A practical method for oral administration of isotretinoin in pediatric oncology patient: A case study of neuroblastoma.

INTRODUCTION: Isotretinoin is a synthetic vitamin A derivative, administered off-label as maintenance therapy for neuroblastoma. This report addresses the challenge of administering isotretinoin to children, given its availability as soft gelatin capsules only. CASE REPORT: A 3-year-old boy diagnosed with stage IV neuroblastoma has undergone multimodal therapy, including six cycles of chemotherapy, followed by tumor resection and radiotherapy. Later, he was initiated on immunotherapy and prescribed isotretinoin 50 mg orally twice daily for two weeks, before each immunotherapy cycle. Isotretinoin is not available in liquid formulation and the patient could not swallow isotretinoin capsules. Therefore, pharmacist counseling was required to ensure appropriate administration of the drug. MANAGEMENT AND OUTCOMES: The patient's parents were instructed to pierce prescribed capsules, and empty and dilute their contents into a small glass containing olive oil after taking safety measures. Isotretinoin's stability in olive oil for 72 h was compared using high-performance liquid chromatography to its stability in soybean oil. The recovery rates were 98.62% and 98.3%, respectively. Drug miscibility was not an issue as isotretinoin is lipophilic. Therefore, it could be administered easily without considerable remaining on the interior wall of the glass. DISCUSSION: To the best of our knowledge, this is the first report that suggests a practical method for administering isotretinoin in liquid form, particularly in pediatric oncology patients. Isotretinoin was noted to be stable in olive oil and its exposure to light and oxygen would not be an issue given the short time from preparation to administration and the low emphasis on exposure by the manufacturer when such a method is recommended.

Novel Therapeutic Approach in PEGylated Chitosan Nanoparticles of Apigenin for the Treatment of Cancer via Oral Nanomedicine.

The goal of this study was to optimize and formulate apigenin (APG)-loaded pegylated chitosan nanoparticles (PEGylated-CNPs) via ionic gelation techniques using the Box-Behnken design (BBD). Three individual variables, X1(chitosan: TPP concentration), X2 (PEG-400 concentration), and X3 (sonication time), were investigated for their influence on response variables (Y1-particle size (PS); Y2-drug entrapment efficiency (DEE); and Y3-zeta potential (ZP). The optimized formula of APG-PEGylated CNPs was picked from the statistical design and was then examined for physical, morphological, release characterization, anti-oxidant, and anti-tumor potential. The average PS, PDI, %DEE, and ZP were found to be 139.63 ± 5.67 nm, 0.296 ± 0.014, 79.55 ± 3.12%, and 24.68 ± 1.84 mV, respectively. The optimized APG formulation was chosen and reformulated based on the desirability function. Results of the observed and predicted values of responses through the BBD process were found to be nearly identical. The resulting APG-PEGylated CNPs were spherical and smooth, according to surface morphology studies. The release study revealed that PEGylated-CNPs exhibited biphasic release patterns distinguished by an initial burst release of APG only at early phases accompanied by a delayed release near 24 h. Furthermore, APG-PEGylated CNPs demonstrated statistically increased antioxidant activities and cytotoxicity against MCF-7 cells compared to pure APG. Based on the findings, it is possible to conclude that BBD was efficient in optimizing the PEGylated CNPs formulation and recognizing the impacts of formulation variables. In conclusion, the developed formulation has a significant potential for anticancer therapy.

Tricyclodecan-9-yl-Xanthogenate (D609): Mechanism of Action and Pharmacological Applications.

Tricyclodecan-9-yl xanthogenate (D609) is a synthetic tricyclic compound possessing a xanthate group. This xanthogenate compound is known for its diverse pharmacological properties. Over the last three decades, many studies have reported the biological activities of D609, including antioxidant, antiapoptotic, anticholinergic, anti-tumor, anti-inflammatory, anti-viral, anti-proliferative, and neuroprotective activities. Its mechanism of action is extensively attributed to its ability to cause the competitive inhibition of phosphatidylcholine (PC)-specific phospholipase C (PC-PLC) and sphingomyelin synthase (SMS). The inhibition of PCPLC or SMS affects secondary messengers with a lipidic nature, i.e., 1,2-diacylglycerol (DAG) and ceramide. Various in vitro/in vivo studies suggest that PCPLC and SMS inhibition regulate the cell cycle, block cellular proliferation, and induce differentiation. D609 acts as a pro-inflammatory cytokine antagonist and diminishes Aß-stimulated toxicity. PCPLC enzymatic activity essentially requires Zn2+, and D609 might act as a potential chelator of Zn2+, thereby blocking PCPLC enzymatic activity. D609 also demonstrates promising results in reducing atherosclerotic plaque formation, post-stroke cerebral infarction, and cancer progression. The present compilation provides a comprehensive mechanistic insight into D609, including its chemistry, mechanism of action, and regulation of various pharmacological activities.

