Polymeric micelles: Basic research to clinical practice.

Rapidly developing polymeric micelles as potential targeting carriers has intensified the need for better understanding of the underlying principles related to the selection of suitable delivery materials for designing, characterizing, drug loading, improving stability, targetability, biosafety and efficacy. The emergence of advanced analytical tools such as fluorescence resonance energy transfer and dissipative particle dynamics has identified new dimensions of these nanostructures and their behavior in much greater details. This review summarizes recent efforts in the development of polymeric micelles with respect to their architecture, formulation strategy and targeting possibilities along with their preclinical and clinical aspects. Literature of the past decade is discussed critically with special reference to the chemistry involved in the formation and clinical applications of these versatile materials. Thus, our main objective is to provide a timely update on the current status of polymeric micelles highlighting their applications and the important parameters that have led to successful delivery of drugs to the site of action.

Association of presenile cataract with galactose-1-phosphate uridyl transferase gene mutations.

BACKGROUND: Presenile cataract is commonly idiopathic in origin. However, patients with presenile cataract could have an underlying genetic abnormality of galactose metabolism. We studied the association, if any, between idiopathic presenile cataract and galactose-1 -phosphate uridyl transferase (GALT) gene mutation. METHODS: We selected 50 patients with idiopathic presenile cataract, <45 years of age, and 50 age- and sex-matched controls for the study. Mutations in the GALT gene were determined by polymerase chain reaction restriction fragment length polymorphism. The classical galactosaemia was characterized by Q188R and K285N mutations, whereas Duarte galactosaemia by N314D mutations (Duarte-2: N314D with IVS5-24G >A and Duarte-1: N314D without IVS5- 24G>A). RESULTS: The most common mutation observed was the N314D (Duarte) mutation. The frequencies of classical and N31 4D alleles in patients with presenile cataract (16%) and controls (26%) were not statistically different (p=0.32, OR 0.54, 95% CI 0.20-1.45). Similarly, there was no statistically significant difference in the frequency distribution of Duarte-1 (p=0.77, OR 0.77, 95% CI 0.23-0.24) and Duarte-2 (p=0.44, OR 0.38, 95% CI 0.07-2.03) galactosaemia mutations in patients and controls. CONCLUSION: Duarte galactosaemia, a milder form of the disease, is more common than classical galactosaemia in the Indian population. Duarte galactosaemia is unlikely to be a causative factor in presenile cataract.

Oral insulin delivery using deoxycholic acid conjugated PEGylated polyhydroxybutyrate co-polymeric nanoparticles.

AIM: To develop insulin loaded deoxycholic acid conjugated PEGylated polyhydroxybutyrate co-polymeric nanoparticles and carry out in vitro and in vivo testing of enteric coated granules comprising these nanoparticles. MATERIALS & METHODS: Insulin loaded nanoparticles were prepared and characterized in vitro. Cellular uptake was studied using hyperspectral and live cell confocal microscopy. Enteric coated granules of nanoparticles were fed orally to diabetic rats and the pharmacokinetic and pharmacodynamic parameters were evaluated. RESULTS: Ultra small (˜10 nm) nanoparticles with polydispersity index of 0.299 were obtained. The enteric coated granules showed a negligible insulin release in acidic pH, but released insulin in alkaline environment. High cellular uptake was observed and nanoparticles were able to maintain the blood glucose levels up to 24 h. CONCLUSION: These enteric-coated nanoparticle granules sustained the release of insulin and showed enhanced insulin bioavailability. Hence, these may serve as a platform device for oral insulin delivery with extended release.

Polysaccharide-based micro/nanohydrogels for delivering macromolecular therapeutics.

Increased interest in developing novel micro/nanohydrogel based formulations for delivering macromolecular therapeutics has led to multiple choices of biodegradable and biocompatible natural polymers. This interest is largely due to the availability of large number of highly pure recombinant proteins and peptides with tunable properties as well as RNA interference technology that are used in treating some of the deadly diseases that were difficult to be treated by the conventional approaches. The majority of marketed drugs that are now available are in the form of injectables that pose limited patient compliance and convenience. On the other hand, micro/nanotechnology based macromolecular delivery formulations offer many alternative routes of administration and advantages with improved patient compliance and efficient or targeted delivery of intracellular therapeutics to the site of action. This review outlines and critically evaluates the research findings on micro and nano-carrier polymeric hydrogels for the delivery of macromolecular therapeutics.

Cytotoxicity and antitumour activity of 5-fluorouracil-loaded polyhydroxybutyrate and cellulose acetate phthalate blend microspheres.

Pharmacokinetics, biodistribution and antitumour activity of 5-fluorouracil (5-FU)-loaded polyhydroxybutyrate (PHB) and cellulose acetate phthalate (CAP) blend microspheres were investigated in chemically induced colorectal cancer in albino male Wistar rats and compared with pristine 5-FU given as a suspension. The microspheres were characterised for particle size, encapsulation efficiency, in vitro release and in vitro cytotoxicity on human HT-29 colon cancer cell line. Spherical particles with a mean size of 44 ± 11 µm were obtained that showed sustained release of 5-FU. A high concentration of 5-FU was achieved in colonic tissues and significant reduction in tumour volume and multiplicity were observed in animals treated with 5-FU-loaded microspheres. The decreased levels of plasma albumin, creatinine, leucocytopenia and thrombocytopenia were observed in animals for 5-FU microspheres compared to the standard 5-FU formulation. The results suggest the extended release of 5-FU from the PHB-CAP blend microspheres in colonic region to enhance the antitumour efficacy.

Polymeric hydrogels for oral insulin delivery.

