Native and polymeric β-cyclodextrins in performance improvement of chitosan films aimed for buccal delivery of poorly soluble drugs

β-Cyclodextrin (βCD) and its soluble polymeric derivative (EPIβCD) were used to improve the effectiveness of chitosan-based bucco-adhesive film formulations containing bupivacaine hydrochloride and triclosan as poorly-soluble model drugs. The film formulations were characterized in terms of swelling, mucoadhesion and in vitro drug release, while possible interactions between the components were investigated by DSC and FTIR analyses. For both drugs EPIβCD showed a higher solubilizing efficiency than βCD; however cyclodextrin effectiveness in improving the release rate from film formulations was influenced by their different interactions with chitosan. Free βCD acted as a channelling agent, favouring the film swelling, while EPIβCD due to interaction with chitosan caused an opposite effect. βCD was the optimal partner for bupivacaine-loaded films in terms of film swelling, mucoadhesion and drug release. Contrariwise, EPIβCD was the best partner for triclosan-loaded films, allowing the highest drug release rate increase, due to its higher solubilizing ability with respect to βCD. Addition of the suitable cyclodextrin enabled formulation of buccal films with suitable drug release properties.     

Application of DSC, IST, and FTIR study in the compatibility testing of nateglinide with different pharmaceutical excipients

Experiments were done to assess the compatibility of nateglinide (NTG) with selected excipients in the development of immediate release tablets of NTG by thermal and isothermal stress testing (IST) techniques. To evaluate the drug excipient compatibility, different techniques such as differential scanning calorimetric (DSC) study, infrared (IR) spectrophotometric study, and IST were adopted. The results of DSC study showed that magnesium stearate exhibited some interaction with NTG. However, the results of IR and IST studies showed that all the excipients used in the formula were compatible with NTG. The optimized formulation developed using the compatible excipients were found to be stable after 3 months of accelerated stability studies (40 ± 2 °C and 75 ± 5% RH). Overall, compatibility of excipients with NTG was successfully evaluated using the combination of thermal and IST methods and the formulations developed using the compatible excipients was found to be stable.     

Preparation and Characterization of Controlled-Release Floating Bilayer Tablets of Esomeprazole and Clarithromycin

Controlled-release effervescent floating bilayer tablets reduce dosage frequency and improve patient compliance with enhanced therapeutic outcomes. Generally, two different tablets of clarithromycin and esomeprazole, respectively, are given for the treatment of Helicobacter pylori infection and it might be worth incorporating both in a single tablet. In the current study, controlled-release floating bilayer tablets of clarithromycin and esomeprazole (F1–F4) were developed with different rates of polymeric materials by a direct compression method. During the formulation, Fourier-transform infrared spectroscopy (FTIR) analysis was performed for possible interactions between drugs and excipients. No interactions between drugs and excipients were noted. Moreover, the bilayer tablets’ thickness, diameter, friability, hardness, weight variation, dissolution, and percent purity were found within the acceptable limits. The floating lag time and total floating time of all formulations were found to be < 25 s and 24 h, respectively. The release of both the clarithromycin and esomeprazole started at the same time from the controlled-release floating bilayer tablets by anomalous non-Fickian diffusion, and the polymeric materials extended the drug release rate up to 24 h. In the case of F1, the results approached ideal zero-order kinetics. The dissolution profiles of the tested and reference tablet formulations were compared, but no significant differences were observed. It can be concluded that such controlled-release effervescent floating bilayer tablets can be efficiently used in clinical practice to reduce dosage frequency and increase patient compliance with continuous drug release for 24 h, which ultimately might enhance therapeutic efficacy.     

Development and Validation of Stability Indicating LC Method to Quantify Captopril in Tablets of Controlled Release

An accurate, simple, reproducible, and sensitive liquid chromatographic method was developed and validated for the captopril determination in controlled release tablets. The analyses were performed at room temperature on a reversed-phase Phenomenex Luna C₁₈ column (250 mm × 4.6 mm). The mobile phase was composed of water:methanol (45:55; v/v) pH 2.5, and it was eluted isocratically at a 1.0 mL min⁻¹ flow rate. The method was validated in terms of specificity, linearity, quantification limit, detection limit, accuracy, precision and robustness. The response was linear in the range 0.3–1.5 mg mL⁻¹ (r ²  = 0.9983). The relative standard deviation values for inter-and intra-day precision were 0.77% and 0.50%, respectively. Recoveries ranged between 97.7 and 99.1%. The method was successfully applied for the determination of captopril in the developed formulations.     