Norfloxacin Loaded Lipid Polymer Hybrid Nanoparticles for Oral Administration: Fabrication, Characterization, In Silico Modelling and Toxicity Evaluation.

Norfloxacin (NOR), widely employed as an anti-bacterial drug, has poor oral bioavailability. Nano based drug delivery systems are widely used to overcome the existing oral bioavailability challenges. Lipid-Polymer Hybrid Nanoparticles (LPHNs) exhibit the distinctive advantages of both polymeric and liposomes nanoparticles, while excluding some of their disadvantages. In the current study, NOR loaded LPHNs were prepared, and were solid amorphous in nature, followed by in vitro and in vivo evaluation. The optimized process conditions resulted in LPHNs with the acceptable particle size 121.27 nm, Polydispersity Index (PDI) of 0.214 and zeta potential of -32 mv. The addition of a helper lipid, oleic acid, and polymers, ethyl cellulose, substantially increased the encapsulation efficiency (EE%) (65% to 97%). In vitro study showed a sustained drug release profile (75% within 12 h) for NOR LPHNs. The optimized NOR LPHNs showed a significant increase (p < 0.05) in bioavailability compared to the commercial product. From the acute toxicity study, the LD50 value was found to be greater than 1600 mg/kg. The molecular modelling studies substantiated the experimental results with the best combination of polymers and surfactants that produced highly stable LPHNs. Therefore, LPHNs proved to be a promising system for the delivery of NOR, as well as for other antibiotics and hydrophobic drugs.

Cholinesterase inhibitory activity of tinosporide and 8-hydroxytinosporide isolated from Tinospora cordifolia: In vitro and in silico studies targeting management of Alzheimer's disease.

Tinosporide and 8-hydroxytinosporide isolated from Tinospora cordifolia were evaluated for acetylcholinesterase (AChE) and butylcholinesterase (BuChE) inhibitory activities. The structure of the compound was confirmed by spectroscopic analysis, whereas cholinesterase inhibition was investigated by Ellman method using donepezil as standard drug and the data were presented as IC50 (µg/ml ± SEM). Furthermore, donepezil, tinosporide and 8-hydroxytinosporide were executed for docking analysis. The results from the isolated compounds TC-16R confirmed as tinosporide promisingly inhibited AChE with IC50 value of 13.45 ± 0.144, whereas TC-19R confirmed as 8-hydroxytinosporide moderately inhibited AChE with IC50 value of 46.71 ± 0.511. In case of BuChE inhibition, the IC50 values were found to be 408.50 ± 17.197 and 317.26 ± 6.918 for tinosporide and 8-hydroxytinosporide, respectively. The in silico studies revealed that the ligand tinosporide fit with the binding sites and inhibited AChE. Overall, the study findings suggested that tinosporide would be a complementary noble molecule of donepezil which is correlated with its pharmacological activity through in vitro studies, while 8-hydroxytinosporide modestly inhibited BuChE and the results are very close to the standard donepezil.

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.

Enhancing Oral Bioavailability of Apigenin Using a Bioactive Self-Nanoemulsifying Drug Delivery System (Bio-SNEDDS): In Vitro, In Vivo and Stability Evaluations.

Apigenin (APG) is a very well-known flavonoid for its anti-inflammatory and anticancer properties. The purpose of this study is to improve the solubility and bioavailability of APG using a stable bioactive self-nanoemulsifying drug delivery system (Bio-SNEDDS). APG was incorporated in an oil phase comprising coconut oil fatty acid, Imwitor 988, Transcutol P, and HCO30 to form a Bio-SNEDDS. This preparation was characterized for morphology, particle size, and transmission electron microscopy (TEM). The APG performance was investigated in terms of loading, precipitation, release and stability tests from the optimal Bio-SNEDDS. An antimicrobial test was performed to investigate the activity of the Bio-SNEDDS against the selected strains. Bioavailability of the Bio-SNEDDS was evaluated using Wister rats against the commercial oral product and the pure drug. The results demonstrated the formation of an efficient nanosized (57 nm) Bio-SNEDDS with a drug loading of 12.50 mg/gm which is around 500-fold higher than free APG. TEM analysis revealed the formation of spherical and homogeneous nanodroplets of less than 60 nm. The dissolution rate was faster than the commercial product and was able to maintain 90% APG in gastro intestinal solution for more than 4 h. A stability study demonstrated that the Bio-SNEDDS is stable at a harsh condition. The in vivo pharmacokinetics parameters of the Bio-SNEDDS formulation in comparison to the pure drug showed a significant increase in maximum concentration (Cmax) and area under the curve (AUC (0-t)) of 105.05% and 91.32%, respectively. Moreover, the antimicrobial study revealed moderate inhibition in the bacterial growth rate. The APG-Bio-SNEDDS could serve as potential carrier aimed at improving the clinical application of APG.

