Intranasal nanotherapeutics for brain targeting and clinical studies in Parkinson's disease.

Parkinson's disease (PD) is the second leading neurodegenerative disease globally, impacting the quality of life of millions of people. It is estimated that the treatment cost of PD in the USA can rise to 79 billion dollars by 2037. Limited drugs are approved by USFDA, which only provides symptomatic relief. Further, the drug efficacy is challenged due to low drug-brain concentration due to first-pass metabolism and blood-brain barrier (BBB). Intranasal drug administration can offer several advantages over systemic administration, providing efficient brain delivery. Nose-to-brain (N2B) drug delivery can enhance brain bioavailability, reduce enzymatic degradation, and reduce systemic adverse effects. However, due to poor absorption from the nasal mucosa, intranasal administration can be challenging for hydrophilic drugs. The drug mucociliary clearance, retention time, and nasal enzymatic degradation can also affect N2B drug delivery. Nanocarriers can enhance residence time, improve nasal permeation, increase brain uptake, and reduce enzymatic degradation. This review discusses the roles and applications of various N2B nanocarriers to treat PD effectively. Clinical trials of antiparkinson molecules is also covered. Lastly, safety aspects and prospects of potential nanotherapeutics for the effective treatment of PD are discussed.

Self-Assembled Lecithin-Chitosan Nanoparticles Improved Rotigotine Nose-to-Brain Delivery and Brain Targeting Efficiency.

Rotigotine (RTG) is a non-ergoline dopamine agonist and an approved drug for treating Parkinson's disease. However, its clinical use is limited due to various problems, viz. poor oral bioavailability (<1%), low aqueous solubility, and extensive first-pass metabolism. In this study, rotigotine-loaded lecithin-chitosan nanoparticles (RTG-LCNP) were formulated to enhance its nose-to-brain delivery. RTG-LCNP was prepared by self-assembly of chitosan and lecithin due to ionic interactions. The optimized RTG-LCNP had an average diameter of 108 nm with 14.43 ± 2.77% drug loading. RTG-LCNP exhibited spherical morphology and good storage stability. Intranasal RTG-LCNP improved the brain availability of RTG by 7.86 fold with a 3.84-fold increase in the peak brain drug concentration (Cmax(brain)) compared to intranasal drug suspensions. Further, the intranasal RTG-LCNP significantly reduced the peak plasma drug concentration (Cmax(plasma)) compared to intranasal RTG suspensions. The direct drug transport percentage (DTP (%)) of optimized RTG-LCNP was found to be 97.3%, which shows effective direct nose-to-brain drug uptake and good targeting efficiency. In conclusion, RTG-LCNP enhanced drug brain availability, showing the potential for clinical application.

Current Treatment Strategies Against Multidrug-Resistant Bacteria: A Review.

There are several bacteria called superbugs that are resistant to multiple antibiotics which can be life threatening specially for critically ill and hospitalized patients. This article provides up-to-date treatment strategies employed against some major superbugs, like methicillin-resistant Staphylococcus aureus, carbapenem-resistant Enterobacteriaceae, vancomycin-resistant Enterococcus, multidrug-resistant Pseudomonas aeruginosa, and multidrug-resistant Escherichia coli. The pathogen-directed therapeutics decrease the toxicity of bacteria by altering their virulence factors by specific processes. On the other hand, the host-directed therapeutics limits these superbugs by modulating immune cells, enhancing host cell functions, and modifying disease pathology. Several new antibiotics against the global priority superbugs are coming to the market or are in the clinical development phase. Medicinal plants possessing potent secondary metabolites can play a key role in the treatment against these superbugs. Nanotechnology has also emerged as a promising option for combatting them. There is urgent need to continuously figure out the best possible treatment strategy against these superbugs as resistance can also be developed against the new and upcoming antibiotics in future. Rational use of antibiotics and maintenance of proper hygiene must be practiced among patients.

Design of Experiment (DoE)-Approach Based RP-HPLC Analytical Method Development and Validation for Estimation of Efavirenz in Bulk and Formulations.

