Antisolvent Precipitation Technique Research Articles

Enhanced Anti-Inflammatory Activity of Tilianin Based on the Novel Amorphous Nanocrystals

Tilianin (Til), a flavonoid glycoside, is well-known for its therapeutic promise in treating inflammatory disorders. Its poor water solubility and permeability limit its clinical applicability. In order to overcome these restrictions, an antisolvent precipitation and ultrasonication technique was used to prepare amorphous tilianin nanocrystals (Til NCs). We have adjusted the organic solvents, oil-to-water ratio, stabilizer composition, and ultrasonic power and time by combining single-factor and central composite design (CCD) methodologies. The features of Til NCs were characterized using powder X-ray diffraction (PXRD), scanning calorimetry (DSC), and transmission electron microscopy (TEM). Specifically, the optimized Til NCs were needle-like with a particle size ranging from 90 to 130 nm. PVA (0.3%, w/v) and TPGS (0.08%, w/v) stabilized them well. For at least two months, these Til NCs stayed amorphous and showed an impressive stability at 4 °C and 25 °C. Remarkably, Til NCs dissolved almost 20 times faster in simulated intestinal fluid (SIF) than they did in crude Til. In RAW264.7 cells, Til NCs also showed a better cellular absorption as well as safety and protective qualities. Til NCs were shown to drastically lower reactive oxygen species (ROS), TNF-α, IL-1β, and IL-6 in anti-inflammatory experiments, while increasing IL-10 levels and encouraging M1 macrophages to adopt the anti-inflammatory M2 phenotype. Our results highlight the potential of amorphous Til NCs as a viable approach to improve Til’s anti-inflammatory effectiveness, solubility, and dissolving rate.

Preparation and in Vitro Characterization of Fatty-Acid Modified Pirarubicin Nanosuspensions Stabilized by Albumin.

Pirarubicin (THP) shows more rapid intracellular uptake, more effective antitumor activity, and less cardiac toxicity, compared to doxorubicin. However, THP is distributed to both tumor and normal tissues indiscriminately. This study aimed to develop a nanosuspension to deliver THP to tumor tissues more efficiently. Fatty-acid-modified THPs (FA-THPs; octanoic acid, dodecanoic acid, palmitic acid-THPs) were synthesized to increase the hydrophobicity of THP. Nanosuspensions of these FA-THPs were then prepared using an antisolvent precipitation technique. Among the FA-THPs, the most efficiently drug-loaded nanosuspension was obtained from palmitic acid-THP (pal-THP) using an aqueous antisolvent containing bovine serum albumin as a stabilizer. The pal-THP nanoparticles in the nanosuspension were confirmed to be of optimal size (100-125 nm) for delivery to tumor tissues using dynamic light scattering and transmission electron microscopy. The pal-THP nanosuspension showed cytotoxicity in colon 26 cells. The nanosuspension was shown to disintegrate in the presence of surfactants such as lecithin, liberating pal-THP, which was converted to free THP in acidic media. It is therefore proposed that pal-THP nanoparticles that reach tumor cells after intravenous administration would exert antitumor effect by liberating pal-THP (i.e., disintegration of nanoparticles by the interaction with cell membrane), followed by the release of free THP in the acidic milieu of tumor cells. These findings indicate that FA-THP nanosuspensions, particularly pal-THP nanosuspension, hold promise as a candidate for cancer treatment. However, further in vivo studies are necessary.

Nanocrystals loaded collagen/alginate-based injectable hydrogels: A promising biomaterial for bioavailability improvement of hydrophobic drugs

