Tailoring of Bilosomal Nanogel for Augmenting the Off-Label Use of Sildenafil Citrate in Pediatric Pulmonary Hypertension.

Pediatric pulmonary hypertension is a serious syndrome with significant morbidity and mortality. Sildenafil is widely used off-label in pediatric patients with pulmonary arterial hypertension. In this study, bile salt-stabilized nanovesicles (bilosomes) were screened for their efficacy to enhance the transdermal delivery of the phosphodiesterase type 5 inhibitor, sildenafil citrate, in an attempt to augment its therapeutic efficacy in pediatric pulmonary hypertension. A response surface methodology was implemented for fabricating and optimizing a bilosomal formulation of sildenafil (SDF-BS). The optimized SDF-BS formulation was characterized in terms of its entrapment efficiency (EE), zeta potential, vesicle size, and in vitro release profile. The optimized formula was then loaded onto hydroxypropyl methyl cellulose (HPMC) hydrogel and assessed for skin permeation, in vivo pharmacokinetics, and pharmacodynamic studies. The optimized SDF-BS showed the following characteristic features; EE of 88.7 ± 1.1%, vesicle size of 185.0 + 9.2 nm, zeta potential of -20.4 ± 1.1 mV, and efficiently sustained SDF release for 12 h. Skin permeation study revealed a remarkable improvement in SDF penetration from bilosomal gel compared to plain SDF gel. In addition, pharmacokinetic results revealed that encapsulating SDF within bilosomal vesicles significantly enhanced its systemic bioavailability (∼3 folds), compared to SDF oral suspension. In addition, pharmacodynamic investigation revealed that, compared to plain SDF gel or oral drug suspension, SDF-BS gel applied topically triggered a significant elevation (p < 0.05) in cGMP serum levels, underscoring the superior therapeutic efficacy of SDF-BS gel. Conclusively, bilosomes can be viewed as a promising nanocarrier for transdermal delivery of SDF that would grant higher therapeutic efficiency while alleviating the limitations encountered with SDF oral administration.

Spanlastic-laden nanogel as a plausible platform for dermal delivery of bimatoprost with superior cutaneous deposition and hair regrowth efficiency in androgenic alopecia.

Bimatoprost (BIM) is a prostaglandin F2α analogs originally approved for the treatment of glaucoma and ocular hypertension. Recent studies have highlighted its potential to boost hair growth. The objective of this investigation is to challenge the potential of spanlastics (SLs) as a surfactant-based vesicular system for promoting the cutaneous delivery of BIM for the management of alopecia. BIM-loaded spanlastics (BIM-SLs), composed of Span as the main vesicle component and Tween as the edge activator, were fabricated by ethanol injection method. The formulated BIM-SLs were optimized by 23 full factorial design. The optimized formula (F1) was characterized for entrapment efficiency, surface charge, vesicle size, and drug release after 12 h (Q12h). The optimized formula (F1) exhibited high drug entrapment efficiency (83.1 ± 2.1%), appropriate zeta potential (-19.9 ± 2.1 mV), Q12h of 71.3 ± 5.3%, and a vesicle size of 364.2 ± 15.8 nm, which favored their cutaneous accumulation. In addition, ex-vivo skin deposition studies revealed that entrapping BIM within spanlastic-based nanogel (BIM-SLG) augmented the dermal deposition of BIM, compared to naïve BIM gel. Furthermore, in vivo studies verified the efficacy of spanlastic vesicles to boost the cutaneous accumulation of BIM compared to naive BIM gel; the AUC0-12h of BIM-SLG was 888.05 ± 72.31 µg/mL.h, which was twice as high as that of naïve BIM gel (AUC0-12h 382.86 ± 41.12 µg/mL.h). Intriguingly, BIM-SLG outperforms both naïve BIM gel and commercial minoxidil formulations in stimulating hair regrowth in an androgenetic alopecia mouse model. Collectively, spanlastic vesicles might be a potential platform for promoting the dermal delivery of BIM in managing alopecia.

Development of Carvedilol Nanoformulation-Loaded Poloxamer-Based In Situ Gel for the Management of Glaucoma.

