Depiction of new flavonoids from Nyctanthus arbor-tristis, their antimicrobial activity and drug-likeness prediction.

Bioactive compounds derived from medicinal plants, such as alkaloids, tannins and flavonoids, possess significant medicinal properties. These compounds have a broad and versatile impact on human nutrition and physiology, contributing to the treatment and management of various diseases. The isolation, structure elucidation and inhibition studies of two novel flavonoids against specific microorganisms, from the leaves of Nyctanthus arbor-tristis are reported in this study. It has been observed for the first time that the presence of an acyl aliphatic moiety, along with the O- glycoside unit at C-7, and the hydroxyl group at C-5, C-4' position in apigenin significantly enhanced antimicrobial activity. Moreover, bioactivity was also investigated through 'Molinspiration' on various parameters followed by the 'rule of five'. This study can be used to highlight the need for the potential development of natural therapeutic products with fewer side effects.

Utilizing the allyl-terminated copolymer methoxy(poly(ethylene glycol))-block-poly(jasmine lactone) in the development of amorphous solid dispersions: A comparative study of functionalized and non-functionalized polymer.

Molecular interactions are crucial to stabilize amorphous drugs in amorphous solid dispersions (ASDs). Most polymers, however, have only a limited ability to form strong molecular interactions with drugs. Polymers tailored to fit the physicochemical properties of the drug molecule to be incorporated, for instance by allowing the incorporation of specific functional groups, would be highly sought-for in this regard. For this purpose, the novel allyl-terminated polymer methoxy(polyethylene glycol)-block-poly(jasmine lactone) (mPEG-b-PJL) has been synthesized and functionalized to potentially enhance specific drug-polymer interactions. This study investigated the use of mPEG-b-PJL in ASDs, using carvedilol (CAR), a weakly basic model drug. The findings revealed that the acidic functionalized form of the polymer (mPEG-b-PJL-COOH) indeed established stronger molecular interactions with CAR compared to its non-functionalized counterpart mPEG-b-PJL. Evaluations on polymer effectiveness in forming ASDs demonstrated that mPEG-b-PJL-COOH outperformed its non-functionalized counterpart in miscibility, drug loading ability, and stability, inferred from reduced molecular mobility. However, dissolution tests indicated that ASDs with mPEG-b-PJL-COOH did not significantly improve the dissolution behaviour compared to amorphous CAR alone, despite potential solubility enhancement through micelle formation. Overall, this study confirms the potential of functionalized polymers in ASD formulations, while the challenge of improving dissolution performance in these ASDs remains an area of further development.

Attenuation of celecoxib cardiac toxicity using Poly(δ-decalactone) based nanoemulsion via oral route.

Celecoxib (CLX), a poorly soluble anti-inflammatory drug, requires administration in higher concentrations to produce therapeutic effects, oftentimes resulting in cardiac toxicity. Therefore, in this study, we employed a nanoemulsion technology to improve the solubility of CLX using poly(δ-decalactone) (PDL) polymer as an oil and mPEG-b-PDL as a surfactant. The nanoemulsion (NE) was successfully prepared via the nanoprecipitation method. In vitro characterization was performed for size, drug release, and stability. In vivo studies were performed to establish anti-inflammatory activity, CLX induced cardiac toxicity, and pharmacokinetic profile of NE, post-oral administration. The globular size of less than 100 nm was obtained in NE with high CLX loading. The in vitro drug release studies suggested ∼90% of CLX release from NE within 96 h. A significant anti-inflammatory activity with lowered cardiac marker values was observed for CLX NE compared to a marketed drug formulation. The pharmacokinetic study revealed that the mean retention time of CLX was significantly increased with NE in contrast to the marketed formulation, suggesting the advantage of administering CLX in the form of NE owing to the higher solubility and sustained release pattern. The long-term storage stability study reveals that NE does not show significant changes in terms of size with only a slight decrement in CLX content was observed after 24 months. The obtained results indicate that CLX bioavailability has been considerably improved without being toxic to the heart with the aid of NE and advocate the use of PDL NE for developing oral formulations for poorly soluble drugs.

Lipid-Polymer Hybrid Nanosystems: A Rational Fusion for Advanced Therapeutic Delivery.

