Uncoated Formulation Research Articles

Formulation, development and evaluation of hyaluronic acid-conjugated liposomal nanoparticles loaded with regorafenib and curcumin and their in vitro evaluation on colorectal cancer cell lines

Colorectal cancer is one of the major causes of global cancer, with chemotherapy and radiation therapy being effective but limited due to low specificity. Regorafenib, a multikinase inhibitor, provides hope to patients with metastatic colorectal cancer and was approved by the FDA in 2012. However, due to resistance issues and adverse events, its efficacy is compromised, necessitating further refinement. Meanwhile, curcumin, a compound of turmeric, exhibits anticancer effects through antioxidant and anti-inflammatory actions, induction of the apoptosis, arrest of cell cycle, inhibition of angiogenesis, and modulation of signaling pathways. Unfortunately, its clinical utility is limited by its poor bioavailability, pointing towards innovative drug delivery strategies for enhanced efficacy in colorectal cancer treatment.Hyaluronic acid (HA)-decorated liposomes (LIPO) have been developed to target colorectal cells through an overexpressed CD44 receptor, increasing antitumor and antimetastasis efficacy. This study investigates the possibility of loading curcumin (CUR) or regorafenib (REGO) into a liposomal formulation for passive and HA-actively targeted treatment, evaluating its critical quality attributes (CQA) (size, zeta potential, polydispersity index) and cytotoxic activity in the HT29 colorectal cancer cell line. The average particle size of the plain liposomes and those decorated with HA was 144.00 ± 0.78 nm and 140.77 ± 1.64 nm, respectively. In contrast, curcumin-loaded plain liposomes and HA-decorated liposomes had 140 ± 2.46 nm and 164.53 ± 15.13 nm, respectively. The prepared liposomes had a spherical shape with a narrow size distribution and an acceptable zeta potential of less than −30 mV. The encapsulation efficiency was 99.2 % ± 0.3 and 99.9 ± 0.2 % for HA-decorated and bare regorafenib loaded. The % EE was 98.9 ± 0.2 % and 97.5 ± 0.2 % for bare liposomal nanoparticles loaded with curcumin and coated with curcumin. The IC50 of free REGO, CUR, REGO-LIPO, CUR-LIPO, REGO-LIPO-HA and CUR-LIPO-HA were 20.17 ± 0.78, 64.4 ± 0.33, 224.8 ± 0.06, 49.66 ± 0.22, 73.66 ± 0.6, and 27.86 ± 0.49 µM, respectively. The MTT assay in HT29 cells showed significant cytotoxic activity of the HA-decorated liposomal formulation compared to the base uncoated formulation, indicating that hyaluronic acid-targeted liposomes loaded with regorafenib or curcumin could be a promising targeted formulation against colorectal cancer cells.

Modulation of mesalamine release from enteric-coated matrix tablets using natural polysaccharides for localized colonic delivery

Background: Inflammatory bowel diseases (IBD) require effective colon-targeted drug delivery for improved therapeutic efficacy and minimized systemic side effects. Objectives: The objective of this research was to develop and evaluate novel colon-targeted matrix tablet formulations of mesalamine (5-aminosalicylic acid) for the treatment of IBD. Materials and Methods: Mesalamine matrix tablets were prepared by wet granulation technique using pH-sensitive polymers (HPMC K4M) and biodegradable natural polysaccharides (pectin, chitosan, and guar gum). Tablets were characterized for physicochemical properties, drug content, and in vitro drug release. Compatibility studies using FTIR and DSC confirmed no interaction between mesalamine and polymers. The optimized formulations were enteric-coated with Eudragit S100 and ethyl cellulose. Drug release kinetics and stability studies were conducted. Results and Discussion: The uncoated formulations (M3, M6, M7) showed adequate protection against drug release in simulated gastric (0-2 h) and intestinal (2-5 h) fluids. The enteric-coated formulations (ME3, ME6, ME7) exhibited a lag time of around 2 hours and restricted drug release (<5%) in simulated gastric and intestinal fluids up to 5 hours. However, in simulated colonic fluid (pH 6.8) containing 4% rat cecal contents, these formulations showed enhanced drug release (71-83% in 12 h) due to biodegradation of polymeric matrices by colonic enzymes. Drug release kinetics indicated anomalous transport or super case-II transport mechanisms. Stability studies at 40°C/75% RH for 3 months revealed no significant changes. Conclusion: The developed colon-targeted mesalamine matrix tablets demonstrated the potential to protect the drug from release in the upper GIT while facilitating targeted drug delivery to the colon, which could improve therapeutic efficacy and minimize systemic side effects in the treatment of IBD.

