Jay Prakash Jain

Spiroindolone KAE609 for Falciparum and Vivax Malaria

BACKGROUND KAE609 (cipargamin; formerly NITD609, Novartis Institute for Tropical Diseases) is a new synthetic antimalarial spiroindolone analogue with potent, dose-dependent antimalarial activity against asexual and sexual stages of Plasmodium falciparum. METHODS We conducted a phase 2, open-label study at three centers in Thailand to assess the antimalarial efficacy, safety, and adverse-event profile of KAE609, at a dose of 30 mg per day for 3 days, in two sequential cohorts of adults with uncomplicated P. vivax malaria (10 patients) or P. falciparum malaria (11). The primary end point was the parasite clearance time. RESULTS The median parasite clearance time was 12 hours in each cohort (interquartile range, 8 to 16 hours in patients with P. vivax malaria and 10 to 16 hours in those with P. falciparum malaria). The median half-lives for parasite clearance were 0.95 hours (range, 0.68 to 2.01; interquartile range, 0.85 to 1.14) in the patients with P. vivax malaria and 0.90 hours (range, 0.68 to 1.64; interquartile range, 0.78 to 1.07) in those with P. falciparum malaria. By comparison, only 19 of 5076 patients with P. falciparum malaria (<1%) who were treated with oral artesunate in Southeast Asia had a parasite clearance half-life of less than 1 hour. Adverse events were reported in 14 patients (67%), with nausea being the most common. The adverse events were generally mild and did not lead to any discontinuations of the drug. The mean terminal half-life for the elimination of KAE609 was 20.8 hours (range, 11.3 to 37.6), supporting a once-daily oral dosing regimen. CONCLUSIONS KAE609, at dose of 30 mg daily for 3 days, cleared parasitemia rapidly in adults with uncomplicated P. vivax or P. falciparum malaria. (Funded by Novartis and others; ClinicalTrials.gov number, NCT01524341.).

Exploiting EPR in Polymer Drug Conjugate Delivery for Tumor Targeting

Treatment of tumor tissue without affecting normal cells has always been formidable task for drug delivery scientists and this task is effectively executed by polymer drug conjugate (PDC) delivery. The novelty of this concept lies in the utilization of a physical mechanism called enhanced permeability and retention (EPR) for targeting tumors. EPR is a physiological phenomenon that is customary for fast growing tumor and solves the problem of targeting the miscreant tissue. PDCs offer added advantages of reduced deleterious effects of anticancer drugs and augmentation of its formulation capability (e.g. Solubility). There are now at least eleven PDCs that have entered phase I/II/III clinical trial as anticancer drugs. PDCs once entered into the tumor tissue, taking advantage of EPR, are endocytosed into the cell either by simple or receptor mediated endocytosis. Various polymeric carriers have been used with hydrolyzable linker arm for conjugation with bioactive moiety. The hydrolyzable linkages of PDC are broken down by acid hydrolyses of lysosomes and releases the drug. High concentrations of the chemotherapeutic agent are maintained near the nucleus, the target site. Passive targeting by PDCs is due to the physiological event of EPR, which is becoming one of the major thrust areas for targeting solid tumors.

Self Assembling Polymers as Polymersomes for Drug Delivery

Polymersomes are one of the most interesting and versatile architectures among various self assembled systems for drug delivery. The stability and ability to load both hydrophilic and hydrophobic molecules make them excellent candidates to use as drug delivery systems. They demand for certain physicochemical parameters; especially hydrophilic to hydrophobic block ratio of copolymer to form vesicular morphologies. Different amphiphilic copolymers as well as their architectures show differences in the requirement of hydrophilic to hydrophobic block ratio to form polymersomes with various types of morphologies. This review focuses on basic the aspects of polymersomes along with a series of copolymers employed for preparation of polymersomes and their potential applications as drug delivery systems.