The study aims to improve the solubility of poorly soluble drug by developing an optimized formulation of nanocrystals and extend its release profile by incorporating optimized nanocrystals in a biopolymer based injectable hydrogel. Nanocrystals of Silymarin (SM) were developed by anti-solvent precipitation technique followed by homogenization. Various stabilizers were investigated and combination of polyvinyl pyrrolidine K30 (PVP K30) and sodium lauryl sulfate (SLS) in a specific ratio was chosen as a stabilizer for nanocrystals. The optimized nanocrystals possessed mean particle size 172 ± 5.23 nm and PDI of 0.228 ± 0.02. Sodium alginate (Alg) and collagen (Col) based injectable hydrogel in combination with pluronic F127 showed good biocompatibility, mechanical strength and biodegradability. The developed formulation was characterized by scanning electron microscopy (SEM), thermogravimetric analysis (TGA), Fourier transform infra-red spectroscopy (FT-IR) and X-ray diffraction (XRD) analysis. The results of FT-IR and TGA showed structural cross-linking between polymers and promising thermal stability of formulation with increasing temperature, respectively. The nanocrystals loaded Alg-Col-F127 injectable hydrogel was degraded completely in 48 h. The results of in vitro release studies and in vivo pharmacokinetic profiling of silymarin nanocrystals laden Alg-Col-F127 injectable hydrogel exhibited controlled release behavior as compared to coarse silymarin suspension and silymarin nanocrystals. Therefore, nanosuspension integrated biopolymer-based hybrid injectable hydrogel system may be used to assist solubility and bioavailability enhancement as well as serve as platform to provide controlled drug release.

Effect of Betulin Colloidal Particles on Proliferation and Cytokine Secretion of Human Skin Fibroblasts.

The aim of the study was to obtain untreated and treated betulin colloidal particles and assess their effect on the viability, morphology, proliferation and cytokine secretion of human dermal fibroblasts. To improve bioavailability, betulin treatment was performed by an antisolvent precipitation technique. The average particle size after treatment in the aqueous dispersion decreased from 552.9 ± 11.3 to 278.2 ± 1.6 nm. Treated betulin colloidal particles showed no cytotoxicity up to a concentration of 400 µg·mL-1 in the colorimetric tetrazolium salt viability test (CCK-8). Moreover, the cell morphology was not changed in the presence of betulin colloidal particles at a concentration range from 0.78 to 400 µg·mL-1. The obtained results also show that betulin particles induce the secretion of the proinflammatory and angiogenesis-stimulating cytokine IL-8. However, further studies would be required to clarify the mechanism of IL-8 secretion induction.

Exploring the synergistic behavior of paclitaxel and vorinostat upon co-loading in albumin nanoparticles for breast cancer management.

Breast cancer is challenging to treat accompanied with poor clinical outcomes. Paclitaxel (PTX) is a first-line chemotherapeutic agent, but possesses limitations due to side effects, high dose, non-specific tissue distribution, and drug resistance. An epigenetic modulator, vorinostat (VOR) is known to enhance PTX efficacy and therefore to resolve the issues of conventional PTX formulations, we designed PTX- and VOR-bound albumin nanoparticles (PTX-VOR-BSA-NPs) using antisolvent precipitation technique where albumin is used as a carrier and a targeting agent. The PTX-VOR-BSA-NPs were of 140nm size, polydispersity index around 0.18, and about 78% and 68% of entrapment efficiency for PTX and VOR, respectively. A bi-pattern release of both PTX and VOR was observed from PTX-VOR-BSA-NPs with a burst release for 2h succeeded by sustained release until 24h. A significantly lower %cell viability was observed in MCF-7 cell lines, while efficient cellular drug uptake was found in MDA-MB-231 cells. Furthermore, a greater apoptotic index was found compared to free PTX and VOR because of the synergistic activity of these drugs. The PTX-VOR-BSA-NPs also showcased superior pharmacokinetic profile and noteworthy reduction in the tumor volume compared to Intaxel in 4T1 cell line-induced breast tumor model. Further, the NPs showed similar levels of toxicity biomarkers as that of control. Overall, the developed PTX-VOR-BSA-NPs were found to have less toxicity and more effectiveness compared to the marketed formulation, thus affirming the generation of a potent as well as and safe product.

Development of Nanosuspension of Artemisia absinthium Extract as Novel Drug Delivery System to Enhance Its Bioavailability and Hepatoprotective Potential.

