Pure Drug Suspension Research Articles

Bioavailability enhancement of atazanavir sulphate using mixed micelles: in vitro characterization and in vivo pharmacokinetic study.

This study aims to enhance the oral bioavailability of atazanavir sulphate, a human immunodeficiency virus-1 protease inhibitor known for its poor oral absorption, by formulating mixed micelles using Soluplus® and Kolliphor HS 15. Mixed micelles were prepared through the thin film hydration technique. The micelles were characterized for particle size, polydispersity index (PDI), zeta potential, entrapment efficiency, drug loading, and confirmed for atazanavir sulphate encapsulation via FTIR studies. In vitro release studies were conducted, and the morphology of the micelles was examined using TEM. Atazanavir sulphate mixed micelles exhibited a particle size of 62.92nm, PDI of 0.221, zeta potential of - 17.8mV, high entrapment efficiency (99.76 ± 1.06), and drug loading (14 ± 0.82). In vitro release studies demonstrated sustained release up to 12h, with maximum solubility observed at 2h under pH 1.2 conditions. TEM analysis revealed spherical micelle morphology. Oral administration of atazanavir sulphate mixed micelles showed a 1.23-fold increase in relative bioavailability compared to pure drug suspension. The formulation of mixed micelles using Soluplus® and Kolliphor HS 15 offers a promising strategy to improve the oral bioavailability of atazanavir sulphate. These findings suggest the potential utility of mixed micelles as an effective delivery system for atazanavir sulphate, offering enhanced therapeutic outcomes for patients.

Development of biocompatible lipid-polymer hybrid nanoparticles for enhanced oral absorption of posaconazole: A mechanistic in vitro and in silico assessment

The current research focuses on the development of lipid-polymer hybrid nanoparticles (LPHNs) designed to enhance the solubility and bioavailability of posaconazole (PCZ). PCZ, an antifungal drug, faces challenges due to its poor water solubility, resulting in inconsistent absorption and limited bioavailability. LPHNs composed of stearic acid and poly-δ-decalactone (PDL) were successfully fabricated and characterized. The optimized formulation (P-LPHN4) exhibited a particle size of 104.0 nm, negative zeta potential (−38.9 mV), high drug loading (19.5 %), and efficient encapsulation (82.6 %). In vitro release studies demonstrated sustained drug release over 18 h, with P-LPHN4 displaying the highest drug release (92 %). Stability studies revealed good physical stability over 45 days with no significant changes in particle size, zeta potential, and PDI. In silico simulations using GastroPlus® predicted significantly improved intestinal absorption and systemic exposure for P-LPHN4 compared to the pure drug suspension in a simulated rat model. The model predicted a higher peak plasma concentration (Cmax) for P-LPHN4 (∼0.012 μg/mL) compared to the PCZ suspension (∼0.0058 μg/mL). The model identified the duodenum and jejunum as primary absorption sites for both formulations, with P-LPHNs showing significantly higher overall absorption (84.5 %) compared to the suspension (47.5 %). Simulation results revealed a dose-dependent increase in both Cmax and AUC with increasing oral P-LPHN4 dose, while Tmax remained unaffected. In conclusion, the developed posaconazole-loaded lipid-polymer hybrid nanoparticles (P-LPHN4) showed promising results in terms of enhanced drug release, stability, and bioavailability.

Biopharmaceutical distribution and pharmacodynamic evaluation of intra nasal in-situ gel of Lamotrigine for brain targeted drug delivery

Background: The present research investigates the nasal delivery of Lamotrigine by incorporating it into a natural in-situ gelling system. Additionally, the retention of the drug in the nasal cavity was enhanced by employing the natural mucoadhesive polymer locust bean gum (LBG). A preliminary investigation was conducted to determine the optimal concentration of gellan gum. The dosage of the drug was calculated using the Robinson Erikson equation. The central composite design was utilized to optimize the influence of individual variables such as gellan gum and locust bean gum on various responses, including gelation time, gel viscosity, mucoadhesive strength, and the time taken for the drug to release half of its initial concentration (t50). The goal of the current study was to evaluate the in-vivo effectiveness of intra nasal in-situ gel of Lamotrigine. Methodology: The pharmacokinetic and tissue distribution studies were carried out to evaluate the brain targeting efficiency of lamotrigine. Blood samples and tissues of various vital organs like brain, liver, kidneys and heart were obtained at different time intervals, plasma and tissue concentration of Lamotrigine was estimated by reverse phase HPLC. Results: According to the pharmacokinetic analysis, Cmax and AUC0-α is found to be significantly more (P<0.05) for nasal route compared to oral route. In comparison to the oral route, Cmax and AUC0-α was 7 and 6.5 folds more for IN route. The absolute bioavailability was found to be 159.07%. with regard to the oral group, minimal drug was present in any of the other tissue samples. In the pharmacodynamic data also the formulation through nasal route showed a significant difference compared to oral route (pure drug suspension) delivery in PTZ induced study. Keywords: Lamotrigine, in-vivo study, tissue distribution, pharmacodynamics