Targeted delivery of budesonide in acetic acid induced colitis: impact on miR-21 and E-cadherin expression

Inflammatory bowel disease (IBD) is characterized by chronic inflammation along the gastrointestinal tract. For IBD effective treatment, developing an orally administered stable drug delivery system capable of targeting inflammation sites is a key challenge. Herein, we report pH responsive hyaluronic (HA) coated Eudragit S100 (ES) nanoparticles (NPs) for the targeted delivery of budesonide (BUD) (HA-BUD-ES-NPs). HA-BUD-ES-NPs showed good colloidal properties (274.8 ± 2.9 nm and − 24.6 ± 2.8 mV) with high entrapment efficiency (98.3 ± 3.41%) and pH-dependent release profile. The negative potential following incubation in simulated gastrointestinal fluids reflected the stability of HA coat. In vitro studies on Caco-2 cells showed HA-BUD-ES-NPs biocompatibility and enhanced cellular uptake and anti-inflammatory effects as shown by the significant reduction in IL-8 and TNF-α. The oral administration of HA-BUD-ES-NPs in an acetic acid induced colitis rat model significantly mitigated the symptoms of IBD, and improved BUD therapeutic efficacy compared to drug suspension. This was proved via the improvement in disease activity index and ulcer score in addition to refined histopathological findings. Also, the assessment of inflammatory markers, epithelial cadherin, and mi-R21 all reflected the higher efficiency of HA-BUD-ES-NPs compared to free drug and uncoated formulation. We thus suggest that HA-BUD-ES-NPs provide a promising drug delivery platform for the management and site specific treatment of IBD.Graphical

Targeted Fisetin-Encapsulated β-Cyclodextrin Nanosponges for Breast Cancer.

Fisetin (FS) is considered a safer phytomedicine alternative to conventional chemotherapeutics for breast cancer treatment. Despite its surpassing therapeutic potential, its clinical utility is hampered by its low systemic bioavailability. Accordingly, as far as we are aware, this is the first study to develop lactoferrin-coated FS-loaded β-cyclodextrin nanosponges (LF-FS-NS) for targeted FS delivery to breast cancer. NS formation through cross-linking of β-cyclodextrin by diphenyl carbonate was confirmed by FTIR and XRD. The selected LF-FS-NS showed good colloidal properties (size 52.7 ± 7.2 nm, PDI < 0.3, and ζ-potential 24 mV), high loading efficiency (96 ± 0.3%), and sustained drug release of 26 % after 24 h. Morphological examination using SEM revealed the mesoporous spherical structure of the prepared nanosponges with a pore diameter of ~30 nm, which was further confirmed by surface area measurement. Additionally, LF-FS-NS enhanced FS oral and IP bioavailability (2.5- and 3.2-fold, respectively) compared to FS suspension in rats. Antitumor efficacy evaluation in vitro on MDA-MB-231 cells and in vivo on an Ehrlich ascites mouse model demonstrated significantly higher activity and targetability of LF-FS-NS (30 mg/kg) compared to the free drug and uncoated formulation. Consequently, LF-FS-NS could be addressed as a promising formulation for the effective management of breast cancer.

Exploring the potential of quercetin/aspirin-loaded chitosan nanoparticles coated with Eudragit L100 in the treatment of induced-colorectal cancer in rats.

