issue. According to drug release studies in vitro, ES-IOCS/5-ASA only released a small amount of drug in simulated gastric fluid with a pH of 1.2. However, in a medium with a pH of 7.5, a relatively rapid and complete release was noted. 5-ASA-loaded iron oxide-chitosan nanocomposites (IOCS/5-ASA) could be effectively taken up by NCM460 cells and performed better anti-inflammatory effects than free 5-ASA. At the same time, IOCS/5-ASA improved barrier damage in DSS-induced NCM460 cells. In vivo models of dextran sulphate sodium (DSS)-induced colitis were used to assess the therapeutic efficacy of oral administration of ES-IOCS/5-ASA. ES-IOCS/5-ASA significantly relieved DSS-induced colitis and enhanced the integrity of the intestinal epithelial barrier. ES-IOCS/5-ASA also reduced the expression of NLRP3, ASC and IL-1ß. Additionally, iron oxide nanoparticles used as nanozymes could alleviate inflammation. In summary, this study indicates that ES-IOCS/5-ASA exert anti-inflammatory effects on DSS-induced colitis by improving intestinal barrier function and inhibiting NLRP3 inflammasome expression, presenting a viable therapeutic choice for the treatment of UC.

A pH-sensitive silica nanoparticles for colon-specific delivery and controlled release of catechin: Optimization of loading efficiency and in vitro release kinetics.

Catechin is a naturally occurring flavonoid of the flavan-3-ol subclass with numerous biological functions; however, these benefits are diminished due to several factors, including low water solubility and degradation in the stomach's harsh environment. So, this study aimed to develop an intelligent catechin colon-targeting delivery system with a high loading capacity. This was done by coating surface-decorated mesoporous silica nanoparticles with a pH-responsive enteric polymer called Eudragit®-S100. The pristine wormlike mesoporous silica nanoparticles (< 100 nm) with high surface area and large total pore volume were effectively synthesized and modified with the NH2 group using the post-grafting strategy. Various parameters, including solvent polarity, catechin-carrier mass ratio, and adsorption time, were studied to improve the loading of catechin into the aminated silica nanoparticles. Next, the negatively charged Eudragit®-S100 was electrostatically coated onto the positively charged aminated nanocarriers to shield the loaded catechin from the acidic environment of the stomach (pH 1.9) and to facilitate site-specific delivery in the acidic environment of the colon (pH 7.4). The prepared nanomaterials were evaluated using several methods, including The Brauner-Emmett-Teller, surface area analyzer, zeta sizer, Field Emission Scanning Electron Microscope, Powder X-Ray Diffraction, Fourier Transform Infrared Spectroscopy, Energy-Dispersive X-ray Spectroscopy, and Differential Scanning Calorimetry. In vitro dissolution studies revealed that Eudragit®-S100-coated aminated nanomaterials prevented the burst release of the loaded catechin in the acidic environment, with approximately 90% of the catechin only being released at colonic pH (pH > 7) with a supercase II transport mechanism. As a result, silica nanoparticles coated with Eudragit®-S100 would provide an innovative and promising approach in targeted nanomedicine for the oral delivery of catechin and related medicines for treating diseases related to the colon, such as colorectal cancer and irritable bowel syndrome.

Polymer Encapsulated Liposomes for Oral Co-Delivery of Curcumin and Hydroxytyrosol.

Curcumin (Cur) is a hydrophobic polyphenol from the rhizome of Curcuma spp., while hydroxytyrosol (HT) is a water-soluble polyphenol from Olea europaea. Both show outstanding antioxidant properties but suffer from scarce bioavailability and low stability in biological fluids. In this work, the co-encapsulation of Cur and HT into liposomes was realized, and the liposomal formulation was improved using polymers to increase their survival in the gastrointestinal tract. Liposomes with different compositions were formulated: Type 1, composed of phospholipids and cholesterol; Type 2, also with a PEG coating; and Type 3 providing an additional shell of Eudragit® S100, a gastro-resistant polymer. Samples were characterized in terms of size, morphology, ζ-potential, encapsulation efficiency, and loading capacity. All samples were subjected to a simulated in vitro digestion and their stability was investigated. The Eudragit®S100 coating demonstrated prevention of early releases of HT in the mouth and gastric phases, while the PEG shell reduced bile salts and pancreatin effects during the intestinal digestion. In vitro antioxidant activity showed a cumulative effect for Cur and HT loaded in vesicles. Finally, liposomes with HT concentrations up to 40 µM and Cur up to 4.7 µM, alone or in combination, did not show cytotoxicity against Caco-2 cells.

