Recent Advancements in Nanodiamond Mediated Brain Targeted Drug Delivery and Bioimaging of Brain Ailments: A Holistic Review

Background: The brain is a vital and composite organ. By nature, the innate make-up of the brain is such that in anatomical parlance, it is highly protected by the “Blood-Brain Barrier”, which is a nexus of capillary endothelial cells, basement membrane, neuroglial membrane and glialpodocytes. The same barrier, which protects and isolates the interstitial fluid of the brain from capillary circulation, also restricts the therapeutic intervention. Many standing pharmaceutical formulations are ineffective in the treatment of inimical brain ailments because of the inability of the API to surpass and subsist inside the Blood Brain Barrier. Objective: This is an integrated review that emphasizes on the recent advancements in brain-targeted drug delivery utilizing nanodiamonds (NDs) as a carrier of therapeutic agents. NDs are a novel nanoparticulate drug delivery system, having carbon moieties as their building blocks and their surface tenability is remarkable. These neoteric carbon-based carriers have exceptional, mechanical, electrical, chemical, optical, and biological properties, which can be further rationally modified and augmented. Conclusion: NDs could be the next“revolution ”in the field of nanoscience for the treatment of neurodegenerative disorders, brain tumors, and other pernicious brain ailments. What sets them apart from other nanocarriers is their versatile properties like diverse size range and surface modification potential, which makes them efficient enough to move across certain biological barriers and offer a plethora of brain targeting and bioimaging abilities. Lay Summary: The blood-brain barrier (BBB) poses a major hurdle in the way of treating many serious brain ailments. A range of nanoparticle based drug delivering systems have been formulated, including solid lipid nanoparticles, liposomes, dendrimers, nanogels, polymeric NPs, metallic NPs (gold, platinum, andironoxide) and diamondoids (carbonnanotubes). Despite this development, only a few of these formulations have shown the ability to cross the BBB. Nanodiamonds, because of their small size, shape, and surface characteristics, have a potential in moving beyond the diverse and intricate BBB, and offer a plethora of brain targeting capabilities.

Development of Dioctyl Phthalate@Fe3O4 Nanocomposite Reinforced Hollow Fiber Solid/ Liquid Phase Microextraction Followed by HPLC-DAD for the Determination of Atorvastatin and Gemfibrozil in Human Urine

Background: The desirable levels of lipids, especially in patients with coronary artery disease, might not be achievable with a single lipid-lowering drug; thus, combination therapy using atorvastatin and gemfibrozil seems to be a promising approach. However, the potential for drug-drug interaction needs to be taken into consideration, and the combination (atorvastatin and gemfibrozil) is recommended only when other options for reducing lipids have been exhausted. Objectives: Many studies are conducted for the determination of atorvastatin or gemfibrozil in biological fluids and tablets; however, the simultaneous determination of the two drugs in complex biological matrices is limited. Consequently, the development of a sensitive method for simultaneous determination of atorvastatin and gemfibrozil in urine samples is urgently needed to make sure that the doses of both medications are given to patients correctly to prevent the risk of side effects outcomes associated with the adverse drug-drug interaction. Methods: A synthesized nanocomposite sorbent, dioctyl phthalate coated on the surface of magnetite (DOP@Fe3O4), was reinforced and immobilized into the pores of 2.5 cm segment hollow fiber microtube via ultrasonication, and the lumen of the microtube was filled with 1-octanol as an organic solvent with two ends heat-sealed. The prepared (DOP@Fe3O4-HF-SLPME) device was directly immersed into 10 mL of a sample solution containing atorvastatin and gemfibrozil with agitation. Subsequently, the microextraction device was transferred to HPLC-micro-vial containing an appropriate solvent, and the selected analytes were desorbed under ultrasonication prior to HPLC-DAD analysis. The main factors influencing the adsorption and desorption process of the selected drugs have been optimized. Results: The DOP@Fe3O4-HF-SLPME combined with the HPLC-DAD method was analytically evaluated for the simultaneous determination of atorvastatin and gemfibrozil in human urine samples using the optimized conditions. In spiked urine samples, the method showed a good linearity R2˃ 0.998, RSD from 1.41- 5.33%, and the limits of detection/ quantification (LOD/ LOQ) were 0.11/ 0.36 and 0.73/ 2.42 µg L-1 for atorvastatin and gemfibrozil, respectively. The enrichment factors of atorvastatin and gemfibrozil were 83.4 and 101.2, with extraction recoveries of 80.9% and 99.0%, respectively. The developed method demonstrated comparable results against referenced methods and a satisfactory result for determining the selected drugs in the patient’s urine samples. Conclusion: The DOP@Fe3O4-HF-SLPME followed by HPLC-DAD was proved to be an efficient, sensitive, and cost-effective biopharmaceutical analysis method for trace levels of atorvastatin and gemfibrozil in the biological fluid matrix.

