Quality-by-Design Based Development of Doxycycline Hyclate-Loaded Polymeric Microspheres for Prolonged Drug Release.

This study explores a novel approach to address the challenges of delivering highly water-soluble drug molecules by employing hydrophobic ion-pairing (HIP) complexes within poly (lactic-co-glycolic acid) (PLGA) microspheres. The HIP complex, formed between doxycycline hyclate (DH) and docusate sodium (DS), renders the drug hydrophobic. The development of the microspheres was done using the QbD approach, namely, Box-Behnken Design (BBD). A comprehensive characterization of the HIP complex confirmed the successful conversion of DH. DH and the HIP complex were effectively loaded into PLGA microspheres using the oil-in-water (O/W) emulsion solvent evaporation method. Results demonstrated significant improvements in percentage entrapment efficiency (% EE) and drug loading (% DL) for DH within the HIP complex-loaded PLGA microspheres compared to DH-loaded microspheres alone. Additionally, the initial burst release of DH reduced to 3% within the initial 15 min, followed by sustained drug release over 8 days. The modified HIP complex strategy offers a promising platform for improving the delivery of highly water-soluble small molecules. It provides high % EE, % DL, minimal initial burst release, and sustained release, thus having the potential to enhance patient compliance and drug delivery efficiency.

Evaluation of Pharmacokinetics, Biodistribution, and Antimalarial Efficacy of Artemether-Loaded Polymeric Nanorods.

Artemether oily injection is recommended for the treatment of severe malaria by the intramuscular route. The major limitations of the artemisinin combination therapy are erratic absorption from the injection site and high dosing frequency due to a very short elimination half-life of the drug. Advanced drug delivery systems have shown significant improvement in the current malaria therapy; the desired drug concentration within infected erythrocytes is yet the major challenge. Recently, we have reported the fabrication of artemether-loaded polymeric nanorods for intravenous malaria therapy which was found to be biocompatible with THP-1 monocytes and rat erythrocytes. The objective of the present study was the evaluation of pharmacokinetics, biodistribution, and antimalarial efficacy of artemether-loaded polymeric nanorods. Scanning electron microscopy and confocal microscopy studies revealed that both nanospheres and nanorods were adsorbed onto the surface of rat erythrocytes after an incubation of 10 min. After intravenous administration to rats, artemether nanorods showed higher plasma concentration and lower elimination rate of artemether when compared with nanospheres. The biodistribution studies showed that, at 30 min, the liver concentration of DiR-loaded nanospheres was higher than that of DiR-loaded nanorods after intravenous administration to BALB/c mice. The in vitro schizont inhibition study showed that both nanorods and nanospheres exhibited concentration-dependent parasitic inhibition, wherein at lower concentrations (2 ppm), nanorods were more effective than nanospheres. However, at higher concentrations, nanospheres were found to be more effective. Nanorods showed higher chemosuppression on day 5 and day 7 than nanospheres and free artemether when studied with the Plasmodium berghei mouse model. Moreover, the survival rate of P. berghei infected mice was also found to be higher after treatment with artemether nanoformulations when compared with free artemether. In conclusion, polymeric nanorods could be a promising next-generation delivery system for the treatment of malaria.

Topical Nanotherapeutics for Treating MRSA-Associated Skin and Soft Tissue Infection (SSTIs).

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) imposes a major challenge for the treatment of infectious diseases with existing antibiotics. MRSA associated with superficial skin and soft tissue infections (SSTIs) is one of them, affecting the skin's superficial layers, and it includes impetigo, folliculitis, cellulitis, furuncles, abscesses, surgical site infections, etc. The efficient care of superficial SSTIs caused by MRSA necessitates local administration of antibiotics, because oral antibiotics does not produce the required concentration at the local site. The topical administration of nanocarriers has been emerging in the area of drug delivery due to its advantages over conventional topical formulation. It enhances the solubility and permeation of the antibiotics into deeper layer of the skin. Apart from this, antibiotic resistance is something that needs to be combated on multiple fronts, and antibiotics encapsulated in nanocarriers help to do so by increasing the therapeutic efficacy in a number of different ways. The current review provides an overview of the resistance mechanism in S. aureus as well as various nanocarriers reported for the effective management of MRSA-associated superficial SSTIs.

