Abhijit A. Date

Nanosuspensions: a promising drug delivery strategy

Nanosuspensions have emerged as a promising strategy for the efficient delivery of hydrophobic drugs because of their versatile features and unique advantages. Techniques such as media milling and high‐pressure homogenization have been used commercially for producing nanosuspensions. Recently, the engineering of nanosuspensions employing emulsions and microemulsions as templates has been addressed in the literature. The unique features of nanosuspensions have enabled their use in various dosage forms, including specialized delivery systems such as mucoadhesive hydrogels. Rapid strides have been made in the delivery of nanosuspensions by parenteral, peroral, ocular and pulmonary routes. Currently, efforts are being directed to extending their applications in site‐specific drug delivery.

Self-nanoemulsifying drug delivery systems: formulation insights, applications and advances

There has been a resurgence of interest in nanoemulsions for various pharmaceutical applications since low-energy emulsification methods, such as spontaneous or self-nanoemulsification, have been described. Self-nanoemulsifying drug delivery systems (SNEDDS) are anhydrous homogenous liquid mixtures consisting of oil, surfactant, drug and coemulsifier or solubilizer, which spontaneously form oil-in-water nanoemulsion of approximately 200 nm or less in size upon dilution with water under gentle stirring. The physicochemical properties, drug solubilization capacity and physiological fate considerably govern the selection of the SNEDDS components. The composition of the SNEDDS can be optimized with the help of phase diagrams, whereas statistical experimental design can be used to further optimize SNEDDS. SNEDDS can improve oral bioavailability of hydrophobic drugs by several mechanisms. The conversion of liquid SNEDDS to solid oral dosage forms or solid SNEDDS has also been achieved by researchers. Solid SNEDDS can offer better patient compliance and minimize problems associated with capsules filled with liquid SNEDDS.

Parenteral microemulsions: An overview

Parenteral delivery of the hydrophobic drugs is a very challenging task. The conventional approaches such as use of co-solvents, oily vehicles and modern approaches such as mixed micelles, liposomes, complexation with cyclodextrins and emulsions have several limitations. Microemulsions have evolved as a novel vehicle for parenteral delivery of the hydrophobic drugs. Their interesting features such as spontaneity of formation, ease of manufacture, high solubilization capacity and self-preserving property make them the vehicle of choice. The review focuses on the excipients available for formulation of the parenteral microemulsions and describes the investigations reported for the various classes of therapeutic agents.

Overcoming poor oral bioavailability using nanoparticle formulations – opportunities and limitations

Oral delivery of drugs with poor aqueous solubility and poor enzymatic and/or metabolic stability is very challenging. However, the advent of nanotechnology has revolutionized the field of oral drug delivery. The review provides an overview of various nano-architectures such as nanosuspensions, lipid and polymeric nanocarriers, inorganic nanostructures and describes advantages and challenges associated with their efficient delivery. Among various nano-architectures, only nanosuspensions and spontaneously emulsifying systems have succeeded in reaching pharmaceutical market.

Tween 80-sodium deoxycholate mixed micelles: structural characterization and application in doxorubicin delivery.

The objective of the present investigation is to develop and characterize anionic mixed micelles of two biocompatible surfactants, Tween 80 (T-80) and sodium deoxycholate (NaDC), and evaluate their potential in the delivery of doxorubicin hydrochloride (DOX), a cationic anticancer drug. The mixed micelles were characterized for their microstructure, intermicellar interactions, and doxorubicin binding ability by dynamic light scattering, small angle neutron scattering (SANS), viscosity, and optical absorption measurements. Salt-induced growth of the mixed micelles at different compositions suggests that both electrostatic interaction of the anionic bile salts and steric repulsion of the ethylene oxide groups in nonionic components are affected by the presence of electrolytes. Addition of bile salt molecules to T-80 micelles suppresses the salt-induced growth of nonionic T-80 micelles. SANS studies indicate that bile salt micelles are prolate ellipsoidal in shape, and the addition of T-80 transforms them toward a spherical shape. The anionic bile salt can successfully bind to the cationic drug doxorubicin. The in vitro cytotoxicity studies in various cancer cell lines revealed that DOX-loaded micelles have greater in vitro anticancer activity as compared to DOX solution, indicating their potential in pharmaceutical applications.

