scholarly journals FORMULATION, OPTIMIZATION, AND IN VITRO CHARACTERIZATION OF DASATINIB LOADED POLYMERIC NANOCARRIERS TO EXTEND THE RELEASE OF THE MODEL DRUG

2021 ◽  
pp. 318-330
Author(s):  
SANDEEP KUMAR REDDY ADENA ◽  
KASI VISWANADH MATTE ◽  
RAMOJI KOSURU
Keyword(s):  
Failure Modes ◽  
Evaluation Studies ◽  
K562 Cells ◽  
Storage Conditions ◽  
Stability Study ◽  
Dependent Manner ◽  
Polymeric Nanocarriers ◽  
Study Results ◽  
Model Drug

Objective: The present research aims to design, develop, optimize, characterize and evaluate dasatinib (DSB) loaded polymeric nanocarriers to treat chronic myeloid leukaemia (CML) by adopting a quality by design (QbD) approach. Methods: Risk assessment was performed by using failure modes and effects analysis, and optimization of nanoformulation was done by adopting 23 full factorial design. The optimized nanoformulation was characterized by different characterization techniques and evaluated by various in vitro studies. Results: Surface morphology and shape were found to be smooth and spherical. Stability study results revealed that the nanoformulation could be stored in all three storage conditions for safe and long-term use since it retained its pharmaceutical properties. Drug release was 32.06 % in the first 4 h and 79.34 % by the end of 48 h which infers a sustained-release pattern. The hemocompatibility results showed no sign of hemolysis. Cellular uptake study showed approximately 10 to 20-fold much higher intracellular fluorescence intensities of nanoformulation than DSB. Cytotoxicity results confirmed that when compared to the pure drug, the optimized nanoformulation have a potential cytotoxic effect in the treatment of CML since it exhibited a significantly more % growth inhibition. Cell apoptosis assay revealed that the nanoformulation could provide significant antileukaemia activity against K562 cells and further induce K562 cell death with a dose and time-dependent manner. Conclusion: The results of the characterization and evaluation studies showed that the developed nanoformulation offered significant advantages, making it a potential delivery system of DSB for more effective treatment of CML.

Novel Swellable/Expandable Gastroretentive Floating Films of Gliclazide Folded in Capsule Shell for the Effective Management of Diabetes Mellitus: Formulation Development, Optimization and In vitro Evaluation

2020 ◽  
Vol 15 ◽  
Author(s):  
Diksha Sharma ◽  
Deepak Sharma
Keyword(s):  
Diabetes Mellitus ◽  
Drug Absorption ◽  
Gastric Fluid ◽  
Stability Study ◽  
Gastric Retention ◽  
Effective Management ◽  
In Vitro Evaluation ◽  
Capsule Shell ◽  
Study Results

Background: Gliclazide (GLZ) belongs to the second-generation of sulphonylureas, is a drug of choice for the management of type II DM. It belongs to BCS Class II. The major site of drug absorption for GLZ is the stomach; it displayed variation in the drug absorption rate and bioavailability due to the shorter gastric retention time. Floating mechanism performance gets affected when the gastric fluid level not sufficiently higher, which ultimately obstructs the floating behavior, which is the major limitation of reported formulations. This limitation can get over by folded the film into the capsule shell that dissolved in gastric fluid and film swell/expands to dimensions higher than pylorus sphincter (12mm), thus prevents its evacuation. Objective: To explore the floating mechanism in the designing of films along with a tendency to expand by swelling and unfolding by utilizing a mixture of hydrophilic and hydrophobic polymer to achieve the controlled drug delivery and prolonged gastric retention of drug. Methods: The gastroretentive floating films were formulated by the solvent casting technique using 32 full factorial design and subjected to in vitro evaluation parameters, drug-excipient compatibility, X-ray diffraction and accelerated stability study. Results: The pre-formulation study established the purity and identification of drug. FTIR study confirmed no drug excipient interaction. F3, F6, and F9 were optimized based on in vitro floating characteristics, swelling/expanding ability, and unfolding time study. All developed formulations were unfolded within 14-22 min after capsule disintegration. The F3 was selected as final formulation as its ability to control the release of drug for 24 hrs followed by Zero-order kinetics having super case 2 transport. XRD confirmed the amorphousness of drug within formulation. The stability study results revealed that formulation was quite stable at extreme storage condition. Conclusion: The developed novel formulation has a good potential for the effective management and treatment of Diabetes Mellitus.