Impact Of Penetratin Stereochemistry On The Oral Bioavailability Of Insulin-Loaded Solid Lipid Nanoparticles.

PURPOSE: This study evaluated the stereoisomeric effect of L- and D-penetratin-cell-penetrating peptides (CPPs)-incorporated insulin-loaded solid lipid nanoparticles (INS-SLNs) on the bioavailability (BA) of oral insulin (INS). METHODS: Insulin-loaded solid nanoparticles, L-penetratin-INS-SLNs (LP-INS-SLNs), and D-penetratin-INS-SLNs (DP-INS-SLNs) were formulated by double emulsification. The developed SLNs were evaluated for particle size, zeta potential (ZP), and drug encapsulation and subjected to differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and evaluated for stability against enzymatic degradation in rat intestinal fluid. Finally, the SLNs were administered to rats to evaluate the BA of INS-SLNs that contained L- and D-penetratin. RESULTS: The mean particle size, PDI, and ZP values of INS-SLNs, LP-INS-SLNs, and DP-INS-SLNs ranged from 618.5 to 973.0 nm, 0.227 to 0.734, and -17.0 to -23.7 mV, respectively. The encapsulation efficiency (%EE) and drug loading (%DL) of INS-SLNs, LP-INS-SLNs, and DP-INS-SLNs ranged from 59.03% to 67.42% and from 1.62% to 1.82%, respectively. Differential scanning calorimetry and FTIR analyses indicated that INS was successfully encapsulated in SLNs. Enzymatic degradation of DP-INS-SLNs was slower in intestinal fluid, and the half-life (t1/2) was significantly prolonged, compared to all other SLNs. The pharmacological availability (PA) and BA of orally administered LP-INS-SLNs, which were the most effective SLNs, were 13.1% and 15.7% relative to s.c. administration, respectively. CONCLUSION: Penetratin stereochemistry significantly impacted oral BA of INS-SLNs, which are promising carriers for oral INS administration.

Evaluation of the bioavailability of hydrocortisone when prepared as solid dispersion.

This study was conducted to formulate, characterize, and investigate the bioavailability of hydrocortisone (HCT) when prepared as solid dispersions. HCT was mixed in an organic solvent with polyethylene glycol 4000 (PEG 4000) and Kolliphor® P 407. Spray drying technique was employed to form a solid dispersion formulation at a specific ratio. Physical and chemical characterization of the formed particles were achieved using differential scanning calorimetry, scanning electron microscopy, Fourier transform infrared spectroscopy, and powder X-ray diffractometry. Furthermore, comparative in vitro and in vivo studies were conducted between the formulated particles against neat HCT. The formulated solid dispersion showed elongated particles with leaf-like structure. Formation of new chemical bonds in the formed particle was suggested due to the change in the vibrational wave numbers and the significant improvement in the bioavailability of the dispersed particles proved the importance of this technique.

Dissolution and bioavailability improvement of bioactive apigenin using solid dispersions prepared by different techniques.

Apigenin (APG) is a poorly soluble bioactive compound/nutraceutical which shows poor bioavailability upon oral administration. Hence, the objective of this research work was to develop APG solid dispersions (SDs) using different techniques with the expectation to obtain improvement in its in vitro dissolution rate and in vivo bioavailability upon oral administration. Different SDs of APG were prepared by microwave, melted and kneaded technology using pluronic-F127 (PL) as a carrier. Prepared SDs were characterized using "thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier transform infra-red (FTIR) spectrometer, powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM)". After characterization, prepared SDs of APG were studied for in vitro drug release/dissolution profile and in vivo pharmacokinetic studies. The results of TGA, DSC, FTIR, PXRD and SEM indicated successful formation of APG SDs. In vitro dissolution experiments suggested significant release of APG from all SDs (67.39-84.13%) in comparison with control (32.74%). Optimized SD of APG from each technology was subjected to in vivo pharmacokinetic study in rats. The results indicated significant improvement in oral absorption of APG from SD prepared using microwave and melted technology in comparison with pure drug and commercial capsule. The enhancement in oral bioavailability of APG from microwave SD (319.19%) was 3.19 fold as compared with marketed capsule (100.00%). Significant enhancement in the dissolution rate and oral absorption of APG from SD suggested that developed SD systems can be successfully used for oral drug delivery system of APG.