A nanosuspension of Artemisia absinthium extract was formulated and characterized for the enhancement of bioavailability and better hepatoprotective efficacy. The nanosuspension of A. absinthium extract was formulated using an antisolvent precipitation technique, and various formulation parameters were optimized using response surface methodology (RSM). The optimized nanosuspension was characterized using AFM and FT-IR spectroscopy. The drug-release profile and oral bioavailability of the optimized nanosuspension were assessed with reference to coarse suspension. The DPPH radical scavenging method was used to measure the nanosuspension's antioxidant activity, and its in vivo hepatoprotective potential was assessed against CCl4-induced hepatic injury in rats. The developed optimized nanosuspension had suitable zeta potential of -11.9 mV, PDI of 0.285, and mean particle size of 253.8 nm. AFM study demonstrated a homogeneous population of nanoparticles with average size of 25 nm. The formulated nanosuspension of A. absinthium showed faster dissolution rate and 1.13-fold enhanced bioavailability as compared to the coarse suspension (plant extract). Furthermore, the nanoformulation had stronger antioxidant and hepatoprotective potential as compared to the unprocessed coarse extract. These results demonstrated that nanosuspension is a promising strategy for improving the oral bioavailability and bioactivities of A. absinthium extract.

The behavior of whey protein isolate-curcumin complex at the oil-water interface

It was very common to use nanoparticles and nanoemulsions with the combination of proteins and hydrophobic bioactives to effectively prevent and treat chronic diseases. This work was to evaluate the stability of whey protein isolate (WPI) and curcumin (CUR) complex made with the anti-solvent precipitation technique and the pH shifting methods in oil-water bulk and interface. The interaction between WPI and CUR were investigated using fluorescence spectroscopy, Fourier transform infrared spectroscopy and molecular docking. The changes of the WPI-CUR in the oil-water bulk and interface were characterized by the circular dichroism spectroscopy, UV spectroscopic, confocal laser scanning microscopy and molecular dynamics simulation. Results indicated that the interactions between WPI and CUR were hydrogen bonding and hydrophobic interaction. The WPI-CUR complex was unstable at the oil-water interface, CUR detached from the complex and migrated to the oil phase. These findings would be of importance in illustrating the behavior of whey protein isolate-curcumin complex at the oil-water interface.

Fabrication and optimization of itraconazole-loaded zein-based nanoparticles in coated capsules as a promising colon-targeting approach pursuing opportunistic fungal infections

Itraconazole (ITZ), a broad-spectrum antifungal drug, was formulated into colon-targeting system aiming to treat opportunistic colonic fungal infections that commonly infect chronic inflammatory bowel diseases (IBD) patients due to immunosuppressive therapy. Antisolvent precipitation technique was employed to formulate ITZ-loaded zein nanoparticles (ITZ-ZNPs) using various zein: drug and aqueous:organic phase ratios. Central composite face-centered design (CCFD) was used for statistical analysis and optimization. The optimized formulation was composed of 5.5:1 zein:drug ratio and 9.5:1 aqueous:organic phase ratio with its observed particle size, polydispersity index, zeta potential, and entrapment efficiency of 208 ± 4.29 nm, 0.35 ± 0.04, 35.7 ± 1.65 mV, and 66.78 ± 3.89%, respectively. ITZ-ZNPs were imaged by TEM that revealed spherical core–shell structure, and DSC proved ITZ transformation from crystalline to amorphous form. FT-IR showed coupling of zein NH group with ITZ carbonyl group without affecting ITZ antifungal activity as confirmed by antifungal activity test that showed enhanced activity of ITZ-ZNPs over the pure drug. Histopathological examination and cytotoxicity tests ensured biosafety and tolerance of ITZ-ZNPs to the colon tissue. The optimized formulation was then loaded into Eudragit S100-coated capsules and both in vitro release and in vivo X-ray imaging confirmed the success of such coated capsules in protecting ITZ from the release in stomach and intestine while targeting ITZ to the colon. The study proved that ITZ-ZNPs is promising and safe nanoparticulate system that can protect ITZ throughout the GIT and targeting its release to the colon with effectual focused local action for the treatment of colon fungal infections.Graphical