Development and Optimization of Proniosomal Formulation of Irbesartan Using a Box-Behnken Design to Enhance Oral Bioavailability: Physicochemical Characterization and In Vivo Assessment.

This research work aimed to develop and evaluate proniosomes for the oral delivery of the lipophilic drug Irbesartan (IRB) to improve its solubility and bioavailability. Proniosomes of Irbesartan were formulated using a lipid, surfactant, and carrier by a slurry method. Based on the prepared preliminary trial batches and their evaluation, the formulation was optimized by employing a Box-Behnken design (BBD) in which concentrations of span 60 (X1), cholesterol (X2), and mannitol (X3) were used as three independent variables and the vesicular size (VS) (Y1), % entrapment efficiency (% EE) (Y2), and % cumulative drug release (% CDR) (Y3) were used as dependent variables. The optimized batch B1 was obtained from the BBD experiment after validation of checkpoint analysis, and their characterization was done for VS, % EE, % CDR, Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) analysis. The optimized batch showed a VS of 199 ± 5.4 nm, a % EE of 99.25 ± 2.24%, and a % CDR of 97.36 ± 1.13% at 24 h. Scanning electron microscopy (SEM) study showed a smooth surface of batch B1. DSC and XRD studies indicated the amorphous nature of the proniosomal formulation. The proniosomal formulation showed increased solubility (2.65 ± 0.2 mg/mL) in phosphate buffer, pH 6.8, as compared to water (0.059 ± 0.02 mg/mL). The pharmacokinetic study in rats confirmed the increased bioavailability of the drug in optimized proniosomal formulation compared with its pure drug suspension. Cmax, Tmax, and AUC0-t of the drug also increased by 2-fold compared to those of drug suspension. Thus, in conclusion, the proniosomal formulation proved to be an efficient carrier for improved oral delivery of Irbesartan by improving the solubility and bioavailability of the drug.

Preparation and Evaluation of a Self-Emulsifying Drug Delivery System for Improving the Solubility and Permeability of Ticagrelor.

Ticagrelor (TCG) is a BCS class IV antiplatelet drug used to prevent platelet aggregation in patients with acute coronary syndrome, having poor solubility and permeability. The goal of this study was to develop a self-nanoemulsifying drug delivery system (SNEDDS) of TCG to improve its solubility and permeability. The excipients were selected based on the maximum solubility of TCG and observed by UV spectrophotometer. Different combinations of oil, surfactant, and co-surfactant (1:1, 2:1, and 3:1) were used to prepare TCG-SNEDDS formulations, and pseudo-ternary phase diagrams were plotted. The nanoemulsion region was observed. Clove oil (10-20%), Tween-80 (45-70%), and PEG-400 (20-45%) were used as an oil, surfactant, and co-surfactant, respectively. The selected formulations (F1, F2, F3, F4, F5, and F6) were analyzed for ζ potential, polydispersity index (PDI), ζ size, self-emulsification test, cloud point determination, thermodynamic studies, entrapment efficiency, Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), in vitro dissolution, ex vivo permeation, and pharmacodynamic study. The TCG-SNEDDS formulations exhibited ζ potential from -9.92 to -6.23 mV, a ζ average of 11.85-260.4 nm, and good PDI. The in vitro drug release in phosphate buffer pH 6.8 from selected TCG-SNEDDS F4 was about 98.45%, and F6 was about 97.86%, displaying improved dissolution of TCG in 0.1 N HCl and phosphate buffer pH 6.8, in comparison to 28.05% of pure TCG suspension after 12 h. While the in vitro drug release in 0.1 N HCl from F4 was about 62.03%, F6 was about 73.57%, which is higher than 10.35% of the pure TCG suspension. In ex vivo permeability studies, F4 also exhibited an improved apparent permeability of 2.7 × 10-6versus 0.6708 × 10-6 cm2/s of pure drug suspension. The pharmacodynamic study in rabbits demonstrated enhanced antiplatelet activity from TCG-SNEDDS F4 compared to that from pure TCG suspension. These outcomes imply that the TCG-SNEDDS may serve as an effective means of enhancing TCG's antiplatelet activity by improving the solubility and permeability of TCG.