Lecithin-Based Novel Cationic Nanocarriers (Leciplex) II: Improving Therapeutic Efficacy of Quercetin on Oral Administration†

The objective of the present investigation was to evaluate ability of the novel self-assembled phospholipid- based cationic nanocarriers (LeciPlex) in improving the therapeutic efficacy of a poorly water-soluble natural polyphenolic agent, quercetin (QR), on oral administration. Quercetin loaded LeciPlex (QR-LeciPlex) were successfully fabricated using a biocompatible solvent Transcutol HP. The QR-LeciPlex were characterized for particle size, encapsulation efficiency, zeta potential, and particle morphology by cryo-TEM. UV and fluorescence spectral characterization was carried out to find out the association of QR with LeciPlex. Small angle neutron scattering studies (SANS) were carried out to understand the internal structure of Leciplex and to evaluate the influence of the incorporation of QR in the LeciPlex. Anti-inflammatory and antitumorigenic activity of QR-LeciPlex was determined in comparison to QR suspension to evaluate the potential of LeciPlex in improving oral delivery of QR. QR-LeciPlex exhibited a particle size of ∼400 nm and had excellent colloidal stability. The QR-LeciPlex had a zeta potential greater than +30 mV and exhibited very high encapsulation efficiency of QR (>90%). UV and fluorescence spectral characterization indicated the interaction/association of QR with LeciPlex components. Cryo-TEM studies showed that LeciPlex and QR-LeciPlex have a unilamellar structure. SANS confirmed the unilamellar structure of LeciPlex and indicated that the incorporation of QR does not have any effect on the internal structure of the LeciPlex. QR-LeciPlex exhibited significantly higher anti-inflammatory and antitumorigenic activity (p < 0.01) as compared to that of QR suspension on oral administration.

A review of nanotechnological approaches for the prophylaxis of HIV/AIDS

Successful treatment and control of HIV/AIDS is one of the biggest challenges of 21st century. More than 33 million individuals are infected with HIV worldwide and more than 2 million new cases of HIV infection have been reported. The situation demands development of effective prevention strategies to control the pandemic of AIDS. Due to lack of availability of an effective HIV vaccine, antiretroviral drugs and nucleic acid therapeutics like siRNA have been explored for HIV prophylaxis. Clinical trials shave shown that antiretroviral drugs, tenofovir and emtricitabine can offer some degree of HIV prevention. However, complete prevention of HIV infection has not been achieved yet. Nanotechnology has brought a paradigm shift in the diagnosis, treatment and prevention of many diseases. The current review discusses potential of various nanocarriers such as dendrimers, polymeric nanoparticles, liposomes, lipid nanocarriers, drug nanocrystals, inorganic nanocarriers and nanofibers in improving efficacy of various modalities available for HIV prophylaxis.

Development and evaluation of a thermosensitive vaginal gel containing raltegravir + efavirenz loaded nanoparticles for HIV prophylaxis

The objective of this investigation was to develop a thermosensitive vaginal gel containing raltegravir+efavirenz loaded PLGA nanoparticles (RAL+EFV-NPs) for pre-exposure prophylaxis of HIV. RAL+EFV-NPs were fabricated using a modified emulsion-solvent evaporation method and characterized for size and zeta potential. The average size and surface charge of RAL+EFV-NP were 81.8±6.4 nm and -23.18±7.18 mV respectively. The average encapsulation efficiency of raltegravir and efavirenz was 55.5% and 98.2% respectively. Thermosensitive vaginal gel containing RAL+EFV-NPs was successfully prepared using a combination of Pluronic F127 (20% w/v) and Pluronic F68 (1% w/v). Incorporation RAL+EFV-NPs in the gel did not result in nanoparticle aggregation and RAL+EFV-NPs containing gel showed thermogelation at 32.5°C. The RAL+EFV-NPs were evaluated for inhibition of HIV-1(NL4-3) using TZM-bl indicator cells. The EC(90) of RAL+EFV-NPs was lower than raltegravir+efavirenz (RAL+EFV) solution but did not reach significance. Compared to control HeLa cells without any treatment, RAL+EFV-NPs or blank gel were not cytotoxic for 14 days in vitro. The intracellular levels of efavirenz in RAL+EFV-NPs treated HeLa cells were above the EC(90) for 14 days whereas raltegravir intracellular concentrations were eliminated within 6 days. Transwell experiments of NPs-in-gel demonstrated rapid transfer of fluorescent nanoparticles from the gel and uptake in HeLa cells within 30 min. These data demonstrate the potential of antiretroviral NP-embedded vagina gels for long-term vaginal pre-exposure prophylaxis of heterosexual HIV-1 transmission.