Diosmin nanocrystal gel alleviates imiquimod-induced psoriasis in rats via modulating TLR7,8/NF-κB/micro RNA-31, AKT/mTOR/P70S6K milieu, and Tregs/Th17 balance

Diosmin is a flavonoid with promising anti-inflammatory and antioxidant properties. However, it has difficult physicochemical characteristics since its solubility demands a pH level of 12, which has an impact on the drug’s bioavailability. The aim of this work is the development and characterization of diosmin nanocrystals using anti-solvent precipitation technique to be used for topical treatment of psoriasis. Results revealed that diosmin nanocrystals stabilized with hydroxypropyl methylcellulose (HPMC E15) in ratio (diosmin:polymer; 1:1) reached the desired particle size (276.9 ± 16.49 nm); provided promising colloidal properties and possessed high drug release profile. Additionally, in-vivo assessment was carried out to evaluate and compare the activities of diosmin nanocrystal gel using three different doses and diosmin powder gel in alleviating imiquimod-induced psoriasis in rats and investigating their possible anti-inflammatory mechanisms. Herein, 125 mg of 5% imiquimod cream (IMQ) was applied topically for 5 consecutive days on the shaved backs of rats to induce psoriasis. Diosmin nanocrystal gel especially in the highest dose used offered the best anti-inflammatory effect. This was confirmed by causing the most statistically significant reduction in the psoriasis area severity index (PASI) score and the serum inflammatory cytokines levels. Furthermore, it was capable of maintaining the balance between T helper (Th17) and T regulatory (Treg) cells. Moreover, it tackled TLR7/8/NF-κB, miRNA-31, AKT/mTOR/P70S6K and elevated the TNFAIP3/A20 (a negative regulator of NF-κB) expression in psoriatic skin tissues. This highlights the role of diosmin nanocrystal gel in tackling imiquimod-induced psoriasis in rats, and thus it could be a novel promising therapy for psoriasis.Graphical abstract

Study of Formulation and Process Variables for Optimization of Piroxicam Nanosuspension Using 32 Factorial Design to Improve Solubility and In Vitro Bioavailability.

Piroxicam is a Biopharmaceutical Classification System (BCS) Class II drug having poor aqueous solubility and a short half-life. The rationale behind the present research was to develop a Piroxicam nanosuspension to enhance the solubility and thereby the in vitro bioavailability of the drug. Piroxicam nanosuspension (PRX NS) was prepared by an anti-solvent precipitation technique and optimized using a full-factorial design. Herein, the nanosuspension was prepared using polymer polyvinylpyrrolidone (PVP) K30® and Poloxamer 188® as a stabilizer to improve the solubility and in vitro bioavailability of the drug. Nine formulations were prepared based on 32 full-factorial experimental designs to study the effect of the formulation variables such as concentration of poloxamer 188 (%) (X1) and stirring speed (rpm) (X2) as a process variable on the response of particle size (nm) and solubility (µg/mL). The prepared NS was characterized by phase solubility, Fourier-transform infrared (FT-IR), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), transmission electron microscopy (TEM), particle size, zeta potential, entrapment efficiency, and percent drug release. DSC and XRPD analysis of freeze-dried NS formulation showed conversion of PRX into a less crystalline form. NS formulations showed a reduction in the size from 443 nm to 228 nm with -22.5 to -30.5 mV zeta potential and % drug entrapment of 89.76 ± 0.76. TEM analysis confirmed the size reduction at the nano level. The solubility was increased from 44 μg/mL to 87 μg/mL by altering the independent variables. The solubility of PRX NS in water was augmented by 14- to 15-fold (87.28 μg/mL) than pure PRX (6.6 μg/mL). The optimized formulation (NS9) at drug-to-stabilizer concentration exhibited a greater drug release of approximately 96.07% after 120 min as compared to the other NS formulations and pure PRX (36.78%). Thus, all these results revealed that the prepared NS formulations have improved the solubility and in vitro dissolution compared to the pure drug. Furthermore, an increase in the drug release was observed from the NS than that of the pure PRX. All these outcomes signified that the prepared PRX NS showed an increase in solubility and in vitro dissolution behavior; which subsequently would aid in attainment of enhanced bioavailability.