Pretreatment With Risperidone Ameliorates Systemic LPS-Induced Oxidative Stress in the Cortex and Hippocampus.

Risperidone (RIS), an atypical antipsychotic has been found to show anti-inflammatory effect against lipopolysaccharide (LPS)-induced inflammation. In vitro study has revealed that RIS inhibits the LPS-induced reactive oxygen species (ROS) formation. We investigated the antioxidant effects of RIS on LPS-induced oxidative stress markers in Swiss albino mice. Ten weeks old male Swiss albino mice (30 ± 2 g) were pretreated with either distilled water (control) or RIS (3 mg/kg) for 7 days. On day 8, animals were challenged with a single dose of LPS (0.8 mg/kg) while control animals received distilled water only. The animals were sacrificed after 24 h of LPS administration and tissue samples were collected. RIS administration significantly (p < 0.05) reduced the LPS-induced elevated levels of lipid peroxidation product malondialdehyde (MDA), advanced protein oxidation products, and nitric oxide (NO) in the cortex. Catalase (CAT) and superoxide dismutase (SOD) levels were also diminished while the level of glutathione (GSH) was enhanced. Hippocampus data showed that RIS significantly (p < 0.05) reduced the LPS-induced increased levels of MDA and NO, and SOD activity. Our results suggest that LPS-induced neuronal oxidative damage can be alleviated by the pretreatment with RIS and the effect is shown presumably by scavenging of the ROS by risperidone as an antioxidant.

Mixing of low-dose cohesive drug and overcoming of pre-blending step using a new gentle-wing high-shear mixer granulator.

The objective of this study was to examine the influence of drug amount and mixing time on the homogeneity and content uniformity of a low-dose drug formulation during the dry mixing step using a new gentle-wing high-shear mixer. Moreover, the study investigated the influence of drug incorporation mode on the content uniformity of tablets manufactured by different methods. Albuterol sulfate was selected as a model drug and was blended with the other excipients at two different levels, 1% w/w and 5% w/w at impeller speed of 300 rpm and chopper speed of 3000 rpm for 30 min. Utilizing a 1 ml unit side-sampling thief probe, triplicate samples were taken from nine different positions in the mixer bowl at selected time points. Two methods were used for manufacturing of tablets, direct compression and wet granulation. The produced tablets were sampled at the beginning, middle, and end of the compression cycle. An analysis of variance analysis indicated the significant effect (p < .05) of drug amount on the content uniformity of the powder blend and the corresponding tablets. For 1% w/w and 5% w/w formulations, incorporation of the drug in the granulating fluid provided tablets with excellent content uniformity and very low relative standard deviation (∼0.61%) during the whole tableting cycle compared to direct compression and granulation method with dry incorporation mode of the drug. Overall, gentle-wing mixer is a good candidate for mixing of low-dose cohesive drug and provides tablets with acceptable content uniformity with no need for pre-blending step.

Preparation and Characterization of Stable Nanosuspension for Dissolution Rate Enhancement of Furosemide: A Quality by Design (QbD) Approach.

BACKGROUND: Nano drug delivery systems have the potential to address the challenges of delivering BCS Class II and IV drugs like furosemide. The purpose of the current study is to prepare stable nanosuspension and investigate in vitro dissolution performance of the model compound furosemide using quality by design (QbD) approach. METHODS: Nanosuspension batches with uniform particle size were prepared for furosemide using the antisolvent precipitation method. A quality by design (Qbd) approach was explored to understand the impact of process parameters (stirring time, stirring speed, temperature, and injection rate) and material attributes (drug concentration, stabilizer type, drug: stabilizer ratio, and antisolvent: solvent ratio) on the quality attributes of furosemide nanosuspension using a full factorial experimental design. Multiple linear regression and ANOVA were employed to estimate and identify the critical process parameters and material attributes. Injection rate and stirring time were identified as the most critical process parameters' affecting the quality attributes of furosemide nanosuspension. RESULTS: Individual material attributes did not show significant impact on the average particle size of the nanocrystals, however two-way interactions between material attributes (stabilizer type/drug concentration and stabilizer type/antisolvent: solvent ratio) significantly affected nanosuspension particle size distribution. Solid state characterization (PXRD, DSC and SEM) did not exhibit any changes of physical form during preparation and optimization of the furosemide nanosuspension. Dissolution of the furosemide nanocrystals in gastric media was significantly higher than that observed for micronized furosemide suspension and raw furosemide powder. Stability study data suggests that optimized batches of furosemide nanosuspensions were stable for three months at 4°C and ambient conditions. CONCLUSION: The antisolvent precipitation method can produce stable furosemide nanosuspensions with desirable quality attributes and enhancement of dissolution rate in the gastric medium as compared to the raw furosemide powder and microsuspension.