Long-Acting Efavirenz and HIV-1 Fusion Inhibitor Peptide Co-loaded Polymer-Lipid Hybrid Nanoparticles: Statistical Optimization, Cellular Uptake, and In Vivo Biodistribution.

The objective of the present study was to develop long-acting efavirenz (Efa)-enfuvirtide (Enf) Co-loaded polymer-lipid hybrid nanoparticles (PLN) with improved intracellular delivery to target T-cells and macrophage cells located in multiple human immunodeficiency virus sanctuaries. The Box-Behnken design was utilized to optimize three high-risk factors, namely, Efa amount, sonication time for primary emulsion, and sonication time for aqueous nanodispersion obtained from preliminary studies. Lyophilized Efa-Enf Co-loaded PLN using trehalose elicited spherical morphology, drug amorphization on incorporation, and absence of drug-excipient interaction. In vitro release studies revealed an sustained release of both the drugs from PLN with the differential release profile. Efa-Enf Co-loaded PLN exhibited low hemolytic, platelet and leukocyte aggregation as well as low cytotoxicity in Jurkat E6.1 T-cells and U937 macrophage cells. Circular dichroism spectra confirmed the presence of an α-helix form of Enf after encapsulation in PLN. Coumarin-6-loaded PLN exhibited enhanced cellular uptake in Jurkat E6.1 T-cells and U937 macrophage cells in comparison to free coumarin-6, as evidenced by fluorescence microscopy and flow cytometry. In vivo biodistribution studies after intravenous administration of near-infrared dye-loaded PLN (surrogate for Efa-Enf PLN) revealed non-uniform distribution within 2 h in the order of spleen ≥ liver > lymph node > thymus > lungs > female reproductive tract (FRT) > heart > kidneys > brain. However, subcutaneous administration caused non-uniform biodistribution after 3 days, eliciting a long-acting slow release from the injection site depot until day 5 in the infection-spread site (lymph nodes and FRT), reservoir sites (liver and spleen) and the difficult-to-access site (brain). Furthermore, it presents a vital illustration of the available tissue-specific drug concentration prediction from simulated surrogate PLN.

Long-term antitrypanosomal effect of quinapyramine sulphate-loaded oil-based nanosuspension in T. evansi-infected mouse model.

The goal of the present work consisted of the formulation development and evaluation of quinapyramine sulphate (QS)-loaded long-acting oil-based nanosuspension for improved antitrypanosomal effect. QS was transformed into a hydrophobic ionic complex using anionic sodium cholate (Na.C). The complex was characterized by FTIR, DSC, and XRD. Oil-based nanosuspension was prepared by dispersing the QS-Na.C complex in thixotropically thickened olive oil. The nanoformulation was found to be cytocompatible (82.5 ± 5.87% cell viability at the minimum effective concentration [MEC]) in THP-1 cell lines and selectively trypanotoxic (p < 0.0001). The pharmacokinetic studies of QS-Na.C complex-loaded oily nanosuspension showed 13.54-fold, 7.09-fold, 1.78-fold, and 17.35-fold increases in t1/2, AUC0-∞, Vz/F, and MRT0-ꝏ, respectively, as compared to free QS. Moreover, a 7.08-fold reduction in plasma clearance was observed after the treatment with the optimized formulation in Wistar rats. Furthermore, treatment with QS-Na.C complex-loaded oily nanosuspension (7.5 mg/kg) in T. evansi-infected mice model showed the absence of parasitaemia for more than 75 days after the treatment during in vivo efficacy studies. The efficacy of the treatment was assessed by observation of blood smear and PCR assay for DNA amplification. To conclude, our findings suggest that the efficient delivery of QS from the developed QS-Na.C complex-loaded oily nanosuspension could be a promising treatment option for veterinary infections against trypanosomiasis.

Recent innovations in topical delivery for management of rheumatoid arthritis: A focus on combination drug delivery.

Rheumatoid arthritis (RA) is an immune-mediated disease that necessitates a thorough understanding of its intricate pathophysiological mechanism for precise and effective therapeutic targeting. The European League Against Rheumatism (EULAR) has established guidelines for RA treatment, endorsing monotherapy or combination therapy with corticosteroids and synthetic disease-modifying antirheumatic drugs (sDMARDs). This review delves into clinical trials and research outcomes related to combination drug delivery, with an emphasis on the role of natural products in combination with synthetic drugs. Given the significant adverse effects associated with systemic administration, topical delivery has emerged as an alternative avenue for effective management of RA.