Growing evidence suggests quercetin and aspirin may have anticancer properties, notably in the case of colorectal cancer. The goal of this study was to create Pluronic F127 and polyethylene glycol4000 solid dispersion-loaded chitosan nanoparticles for colonic quercetin and aspirin delivery. In 1:1 polymeric stoichiometric ratio, solubility and complex formation were verified. Solid dispersion-loaded chitosan nanoparticles with a diameter of 244.45 ± 8.5nm, a surface charge of 34.1 ± 3.3mV, and encapsulation effectiveness of 76.3 ± 4.3% were generated under ideal conditions. In some cases, coating with Eudragit L100 resulted in a decrease in zeta potential and an increase in particle size. The coated formulation released the actives in a pH-dependent manner, considering their physicochemical features. Surprisingly, when compared to the actives' suspension and uncoated formulation, the coated formulation had greater anti-inflammatory efficacy, with a substantial reduction of PGE2 and IL-8 production in colonic tissues (16.9 ± 7.9ng/g tissue and 134.9 ± 10.1pg/g tissue, respectively). It also reversed most of the dimethyl hydrazine-induced histological alterations in the colon. It also demonstrated a greater reduction in TNF expression in colonic tissues. As a result, Eudragit L100-coated QT/AS-loaded chitosan nanoparticles are suggested to provide a potential platform for colonic delivery of quercetin and aspirin.

Alginate-coated chitosan nanoparticles for pH-dependent release of tamoxifen citrate

Chitosan-based nano-sized particles increase the penetration of the drug through the narrow junction into the bloodstream and target the specific site. The objective of this study was to prepare chitosan nanoparticles to entrap a hydrophobic drug (tamoxifen citrate), followed by the alginate coating of the developed nanoparticles to decrease their degradation in the acidic pH. Drug-loaded chitosan nanoparticles were prepared by the ionic gelation method. Alginate coating was done by dissolving sodium alginate to buffer solution and drug-loaded chitosan nanoparticles drop-wise under mild agitation. The size of alginate coated chitosan nanoparticles, zeta potential, surface morphology, in-vitro drug release, and entrapment efficiency was measured. The optimised formulation of both uncoated (SH3) and coated (SH7) formulation showed the particle size, PDI, and zeta potential with values 221 & 338 nm, 0.161 & 0.230 and 36.5 & −20.7 mV, respectively. The resulted nanoparticle surface was non-porous. The percentage yield of the optimised formulation SH3 was 28% and SH6 was 33%. The entrapment efficiency of the optimised formulation SH3 (uncoated formulation) and SH6 (coated formulation) is 69.5 and 58.51%, respectively. Chitosan nanoparticles were successfully prepared to entrap tamoxifen citrate. The coating of chitosan nanoparticles decreased their degradation in the acidic pH.

Composition of Piperine with Enteric-Coated Chitosan Microspheres Enhances the Transepithelial Permeation of Curcumin in Sheep Intestinal Mucosa and Caco-2 Cells