The Preparation of Apigenin Nanoparticles and the Study of Their Anti-Inflammatory and Anti-Tumor Activities In Vitro

Apigenin (API) has many biological activities, but its poor solubility limits its clinical application. In this research, API nanoparticles were prepared by the liquid antisolvent precipitation (LAP) technique, which effectively improved the solubility and bioavailability of API. Through the design of a single-factor test, the effects of the type and dosage of surfactants, API concentration, the antisolvent to solvent volume ratio, the speed and time of stirring, the temperature of precipitation, and the dropping speed on the MPS (mean particle size) of API nanosuspension were carried out. The optimum technological conditions were determined as follows: 5 mg/mL of tween 80 as a surfactant, 20 mg/mL of API, an antisolvent/solvent volume ratio of 10, a 1200 r/min stirring speed for 5 min, a 45 °C precipitation temperature, and a 1 mL/min dropping speed. Under the optimum conditions, we obtained API nanosuspension with 170.5 nm MPS and then it was freeze-dried to obtain the API nanoparticles. Moreover, we characterized the API nanoparticles by SEM, FTIR, XRD, DSC, and TG. Results showed that although API nanoparticles transformed into an amorphous form, their internal chemical structure had not been changed and had a higher solubility. Finally, API nanoparticles’ anti-inflammatory activities were evaluated by observing the effect of API on nitric oxide (NO) production and IL-10 production toward RAW264.7 cells induced by lipopolysaccharide (LPS). Moreover, the anti-tumor effect of API was determined by testing cell viability and apoptosis. The results suggested that API nanoparticles exhibited much better anti-inflammatory and anti-tumor activities compared to raw API.

Enhancement of cytotoxic and antioxidant activities of Digenea simplex chloroform extract using the nanosuspension technique

Digenea simplex (D. simplex), an Egyptian marine red macroalga, contains a diverse group of phytochemicals with unique bioactivities. At the same time, the synthesis of nanosuspension (NS) has received increasing interest to optimize the technological aspects of drugs. Thence, the main objective of this work was to use the chloroform extract (ChlE) of D. simplex to prepare its nanosuspension (ChlE-NS) formulation to increase its aqueous solubility, thereby improving its bioactivity. By using FTIR, GC/MS analysis, and phytochemical screening assays, the chemical profiling of ChlE was assessed. NS was prepared by the antisolvent precipitation technique using 1.5% w/v polyvinyl alcohol (PVA). A light microscope, FTIR, particle size distribution, polydispersity index (PDI), and zeta potential (ZP) measurements was used to characterize the prepared NS. Four cancer cell lines were used in the MTT experiment to investigate the anticancer potential of ChlE and ChlE-NS. An apoptotic mechanism was established using acridine orange/ethidium bromide (AO/EB) dual staining, DNA fragmentation, and increased caspase activity. ChlE and ChlE-NS were also evaluated as antioxidants using DPPH and ABTS free radical assays. The results showed that, when compared to ChlE, ChlE-NS had greater cytotoxic activity against the four cancer cell lines. However, results of antioxidant activity showed that ChlE-NS had an IC50 of 36.86 ± 0.09 and 63.5 ± 0.47%, while ChlE had values of 39.90 ± 0.08 and 86.5 ± 0.8% in DPPH and ABTS assays, respectively. Based on the results of this research, D. simplex ChlE-NS may be an effective strategy for enhancing ChlE's cytotoxic and antioxidant activities.Graphical abstract

A Brief Review of the Supercritical Antisolvent (SAS) Technique for the Preparation of Nanocatalysts to Be Used in Biodiesel Production

In an era where sustainability is becoming the main driving force for research and development, supercritical fluids-based techniques are presented as a very efficient alternative technology to conventional extraction, purification, and recrystallization processes. Supercritical antisolvent (SAS) precipitation is a novel technique that can replace liquid antisolvent precipitation techniques. Additionally, through the optimization of precipitation operating conditions, morphology, particle size, and particle size distribution of nanoparticles can be controlled. As an antisolvent, supercritical carbon dioxide (scCO2) is far more sustainable than its conventional liquid counterparts; not only does it have a critical point (304 K and 73.8 bar) on its phase diagram that allows for the precipitation processes to be developed so close to room temperature, but also its recovery and, consequently, the precipitated solute purification stage is considerably simpler. This technique can be used efficiently for preparing nanocatalysts to be used in biodiesel production processes.