Precise Fabrication of Ocular Inserts Using an Innovative Laser-Driven CaliCut Technology: In Vitro and in Vivo Evaluation.

Ocular inserts offer distinct advantages, including a preservative-free drug delivery system, the ability to provide tailored drug release, and ease of administration. The present research paper delves into the development of an innovative ocular insert using CaliCut technology. Complementing the hot melt extrusion (HME) process, CaliCut, an advanced technology in ocular insert development, employs precision laser gauging to achieve impeccable cutting of inserts with desired dimensions. Its intelligent control over the stretching process through auto feedback-based belt speed adjustment ensures unparalleled accuracy and consistency in dosage form manufacturing. Dry eye disease (DED) poses a significant challenge to ocular health, necessitating innovative approaches to alleviate its symptoms. In this pursuit, castor oil has emerged as a promising therapeutic agent, offering beneficial effects by increasing the thickness of the lipid layer in the tear film, thus improving tear film stability, and reducing tear evaporation. To harness these advantages, this study focuses on the development and comprehensive characterization of castor oil-based ocular inserts. Additionally, in-vivo irritancy evaluation in rabbits has been undertaken to assess the inserts' safety and biocompatibility. By harnessing the HME and CaliCut techniques in the formulation process, the study demonstrates their instrumental role in facilitating the successful development of ocular inserts.

Nanocarrier based active targeting strategies against erythrocytic stage of malaria.

The Global Technical Strategy for Malaria 2016-2030 aims to achieve a 90% reduction in malaria cases, and strategic planning and execution are crucial for accomplishing this target. This review aims to understand the complex interaction between erythrocytic receptors and parasites and to use this knowledge to actively target the erythrocytic stage of malaria. The review provides insight into the malaria life cycle, which involves various receptors such as glycophorin A, B, C, and D (GPA/B/C/D), complement receptor 1, basigin, semaphorin 7a, Band 3/ GPA, Kx, and heparan sulfate proteoglycan for parasite cellular binding and ingress in the erythrocytic and exo-erythrocytic stages. Synthetic peptides mimicking P. falciparum receptor binding ligands, human serum albumin, chondroitin sulfate, synthetic polymers, and lipids have been utilized as ligands and decorated onto nanocarriers for specific targeting to parasite-infected erythrocytes. The need of the hour for treatment and prophylaxis against malaria is a broadened horizon that includes multiple targeting strategies against the entry, proliferation, and transmission stages of the parasite. Platform technologies with established pre-clinical safety and efficacy should be translated into clinical evaluation and formulation scale-up. Future development should be directed towards nanovaccines as proactive tools against malaria infection.

Long-acting parenteral drug delivery systems for the treatment of chronic diseases.

The management of chronic conditions often requires patients to take daily medication for an extended duration. However, the need for daily dosing can lead to nonadherence to the therapy, which can result in the recurrence of the disease. Long-acting parenteral drug delivery systems have the potential to improve the treatment of chronic conditions. These systems use various technologies, such as oil-based injectables, PLGA-based microspheres, and in situ forming gel-based depots, to deliver different types of drugs. The use of long-acting parenteral formulations for the treatment of chronic infections such as HIV/AIDS and tuberculosis is a recent development in the field. Researchers are also exploring the use of long-acting parenteral formulations for the treatment of malaria, with the aim of reducing dosing frequency and improving adherence to treatment. This review discusses various aspects of long-acting formulation development, including the impact of the physicochemical properties of the drug, the type of long-acting formulation, and the route of administration. The clinical significance of long-acting formulations and recent advances in the field, such as long-acting nanoformulations and long-acting products currently in clinical trials, have also been highlighted.

Recent Advances in Teriparatide Delivery by-virtue-of Novel Drug Delivery Approaches for the Management of Osteoporosis.