Lipid nanoparticles (LNPs) are spherical vesicles composed of ionizable lipids that are neutral at physiological pH. Despite their benefits, unmodified LNP drug delivery systems have substantial drawbacks, including a lack of targeted selectivity, a short blood circulation period, and in vivo instability. lipid-polymer hybrid nanoparticles (LPHNPs) are the next generation of nanoparticles, having the combined benefits of polymeric nanoparticles and liposomes. LPHNPs are being prepared from both natural and synthetic polymers with various techniques, including one- or two-step methods, emulsification solvent evaporation (ESE) method, and the nanoprecipitation method. Varieties of LPHNPs, including monolithic hybrid nanoparticles, core-shell nanoparticles, hollow core-shell nanoparticles, biomimetic lipid-polymer hybrid nanoparticles, and polymer-caged liposomes, have been investigated for various drug delivery applications. However, core-shell nanoparticles having a polymeric core surrounded by a highly biocompatible lipid shell are the most commonly explored LPHNPs for the treatment of various diseases. In this review, we will shed light on the composition, methods of preparation, classification, surface functionalization, release mechanism, advantages and disadvantages, patents, and clinical trials of LPHNPs, with an emphasis on core-shell-structured LPHNPs.

Functional block copolymer micelles based on poly (jasmine lactone) for improving the loading efficiency of weakly basic drugs.

Functionalization of polymers is an attractive approach to introduce specific molecular forces that can enhance drug-polymer interaction to achieve higher drug loading when used as drug delivery systems. The novel amphiphilic block copolymer of methoxy poly(ethylene glycol) and poly(jasmine lactone) i.e., mPEG-b-PJL, derived from renewable jasmine lactone provides free allyl groups on the backbone thus, allowing flexible and facile post-synthesis functionalization. In this study, mPEG-b-PJL and its carboxyl functionalized polymer mPEG-b-PJL-COOH were utilised to explore the effect of ionic interactions on the drug-polymer behaviour. Various drugs with different pK a values were employed to prepare drug-loaded polymeric micelles (PMs) of mPEG-b-PJL, mPEG-b-PJL-COOH and Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) via a nanoprecipitation method. Electrostatic interactions between the COOH pendant on mPEG-b-PJL-COOH and the basic drugs were shown to influence the entrapment efficiency. Additionally, molecular dynamics (MD) simulations were employed to understand the polymer-drug interactions at the molecular level and how polymer functionalization influenced these interactions. The release kinetics of the anti-cancer drug sunitinib from mPEG-b-PJL and mPEG-b-PJL-COOH was assessed, and it demonstrated a sustainable drug release pattern, which depended on both pH and temperature. Furthermore, the cytotoxicity of sunitinib-loaded micelles on cancer cells was evaluated. The drug-loaded micelles exhibited dose-dependent toxicity. Also, haemolysis capacity of these polymers was investigated. In summary, polymer functionalization seems a promising approach to overcome challenges that hinder the application of polymer-based drug delivery systems such as low drug loading degree.

Fundamental Aspects of Lipid-Based Excipients in Lipid-Based Product Development.

Poor aqueous solubility of drugs is still a foremost challenge in pharmaceutical product development. The use of lipids in designing formulations provides an opportunity to enhance the aqueous solubility and consequently bioavailability of drugs. Pre-dissolution of drugs in lipids, surfactants, or mixtures of lipid excipients and surfactants eliminate the dissolution/dissolving step, which is likely to be the rate-limiting factor for oral absorption of poorly water-soluble drugs. In this review, we exhaustively summarize the lipids excipients in relation to their classification, absorption mechanisms, and lipid-based product development. Methodologies utilized for the preparation of solid and semi-solid lipid formulations, applications, phase behaviour, and regulatory perspective of lipid excipients are discussed.

Evolution of Nanotechnology in Delivering Drugs to Eyes, Skin and Wounds via Topical Route.