Redox responsive poly(allylamine)/eudragit S-100 nanoparticles for dual drug delivery in colorectal cancer.

Herein, we report redox responsive, colon cancer targeting poly(allylamine) (PA)/eudragit S-100 (EU) nanoparticles (PAEU NPs) (≈59 nm). These disulfide crosslinked PAEU NPs are developed via air oxidation of thiolated PA and thiolated EU, eliminating the need of any external crosslinking agent for dual drug delivery. PAEU NPs can effectively encapsulate both hydrophilic doxorubicin (DOX) and hydrophobic curcumin (Cur) drug with ≈85 % and ≈97 % encapsulation efficiency respectively. Here, the combination of drugs having different anticancer mechanism offers the possibility of developing nanosystem with enhanced anticancer efficacy. The developed PAEU NPs show good colloidal stability and low drug release under physiological conditions, while high DOX (≈98 %) and Cur (≈93 %) release is observed in reducing environment (10 mM GSH). Further, DOX and Cur loaded PAEU NPs exhibit higher cancer cell killing efficiency as compared to individual free drugs. In vivo biodistribution studies with Balb/C mice display the retention of PAEU NPs in the colon region up to 24 h presenting the developed approach as an efficient way for colorectal cancer therapy.

Development of microparticles for oral administration of Periplaneta americana extract to treat ulcerative colitis.

Ulcerative colitis (UC) is a chronic disease, which can result the inflammation of the rectum, mucosa of the colon, and submucosa. The active component such as polypeptide in Periplaneta americana, which is one of the most common insects in the nature, can be extracted to treat UC. However, the active components in Periplaneta americana extract (PAE) can be degraded in the stomach due to its extreme acidic environment and enzyme. In this study, we developed a pH-dependent drug delivery method using polymer cellulose acetate (Eudragit S100) as a carrier to deliver high concentration PAE to inflamed colon. Both in vitro and in vivo results showed the PAE-Eudragit-S100 could treat UC through delivering active drug components to colon without degradation.

Formulation and Characterization of Doxycycline-Loaded Polymeric Nanoparticles for Testing Antitumor/Antiangiogenic Action in Experimental Colon Cancer in Mice.

Nanotherapeutics can enhance the characteristics of drugs, such as rapid systemic clearance and systemic toxicities. Polymeric nanoparticles (PRNPs) depend on dispersion of a drug in an amorphous state in a polymer matrix. PRNPs are capable of delivering drugs and improving their safety. The primary goal of this study is to formulate doxycycline-loaded PRNPs by applying the nanoprecipitation method. Eudragit S100 (ES100) (for DOX-PRNP1) and hydroxypropyl methyl cellulose phthalate HP55 (for DOX-PRNP2) were tested as the drug carrying polymers and the DOX-PRNP2 showed better characteristics and drug release % and was hence selected to be tested in the biological study. Six different experimental groups were formed from sixty male albino mice. 1,2,-Dimethylhydrazine was used for 16 weeks to induce experimental colon cancer. We compared the oral administration of DOX-PRNP2 in doses of 5 and 10 mg/kg with the free drug. Results indicated that DOX-PRNP2 had greater antitumor activity, as evidenced by an improved histopathological picture for colon specimens as well as a decrease in the tumor scores. In addition, when compared to free DOX, the DOX-PRNP2 reduced the angiogenic indicators VEGD and CD31 to a greater extent. Collectively, the findings demonstrated that formulating DOX in PRNPs was useful in enhancing antitumor activity and can be used in other models of cancers to verify their efficacy and compatibility with our study.

pH-sensitive nanoparticles containing 5-fluorouracil and leucovorin as an improved anti-cancer option for colon cancer.

Background: Parenteral administration of chemotherapeutic drugs, 5-fluorouracil (5-FU) and leucovorin (LV), is commonly used to treat large bowel carcinomas such as colon cancer (CC) and colorectal carcinoma (CRC). Aim: Our study aims to design a novel nanoparticulate drug-delivery vehicle for oral use capable of colon-specific release. Methods: A modified double-emulsion solvent evaporation method was used in the preparation of pH-responsive Eudargit® S100 polymeric nanoparticles, loaded with 5-FU/LV combination (5-FU/LV-loaded Eudargit S100 NPs). Results: Our optimized drug-loaded NP showed a pH-responsive drug release and exhibited significantly more cytotoxic actions in cancer-cell lines than free drugs. Conclusion: These findings open the way for conducting clinical trials for colon malignancies treated with nanoparticles.