The objective of the current study was to fabricate a thermosensitive in situ gelling system for the ocular delivery of carvedilol-loaded spanlastics (CRV-SPLs). In situ gel formulations were prepared using poloxamer analogs by a cold method and was further laden with carvedilol-loaded spanlastics to boost the precorneal retention of the drug. The gelation capacity, rheological characteristics, muco-adhesion force and in vitro release of various in situ gel formulations (CS-ISGs) were studied. The optimized formula (F2) obtained at 22% w/v poloxamer 407 and 5% w/v poloxamer 188 was found to have good gelation capacity at body temperature with acceptable muco-adhesion properties, appropriate viscosity at 25 °C that would ease its ocular application, and relatively higher viscosity at 37 °C that promoted prolonged ocular residence of the formulation post eye instillation and displayed a sustained in vitro drug release pattern. Ex vivo transcorneal penetration studies through excised rabbit cornea revealed that F2 elicited a remarkable (p ˂ 0.05) improvement in CRV apparent permeation coefficient (Papp = 6.39 × 10-6 cm/s) compared to plain carvedilol-loaded in situ gel (CRV-ISG; Papp = 2.67 × 10-6 cm/s). Most importantly, in normal rabbits, the optimized formula (F2) resulted in a sustained intraocular pressure reduction and a significant enhancement in the ocular bioavailability of carvedilol, as manifested by a 2-fold increase in the AUC0-6h of CRV in the aqueous humor, compared to plain CRV-ISG formulation. To sum up, the developed thermosensitive in situ gelling system might represent a plausible carrier for ophthalmic drug delivery for better management of glaucoma.

Diosmin-Loaded Nanoemulsion-Based Gel Formulation: Development, Optimization, Wound Healing and Anti-Inflammatory Studies.

The wound-healing process is complex and prone to interruption or failure, which can result in the development of chronic wounds that never heal. This can be overcome by seeking prompt medical attention, which will reduce the likelihood of complications and speed up the healing of the cutaneous wound. It has been established that functionalized engineered biomaterials are a possible strategy for starting skin wound care. The purpose of the current study is to develop a diosmin (DSM)-loaded nanoemulsion (NE)-based gel formulation and to investigate its wound healing and anti-inflammatory activity on rats. The DSM-loaded NEs (F1-F17) were developed and optimized with the help of Box-Behnken Design Expert. The DSM-Nes were developed using lauroglycol 90 (LG90®) as oil, Tween-80 as surfactant and transcutol-HP (THP) as co-surfactant. The optimized Nes showed globule size (41 ± 0.07 nm), polydispersity index (PDI) (0.073 ± 0.008) and percentage of entrapment efficiency (%EE) (87 ± 0.81%). This optimized DSM-loaded NEs (F1) was further evaluated and incorporated into 1% carbopol 940 gel. F1-loaded gel was then characterized for drug content, spreadability, in vitro release, wound healing, and anti-inflammatory studies. The developed gel of DSM was found to show significantly better (p < 0.05) wound-healing and anti-inflammatory activity.

Tailoring of Novel Bile Salt Stabilized Vesicles for Enhanced Transdermal Delivery of Simvastatin: A New Therapeutic Approach against Inflammation.

Simvastatin (SMV), a cholesterol-lowering agent, has antioxidant and anti-inflammatory effects. Nevertheless, the oral use of SMV is linked with poor systemic bioavailability owing to its limited aqueous solubility and extensive first-pass metabolism. The aim of this study was to evaluate the feasibility of transdermal delivery of SMV using bile salt stabilized vesicles (bilosomes) for enhancing the anti-inflammatory potential of SMV. SMV-loaded bilosomes (SMV-BS) were prepared by the thin film hydration technique and optimized by 33 Box-Behnken design. The fabricated SMV-BS were assessed for vesicle size, entrapment efficiency (% EE) and cumulative drug release. The optimized formula was incorporated into HPMC gel and investigated for physical properties, ex vivo permeation, in vivo pharmacokinetic study and anti-inflammatory potential in inflamed paw edema rat model. The optimized SMV-BS showed vesicle size of 172.1 ± 8.1 nm and % EE of 89.2 ± 1.8%. In addition, encapsulating SMV within bilosomal vesicles remarkably sustained drug release over 12 h, compared to plain drug suspension. Furthermore, SMV-loaded bilosomal gel showed a three-fold enhancement in SMV transdermal flux, compared to plain drug suspension. Most importantly, the relative bioavailability of SMV-BS gel was ~2-fold and ~3-fold higher than those of oral SMV suspension and SMV gel, respectively. In carrageenan-induced paw edema model, SMV-BS gel induced a potent anti-inflammatory effect, as evidenced by a remarkable reduction in paw edema, which was comparable to that of the standard anti-inflammatory drug, indomethacin. Collectively, bilosomes might represent a plausible transdermal drug delivery system that could enhance the anti-inflammatory activity of SMV by boosting its skin permeation and its systemic bioavailability.

