Rajan Rajabalaya

Oral and transdermal drug delivery systems: role of lipid-based lyotropic liquid crystals

Liquid crystal (LC) dosage forms, particularly those using lipid-based lyotropic LCs (LLCs), have generated considerable interest as potential drug delivery systems. LCs have the physical properties of liquids but retain some of the structural characteristics of crystalline solids. They are compatible with hydrophobic and hydrophilic compounds of many different classes and can protect even biologicals and nucleic acids from degradation. This review, focused on research conducted over the past 5 years, discusses the structural evaluation of LCs and their effects in drug formulations. The structural classification of LLCs into lamellar, hexagonal and micellar cubic phases is described. The structures of these phases are influenced by the addition of surfactants, which include a variety of nontoxic, biodegradable lipids; these also enhance drug solubility. LLC structure influences drug localization, particle size and viscosity, which, in turn, determine drug delivery properties. Through several specific examples, we describe the applications of LLCs in oral and topical drug formulations, the latter including transdermal and ocular delivery. In oral LLC formulations, micelle compositions and the resulting LLC structures can determine drug solubilization and stability as well as intestinal transport and absorption. Similarly, in topical LLC formulations, composition can influence whether the drug is retained in the skin or delivered transdermally. Owing to their enhancement of drug stability and promotion of controlled drug delivery, LLCs are becoming increasingly popular in pharmaceutical formulations.

Medicinal Plants: A Potential Source of Compounds for Targeting Cell Division

Modern medicinal plant drug discovery has provided pharmacologically active compounds targeted against a multitude of conditions and diseases, such as infection, inflammation, and cancer. To date, natural products from medicinal plants remain a solid niche as a source from which cancer therapies can be derived. Among other properties, one favorable characteristic of an anticancer drug is its ability to block the uncontrollable process of cell division, as cancer cells are notorious for their abnormal cell division. There are numerous other documented works on the potential anticancer activity of drugs derived from medicinal plants, and their effects on cell division are an attractive and growing therapeutic target. Despite this, there remains a vast number of unidentified natural products that are potentially promising sources for medical applications. This mini review aims to revise the current knowledge of the effects of natural plant products on cell division.

Parasitic Mistletoes of the Genera Scurrula and Viscum: From Bench to Bedside

The mistletoes, stem hemiparasites of Asia and Europe, have been used as medicinal herbs for many years and possess sophisticated systems to obtain nutrients from their host plants. Although knowledge about ethnomedicinal uses of mistletoes is prevalent in Asia, systematic scientific study of these plants is still lacking, unlike its European counterparts. This review aims to evaluate the literature on Scurrula and Viscum mistletoes. Both mistletoes were found to have anticancer, antimicrobial, antioxidant and antihypertensive properties. Plants from the genus Scurrula were found to inhibit cancer growth due to presence of phytoconstituents such as quercetin and fatty acid chains. Similar to plants from the genus Viscum, Scurrula also possesses TNFα activity to strengthen the immune system to combat cancer. In line with its anticancer activity, both mistletoes are rich in antioxidants that confer protection against cancer as well as neurodegeneration. Extracts from plants of both genera showed evidence of vasodilation and thus, antihypertensive effects. Other therapeutic effects such as weight loss, postpartum and gastrointestinal healing from different plants of the genus Scurrula are documented. As the therapeutic effects of plants from Scurrula are still in exploration stage, there is currently no known clinical trial on these plants. However, there are few on-going clinical trials for Viscum album that demonstrate the functionalities of these mistletoes. Future work required for exploring the benefits of these plants and ways to develop both parasitic plants as a source of pharmacological drug are explained in this article.

Tolterodine Tartrate Proniosomal Gel Transdermal Delivery for Overactive Bladder

The goal of this study was to formulate and evaluate side effects of transdermal delivery of proniosomal gel compared to oral tolterodine tartrate (TT) for the treatment of overactive bladder (OAB). Proniosomal gels are surfactants, lipids and soy lecithin, prepared by coacervation phase separation. Formulations were analyzed for drug entrapment efficiency (EE), vesicle size, surface morphology, attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, in vitro skin permeation, and in vivo effects. The EE was 44.87%–91.68% and vesicle size was 253–845 nm for Span formulations and morphology showed a loose structure. The stability and skin irritancy test were also carried out for the optimized formulations. Span formulations with cholesterol-containing formulation S1 and glyceryl distearate as well as lecithin containing S3 formulation showed higher cumulative percent of permeation such as 42% and 35%, respectively. In the in vivo salivary secretion model, S1 proniosomal gel had faster recovery, less cholinergic side effect on the salivary gland compared with that of oral TT. Histologically, bladder of rats treated with the proniosomal gel formulation S1 showed morphological improvements greater than those treated with S3. This study demonstrates the potential of proniosomal vesicles for transdermal delivery of TT to treat OAB.