Eudragit S100 prepared pH-responsive liposomes-loaded betulinic acid against colorectal cancer in vitro and in vivo.

This study aimed to develop polymer Eudragit S100 for preparing pH-responsive liposomes-loaded betulinic acid (pH-BA-LP) to improve the therapeutic index of chemotherapy for colorectal cancer. BA-loaded liposomes were coated with Eudragit S100 by a thin film dispersion and easily scalable pH-driven method. The prepared liposomes were evaluated for size, surface morphology, entrapment efficiency, stability, in vitro drug release, and antitumor activity. In particular, pH-BA-LP showed advantages such as lower size (<100 nm), encapsulation efficiency of 90%, high stability, and stably cumulative release. By detecting the antitumor effects of pH-BA-LP in vivo, it showed that the tumor proliferation and cell migration were significantly inhibited in colorectal cancer. The pH-BA-LP also inhibited tumor growth via the regulation of Akt/TLR-mediated signalling and significantly down-regulated the expression of NFAT1 and NFAT4 proteins. It was found that pH-BA-LP can increase NK cells and CD3+ cells in tumor tissues, and the proportion of CD8+ cells in CD3+ cells was also increased, which proved that pH-BA-LP can play an antitumor effect by enhancing the autoimmunity level in tumor-bearing mice. The positive infiltration rates of CD8 and CD68 were increased and CD163 was relatively decreased by using pH-BA-LP, which proved that pH-BA-LP can regulate the immune infiltration levels in tumor-bearing mice. Therefore, the present work provides an effective method to prepare pH-responsive polymer-coated liposomes for colonic delivery with biologically active compounds.

Eudragit S-100 Surface Engineered Nanostructured Lipid Carriers for Colon Targeting of 5-Fluorouracil: Optimization and In Vitro and In Vivo Characterization.

5-Fluorouracil (5-FU) is the most preferred chemotherapeutic agent in the management of colon cancer but is associated with poor therapeutic efficacy and lack of site specificity. Hence, it was aimed to employ Eudragit S100 surface engineered 5-FU nanostructured lipid carriers for the spatial and temporal release of the drug for the treatment of colon cancer. Hot high-pressure homogenization (HPH) technique was employed in the preparation of 5-FU-NLCs. The optimization of 5-FU-NLCs was performed using a Quality by Design (QbD) approach. A 32 factorial design was employed wherein the relationship between independent variables [amount of oleic acid (X1) and concentration of Tween®80 (X2)] and dependent variables [particle size (Y1) and % entrapment efficiency (Y2)] was studied. Optimized 5-FU-NLCs were surface treated to obtain Eudragit S100-coated 5-FU-NLCs (EU-5-FU-NLCs). The evaluation parameters for 5-FU-NLCs and EU-5-FU-NLCs included surface morphology, particle size, PDI, and zeta potential. In vitro release from EU-5-FU-NLCs revealed a selective and controlled 5-FU release in the colonic region for 24 h. In vitro cytotoxicity (MTT assay) was performed against Caco-2 cancer cells, wherein EU-5-FU-NLCs exhibited a 2-fold greater cytotoxic potential in comparison to a 5-FU solution (5-FU-DS). Oral administration of EU-5-FU-NLCs in Albino Wistar rats depicted a higher Cmax (2.54 folds) and AUC (11 folds) as well as prolonged Tmax (16 folds) and MRT (4.32 folds) compared to 5-FU-DS confirming higher bioavailability along with the spatial and temporal release in the colonic region. Thus, a multifaceted strategy involving abridgement of nanotechnology along with surface engineering is introduced for effective chemotherapy of colon cancer via oral administration of 5-FU with uncompromised safety and higher efficacy.Graphical abstract.

Fixed Dose Single Tablet Formulation with Differential Release of Amlodipine Besylate and Simvastatin and Its Pharmacokinetic Profile: QbD and Risk Assessment Approach.