scholarly journals In Vitro Evaluation of Eslicarbazepine Delivery via Enteral Feeding Tubes

2017 ◽  
Vol 52 (11) ◽  
pp. 752-760 ◽  
Author(s):  
Kristin Reindel ◽  
Fang Zhao ◽  
Susan Hughes ◽  
Vivek S. Dave
Keyword(s):  
Enteral Feeding ◽  
Hplc Method ◽  
Stability Study ◽  
Eslicarbazepine Acetate ◽  
Particle Size Reduction ◽  
Feeding Tubes ◽  
Stability Indicating ◽  
Acceptable Range ◽  
Study Results

Purpose: The feasibility of preparing an eslicarbazepine acetate suspension using Aptiom tablets for administration via enteral feeding tubes was evaluated. Methods: Eslicarbazepine acetate suspension (40 mg/mL) was prepared using Aptiom tablets after optimizing the tablet crushing methods and the vehicle composition. A stability-indicating high-performance liquid chromatography (HPLC) method was developed to monitor the eslicarbazepine stability in the prepared suspension. Three enteric feeding tubes of various composition and dimensions were evaluated for the delivery of the suspensions. The suspension was evaluated for the physical and chemical stability for 48 hours. Results: The reproducibility and consistency of particle size reduction was found to be best with standard mortar/pestle. The viscosity analysis and physical stability studies showed that ORA-Plus:water (50:50 v/v) was optimal for suspending ability and flowability of suspension through the tubes. The developed HPLC method was found to be stability indicating and suitable for the assay of eslicarbazepine acetate in the prepared suspension. The eslicarbazepine concentrations in separately prepared suspensions were within acceptable range (±3%), indicating accuracy and reproducibility of the procedure. The eslicarbazepine concentrations in suspensions before and after delivery through the enteric feeding tubes were within acceptable range (±4%), indicating absence of any physical/chemical interactions of eslicarbazepine with the tubes and a successful delivery of eslicarbazepine dosage via enteric feeding tubes. The stability study results showed that eslicarbazepine concentration in the suspension remained unchanged when stored at room temperature for 48 hours. Conclusion: The study presents a convenient procedure for the preparation of a stable suspension of eslicarbazepine acetate (40 mg/mL) using Aptiom tablets, for administration via enteral feeding tubes.

scholarly journals A Precise Nanostructure of Folate-Overhung Mitoxantrone DNA Tetrahedron for Targeted Capture Leukemia

Nanomaterials ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 951
Author(s):  
Ying-Zi Bu ◽  
Jia-Rui Xu ◽  
Qian Luo ◽  
Ming Chen ◽  
Li-Min Mu ◽  
...  
Keyword(s):  
Anticancer Agent ◽  
Evaluation Studies ◽  
Drug Loading ◽  
K562 Cells ◽  
Leukemic Cells ◽  
Dna Nanostructure ◽  
Dna Tetrahedron ◽  
Targeted Capture ◽  
Dna Strand

Regular chemotherapy cannot eliminate leukemic cells, due to the sparse distribution of cancer cells in leukemia patients. Here, we report a precise nanostructure of folate-overhung mitoxantrone DNA tetrahedron that enables the treatment of leukemic cells by targeted action. Folate is used as a targeting molecule and synthesized with DNA strand in forming the folate-overhang DNA complement, and the complement is then separately base-paired onto six sides of the fabricated DNA tetrahedron. Mitoxantrone is used as an anticancer agent and intercalated into the double strands of the folate-overhung DNA tetrahedron for drug loading. The evaluation studies are performed on leukemia BALL-1 and K562 cells. The results demonstrate that the folate-overhung mitoxantrone DNA tetrahedra (approximately 25nm) are able to target leukemic cells, transport across the nuclei membrane, induce the apoptosis, and enhance the overall efficacy of treating leukemic cells in vitro and in leukemia-bearing mice. This study provides a potential drug-containing DNA nanostructure, to clean the sparsely distributed leukemic cells in patients.

