Jwala Renukuntla

Approaches for Enhancing Oral Bioavailability of Peptides and Proteins

Oral delivery of peptide and protein drugs faces immense challenge partially due to the gastrointestinal (GI) environment. In spite of considerable efforts by industrial and academic laboratories, no major breakthrough in the effective oral delivery of polypeptides and proteins has been accomplished. Upon oral administration, gastrointestinal epithelium acts as a physical and biochemical barrier for absorption of proteins resulting in low bioavailability (typically less than 1-2%). An ideal oral drug delivery system should be capable of (a) maintaining the integrity of protein molecules until it reaches the site of absorption, (b) releasing the drug at the target absorption site, where the delivery system appends to that site by virtue of specific interaction, and (c) retaining inside the gastrointestinal tract irrespective of its transitory constraints. Various technologies have been explored to overcome the problems associated with the oral delivery of macromolecules such as insulin, gonadotropin-releasing hormones, calcitonin, human growth factor, vaccines, enkephalins, and interferons, all of which met with limited success. This review article intends to summarize the physiological barriers to oral delivery of peptides and proteins and novel pharmaceutical approaches to circumvent these barriers and enhance oral bioavailability of these macromolecules.

Enhancing targeted antibiotic therapy via pH responsive solid lipid nanoparticles from an acid cleavable lipid

An acid cleavable lipid (SA-3M) was synthesized and used to develop pH-responsive solid lipid nanoparticles (SLNs) to deliver vancomycin base (VM-FB) to acidic infection sites. The size, polydispersity index and zeta potential of VM-FB_SA-3M_SLNs were 132.9±9.1nm, 0.159±0.01 and -26±4.4mV respectively, with 57.80±1.1% encapsulation efficiency. VM-FB release was significantly faster at pH6.5 than pH7.4. In vitro antibacterial activity against methicillin-susceptible and resistant Staphylococcus aureus (MSSA and MRSA) revealed that SLNs had enhanced activity at pH6.5 than pH7.4. In vivo study showed that the amount of MRSA remaining in the skin of VM-FB_SA-3M_SLNs treated mice was approximately 22-fold lower than VM-FB treated mice. Histological investigations revealed that signs of inflammation in the skin treated with VM-FB_SA-3M_SLNs were minimal. In conclusion, this study confirmed that SA-3M can form pH-responsive SLNs capable of releasing antibiotic specifically at acidic infection sites.

pH-responsive chitosan nanoparticles from a novel twin-chain anionic amphiphile for controlled and targeted delivery of vancomycin

The design and synthesis of novel pH-responsive nanoantibiotics is an emerging research area to address the antibiotic resistance crisis. The purpose of this study was therefore to synthesize a new anionic gemini surfactant (AGS) that could result in the formulation of pH-responsive chitosan nanoparticles (CSNPs) to treat methicillin-resistant Staphylococcus aureus (MRSA) infections. The coupling of oleic acid with 2,2-dimethyl-5,5-bis(hydroxymethyl)-1,3-dioxane and subsequent deprotection followed by a reaction with succinic anhydride and sodium bicarbonate yielded AGS. Critical micelle concentration (CMC) was determined using conductometry and in vitro cytotoxicity was performed using a MTT assay. Vancomycin loaded CSNPs containing AGS (DL_CSSNPs) were prepared by ionotropic gelation of chitosan with pentasodium tripolyphosphate. CSNPs were characterized for size, polydispersity index (PDI), zeta potential (ZP), entrapment efficiency, surface morphology, in vitro drug release and in vitro antibacterial activity (at pH 6.5 and 7.4). Results from the in vitro antibacterial activity were further supported by an in vivo study using a mice skin infection model. The CMC of AGS was found to be 1.3mM/L and it was non-toxic. The DL_CSSNPs were spherical with size, PDI and ZP of 220.57±5.9nm, 0.299±0.004 and 21.9±0.9mV respectively. An increase in the vancomycin release from the DL_CSSNPs was observed at pH 6.5 compared to pH 7.4. The minimum inhibitory concentration values at pH 6.5 and 7.4 against MRSA were 7.81 and 62.5μg/ml respectively. In vivo antibacterial activity showed that the MRSA burden in mice treated with DL_CSSNPs was reduced by almost 8-fold compared to those treated with pure vancomycin.

