Preparation and Evaluation of Different Liquisolid Compacts Containing Model Hydrophobic Drugs: Norfloxacin and CCinnarizine

The project started with studying the unique characteristics of the zwitterionic drug (norfloxacin), considered as an example of very slightly water soluble drug. The study focused on the effects of its chemical structure on its interaction with surfactants (PEG200 and Synperonic TM PE/L-61) in liquisolid systems and, consequently, on its release into water dissolution medium. The next stage was an approach to solve the problems of the dissolution, compressibility and flowability of norfloxacin liquisolid formulations through adding water as a liquid binder to make wet granulated liquisolid formulations. The water in the liquisolid formulations works as a liquid binder to the carrier and coating particles, creating a wider space inside their structure, which allows the amount of the liquid vehicle (PEG200 and Synperonic TM PE/L-61) to increase inside the formulations. This feature reflects positively on the flowability (decreasing the angle of the slide), compressibility (increasing the load factor) and the dissolution behaviour of norfloxacin (increasing drug release to more than 20%). Another liquid binder (PVP) was used in the wet granulations and a comparison was made between PVP solutions, water and classical liquisolid formulations in terms of dissolutions, flowability, compressibility, DSC thermographs and FTIR spectra. The successful application of wet granulation techniques with liquisolid formulations was tested with a very hydrophobic drug (cinnarizine). Due to its hydrophobicity, traditional mixing of surfactants and the drug particles did not improve its dissolution in water medium, although the solubility was relatively high. ii The methodology was again applied to investigate how the dissolution of cinnarizine altered with several different types of surfactants. The results lead to a change from traditional mixing to a self-nano emulsifying drug delivery system (SNEDD). Optimization to select a suitable oil (Capmul® MCM EP), surfactant (Kolliphor® RH40) and co-surfactant (PEG400) was found to depend initially on the solubility of cinnarizine. Further optimisation identified the relative percentages (66.6:16.6:16.6 for oil, surfactant and co-surfactant, respectively) and the drug concentration required for the SNEDD (6.0% w/w) was found to depend on the mixture experimental design, using dissolution trends as an indicator. Finally, the selected SNEDD system was converted to a liquisolid system using the water granulation technique to make tablets with acceptable compressibility and flowability. Due to the negative effect of coating material (Cab-O-Sil® M-5P) on the dissolution behaviour, a new method was developed to determine the compressibility load factor using a central composite design and response surface methodology. The predicted model was validated and the accuracy was over 95%, allowing it to be used for preparation of the SNEDDs. The new preparations were compared to tablets from the commercial sources. The new formulations show significant enhancement in the percentage of the drug releases in distilled water dissolution medium

Application of general multilevel factorial design with formulation of fast disintegrating tablets containing croscaremellose sodium and Disintequick MCC-25

Despite the popularity of orally fast disintegrating tablets (FDTs), their formulation can sometimes be challenging, producing tablets with either poor mechanical properties or high disintegration times. The aim of this research was to enhance the properties of FDTs produced by direct compression to have both sufficient hardness to withstand manual handling, and rapid disintegration time. General multilevel factorial design was applied to optimise and evaluate main and interaction effects of independent variables (i) disintegrant concentration, (ii) % filler (Disintequick MCC-25) to mannitol on the responses hardness, tensile strength and disintegration time. In this experiment mannitol was used as a diluent, Disintequick MCC-25 (to best of our knowledge there is no publication available yet for its use with FDTs) was termed in this study as a filler and croscaremellose sodium was used as the superdisintegrant. Seven formulations were prepared following a progressive two-stage approach. Each stage involved the change in the ratio of excipients (Mannitol:Filler) (1:0), (1:0.25), (1:0.50), (1:1), (0.50:1), (0.25:1), (0:1) w/w and concentration of superdisintegrant (1%, 3%, 5%, 7%, 10% w/w). All FDTs were tested for different parameters such as diameter, hardness, tensile strength, thickness, friability and disintegration time. The results of multiple linear regression analysis show a good degree of correlation between experimental (R2:0.84, 0.94, 0.91) and predicted response (R2:0.83, 0.96, 0.95) for hardness, tensile strength and disintegration time respectively. The optimum formulations (regarding disintegration time with acceptable hardness and friability properties) consisted of: (i) 5% w/w disintegrant and 20% w/w filler to mannitol, showing a disintegration time of 30 s, a hardness of 66.6 N (6.8 kg/cm2) and friability of 2.2%; (ii) 7% or 10% w/w disintegrant with 33.33% w/w filler to mannitol, showing disintegration time of 84 s (for 7% disintegrant) and 107 s (for 10% disintegrant), hardness of 73.86 N (for 7% disintegrant) and 72.68 N (for 10% disintegrant) and friability of 1.44 (for 7% disintegrant) and 1.15% (for 10% disintegrant)