Self-nanoemulsifying drug delivery system for adefovir dipivoxil: Design, characterization, in vitro and ex vivo evaluation

Adefovir dipivoxil (ADV) is an anti-viral drug having low bioavailability due to low permeability and pH dependent solubility. In this study, self-nanoemulsifying drug delivery systems (SNEDDS) of ADV were developed with the objective of increasing its bioavailability by enhancing its intestinal permeability and minimizing the effect of pH. Preliminary screening was carried out to select oil, surfactant and co-surfactant. Ternary phase diagrams were constructed to identify the area of nanoemulsification. The nanoemulsion system selected from the phase diagram was transformed into solid-SNEDDS (S-SNEDDS) by lyophilization using D-mannitol as cryoprotectant. The formulations were characterized for transmittance, globule size, polydispersity index, zeta potential, cloud point, robustness to dilution, effect of pH and temperature, microscopic properties, in vitro and ex vivo drug release parameters. The liquid SNEDDS (L-SNEDDS) showed mean globule size of 110 ± 10 nm while mean globule size of 150 ± 16 nm was obtained with S-SNEDDS. The formulations were found to be robust to dilution and showed cloud point at 80-85 °C. TEM and SEM studies of nanoemulsion reconstituted from S-SNEDDS demonstrated the spherical shape and size of the globules. Results of DSC and XRD studies confirmed that the drug was incorporated in the S-SNEDDS. No significant difference was observed in the globule size within physiological variations of pH and temperature. The in vitro and ex vivo drug release from ADV SNEDDS was found to be significantly higher in comparison to that from plain drug suspension, irrespective of pH. Thus, SNEDDS were found to be instrumental in reducing the effect of pH variability of ADV and improving the release performance of ADV, indicating their potential to improve the oral bioavailability and thus the therapeutic efficacy of ADV.     

Chitosan and a modified chitosan as agents to improve performances of mucoadhesive vaginal gels

New mucoadhesive formulations were designed and studied in order to improve local vaginal therapy by increasing formulation retention prolonging thus drug-mucosa contact time. Some gels were prepared using hydroxyethylcellulose (HEC) alone or mixed with chitosan (CS) or its derivative 5-methyl-pyrrolidinone-chitosan (MPCS) and were loaded with the antibacterial metronidazole (MET) (0.75%). All formulations showed pseudoplastic flow and viscosity increase was observed proportionally to chitosan content (CS>MPCS). Prepared gels showed better extrusion properties (yield stress) than market formulation Zidoval. Mucoadhesion force studies permitted to point out that: (i) CS decreases mucoadhesion force; (ii) MPCS addition increases the mucoadhesion force at high percentage; (iii) all gels containing chitosan showed better mucoadhesive performances than Zidoval. Gels containing MPCS showed higher and faster drug release than those containing CS. All the preparations were able to release higher drug amounts if compared to market formulation. In conclusion MPCS improved gel characteristics in terms of mucoadhesion force, rheological behaviour and drug release pointing out that this modified chitosan is very suitable to obtain manageable and more acceptable vaginal formulation.     