Abstract Objectives The purpose of this study was to investigate the efficacy of enteric-coated chitosan microspheres with herbal bioenhancer, piperine, as a suitable composition for improving the permeation of curcumin through biological membranes using suitable ex vivo models. Material and Methods Chitosan microspheres of curcumin and piperine were prepared by an emulsion cross-linking method using glutaraldehydes the cross-linking agent and characterized for size, shape, entrapment efficiency, mucoadhesion, and in vitro release. The effect of piperine on the permeation of curcumin through excised sheep intestinal mucosa and Caco-2-cell monolayer was investigated. Statistical Analysis The data from permeation studies were analyzed by Student's t-test using Statistical Package for the Social Sciences (SPSS) software (SPSS, Chicago, IL, United States) with p-values &lt;0.05 indicating statistical significance. Results The formulations showed mucoadhesion for a period of more than 6 hours which was influenced by the chitosan content. The rate of drug release of uncoated formulation followed first-order kinetics, and the mechanism of release was non-Fickian transport. Optimized formulation was coated with a pH-sensitive polymer, Eudragit S-100, by a solvent evaporation technique in different concentrations and evaluated for ex vivo permeation through sheep intestinal mucosa and Caco-2-cell monolayer. Scanning electron microscopy images of the optimized coated formulation showed spherical particles with smooth surfaces. The calculated permeation flux and permeability coefficient of curcumin from microspheres were at least 20% greater in the presence of piperine through the intestinal mucosa and 30% through the Caco-2-cell monolayer model. The permeability coefficient of curcumin from microspheres with piperine was 1.93 × 10 to 5 cm/sec and significantly greater (p &lt; 0.05) than that of microspheres devoid of piperine and from aqueous dispersion (p &lt; 0.005). Conclusion The study confirmed the contribution of piperine and mucoadhesive microspheres toward improved permeation of curcumin through biological membranes, thereby providing an approach that has the potential of increasing transport through intestinal epithelial cells and possibly enhancing the oral bioavailability of this drug.

Development and characterization of pellets for targeted delivery of 5-fluorouracil and phytic acid for treatment of colon cancer in Wistar rat

The present study was designed to investigate the therapeutic efficacy of metal chelator and anticancer drug in the treatment of colorectal cancer (CRC). Pellets containing Phytic acid, 5- Fluorouracil (5-FU), Microcrystalline cellulose (MCC) PH 101, Hydroxypropyl Methylcellulose (HPMC) and Barium sulfate were prepared by using extrusion spheronization technique. Prepared pellets were coated with Eudragit S100 to achieve colon-specific drug delivery. Pellets were characterized for various pharmaceutical and micromeritic attributes. The in vivo therapeutic efficacy comprising of both pharmacokinetic and pharmacodynamic parameters was determined in Ehrlich ascites carcinoma (EAC) induced cancer animal model. Phytic acid and 5-FU combinations seem to exert higher cytotoxic activity via increased reactive oxygen species (ROS) level by chelating manganese. Further pharmacokinetic studies reveled approximately 50% lower Cmax in the finished formulation, indicates lower systemic exposure to the drug. X-ray radiography ensures the localized delivery of the encapsulated drug. Histopathological studies indicated no significant local toxicity compared to the uncoated formulation. Results inferred that the proposed combination has superior anticancer activity with minimum systemic and local toxicity and it opens a new avenue in the treatment of colorectal cancer.

FORMULATION DEVELOPMENT OF COLON TARGETED MESALAMINE PELLETS: IN VITRO-IN VIVO RELEASE STUDY

Objective: This study was intended to investigate the potential of the colon specificity approach comprising of use of pH-sensitive and time-dependent polymers in combination for precise colonic release of Mesalamine or 5-Aminosalicylic acid (5-ASA).&#x0D; Methods: The extrusion and spheronization method, preferably employed in industry for allowing high dose capacity to formulate, was used to prepare drug pellets. The Wurster coating technique used for aqueous coatings of Eudragit NE 40D as an inner coat and Eudragit FS30D as outer coat. The changing pH media used for in vitro release study of optimization batches for both the coating levels. A scanning electron microscope (SEM) was used to evaluate coating thickness and surface morphology.&#x0D; Results: The pharmacokinetic parameters of formulation evaluated by in vivo study in rabbits revealed that the uncoated formulation released the drug too early in the gastrointestinal tract (GIT) with a mean Cmax of 1205.28±0.37 µg/ml at 2 h after administration, whereas desired lag time was achieved in case of coated pellets exhibiting mean Cmax 465.94±0.21 µg/ml and tmax of 8 h.&#x0D; Conclusion: The in vitro and in vivo release study divulge the reliability of approach involving the use of pH sensitivity and time dependency of polymer for drug release in a single formulation for the treatment of colonic diseases. Hence, the present study provides constructive results for colon targeting of 5-ASA pellets with industrially feasible processes.

