Enhanced Codelivery of Gefitinib and Azacitidine for Treatment of Metastatic-Resistant Lung Cancer Using Biodegradable Lipid Nanoparticles.

Lung cancer is a formidable challenge in clinical practice owing to its metastatic nature and resistance to conventional treatments. The codelivery of anticancer agents offers a potential solution to overcome resistance and minimize systemic toxicity. The encapsulation of these agents within nanostructured lipid carriers (NLCs) provides a promising strategy to enhance lymphatic delivery and reduce the risk of relapse. This study aimed to develop an NLC formulation loaded with Gefitinib and Azacitidine (GEF-AZT-NLC) for the treatment of metastatic-resistant lung cancer. The physicochemical properties of the formulations were characterized, and in vitro drug release was evaluated using the dialysis bag method. The cytotoxic activity of the GEF-AZT-NLC formulations was assessed on a lung cancer cell line, and hemocompatibility was evaluated using suspended red blood cells. The prepared formulations exhibited nanoscale size (235-272 nm) and negative zeta potential values (-15 to -31 mV). In vitro study revealed that the GEF-AZT-NLC formulation retained more than 20% and 60% of GEF and AZT, respectively, at the end of the experiment. Hemocompatibility study demonstrated the safety of the formulation for therapeutic use, while cytotoxicity studies suggested that the encapsulation of both anticancer agents within NLCs could be advantageous in treating resistant cancer cells. In conclusion, the GEF-AZT-NLC formulation developed in this study holds promise as a potential therapeutic tool for treating metastatic-resistant lung cancer.

The role of sodium lauryl sulfate on formulation of directly compressed tablets containing simvastatin and aspirin: Effect on drugs dissolution and gastric mucosa.

According to the American College of Cardiology/American Heart Association (ACC/AHA), both aspirin and statin are used in the primary prevention of cardiovascular diseases. Aspirin (ASA) is contraindicated if there is gastrointestinal bleeding because it will exaggerate the condition. In this study, the effect of surfactant; sodium lauryl sulfate (SLS), in enhancing the in vitro dissolution of simvastatin (SIM) and ASA, as well as gastric irritation and upset, was studied. Oral tablets containing both ASA and SIM with and without the SLS were manufactured using the direct compression technique. The prepared tablets were characterized with respect to hardness, friability, uniformity of dosage units, in vitro disintegration, and dissolution. The effect of the addition of SLS in reducing the in vivo irritation and protection of gastric mucosa were also investigated. The results showed that the compressed tablets possessed sufficient hardness, acceptable friability, and are uniform with respect to disintegration, drugs contents, and tablet weight. The results showed that SIM alone exhibited a gastroprotective effect on the induced irritation. In addition, the incorporation of the SLS in the tablets containing SIM and ASA significantly enhanced the dissolution rates of both drugs and significantly decreased the gastric irritation and the ulcer index. The ulcer index of aspirin was decreased from 2.3 for tablets manufactured without SLS to 0.8 for tablets containing SLS. In a conclusion, the addition of pH modifier surfactant; SLS could enhance the dissolution rate of poorly soluble acidic drugs, reduce gastric upset and irritation without any effect on the main characters of the tablets. Moreover, the addition of SLS is very useful in improving the therapeutic activities and reducing the side effects of ASA and SIM for patients who require long-term administration of these drugs.

Formulation and Evaluation of Transdermal Gel Containing Tacrolimus-Loaded Spanlastics: In Vitro, Ex Vivo and In Vivo Studies.

Our goal was to prepare Span 60-based elastic nanovesicles (spanlastics (SPLs)) of tacrolimus (TCR) using the adapted ethanol injection method, characterize them, and evaluate their ability to improve the transdermal permeation of the active substance. The impact of two different concentrations of penetration enhancers, namely, propylene glycol and oleic acid, on the entrapment efficiency, vesicle size, and zeta potential was assessed. Moreover, in vitro release through a semipermeable membrane and ex vivo penetration through hairless rat skin were performed. Morphological examination and pharmacokinetics were performed for one selected formulation (F3OA1). TCR-loaded SPLs were effectively formulated with two different concentrations of permeation enhancers, and the effect of these enhancers on their physicochemical properties differed in accordance with the concentration and kind of enhancer used. The results of in vitro release displayed a considerable (p < 0.05) enhancement compared to the suspension of the pure drug, and there was a correlation between the in vitro and ex vivo results. The selected TCR-loaded nanovesicles incorporated into a gel base showed appreciable advantages over the oral drug suspension and the TCR-loaded gel. Additionally, the pharmacokinetic parameters were significantly (p < 0.05) improved based on our findings. Moreover, the AUC0−7 ng·h/mL form F3 OA1 was 3.36-fold higher than that after the administration of the TCR oral suspension.

Formulation of sublingual promethazine hydrochloride tablets for rapid relief of motion sickness.