Osteoporosis is a bone incapacitating malady which globally accounts for over hundred million fractures annually. Therapeutic interventions for management of osteoporosis are divided as antiresorptive agents and osteoanabolic agents. Teriparatide is the only osteoana-bolic peptide which is available world-wide for the treatment of osteoporosis. It is administered as a daily subcutaneous injection for the treatment of osteoporosis which results in both poor patient compliance and increase in the cost of the therapy. Even after 20 years of clinical use of teriparatide, no formulation of teriparatide has yet been translated from lab to clinic which can be delivered by non-invasive route The present review critically discusses attempts made by the researchers for efficient delivery of teriparatide through various non-invasive routes such as oral, nasal, pulmonary, and transdermal route. It also discusses long-acting injectable formulations of teriparatide to improve patient compliance. Understanding on the pharmacology of teriparatide highlights the enhanced effectiveness of intermittent/pulsatile mode of teriparatide delivery which has also been elaborated. In addition, targeted delivery of teriparatide using different bone specific targeting moieties has been also discussed.

Bugs as Drugs: Understanding the Linkage between Gut Microbiota and Cancer Treatment.

The commensal microbiota is known to regulate host physiology. Dysbiosis or compromised resilience in the microbial ecology is related to the impending risk of cancer. A potential link between cancer and microbiota is indicated by a lot of evidence. The current review explores in detail the various links leading to and /or facilitating oncogenesis, providing sound reasoning or a basis for its utilization as potential therapeutic targets. The present review emphasizes the existing knowledge of the microbiome in cancer and further elaborates on the factors, like genetic modifications, effects of dietary components, and environmental agents, that are considered to assess the direct and indirect effect of microbes in the process of oncogenesis and on the host's health. Strategies modulating the microbiome and novel biotherapeutics are also discussed. Pharmacomicrobiomics is one such niche accounting for the interplay between the microbiome, xenobiotic, and host responses, which is also looked upon. The literature search strategy for this review was conducted by following the methodology of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). The method includes the collection of data from different search engines, like PubMed, ScienceDirect, SciFinder, etc., to get coverage of relevant literature for accumulating appropriate information regarding microbiome, cancer, and their linkages. These considerations are made to expand the existing literature on the role of gut microbiota in the host's health, the interaction between host and microbiota, and the reciprocal relationship between the microbiome and modified neoplastic cells. Potential therapeutic implications of cancer microbiomes that are yet unexplored and have rich therapeutic dividends improving human health are discussed in detail in this review.

Recent Progress in Hot Melt Extrusion Technology in Pharmaceutical Dosage Form Design.

BACKGROUND: The Hot Melt Extrusion (HME) technique has shown tremendous potential in transforming highly hydrophobic crystalline drug substances into amorphous solids without using solvents. This review explores in detail the general considerations involved in the process of HME, its applications and advances. OBJECTIVE: The present review examines the physicochemical properties of polymers pertinent to the HME process. Theoretical approaches for the screening of polymers are highlighted as a part of successful HME processed drug products. The critical quality attributes associated with the process of HME are also discussed in this review. HME plays a significant role in the dosage form design, and the same has been mentioned with suitable examples. The role of HME in developing several sustained release formulations, films, and implants is described along with the research carried out in a similar domain. METHODS: The method includes the collection of data from different search engines like PubMed, ScienceDirect, and SciFinder to get coverage of relevant literature for accumulating appropriate information regarding HME, its importance in pharmaceutical product development, and advanced applications. RESULTS: HME is known to have advanced pharmaceutical applications in the domains related to 3D printing, nanotechnology, and PAT technology. HME-based technologies explored using Design-of- Experiments also lead to the systematic development of pharmaceutical formulations. CONCLUSION: HME remains an adaptable and differentiated technique for overall formulation development.

Fabrication and evaluation of artemether loaded polymeric nanorods obtained by mechanical stretching of nanospheres.

The objective of the present study was to prepare and evaluate artemether-loaded poly (lactic-co-glycolic acid) (PLGA) nanorods by mechanical stretching of nanospheres. Artemether-loaded PLGA nanospheres were prepared by the standard nanoprecipitation method. To prepare the nanorods, nanospheres (129 nm) were embedded in polyvinyl alcohol film. The film was stretched by using an in-house fabricated film stretching apparatus in one dimension at the rate of 10 mm/min in acetone or silicon oil. Nanorods were recovered by dissolving the film in Milli-Q-water after stretching. The effect of film thickness (100 µm vs 150 µm), the ratio of lactide to glycolide in PLGA (50:50 vs 75:25), extent of stretching (2x vs 4x), on the aspect ratio of the nanorods was studied. A sustained release of artemether was observed from both nanospheres and nanorods with almost 85% drug release at the end of 72 h. In cytotoxicity study, almost 90% cell viability was found when THP-1 cells were treated with artemether, nanospheres, and nanorods equivalent to 0.001 to 100 µg/mL of artemether. At all the concentrations of artemether, nanorods showed less haemolysis of RBCs than the nanospheres. Artemether-loaded PLGA nanorods could be successfully prepared by the film stretching method for intravenous delivery of antimalarial drugs.