Synergic Effects of Proteasome Inhibitor PS-341 and Tyrosine Kinase Inhibitor STI571 on Chronic Myeloid Leukemia Cells and BCR-ABL Oncoprotein In Vitro and In Vivo.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4771-4771
Author(s):  
Guangbiao Zhou ◽  
Zheng Hu ◽  
Dapeng Liu ◽  
Fuqun Wu ◽  
Jiang Zhu ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tumor Growth ◽  
Proteasome Inhibitor ◽  
Myeloid Leukemia ◽  
K562 Cells ◽  
Leukemic Cells ◽  
Great Promise ◽  
Dependent Manner

Abstract STI571/Gleevec/imatinib, a rationally-designed agent that occupies the ATP-binding site of BCR-ABL and stabilizes the protein in its closed, inactive conformation, has been a remarkable success for the treatment of chronic myeloid leukemia (CML). However, a significant proportion of patients chronically treated with STI571 develop resistance because of the acquisition of mutations in the kinase domain of BCR-ABL. Furthermore, the effects of STI571 on CML patients in accelerated phase or blastic crisis are unsatisfactory since many patients relapse after transient remission. Hence, additional drugs or STI571-based combination regimens are desired to circumvent resistance and to improve response rates. Here we reported that PS-341, a proteasome inhibitor which offers great promise to patients with multiple myeloma (MM), significantly enhanced the antileukemia activity of STI571 in vitro and in vivo. We found a synergy exists between low concentrations of PS-341 (5–10 nM) and STI571 (0.1–0.2 μM) in inhibition of cell growth and induction of apoptosis in K562 cell line and CD34+ leukemic cells isolated from CML patients. In K562 cells, combined use of PS-341 and STI571 accelerated activation of caspase-3, 9, and facilitated cleavage of poly-(ADP-ribose) polymerase (PARP) as compared to those in cells treated with PS-341 or STI571 alone. Moreover, PS-341/STI571 combination resulted in potentiated degradation of BCR-ABL and downregulation of phosphorylated BCR-ABL as compared to those in mono treatment. In nude mice inoculated subcutaneously with K562 cells, treatment with PS-341 (injected intraperitoneally, ip) alone (at doses of 0.05, 0.5, 1 mg/kg/d, twice a week for 4 weeks, respectively) decreased tumor growth in a dose-dependent manner. STI571 (ip) at 10 mg/kg/d also inhibited tumor growth. Intriguingly, combinatory administration of low dose PS-341 (0.05 mg/kg/d, twice a week for 4 weeks) and STI571 (10 mg/kg/d) yielded a much more profound inhibition of tumor growth and even clearance of leukemic cells in mice compared to either monotherapy. Taken together, these results demonstrate synergic effects of PS-341 and STI571, and provide the rationale to evaluate PS-341/STI571 combination in treating CML aiming to further improve clinical outcome of patients.

Abi-1-bridged tyrosine phosphorylation of VASP by Abelson kinase impairs association of VASP to focal adhesions and regulates leukaemic cell adhesion

2012 ◽  
Vol 441 (3) ◽  
pp. 889-901 ◽  
Author(s):  
Masahiro Maruoka ◽  
Mizuho Sato ◽  
Yunfeng Yuan ◽  
Masayoshi Ichiba ◽  
Ryosuke Fujii ◽  
...  
Keyword(s):  
Focal Adhesions ◽  
K562 Cells ◽  
Dependent Manner ◽  
Wild Type ◽  
Abelson Kinase ◽  
Leukaemic Cells ◽  
Phosphoinositide 3 Kinase ◽  
Proline Rich Region