PURPOSE: A differential release fixed dose matrix tablet of amlodipine besylate (AML-B) and simvastatin (SIM) was formulated to enhance patient compliance. MATERIAL AND METHOD: In the first phase, release controlling parameters of AML-B and SIM granules were identified and in the second phase a fixed dose AML-B and SIM tablet formulation was prepared and optimized for a differential release of the drugs using a quality by design (QbD) and risk assessment approach. A validated HPLC method was employed for simultaneous determination of AML-B and SIM for FDC formulation. A pharmacokinetics of the above drugs was studied in healthy dogs in the third phase. RESULTS: In QbD-based optimized formulation, Eudragit® RSPO-dicalcium phosphate (DCP) blend controlled the release of AML-B over 8 h, though this diffusion-controlled release assumed first order kinetics. DCP and Eudragit® RS 100 also retarded release of SIM causing SIM release over 8 h after AML-B release from the optimized FDC tablet formulation. The HPLC retention times of AML-B and SIM were 2.10 and 15.52 min, respectively. Linearity for AML-B was 5.0-50 ng/mL and 0.01-2.0 µg/mL for SIM with percent recoveries of 92.85-101.53% and 94.51-117.75% for AML-B and SIM. AUC0-∞ of AML-B was increased 3 fold, while AUC0-∞ of SIM was decreased 2 fold. The tmax values for AML-B and SIM were 12 and 6 h, respectively. AML-B was absorbed without any lag time (tlag) while tlag was 6.33 ± 0.81 h for SIM, thus met the study objective. CONCLUSION: The pharmacokinetic study showed an immediate absorption of AML-B while that of SIM was withheld for 6 h, close to the desired delay time of 8 h.

Loading of doxorubicin on poly(methyl methacrylate-co-methacrylic acid) nanoparticles and release study.

Nanoparticles (NP) of 12.7 nm in diameter of the poly(methyl methacrylate (MMA)-co-methacrylic acid (MAA)) copolymer were prepared. 13C-NMR results showed a MMA:MAA molar ratio of 0.64:0.36 in the copolymer, which is similar to the poly(MMA-co-MAA) commercially known as the FDA approved Eudragit S100 (0.67:0.33). The NP prepared in this study were loaded at pH 5 with varying amounts (from 0.54 to 6.91%) of doxorubicin (DOX), an antineoplastic drug. 1H-NMR results indicated the electrostatic interactions between the ionized carboxylic groups of the MAA units in the copolymer and the proton of the glycosidic amine in DOX. Measurements by QLS and TEM indicated that the loading destabilizes the NP, and that for increase stability, they aggregate in a reversible way, forming aggregates with a diameter up to 99.5 nm at a DOX load of 6.91%. The analysis of drug release data at pH 7.4 showed that loaded NP with at least 4.38% DOX release the drug very slowly and follows the Higuchi model; the former suggests that they could remain for long periods in the bloodstream to reach and destroy cancer cells.

Simvastatin nanosuspensions prepared using a combination of pH-sensitive and timed-release approaches for potential treatment of colorectal cancer.

A dual pH- and time-dependent polymeric coated capsule was developed to achieve the site specificity of simvastatin (SIM) release in the colon. To improve the SIM solubility, soluplus-based nanosuspension of the drug were prepared by applying the anti-solvent crystallization technique; this was then followed by lyophilization. Particle size, polydispersity index, and saturation solubility were evaluated. The optimized nanosuspension was combined with SLS and freeze-dried before filling into hard gelatin capsules. Drug release characteristics of the coated capsules were studied in HCl 0.1 N, the phosphate buffers 6.8 and 7.4, and the simulated colonic fluid (pH 6.8). The in-vitro cytotoxic effects of SIM nanoparticles against HT29 cells were then evaluated using the MTT assay. The prepared nanoparticles were spherical with a mean size of 261.66 nm, the zeta potential of -18.20 and the dissolution efficiency of 59.71%. X-ray diffraction and differential scanning calorimetry studies showed that the nanosizing technique transformed the crystalline drug into the more soluble amorphous form. The coated capsules had no release in the gastric media, providing the specific delivery of SIM in the colon. The cytotoxic effect of the SIM nanoparticles was significantly increased, as compared to the free SIM. The findings, therefore, showed that the coated capsules using the two polymers of ethyl cellulose and Eudragit S100 could be suitable for the colon target delivery of SIM.