Development of cationic Isometamidium chloride loaded long-acting lipid nanoformulation: optimization, cellular uptake, pharmacokinetics, biodistribution, and immunohistochemical evaluation.

The aim of the present work involved the development and evaluation of long-acting Isometamidium chloride (ISMM)-Docusate sodium (DS) complex loaded lipid nanoparticles (LA ISMM-DS LNP). The development involved screening various anionic complexing agents, including DS, dextran sulphate, and sodium alginate. Anionic DS was selected to synthesize hydrophobic ionic complex (ISMM-DS HIC), which was loaded into lipid nanoparticles (LA ISMM-DS LNP) by in situ complexation followed by the solvent evaporation method. 35-5-folds increase in the drug loading of hydrophilic cationic ISMM within nanoparticles was observed due to ISMM-DS HIC. The LA ISMM-DS LNP were non-hemolytic (0-2.52%), cytocompatible (80.6-47.5% cell viability), and enhanced THP-1 cellular uptake (2.3-folds higher) compared with free ISMM. The LA ISMM-DS LNP engender protracted in vivo plasma drug concentration for seven days with enhanced AUC0-ꝏ, MRT0-ꝏ, and t1/2, along with reduced Cl compared with free ISMM. Interestingly, the amount of ISMM was 2.9-, 4.2- and 2.0-folds higher in target reticuloendothelial (RES) organs like liver (Kupffer cells), spleen (spleenotropic macrophages and 15% T-lymphocytes), and lymph nodes (75% T-lymphocytes), respectively in LA ISMM-DS LNP group compared with free ISMM. Furthermore, LA ISMM-DS LNP caused higher peripheral blood mononuclear cells (PBMC) infiltration with diminished toxicity and inflammation. Therefore, the in vitro and in vivo studies predicted enhanced safety and efficacy of LA ISMM-DS LNP compared with free ISMM. To conclude, successfully developed LA ISMM-DS LNP would elicit a tremendous clinical potential for treatment and prevention against trypanosomiasis.

Preparation and Evaluation of Quinapyramine Sulphate-Docusate Sodium Ionic Complex Loaded Lipidic Nanoparticles and Its Scale Up Using Geometric Similarity Principle.

The objective of the present work is to prepare and evaluate ionically complexed Quinapyramine sulphate (QS) loaded lipid nanoparticles and its scale up using geometric similarity principle. Docusate sodium (DS), at a molar ratio of 1:2 of QS to DS, was used to prepare hydrophobic Quinapyramine sulphate-Docusate sodium (QS-DS) ionic complex. Based on the difference in total solubility parameter and polarity of QS-DS complex and different lipids, precirol was selected as a lipid for the preparation of lipidic nanoparticles. The particle size, zeta potential, and % entrapment efficiency (%EE) of QS-DS ionic complex loaded solid lipid nanoparticles (QS-DS-SLN) was found to be 250.10 ± 26.04 nm, -27.41 ± 4.18 mV and 81.26 ± 4.67% respectively. FTIR studies confirmed the formation of QS-DS ionic complex. DSC and XRD studies revealed the amorphous nature of QS in QS-DS-SLN. The spherical shape of nanoparticles was confirmed by scanning electron microscopy. QS-DS-SLN showed sustained release of QS for up to 60 h. No significant difference was observed in particle size, zeta potential, and % entrapment efficiency of pilot-scale batch prepared by using rotational speed of 700 rpm. In conclusion, ionic complexation approach can be used to increase % EE of charged drugs into lipid nanoparticles.

Recent advances in long-acting nanoformulations for delivery of antiretroviral drugs.