FORMULATION AND IN VIVO EVALUATION OF PEMIGATINIB SUPER SATURABLE SELF-NANO EMULSIFYING DRUG DELIVERY SYSTEM

Objective: Pemigatinib is an active component in treatment of cholangiocarcinoma, but the low solubility and bioavailability of Pemigatinib limit its wide application. The aim of the present study was to prepare and evaluate supersaturable self-nanoemulsifying drug delivery systems (sSNEDDS) followed by investigating and comparing the pharmacokinetic profiles of Pemigatinib and Pemigatinib sSNEDDS in rat plasma by HPLC. Methods: Pemigatinib loaded SNEDDS were obtained by dissolving drug in the isotropic mixture of oil, surfactant, and co-surfactant. The conventional SNEDDS were converted to sSNEDDS by precipitation method by using an experimented polymer. An appropriate high sensitivity and selectivity was applied to the comparison of plasma pharmacokinetics in Pemigatinib and Pemigatinib sSNEDDS using Entrectinib as an internal standard (IS). Results: The droplet of sSNEDDS ranges from 166.78±3.14 to 178.86±1.24 nm with PDI 0.212–0.256, transmission electron microscopy images revealed the spherical shape of the nanodroplets, emulsification time was 15 secs when added to physiological fluids, percent transmittance of the diluted formulation was 99.12±0.46, and viscosity was 574±26 centipoises indicating the good flow ability. FTIR and DSC studies indicated the amorphization of the drug. The dissolution profile of sSNEDDS indicated the faster release of drug compared to both pure drug suspension and SNEDDS formulation. Cmax of the sSNEDDS 3.52±0.13ng/ml was significant (P<0.05) as compared to the pure drug suspension formulation 2.82±0.42 ng/ml. The AUC0-t, AUC0–∞ of sSNEDDS was increased, while the Tmax and t1/2 was decreased. Moreover, the AUC value in the sSNEDDS group was significantly increased and the relative bioavailability was calculated to be 69% when compared with that of the Pemigatinib group. Conclusion: These results concluded that Pemigatinib sSNEDDS when compared with pure drug after a single oral administration and the formulation modification of Pemigatinib into sSNEDDS can effectively enhance gastrointestinal absorption and relative bioavailability by improving solubility and dissolution rate.

Novel lipid-based nanocarrier of nitrofurantoin for improved oral bioavailability and reduced variability in absorption

The current research aims to improve oral bioavailability, reduce the variability in absorption, and decrease GI intolerance of Nitrofurantoin (NFT) by presenting in a lipid-based liquid self-nanoemulsifying drug delivery system (L-SNEDDS). L-SNEDDS formulations were developed using a thermosolvency technique. Physicochemical properties including in-vitro drug diffusion were exercised to optimize the formula, further, comparative ex-vivo permeability, in-vitro cell line, in-vitro anti-microbial, and in-vivo pharmacokinetic evaluation of optimized formulation was carried out. Based on the highest saturation solubility, soybean oil, oleoyl polyoxyl-6-glycerides, and diethylene glycol monoethyl ether were selected as oil, surfactant, and co-surfactant, respectively. A Smix ratio of 1:2 was selected based on pseudoternary phase diagrams. The formulation prepared with an equal ratio of oil and Smix exhibited the lowest globule size (59.4 ± 0.8 nm), optimum zeta potential (−21.3 ± 1.1 mV), and faster drug release (95.4 ± 4.2 % in 30 min), and hence was selected for further evaluation. Optimized formulation (SF5) was found stable and showed improved membrane permeability against pure drug suspension (1.84 times) and marketed suspension formulation (1.15 times). SF5 exhibited similar % cell viability and % cell toxicity in Caco-2 cell lines compared to the marketed suspension. However, it showed the highest zone of inhibition against both the gram-negative and gram-positive organisms. The relative bioavailability of NFT-loaded L-SNEDDS was enhanced by 1.46 and 1.55 times compared to the marketed and pure drug, respectively. Thus, it can be concluded that the variability of oral absorption is minimized, and oral bioavailability is improved by the novel lipid-based nanocarrier system of NFT.