99mTc-labelled and pH-awakened microbeads entrapping surface-modified lipid nanoparticles for the augmented effect of oxaliplatin in the therapy of colorectal cancer.

AIM: This study was aimed to develop Eudragit S100-coated, pH-awakened microbeads (MBs) encapsulating folic acid (FA)-modified tristearin solid lipid nanoparticles (SLNs) loaded with oxaliplatin (OP). Afterward, these formulations were evaluated (in vitro and in vivo) for their potential against colorectal cancer (CRC). METHODS: The SLNs were synthesised by employing the solvent diffusion technique and then they were entrapped in the MBs. The prepared uncoupled and coupled SLNs (SLN-OP and FA-SLN-OP, respectively) were examined for in vitro cytotoxicity effect against COLO-205. Gamma-scintigraphy study was used for determining biodistribution (in vivo) of drug in different organs through MBs. RESULTS: Outcomes for FA-SLN-OP revealed more cytotoxicity (50% inhibitory concentration [IC50] = 6.8 µg/ml) against COLO-205 cells (in vitro) than OP solution (IC50 = 8.0 µg/ml) and SLN-OP (IC50= 7.5 µg/ml). MBs were also investigated in vivo using Gamma-scintigraphy study. After 48 h study, 99mTc-EuB-FA-SLN-OP confirmed an elevated level of drug in the colonic tumour, which was found significantly (p< 0.0001) higher than that of 99mTc-EuB-SLN-OP. CONCLUSIONS: In conclusion, developed MBs formulation (99mTc-EuB-FA-SLN-OP) suggested promising results against therapy of CRC using dual targeting (i.e. ligand-directed and pH-awakened) approach.

Functionalized layer-by-layer assembled film with directional 5-fluorouracil release to target colon cancer.

The objective of this work was to prepare and characterize pH-sensitive capsule containing functionalized layer-by-layer (LbL) assembled polymeric film with directional drug release and evaluate its effectiveness against colon cancer. 5-Fluorouracil (5FU) loaded LbL film was prepared by sequential adsorption of chitosan and alginate polyelectrolytes. This LbL film was coated with polycaprolactone (PCL, 95% w/w) as a backing layer to restrict 5FU release on one-side. The other side constituted the folic acid conjugated chitosan layer for cancer targeting. This film was encapsulated into a gelatin capsule coated with pH-sensitive Eudragit S100. 5FU loaded LbL film was characterized for physical and mechanical properties. Mucoadhesion studies performed using excised rabbit colon showed that chitosan-side of LbL film adhered with significantly (p < 0.05) greater strength compared with PCL-side. Non-everted rat colon-sac model and open colon membrane model studies showed greater permeation of 5FU across the colon wall when adhered to chitosan-side of LbL film compared with PCL-side of the film. Cell monolayer and 3D-spheroid model studies using Caco-2 and COLO 320DM colorectal cancer cells showed significant (p < 0.05) growth inhibition by 5FU loaded LbL film compared with free 5FU solution. In conclusion, pH-sensitive capsule containing 5FU loaded LbL film can be developed to target colorectal cancer for regional drug delivery.

Oral delivery of pH-responsive alginate microbeads incorporating folic acid-grafted solid lipid nanoparticles exhibits enhanced targeting effect against colorectal cancer: A dual-targeted approach.

To achieve an enhanced anticancer effect of drug to treat colorectal cancer, a dual-targeted (i.e., ligand-tailored and pH-triggered) multiparticulate system has been designed to deliver drug directly into the colon domain. In this regard, folic acid-grafted solid lipid nanoparticles (SLNs) bearing irinotecan were encapsulated in microbeads of alginates. Afterward, these microbeads were coated with enteric polymer (i.e., Eudragit S100) to make them pH-responsive. COLO-205 cells were used to determine in vitro cytotoxicity potential of various formulations. Findings for IHT loaded FA-coupled SLNs suggested significantly (p < 0.05) higher cytotoxic effect against COLO-205 cells (in vitro) as compared to drug solution and uncoupled SLNs. Further, the microbeads incorporating SLNs were evaluated for drug release in various simulated gastrointestinal fluids (i.e., pH, 1.2, 4.5, 7.4, and 6.8). Findings confirmed the release of the drug in the intestinal region only (i.e., pH > 7.0). In therapeutic experiments (in vivo), the optimized radiolabeled microbeads (99mTc-EuBIRSLN3 and 99mTc-EuBIRSLNF3) were administered via oral route to Balb/c mice. The results suggested that FA-coupled microbeads (99mTc-EuBIRSLNF3) distributed higher (19.62 ± 0.78%) amount of drug (i.e., 99mTc-IHT/g of tissue) as compared to uncoupled microbeads (99mTc-EuBIRSLN3, 7.63 ± 0.49%) in the colon tumor after 48 h, which confirmed its targeting ability to the tumor in the colon region. Further, 99mTc-EuBIRSLNF3 showed significantly (p < 0.01) higher antitumor effect against HT-29 cells bearing Balb/c mice over uncoupled microbeads and advocated their potential for enhanced antitumor efficacy for the treatment of colorectal cancer.

