Development and Characterization of Thermosensitive and Bioadhesive Ophthalmic Formulations Containing Flurbiprofen Solid Dispersions.

In this study, we aimed to develop thermosensitive and bioadhesive in situ gelling systems containing solid dispersions of flurbiprofen (FB-SDs) using poloxamer 407 (P407) and 188 (P188) for ophthalmic delivery. FB-SDs were prepared with the melt method using P407, characterized by solubility, stability, SEM, DSC, TGA, and XRD analyses. Various formulations of poloxamer mixtures and FB-SDs were prepared using the cold method and P407/P188 (15/26.5%), which gels between 32 and 35 °C, was selected to develop an ophthalmic in situ gelling system. Bioadhesive polymers Carbopol 934P (CP) or carboxymethyl cellulose (CMC) were added in three concentrations (0.2, 0.4, and 0.6% (w/w)). Gelation temperature and time, mechanical properties, flow properties, and viscosity values were determined. The in vitro release rate, release kinetics, and the release mechanism of flurbiprofen (FB) from the ophthalmic formulations were analyzed. The results showed that FB-SDs' solubility in water increased 332-fold compared with FB. The oscillation study results indicated that increasing bioadhesive polymer concentrations decreased gelation temperature and time, and formulations containing CP gel at lower temperatures and in a shorter time. All formulations except F3 and F4 showed Newtonion flow under non-physiological conditions, while all formulations exhibited non-Newtonion pseudoplastic flow under physiological conditions. Viscosity values increased with an increase in bioadhesive polymer concertation at physiological conditions. Texture profile analysis (TPA) showed that CP-containing formulations had higher hardness, compressibility, and adhesiveness, and the gel structure of formulation F4, containing 0.6% CP, exhibited the greatest hardness, compressibility, and adhesiveness. In vitro drug release studies indicated that CP and CMC had no effect below 0.6% concentration. Kinetic evaluation favored first-order and Hixson-Crowell kinetic models. Release mechanism analysis showed that the n values of the formulations were greater than 1 except for formulation F5, suggesting that FB might be released from the ophthalmic formulations by super case II type diffusion. When all the results of this study are evaluated, the in situ gelling formulations prepared with FB-SDs that contained P407/P188 (15/26.5%) and 0.2% CP or 0.2% CMC or 0.4 CMC% (F2, F5, and F6, respectively) could be promising formulations to prolong precorneal residence time and improve ocular bioavailability of FB.

Preparation and characterization of naproxen-loaded electrospun thermoplastic polyurethane nanofibers as a drug delivery system.

The design and production of drug-loaded nanofiber based materials produced by electrospinning is of interest for use in innovative drug delivery systems. In the present study, ultra-fine fiber mats of thermoplastic polyurethane (TPU) containing naproxen (NAP) were successfully prepared by electrospinning from 8 and 10% (w/w) TPU solutions. The amount of NAP in the solutions was 10 and 20% based on the weight of TPU. The collection period of the drug-loaded electrospun TPU fibers was 5, 10 and 20h, and they were characterized by FTIR, DSC and TGA analysis. The morphology of the NAP-loaded electrospun TPU fiber mats was smooth, and the average diameters of these fibers varied between 523.66 and 723.50nm. The release characteristics of these fiber mats were determined by the total immersion method in the phosphate buffer solution at 37°C. It was observed that the collection period in terms of the mat thickness played a major role in the release rate of NAP from the electrospun TPU mats.

Properties of bioadhesive ketoprofen liquid suppositories: preparation, determination of gelation temperature, viscosity studies and evaluation of mechanical properties using texture analyzer by 4 × 4 factorial design.

CONTEXT: Development and evaluation of thermosensitive and bioadhesive liquid suppositories containing ketoprofen (KP). OBJECTIVE: This study was conducted to develope thermosensitive and bioadhesive liquid suppositories containing KP using poloxamer and different bioadhesive polymers and to investigate their gelation temperature, viscosity and mechanical properties. MATERIALS AND METHODS: Bioadhesive liquid suppositories were prepared by the cold method using poloxamer 407 (P 407), Poloxamer 188 (P 188) and various amounts of different bioadhesive polymers. Their gelation temperatures, viscosity values and mechanical properties were determined using texture analyzer by 4 × 4 factorial design. RESULTS: It was seen that in presence of KP, gelation temperature of formulation P 407/P 188 (4/20%) significantly decreased from 64 to 37.1 °C. It is to be noted that addition of increasing concentrations of bioadhesive polymers lowered gelation temperature and its decrease was highest with addition of Carbopol 934 P (C). Results of texture profile analysis (TPA) showed that formulations containing C have significantly higher hardness and adhesiveness values than other bioadhesive formulations. According to TPA, gel structure of liquid suppository formulation F5, containing P 407/P 188/KP/C (4/20/2.5/0.8%), exhibited the greatest hardness, compressibilty, adhesiveness and besides greatest viscosity. DISCUSSION AND CONCLUSION: According to mechanical properties and viscosity values, it was concluded that F5 could be a promising formulation.