Nanoformulations of Rilpivirine for Topical Pericoital and Systemic Coitus-Independent Administration Efficiently Prevent HIV Transmission

Vaginal HIV transmission accounts for the majority of new infections worldwide. Currently, multiple efforts to prevent HIV transmission are based on pre-exposure prophylaxis with various antiretroviral drugs. Here, we describe two novel nanoformulations of the reverse transcriptase inhibitor rilpivirine for pericoital and coitus-independent HIV prevention. Topically applied rilpivirine, encapsulated in PLGA nanoparticles, was delivered in a thermosensitive gel, which becomes solid at body temperature. PLGA nanoparticles with encapsulated rilpivirine coated the reproductive tract and offered significant protection to BLT humanized mice from a vaginal high-dose HIV-1 challenge. A different nanosuspension of crystalline rilpivirine (RPV LA), administered intramuscularly, protected BLT mice from a single vaginal high-dose HIV-1 challenge one week after drug administration. Using transmitted/founder viruses, which were previously shown to establish de novo infection in humans, we demonstrated that RPV LA offers significant protection from two consecutive high-dose HIV-1 challenges one and four weeks after drug administration. In this experiment, we also showed that, in certain cases, even in the presence of drug, HIV infection could occur without overt or detectable systemic replication until levels of drug were reduced. We also showed that infection in the presence of drug can result in acquisition of multiple viruses after subsequent exposures. These observations have important implications for the implementation of long-acting antiretroviral formulations for HIV prevention. They provide first evidence that occult infections can occur, despite the presence of sustained levels of antiretroviral drugs. Together, our results demonstrate that topically- or systemically administered rilpivirine offers significant coitus-dependent or coitus-independent protection from HIV infection.

Sulfobutyl Ether7 β-Cyclodextrin (SBE7 β-CD) Carbamazepine Complex: Preparation, Characterization, Molecular Modeling, and Evaluation of In Vivo Anti-epileptic Activity

The objective of the present investigation was to study the ability of sulfobutyl ether7-β-cyclodextrin to form an inclusion complex with carbamazepine, an anti-epileptic drug with poor water solubility. The formation of the complex was carried out using the industrially feasible spray-drying method. The inclusion complex and physical mixtures were characterized by various techniques such as differential scanning calorimetry (DSC), infrared (IR), nuclear magnetic resonance (NMR), X-ray diffraction (XRD), and molecular modeling. The DSC, IR, and NMR studies confirmed the formation of an inclusion complex between carbamazepine and sulfobutyl ether7 β-cyclodextrin whereas XRD studies indicated an amorphous nature of the inclusion complex. Molecular modeling studies disclosed different modes of interaction between carbamazepine and sulfobutyl ether7 β-cyclodextrin with good correlation with experimental observations. The inclusion complex exhibited significantly higher in vitro dissolution profile as compared with pure carbamazepine powder. The in vivo anti-epileptic activity of carbamazepine/sulfobutyl ether7 β-cyclodextrin complex was evaluated in pentylenetetrazole-induced convulsions model. The carbamazepine/sulfobutyl ether7 β-cyclodextrin complex showed significantly higher anti-epileptic activity (p <0.01) as compared with that of carbamazepine suspension on oral administration.