The search for an effective and reliable oral insulin delivery system has been a major challenge facing pharmaceutical scientists for over many decades. Even though innumerable carrier systems that protect insulin from degradation in the GIT with improved membrane permeability and biological activity have been developed, yet a clinically acceptable device is not available for human application. Efforts in this direction are continuing at an accelerated speed. One of the preferred systems widely explored is based on polymeric hydrogels that protect insulin from enzymatic degradation in acidic stomach and delivers effectively in the intestine. Swelling and deswelling mechanisms of the hydrogel under varying pH conditions of the body control the release of insulin. The micro and nanoparticle (NP) hydrogel devices based on biopolymers have been widely explored, but their applications in human insulin therapy are still far from satisfactory. The present review highlights the recent findings on hydrogel-based devices for oral delivery of insulin. Literature data are critically assessed and results from different laboratories are compared.

Cyclodextrin-based siRNA delivery nanocarriers: a state-of-the-art review.

INTRODUCTION: The discovery of synthetic small interfering RNA (siRNA) has led to a surge of interest in harnessing RNA interference (RNAi) technology for biomedical applications and drug development. Even though siRNA can be a powerful therapeutic drug, its delivery remains a major challenge, due to the difficulty in its cellular uptake. Naked siRNA has a biological half-life of less than an hour in human plasma. To increase the lifetime and improve its therapeutic efficacy, non-viral vectors have been developed. As a natural evolution, cyclodextrins (CDs), which are natural cyclic oligosaccharides, have recently been applied as delivery vehicles for siRNA, and this in turn, has led to a surge of interest in this area. AREAS COVERED: This review discusses the recent advances made in the design of delivery strategies for siRNA, focusing on CD-based delivery vectors, because these have demonstrated clinical success. The methods of preparation of CD-based vectors, their characterization, transfection efficiencies, cellular toxicity, preclinical and clinical trials are also addressed, as well as future therapeutic applications. EXPERT OPINION: siRNA-mediated RNAi therapeutics is beginning to transform healthcare, particularly, for the treatment of solid tumors. For example, CALAA01, a targeted, self-assembling nanoparticle system based on CD complexed with siRNA has been effective in phase I clinical trials. Although siRNA therapeutics suffers from problems related to off-target effects and non-specific gene silencing, these problems can be overcome by reducing the nanoparticle size, improving the targeting efficiency and by modifying the primary sequence of the siRNA.

Floating matrix dosage form for propranolol hydrochloride based on gas formation technique: development and in vitro evaluation.

Gastroretentive tablets of propranolol hydrochloride were developed by direct compression method using citric acid and sodium bicarbonate as the effervescent base. Hydroxypropyl methylcellulose; HPMC K15M was used to prepare the floating tablets to retard the drug release for 12h in stomach. Na-carboxymethyl cellulose (NaCMC) or carbopol 934P was added to alter the drug release profile or the dimensional stability of the formulation. Dicalcium phosphate (DCP) was used as filler. Formulations were evaluated for floating lag time, duration of floating, dimensional stability, drug content and in vitro drug release profile. The formulations were found to have floating lag time less than 1min. It was found that the dimensional stability of the formulations increase with increasing concentration of the swelling agent. The release mechanism of propranolol hydrochloride from floating tablets was evaluated on the basis of Peppas and Higuchi model. The ânâ value of the formulations ranged from 0.5201 to 0.7367 (0.5

Stomach-specific drug delivery of 5-fluorouracil using ethylcellulose floating microspheres.

A multiple-unit-type oral floating dosage form (FDF) of 5-Fluorouracil (5-FU) was developed to prolong gastric residence time for the treatment of stomach cancer. The floating microspheres were prepared by solvent evaporation method. The prepared microspheres were characterized for their micromeretic properties, floating behavior and entrapment efficiency; as well by Fourier transform infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), thin layer chromatography (TLC) and scanning electron microscopy (SEM). The in vitro release studies and floating behavior were performed in HCl buffer pH 1.2, Phosphate buffer pH 4.5 and in Simulated Gastric Fluid (SGF). The best fit release kinetics was achieved with Higuchi plot. The yields of preparation were very high and low entrapment efficiencies were noticed with larger particle size for all the formulations. Mean particle size, entrapment efficiency and production yield were highly influenced by polymer concentration. It was concluded from the present investigation that porous Ethylcellulose microspheres are promising controlled release as well as stomach targeted carriers for 5-FU.

Rectal cancer: a compartmental disease. the mesorectum and mesorectal lymph nodes.

Even though the technique of total mesorectal excision has been widely used, there have been few detailed descriptions of the distribution of lymph nodes within the rectal mesentery. We describe the results of our anatomic study of lymph node size and distribution within the mesorectum and pelvic side-wall tissue using a fat-clearing solvent in seven male cadavers, and we used a similar technique to examine the mesorectum in a patient who underwent total mesorectal excision after preoperative chemoradiation for a uT3 rectal cancer. In both the cadavers and our patient, the majority of lymph nodes were located within the posterior upper two-thirds of the mesorectum. Few lymph nodes were located in the distal mesorectum or anteriorly. In the cadavers, the majority of lymph nodes were less than 3 mm in diameter. In the patient who had received preoperative chemoradiation, routine tissue processing yielded only four lymph nodes, whereas processing in fat-clearing solvent yielded 25 additional nodes. The majority of these nodes, in contrast to those observed in cadavers, were less than 1 mm in diameter. The majority of mesorectal lymph nodes were located within the upper two-thirds of the posterior mesorectum. Complete removal of nodes in this area may, in part, explain the superior results of total mesorectal excision with respect to local recurrence.