Nishikant A. Raut

Excipient Variability and Its Impact on Dosage Form Functionality

Pharmaceutical excipients are essential components of most modern dosage forms. Although defined as pharmacologically inert, excipients can be thought of as the true enablers of drug product performance. Unintentional variability in the properties of the excipients may be unavoidable, albeit minimizable. The variability may originate from the source, the excipient-manufacturing process, or during the manufacturing of dosage forms. Excipient variability may have a range of influences on their functionality and performance in the dosage form. A better understanding of these influences on the critical quality attributes of the final product is of prime importance. Modern analytical tools provide a significant assistance in characterizing excipient variability to achieve this understanding. The principles and concepts of Quality-by-Design, process analytical technology, and design space, provide a holistic risk-based approach toward manufacture and application of excipients in pharmaceutical formulations. The International Pharmaceutical Excipients Council (IPEC) has developed guidelines for proper selection, use, and evaluation of excipients in pharmaceutical products.

Influence of the Component Excipients on the Quality and Functionality of a Transdermal Film Formulation

The influence of formulation variables, i.e., a hydrophilic polymer (Methocel® E15) and a film-forming polymer (Eudragit® RL 100 and Eudragit® RS 100), on the physicochemical and functional properties of a transdermal film formulation was assessed. Several terpenes were initially evaluated for their drug permeation enhancement effects on the transdermal film formulations. d-Limonene was found to be the most efficient permeation enhancer among the tested terpenes. Transdermal film formulations containing granisetron (GRN) as a model drug, d-limonene as a permeation enhancer, and different ratios of a hydrophilic polymer (Methocel® E15) and a film-forming polymer (Eudragit® RL 100 or Eudragit® RS 100) were prepared. The prepared films were evaluated for their physicochemical properties such as weight variation, thickness, tensile strength, folding endurance, elongation (%), flatness, moisture content, moisture uptake, and the drug content uniformity. The films were also evaluated for the in vitro drug release and ex vivo drug permeation. The increasing ratios of Methocel®:Eudragit® polymers in the formulation linearly and significantly increased the moisture content, moisture uptake, water vapor transmission rate (WVTR), and the transdermal flux of GRN from the film formulations. Increasing levels of Methocel® in the formulations also increased the rate and extent of the GRN release and the GRN permeation from the prepared films.

Enhancement of the Aqueous Solubility and Permeability of a Poorly Water Soluble Drug Ritonavir Via Lyophilized Milk-based Solid Dispersions

Abstract In the present study, a lyophilized milk-based solid dispersion (SD) of ritonavir (RTV) was developed with the goal of improving its aqueous solubility. The SD was prepared by lyophilization, and characterized for its physicochemical and functional properties. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), photomicroscopy and powder X-ray diffraction (PXRD) were used to confirm the formation and robustness of the SD formulation. The prepared SD formulations were functionally evaluated by saturation solubility, in vitro drug release and ex vivo permeation studies. The optimized SD formulation exhibited a significantly higher (30-fold) aqueous solubility (11.36 ± 0.06 μg/mL), compared to the pure RTV (0.37 ± 0.03 μg/mL). The in vitro dissolution studies revealed a significantly higher (∼10-fold) efficiency of the optimized SD formulation in releasing the RTV, compared to the pure RTV. The ex vivo permeation studies with the everted intestine method showed that prepared SD formulation significantly improved the permeation of RTV (75.6 ± 3.09, % w/w), compared to pure RTV (20.45 ± 1.68, % w/w). Thus, SD formulation utilizing lyophilized milk as a carrier appears to be a promising alternative strategy to improve the aqueous solubility of poorly water soluble drugs.

The role of phospholipid as a solubility- and permeability-enhancing excipient for the improved delivery of the bioactive phytoconstituents of Bacopa monnieri

&NA; In an attempt to improve the solubility and permeability of Standardized Bacopa Extract (SBE), a complexation approach based on phospholipid was employed. A solvent evaporation method was used to prepare the SBE‐phospholipid complex (Bacopa Naturosome, BN). The formulation and process variables were optimized using a central‐composite design. The formation of BN was confirmed by photomicroscopy, Scanning Electron Microscopy (SEM), Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), and Powder X‐ray Diffraction (PXRD). The saturation solubility, the in‐vitro dissolution, and the ex‐vivo permeability studies were used for the functional evaluation of the prepared complex. BN exhibited a significantly higher aqueous solubility compared to the pure SBE (20‐fold), or the physical mixture of SBE and the phospholipid (13‐fold). Similarly, the in‐vitro dissolution revealed a significantly higher efficiency of the prepared complex (BN) in releasing the SBE (> 97%) in comparison to the pure SCE (˜ 42%), or the physical mixture (˜ 47%). The ex‐vivo permeation studies showed that the prepared BN significantly improved the permeation of SBE (> 90%), compared to the pure SBE (˜ 21%), or the physical mixture (˜ 24%). Drug‐phospholipid complexation may thus be a promising strategy for solubility enhancement of bioactive phytoconstituents. Graphical abstract Figure. No caption available.

Evaluation of Antidiabetic Potential of Ipomoea turpethum R.Br. and Ipomoea batata L. (Convolvulaceae) in Alloxan Induced Diabetes in Rats: A Comparative Study.

In order to explore the intra-genera variation for biological activity, the antidiabetic activity of Ipomoea turpethum and Ipomoea batata was carried out in alloxan induced diabetes in rats. Dried powdered material of both plants was defatted with petroleum ether 60-80 °C and cold macerated with hydro-ethanol for seven days. These extracts were screened for antidiabetic activity using alloxan induced diabetes in rats. Diabetes was induced by intra-peritoneal administration of alloxan monohydrate (120 mg/kg) on days 1 and 12 and blood glucose levels were estimated on 15 th day. Hydro-ethanol extracts of both the plants at the dose of 500 mg/kg, oral, significantly lowered the blood glucose levels in diabetic rats treated for 7 days. The antidiabetic activity of these plants was insignificantly different from each other. This suggests that, different species from same genera may have similar chemical constituents and pharmacological activity.

Chapter 9 – Selected Bioactive Natural Products for Diabetes Mellitus

Abstract According to WHO, by the year 2030, diabetes is predicted to become the seventh leading cause of death in the world, and mortality because of diabetes are projected to rise by more than 50% in the next 10 years. Synthetic hypoglycemic or antihyperglycemic agents are associated with several adverse effects and therefore search for the ideal remedy from natural sources for the control of diabetes remain on the frontline. Hitherto, hundreds of plants have been screened for the treatment of diabetes and several bioactive compounds are isolated from them. The review aims to gather the information of such bioactive natural products isolated from plants and to put forward the chemistry and biological activities of these compounds. Based on the bioactivity of the natural products, the attempts have been made to correlate the pharmacological activity and the chemical structure. The information of the structure–activity relationship of bioactive natural products, reported to be effective in diabetes, will be helpful in deciding various approaches for the control of diabetes through identification and development of lead compounds for diabetes.