Evaluation of Oral Bioavailability and In-vivo Anti-leukemic Potential of Dasatinib Loaded Solid Lipid Nanoparticles

Dasatinib is one of the second-generation tyrosine kinase inhibitors (TKI) that is taken orally and has antiproliferative activity against chronic myeloid leukemia (CML). Dasatinib/hesperidin loaded-SLNs were synthesized in-house using a high-shear homogenizer and optimized by central composite design (CCD). Oral bioavailability and in-vivo anti-leukemic potential of developed dasatinib/hesperidin-loaded-solid lipid nanoparticles (SLNs) were determined using intravenous injection of leukemia cells in mice model. Dasatinib was administered as pure drug (suspension) and SLN formulation in leukemic mice modal. The pharmacokinetic profile was studied and compared with drug suspension using HPLC. Results denoted mean maximum plasma concentrations Cmax as 184.52 and 390.43 ng/mL, mean Tmax as 2 and 4 hours, mean half-life as 4.63 and 8.06 hours., for pure drug (suspension) and SLN formulation, respectively. The mean area under the curve (AUClast) was 1080.94 and 3669.49 hr*ng/mL for the same. SLN also showed statistically significant survival. A comparison of SLN and free drugs revealed that SLN was more effective at cytotoxicity. Therefore, the developed dual-targeted SLN formulation of dasatinib demonstrated higher sensitivity of cells to the drug entrapped in SLN than the drug suspension.

Nanoemulsion-Based Strategy for Maximizing Nitrofurantoin Absorption: In-vitro and In-vivo Investigations.

The main objective of the current research work is to improve the absorption of Nitrofurantoin (NFT) by minimizing gastrointestinal (GI) intolerance and variations in its absorption by formulating the drug into a nanoemulsion (NE). Based on the highest saturation solubility of NFT, soybean oil, transcutol HP, and labrafil M1944CS were selected as oil, co-surfactant, and surfactant, and a Smix ratio of 1:2 was selected based on pseudoternary phase diagrams. The formulation prepared with an equal ratio of oil and Smix exhibited the lowest globule size, highest zeta potential, and higher drug release and hence was selected for further evaluation. Optimized formulation (NF5) showed improved membrane permeability against pure drug suspension (2.30 times) and marketed suspension formulation (1.43 times). NF5 exhibited similar % cell viability and % cell toxicity in Caco-2 cell lines compared to the marketed suspension. The relative bioavailability of NFT-NE was enhanced by 1.10 and 1.17 times compared to the marketed and pure drug suspension, respectively. Thus, it can be concluded that the optimized nanoemulsion formulation of NFT exhibited improved membrane permeability, comparable cell viability, and increased relative bioavailability. These findings suggest the potential of the nanoemulsion approach as a strategy to overcome the variability of oral absorption and GI intolerance of NFT.

BOX-BEHNKEN DESIGN-BASED DEVELOPMENT AND CHARACTERIZATION OF POLYMERIC FREEZE-DRIED NANOPARTICLES OF ISRADIPINE FOR IMPROVED ORAL BIOAVAILABILITY

Objective: This study aimed to develop and optimize isradipine-loaded polymeric freeze-dried nanoparticles prepared by solvent shifting method with the help of the experiment design for improving oral drug bioavailability and minimizing dosing intervals. Methods: Isradipine is a potent anti-hypertensive drug that is matrixed in polymeric freeze-dried nanoparticles using solvent shifting. In this work, a 3-factor, 3-level box-Behnken design was used to optimize the process parameters like a drug: PLA concentration (A), poloxamer 407 concentration (B), and stirring speed (C). In addition, responses were measured as dependent variables such as percentage drug release, particle size (nm), Zeta potential (mV), and % entrapment efficiency. Results: Mathematical equations and response surface plots were used to relate the dependent and independent variables. The optimization model exhibited 97.36 % drug release, 153.14 nm particle size,-25.9 mV Zeta potential, and 78.25% entrapment efficiency, respectively. The observed responses were in close agreement with the predicted values of the optimized process. Fourier transform infrared spectroscopy, morphological studies, and in vitro drug release studies characterized the prepared polymeric nanoparticles. Conclusion: The improved freeze-dried polymeric nanoparticle samples exhibited an in vitro drug release rate of more than 90% at 24h. Based on in vivo pharmacokinetic parameters, the isradipine-loaded polymeric nanoparticles show better bioavailability than pure drug's suspension form.

QbD-Optimized, Phospholipid-Based Elastic Nanovesicles for the Effective Delivery of 6-Gingerol: A Promising Topical Option for Pain-Related Disorders.