Inhaled Atorvastatin Nanoparticles for Lung Cancer.

Lung cancer is one of the main causes of mortality globally. This research paper aims a the development of inhaled nanotechnology for lung cancer to deliver an atorvastatin calcium compound, for lung cancer, capable of reaching the tumor site directly via inhalation. Atorvastatin calcium micellar nanoparticles (ATO-NPs) encapsulated with Pluronic F-127 and polyvinyl alcohol (PVA) were manufactured utilizing the solvent and anti-solvent precipitation technique. The physicochemical features of the formulation were evaluated in terms of their physicochemical characteristics using Fourier transform infrared spectroscopy, differential scanning calorimetry, and dynamic light scattering. Additionally, the Andersen Cascade impactor was used at 15 L/minutes to assist in the aerosols performances of the formulation. The ATO-NPs formula's cell viability was tested in vitro using the A549 non-small cell lung cancer cell type. Transmission electron microscopy was utilized to determine the ATO-NPs particle morphology, demonstrating a spherical shape with a smooth surface. The fine particle fraction of the aerosol produced was 62.70 ± 1.18%. This finding suggests that atorvastatin micellar nanoparticles are suitable for medication administration by inhalation with a wide particle size dispersion. Moreover, it was found in vitro that concentrations of up to 21 μg/mL of the atorvastatin nanoparticles were safe and non-toxic in the cell model. This study found that atorvastatin micellar nanoparticles for inhalation could potentially be used for lung cancer treatment.

Characterization of hydrophilic and hydrophobic core-shell microcapsules prepared using a range of antisolvent approaches

This study describes three straightforward approaches to leveraging gel network-restricted antisolvent precipitation techniques as a means of preparing hydrophilic hydrophobic core-shell microparticles. Briefly, hydrophilic polysaccharides (sodium alginate (ALG), κ-carrageenan (CAR), and agar (AG)) were utilized to prepare microgel beads that were then immersed in zein solutions (70% ethanol aqueous solution, 70% urea aqueous solution, and zein in 70% acetic acid, respectively), thereby facilitating the controlled, slow antisolvent precipitation of the protein layer on the microbead surfaces and inducing hydrophilic hydrophobic core-shell structure formation. This technique can be readily applied to a range of gelling systems and can be tailored to target particle sizes and shell thicknesses. The resultant core-shell particles offer great promise for controlled delivery of fragrances, drugs, or other bioactive compounds in an application-specific fashion, and can be individually tailored based upon the selected input concentrations and preparation methods. Importantly, this technique is generalizable and can be extended to prepare diverse particles with a range of core-shell structures produced from a wide assortment of hydrophobic materials. • Core-shell microcapsules were prepared using a range of antisolvent approaches. • Size and shell thickness of microcapsules can be regulated. • Core-shell particles offer great promise for controlled delivery in an application-specific fashion.

Pharmacokinetics and Anti-Diabetic Studies of Gliclazide Nanosuspension.