A First-in-Human Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Ascending Oral Dose Study of Novel Antimalarial Spiroindolone KAE609 (Cipargamin) To Assess Its Safety, Tolerability, and Pharmacokinetics in Healthy Adult Volunteers

ABSTRACT This first-in-human randomized, double-blind, placebo-controlled, ascending-single and -multiple oral dose study was designed to evaluate the safety, tolerability, and pharmacokinetics in healthy volunteers of KAE609 (cipargamin; formerly NITD609), a spiroindolone now in trials for malaria treatment. It was studied in single-dose cohorts (1 to 300 mg, including one 30-mg food effect cohort) with 4 to 10 subjects in each cohort and in multiple-dose cohorts (10 to 150 mg once daily for 3 days) with 8 subjects in each cohort. The follow-up period was 6 to 8 days post-last dose. Safety and pharmacokinetics were assessed at scheduled time points during the study. Systemic exposure in terms of the area under the concentration-time curve from 0 h extrapolated to infinity (AUC0–∞) increased in a dose-proportional manner over the dose range of 1 to 300 mg. The AUC from time zero to the time of the last quantifiable concentration (AUClast) and the maximum concentration of drug in plasma (Cmax) also increased in an approximately dose-proportional manner. When administered daily for 3 days, the accumulation ratio on day 3 (the AUC from time zero to 24 h postdosing [AUC0–24] on day 3/AUC0–24 on day 1) was in the range of 1.5 to 2 in the studied dose range (10 to 150 mg) and was consistent with an elimination half-life of around 24 h. Urine analysis for unchanged KAE609 revealed negligible amounts (≤0.01%) were excreted renally. The high fat food intake did not affect the extent of KAE609 absorption (AUC); however, the Cmax was reduced by around 27%. KAE609 was tolerated in this study, with transient gastrointestinal and genitourinary adverse events of mild to moderate intensity (semen discoloration, diarrhea, nausea and abdominal discomfort, dizziness and headache, catheter site hematoma). Gastrointestinal and genitourinary adverse events increased with rising doses.

Self Assembly of Amphiphilic (PEG)3-PLA Copolymer as Polymersomes: Preparation, Characterization, and Their Evaluation As Drug Carrier

(PEG)(3)-PLA copolymer has been explored for the formation of polymersomes. For this, three chains of methoxy-PEG(1100) were directly attached to citric acid by esterification. (Methoxy-PEG(1100))(3)-citrate was then reacted at its hydroxyl terminal with different moles of d,l-lactide by ring-opening polymerization to obtain polymers with five different PEG-to-PLA ratios ranging from 10:90 to 90:10. Polymers were characterized by GPC, FTIR, (1)H NMR, and DSC, films were characterized for hydrophilicity by contact angle, and surface topography was observed by SEM and AFM. All five polymers were evaluated for the formation of polymersomes. Among these, polymers with PEG content of 10-30% were able to self-assemble into polymersomes. To affirm their self-arrangement and drug carrier properties, hydrophilic and hydrophobic dyes were simultaneously encapsulated in these structures. SEM and TEM analysis of the blank polymersomes confirmed the vesicular nature of the polymersomes, whereas CLSM analysis of dye-loaded polymersomes demonstrated the presence of two separate regions viz. hydrophilic core and hydrophobic wall. Hydrophobic dye, fluorescein was released relatively faster from the wall of polymersomes, whereas hydrophilic dye, propidium iodide, was released in controlled fashion up to 18 days. It is expected that these systems may serve as a suitable carrier for simultaneous or separate delivery of drug molecules with varying physicochemical properties.

Fatty acid based biodegradable polymer

Synthetic polymers have become an indispensable part of the daily‐life of human beings and the biodegradable class of polymers hold immense value in therapeutics. Fatty acid incorporation in biodegradable polymers renders flexibility, low melting point, hydrophobicity, and pliability properties. At the same time, degradation into naturally occurring compounds makes them environmentally friendly besides their utility in various applications like drug delivery and as implantable devices. Fatty acid monomers are integrated in the polymeric chain using carboxylic acid functional groups. Most fatty acids are monofunctional in nature and act only as chain terminator during polymerization. This limitation has been overcome by the dimerization of unsaturated fatty acids or by creating a functional group on the monomers. The most recent addition to this series is ricinoleic acid based polyanhydrides and copolyesters. In this article, the synthesis methods, the physical properties, the degradation, the stability, and the toxicological aspect and applications of each class of fatty acid based polymers are discussed.