Mena [mammalian Ena (Enabled)]/VASP (vasodilator-stimulated phosphoprotein) proteins are the homologues of Drosophila Ena. In Drosophila, Ena is a substrate of the tyrosine kinase DAbl (Drosophila Abl). However, the link between Abl and the Mena/VASP family is not fully understood in mammals. We previously reported that Abi-1 (Abl interactor 1) promotes phosphorylation of Mena and BCAP (B-cell adaptor for phosphoinositide 3-kinase) by bridging the interaction between c-Abl and the substrate. In the present study we have identified VASP, another member of the Mena/VASP family, as an Abi-1-bridged substrate of Abl. VASP is phosphorylated by Abl when Abi-1 is co-expressed. We also found that VASP interacted with Abi-1 both in vitro and in vivo. VASP was tyrosine-phosphorylated in Bcr-Abl-positive leukaemic cells in an Abi-1-dependent manner. Co-expression of c-Abl and Abi-1 or the phosphomimetic Y39D mutation in VASP resulted in less accumulation of VASP at focal adhesions. VASP Y39D had a reduced affinity to the proline-rich region of zyxin. Interestingly, overexpression of both phosphomimetic and unphosphorylated forms of VASP, but not wild-type VASP, impaired adhesion of K562 cells to fibronectin. These results suggest that the phosphorylation and dephosphorylation cycle of VASP by the Abi-1-bridged mechanism regulates association of VASP with focal adhesions, which may regulate adhesion of Bcr-Abl-transformed leukaemic cells.

FORMULATION AND EVALUATION OF THYROID HORMONE(T3) IMMEDIATE RELEASE TABLETS

2021 ◽  
Vol 1 (10) ◽  
pp. 383-388
Author(s):  
Farghana Begam ◽  
Rajalakshmi A. N ◽  
Padmapriya S
Keyword(s):  
Thyroid Hormone ◽  
Chemical Characterization ◽  
Immediate Release ◽  
Magnesium Stearate ◽  
Stability Study ◽  
Direct Compression ◽  
Maize Starch ◽  
Disintegration Time ◽  
Study Results

The study was aimed to formulate and evaluate Thyroid hormone (T3) immediate release tablets of a model Reference Listed Drug (RLD). The objective was to develop a cost effective immediate release tablet formulation and to optimize the formula in product development same that of the reference product. The ingredients used were API (thyroid hormone), lactose monohydrate (diluent), acacia (binder), maize starch (disintegrant), sodium chloride (alkalinizing agent) and magnesium stearate (lubricant). The concentration of maize starch and magnesium stearate were altered to reach the objective. Totally five formulations (F1 - F5) were prepared by direct compression method. The plan of work involved involved in the study was1 Selection of drug and excipients, 2Physico–chemical characterization and drug identification, 3Preformulation parameters of the drug, 4Pre–compression parameters for the tablet blend, 5Formulation and development of the tablet dosage form, 6Post compression parameters of the tablet and 7Stability study. The stability studies were performed as per ICH guidelines. Among all the formulations F5 was found to be the best as it showed better results than the other formulations. In vitro disintegration time and percentage drug release results shown satisfactory results. Stability study results showed no significant changes in the formulation. Keywords: Thyroid hormone (T3), Immediate release tablets, Direct compression, Dissolution.

scholarly journals Experimental Assessment ofMoringa oleiferaLeaf and Fruit for Its Antistress, Antioxidant, and Scavenging Potential UsingIn VitroandIn VivoAssays

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Suaib Luqman ◽  
Suchita Srivastava ◽  
Ritesh Kumar ◽  
Anil Kumar Maurya ◽  
Debabrata Chanda
Keyword(s):  
Aqueous Extract ◽  
Moringa Oleifera ◽  
Evaluation Studies ◽  
Antioxidant Properties ◽  
Radical Scavenging ◽  
Reducing Power ◽  
Ethanolic Extract ◽  
Dependent Manner ◽  
Concentration Dependent Manner

We have investigated effect ofMoringa oleiferaleaf and fruit extracts on markers of oxidative stress, its toxicity evaluation, and correlation with antioxidant properties usingin vitroandin vitroassays. The aqueous extract of leaf was able to increase the GSH and reduce MDA level in a concentration-dependent manner. The ethanolic extract of fruit showed highest phenolic content, strong reducing power and free radical scavenging capacity. The antioxidant capacity of ethanolic extract of both fruit and leaf was higher in thein vitroassay compared to aqueous extract which showed higher potentialin vivo. Safety evaluation studies showed no toxicity of the extracts up to a dose of 100 mg/kg body weight. Our results support the potent antioxidant activity of aqueous and ethanolic extract ofMoringa oleiferawhich adds one more positive attribute to its known pharmacological importance.