Cyclodextrin Diethyldithiocarbamate Copper II Inclusion Complexes: A Promising Chemotherapeutic Delivery System against Chemoresistant Triple Negative Breast Cancer Cell Lines

Diethyldithiocarbamate Copper II (DDC-Cu) has shown potent anticancer activity against a wide range of cancer cells, but further investigations are hindered by its practical insolubility in water. In this study, inclusion complexes of DDC-Cu with hydroxypropyl beta-cyclodextrin (HP) or sulfobutyl ether beta-cyclodextrin (SBE) were prepared and investigated as an approach to enhance the apparent solubility of DDC-Cu. Formulations were prepared by simple mixing of DDC-Cu with both cyclodextrin (CDs) at room temperature. Phase solubility assessments of the resulting solutions were performed. DDC-Cu CD solutions were freeze-dried for further characterisations by DSC, thermogravimetric analysis (TGA) and FT-IR. Stability and cytotoxicity studies were also performed to investigate the maintenance of DDC-Cu anticancer activity. The phase solubility profile deviated positively from the linearity (Ap type) showing significant solubility enhancement of the DDC-Cu in both CD solutions (approximately 4 mg/mL at 20% w/w CD solutions). The DSC and TGA analysis confirmed the solid solution status of DDC-Cu in CD. The resulting solutions of DDC-Cu were stable for 28 days and conveyed the anticancer activity of DDC-Cu on chemoresistant triple negative breast cancer cell lines, with IC50 values less than 200 nM. Overall, cyclodextrin DDC-Cu complexes offer a great potential for anticancer applications, as evidenced by their very positive effects against chemoresistant triple negative breast cancer cells

Norfloxacin as a model hydrophobic drug with unique release from liquisolid formulations prepared with PEG200 and Synperonic PE/L-61 non-volatile liquid vehicles.

The purpose of the study is to investigate dissolution behaviour of norfloxacin as a model hydrophobic drug through application of liquisolid technology. Norfloxacin was prepared as liquisolid formulations using either flowability or compressibility liquisolid tests. The dissolution profiles were evaluated and compared to counterpart conventional norfloxacin tablets. Two non-volatile liquid vehicles were used in the preparation of norfloxacin liquisolid formulations; Poly Ethylene Glycol (PEG200) and Synperonic PE/L-61. The liquisolid formulations of norfloxacin were tested according to the specification of British Pharmacopoeia (BP) quality control tests. Moreover, the pre-preparation evaluation tests, such as powder flowability Carr index, differential scanning calorimetry (DSC) and Fourier transform infrared (FT-IR), were applied for further investigation of the physicochemical properties of the liquisolid formulations. The results indicated that the percentage of norfloxacin release in acetate buffer solution (pH = 4.0) is higher than in distilled water. Also, at the first 20 min, the percentage of the drug release is higher only in the decreased amount of liquid vehicle formulations compared with the conventional tablet. Generally, the conventional tablet dissolution profile is either similar or higher than liquisolid tablets. Moreover, Synperonic PE/L-61 liquisolid tablets showed higher dissolution profiles than PEG200 liquisolid tablets, although the solubility of norfloxacin in PEG200 (2.507 mg/ml) is much higher than in Synperonic PE/L-61 (0.167 mg/ml). In conclusion, increasing the percentage of liquid vehicle in the prepared norfloxacin liquisolid formulations does not necessarily lead to increase in the percentage of the drug release in distilled water dissolution medium

Preparation of novel optimum liquisolid compacts via incorporating water granulation process to enhance the powder characterizations and dissolution behavior of a poorly soluble drug: Norfloxacin

The aim of this work is to investigate the addition of wet granulation technique into liquisolid process in order to enhance the characterizations of liquisolid compacts, such as flowability, compressibility and the percentage of drug release (using norfloxacin as a model of poorly soluble-permeable drug) in neutral dissolution medium. The water in the liquisolid formulations works as a liquid binder to the carrier and coating particles, creating a wider space inside their structure, which allows the amount of the liquid vehicle (PEG200 or Synperonic ™ PE/L-61) to increase inside the formulations. This feature reflects positively on: the flowability (decreasing the angle of the slide up to 10 degrees), the compressibility (increasing the load factor from 0.2 to >0.4 in PEG200 liquisolid compacts and from 0.14 to 0.29 in the case of Synperonic ™ PE/L-61iquisolid compacts) and the dissolution behaviour of norfloxacin (increasing drug release). The applied accelerated stability study on the water granulated liquisolid compacts showed no significant differences in the dissolution profiles. Also, the DSC thermographs indicated that the water granulated liquisolid compacts resist the applied stressful conditions. As a consequence, the positive outcomes of the combination between liquisolid and water granulation process open the door for robust tablet production on a large scale in pharmaceutical industries

Cyclodextrin diethyldithiocarbamate copper ii inclusion complexes: A promising chemotherapeutic delivery system against chemoresistant triple negative breast cancer cell lines