Design and in vitro evaluation of zidovudine oral controlled release tablets prepared using hydroxypropyl methylcellulose

Oral controlled release matrix tablets of zidovudine were prepared using different proportions and different viscosity grades of hydroxypropyl methylcellulose. The effect of various formulation factors like polymer proportion, polymer viscosity and compression force on the in vitro release of drug were studied. In vitro release studies were carried out using United States Pharmacopeia (USP) type 1 apparatus (basket method) in 900 ml of pH 6.8 phosphate buffer at 100 rpm. The release kinetics were analyzed using Zero-order model equation, Higuchi's square-root equation and Ritger-Peppas' empirical equation. Compatibility of drug with various formulations excipients used was studied. In vitro release studies revealed that the release rate decreased with increase in polymer proportion and viscosity grade. Increase in compression force was found to decrease the rate of drug release. Matrix tablets containing 10% hydroxypropyl methylcellulose (HPMC) 4000 cps were found to show a good initial drug release of 21% in the first hour and extended the release upto 16 h. Matrix tablets containing 20% HPMC 4000 cps and 10% HPMC 15000 cps showed a first hour release of 18% and extended the release upto 20 h. Mathematical analysis of the release kinetics indicated that the nature of drug release from the matrix tablets followed non-Fickian or anomalous release. No incompatibility was observed between the drug and excipients used in the formulation of matrix tablets. The developed controlled release matrix tablets of zidovudine, with good initial release (17-25% in first hour) and which extend the release upto 16-20 h, can overcome the disadvantages of conventional tablets of zidovudine.     

A controlled porosity osmotic pump system with biphasic release of theophylline: influence of weight gain on its in vivo pharmacokinetics

In our previous work, a controlled porosity osmotic pump system with biphasic release of theophylline, a system composed of a tablet-in-tablet (TNT) core and a controlled porosity coating membrane, was developed for the nocturnal therapy of asthma. Sodium phosphate and sodium chloride were selected as the osmotic agents in inner and outer layer of the TNT core respectively, and CA-PEG400-DEP (54.5%-36.4%-9.1%, w/w) was chosen as coating solution. Formulations with weight gain of 19 mg/T (mg per tablet), 9 mg/T and 6 mg/T were prepared respectively and their pharmacokinetics in beagle dogs were also studied to examine the influence of weight gain on their in vivo pharmacokinetics. Sustained release tablet of theophylline (SRT) was selected as reference to evaluate the in vitro and in vivo difference between conventional sustained release tablets and the developed formulation. T(max) and mean residence time (MRT) of the developed formulations were prolonged compared to that of SRT and a satisfying bioavailability was achieved at weight gain of 6 mg/T. If applied to the chronotherapy of asthma at night, the developed formulation with a weight gain of 6 mg/T might help to reduce the inconvenience brought by too later administration of conventional dosage forms and maintain a relatively high blood drug concentration 7 h after administration.     

Nanostructured lipid carriers based suppository for enhanced rectal absorption of ondansetron: In vitro and in vivo evaluations

The current research aimed to fabricate ondansetron nanostructured lipid carriers (OND-NLCs) and incorporate them into a suppository base to manage chemotherapy-induced vomiting and nausea, which offer the advantage of both rapid onset and prolonged release. NLCs were fabricated by adopting the solvent diffusion method. The binary lipid mixture of oleic acid (liquid lipid) and lauric acid (solid lipid) were prepared in distinct ratios. The NLCs were characterized concerning the surface charge, size, drug encapsulation efficiency, and surface morphology. In addition, the influence of surfactant, co-surfactant, and lipid on entrapment efficiency and particle size was investigated. Phosphate buffer having pH 7.4 is used for evaluating in vitro drug release by utilizing a dialysis membrane. Various kinetics models were used to estimate the drug release kinetics of fabricated nanostructured lipid carriers. The particle size of the NLCs was calculated between 101 and 378 nm with negative zeta potential on the NLC’s surface. The entrapment efficiency was found between 68 and 87%. Scanning Electron Microscopic analysis showed the spherical shape of nanostructured lipid carriers. The dissolution profile of the ondansetron-loaded NLC suppository depicts biphasic behavior of firstly burst release then slow release was observed. The diffusion controlled release was evident from kinetic modeling. The succeeding step comprehended the fabrication and characterization of NLC-based suppositories utilizing NLC formulations that demonstrated the combined advantage of rapid onset, prolonged release, and better in vivo bioavailability as compared to control suppository.     