Functionalized polymersomes for biomedical applications

Polymersomes are latest entry to the drug carrier systems and have proven their utility to deliver therapeutic agents to specific tissues/organs due to their versatile polymeric architectures and self-assembly of polymeric chains into vesicular containers of therapeutic agents. Recent research has focused on the development of multi-functional polymersomes as targeted drug delivery systems for combined therapeutic applications and theranostic applications where therapeutic delivery via passive or active targeting can be simultaneously combined with diagnostic capabilities. Functionalized polymersomes have been prepared by (a) conjugation of functional ligands to preformed polymeric vesicles, (b) self-assembly of end-group functionalized block copolymers, or (c) use of polymers with functionalized hydrophilic blocks. This review focuses on various strategies used for developing functionalized polymersomes, as a means to achieve multiple goals of therapy as well as diagnosis by use of specific ligands, while maintaining their ability to encapsulate and deliver desired therapeutic or diagnostic principles. Various ligands used for such functionalization have been discussed with a focus on cellular/tissue targeting as well as other biomedical applications of the same.

Development of amphotericin B loaded polymersomes based on (PEG)3-PLA co-polymers: factors affecting size and in vitro evaluation.

Amphotericin B (AmB) is a broad spectrum antifungal and antileishmenial agent and its clinical use is limited due to substantial dose limiting toxicities such as nephrotoxicity. In this work, amphotericin B is formulated in polymersomes of branched (PEG)(3)-PLA co-polymer. Polymersomes were prepared by solvent injection method and the effects of various formulation and process parameters on size and size distribution were studied. The results showed that viscosity of biphasic solution during formulation has significant influence on the size and size distribution of the polymersomes. Further, drug-loaded polymersomes with size of 199.6+/-14.1nm, PDI of 0.258+/-0.18, zeta potential (zeta) of -18.07+/-4.91mV and loading of 16.26+/-2.50% were obtained. Drug was found to be intercalated in the wall of polymersomes as observed using FITC tagged drug and CLSM study. An in vitro release media containing sodium deoxycholate was developed and a significant amount of drug release was observed up to 24h there after a very slow release was obtained. Free drug was not found in the formulation and different molecular forms of the drug (AmB) were observed by UV-visible spectroscopy and circular dichroism. This was further supported by hemolysis experiments, where negligible hemolysis in the test formulation was observed as compared to 100% hemolysis in a marketed formulation (Fungizone).

Polyanhydrides as localized drug delivery carrier: an update

Background: There is a continuing thrust to increase the efficacy and reduce the toxicity of existing and new drug molecules for their better usage to treat disease. Localized drug delivery has been explored in the same way, which can provide a platform to target local diseased tissues and can reduce the burden on the body by reducing the dose size and hence the dose-related toxicity of the molecules. Various polymers have evolved for the purpose of localized drug delivery, however, polyanhydrides are considered the best, supported by products in the clinical phases. Objective: To demonstrate the advantages of localized delivery using basic concepts and describing polyanhydride carrier with products such as Gliadel® and Septacin™. Methods: The rationale behind localized drug delivery and the carrier for the same are dealt with. Polyanhydrides discussed in detail are those from subclasses that have been given less emphasis previously and have been developed or investigated in the last 5 years. Results/conclusion: From the recent update on polyanhydrides, it can be concluded that these polymers have great potential as localized drug delivery carriers due to the versatility of their properties. However, the quest to stabilize the system in order to achieve a long shelf life remains ongoing.

Amphotericin-B-Loaded Polymersomes Formulation (PAMBO) Based on (PEG)3-PLA Copolymers: An in Vivo Evaluation in a Murine Model

This paper deals with in vivo evaluation of a new amphotericin-B-loaded polymersomes (PAMBO) formulation in terms of pharmacokinetics, toxicity, tissue distribution profile, and its efficacy in a murine model of disseminated candidiasis. Pharmacokinetic and tissue distribution studies of the PAMBO showed sustained levels of the drug in plasma as well as in target organs which harbor fungal and leishmanial infection. PAMBO was found to be much less toxic than Fungizone. It was observed that 700% increment in the dose is tolerated without observable toxicity which is supported by survival, biochemical, and histopathological results. PAMBO showed a significant improvement in the survival rate of immunosuppressed mice infected with Candida albicans as compared to control. It also showed better dose to dose (1 mg/kg) efficacy as compared to Fungizone and a significant improvement in the life expectancy at 3 and 5 mg/kg dose levels in the animals. Colony forming unit (CFU) counts in the target organs revealed significant reduction in Candida burden with PAMBO treatment. Kidney, spleen, and lung were cleared of infection, although liver was carrying a very low level of infection. Overall, PAMBO formulation is found to be more efficacious and less toxic in a fungal mice model.