The topical route is the most preferred one for administering drugs to eyes, skin and wounds for reaching enhanced efficacy and to improve patient compliance. Topical administration of drugs via conventional dosage forms such as solutions, creams and so forth to the eyes is associated with very low bioavailability (less than 5%) and hence, we cannot rely on these for delivering drugs to eyes more efficiently. An intravitreal injection is another popular drug delivery regime but is associated with complications like intravitreal hemorrhage, retinal detachment, endophthalmitis, and cataracts. The skin has a complex structure that serves as numerous physiological barriers to the entry of exogenous substances. Drug localization is an important aspect of some dermal diseases and requires directed delivery of the active substance to the diseased cells, which is challenging with current approaches. Existing therapies used for wound healing are costly, and they involve long-lasting treatments with 70% chance of recurrence of ulcers. Nanotechnology is a novel and highly potential technology for designing formulations that would improve the efficiency of delivering drugs via the topical route. This review involves a discussion about how nanotechnology-driven drug delivery systems have evolved, and their potential in overcoming the natural barriers for delivering drugs to eyes, skin and wounds.

Facile methodology of nanoemulsion preparation using oily polymer for the delivery of poorly soluble drugs.

Aqueous solubility of an active pharmaceutical ingredient (API) is a determining factor that has a direct impact on formulation strategies and overall bioavailability. Fabrication of nanoemulsions of poorly soluble drugs is one of the widely utilized approaches to overcome this problem. However, thermodynamic instability and tedious manufacturing processes of nanoemulsions limit their clinical translation. Therefore, this study was focused on circumventing the abovementioned hurdles by utilizing the polymer as an oil phase, instead of conventional oils. The nanoemulsion was prepared via a facile low-energy nanoprecipitation method using renewable poly(δ-decalactone) (PDL), as an oil phase and Pluronic F-68 as surfactant. The prepared nanoemulsions were characterized in terms of size, drug encapsulation efficiency, stability, and toxicity. Five different hydrophobic drugs were utilized to evaluate the drug delivery capability of the PDL nanoemulsion. The prepared nanoemulsions with sizes less than 200 nm were capable to enhance the aqueous solubility of the drugs by 3 to 10 times compared with the well-established Pluronic F-68 micelles. No phase separation or significant changes in size and drug content was observed with PDL nanoemulsions after high-speed centrifugation and 3 months of storage at two different temperatures (20 °C and 50 °C). PDL nanoemulsions were found to be non-heamolytic up to concentrations of 1 mg/mL, and the cell cytotoxicity studies on MDA-MB-231 and MEF cells suggest a concentration and time-dependent toxicity, where the PDL polymer itself induced no cytotoxicity. The results from this study clearly indicate that the PDL polymer has a tremendous potential to be utilized as an oil phase to prepare stable nanoemulsions via a facile methodology, ultimately favouring clinical translations. Graphical abstract TOC graphic.

Green Nanotechnology: Advancement in Phytoformulation Research.

The ultimate goal of any scientific development is to increase well-being and human health. Novel strategies are required for the achievement of safe and effective therapeutic treatments beyond the conventional ones, and society needs new requirements for new technologies, moving towards clean and green technology development. Green nanotechnology is a branch of green technology that utilizes the concepts of green chemistry and green engineering. It reduces the use of energy and fuel by using less material and renewable inputs wherever possible. Green nanotechnology, in phytoformulations, significantly contributes to environmental sustainability through the production of nanomaterials and nanoproducts, without causing harm to human health or the environment. The rationale behind the utilization of plants in nanoparticle formulations is that they are easily available and possess a broad variability of metabolites, such as vitamins, antioxidants, and nucleotides. For instance, gold (Au) nanoparticles have attracted substantial attention for their controllable size, shape, and surface properties. A variety of copper (Cu) and copper oxide (CuO) nanoparticles have also been synthesized from plant extracts. Titanium dioxide and zinc oxide nanoparticles are also important metal oxide nanomaterials that have been synthesized from a number of plant extracts. International and domestic laws, government and private-party programs, regulations and policies are being carefully reviewed and revised to increase their utility and nurture these nanoscale materials for commercialization. Inspiring debates and government initiatives are required to promote the sustainable use of nanoscale products. In this review, we will discuss the potential of the utilization of plant extracts in the advancement of nanotechnology.

Role of Polymers in 3D Printing Technology for Drug Delivery - An Overview.