The delivery of antihistaminic agents via the oral route is problematic, especially for elderly patients. This study aimed to develop a sublingual formulation of promethazine hydrochloride by direct compression, and to mask its intensely bitter taste. Promethazine hydrochloride (PMZ) sublingual tablets prepared by direct compression were optimized using Box-Behnken full factorial design. The effect of a taste-masking agent (Eudragit E 100, X1), superdisintegrant (crospovidone; CPV, X2) and lubricant (sodium stearyl fumarate; SSF, X3) on sublingual tablets' attributes (responses, Y) was optimized. The prepared sublingual tablets were characterized for hardness (Y1), disintegration time (Y2), initial dissolution rate (IDR; Y3) and dissolution efficiency after 30 min (Dissolution Efficiency (DE); Y4). The obtained results showed a significant positive effect of the three independent factors on tablet hardness (P < 0.05), and the interactive effect of Eudragit E 100 and CPV on tablet hardness was significant. Disintegration time was mainly affected by Eudragit E 100 and CPV concentrations. Moreover, IDR was employed to assess the taste masking effect, lower values were obtained at higher Eudragit E 100 concentration despite it was statistically insignificant (p > 0.05). Optimized formulation that was suggested by the software was composed of: Eudragit E 100 (X1) = 2.5% w/w, CPV (X2) = 4.13% w/w, and SSF (X3) = 1.0% w/w. The observed values of the optimized formula were found to be close to the predicted optimized values. The Differential Scanning Calorimetric (DSC) studies indicated no interaction between PMZ and tablet excipients.

In vitro and in vivo characterization of domperidone-loaded fast dissolving buccal films.

The delivery of drugs via fast dissolving films is an effective alternative for drugs with low bioavailability when administered by other routes. This is the case of domperidone (DMP) an anti-emetic drug with low water solubility and vulnerable to extensive first-pass effect. To overcome these limitations, in this work, we designed and produced fast dissolving muco-adhesive buccal films of domperidone using varying amount polyvinylpyrrolidone (PVP K-90) using the solvent casting method. Films loaded with more than 10% of drug were not homogenous and opaque as indicated by white patches of drug in the film matrix. Formulation of DMP in the film form resulted in conversion of the drug from crystalline state to the semi-crystalline state as indicated by X-ray powder diffraction analysis. Moreover, about 40% of drug loaded within the films was released during the first five minutes compared to only about only 6.5% of pure drug in drug dissolution assays in vitro. In vivo pharmacokinetics analysis revealed that the DMP-loaded film had higher maximum plasma concentration (Cmax) and shorter time to reach Cmax (Tmax) than a commercially available tablet formulation. In conclusion, the produced DMP buccal film formulation showed high absorption rate, rapid onset of action, and improved bioavailability compared with the conventional tablet. Our findings may support the development of novel dosage forms for the transmucosal delivery of DMP for convenient, rapid, and effective treatment of nausea and vomiting.

Co-stabilization of pioglitazone HCL nanoparticles prepared by planetary ball milling: in-vitro and in-vivo evaluation.

Pioglitazone (PGZ) is an oral antidiabetic agent that increases cell resistance to insulin, thereby decreasing blood glucose levels. PGZ is a class II drug. Because of its pH-dependent solubility, it precipitates at the intestinal pH, resulting in an erratic and incomplete absorption following oral administration, which causes fluctuations in its plasma concentration. A nanoparticle drug delivery system offers a solution to enhance the dissolution rate of this poorly water-soluble drug. PGZ nanoparticles were formulated by the wet milling technique using a planetary ball mill. The effects of the steric stabilizer (Pluronic F-127, PL F-127), electrostatic stabilizer (sodium deoxycholate, SDC), and number of milling cycles were optimized using a Box-Behnken factorial design. The results showed that the ratio of PL F-127: SDC significantly affected the zeta potential and the dissolution efficiency (DE%) of PGZ. The optimized PGZ nanoparticle formulation enhanced the dissolution to reach 100% after 5 min. The in-vivo results showed significant enhancement in Cmax (1.3-fold) compared to that of the raw powder, and both AUC0-24 and AUC0-∞ were significantly (p < 0.05) enhanced. In conclusion, PGZ nanoparticle formulation had enhanced dissolution rate in the alkaline media, which improved its drug bioavailability relative to that of the untreated drug.

Rosuvastatin calcium nanoparticles: Improving bioavailability by formulation and stabilization codesign.

PURPOSE: Rosuvastatin calcium (ROSCa) is a poorly soluble drug with bioavailability not exceeding 20%. Decreasing the particle size may enhance its solubility, dissolution rate and bioavailability. Therefore, the aim of the current study is to prepare ROSCa nanoparticles by wet milling technique using planetary ball mill. The codesign between formulation and stabilization of nanoparticles was studied to achieve both high dissolution as well as bioavailability. METHODOLOGY: ROSCa nanosuspensions was prepared by wet milling technique using planetary ball mill, by applying milling ball size of 0.1 mm at speed of 800 rpm for 3 cycles each cycle composed of 10 minutes. HPMC, PVP k-30, pluronic F-127, Tween 80 and PEG 6000 were used as stabilizers. The nanosuspensions were then freeze-dried, and the dried nanoparticles were evaluated for particle size, zeta potential, in-vitro dissolution test, XRPD and in-vivo study. RESULTS: ROSCa nanoparticles stabilized with 10% PVP (P3) had a good stability with smallest particle size, which in turn enhanced the dissolution rate. The particle size of the leading formula was 461.8 ± 16.68 nm with zeta potential of -31.8 ± 7.22 mV compared to untreated drug that has a particle size of 618µm. The percent of ROSCa dissolved after 1 hour enhanced significantly which reached 72% and 58.25% for leading nanoparticle formula and untreated ROSCa, respectively (P < 0.05). The in-vivo study of ROSCa from the leading nanoparticle formula showed a significant enhancement in the Cmax after 2 h (82.35 ng/ml) compared to 9.2 ng/ml for untreated drug. CONCLUSION: Wet milling technique is a successful method to prepare ROSCa nanoparticles. From different stabilizer used, PVP (10%) was able to produce stable nanoparticle with small particle size which significantly enhance the dissolution rate and pharmacokinetics parameters of ROSCa.