Optimization of tamoxifen solubility in carbon dioxide supercritical fluid and investigating other molecular targets using advanced artificial intelligence models.

Particle size, shape and morphology can be considered as the most significant functional parameters, their effects on increasing the performance of oral solid dosage formulation are indisputable. Supercritical Carbon dioxide fluid (SCCO2) technology is an effective approach to control the above-mentioned parameters in oral solid dosage formulation. In this study, drug solubility measuring is investigated based on artificial intelligence model using carbon dioxide as a common supercritical solvent, at different pressure and temperature, 120-400 bar, 308-338 K. The results indicate that pressure has a strong effect on drug solubility. In this investigation, Decision Tree (DT), Adaptive Boosted Decision Trees (ADA-DT), and Nu-SVR regression models are used for the first time as a novel model on the available data, which have two inputs, including pressure, X1 = P(bar) and temperature, X2 = T(K). Also, output is Y = solubility. With an R-squared score, DT, ADA-DT, and Nu-SVR showed results of 0.836, 0.921, and 0.813. Also, in terms of MAE, they showed error rates of 4.30E-06, 1.95E-06, and 3.45E-06. Another metric is RMSE, in which DT, ADA-DT, and Nu-SVR showed error rates of 4.96E-06, 2.34E-06, and 5.26E-06, respectively. Due to the analysis outputs, ADA-DT selected as the best and novel model and the find optimal outputs can be shown via vector: (x1 = 309, x2 = 317.39, Y1 = 7.03e-05).

Computational simulation and target prediction studies of solubility optimization of decitabine through supercritical solvent.

Computational analysis of drug solubility was carried out using machine learning approach. The solubility of Decitabine as model drug in supercritical CO2 was studied as function of pressure and temperature to assess the feasibility of that for production of nanomedicine to enhance the solubility. The data was collected for solubility optimization of Decitabine at the temperature 308-338 K, and pressure 120-400 bar used as the inputs to the machine learning models. A dataset of 32 data points and two inputs (P and T) have been applied to optimize the solubility. The only output is Y = solubility, which is Decitabine mole fraction solubility in the solvent. The developed models are three models including Kernel Ridge Regression (KRR), Decision tree Regression (DTR), and Gaussian process (GPR), which are used for the first time as a novel model. These models are optimized using their hyper-parameters tuning and then assessed using standard metrics, which shows R2-score, KRR, DTR, and GPR equal to 0.806, 0.891, and 0.998. Also, the MAE metric shows 1.08E-04, 7.40E-05, and 9.73E-06 error rates in the same order. The other metric is MAPE, in which the KRR error rate is 4.64E-01, DTR shows an error rate equal to 1.63E-01, and GPR as the best mode illustrates 5.06E-02. Finally, analysis using the best model (GPR) reveals that increasing both inputs results in an increase in the solubility of Decitabine. The optimal values are (P = 400, T = 3.38E + 02, Y = 1.07E-03).

Application of CO2 Supercritical Fluid to Optimize the Solubility of Oxaprozin: Development of Novel Machine Learning Predictive Models.