BACKGROUND: 3D printing (3DP) is an emerging technique for fabrication of a variety of structures and complex geometries using 3D model data. In 1986, Charles Hull introduced stereolithography technique that took advances to beget new methods of 3D printing such as powder bed fusion, fused deposition modeling (FDM), inkjet printing, and contour crafting (CC). Being advantageous in terms of less waste, freedom of design and automation, 3DP has been evolved to minimize incurred cost for bulk production of customized products at the industrial outset. Due to these reasons, 3DP technology has acquired a significant position in pharmaceutical industries. Numerous polymers have been explored for manufacturing of 3DP based drug delivery systems for patient-customized medication with miniaturized dosage forms. METHOD: Published research articles on 3D printed based drug delivery have been thoroughly studied and the polymers used in those studies are summarized in this article. RESULTS: We have discussed the polymers utilized to fabricate 3DP systems including their processing considerations, and challenges in fabrication of high throughput 3DP based drug delivery systems. CONCLUSION: Despite several advantages of 3DP in drug delivery, there are still a few issues that need to be addressed such as lower mechanical properties and anisotropic behavior, which are obstacles to scale up the technology. Polymers as a building material certainly plays crucial role in the final property of the dosage form. It is an effort to bring an assemblage of critical aspects for scientists engaged in 3DP technology to create flexible, complex and personalized dosage forms.

Solid Lipid Nanoparticles: Emerging Colloidal Nano Drug Delivery Systems.

Solid lipid nanoparticles (SLNs) are nanocarriers developed as substitute colloidal drug delivery systems parallel to liposomes, lipid emulsions, polymeric nanoparticles, and so forth. Owing to their unique size dependent properties and ability to incorporate drugs, SLNs present an opportunity to build up new therapeutic prototypes for drug delivery and targeting. SLNs hold great potential for attaining the goal of targeted and controlled drug delivery, which currently draws the interest of researchers worldwide. The present review sheds light on different aspects of SLNs including fabrication and characterization techniques, formulation variables, routes of administration, surface modifications, toxicity, and biomedical applications.

Renewable poly(δ-decalactone) based block copolymer micelles as drug delivery vehicle: in vitro and in vivo evaluation.

Polymers from natural resources are attracting much attention in various fields including drug delivery as green alternatives to fossil fuel based polymers. In this quest, novel block copolymers based on renewable poly(δ-decalactone) (PDL) were evaluated for their drug delivery capabilities and compared with a fossil fuel based polymer i.e. methoxy-poly(ethylene glycol)-b-poly(ε-caprolactone) (mPEG-b-PCL). Using curcumin as a hydrophobic drug model, micelles of PDL block copolymers with different orientation i.e. AB (mPEG-b-PDL), ABA (PDL-b-PEG-b-PDL), ABC (mPEG-b-PDL-b-poly(pentadecalactone) and (mPEG-b-PCL) were prepared by nanoprecipitation method. The size, drug loading and curcumin stability studies results indicated that mPEG-b-PDL micelles was comparable to its counterpart mPEG-b-PCL micelles towards improved delivery of curcumin. Therefore, mixed micelles using these two copolymers were also evaluated to see any change in size, loading and drug release. Drug release studies proposed that sustained release can be obtained using poly(pentadecalactone) as crystalline core whereas rapid release can be achieved using amorphous PDL core. Further, mPEG-b-PDL micelles were found to be non-haemolytic, up to the concentration of 40 mg/mL. In vivo toxicity studies on rats advised low-toxic behaviour of these micelles up to 400 mg/kg dose, as evident by histopathological and biochemical analysis. In summary, it is anticipated that mPEG-b-PDL block copolymer micelles could serve as a renewable alternative for mPEG-b-PCL copolymers in drug delivery applications.

Synthesis, characterization and evaluation of in vitro toxicity in hepatocytes of linear polyesters with varied aromatic and aliphatic co-monomers.