Present study reports design of experiment (DoE) based development and validation of a simple, rapid and sensitive reversed-phase high-performance liquid chromatography (RP-HPLC) method for estimation of efavirenz (EFZ), a non-nucleotide reverse transcriptase inhibitor (NNRTs), used in the treatment of acquired immunodeficiency syndrome (AIDS). Plackett-Burman design was explored to screen the critical method variables (CMVs) for the RP-HPLC method. A response surface Box-Behnken design was employed to optimize the screened CMVs which affect the analytical responses (ARs) of RP-HPLC method. Using the optimized CMVs the HPLC method was developed and validated according to International Conference on Harmonization (ICH) guidelines. EFZ in marketed formulation was estimated using the validated method. Acetonitrile proportion, pH of the phosphate buffer and mobile phase flow rate were the CMVs and retention time and number of theoretical plates were the ARs for the study. The optimized chromatographic parameters were acetonitrile proportion in mobile phase: 51.17%v/v, pH of phosphate buffer: 4.04 and flow rate: 1.25 mL/min. Use of these optimized parameters resulted in retention time of 11.031 min and 9,498.787 number of theoretical plates as ARs of the HPLC method. The method was further validated in harmony with current ICH guidelines Q2 (R1). The method was capable of the successful estimation of EFZ in marketed formulation. The study depicts successful development and validation of a simple RP-HPLC method of EFZ using DoE approach.

DoE-based validation of a HPLC-UV method for quantification of rotigotine nanocrystals: Application to in vitro dissolution and ex vivo nasal permeation studies.

The current work is focused on optimization, development, and validation of a sensitive and specific reversed-phase high-performance liquid chromatography (RP-HPLC) method for the estimation of rotigotine (RTG) in bulk and nanoformulations. The RP-HPLC method was effectively optimized using the concepts of design of experiments. Critical method variables (CMVs) were screened using Plackett-Burman design. Box-Behnken, a surface response methodology-based design, was further used for the optimization of CMVs with the number of theoretical plates and retention time (min) as responses. The optimized chromatographic conditions for the RP-HPLC method were: acetonitrile proportion: 54% v/v, pH of buffer: 5.0 (10 mM), and flow rate: 0.65 mL/min. The number of theoretical plates and retention time in the study were found to be 11206 and 7.65 min, respectively. The developed method exhibited good linearity (R2 = 0.9995) within a range of 25-600 ng/mL and LOD and LOQ were found to be 9 and 12 ng/mL, respectively. The developed RP-HPLC method was found sensitive, accurate, precise, specific, robust, and stability indicating according to the regulatory guidelines. The validated method was efficiently applied for in vitro dissolution study, ex vivo nasal permeation study, and estimation of drug content of RTG nanocrystals.

A new fluorescence-based method for rapid and specific quantification of rotigotine in chitosan nanoparticles.

A new, simple, rapid and sensitive fluorescence-based method has been developed and validated for the estimation of rotigotine (RTG) in bulk and nanoformulations. RTG is a dopamine agonist approved by both the United States Food and Drug Administration and the European Medicines Agency for the treatment of Parkinson's disease and restless leg syndrome. To date, no fluorescence-based analytical method has been reported for the estimation of RTG in any pharmaceutical dosage forms. The developed method is validated as per the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use guidelines. A solution of the pure drug in phosphate buffer pH 6.4 exhibited strong fluorescence emission (λem) at a wavelength of 298 nm when excited (λex) at a wavelength of 277 nm. The developed method demonstrated good linearity over a range of 250-2500 ng/mL. Limit of detection and limit of quantitation values were found to be 36.25 ng/mL and 109.85 ng/mL respectively. The developed method was found to be accurate, precise, specific and robust. The validated method was successfully applied for the estimation of entrapment efficiency and drug loading of in-house intranasal RTG-loaded chitosan nanoparticles.

UV Spectrophotometric method for characterization of curcumin loaded nanostructured lipid nanocarriers in simulated conditions: Method development, in-vitro and ex-vivo applications in topical delivery.