Investigation of the combined effect of MgO and PEG on the release profile of mefenamic acid prepared via hot-melt extrusion techniques.

This study aimed to investigate the combined effect of magnesium oxide (MgO) as an alkalizer and polyethylene glycol (PEG) as a plasticizer and wetting agent in the presence of Kollidon® 12 PF and 17 PF polymer carriers on the release profile of mefenamic acid (MA), which was prepared via hot-melt extrusion technique. Various drug loads of MA and various ratios of the polymers, PEG 3350 and MgO were blended using a V-shell blender and extruded using a twin-screw extruder (16-mm Prism EuroLab, ThermoFisher Scientific, Carlsbad, CA) at different screw speeds and temperatures to prepare a solid dispersion system. Differential scanning calorimetry and X-ray diffraction data of the extruded material confirmed that the drug existed in the amorphous form, as evidenced by the absence of corresponding peaks. MgO and PEG altered the micro-environmental pH to be more alkaline (pH 9) and increased the hydrophilicity and dispersibility of the extrudates to enhance MA solubility and release, respectively. The in vitro release study demonstrated an immediate release for 2 h with more than 80% drug release within 45 min in matrices containing MgO and PEG in combination with polyvinylpyrrolidone when compared to the binary mixture, physical mixture and pure drug.

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.

Influence of Molecular Weight of Carriers and Processing Parameters on the Extrudability, Drug Release, and Stability of Fenofibrate Formulations Processed by Hot-Melt Extrusion.

The objective of this study was to investigate the extrudability, drug release, and stability of fenofibrate (FF) formulations utilizing various hot-melt extrusion processing parameters and polyvinylpyrrolidone (PVP) polymers of various molecular weights. The different PVP grades selected for this study were Kollidon® 12 PF (K12), Kollidon® 30 (K30), and Kollidon® 90 F (K90). FF was extruded with these polymers at three drug loadings (15%, 25%, and 35% w/w). Additionally, for FF combined with each of the successfully extruded PVP grades (K12 and K30), the effects of two levels of processing parameters for screw design, screw speed, and barrel temperature were assessed. It was found that the FF with (K90) was not extrudable up to 35% drug loading. With low drug loading, the polymer viscosity significantly influenced the release of FF. The crystallinity remaining was vital in the highest drug-loaded formulation dissolution profile, and the glass transition temperature of the polymer significantly affected its stability. Modifying the screw configuration resulted in more than 95% post-extrusion drug content of the FF-K30 formulations. In contrast to FF-K30 formulations, FF release and stability with K12 were significantly influenced by the extrusion temperature and screw speed.

Mefenamic acid taste-masked oral disintegrating tablets with enhanced solubility via molecular interaction produced by hot melt extrusion technology.

The objective of this study was to enhance the solubility as well as to mask the intensely bitter taste of the poorly soluble drug, Mefenamic acid (MA). The taste masking and solubility of the drug was improved by using Eudragit® E PO in different ratios via hot melt extrusion (HME), solid dispersion technology. Differential scanning calorimetry (DSC) studies demonstrated that MA and E PO were completely miscible up to 40% drug loads. Powder X-ray diffraction analysis indicated that MA was converted to its amorphous phase in all of the formulations. Additionally, FT-IR analysis indicated hydrogen bonding between the drug and the carrier up to 25% of drug loading. SEM images indicated aggregation of MA at over 30% of drug loading. Based on the FT-IR, SEM and dissolution results for the extrudates, two optimized formulations (20% and 25% drug loads) were selected to formulate the orally disintegrating tablets (ODTs). ODTs were successfully prepared with excellent friability and rapid disintegration time in addition to having the desired taste-masking effect. All of the extruded formulations and the ODTs were found to be physically and chemically stable over a period of 6 months at 40°C/75% RH and 12 months at 25°C/60% RH, respectively.