Gliclazide (GCZ), an antidiabetic medication, has poor solubility and limited oral bioavailability due to substantial first-pass metabolism. Thus, the purpose of the current study was to optimize and formulate a GCZ nanosuspension (NS) employing the antisolvent precipitation technique. A three-factor, three-level Box–Behnken design (BBD) was used to examine the impact of the primary formulation factors (drug concentration, stabilizer, and surfactant %) on particle size. The optimized NS contains 29.6 mg/mL drug, 0.739% lecithin, and 0.216% sodium dodecyl sulfate (SDS). Under scanning microscopy, the topography of NS revealed spherical particles. Furthermore, NS had a much better saturation solubility than the pure material, which resulted in a rapid dissolving rate, which was attributed to the amorphous structure and smaller particle size of the NS particles. Studies on intestinal permeability using the in vitro noneverted intestinal sac gut method (duodenum, jejunum, and ileum) and single-pass intestinal permeability (SPIP) techniques showed that the effective permeability was also increased by more than 3 fold. In the pharmacokinetic study, the Cmax and AUC0–t values of NS were approximately 3.35- and 1.9-fold higher than those of the raw medication and marketed formulation (MF). When compared to plain drug and commercial formulations, the antidiabetic efficacy of NS demonstrated that it had a significant impact on lowering glucose levels.

Lipid- and TPGS-Based Core-Shell-Type Nanocapsules Endowed with High Paclitaxel Loading and Enhanced Anticancer Potential.

The current study elucidates the improved drug loading of paclitaxel (PTX) in lipid- and D-α-tocopheryl polyethylene glycol succinate (TPGS)-based core-shell-type lipid nanocapsules (PTX-TPGS-LNC) for augmenting the therapeutic efficacy and curbing the toxicity. PTX-TPGS-LNCs were formulated by employing anti-solvent precipitation technique and displayed a particle size of 162.1 ± 4.70nm and % practical drug loading of 15.04 ± 2.44%. Electron microscopy revealed that PTX-TPGS-LNCs have spherical morphology and the inner core was surrounded by a relatively lighter region, i.e., layer of lipids and TPGS. The nature of loaded PTX inside the PTX-TPGS-LNC was also confirmed using DSC and PXRD analysis. The in vitro release study showed biphasic and sustained release pattern of PTX from PTX-TPGS-LNC and it showed ~ threefold higher PTX uptake in MCF-7 cell line in comparison to free PTX. Moreover, it was apparent from the cytotoxicity assay that PTX-TPGS-LNC displayed higher cytotoxicity in MCF-7 cells and revealed ~ 2.92-fold decrease in IC50 value as against free PTX when incubated for 72h. The apoptotic index in case of PTX-TPGS-LNC was ~ twofold higher than free PTX. The pharmacokinetic profile of PTX-TPGS-LNC revealed a ~ 3.18-fold increase in t1/2 and a ~ 2.62-fold higher AUC(0→∞) compared to Intaxel®. Finally, treatment with PTX-TPGS-LNC demonstrated significant lowering in the % tumor burden and serum toxicity markers compared to marketed formulation Intaxel®. Thus, the lipid- and TPGS-based core-shell-type LNC with high PTX loading can advance the existing standards of therapy for overshadowing cancer.

Quality by design-based optimization of formulation and process parameters for berberine nanosuspension for enhancing its dissolution rate, bioavailability, and cardioprotective activity.

Berberine (BER) possesses dissolution rate limited oral bioavailability. The present study deciphers the formulation of nanosuspension loaded with BER for enhancing its cardioprotective potential. The nanosuspension was prepared by a liquid antisolvent precipitation technique using sodium lauryl sulfate as a surfactant and polyvinyl pyrrolidone K30 (PVP K30) as a polymer. The optimized formulation showed a particle size of 251.32 ± 4.18 nm, zeta potential of -24.10 ± 1.16 mV, and drug loading capacity of 98.22 ± 2.24%. The results showed about 6.01-fold and 3.54-fold enhancement in the dissolution rate and permeability, respectively, upon loading berberine into nanosuspension. About 8.44-fold increase in Cmax , 27.22-fold increase in AUC0-t , and 27.38-fold increase in AUC0-∞ were observed in the case of BER nanosuspension, compared to its naïve form. The results of particle size, zeta potential, and drug loading showed a nonsignificant change in the response of fresh and aged nanosuspension, which indicated that the formulation was stable. In vitro results on H9C2 cell line indicated a lower cellular proliferation rate after treatment with BER nanosuspension with decreased cytoplasmic expression of angiotensin converting enzyme (ACE) protein. Overall, the results indicated the successful development of BER nanosuspension with an enhanced dissolution rate, permeability, bioavailability, and cardioprotective activity. Practical applications The present study provides the evidence that the formulation of nanosuspension loaded with berberine enhance the cardioprotective activity of berberine. The results of the study supports the improved bioavailability of nanosuspension of berberine showed enhanced cardioprotective activity.