Over the last years, extensive motivation has emerged towards the application of supercritical carbon dioxide (SCCO2) for particle engineering. SCCO2 has great potential for application as a green and eco-friendly technique to reach small crystalline particles with narrow particle size distribution. In this paper, an artificial intelligence (AI) method has been used as an efficient and versatile tool to predict and consequently optimize the solubility of oxaprozin in SCCO2 systems. Three learning methods, including multi-layer perceptron (MLP), Kriging or Gaussian process regression (GPR), and k-nearest neighbors (KNN) are selected to make models on the tiny dataset. The dataset includes 32 data points with two input parameters (temperature and pressure) and one output (solubility). The optimized models were tested with standard metrics. MLP, GPR, and KNN have error rates of 2.079 × 10-8, 2.173 × 10-9, and 1.372 × 10-8, respectively, using MSE metrics. Additionally, in terms of R-squared, they have scores of 0.868, 0.997, and 0.999, respectively. The optimal inputs are the same as the maximum possible values and are paired with a solubility of 1.26 × 10-3 as an output.

Preparation and Characterization of a Novel Mucoadhesive Carvedilol Nanosponge: A Promising Platform for Buccal Anti-Hypertensive Delivery.

Carvedilol (CRV) is a non-selective third generation beta-blocker used to treat hypertension, congestive heart failure and angina pectoris. Oral administration of CRV showed poor bioavailability (25%), which might be ascribed to its extensive first-pass metabolism. Buccal delivery is known to boost drugs bioavailability. The aim of this study is to investigate the efficacy of bilosomes-based mucoadhesive carvedilol nanosponge for enhancing the oral bioavailability of CRV. The bilosomes were prepared, optimized and characterized for particle size, surface morphology, encapsulation efficiency and ex-vivo permeation studies. Then, the optimized formula was incorporated into a carboxymethyl cellulose/hydroxypropyl cellulose (CMC/HPC) composite mixture to obtain buccal nanosponge enriched with CRV bilosomes. The optimized bilosome formula (BLS9), showing minimum vesicle size, maximum entrapment, and highest cumulative in vitro release, exhibited a spherical shape with 217.2 nm in diameter, 87.13% entrapment efficiency, and sustained drug release for up to 24 h. In addition, ex-vivo drug permeation across sheep buccal mucosa revealed enhanced drug permeation with bilosomal formulations, compared to aqueous drug suspension. Consecutively, BLS9 was incorporated in a CMC/HPC gel and lyophilized for 24 h to obtain bilosomal nanosponge to enhance CRV buccal delivery. Morphological analysis of the prepared nanosponge revealed improved swelling with a porosity of 67.58%. The in vivo assessment of rats indicated that CRV-loaded nanosponge efficiently enhanced systolic/diastolic blood pressure, decreased elevated oxidative stress, improved lipid profile and exhibited a potent cardio-protective effect. Collectively, bilosomal nanosponge might represent a plausible nanovehicle for buccal delivery of CRV for effective management of hypertension.

In silico identification of MicroRNAs targeting the key nucleator of stress granules, G3BP: Promising therapeutics for SARS-CoV-2 infection.

Stress granules (SGs) are non-membrane ribonucleoprotein condensates formed in response to environmental stress conditions via liquid-liquid phase separation (LLPS). SGs are involved in the pathogenesis of aging and aging-associated diseases, cancers, viral infection, and several other diseases. GTPase-activating protein (SH3 domain)-binding protein 1 and 2 (G3BP1/2) is a key component and commonly used marker of SGs. Recent studies have shown that SARS-CoV-2 nucleocapsid protein via sequestration of G3BPs inhibits SGs formation in the host cells. In this study, we have identified putative miRNAs targeting G3BP in search of modulators of the G3BP expression. These miRNAs could be considered as new therapeutic targets against COVID-19 infection via the regulation of SG assembly and dynamics.

Design of Olmesartan Medoxomil-Loaded Nanosponges for Hypertension and Lung Cancer Treatments.