Transdermal delivery of oxybutynin chloride proniosomal gels for the treatment of overactive bladder

Abstract Context: Overactive bladder (OAB) is a common problem and anticholinergic drugs are first-line therapy, but they have side effects. Objective: Development of oxybutynin chloride (OC) proniosomal gels and analyses of its efficacy for OAB treatment. Materials and methods: Phase separation coacervation was used to prepare proniosomal gels using various non-ionic surfactants, lipids, soy lecithin and isopropyl alcohol. Gels were characterized with regard to entrapment efficiency (EE), vesicle size, surface morphology (using environmental scanning electron microscopy [E-SEM]), stability, attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, in vitro skin permeation, in vivo animal studies and histopathology. Results and discussion: EE was 87–92%, vesicle size was 0.38–5.0 μm, and morphology showed some loosened pores in proniosomes after hydration. ATR-FTIR spectroscopy showed no significant shifts in peaks corresponding to OC and excipients. Most formulations exhibited >50% permeation but the cholesterol-containing formulations P3 (Span 20:Span 60 [1:1]) and P4 [Tween 20:Tween 80 (1:1)] had the highest percent cumulative permeation. P3 and P4 also showed faster recovery of cholinergic effects on salivary glands than oral formulations. P3 and P4 had pronounced therapeutic effects in reduction of urinary frequency and demonstrated improvements in bladder morphology (highly regenerative surface of the transitional epithelium). Conclusion: These results suggest that OC could be incorporated into proniosomal gels for transdermal delivery in the treatment of OAB.

Development and evaluation of exemestane-loaded lyotropic liquid crystalline gel formulations

Introduction: The use of liquid crystalline (LC) gel formulations for drug delivery has considerably improved the current delivery methods in terms of bioavailability and efficacy. The purpose of this study was to develop and evaluate LC gel formulations to deliver the anti-cancer drug exemestane through transdermal route. Methods: Two LC gel formulations were prepared by phase separation coacervation method using glyceryl monooleate (GMO), Tween 80 and Pluronic® F127 (F127). The formulations were characterized with regard to encapsulation efficiency (EE), vesicle size, Fourier transform infrared (FTIR) spectroscopy, surface morphology (using light and fluorescence microscopy), in vitro release, ex vivo permeation, in vitro effectiveness test on MDA-MB231 cancer cell lines and histopathological analysis. Results: Results exhibited that the EE was 85%-92%, vesicle size was 119.9-466.2 nm while morphology showed spherical vesicles after hydration. An FTIR result also revealed that there was no significant shift in peaks corresponding to Exemestane and excipients. LC formulations release the drug from cellulose acetate and Strat-MTM membrane from 15%-88.95%, whereas ex vivo permeation ranges from 37.09-63%. The in vitro effectiveness study indicated that even at low exemestane concentrations (12.5 and 25 μg/mL) the formulations were able to induce cancer cell death, regardless of the surfactant used. Histopathological analysis thinning of the epidermis as the formulations penetrate into the intercellular regions of squamous cells. Conclusion: The results conjectured that exemestane could be incorporated into LC gels for the transdermal delivery system and further preclinical studies such as pharmacokinetic and pharmacodynamic studies will be carried out with suitable animal models.

Development of controlled release silicone adhesive–based mupirocin patch demonstrates antibacterial activity on live rat skin against Staphylococcus aureus