Excipients and Non-medicinal Agents as Active Pharmaceutical Ingredients

“Atypical Actives” are a class of excipients that serve as Active Pharmaceutical Ingredients (APIs) in over-the-counter (OTC) medications. Atypical actives are present in a variety of dosage forms administered through oral, topical, parenteral and ophthalmic routes. Most atypical actives are derived from a natural source and hence pose fewer side effects compared to prescription medications. In spite of the advantages associated with the use of atypical actives, they have never shared the spotlight with APIs and are continuously disregarded or ignored. This chapter intends to highlight atypical actives and non-medicinal agents in OTC drug products with an emphasis on their therapeutic properties.

Tailoring the Release of Drugs Using Excipients

Current efforts in the area of drug delivery include the development of modified release technologies for improving product efficacy, safety, and patient compliance. Polymeric excipients play a critical role in determining the mechanism and rate of drug release from the solid oral dosage forms. Regardless of the physicochemical properties of drug molecules and physiological conditions of the body, it is now possible to achieve site-specific delivery of drugs in a sustained manner. This chapter highlights the polymeric excipients that are widely used in modulating the release and enhancing the oral absorption of drugs.

Transscleral Iontophoretic Drug Delivery for Treating Retinal Diseases

Drug delivery to the eye still is a challenge due to its intricate anatomical structure. Posterior segment delivery is much more challenging due to the acellular nature of the vitreous humor and the longer diffusion distance to the retina. Iontophoresis is a noninvasive technique that facilitates the movement of charged drug molecules into tissues by an electric field. Using iontophoresis, it is possible to achieve therapeutic concentrations faster by modulating the intensity and duration of the applied current. Transscleral iontophoretic delivery is gaining pace and is considered as an alternative for a safe and more effective treatment to retinal disorders. This chapter intends to highlight various aspects of iontophoresis, with a special emphasis on transscleral delivery of drugs and drug-loaded nanocarrier systems for treating disorders in the back of the eye. Finally, a section on toxic effects of iontophoresis to various ocular tissues is included.

FSE–Ag complex NS: preparation and evaluation of antibacterial activity

Silver (Ag) complexes of drugs and their nanosystems have great potential as antibacterials. Recently, an Ag complex of furosemide (Ag-FSE) has shown to be a promising antimicrobial. However, poor solubility of Ag-FSE could hamper its introduction into clinics. Therefore, the authors developed a nanosuspension of Ag-FSE (Ag-FSE_NS) for its solubility and antibacterial activity enhancement. The aim of this study was to introduce a novel nanoantibiotic with enhanced antibacterial efficacy. Ag-FSE_NS was prepared by precipitation-ultrasonication technique. Size, polydispersity index (PI) and zeta potential (ZP) of prepared Ag-FSE_NS were measured by dynamic light scattering, whereas surface morphology was determined using scanning electron microscopy (SEM). In vitro antibacterial activity was evaluated against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa using broth microdilution method. Size, PI and ZP of optimised Ag-FSE_NS1 were 191.2 ± 19.34 nm, 0.465 ± 0.059 and -55.7 ± 8.18 mV, respectively. SEM revealed that Ag-FSE_NS1 particles were rod or needle-like with smooth surfaces. Saturation solubility of Ag-FSE in NS increased eight-fold than pure Ag-FSE. Ag-FSE_NS1 exhibited two-fold and eight-fold enhancements in activity against E. coli and S. aureus, respectively. The results obtained showed that developed Ag-FSE_NS1 holds a promise as a topical antibacterial.

Thermo- and pH dual responsive polymeric micelles and nanoparticles

A new generation of the more effective polymeric micelle and nanoparticle drug delivery systems evolved due to the emergence of stimuli-responsive polymers. Among various stimuli, pH and temperature are most widely studied for enhanced drug release at the site of action. Researchers are focusing on dual (pH and temperature) responsive polymeric micelles and nanoparticles for controlled and enhanced drug release at the site of action. These dual responsive systems are mainly evaluated for cancer therapy as certain malignancies can cause a slight increase in temperature and decrease in extracellular pH around the tumor site. Fabrication of dual responsive polymeric micelles and nanoparticles has been possible for drug delivery and imaging purposes; due to advancement in the synthesis of non-toxic dual pH- and thermo-responsive polymers. Adequately designed polymeric micelles and nanoparticles sensitive to both pH and temperature can achieve better targeting and treatment. These systems can be very efficient due to their ability to wisely distinguish between pathological and healthy tissues. Our review manuscripts primary focus is on pH- and thermo-dual responsive polymeric nanoparticles and micelles for application in precision drug delivery.