Anti-Tumor Activity of a Novel Bcr-Abl/Lyn Dual Inhibitor, NS-187, in Murine CNS Ph+ Leukemia Models.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 493-493
Author(s):  
Asumi Yokota ◽  
Shinya Kimura ◽  
Tatsuya Oyama ◽  
Eishi Ashihara ◽  
Haruna Naito ◽  
...  
Keyword(s):  
Cell Line ◽  
Leukemic Cell ◽  
K562 Cells ◽  
Leukemic Cells ◽  
Dependent Manner ◽  
Dual Inhibitor ◽  
Imatinib Resistance ◽  
The Brain

Abstract The penetration of imatinib mesylate (Gleevec™) into the central nervous system (CNS) is poor. Hence the CNS becomes a sanctuary site for patients who are on prolonged imatinib therapy. P-glycoprotein (P-gp) plays an important role in limiting the distribution of imatinib to the CNS, and it is well known that imatinib is a substrate of P-gp. We have recently identified a specific dual Bcr-Abl/Lyn inhibitor, NS-187, which can override imatinib-resistance. NS-187 was 25–55 and at least 10 times more potent than imatinib in vitro and in vivo, respectively. The purpose of this study was to investigate whether NS-187 can inhibit the growth of Ph+ leukemic cells in the CNS. In our preliminary pharmacokinetic study, the intracranial concentration of NS-187 was 10% of its serum concentration, suggesting the involvement in P-gp. To determine whether NS-187 is effluxed by P-gp, we examined the growth-inhibitory effects of NS-187 alone and in combination with a P-gp inhibitor, verapamil or cyclosporin A, on K562 cells and on a multidrug-resistant (MDR) K562/D1-9 cell line overexpressing P-gp. The K562/D1-9 cell line was 10 times more resistant to NS-187 than the parental K562 cell line, and P-gp inhibitors abolished this resistance, indicating that the action of NS-187, like that of imatinib, is affected by the P-gp-related MDR system. Even though NS-187 was found to be a substrate for P-gp, it inhibited the growth of K562/D1-9 cells at a concentration which could be achieved in the brain. we therefore tested the anti-tumor effects of NS-187 in murine CNS leukemia models. mice were inoculated into right cerebral ventricle with 1×105 BaF3/wt bcr-ablGFP cells (Balb/c-nu/nu mice) or 1×106 K562GFP cells (NOD/SCID mice). Five days after inoculation, mice were randomized into groups of 4 and orally administrated twice a day with vehicle, imatinib or NS-187 for 14 consecutive days. Sixteen days after inoculation, three mice from each group were sacrificed and their brains were examined under a fluorescent stereoscopic microscope. NS-187 inhibited the proliferation of leukemic cells in the brain, whereas imatinib did not. Moreover, NS-187 significantly prolonged the survival of the mice in a dose-dependent manner in both murine models compared with imatinib (Figure). In conclusion, NS-187 can inhibit Ph+ leukemic cell growth in the CNS in spite of efflux of the compound by P-gp. Figure Figure

Reversal of P-Glycoprotein-Dependent Resistance to Adriamycin by 5-bromotetrandrine in K562/A02 Cell Line.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4175-4175
Author(s):  
Bao-An Chen ◽  
Jue-Qiong Wang ◽  
Jia-Hua Ding ◽  
Feng Gao ◽  
Jian Chen ◽  
...  
Keyword(s):  
Fluorescence Intensity ◽  
K562 Cells ◽  
Control Group ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Intracellular Accumulation ◽  
Protein Levels ◽  
P Glycoprotein ◽  
Mdr Reversal