Polyesters are extensively used in drug delivery because of their controllable biodegradation properties and perceived favorable cytocompatibility. However, new ester-based materials are continually being sought which can be produced from readily accessible monomers, which can be tuned for drug encapsulation and which retain good cellular compatibilities. In this study, 5 polyesters of similar molar mass were synthesized by reacting 1,10-decanediol with different ratios of succinic acid/phenylsuccinic acid and the effect of the phenyl side-chain group addition on polymer properties relevant to drug delivery was investigated. A polymer with a 70/30 ratio of succinic acid and phenylsuccinic acid was selected based on its ability to encapsulate a model dye in nanoparticle (NP) formulations, and was found to be slowly degradable in phosphate buffered saline (PBS) but more rapidly degraded in the presence of a lipase. The compatibility of NP formulations of this polymer either with or without a Pluronic F68 stabilizing coating was assessed in vitro using the C3A hepatocyte cell line. Cell viability was assessed, at NP concentrations ranging from 4.68-300µgmL-1 24h post-exposure, using the Alamar Blue, CDFA and Neutral Red assays. C3A cells internalized both coated and uncoated polyester NPs to a similar extent, with uptake observed to increase over time (10-1440min). Although cell viability was >80% at the concentrations tested, in all assays, it was found that a Pluronic F68 coated poly (decanediol-phenylsuccinate-co-succinate) stimulated significant DNA damage driven by an oxidant mechanism, whereas the non-coated polyester analogue and the Pluronic F68 alone had no effect. The results obtained suggest that new polyesters can be synthesized with desirable properties from the materials perspective but formulation with additional excipients requires careful evaluation for drug delivery applications.

Amphiphilic block copolymers from a renewable ε-decalactone monomer: prediction and characterization of micellar core effects on drug encapsulation and release.

Here we describe a methoxy poly(ethyleneglycol)-b-poly(ε-decalactone) (mPEG-b-PεDL) copolymer and investigate the potential of the copolymer as a vehicle for solubilisation and sustained release of indomethacin (IND). The indomethacin loading and release from mPEG-b-PεDL micelles (amorphous cores) was compared against methoxy poly(ethyleneglycol)-b-poly(ε-caprolactone)(mPEG-b-PCL) micelles (semicrystalline cores). The drug-polymer compatibility was determined through a theoretical approach to predict drug incorporation into hydrated micelles. Polymer micelles were prepared by solvent evaporation and characterised for size, morphology, indomethacin loading and release. All the formulations generated spherical micelles but significantly larger mPEG-b-PεDL micelles were observed compared to mPEG-b-PCL micelles. A higher compatibility of the drug was predicted for PCL cores based on Flory-Huggins interaction parameters (χsp) using the Hansen solubility parameter (HSP) approach, but higher measured drug loadings were found in micelles with PεDL cores compared to PCL cores. This we attribute to the higher amorphous content in the PεDL-rich regions which generated higher micellar core volumes. Drug release studies showed that the semicrystalline PCL core was able to release IND over a longer period (80% drug release in 110 h) compared to PεDL core micelles (80% drug release in 72 h).

Development and characterization of triazine based dendrimers for delivery of antitumor agent.

In the present study we developed the novel kind of triazine dendrimers by utilizing differential reactivity of the cyanuric chloride (triazine trichloride) which overcome the limitations associated with the others classes of dendrimers like toxicity, low yield, high synthesis cost etc. Triazine dendrimers were synthesized by divergent method using triazine trichloride as core and diethanolamine as branching unit to avoid the use of protecting group and functional group interconversion up to third generation. These hydroxyl terminated dendrimers were characterized by FTIR, 1HNMR, 13CNMR, ES mass spectroscopy, and by elemental analysis. The yield of pure G3 dendrimers was 63%. This novel dendrimers increases the aqueous solubility of hydrophobic drug Paclitaxel up to 0.562 mg/ml as well as showed control release behavior. Hemolytic and toxicology studies of this dendrimer in mice showed no adverse toxicity to the kidneys and the liver up to 200 mg/kg dose (i.p). Triazine being a hydrophobic compound, the core of this dendrimer is hydrophobic and supposed to easily incorporate the hydrophobic guest while presence of hydroxyl group on periphery increases its water solubility and reduces its toxicity; and thus it is useful in various fields like gene delivery, MRI contrasting agents, vaccines or as solubilization tool.