In this study, elastic nanovesicles, constructed of phospholipids optimized by Quality by Design (QbD), release 6-gingerol (6-G), a natural chemical that may alleviate osteoporosis and musculoskeletal-related pain. A 6-gingerol-loaded transfersome (6-GTF) formulation was developed using a thin film and sonication approach. 6-GTFs were optimized using BBD. Vesicle size, PDI, zeta potential, TEM, in vitro drug release, and antioxidant activity were evaluated for the 6-GTF formulation. The optimized 6-GTF formulation had a 160.42 nm vesicle size, a 0.259 PDI, and a -32.12 mV zeta potential. TEM showed sphericity. The 6-GTF formulation's in vitro drug release was 69.21%, compared to 47.71% for the pure drug suspension. The Higuchi model best described 6-G release from transfersomes, while the Korsmeyer-Peppas model supported non-Fickian diffusion. 6-GTF had more antioxidant activity than the pure 6-G suspension. The optimized transfersome formulation was converted into a gel to improve skin retention and efficacy. The optimized gel had a spreadability of 13.46 ± 4.42 g·cm/s and an extrudability of 15.19 ± 2.01 g/cm2. The suspension gel had a 1.5 μg/cm2/h ex vivo skin penetration flux, while the 6-GTF gel had 2.71 μg/cm2/h. Rhodamine B-loaded TF gel reached deeper skin layers (25 μm) compared to the control solution in the CLSM study. The gel formulation's pH, drug concentration, and texture were assessed. This study developed QbD-optimized 6-gingerol-loaded transfersomes. 6-GTF gel improved skin absorption, drug release, and antioxidant activity. These results show that the 6-GTF gel formulation has the ability to treat pain-related illnesses effectively. Hence, this study offers a possible topical treatment for conditions connected to pain.

Atorvastatin-loaded pro-nanolipospheres with ameliorated oral bioavailability and antidyslipidemic activity

Despite significant advances in oral drug delivery technologies, many drugs are prone to limited oral bioavailability due to biological barriers that hinder drug absorption. Pro-nanolipospheres (PNL) are a form of delivery system that can potentiate the oral bioavailability of poorly water-soluble drugs through a variety of processes, including increased drug solubility and protecting them from degradation by intestinal or hepatic first-pass metabolism. In this study, pro-nanolipospheres were employed as a delivery vehicle for improving the oral bioavailability of the lipophilic statin, atorvastatin (ATR). Various ATR-loaded PNL formulations, composed of various pharmaceutical ingredients, were prepared by the pre-concentrate method and characterized by determining particle size, surface charge, and encapsulation efficiency. An optimized formula (ATR-PT PNL) showing the smallest particle size, highest zeta potential, and highest encapsulation efficiency was selected for further in vivo investigations. The in vivo pharmacodynamic experiments demonstrated that the optimized ATR-PT PNL formulation exerted a potent hypolipidemic effect in a Poloxamer® 407-induced hyper-lipidaemia rat model by restoring normal cholesterol and triglyceride serum levels along with alleviating serum levels of LDL while elevating serum HDL levels, compared to pure drug suspensions and marketed ATR (Lipitor®). Most importantly, oral administration of the optimized ATR-PT PNL formulation showed a dramatic increase in ATR oral bioavailability, as evinced by a 1.7- and 3.6-fold rise in systemic bioavailability when compared with oral commercial ATR suspensions (Lipitor®) and pure drug suspension, respectively. Collectively, pro-nanolipospheres might represent a promising delivery vehicle for enhancing the oral bioavailability of poorly water-soluble drugs.

Simultaneous estimation of neratinib and naringenin from pharmaceuticals using a stability-indicating liquid chromatographic method: Application to analytical quality by design concept and multi-tool method greenness assessment

A validated stability-indicating simultaneous liquid chromatographic method was developed to estimate neratinib (NRB) and naringenin (NRN). We used the principles of analytical quality by design (AQbD) to develop a robust analytical method. The ACN%, pH, and flow rate were the three method variables investigated and optimized using the Box-Behnken experimental design (BBD). The optimized chromatographic condition used a mobile phase of ACN: phosphate buffer pH 3.8 (70:30 v/v) flowing at 0.6 mL.min−1 on a 250 mm C-18 column. Diode array detection was performed at 277 nm. The method was robust, linear (r2 = 0.999), accurate and precise. The detection and quantitation limits were 0.275 and 1.0 µg.mL−1 for both drugs. Forced degradation revealed non-interference of degradation peaks with the analyte peaks and ensured method specificity. The LC estimation demonstrated higher solubility of NRB and NRN in Precirol ATO5 and Tween 80 as solid lipid and surfactant, respectively. In addition, the entrapment efficiencies were 78 % and 86 % for SLNs of NRB and NRN, respectively. After 24 h, the In-vitro release study indicated that 40 % of the drugs were released from the pure drug suspension and >95 % released from the SLN. Afterwards, the results from five different greenness assessment approach established the present method's green nature. Overall, a green, federally robust, and flexible liquid chromatographic method was developed and can be applied routinely to estimate NRB and NRN from the developed nano formulation.