Abstract Objective: The present study aimed to evaluate the MDR reversal activity of bromotetrandrine (BrTet), a bromized derivative of tetrandrine (Tet), in vitro. Methods: Drug sensitivity was determined using the MTT assay. Adriamycin (ADM) accumulation, the protein levels of P-glycoprotein (P-gp) and the apoptotic changes were analyzed by fluorospectrophotometry, respectively. The mRNA levels of P-gp was determined by RT-PCR. Results: BrTet at 0.25, 0.5 and reversed ADM resistance in MDR K562/A02 cells dose-dependently and its potency was greater than that of Tet at the same concentrations. The IC50 of ADM for K562 and K562/A02 cells were 55.122 mg/l and 1.1373 mg/l, respectively. Treating K562/A02 cells with BrTet(1uM)and TTD(1uM)both for 48 hours partially restored the sensitivity of K562/A02 cells to ADM (IC50 were 4.7729 mg/l and 13.584 mg/l respectively) but had not effect on K562 cells. The fold reversal (FR) were 11.55 and 4.06 respectively. K562/A02 cells showed apoptotic characteristics after treated with Brtet and Tet both for 48 hours compared with control group(apoptosis rate was 61.1%, 11.1% and 9.9%,respectively); Fluorospectrophotometric assay showed that BrTet significantly increased the intracellular accumulation of ADM in K562/A02 cells in a dose-dependent manner. The fluorescence intensity of intracellelar ADM in K562/A02 cells treated with ADM(1mg/L)was 33% of that in K562 cells. BrTet and Tet elevated the intracellular ADM concentration in K562/A02 cells up to 52% and 69%,respectively. BrTet also inhibited the overexpression of P-gp in K562/A02 cells. The fluorescence intensity of P-gp in K562 and K562/A02 cells was 0.5 and 97.97.The P-gp expression was down after treated with BrTet and TTD (65.05 and 54.86). The mdr1 mRNA was also down regulated. Conclusions: BrTet showed significant MDR reversal activity in vitro. Its activity may be related to the inhibition of P-gp overexpression and the increase in intracellular accumulation of anticancer drugs. BrTet may be a promising MDR modulator for eventual assessment in the clinic.

scholarly journals EFFECT PROCESSING VARIABLES ON THE CHARACTERISTICS OF ITRACONAZOLE HOLLOW MICROSPHERES

2019 ◽  
pp. 108-115
Author(s):  
SURBHI ROHILLA ◽  
D. C. BHATT ◽  
SHAVETA AHALWAT
Keyword(s):  
Drug Release ◽  
Spherical Surface ◽  
Entrapment Efficiency ◽  
Storage Conditions ◽  
Physicochemical Analysis ◽  
Stability Study ◽  
Hollow Microspheres ◽  
Release Mechanism ◽  
Low Density

Objective: The purpose of the study was to develop the multiple unit non-effervescent gastroretentive floating hollow microspheres to enhance the bioavailability of the drug by varying the concentration of low-density polymer and release modifier to retaining the formulation at its absorption site. Design of experiment approach applied to get the best possible formulation with minimum assets and experimentation. Methods: The hollow microspheres were prepared by emulsion solvent diffusion-evaporation technique using ethylcellulose as low-density polymer and Eudragit E100 as release modifier. The central composite design was used for the optimization of independent variables and was evaluated for particle size, entrapment efficiency, in vitro floating ability and drug release characteristics. Results: The physicochemical analysis was done to confirm any interaction between drug and excipients. The Scanning Electron Microscopy (SEM) showed a smooth, spherical surface with an inner hollow cavity. The stability study proves that the hollow microspheres were more stable under different storage conditions with no significant changes in formulation. The drug release mechanism of the optimized batch can be explained by Korsmeyer Peppas model. Conclusion: Based on the results, the hollow microspheres with a release modifying polymer offers a superior approach to retain the formulation in the stomach.

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