Novel carriers ensuring enhanced anti-cancer activity of Cornus mas (cornelian cherry) bioactive compounds.

Cornusmas' bioactive compounds are powerful antioxidants. In this study, we evaluated the antioxidant activity of the encapsulated bioactive compounds of Cornus mas extract (CME) and its release in semi digestive condition via enteric coated nanocarriers (NCs). The two forms of CME, encapsulated into enteric coated nanocarriers (CME-NCs) and free CME, were studied to determine the effect of encapsulation on the stability of antioxidants. Then, their effect on cell cycle, cell viability and apoptosis of cancer cells were studied. The characterization analysis reported the mean particle size and zeta potential value of NCs equal to 22.7 ± 6.58 nm and -16 ± 5 mV. The results showed that CME-NCs could improve IC50 value 1.33 and 1.47 times more than the free CME after 24 and 48 h of incubation. These findings confirmed that CME-NCs could stop the cells proliferation in G1 phase, and caused apoptosis in cancer cell line HT-29.

Screening of Ketoprofen-Poloxamer and Ketoprofen-Eudragit solid dispersions for improved physicochemical characteristics and dissolution profile

The aim of the present study was to enhance the dissolution rate of an NSAID drug Ketoprofen by formulating it into solid dispersions with water soluble carrier Poloxamer 188 and Eudragit S 100. The solid dispersions of Ketoprofen with Poloxamer 188 were prepared at 1:1, 1:1.5 and 1:2 (Ketoprofen: Poloxamer 188) ratio by Solvent evaporation methods. The same concentration ratio was used for the preparation of solid dispersion with Eudragit S 100 by melting/fusion technique. Further, solid dispersions were investigated by solubility, ATR-FTIR, XRD, DSC, surface morphology, in-vitro dissolution and accelerated stability study. Results demonstrated that both Poloxamer 188 and Eudragit S 100 improve solubility of drugs by 8­10 folds. The result of ATR-FTIR study showed the slight shifting/broadening of principle peaks. In vitro dissolution studies showed that in the solid dispersion system containing Ketoprofen: Poloxamer 188 batch P2 (1:1.5) gives faster dissolution rate of Ketoprofen than the physical mixtures. The solid dispersion with Eudragit S 100, batch E1 (1:1) gives faster dissolution rate of Ketoprofen than the physical mixtures. In phase solubility study with Poloxamer 188 showed concentration dependent solubilization of drug but Eudragit S 100 produced opposite result. The effect of pH on solubility of Eudragit S 100 was carried out which showed solubility at pH 7.4. The dissolution profile of solid dispersion with Eudragit S 100 at pH 7.4 gives excellent result. The Accelerated stability of solid dispersions & its physical mixtures were studied at 400±2 °C/75 ± 5% RH for a period of 1 month. In these studies, Solid Dispersion batches produced an unstable formulation. The Ketoprofen solid dispersions with Poloxamer 188 and Eudragit S 100 could be introduced as a suitable form with improved solubility

Colon targeted beads loaded with pterostilbene: Formulation, optimization, characterization and in vivo evaluation.