Engineering of Lurasidone Hydrochloride Loaded Niosomes for Enhancing the Antipsychotic Potential for Nasal Administration

Background: Drugs having high first-pass metabolism or that are susceptible to enzymatic degradation can be administered through the nasal route to avoid their degradation. Lurasidone exhibits less toxicity and side effects as compared to its sister drugs like risperidone, ziprasidone, clozapine, etc. Objectives: The present study aimed to develop Lurasidone loaded niosomes for nasal delivery. Methods: Lurasidone niosomes were developed by adapting the ether injection method and optimized using a central composite design. In vitro and in vivo studies were conducted using optimized formulation. Results: The findings showed that the optimized formulation exhibited a particle size of 159.02 ± 0.58 nm and an entrapment efficiency of 91.6 ± 1.6%. The findings from the nasal histopathological analysis revealed that the optimized formulation was non-irritant and non-toxic for nasal mucosa. The findings from in vitro studies revealed 94.61 ± 0.27% of drug release from optimized formulation F7 throughout 24 hrs. The findings of in vivo (Albino Wistar rats) studies demonstrated that various pharmacokinetic parameters (Cmax, Tmax, AUC(0-24), T1/2, Vd and Cl) and pharmcodynamic parameters (conditioned avoidance response, biochemical estimation using oxidative markers such as superoxide dismutase, malondialdehyde and glutathione) were significantly improved compared to marketed tablets (Lurasid® 40 mg) and pure drug suspension. Optimized formulation F-7 exhibited 4.9 times more bioavailability than that of pure drug suspension following intranasal administration. Conclusion: These findings indicate that nasal niosomal formulation of Lurasidone HCl is a promising nanoplatform for enhancing the overall performance of Lurasidone. These results could open new avenues into the future of nanomedicine.

Enhancing the biopharmaceutical attributes of atorvastatin calcium using polymeric and lipid-polymer hybrid nanoparticles: An approach for atherosclerosis treatment

Atherosclerosis is associated with inflammation in the arteries, a significant cause of heart attacks and strokes. Although statin therapy can reduce the chances of atherosclerotic plaque formation, they need to be administered in high doses due to low systemic bioavailability and encountered with side effects. To overcome these challenges, we developed nanoparticles using biocompatible and biodegradable lipids and polymers for improving systemic drug absorption and therapeutic response. The polymeric nanoparticles were prepared using PLGA and PVA, while hybrid nanoparticles were prepared using PLGA and Phospholipon 90 G. Both nanoparticles were systematically optimized by I-optimal response surface design. The optimum formulation composition exhibited particle size of less than 250 nm, polydispersity index of less than 0.3, entrapment efficiency of more than 70%, and sustained drug release up to 6 h. In vivo pharmacokinetic evaluation in rats indicated multi-fold improvement in the extent of drug absorption (Cmax and AUCtotal) for atorvastatin from the nanoparticles vis-à-vis the pure drug suspension. In vivo pharmacodynamic studies also indicated the excellent ability of nanoparticles to lower the elevated levels of lipids (total cholesterol, triglycerides, and low-density lipoproteins) and increase the level of high-density lipoproteins as compared to that of the pure drug suspension.