New solid mucoadhesive systems for benzydamine vaginal administration

The aim of this work was the realization of new formulations for vaginal application to improve the pharmacological effect of benzydamine, displaying both anti-inflammatory and antiseptic activities. For this reasons, this drug was formulated in solid dispersions, by using the mucoadhesive polymers HPMC and/or Carbopol(?), then compressed. Tablets were characterized by studies of friability, hardness, hydration, DSC, mucoadhesion and in vitro release. Kinetics, responsible for drug delivery, was investigated as well. Tablets prepared by using only HPMC showed the best results in terms of swelling and mucoadhesion (time and force) together with prolonged and complete drug release, by diffusive mechanism, through gelled layer. Despite the good mucoadhesive properties, Carbopol(?) does not represent a good excipient because, after the contact with water, it generates a spongy gel layer, not homogeneous, stiff, brittle and with breaking tendency when highly swelled. This kind of gel does not guarantee a linear drug release and could provoke discomfort because of fragment release. HPMC mucoadhesive tablets could be a proper delivery system for benzydamine administration representing a good alternative to traditional dosage forms for vaginal topical therapy.     

Modified drug release system based on Sulindac and layered double hydroxide: An in vivo Raman investigation

In this study, the capability of a Layered Double Hydroxide (LDH) to promote the modified-release of Sulindac (Sul), a non-steroid anti-inflammatory drug, was followed by Raman spectroscopy through in vitro and in vivo assays. The drug and the LDH-Sul system were pressed into pellets and their dissolution under controlled conditions was monitored in vitro for 80 h. For the in vivo assays, LDH-drug and LDH-Cl (with chloride in the interlayer space) pellets were implanted between the external and internal oblique muscles of Wistar rats. The pellets were removed after 7, 21, 28 and 35 days from implantation and up to 21 days there was an increase in the amount of intercalated carbonate ions as followed over time by Raman microscopy. The carbonate ions are from the extracellular fluid (conjunctive tissue) and replace the chloride ions between the LDH layers. The same kind of ion exchange was observed for LDH-Sulindac: ca. 50% of the drug was released in vivo after 21 days, whereas in vitro the same amount of drug was delivered within 24 h. The release kinetics was much slower in the in vivo assay due to a significantly smaller hydrodynamic interaction inside the muscle.     

Synthesis and controlled release properties of β-naphthoxyacetic acid intercalated Mg–Al layered double hydroxides nanohybrids

Controlled release formulations have been proven to have potential in overcoming the drawbacks of conventional plant growth regulators. Novel controlled-release formulation of β-naphthoxyacetic acid (BNOA) intercalated MgAl-layered double hydroxides (LDHs) was prepared by co-precipitation method. The effects of temperature, pH value, and release medium on BNOA release were studied and the releasing mechanisms were discussed. The results of release show that the increase of temperature induces the increase of BNOA release extent. The release rate and accumulated release amount of BNOA are found to be dependent to the anion in the aqueous solution in the order of CO₃²⁻ > SO₄²⁻ > Cl⁻. Moreover, the pH is the key controlling factor for the BNOA release processes, and with strong acid medium, the release character of BNOA is different from those at pH 7 and 12, which accompanies with fast collapse of LDHs nanolayered structure. The nanohybrid of BNOA intercalated LDHs possessed good controlled release properties and the BNOA release character from the nanohybrid fitted pseudo-second-order model in neutral medium.     

Determination of melatonin in commercial preparations by micellar electrokinetic chromatography and spectrofluorimetry

Melatonin was determined in pharmaceutical preparations by means of two simple and reliable analytical methods based on micellar electrokinetic chromatography (MEKC) and spectrofluorimetry. The fluorescence emission values were measured at λ=350 nm when exciting at λ=275 nm. The MEKC analysis was achieved using a system consisting of 40 mM SDS in phosphate buffer (20 mM, pH 7.5). The extraction of melatonin from the tablets was achieved by means of a simple one-step dissolution with methanol/water. Both methods were applied for the determination of melatonin in commercial formulations and galenic preparations. The MEKC procedure allows the quantitative determination of melatonin in all pharmaceutical preparations tested. On the contrary, the spectrofluorimetric method is not suitable for tablets which also contain tryptophan; this interference can be eliminated by a suitable liquid-liquid extraction procedure. The results obtained with the two methods are in good agreement and satisfactory in terms of precision and accuracy.     