Antifungal and Mucoadhesive Properties of an Orally Administered Chitosan-Coated Amphotericin B Nanostructured Lipid Carrier (NLC).

Surface-modified nanostructured lipid carriers (NLC) represent a promising mode of drug delivery used to enhance retention of drugs at absorption site. Formulated chitosan-coated amphotericin-B-loaded NLC (ChiAmp NLC) had a size of 394.4 ± 6.4 nm, encapsulation and loading efficiencies of 86.0 ± 3% and 11.0 ± 0.1% respectively. Amphotericin-B release from NLCs was biphasic with no changes in physical properties upon exposure to simulated gastrointestinal conditions. Antifungal properties of Amphotericin-B and ChiAmpB NLC were comparable but ChiAmpB NLC was twice less toxic to red blood cells and ten times safer on HT-29 cell lines. In vitro mucoadhesion data were observed ex vivo, where ChiAmpB NLC resulted in higher retention within the small intestine compared to the uncoated formulation. The data strongly offers the possibility of orally administering a non-toxic, yet effective Amphotericin-B nanoformulation for the treatment of systemic fungal infections.

Mucoadhesive chitosan-coated nanostructured lipid carriers for oral delivery of amphotericin B

This study describes the properties of an amphotericin B-containing mucoadhesive nanostructured lipid carrier (NLC), with the intent to maximize uptake within the gastrointestinal tract. We have reported previously that lipid nanoparticles can significantly improve the oral bioavailability of amphotericin B (AmpB). On the other hand, the aggregation state of AmpB within the NLC has been ascribed to some of the side effects resulting from IV administration. In the undissolved state, AmpB (UAmpB) exhibited the safer monomeric conformation in contrast to AmpB in the dissolved state (DAmpB), which was aggregated. Chitosan-coated NLC (ChiAmpB NLC) presented a slightly slower AmpB release profile as compared to the uncoated formulation, achieving 26.1% release in 5 hours. Furthermore, the ChiAmpB NLC formulation appeared to prevent the expulsion of AmpB upon exposure to simulated gastrointestinal pH media, whereby up to 63.9% of AmpB was retained in the NLC compared to 56.1% in the uncoated formulation. The ChiAmpB NLC demonstrated mucoadhesive properties in pH 5.8 and 6.8. Thus, the ChiAmpB NLC formulation is well-primed for pharmacokinetic studies to investigate whether delayed gastrointestinal transit may be exploited to improve the systemic bioavailability of AmpB, whilst simultaneously addressing the side-effect concerns of AmpB.

Novel PEG-Modified Hybrid PLGA-Vegetable Oils Nanostructured Carriers for Improving Performances of Indomethacin Delivery.

The purpose of this work was to more exhaustively study the influence of nanocarrier matrix composition and also the polyethylene glycol (PEG)-modified surface on the performances of formulations as lipophilic drug delivery systems. Poly (d,l-lactide-co-glycolide), two vegetable oils (Nigella sativa oil and Echium oil) and indomethacin were employed to prepare novel PEG-coated nanocarriers through emulsion solvent evaporation method. The surface modification was achieved by physical PEG adsorption (in the post-production step). Transmission electron microscopy (TEM) nanographs highlighted the core-shell structure of hybrid formulations while scanning electron microscopy (SEM) images showed no obvious morphological changes after PEG adsorption. Drug loading (DL) and entrapment efficiency (EE) varied from 4.6% to 16.4% and 28.7% to 61.4%, solely depending on the type of polymeric matrix. The oil dispersion within hybrid matrix determined a more amorphous structure, as was emphasized by differential scanning calorimetry (DSC) investigations. The release studies highlighted the oil effect upon the ability of nanocarrier to discharge in a more sustained manner the encapsulated drug. Among the kinetic models employed, the Weibull and Korsmeyer-Peppas models showed the better fit (R2 = 0.999 and 0.981) with n < 0.43 indicating a Fickian type release pattern. According to cytotoxic assessment the PEG presence on the surface increased the cellular viability with ~1.5 times as compared to uncoated formulations.