In spite of introduction of combination antiretroviral therapy (cART) against human immunodeficiency virus (HIV) infection; inaccessibility and poor adherence to oral cART costs 10 in 100,000 death worldwide. Failure in adherence leads to viral rebound, emergence of drug resistance and anticipated HIV infection in high risk individuals. Various Long-acting antiretroviral (LA ARV) nanoformulations including nano-prodrug, solid drug nanoparticles (SDN), nanocrystals, aspherical nanoparticles, polymeric and lipidic nanoparticles have shown plasma/tissue drug concentration in the therapeutic range for several weeks during pre-clinical evaluation. LA ARV nanoformulations therefore have replaced cART as better alternative for the treatment of HIV infection. Cabenuva™ is recently approved by Health Canada containing LA cabotegravir+LA rilpivirine nanocrystals (ViiV healthcare) for once monthly administration by intramuscular route. The LA nanoformulation due to its nanosize insist on better stability, delivery to lymphatic, slow release into systemic circulation via lymphatic-circulatory system conjoint and secondary drug depot within infiltered immune cells at site of administration and systemic circulation in contrast to conventional drugs. However, the pharmacokinetic, biodistribution and efficacy of LA nanoformulations hinge onto physicochemical properties of the drugs and route of administration. Therefore, current review emphasizes on these contradistinctive factors that affects the reproducibility, safety, efficacy and toxicity of LA anti-HIV nanoformulations. Moreover, it expatiates on application of profuse nanoformulations for long-acting effect with promising preclinical discoveries and two clinical leads. To add on, utilization of physiology-based and mechanism-based pharmacokinetic modelling and in vivo animal models which could lead to enhanced safety and efficacy of LA ARV nanoformulations in humans have been included.

Nanotechnological interventions for treatment of trypanosomiasis in humans and animals.

Trypanosomiasis is a parasitic infection caused by Trypanosoma. It is one of the major causes of deaths in underprivileged, rural areas of Africa, America and Asia. Depending on the parasite species responsible for the disease, it can take two forms namely African trypanosomiasis (sleeping sickness) and American trypanosomiasis (Chagas disease). The complete life-cycle stages of trypanosomes span between insect vector (tsetse fly, triatomine bug) and mammalian host (humans, animals). Only few drugs have been approved for the treatment of trypanosomiasis. Moreover, current trypanocidal therapy has major limitations of poor efficacy, serious side effects and drug resistance. Due to the lack of economic gains from tropical parasitic infection, it has always been neglected by the researchers and drug manufacturers. There is an immense need of more effective innovative strategies to decrease the deaths associated with this diseases. Nanotechnological approaches for delivery of existing drugs have shown significant improvement in efficacy with many-fold decrease in their dose. The review emphasizes on nanotechnological interventions in the treatment of trypanosomiasis in both humans and animals. Current trypanocidal therapy and their limitations have also been discussed briefly. Graphical abstract.

Development and validation of reverse-phase high-performance liquid chromatographic (RP-HPLC) method for quantification of Efavirenz in Efavirenz-Enfuvirtide co-loaded polymer-lipid hybrid nanoparticles.

The objective of present work was to develop rapid, sensitive, selective, accurate and precise RP-HPLC method for analysis of Efavirenz from combination anti-HIV drug (Efavirenz-Enfuvirtide) incorporated into polymer-lipid hybrid nanoparticles (PLN). Chromatographic separation of Efavirenz was performed on Waters Spherisorb® 5 µm ODS (C18) column (4.6 x 250 mm) with acetonitrile and 10 mM phosphate buffer pH 6.8 (70:30, v/v) as mobile phase. The UV detection wavelength was 246 nm. The method was found to be linear between the concentration range of 500-20000 ng/ml with 160 ng/ml and 480 ng/ml as limit of detection and limit of quantitation respectively. Heteroscedasticity of calibration curve responses was minimized using weighted least square regression analysis. The method was found to be specific for analysis of Efavirenz in presence of Enfuvirtide (a fusion inhibitor peptide), formulation excipients and release media, accurate (average recovery rate: 99.9 ±â€¯9.39%) and precise (%RSD < 2%). The validated RP-HPLC method could be effectively utilized to determine % entrapment efficiency (%EE), % drug loading (%DL), % cumulative drug release and drug content of Efavirenz from Efavirenz-Enfuvirtide co-loaded PLN.