ISOLATION AND CHARACTERISATION OF NOVEL IMPURITY OF LANSOPRAZOLE FORMED IN THERMAL STRESS CONDITION

Objective: The aim of the research work is to study the degradation of Lansoprazole in stress condition which is a proton pump inhibitor and controls the production of gastric acid in stomach. Thermal stress condition has been used to check the stability of the compound, in which one new degradation product was generated.Methods: The USP method for the identification of related compounds of Lansoprazole shows three known impurities N-Oxide impurity, Sulphone impurity and sulphide impurity. New degradation product formed in stress condition has been separated from the drug product and other known impurities by using Clarity Oligo RP column (250 mm x 4.6 mm, 5µ) and 10 mM Ammonium Acetate -Acetonitrile as a mobile phase. Same method has been scaled up on mass based preparative HPLC for the isolation of new degradation product.Results: The isolated impurity was structurally elucidated with 1H NMR, [13]C NMR, HMBC, HSQC and HRMS. From the characterization studies it was found that novel impurity has 164.04 molecular weight with molecular formula C8H8N2S. The degradation product's structure was matched with 2-(Methylthio)-1H-benzo[d]imidazole per recorded analysis data.Conclusion: Isolated impurity was found to be novel and not reported in the literature. This method can be used for the degradation study of Lansoprazole and purification of novel impurity from drug and other degradation product

Lansoprazole and its Metabolites in the Treatment of TNBC and the Contribution of ABCG2 to CC-115 Resistance

Indiana University-Purdue University Indianapolis (IUPUI)Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer with a dismal prognosis. Targeted therapies for breast cancer with expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are currently available; however, due to the lack of ER, PR, and HER2 in TNBC, targeted therapies are limited. While surgery and traditional chemotherapy remain the standard of care, development of a new treatment strategy for TNBC is needed to improve clinical outcomes. Fatty acid synthase (FASN) has been implicated as a metabolic oncogene and has given cancer cells a survival advantage by increasing NHEJ repair. Recently, it has been shown that FDA-approved proton pump inhibitors, used for the treatment of acid related digestive diseases, have antitumor effects. Here, I show that a metabolite of lansoprazole, 5-hydroxy lansoprazole sulfide, has increased potency over parent compound lansoprazole. 5-hydroxy lansoprazole sulfide inhibits FASN, leading to a decrease in PARP and NHEJ DNA repair activity in TNBC. Ultimately, this leads to an increase in DNA damage and cell death via apoptosis. These findings suggest that 5-hydroxy lansoprazole sulfide, as a metabolite of lansoprazole, may have better activity in suppressing TNBC cells and that 5-hydroxy lansoprazole sulfide may be developed as a therapeutic for TNBC treatment. Furthermore, due to the role of FASN in increasing NHEJ repair, we hypothesized that FASN played a role in resistance to CC-115, a dual mTOR/DNA-PK inhibitor currently in clinical trials, by increasing DNA-PK activity. However, it was found that ABCG2, an ATP-binding cassette transporter, and not FASN, has a role in CC-115 resistance. ABCG2 effluxes CC-115 from cancer cells, increasing resistance to treatment. Inhibition of ABCG2 by FTC or PZ39C8 led to accumulation of CC-115 within cells and sensitization to treatment. Therefore, ABCG2 status should be assessed to stratify patients into treatment groups, increasing the efficacy of CC-115 treatment.2020-02-2

Formulation and evaluation of lansoprazole loaded enteric coated microspheres

The research focuses on the development of multiparticulate delivery system for acid-labile Lansoprazole to prevent its degradation in the acidic environment of the stomach and enhance its bioavailability via intestinal absorption. This problem can be solved by enteric coating. In this project, cellulose acetate phthalate a polymer usually utilized for gastrointestinal film coating of tablets, was used to prepare enteric microspheres of lansoprazole with solvent evaporation technique in various formulations such as F1, F2, F3, F4, F5 with drug: polymer ratios of 1:1, 1:2, 1:3, 1:4, 1:5 respectively. FTIR study indicated compatibility between drug and polymer. Increase in concentration of polymer increased spheriocity and mean diameter of the microspheres. The drug entrapment efficiency was in the range of 72.23% to 88.64%. SEM revealed that microspheres were found spherical and porous. In-vitro study proves that drug release slowly increases as the pH of the medium increased and prevents degradation of drug in acidic pH. In-vitro drug release was found to be 92.80%, 94.55%, 92.72%, 96.34%, 98.65% in all 5 formulations. All 5 formulations showed gastric resistance around 80-90%. So it is concluded that the developed enteric coated microspheres of Lansoprazole prevented drug release in the stomach which would lead to significant improvement in its bioavailability through enhanced intestinal absorption