Curcumin the extract obtained from the dried rhizome of turmeric, Curcuma longa is a hydrophobic phenol that delivers numerous pharmacological actions like anti-inflammatory, anti-microbial and anti-oxidant, anti-psoriasis, antidiabetic, anticancer. But curcumin has low bioavailability issues that accompany low aqueous solubility, further, when administered orally, >90% of the drug degrades rapidly in the alkaline medium. Administering the drug topically can bypass the problem as well as first-pass metabolism and therefore delivering the drug at the targeted site of action. Encapsulating curcumin in nanostructured lipid nanocarriers (NLC) is an excellent novel strategy. Further, these NLC provides both the controlled release and helps in the enhanced permeation of the drug through the skin's physiological barrier, stratum corneum. For the NLC characterization, a reliable method must be developed that can accurately and precisely determine the drug content in the formulation and also for its in-vitro and ex-vivo characterization. This experiment describes the analytical validation parameters described as per International Conference of Harmonization guidelines to develop a method using the UV-Visible spectroscopy. The method was developed in two solvent systems i.e. methanol and 6.4 pH phosphate buffer with 1.5% polysorbate 80. Methanol solvent was used for the determination of curcumin in the NLC formulation via determining the encapsulation efficiency and 6.4 pH phosphate buffer with 1.5% polysorbate 80 solvent was used for in-vitro and ex-vivo characterization of the developed NLC formulation (cream and gel). These methods were validated in response to linearity, the limit of detection, the limit of quantification, precision, accuracy, repeatability, and specificity.

Microneedles: A smart approach and increasing potential for transdermal drug delivery system.

The most widely used methods for transdermal administration of the drugs are hypodermic needles, topical creams, and transdermal patches. The effect of most of the therapeutic agents is limited due to the stratum corneum layer of the skin, which serves as a barrier for the molecules and thus only a few molecules are able to reach the site of action. A new form of delivery system called the microneedles helps to enhance the delivery of the drug through this route and overcoming the various problems associated with the conventional formulations. The primary principle involves disruption of the skin layer, thus creating micron size pathways that lead the drug directly to the epidermis or upper dermis region from where the drug can directly go into the systemic circulation without facing the barrier. This review describes the various potential and applications of the microneedles. The various types of microneedles can be fabricated like solid, dissolving, hydrogel, coated and hollow microneedles. Fabrication method selected depends on the type and material of the microneedle. This system has increased its application to many fields like oligonucleotide delivery, vaccine delivery, insulin delivery, and even in cosmetics. In recent years, many microneedle products are coming into the market. Although a lot of research needs to be done to overcome the various challenges before the microneedles can successfully launch into the market.

Dissolution enhancement of felodipine by amorphous nanodispersions using an amphiphilic polymer: insight into the role of drug-polymer interactions on drug dissolution.

CONTEXT: Felodipine, a poorly soluble drug, is widely used in the treatment of angina pectoris and hypertension. OBJECTIVE: This study aimed at the preparation of amorphous solid dispersion (SD) of felodipine using an amphiphilic polymer, soluplus, for the potential enhancement in solubility of the drug. MATERIALS AND METHODS: Solid dispersions with varying proportions of drug and soluplus were prepared and the rate and extent of dissolution from SDs was compared with that of the pure drug. FT-IR and (1)H NMR spectroscopic analysis were carried out to examine the formation mechanism of SDs. Various techniques were used for solid state characterization of designed SDs. RESULTS: Formation of amorphous solid dispersions with particle size in nanometer range indicated suitability of polymer and method used in the preparation. FT-IR and (1)H NMR spectroscopy revealed that soluplus was involved in strong hydrogen bonding with felodipine molecules which resulted in the conversion of crystalline felodipine into amorphous form. Solid dispersion with 1:10 drug/polymer ratio showed more than 90% drug dissolution in 30 min whereas pure felodipine showed less than 19% drug dissolution in 1 h. DISCUSSION AND CONCLUSION: Amorphous SDs of felodipine were prepared using soluplus resulting in substantial enhancement in the rate and extent of dissolution of felodipine.