Background Peritonitis is the most serious complication of peritoneal dialysis. Staphylococcus aureus infections could lead to peritonitis which causes reversal of peritoneal dialysis treatment back to hemodialysis. The aim of this study was to develop a controlled release silicone adhesive-based mupirocin patch for prophylactic effect and analyze its antibacterial effectiveness against S. aureus. Methods The matrix patches were prepared by using different polymers, with and without silicone adhesive, dibutyl sebacate and mupirocin. The patches were characterized for mechanical properties, drug content, moisture content, water absorption capacity and Fourier transform infrared spectrum. In vitro release studies were performed by using Franz diffusion cell. In vitro disk diffusion assay was performed on the Mueller–Hinton Agar plate to measure the zone of inhibition of the patches. The in vivo study was performed on four groups of rats with bacterial counts at three different time intervals, along with skin irritancy and histopathologic studies. Results The patches showed appropriate average thickness (0.63–1.12 mm), tensile strength (5.08–10.08 MPa) and modulus of elasticity (21.53–42.19 MPa). The drug content ranged from 94.5% to 97.4%, while the moisture content and water absorption capacities at two relative humidities (75% and 93%) were in the range of 1.082–3.139 and 1.287–4.148 wt%, respectively. Fourier transform infrared spectra showed that there were no significant interactions between the polymer and the drug. The highest percentage of drug release at 8 hours was 47.94%. The highest zone of inhibition obtained was 28.3 mm against S. aureus. The in vivo studies showed that the bacterial colonies were fewer at 1 cm (7×101 CFU/mL) than at 2 cm (1.3×102 CFU/mL) over a 24-hour period. The patches were nonirritant to the skin, and histopathologic results also showed no toxic or damaging effects to the skin. Conclusion The in vitro and in vivo studies indicated that controlled release patches reduced the migration of S. aureus on the live rat skin effectively, however, a longer duration of study is required to determine the effectiveness of the patch on a suitable peritonitis-induced animal model.

Ethosomes as Novel Vesicular Carrier: An Overview of the Principle, Preparation and its Applications

BACKGROUND In the study of lipid vesicular carriers in permeation enhancement of drug molecules across skin after the success story of liposomes, ethosomes are a recent addition. There are a number of published reviews but still, there is a lack of reviews representing various aspects in a systematic way with a detailed description of current research works. This review serves to fill this deficiency along with special emphasize on its preparation methods and applications. METHODS Information was collected from previously published literatures which were represented after analysis in terms of various aspects such as principles, composition, preparation, mechanism of penetration, modified forms, characterization, marketed preparations and its applications. RESULT This review is represented in an informative and easily understandable way. Basic principles and background were covered in the introduction section. Composition section contains the basic components of formulations along with the impact of various parameters on the characterization of the ethosome. A detailed discussion of all the methods along with their own utility is elaborately provided. Various aspects of characterization studies of ethosomes are also discussed. Therapeutic and cosmetic applications of ethosomes are also outlined here. CONCLUSION In spite of having a excellent permeation-enhancing and targeted drug release profile, ethosome suffers from limited commercialization. Various challenges regarding their commercialization and product development are also discussed in this review with an objective of acting as a directional route for the researchers.

A hidden treasure: The borneo mistletoes

The European mistletoe, Viscum album, is the most common consumed adjuvant among cancer patients in Europe. Its success warrants a report on three most apparent mistletoes found in Borneo Island, namely Scurrula ferruginea, Macrosolen cochinchinensis, and Dendrophthoe curvata. The traditional and pharmacological uses of these mistletoes include antibacterial, anticancer, antiviral, antihypertensive, antioxidative, and cytotoxic effects. Phytochemicals such as flavonols, alkaloids, tannins, and gallic acid have been reported in one of these mistletoes. This review discusses the potential of these mistletoes as therapeutic agents.

Melastoma malabathricum ethyl acetate fraction induces secondary necrosis in human breast and lung cancer cell lines

Background: Melastoma malabathricum (MM) is a traditional plant used in the Borneo region. The cytotoxic effects of methanol extracts from MM leaves have been reported in a number of human cancer cell lines. However, the mode of cell death by MM has not been investigated. Objective: We investigated the cytotoxic effects of MM in both human breast and lung cancer cell lines, MCF-7 and A549, respectively, and defined the mode of cell death. Materials and Methods: Cell viability was measured using the 3-(4-, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Annexin-V/propidium iodide (PI) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining was done to determine the mode of cell death. Results: The MTT assay revealed that MM extract had an IC50 of >400 μ g/ml on both cell lines at 24 h posttreatment. Flow cytometric and fluorescence microscopy analysis of Annexin-V/PI stained MM-treated cells revealed that the majority of the cells underwent secondary necrosis/late apoptosis. TUNEL assay showed that little to no DNA nicks were present in MM-treated cells, suggesting that cells have undergone secondary necrosis, not late apoptosis, at that time point. Conclusion: MCF-7 and A549 cells undergoes secondary necrosis 24 h post-treatment with MM extract. MM leaf extract could be a potential source for a novel anti-tumor agent for cancer therapy. Abbreviations used: DMSO: Dimethyl sulfoxide; MM: Melastoma malabathricum; MTT: 3-(4-, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; PI: Propidium iodide; TUNEL: Terminal deoxynucleotidyl transferase dUTP nick-end labeling.