Prevention of NSAID-Induced Small Intestinal Mucosal Injury: Prophylactic Potential of Lansoprazole

Non-steroidal anti-inflammatory drugs (NSAIDs), which are used for the treatment of several inflammatory disorders including rheumatoid arthritis, are well known to cause gastroduodenal mucosal lesions as an adverse effect. Recently, the serious problem of NSAID-induced small intestinal damage has become a topic of great interest to gastroenterologists, since capsule endoscopy and double-balloon enteroscopy are available for the detection of small intestinal lesions. Such lesions have been of great concern in clinical settings, and their treatment and prevention must be devised as soon as possible. Proton pump inhibitors (PPI), such as lansoprazole and omeprazole, show a potent anti-secretory effect. PPIs also have a gastroprotective effect, independent of their anti-secretory actions, which is probably mediated by inhibition of neutrophil functions as well as antioxidant actions. Administration of lansoprazole reduced the severity of the intestinal lesions in a dose-dependent manner, but omeprazole had no effect. The amount of heme oxygenase-1 (HO-1) protein in the intestinal mucosa was significantly increased by lansoprazole, but not by omeprazole. These results suggest that lansoprazole, but not omeprazole, ameliorates indomethacin-induced small intestinal ulceration through upregulation of HO-1/carbon monoxide. Therefore, lansoprazole may be useful for preventing the adverse effects of NSAIDs not only in the stomach but also in the small intestine

Antioxidant Action of Mangrove Polyphenols against Gastric Damage Induced by Absolute Ethanol and Ischemia-Reperfusion in the Rat

Rhizophora mangle, the red mangrove, has long been known as a traditional medicine. Its bark has been used as astringent, antiseptic, hemostatic, with antifungic and antiulcerogenic properties. In this paper, we aimed to evaluate the antioxidant properties of a buthanolic fraction of the R. mangle bark extract (RM) against experimental gastric ulcer in rats. Unib-Wh rats received pretreatment of R. mangle after the induction of gastric injury with absolute ethanol and ischemia-reperfusion. Gastric tissues from both methods were prepared to the enzymatic assays, the levels of sulfhydril compounds (GSH), lipid peroxides (LPO), and the activities of glutathione reductase (GR), glutathione peroxidase (GPx), superoxide dismutase (SOD) and myeloperoxidase (MPO) were measured. The RM protected the gastric mucosa in both methods used, ethanol-induced gastric ulcer and ischemia-reperfusion, probably, by modulating the activities of the enzymes SOD, GPx, and GR and increasing or maintaining the levels of GSH; in adittion, LPO levels were reduced. The results suggest that the RM antioxidant activity leads to tissue protection; thus one of the antiulcer mechanisms present on the pharmacological effects of R. mangle is the antioxidant property

Lansoprazole inhibits mitochondrial superoxide production and cellular lipid peroxidation induced by indomethacin in RGM1 cells

Lansoprazole is effective in healing non-steroidal anti-inflammatory drugs induced ulcers, and antioxidant properties have been thought to play a key role in healing ulcers. We hypothesize that lansoprazole exerts a cytoprotective effect by inhibiting reactive oxygen species leakage from mitochondria and lipid peroxidation. We pretreated gastric epithelial RGM1 cells with lansoprazole and then treated them with indomethacin in vitro. We found that the lansoprazole pretreatment significantly reduced cellular injury, maintained mitochondrial transmembrane potential, and decreased lipid peroxidation. Furthermore, the signal intensity of the electron spin resonance spectrum of the indomethacin-treated mitochondria which were pretreated with lansoprazole showed considerable reduction compared to those without the lansoprazole pretreatment. These results suggest that lansoprazole reduced superoxide production in the mitochondria of indomethacin treated cells, and subsequently inhibited lipid peroxide and cellular injury in gastric epithelial cells

Design, development and evaluation of controlled release multiple unit pellets for potential delivery of antiulcerants