Encapsulation and release of biomolecules from Ca-P/PHBV nanocomposite microspheres and three-dimensional scaffolds fabricated by selective laser sintering

This study focused on the fabrication of calcium phosphate (Ca-P)/poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) nanocomposite scaffolds loaded with biomolecules using the selective laser sintering (SLS) technique and their evaluation. Ca-P/PHBV nanocomposite microspheres loaded with bovine serum albumin (BSA) as the model protein were fabricated using the double emulsion solvent evaporation method. The encapsulation efficiency of BSA in PHBV polymer microspheres and Ca-P/PHBV nanocomposite microspheres were 18.06 ± 0.86% and 24.51 ± 0.60%, respectively. The BSA loaded Ca-P/PHBV nanocomposite microspheres were successfully produced into three-dimensional porous scaffolds with good dimensional accuracy using the SLS technique. The nanocomposite microspheres served as protective carriers and maintained the bioactivity of BSA during SLS. The effects of SLS parameters such as laser power and scan spacing on the encapsulation efficiency of BSA in the scaffolds and in vitro BSA release were studied. An initial burst release was observed, which was followed by a slow release of BSA. After 28-day release, The PHBV matrix was slightly degraded after 28-day in vitro release study. It was shown that nanocomposite scaffolds with controlled architecture obtained via SLS could be incorporated with biomolecules, enhancing them with more functions for bone tissue engineering application or making them suitable for localized delivery of therapeutics.     

大豆蛋白基茶碱控释片的制备及稳定性研究

以茶碱为模型药物,大豆蛋白和海藻酸钠作为骨架材料,采用混合压片法制备了不同比例的药物片剂。采用紫外比色法测定释放效果,考察了大豆蛋白与海藻酸钠不同比例以及不同pH释放介质和高湿度对茶碱片稳定性的影响。结果表明:大豆蛋白和海藻酸钠作为骨架材料的片剂释药时间都达到了8h以上,在pH6.8PBS中的释药率相对pH1.2盐酸溶液要快,具有良好的定向控释特性。随着湿度的增加,茶碱释放率略有下降,具有较好的湿度稳定性。通过适度调节大豆蛋白和海藻酸钠的比例可实现不同控释效果。实验结果表明大豆蛋白和海藻酸钠共混物是一种良好的天然药物缓控释骨架材料,其释放过程符合一级动力学特征,是药物扩散和骨架溶蚀二者共同作用的结果。     

Partial least squares-near infrared determination of pesticides in commercial formulations

A solvent free, fast and environmentally friendly near infrared-based methodology (NIR) was developed for pesticide determination in commercially available formulations. This methodology was based on the direct measurement of the diffuse reflectance spectra of solid samples and a multivariate calibration model (partial least squares, PLS) to determine the active principle concentration in commercial formulations. The PLS calibration set was built on using the spiked samples by mixing different amounts of pesticide standards and powdered samples. Buprofezin, Diuron and Daminozide were used as test analytes. Concentration of Buprofezin in the samples was calculated employing a 4-factors PLS calibration using the spectral information in the range between 2231–2430 and 1657–1784 nm. For Diuron determination a 1-factor PLS calibration model using the spectral range 1110–2497 nm, after a linear removed correction. Daminozide determination was carried out employing a 4-factors PLS model using the spectral information in the ranges 1644–1772 and 2014–2607 nm without baseline correction. The root mean square errors of prediction (RMSEP) found were 1.1, 1.7 and 0.7% (w/w) for Buprofezin, Diuron and Daminozide determination, respectively. The developed PLS-NIR procedure allows the determination of 120 samples/h, does not require any sample pre-treatment and avoids waste generation.     