PUB029 Eudragit Coated Chitosan Nanoparticles for Colon Cancer

Cancer is the second leading cause of death worldwide, the deaths projected to continue rising, with an estimated 12 million deaths in 2030. Aim of the present investigation is to prepare and compare the uncoated (U-CH NP) and eudragit S 100 coated (E-U-CH NP) chitosan nanoparticles encapsulating a caspase 3 activator (UCN 01), by ionic gelation method. The prepared formulations were studied for various parameters like particles size, zeta potential, transmission electron microscopy, atomic force microscopy, in vitro release study, ex vivo study using Caco 2 colon cancer cell line and in vivo studies. Developed formulation showed particle size of 168 ± 3.7 nm and 265 ± 4.1 nm for U-CH NP and E-U-CH NP, respectively. The cytotoxicity of prepared formulations was performed on Caco2 cell line by MTT assay. U-CH NP showed enhanced cytotoxicity as compared to blank (without drug) formulation. There was an increase in caspase 3 activity of U-CH NP as compared to UCN 01 alone. The E-U-CH NP showed better in vitro release than uncoated formulation in SCF (pH 6.8) than in SGF (pH 1.2) due to eudragit S 100 coating. E-U-CH NP showed better tumor regression ability than U-CH NP. The results obtained demonstrated that E-U-CH NP has continuous release profile of UCN 01 and comprehensive residence time. Thus, it is better acceptable than free UCN 01 and may be a potential delivery system for the targeting and treatment of colon cancer.

Constructing Slow-Release Formulations of Ammonium Nitrate Fertilizer Based on Degradable Poly(3-hydroxybutyrate).

The present study describes construction and investigation of experimental formulations of ammonium nitrate embedded in a matrix of degradable natural polymer poly-3-hydroxybutyrate [P(3HB)] and P(3HB) blended with wood flour shaped as tablets, some of them coated with P(3HB). Kinetics of ammonium release into soil as dependent on the composition of the polymer matrix was investigated in laboratory experiments. The rates of fertilizer release from formulations coated with a biopolymer layer were considerably (two months or longer) slower than the rates of fertilizer release from uncoated formulations, while release from polymer and composite (polymer/wood flour) formulations occurred with comparable rates. The use of the experimental formulations in laboratory ecosystems with wheat (Triticum aestivum L.) was more effective than application of free ammonium nitrate. The advantage of the slow-release fertilizer formulations is that they are buried in soil together with the seeds, and the fertilizer remains effective over the first three months of plant growth. The use of such slow-release formulations will reduce the amounts of chemicals released into the environment, which will curb their accumulation in food chains of ecosystems and mitigate their adverse effects on the biosphere.

Solid state properties and drug release behavior of co-amorphous indomethacin-arginine tablets coated with Kollicoat® Protect.

A promising approach to improve the solubility of poorly water-soluble drugs and to overcome the stability issues related to the plain amorphous form of the drugs, is the formulation of drugs as co-amorphous systems. Although polymer coatings have been proven very useful with regard to tablet stability and modifying drug release, there is little known on coating co-amorphous formulations. Hence, the aim of the present study was to investigate whether polymer coating of co-amorphous formulations is possible without inducing recrystallization. Tablets containing either a physical mixture of crystalline indomethacin and arginine or co-amorphous indomethacin-arginine were coated with a water soluble polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat® Protect) and stored at 23°C/0% RH and 23°C/75% RH. The solid state properties of the coated tablets were analyzed by XRPD and FTIR and the drug release behavior was tested for up to 4h in phosphate buffer pH 4.5. The results showed that the co-amorphous formulation did not recrystallize during the coating process or during storage at both storage conditions for up to three months, which confirmed the high physical stability of this co-amorphous system. Furthermore, the applied coating could partially inhibit recrystallization of indomethacin during drug release testing, as coated tablets reached a higher level of supersaturation compared to the respective uncoated formulations and showed a lower decrease of the dissolved indomethacin concentration upon precipitation. Thus, the applied coating enhanced the AUC of the dissolution curve of the co-amorphous tablets by about 30%. In conclusion, coatings might improve the bioavailability of co-amorphous formulations.