Olmesartan medoxomil (OLM) is one of the prominent antihypertensive drug that suffers from low aqueous solubility and dissolution rate leading to its low bioavailability. To improve the oral bioavailability of OLM, a delivery system based on ethylcellulose (EC, a biobased polymer) nanosponges (NSs) was developed and evaluated for cytotoxicity against the A549 lung cell lines and antihypertensive potential in a rat model. Four OLM-loaded NSs (ONS1-ONS4) were prepared and fully evaluated in terms of physicochemical properties. Among these formulations, ONS4 was regarded as the optimized formulation with particle size (487 nm), PDI (0.386), zeta potential (ζP = -18.1 mV), entrapment efficiency (EE = 91.2%) and drug loading (DL = 0.88%). In addition, a nanosized porous morphology was detected for this optimized system with NS surface area of about 63.512 m2/g, pore volume and pore radius Dv(r) of 0.149 cc/g and 15.274 Å, respectively, measured by nitrogen adsorption/desorption analysis. The observed morphology plus sustained release rate of OLM caused that the optimized formulation showed higher cytotoxicity against A549 lung cell lines in comparison to the pure OLM. Finally, this system (ONS4) reduced the systolic blood pressure (SBP) significantly (p < 0.01) as compared to control and pure OLM drug in spontaneously hypertensive rats. Overall, this study provides a scientific basis for future studies on the encapsulation efficiency of NSs as promising drug carriers for overcoming pharmacokinetic limitations.

Exploitation of Design-of-Experiment Approach for Design and Optimization of Fast-Disintegrating Tablets for Sublingual Delivery of Sildenafil Citrate with Enhanced Bioavailability Using Fluid-Bed Granulation Technique.

Sildenafil citrate undergoes first-pass metabolism, resulting in poor oral bioavailability at 25-41% of the administered dose. This study aimed to design and optimize fast-disintegrating tablets for the sublingual delivery of sildenafil citrate to improve bioavailability and facilitate rapid onset of action. The design-of-experiment (DoE) approach using 32 full factorial design was conducted to develop a new formulation of sildenafil fast-disintegrating sublingual tablets (FDSTs) using the fluid-bed granulation technique. The levels of partially pre-gelatinized starch (5-15%) and microcrystalline cellulose (10-60%) were selected as independent formulation variables. The prepared FDSTs were investigated for physical properties. Further, the optimum formulation was chosen for in vivo study in rabbits. Regression analysis showed that independent variables have a significant (p < 0.05) influence on critical attributes of FDSTs. The optimized formulation showed acceptable mechanical strength (friability < 1.0%) with very fast disintegration (14.561 ± 0.84 s) and dissolution (94.734 ± 2.76% after 15 min). Further, the optimized formulation demonstrated a significant increase (p < 0.01) in Cmax and AUC0-∞ with short tmax compared to the market product (Viagra®). Based on these results, using the DoE approach, a high level of assurance was achieved for FDSTs' product quality and performance.

Formulation of Piperine-Chitosan-Coated Liposomes: Characterization and In Vitro Cytotoxic Evaluation.

The present research work is designed to prepare and evaluate piperine liposomes and piperine-chitosan-coated liposomes for oral delivery. Piperine (PPN) is a water-insoluble bioactive compound used for different diseases. The prepared formulations were evaluated for physicochemical study, mucoadhesive study, permeation study and in vitro cytotoxic study using the MCF7 breast cancer cell line. Piperine-loaded liposomes (PLF) were prepared by the thin-film evaporation method. The selected liposomes were coated with chitosan (PLFC) by electrostatic deposition to enhance the mucoadhesive property and in vitro therapeutic efficacy. Based on the findings of the study, the prepared PPN liposomes (PLF3) and chitosan coated PPN liposomes (PLF3C1) showed a nanometric size range of 165.7 ± 7.4 to 243.4 ± 7.5, a narrow polydispersity index (>0.3) and zeta potential (-7.1 to 29.8 mV). The average encapsulation efficiency was found to be between 60 and 80% for all prepared formulations. The drug release and permeation study profile showed biphasic release behavior and enhanced PPN permeation. The in vitro antioxidant study results showed a comparable antioxidant activity with pure PPN. The anticancer study depicted that the cell viability assay of tested PLF3C2 has significantly (p < 0.001)) reduced the IC50 when compared with pure PPN. The study revealed that oral chitosan-coated liposomes are a promising delivery system for the PPN and can increase the therapeutic efficacy against the breast cancer cell line.

Development and Characterization of Sustained-Released Donepezil Hydrochloride Solid Dispersions Using Hot Melt Extrusion Technology.