Pain Management with Topical Aceclofenac Nanosuspension In-Vitro/In- Vivo and Proof of Concept Studies

Introduction: Pain is one of the most common medical conditions and affects more than diabetes, heart disease, and cancer combined. Current pain treatments mainly rely on NSAIDs analgesics and remain unsatisfactory. Due to associated adverse effects such as gastrointestinal ulcers and bleeding and low solubility limits its uses. Objective: The present research focus on advance in the field of pain treatment by topical delivery of NSAIDs (aceclofenac) drugs via enhancing its solubility and diminishing related side effects. Materials and Methods: ACE-nanosuspension (ACE-NS) prepared by anti-solvent precipitation technique was characterized for particle size, PDI, zeta-potential, total drug content, DSC, FTIR, P-XRD and FESEM. Further spreadabilty, ex-vivo occlusivity, in-vitro release, ex-vivo skin permeation and retention and stability studies were performed. Dermal irritation and histopathological examinations were conducted in accordance to OECD guidelines. Proof of concept studies were accomplished using radiant tail flick and paw-licking animal model. Results: ACE-NS showed particle size of 148 ±15 nm with PDI: 0.170, zeta potential: 21.2 mV and total drug content of 86±0.23% respectively. DSC, FT-IR, P-XRD and FESEM studies revealed the thermal behavior, compatibility, solid state characterization and morphology of ACE-NS. ACE-NS loaded ointment showed a spreadability ratio of 0.23 and a drug content of 84±1.15%. In-vitro release of ACE from nano-ACE-ointment (88.07%) was higher than marketed formulation (70.55%) and free drug ointment (70.45%) after 24 hours. Release profile of nano-ACE-ointment fitted best for Higuchi model with r2 = 0.94 and n = 0.45 and its permeation flux was 9.2312 ± 0.8430 mg/cm2/h, which was significantly higher (p ≤0.05) than ACE marketed gel (2.6158 ± 0.4352 mg/cm2/h). Cutaneous irritation and histological studies revealed no inflammatory skin lesions post treatment with ACE-NS. Furthermore, ACE-NS-ointment showed better analgesic effect than marketed formulation in both radiant tail flick model (2.87 times) and paw-licking (2.73 times) animal model. Conclusion: Studies highlighted the potential of topical nano-ACE-ointment for pain management.

Silymarin nanocrystals-laden chondroitin sulphate-based thermoreversible hydrogels; A promising approach for bioavailability enhancement

Hydrogels has gained tremendous interest as a controlled release drug delivery. However, currently it is a big challenge to attain high drug-loading as well as stable and sustained release of hydrophobic drugs. The poor aqueous solubility and low bioavailability of many drugs have driven the need for research in new formulations. This manuscript hypothesized that incorporation of nanocrystals of hydrophobic drug, such as silymarin into thermoreversible hydrogel could be a solution to these problems. Herein, we prepared nanocrystals of silymarin by antisolvent precipitation technique and characterized for morphology, particle size, polydispersity index (PDI) and zeta potential. Moreover, physical cross-linking of hydrogel formulations based on chondroitin sulphate (CS), kappa-Carrageenan (κ-Cr) and Pluronic® F127 was confirmed by Fourier transformed infrared spectroscopy (FT-IR). The hydrogel gelation time and temperature of optimized hydrogel was 14 ± 3.2 s and 34 ± 0.6 °C, respectively. The release data revealed controlled release of silymarin up to 48 h and in-vivo pharmacokinetic profiling was done in rabbits and further analyzed by high-performance liquid chromatography (HPLC). It is believed that the nanocrystals loaded thermoreversible injectable hydrogel system fabricated in this study provides high drug loading as well as controlled and stable release of hydrophobic drug for extended period.