An investigation into moisture barrier film coating efficacy and its relevance to drug stability in solid dosage forms

Barrier coatings are frequently employed on solid oral dosage forms under the assumption that they prevent moisture sorption into tablet cores thereby averting premature degradation of moisture-sensitive active ingredients. However, the efficacy of moisture barrier coatings remains unproven and they may actually accelerate degradation. This study aimed to investigate the barrier performance of four coating systems following application onto a low hygroscopic tablet formulation containing aspirin as a model moisture sensitive drug. Tablets were prepared by direct compaction and coated with aqueous dispersions of Eudragit® L30 D-55, Eudragit® EPO, Opadry® AMB and Sepifilm® LP at the vendors’ recommended weight gains. Moisture uptake was studied by dynamic vapor sorption at 0 and 75% RH (25°C). Accelerated stability studies were undertaken at 75% RH/25°C for 90 days and HPLC assay was used to determine aspirin content. Uncoated tablet cores equilibrated rapidly and took up very little water (0.09%). The mean water uptake for coated cores was higher than for the uncoated formulation and varied as follows: 0.19% (Eudragit® L30 D-55), 0.35% (Opadry® AMB), 0.49% (Sepifilm® LP) and 0.76% (Eudragit® EPO). The level of aspirin decreased in all the samples such that by the time the study was terminated, the mean aspirin recovered was as follows: uncoated cores 80.0%; Eudragit® L30 D-55 coated cores 78.8%; Opadry® AMB coated cores 76.2%, Sepifilm® LP coated cores 76.0% and Eudragit® EPO coated samples 66.5%. From these results, it is concluded that the efficacy of moisture barrier polymer coatings on low hygroscopic cores is limited, and application of these coatings can, instead, enhance drug degradation in solid dosage forms.

Coated chitosan nanoparticles encapsulating caspase 3 activator for effective treatment of colorectral cancer.

Cancer is the second leading cause of death worldwide, the deaths are projected to continue rising, with an estimated 12 million deaths in 2030. The aim of the present investigation is to prepare and compare the uncoated (U-CH NP) and eudragit S 100-coated (E-U-CH NP) chitosan nanoparticles encapsulating a caspase 3 activator (UCN 01), by ionic gelation method. The prepared formulations were studied for various parameters like particles size, zeta potential, transmission electron microscopy, atomic force microscopy, in vitro release study, ex vivo study using Caco 2 colon cancer cell line, and in vivo studies. The particle size and zeta potential of developed formulation was found to be particle size of 168 ± 3.7 nm and +35.8 ± 3.7 for U-CH NP and 265 ± 4.1 nm and +22.3 ± 1.1 for E-U-CH NP. TEM and AFM images revealed that U-CH NPs were round in shape and smoother at surface as compared to E-U-CH NP which have irregular surface due to coating. The E-U-CH NP showed better in vitro release than uncoated formulation in SCF (pH6.8) than in SGF (pH1.2). The cytotoxicity was performed by MTT assay. U-CH NP showed enhanced cytotoxicity as compared to blank (without drug) formulation. There was an increase in caspase 3 activity of U-CH NP as compared to UCN 01 alone. E-U-CH NP showed better tumor regression ability than U-CH NP. The results of plasma profile and tumor regression study demonstrated that E-U-CH NP has continuous release profile of UCN 01 and comprehensive residence time. Thus, it is better acceptable than free UCN 01 and may be a potential delivery system for the targeting and treatment of colon cancer.