Formulation development, optimization and characterization of Pemigatinib-loaded supersaturable self-nanoemulsifying drug delivery systems

BackgroundPemigatinib is a small molecule tyrosine kinase inhibitor of fibroblast growth factor receptor inhibitors. The oral bioavailability of Pemigatinib is constricted due to its limited solubility at physiological pH. It is essential to develop a novel formulation of Pemigatinib to improve the intrinsic solubility and to reduce the pharmacokinetic variability. Self-nanoemulsifying drug delivery system is an effective, smart and more adequate formulation approach for poorly soluble drugs. Different from conventional self-nanoemulsifying drug delivery system, a supersaturable self-nanoemulsifying drug delivery system of Pemigatinib was prepared by using a supersaturation promoter.ResultsAmong all the oils, Captex® 300 have shown maximum solubility of Pemigatinib. Considering the solubilization potential and emulsification ability Kolliphor®RH 40 was selected as surfactant. Transcutol®HP was selected as co-surfactant. The composition of oil, surfactant and co-surfactant was identified using phase diagrams and further adjusted by simplex-lattice design. HPMC K4M as precipitation inhibitor at 5% concentration resulted in effective supersaturating with increased self-emulsification time. The droplet of sSNEDDS ranges from 166.78 ± 3.14 to 178.86 ± 1.24 nm with PDI 0.212 – 0.256, which is significantly smaller than that observed with plain SNEDDS. TEM images revealed the spherical shape of the nanodroplets. The final optimized formulation formed spontaneous nanoemulsion within 15 secs when added to physiological fluids. The percent transmittance of the diluted formulation was found to be 99.12 ± 0.46. The viscosity was found to be 574 ± 26 centipoises indicating the good flow ability. FTIR and DSC studies indicated the amorphization of the drug. The dissolution profile of sSNEDDS indicated the faster release of drug compared to both pure drug suspension and SNEDDS formulation. The drug release rate is directly proportional to the concentration of the drug. The drug release from the insoluble matrix is a square root of time-dependent Fickian diffusion process. The formulation was found to be stable and transparent at all pH values and the percent transmittance was more than 95%. Any kind of separation or precipitation was not observed at different temperatures cycles. No significant difference was observed with all the samples exposed at different storage conditions.ConclusionsThis study demonstrated the feasibility of stabilizing and improving the in-vitro performance of self-nanoemulsifying drug delivery systems of Pemigatinib by incorporating HPMC K4M as precipitation inhibitor.

Design, Development and In vivo Evaluation of Core in Cup Tablets of Budesonide

Budesonide is widely used drug for treatment of active inflammatory bowel disease (IBD). Core in-cup tablets were prepared to achieve a prolonged release of Budesonide and for alleviating the symptoms of inflammatory bowel disease. The objective of this study was to investigate differences in the pharmacokinetic patterns between an optimized core in cup tablet formulation and pure Budesonide suspension. In-vivo evaluation studies were performed based on the uniform and reliable results of in-vitro drug release studies. Various pharmacokinetic parameters were compared to obtain mean plasma drug concentration curve versus time. The pure drug suspension and Core-in-cup tablets formulation of Budesonide were administered to two groups of white New Zealand rabbits (n=6) through the oral route following cross over design pattern. The drug concentration in plasma samples were measured using LC-MS/MS method. Pharmacokinetic parameters were determined for each formulation. The comparison of the plasma time curves of the dosage forms showed that each dosage form caused significant differences in the drug plasma levels. The optimized core in cup tablet formulation shown some lag phase initially before releasing the drug. The mean residence time of core in cup tablet formulation was found to be more than the pure drug suspension formulation. The oral administration of Budesonide resulted in a low and quite variable AUC of 154.1±1.44 ng/ml/hr., whereas the optimized core-in-cup tablets resulted in AUC of 918.2±3.11 ng/ml/hr. The bioavailability of optimized formulation was enhanced six times compared with pure drug suspension. From the above results, it can be concluded that the prepared core in cup tablet can be considered as one of the promising formulation techniques for chronotherapeutic management of inflammatory bowel disease.

Formulation and Evaluation of Zolmitriptan Loaded Nano-Structured Lipid Carriers for Effective Treatment in Migraine

Objective: Zolmitriptan is a BCS class II drug having low solubility and poor bioavailability by formulating Nanostructured lipid carriers that will sustain the release of the drug for a longer period which leads to reduced dose and frequency of dose.
 Method: Zolmiptriptan-loaded Nanostructured lipid carriers were fabricated by a solvent diffusion evaporation method. The formulation parameters like the selection of solid (Precirol ATO 5) and liquid lipid (Miglyol 812), solid to liquid lipid ratio (3:1), drug: solid lipid ratio (1:4), the ratio of the organic phase (Acetone: Ethanol, 1:1), the concentration of surfactant (1.5% Tween 80) and temperature (70 °C) of secondary phase were optimized. NLC dispersion was finally lyophilized and converted into a tablet. A stability study of freeze-dried NLCs tablet was performed according to ICH Q1A (R2) guidelines.
 Result: Optimized formulation contained Particle size 11.39 ± 0.85 nm, Zeta potential -38.30 and %EE 76.56 ± 0.12. Characterization was performed by TEM and FTIR analysis. The residual solvent test confirms the concentration of organic solvents was in the acceptable range as per ICH guidelines. In-vitro drug permeation study of NLCs shows 88.91±0.238 % drug release while pure drug suspension shows 58.9±0.578 % drug release after 12 hrs. 
 Conclusion: Zolmitriptan-loaded NLCs show better absorption as compared to pure drug suspension which indicates prolonged release of medicament which may reduce dose or dose frequency.