BACKGROUND: Pterostilbene has a proven chemopreventive effect for colon carcinogenesis but suffers low bioavailability limitations and therefore unable to reach the colonic tissue. OBJECTIVE AND METHODOLOGY: To overcome the issue of low bioavailability, pterostilbene was formulated into an oral colon targeted beads by ionic gelation method using pectin and zinc acetate. Optimization was carried out by 23 factorial design whereby the effect of pectin concentration (X 1), zinc acetate concentration (X 2) and pterostilbene:pectin ratio (X 3) were studied on entrapment efficiency (Y 1) and in vitro drug release till 24 h (Y 2). The optimized beads were characterized for shape and size, swelling and surface morphology. The optimized beads were uniformly coated with Eudragit S-100 using fluidized bed coater. Optimized coated beads were characterized for in vitro drug release till 24 h and surface morphology. Pharmacokinetic and organ distribution study were performed in rats to ascertain the release of pterostilbene in colon. RESULTS: The optimized formulation comprised of 2% w/v of pectin concentration (X 1), 2% w/v of zinc acetate concentration (X 2) and 1:4 of pterostilbene:pectin ratio (X 3), which showed a satisfactory entrapment efficiency (64.80%) and in vitro release (37.88%) till 24 h. The zinc pectinate beads exhibited sphericity, uniform size distribution, adequate swelling and rough surface. The optimized coated beads achieved 15% weight gain, displayed smooth surface and optimum drug release. Pterostilbene from optimized coated beads appeared in the plasma at 14 h and reached the Cmax at 22 h (Tmax), whereas plain pterostilbene exhibited Tmax of 3 h. DISCUSSION AND CONCLUSION: Thus, larger distribution of pterostilbene was obtained in the colonic tissue compared to stomach and small intestinal tissues. Thus, delayed Tmax and larger distribution of pterostilbene in colonic tissue confirmed the targeting of beads to colon.

Enhanced oral absorption of sorafenib via the layer-by-layer deposition of a pH-sensitive polymer and glycol chitosan on the liposome.

This study aimed to design the effective formulation of sorafenib (SF) to enhance the oral drug absorption. Three liposomal formulations of SF were prepared including uncoated liposome (SF-Lip), glycol chitosan-coated liposome (GC-SF-Lip), and Eudragit S100-glycol-chitosan coated liposome (SGC-SF-Lip). All formulations showed a narrow size distribution with a high encapsulation efficiency. Both GC-SF-Lip and SGC-SF-Lip exhibited good stability at acidic and neutral pHs without any significant drug leakage, while SF-Lip appeared to be unstable at pH 1.2. In the case of double coated SGC-SF-Lip, its size changed significantly at pH 7.4, due to the dissolution of Eudragit S100 coating layer into the surrounding medium. Compared to SF solution, all liposomal formulations demonstrated a higher cellular uptake in Caco-2 cells. In particular, SGC-SF-Lip displayed a lower cellular uptake than GC-SF-Lip at pH 6.5, but it achieved a similar cellular uptake to GC-SF-Lip at pH 7.4. Consistently, SGC-SF-Lip was less cytotoxic than GC-SF-Lip at pH 6.5, whereas it showed a comparable cytotoxicity to GC-SF-Lip at pH 7.4, implying the removal of the Eudragit S100 coating layer at pH 7.4. After an oral administration to rats, SGC-SF-Lip significantly improved the systemic exposure of SF, where its Cmax and AUC were approximately fourfold higher than the untreated drug. Collectively, SGC-SF-Lip appeared to be promising to enhance the oral absorption of SF.

Liquid Nanosize Emulsion-Filled Enteric-Coated Capsules for Colon Delivery of Immunosuppressant Peptide.

Present study aims at solubilizing slightly water-soluble peptide into a nanosize emulsion which is filled into a hard gelatin capsule in the form of preconcentrate. Further, liquid-filled capsule was dip-coated with ethyl cellulose and Eudragit S100 for colon targeting. An in vitro release profile was studied for selected formulations, i.e., Formulation A (5 mg ethyl cellulose and 40 mg Eudragit S100), Formulation B (10 mg ethyl cellulose and 30 mg Eudragit S100), and Formulation C (10 mg ethyl cellulose and 20 mg Eudragit S100). Formulations B and A showed an immediate release after 5 and 6 h, respectively, which represents ileo-ceacal transit time. The nanosize of emulsion, i.e., below 100 nm, was confirmed by transmission electron microscopy. Also, a phase transition of nanosize emulsion from water in oil to oil in water on dilution with water was observed through TEM. This novel approach of filling poorly water-soluble protein in solubilized form of nanosize emulsion preconcentrate into coated hard gelatin capsules for colon targeting has been reported first time. This approach could be a breakthrough for the better management of local intestinal pathologies.