Synthesis,biological and physicochemical properties of Zinc(II) salicylate and 5-chlorosalicylate complexes with theophylline and urea

New zinc(II) salicylate complex compounds of general formula (X-C₆H₃-2-(OH)COO)₂Zn · L_n · xH₂O (where X = H, 5-Cl; L = theophylline, urea; n = 2, 4; x = 1, 2, 4) were prepared and their thermal, spectral and biological properties were studied. It was found that the thermal decomposition of hydrated compounds starts with the release of water. During the thermal decomposition of anhydrous compounds, the release of salicylic acid, theophylline, urea, CO₂, H₂O and C₆H₅Cl takes place. Zinc oxide was found as the final product of the thermal decomposition heated up to 900 °C. The complexes were tested against bacteria, yeasts and filamentous fungi. The highest biological activity show 5-chlorosalicylate compounds.     

In situ photopolymerization-coated pellets for pH-dependent drug delivery

An in situ photopolymerization-coating technique was applied to wrap the pellets surface with a pH-sensitive hydrogel layer made from acrylic acid and hydrophobic acrylate monomers. Powdered cellulose (Elcema^® P100) and poly(vinylpyrrolidone) (Kollidon^® 30) pellets containing theophylline were prepared by extrusion-spheronization, sprayed with an ethanol:water 50:50 v/v solution of the monomers, the cross-linker (N,N′-methylenebis(acrylamide)) and the initiator (Irgacure^® 2959), and immediately irradiated at 366 nm. The composition of coating mixture and the time of irradiation were optimized using oscillatory rheometry and analyzing the swelling and the drug release behaviour of the resultant hydrogels. When acrylic acid:lauryl acrylate 88:12 molar ratio was used, the coating did not significantly change the shape, size, or friability of the pellets, but remarkably modified theophylline release profiles. The thicker the coating layer, the better the pH-dependent control of drug release.     

Fabrication and characterization of boric acid-crosslinked ethyl cellulose and polyvinyl alcohol films as potential drug release systems for topical drug delivery

In this study, boric acid (BA) is employed as a crosslinking agent to improve the characteristics of two commonly used polymeric films, ethyl cellulose (EC) and polyvinyl alcohol (PVA), for topical drug delivery applications. The developed films are characterized by FTIR spectroscopy and SEM analysis. The results show that the surfaces of the prepared films are even and transparent, except for the BA-modified EC sample. The initial cumulative release for erythromycin (EM) is found to be 0.30 and 0.36 mg/mL for EC and PVA films, which drops to 0.25 and 0.20 mg/mL after BA crosslinking, respectively, after 1 h at 25 °C. Further, the developed formulations are stable for 75 days. Also, the antibacterial activity of the developed formulations is investigated against S. aureus (ATCC® 25923™ and ATCC® 29213™). The obtained data confirm that the application of BA as the crosslinking agent extends the release of EM from EC and PVA polymeric films. The findings of this study suggest that BA-crosslinked EC and PVA films are promising carriers for controlled topical drug delivery applications.     

Unusual degradation behavior of citric acid-crosslinked gelatin in vitro and in vivo

The aim of this study was to evaluate the biodegradability and biocompatibility of gelatin matrices designed for drug-eluting stents (DESs). The matrices were prepared by crosslinking alkali-treated gelatin (AlGelatin) with a citric acid-based crosslinker, trisuccinimidyl citrate (TSC), to form AlGelatin-TSC. The biodegradation behavior of the matrices was evaluated in vitro and in vivo. An in vitro enzymatic degradation test showed that AlGelatin-TSC prepared at a TSC concentration of 20 mM is the most stable in collagenase solution compared to AlGelatin-TSC prepared at TSC concentrations higher or lower than 20 mM. Then, AlGelatin-TSC were implanted subcutaneously in rats to evaluate their biodegradability and tissue reaction in vivo. Similar to the in vitro degradation behavior, AlGelatin-TSC with TSC concentration of 20 mM exhibited the lowest biodegradable rate in vivo among all AlGelatin-TSC. In addition, strong inflammation and calcification were not observed for AlGelatin-TSC at any TSC concentration. From an analysis of the crosslinking density of the resulting AlGelatin-TSC, the lowest biodegradability of AlGelatin-TSC with TSC concentration of 20 mM was due to the highest crosslinking density of the matrix. These results suggest that AlGelatin-TSC is suitable for use as matrices in DESs because of its excellent biocompatibility and biodegradability.