A Review on Recent Controlled Release Strategies for Oral Drug Delivery of Repaglinide (a BCS Class II Drug)

: Repaglinide is an antidiabetic drug that works by stimulating insulin secretion from pancreatic beta cells. Repaglinide is practically insoluble in water with a water solubility of 34 µg/mL at 37 ˚C, and it has a high absorption rate from the gastrointestinal tract following oral administration since the log P value of repaglinide is 3.97. The low aqueous solubility and the high permeability of repaglinide represent a typical behavior for drugs that belong to class II Biopharmaceutical Classification System (BCS II). Managing type-2 diabetes mellitus with repaglinide is considered a burdensome therapy, as it requires frequent dosing of repaglinide before each meal to maintain its therapeutic plasma concentration due to its short plasma half-life of approximately one hour. Hence the present review aims to discuss thoroughly the various approaches investigated in recent years to develop drug delivery systems that improve oral delivery of repaglinide, including nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, sustained-release hydrophilic matrix, floating microspheres, and nanocomposites.

Invasomes for enhanced delivery through the skin: Evaluation of systems with meet clinical challenges

Background: Portage of therapeutic agents directly to the skin (cutaneous/dermal delivery) is the preferable approach in mitigating and curing a variety of skin manifestations, including itching, eczema, acne, psoriasis keratinization, and skin cancer. Dermal delivery reduces side effects associated with systemic therapy and allows maximum utilization of the available doses. Invasomes are the next generation of liposomes with greater flexibility, elasticity, and permeability through the skin than liposomes and ethosomes. Objective: This review article highlights various aspects of invasomes, including the structure and composition of invasomes, methods of preparation of invasomes, the mechanism involved in better penetration through the skin, key parameters to be considered for effective permeation, therapeutic applications of invasomes as novel drug delivery systems, and future development and challenges. Methods: The authors have reviewed various primary and secondary sources, including PUBMED, SCIENCE DIRECT, INFORMA, and patents.com, to collect information on various aspects of invasomes. Results and Conclusion: Invasomes are novel vesicular drug delivery systems that have been used for dermal delivery of drugs for various therapeutic applications. These novel carriers have great ability, and their properties can be highly modulated by varying their composition and concentration of terpenes. Based on all the research reports gathered, it is well proven that these systems have a much higher potential for delivering drugs for skin manifestations and could expand the opportunities for treating various dermatological issues, increasing day by day.

Fabrication of cefixime nanoparticles loaded films and their ex vivo antimicrobial effect on periodontitis patient’s saliva

Aim: This study was designed to prepare and evaluate cefixime-loaded nanoparticles containing low molecular weight chitosan films for the enhanced topical treatment of periodontitis. Methods: To fabricate the enhanced antimicrobial films, a nanoprecipitation method for cefixime nanoparticles followed by a solvent evaporation method for these nanoparticles loaded films were adopted in this study. Nine batches of nanoparticles (NPs) with different concentrations of ethyl cellulose and polyvinyl alcohol were prepared and evaluated. Furthermore, nine batches of optimized NPs loaded films with different concentrations of low molecular weight chitosan and glycerol were fabricated and evaluated. Optimized NPs loaded films were assessed for their antimicrobial activity against the periodontitis patient’s saliva samples. Results: The FT-IR spectroscopy and XRD study revealed that there was no interaction between the drug and all other excipients and the drug remained amorphous form in chitosan film. The SEM study revealed that the prepared NPs were spherical in shape and uniformly distributed in chitosan film. In vitro drug release study revealed the NPs have a sustained release profile up to 8 days and NPs loaded films have up to 11 days. The conventional marketed mouth wash shows a low inhibition zone of 5.70 ± 0.043 mm, whereas NPs loaded film shows a higher inhibition zone of 6.72 ± 0.063 mm against periodontal microorganisms present in the patient’s saliva. The stability study revealed that the optimized NPs loaded film shows no dramatic change in drug release profile and folding endurance after six months. Conclusion: This present study highlights the possible usage of cefixime NPs loaded films in enhanced periodontal treatment.