The aim of this work was to develop the sustained release formulation of donepezil hydrochloride (DH) using the hot-melt extruded solid dispersion technique via the rational screening of hydrophobic carriers. Hydrophobic carriers with different physicochemical properties such as pH-independent swellability, low-permeability (Eudragit® RS PO (E-RS)), pH-independent non-swellability (ethyl cellulose N7 (EC-N7)), and the presence of lipids (Compritol® 888 ATO (C-888)) with or without pore-forming agents were used to achieve the sustained release profile of DH. Mannitol (MNT) was chosen as the temporary pore-forming agent. The thermal analysis showed that both the drug and C-888 preserved their crystallinity within a solid dispersion. During a dissolution test, MNT could generate pores, and the drug release rate was proportionally correlated to the MNT content. Tailoring of the ratio of C-888 and MNT in the formulations along with an appropriate extrusion temperature profile resulted in the modified release of DH, and a preferable release pattern was obtained under these conditions. C-888 was chosen for the further investigations to obtain tablets with a high integrity. The optimized tablets were compared to the marketed formulation of Aricept® in terms of drug release profiles. The optimized formulation showed the stable and sustained release behavior of extended release profile, which was close to the release behavior of Aricept® with good tablet characteristics. It was concluded that the hot-melt extrusion technique can be utilized for the manufacturing of DH sustained release tablets with improved tablet integrity and characteristics by co-processing the tablet excipient with DH/C-888.

Enhancing the Poor Flow and Tableting Problems of High Drug-Loading Formulation of Canagliflozin Using Continuous Green Granulation Process and Design-of-Experiment Approach.

Maximization of drug-loading can significantly reduce the size of dosage form and consequently decrease the cost of manufacture. In this research, two challenges were addressed: poor flow and tableting problems of high-drug loading (>70%) formulation of canagliflozin (CNG), by adopting the moisture-activated dry granulation (MADG) process. In this method, heating and drying steps were omitted so, called green granulation process. A 32 full-factorial design was performed for optimization of key process variables, namely the granulation fluid level (X1) and the wet massing time (X2). Granulation of CNG was carried out in the presence of polyvinylpyrrolidone, and the prepared granules were compressed into tablets. Regression analysis demonstrated the significant (p ≤ 0.05) effect of X1 and X2 on properties of granules and corresponding tablets, with pronounced impact of X1. Additionally, marked improvement of granules' properties and tableting of CNG were observed. Furthermore, the optimized process conditions that produced good flow properties of granules and acceptable tablets were high level of granulation fluid (3.41% w/w) and short wet massing time (1.0 min). Finally, the MADG process gives the opportunity to ameliorate the poor flow and tableting problems of CNG with lower amounts of excipients, which are important for successful development of uniform dosage unit.

Estimating the Solubility, Solution Thermodynamics, and Molecular Interaction of Aliskiren Hemifumarate in Alkylimidazolium Based Ionic Liquids.

Estimating the solubility and solution thermodynamics parameters of aliskiren hemifumarate (AHF) in three different room temperature ionic liquids (RTILs), Transcutol-HP (THP) and water are interesting as there is no solubility data available in the literature. In the current study, the solubility and solution thermodynamics of AHF in three different RTILs, THP and water at the temperature range from 298.2 to 318.2 K under air pressure 0.1 MP were evaluated. The solid phase evaluation by Differential Scanning Calorimetry (DSC) and Powder X-ray Diffraction (PXRD) indicated no conversion of AHF into polymorph. The mole fraction solubility of AHF was found to be highest in 1-hexyl-3-methylimidazolium hexafluorophosphate (HMMHFP) ionic liquid (7.46 × 10-2) at 318.2 K. The obtained solubility values of AHF was regressed by the Apelblat and van't Hoff models with overall root mean square deviations (RMSD) of 0.62% and 1.42%, respectively. The ideal solubility of AHF was higher compared to experimental solubility values at different temperatures. The lowest activity coefficient was found in HMMHFP, which confirmed highest molecular interaction between AHF-HMMHFP. The estimated thermodynamic parameters confirmed endothermic and entropy driven dissolution of AHF in different RTILs, THP, and water.

Preparation and evaluation of enteric coated tablets of hot-melt extruded lansoprazole.