Formulation, characterization and permeability study of nano particles of lipo-endomorphin-1 for oral delivery

Three different formulations of a lipid-modified endomorphin-1 peptide (C10LAA-Endo-1) were prepared, characterized, and evaluated for their permeability through Caco-2 cell membranes. Solid lipid nanoparticles (SLN), enteric coated (EC), and the EC-SLN of C10LAA-Endo-1 is a modified structure of endomorphin-1 for oral delivery. Physico–chemical characterization of the formulations showed that among all formulations, EC-[C10LAA-Endo-1] had the lowest particle size and the highest EE% and absolute zeta potential. Release of drug from SLN, EC-SLN and EC-[C10LAA-Endo-1] in acid media was 14.30 (±2.7)%, 3.0 (±1.0)% and 10.2 (±3.0)%, respectively. Release data in buffer media (pH = 7.4) showed that enteric coated formulations released C10LAA-Endo-1 more slowly than uncoated formulations. It was also demonstrated that direct coating of C10LAA-Endo-1 with Eudragit® S100 significantly enhanced the permeability of the compound through Caco-2 cell membranes with a 39-fold higher Papp compared to C10LAA-Endo-1. These findings indicated that EC-C10LAA-Endo-1 is a promising candidate to promote the oral delivery of the previously modified endomorphin-1 peptide analogue and is worthy of future animal investigations.

Formulation and optimization of coated PLGA – Zidovudine nanoparticles using factorial design and in vitro in vivo evaluations to determine brain targeting efficiency

In the current study zidovudine loaded PLGA nanoparticles were prepared, coated and further investigated for its effectiveness in brain targeting. IR and DSC studies were performed to determine the interaction between excipients used and to find out the nature of drug in the formulation. Formulations were prepared by adopting 23 factorial designs to evaluate the effects of process and formulation variables. The prepared formulations were subjected for in vitro and in vivo evaluations. In vitro evaluations showed particle size below 100nm, entrapment efficiency of formulations ranges of 28–57%, process yield of 60–76% was achieved and drug release for the formulations were in the range of 50–85%. The drug release from the formulations was found to follow Higuchi release pattern, n–value obtained after Korsemeyer plot was in the range of 0.56–0.78. In vivo evaluations were performed in mice after intraperitoneal administration of zidovudine drug solution, uncoated and coated formulation. Formulation when coated with Tween 80 achieved a higher concentration in the brain than that of the drug in solution and of the uncoated formulation. Stability studies indicated that there was no degradation of the drug in the formulation after 90days of preparation when stored in refrigerated condition.

Colon Targeting of 5-Fluorouracil Using Polyethylene Glycol Cross-linked Chitosan Microspheres Enteric Coated with Cellulose Acetate Phthalate

Polyethylene glycol cross-linked chitosan microspheres loaded with 5-fluorouracil (5-FU) have been prepared by emulsion cross-linking and enteric coated with cellulose acetate phthalate (CAP) to facilitate direct targeting of 5-FU to the colon. Spherical microspheres with surface ridges to moderate smooth surfaces loaded with different concentrations (i.e., 10, 20, and 30% w/w) of 5-FU have been evaluated for encapsulation efficiency, swelling and in vitro release characteristics in simulated gastro intestinal tract (GIT) conditions for both enteric coated and uncoated microspheres. In acidic pH, 8 to 17%, but in alkaline pH, approximately 88 to 97% of 5-FU was released with CAP coated microspheres. In the case of uncoated microspheres, 46 to 77% release of 5-FU occurred in acidic pH, but 93 to 97% was released in alkaline pH. The study demonstrates that chitosan coating with CAP and cross-linking with PEG is necessary for targeted delivery of 5-FU to the colon. The coated microspheres are found to be more suitable for colon targeting than the uncoated formulations as the former prolonged the 5-FU release from 6 to 12 h by protecting 5-FU in acidic environment of the stomach. Kinetics of drug release as investigated by empirical equations suggested Super Case II transport mechanism.