Diethyldithiocarbamate Copper II (DDC-Cu) has shown potent anticancer activity against a wide range of cancer cells, but further investigations are hindered by its practical insolubility in water. In this study, inclusion complexes of DDC-Cu with hydroxypropyl beta-cyclodextrin (HP) or sulfobutyl ether beta-cyclodextrin (SBE) were prepared and investigated as an approach to enhance the apparent solubility of DDC-Cu. Formulations were prepared by simple mixing of DDC-Cu with both cyclodextrin (CDs) at room temperature. Phase solubility assessments of the resulting solutions were performed. DDC-Cu CD solutions were freeze-dried for further characterisations by DSC, thermogravimetric analysis (TGA) and FT-IR. Stability and cytotoxicity studies were also performed to investigate the maintenance of DDC-Cu anticancer activity. The phase solubility profile deviated positively from the linearity (Ap type) showing significant solubility enhancement of the DDC-Cu in both CD solutions (approximately 4 mg/mL at 20% w/w CD solutions). The DSC and TGA analysis confirmed the solid solution status of DDC-Cu in CD. The resulting solutions of DDC-Cu were stable for 28 days and conveyed the anticancer activity of DDC-Cu on chemoresistant triple negative breast cancer cell lines, with IC50 values less than 200 nM. Overall, cyclodextrin DDC-Cu complexes offer a great potential for anticancer applications, as evidenced by their very positive effects against chemoresistant triple negative breast cancer cells.Funding: This research is funded by NPRP grant (NPRP9-337-3-069) from the Qatar National Funding: This research is funded by NPRP grant (NPRP9-337-3-069) from the Qatar National Re-Research Fund (a member of Qatar Foundation). The findings herein reflect the work, and are solely search Fund (a member of Qatar Foundation). The findings herein reflect the work, and are solely the responsibility, of the authors. the responsibility, of the authors.Scopu

Development, characterization and stability evaluation of ciprofloxacin-loaded parenteral nutrition nanoemulsions

In this study, two licensed total parenteral nanoemulsion formulations (Clinoleic® and Intralipid®) were loaded with ciprofloxacin (CP). The physicochemical characteristics and stability profiles of the formulations were investigated using a range of drug concentrations. Furthermore, formulation stability was evaluated over a period of six months at room temperature or 4 °C. Loading CP into nanoemulsions resulted in no significant differences in their measured droplet size, polydispersity index (PI), zeta potential and pH. Drug entrapment efficiency (EE) was relatively high for all formulations, regardless of nanoemulsion type, and the drug release was sustained over 24 h. Stability studies of all formulations were performed at 4 °C and room temperature (RT) for 180 and 60 days, respectively. At 4 °C for 180 days, both Clinoleic and Intralipid formulations at a range of drug concentrations (1-10 mg/ml) showed high stabilities measured periodically by the average droplet sizes, PI, pH and zeta potential values. Similar results, but pH values, were shown when the formulations for both nanoemulsion stored at RT for 60 days. Overall, this study has shown that CP was successfully loaded into clinically licensed TPN lipid nanoemulsions. The resultant CP-loaded nanoemulsion formulations demonstrated desirable physicochemical properties and were stable upon storage at 4 °C for up to six months

Pancreatic surgery outcomes: multicentre prospective snapshot study in 67 countries

Background: Pancreatic surgery remains associated with high morbidity rates. Although postoperative mortality appears to have improved with specialization, the outcomes reported in the literature reflect the activity of highly specialized centres. The aim of this study was to evaluate the outcomes following pancreatic surgery worldwide.Methods: This was an international, prospective, multicentre, cross-sectional snapshot study of consecutive patients undergoing pancreatic operations worldwide in a 3-month interval in 2021. The primary outcome was postoperative mortality within 90 days of surgery. Multivariable logistic regression was used to explore relationships with Human Development Index (HDI) and other parameters.Results: A total of 4223 patients from 67 countries were analysed. A complication of any severity was detected in 68.7 percent of patients (2901 of 4223). Major complication rates (Clavien-Dindo grade at least IIIa) were 24, 18, and 27 percent, and mortality rates were 10, 5, and 5 per cent in low-to-middle-, high-, and very high-HDI countries respectively. The 90-day postoperative mortality rate was 5.4 per cent (229 of 4223) overall, but was significantly higher in the low-to-middle-HDI group (adjusted OR 2.88, 95 per cent c.i. 1.80 to 4.48). The overall failure-to-rescue rate was 21 percent; however, it was 41 per cent in low-to-middle-compared with 19 per cent in very high-HDI countries.Conclusion: Excess mortality in low-to-middle-HDI countries could be attributable to failure to rescue of patients from severe complications. The authors call for a collaborative response from international and regional associations of pancreatic surgeons to address management related to death from postoperative complications to tackle the global disparities in the outcomes of pancreatic surgery (NCT04652271; ISRCTN95140761)