The objective of this work was to use hot-melt extrusion (HME) technology to improve the physiochemical properties of lansoprazole (LNS) to prepare stable enteric coated LNS tablets. For the extrusion process, we chose Kollidon® 12 PF (K12) polymeric matrix. Lutrol® F 68 was selected as the plasticizer and magnesium oxide (MgO) as the alkalizer. With or without the alkalizer, LNS at 10% drug load was extruded with K12 and F68. LNS changed to the amorphous phase and showed better release compared to that of the pure crystalline drug. Inclusion of MgO improved LNS extrudability and release and resulted in over 80% drug release in the buffer stage. Hot-melt extruded LNS was physically and chemically stable after 12 months of storage. Both formulations were studied for compatibility with Eudragit® L100-55. The optimized formulation was compressed into a tablet followed by coating process utilizing a pan coater using L100-55 as an enteric coating polymer. In a two-step dissolution study, the release profile of the enteric coated LNS tablets in the acidic stage was less than 10% of the LNS, while that in the buffer stage was more than 80%. Drug content analysis revealed the LNS content to be 97%, indicating the chemical stability of the enteric coated tablet after storage for six months. HME, which has not been previously used for LNS, is a valuable technique to reduce processing time in the manufacture of enteric coated formulations of an acid-sensitive active pharmaceutical ingredient as compared to the existing methods.

Optimization of hot melt extrusion parameters for sphericity and hardness of polymeric face-cut pellets.

The aim of this study was to formulate face-cut, melt-extruded pellets, and to optimize hot melt process parameters to obtain maximized sphericity and hardness by utilizing Soluplus(®) as a polymeric carrier and carbamazepine (CBZ) as a model drug. Thermal gravimetric analysis (TGA) was used to detect thermal stability of CBZ. The Box-Behnken design for response surface methodology was developed using three factors, processing temperature ( °C), feeding rate (%), and screw speed (rpm), which resulted in 17 experimental runs. The influence of these factors on pellet sphericity and mechanical characteristics was assessed and evaluated for each experimental run. Pellets with optimal sphericity and mechanical properties were chosen for further characterization. This included differential scanning calorimetry, drug release, hardness friability index (HFI), flowability, bulk density, tapped density, Carr's index, and fourier transform infrared radiation (FTIR) spectroscopy. TGA data showed no drug degradation upon heating to 190 °C. Hot melt extrusion processing conditions were found to have a significant effect on the pellet shape and hardness profile. Pellets with maximum sphericity and hardness exhibited no crystalline peak after extrusion. The rate of drug release was affected mainly by pellet size, where smaller pellets released the drug faster. All optimized formulations were found to be of superior hardness and not friable. The flow properties of optimized pellets were excellent with high bulk and tapped density.

Preparation and Evaluation of Hot-Melt Extruded Patient-Centric Ketoprofen Mini-Tablets.

BACKGROUND: Bitter tasting drugs represent a large portion of active pharmaceutical ingredients. Mini-tablets are specifically designed for patients with difficulty in swallowing particular in young children up to 10 years of age, geriatric patients and patients with esophagitis. OBJECTIVE: The present study was aimed to prepare, taste-masked mini-tablets, which are easily swallowed dosage forms, primarily to be used by pediatric and geriatric patients. METHODS: Ketoprofen (10%-50% w/w) and Eudragit® EPO were blended and extruded with a 5-mm strand die and cut into consistent mini-tablets by using an adapted downstream pelletizer. RESULTS: Differential scanning calorimetry and polarized light microscopy-hot stage microscopy studies confirmed that the binary mixtures were miscible under the employed extrusion temperatures. In-vitro release studies showed that drug release was less than 0.5% within the first 2 min in simulated salivary fluid (pH 6.8) and more than 90% in the first 20 min in gastric media (pH 1.0). The results of the electronic tongue analysis were well correlated with the drug release profile of the mini-tablets in the artificial saliva. Scanning electron microscopy revealed no cracks on the surface of the minitablets, confirming that the mini-tablets were compact solids. Chemical imaging confirmed the uniform distribution of ketoprofen inside the polymer matrices. CONCLUSION: Eudragit® EPO containing ketoprofen at various drug loads were successfully melt extruded into tastedmasked mini-tablets. The reduced drug release at salivary pH correlated well with Astree e-Tongue studies for taste masking efficiency.