AIM AND OBJECTIVES: The main aim of the present study was to formulate and evaluate enteric coated, controlled release multiple unit pellets of Esomprazole magnesium and Rabeprazole sodium using natural and synthetic polymers. OBJECTIVES: 1. To formulate Esomeprazole magnesium and Rabeprazole Sodium Controlled release Multiple Unit Pellets using various concentrations of Hydroxy Propyl Methyl Cellulose K15, Hydroxy Propyl Methyl Cellulose K100, Ethyl Cellulose, and Xanthan gum by Extrusion Spheronization process. 2. To evaluate the pre - compression parameters like drug excipient interaction study, bulk density, tapped density, compressibility index and angle of repose. 3. To evaluate various post compression evaluation parameters like friability, drug content and in vitro dissolution studies and Scanning Electron Microscopy (SEM) study. 4. To formulate gastric protection for the prepared multiple unit pellets using Hydroxy Propyl Methyl Cellulose Phthalate as enteric polymer. 6. To determine the mechanism and kinetics of drug release. 7. To conduct stability studies on optimized formulation as per ICH guidelines. SUMMARY: In the modern era of Pharmaceutical research much attention has been focussed on patient’s health in terms of therapeutic efficacy and safety. Modified Dosage Form (MRDF) has always been more effective therapeutic alternative to conventional or immediate release. The term modified release drug product is used to describe product that alter the timing and /or the rate of release of the drug substances. There are two types of MRDF .i) Delayed release ii) Extended release. The terms Controlled release (CR), Sustained release (SR) Prolong release (PR) has been used synonymously with extended release dosage forms. Controlled release drug delivery is one which delivers the drug at a predetermined rate for locally (or) systemically for a specified period of time. Controlled release drug delivery system aim to maintain plasma concentration of drugs within the therapeutic window for a longer period of time. Delayed release products are formulated with acid resistance (or) enteric coating protects acid labile drug substance from the gastric environment (or) to prevent adverse events such as irritation. A peptic ulcer is an open sore on the lining of the stomach or duodenum. Gastric and duodenal ulcer is produced by an imbalance between mucosal defences particularly gastric acid and pepsin. In addition, H.pylori infection is a major factor in the pathogenic of peptic ulcer. Proton pump inhibitors (PPI) rank among the top 10 prescribed classes of drugs and are commonly used to treat acid reflux, indigestion and peptic ulcers. PPIs are among the most widely sold drugs in the world and the first one in antiulcer medicine is omeprazole(WHO model list of essential medicines). Among seven available PPI drugs Esomeprazole magnesium and Rabeprazole sodium are classical examples of proton pump inhibitors and are approved by FDA for the treatment of GERD, Peptic ulcer and maintains of erosive esophagites. These drugs will degrading in acidic environment of stomach and will lead to therapeutic in efficacy so it is necessary to bypass the acidic pH of the stomach which can be achieved by formulating delayed release dosage forms by using different enteric polymers. The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body to achieve promptly and then maintain the desired drug concentration. Many marketed Esomeprazole and Rabeprazole tablets/pellets are available as enteric coated formulation only. The main aim of the present study was to develop and evaluate enteric coated, controlled release tablets of Esomeprazole magnesium and Rabeprazole sodium using natural and synthetic polymers gives better and more uniform drug absorption and greater bioavailability. To design the multiple unit pellets, we have developed two different spheroid unit of uniform drug content with varying in polymer concentration to achieve rate controlled drug release as per our specification. The first group spheroid unit which contain only drug with spheroidizing polymers was prepared to achieve the minimum effective concentration. The second group of spheroid unit was prepared by using the controlled release polymers HPMC K100, HPMC K15, Ethyl cellulose and Xanthan gum. Among the four polymers HPMC K100 the drug Polymer ratio 1:1.5 shows good controlled release characters in Esomeprazole magnesium and HPMC K 15 the drug and polymer ratio 1:2 shows good controlled release profile in Rabeprazole sodium. The MUPS were prepared by Extrusion -Spheronization a promising pelletization technique. In this process the pellets were prepared by mixing the drug with excipient along with binder solution the resultant mass was extruded through extruder followed by spheronizer and finally dried. The possible interactions between drugs and distinct polymers were investigated via FT-IR Studies. Results proved that Rabeprazole sodium and Esomeprazole magnesium was found to be compatible with excipient as no disappearance of the peaks or shift of the peaks indicating that the drugs are compatible with ingredients. The micromeritics evaluation like Bulk density, Tapped density, Angle of repose, Carr’s index and Hauser’s ratio of the prepared pellets shows good flow property. The post formulation parameters like friability, drug content were carried out and found to be within acceptable limit. SEM study shows the surface morphology of the optimized formulations E2 and R6 the pellets was compact, continuous and was porous in nature, demonstrated the spherical nature of the pellets. Based on in vitro dissolution profile the enteric coated, controlled release multiple unit pellets of Esomeprazole magnesium and Rabeprazole sodium was developed using HPMCK100 in the ratio 1:1.5 ( drug :polymer) and HPMC K15 in the ratio 1:1.5 ( drug :polymer) respectively as controlled release polymer and Hypromellose phthalate HP55 as enteric coated polymer. The optimized formulations E2 (Esomeprazole) and R6 (Rabeprazole) had better resistant to 0.1N HCl and better cumulative percent drug release as compared to other formulation. After 12 hours E2 shows 97.88% and R6 shows 97.59 % cumulative percent drug release as compared to other formulation. So E2 (Esomeprazole) R6 (Rabeprazole) was selected as optimized formulation from the trail batches. The in vivo pharmacokinetic plasma concentration and time curve parameters shows that less plasma concentration fluctuation, lower Cmax, prolonged tmax and MRT of formulated MUPS than that of marketed enteric coated formulations. Stability study revealed there was no significant change in in vitro release profile. All the parameters were within limit after 90 days. CONCLUSION: From the above research finding it can be concluded that controlled release of Esomeprazole Magnesium and Rabeprazole Sodium Multiple Unit Pellets could be developed by using HPMC K100 the drug Polymer ratio 1:1.5 and HPMC K 15 the drug and polymer ratio 1:2 prepared by Extrusion -Spheronization to achieve better bioavailability and extended drug release. Further, the first group spheroid unit could maintain the minimum effective concentration and the second group spheroid unit could release the medicament in control release manner. Hence the prepared Multiple Unit Pellets could achieve both enteric coating and controlled release approach for the potential delivery of Antiulcerants