The Potency of Wound Healing of Nanogel Containing Mikania Micrantha Leaves Extract in Hyperglycemic Rats

Introduction: Mikania micrantha has been used traditionally for wound dressings and promoted the healing of sores. This is due to the content of alkaloids and terpenoids/steroids compounds. Hyperglycemic is a good medium for bacterial growth and inhibits the wound healing process. Purpose: This study aimed to determine the wound healing of nanogels containing MMLE in hyperglycemic rats, as a model for diabetic wounds. Methods: Mikania micrantha leaves were extracted with the maceration method using ethanol 96% in 5 days. Carbopol 940 was used as the gelling agent. The parameters observed during the physical testing of nanogels were organoleptic, homogeneity, pH, and size of the particle. Antibacterial activity was tested on Staphylococcus aureus, Staphylococcus epidermis, Escherichia coli, and wound healing activity in hyperglycemic rats for 14 days observation. Diabetic wound healing was treated with 4 groups (P1, P2, K1, K2). Data were analyzed using SPSS. Results: Nanogel showed homogeneity, dark green color, transparency, pH 6.1± 0.1, and particle size range in 255-456 nm. Inhibition zone of antibacterial testing i.e. Staphylococcus aureus, Staphylococcus epidermis, and Escherichia coli was 10.57 ± 0.26 mm; 9.73 ± 0.21 mm; 8.4 ± 0.1 mm. The percentage of diabetic wound healing was in the range of 92.79±3.81% to 94.08 ± 2.33% for 14 days of observation. Conclusion: MMLE nanogels have the potential as a treatment for diabetic wound healing.

Purification of Drug Loaded Liposomal Formulations by a Novel Stirred Cell Ultrafiltration Technique

Background: Presently reported methods for purification of liposomal formulations at laboratory scale have drawbacks of adversely affecting critical quality attributes (CQAs) of liposomes such as particle size, PDI, drug entrapment efficiency, etc., and are also not amenable for large scale processing. Objective: The present study was aimed to explore stirred cell ultrafiltration technique as a novel liposome purification method for removal of unentrapped free drug and excess external aqueous fluid, maintaining the physical integrity of liposomes. Method: Purification of brimonidine loaded liposomes (model formulation) was performed by stirred cell ultrafiltration method, and its functional performance and impact on liposomal particle size, PDI, and entrapment efficiency were compared with two widely used laboratory scale methods, i.e., ultracentrifugation and centrifugal ultrafiltration. Results: The novel stirred cell ultrafiltration method demonstrated liposomal purification within ~30 min with complete liposomal recovery showing minimal processing impact, i.e., ˂0.25 fold rise in particle size, ~0.5 fold rise in PDI, and ~4% loss in % entrapment efficiency, respectively. Whereas ultracentrifugation and centrifugal ultrafiltration methods resulted in ~4 fold and ˃2 fold rise in particle size, ˃10 fold and ˃5 fold rise in PDI, and ˃25% and ~6% loss in entrapment efficiency, respectively. Conclusion: The unique and product-friendly operational features of stirred cell ultrafiltration method demonstrated simple, rapid, and efficient liposomal purification without affecting CQAs of liposomal vesicles. This method was also evidently found to be product-friendly, rugged, versatile, and scalable up to large production batch processing, overcoming major drawbacks of presently used methods.

Advanced nanoparticular approaches to combat Alzheimer's disease

: Alzheimer's disease (AD) is a neurological disease that affects many of the world's rapidly ageing population. In the etiology of Alzheimer’s disease (AD), the involvement of amyloid β (Aβ) plaque accumulation and oxidative stress in the brain have important roles. Various drugs have been proposed to prevent and treat AD, but delivering these therapeutic agents to the brain is difficult. Over the last decade, nanoparticle-mediated drug delivery represents one promising strategy to increase the CNS penetration of several therapeutic moieties successfully. Different nanocarriers are being investigated to treat and diagnose AD. NTDDS (nanotechnology-based drug delivery systems) can be used in various methods to improve patient compliance and treatment outcomes. However, literature analysis revealed that clinical activities such as NTDDS application in Alzheimer's disease research lag behind despite extensive research. This review gives an account of the BBB and discusses the literature on some drugs which are successfully encapsulated as nanoparticles for a future therapeutic approach. It also emphasizes the current clinical studies for Alzheimer's disease therapy.