FORMULATION AND EVALUATION OF SOLID-SUPERSATURABLE-SNEDDS OF IBRUTINIB

Objective: The aim of current research is to develop a solid supersaturable self-nanoemulsifying drug delivery system (S-SNEDDS) of ibrutinib for enhancing the solubility and Bioavailability. Methods: Crossential O 94–Croduret 40SS–carbitol are chosen based on the maximum solubility of ibrutinib and were used to construct ternary phase diagrams with Smix in 3:1 ratio and 70 mg drug loading was done and evaluated for particle size, zeta potential, polydispersity index, entrapment efficiency, drug content and in vitro drug release. Final optimised one is characterised for FTIR, DSC, stability studies and in-vivo studies in rats. To choose a precipitation inhibitor, in vitro precipitation studies were carried out, and supersaturable SNEDDS were made the prepared formulations were evaluated for micromertitic properties and the final optimised one is characterized for FTIR, DSC, SEM and stability studies. Results: Out of all formulations, F15 exhibited good results with the highest drug release of 98.25% in 60 min. LSS9 with 3% HPMC E4M as the best precipitation inhibitor (PPI) exhibited the smallest droplet size of 65.4 nm, a zeta potential of-17.7 mV, and a PDI of 0.453. SSS1 with magnesium trisilicate as an adsorbent showed best flow characteristics and the highest drug content of 99.72%. The DSC, FT-IR and stability studies confirmed the complexation of ibrutinib and amorphous state of the drug and formulation to be stable for 3 mo. Cmax of the solid supersaturable SNEDDS 139.42±2.16 mg/l was significant (p<0.05) as compared to the pure drug suspension formulation 38.15±1.46 mg/l. Tmax of solid supersaturable SNEDDS formulation and pure drug suspension was 1.00±0.06 h and 1.50±0.02h, respectively. Statistically, AUC of the solid supersaturable SNEDDS formulation was significantly higher (p<0.05) as compared to pure drug suspension formulation. Conclusion: Thus, this study indicated that the solid SNEDDS could be used as a potential drug carrier for ibrutinib with improved solubility and and bioavailability.

FORMULATION, IN VITRO AND IN VIVO EVALUATION OF PALBOCICLIB SOLID DISPERSIONS

Objective: The current research is aimed to enhance the dissolution and bioavailability of Palbociclib by formulating into solid dispersion Methods: The Palbociclib solid dispersions (SD) prepared by adopting different methods: Surface solid dispersion technique (SSD1-SSD15), Melt granulation (MG1-MG15) and Liquisolid compacts (LSC1-LSC9). All formulations were evaluated for physico-chemical parameters followed by in vitro dissolution studies. The optimised formulation was subjected to bioavailability studies in rats. Results: The results indicated that the prepared formulation satisfactory results for all the evaluated parameters. The SD formulations prepared by liquisolid compact and Melt Granulation technique (LSC1 and MG 3) displayed maximum dissolution of 99.64% and 99.58%. The FTIR of LSC1 displayed no interaction among drug and excipients while XRD, SEM displayed amorphous nature of drug in formulation. The stability study results indicated that LSC 1 was stable over 3 mo. The in vivo bioavailability studies conducted on rats indicate that at any time point, the drug plasma concentrations in animals administrated with the SD formulation was higher than pure drug. The Cmax of the palbociclib SD was 970.76±1.22 ng/ml and was significant (p<0.05) when compared to pure drug suspension formulation (105.84±0.19 ng/ml). The Tmax of both SD formulation and pure drug were 2.0±0.04 and 4±0.01 h, respectively. The AUC0-∞ for SD was higher 7816.61±1.37 ng. h/ml) than the pure drug suspension 2501.4±1.46 ng. h/ml indicating better systemic drug absorption from SD formulation prepared using Melt granulation technique. Conclusion: A significant enhancement in vitro dissolution profile and bioavailability of the melt granules was observed compared to the pure Palbocicilib and marketed product.