MULTIPARTICULATE DRUG DELIVERY SYSTEMS USING NATURAL POLYMERS AS RELEASE RETARDANT MATERIALS

Now-a-days, the emphasis of pharmaceutical researchers is turned towards the development of more efficacious drug delivery systems with already existing molecule. However, in recent applications, Multiparticulate drug delivery systems (MDDS) are gaining much favor over single- unit dosage forms because of their potential benefits like predictable gastric emptying, least risk of dose dumping, flexible release pattern and increased bioavailability with minimum inter- and intra- subject variability. The advances in such drug delivery systems have simultaneously urged the discovery of novel excipients which are safe and fulfill specific functions and directly or indirectly influence the rate and extent of release and/or absorption. The plant derived gums and mucilages comply with many requirements of pharmaceutical excipients as they are non-toxic, stable, easily available, associated with less regulatory issues as compared to their synthetic counterpart and inexpensive; also these can be easily modified to meet the specific need. The pharmaceutical scientists have achieved a great success in developing most therapeutic systems with suitable natural polymer. The current article focuses on the merits, limitations, types of MDDS and application of natural polymer as drug release retardant material for MDDS with supportive studies on natural polymer and MDDS currently available in the market

Molecular mechanism of orlistat hydrolysis by the thioesterase of human fatty acid synthase for targeted drug discovery

Indiana University-Purdue University Indianapolis (IUPUI)Fatty acid synthase (FASN) is over-expressed in many cancers, and novel inhibitors that target FASN may find use in the treatment of cancers. It has been shown that orlistat, an FDA approved drug for weight loss, inhibits the thioesterase (TE) of FASN, but can be hydrolyzed by TE. To understand the mechanisms of TE action and for designing better FASN inhibitors, I examined the mechanism of orlistat hydrolysis by TE using molecular dynamics simulations. I found that the hexyl tail of orlistat undergoes a conformational transition, destabilizing a hydrogen bond that forms between orlistat and the active site histidine. A water molecule can then hydrogen bond with histidine and become activated to hydrolyze orlistat. These findings suggest that rational design of inhibitors that block hexyl tail transition may lead to a more potent TE inhibitor. To search for novel inhibitors of TE, I performed virtual DOCK screening of FDA approved drugs followed by a fluorogenic assay using recombinant TE protein and found that proton pump inhibitors (PPIs) can competitively inhibit TE. PPIs, which are used for the treatment of gastroesophageal reflux and peptic ulcers, work to decrease gastric acid production by binding irreversibly with gastric hydrogen potassium ATPase in the stomach. Recently, PPIs have been reported to reduce drug resistance in cancer cells when used in combination with chemotherapeutics, although the mechanism of resistance reduction is unknown. Further investigation showed that PPIs are able to decrease FASN activity and cancer cell proliferation in a dose-dependent manner. These findings provide new evidence that FDA approved PPIs may synergistically suppress cancer cells by inhibiting TE of FASN and suggests that the use of PPIs in combinational therapies for the treatment of many types of cancer, including pancreatic cancer, warrants further investigation