In vitro-in vivo evaluation of in situ gelling and thermosensitive ketoprofen liquid suppositories.

The main objective of this study was to investigate the release and pharmacokinetic profiles of ketoprofen (KP) from developed thermosensitive and mucoadhesive liquid suppositories. Thermosensitive liquid suppositories were prepared using KP, poloxamer 407 (P 407), poloxamer 188 (P 188) and various amounts of different mucoadhesive polymers. In vitro release studies was monitored by the USP XXVI paddle method. The results thus obtained were evaluated kinetically and mechanism of release was analyzed. Identification of poloxamer gel localization in vivo was conducted using white male rabbits by adding 1 % methylene blue. For in vivo studies, twenty-four white male rabbits were randomly divided into three groups. The rabbits in each group were administered with liquid suppository F1 [P407/P188/KP (4/20/2.5 %)], F5 [P407/P188/KP/C (4/20/2.5/0.8 %)] or conventional suppository (F-C) into the rectum. The plasma concentration of KP was analyzed by high performance liquid chromatography (HPLC). C max, AUC, MRT and T max were evaluated. The release of KP was variously affected by the mucoadhesive polymers. In vitro release studies showed that Carbopol 934 P(C) has significant effect on release rate among the mucoadhesive polymers. When the formulations were evaluated kinetically, different kinetic models were obtained. Formulation F6 [P407/P188/KP/C (4/20/2.5/1.6 %)] which contains the highest C concentration and very high viscosity, shows a significantly better fit with Higuchi kinetic model. n value of this formulation was also found approximately 0.5. n exponent results of the other formulations showed that KP might be released from the suppositories by non-Fickian diffusion. Identification of poloxamer gel localization in vivo showed that the suppositories remain in the rectum without leakage after administration. With regard to the results of in vivo studies, the AUC6→14 values of KP in liquid suppository containing C are significantly higher than those in liquid suppository without C. MRT0→24 and MRT0→∞ values of liquid suppository containing C are significantly higher than those in liquid suppository without C and conventional suppository. Conventional suppository and liquid suppository without C significantly gave faster time to reach the maximum plasma concentrations of KP. With regard to the in vitro and in vivo experiments, liquid suppository formulation F5 might be a promising formulation for the development of an effective rectal dosage form.

Acceleration of in vitro dissolution studies of sustained release dosage form of theophylline and in vitro-in vivo evaluations in terms of correlations.

The aim of the study was to accelerate the dissolution of the sustained release dosage forms using both elevated temperature and high rpm rates. Teokap(®) SR 200 mg pellets were tested by in vitro sustained and accelerated dissolution studies using USP XXIII rotating paddle method. Sustained dissolution studies were carried out for 12 h in phosphate buffer at 37 ± 0.5°C and 50 rpm. Accelerated dissolution studies were performed for 48 min in distilled water at 90 ± 1°C and 250 rpm. The results obtained from accelerated and sustained dissolution studies were correlated using both linear and linear kinetic correlation methods by a computer program. While r (2) and maximum error between calculated and observed drug release rates were found to be 0.9129 and 15.9%, respectively, in linear correlation method, these values were observed as 0.9938 and 3.6%, respectively, in linear kinetic correlation method. In vivo plasma concentration data were obtained from six New Zealand rabbits after administration of a single dose of Teokap(®) SR 200 mg pellet. Then, the results of in vivo study were evaluated with in vitro accelerated and sustained dissolution results by applying them to in vitro-in vivo linear correlations. As a result of these correlations, it was shown that the in vitro correlation plots were very similar to the plot which was obtained by the in vivo study (f (2) = 73.81-77.11). This study suggested a way to prevent the loss of time for routine dissolution studies of sustained release preparations for quality control procedures using in vitro accelerated dissolution tests. The storage and quarantine periods of the product in process and process controls in the manufactories could be shortened by this method. Calculation of the in vivo performance of sustained release dosage forms using the results of the accelerated dissolution studies may be counted as another advantage of the method.

Development and characterization of extended release Kollidon SR mini-matrices prepared by hot-melt extrusion.

Kollidon SR as a drug carrier and two model drugs with two different melting points, ibuprofen and theophylline, were studied by hot-melt extrusion. Powder mixtures containing Kollidon SR were extruded using a twin-screw extruder at temperatures 70 and 80 degrees C for ibuprofen and 80 and 90 degrees C for theophylline. The glass transition temperature (T(g)) and maximum torque were inversely related to ibuprofen concentrations, indicating its plasticizing effect. The results of differential scanning calorimetry (DSC) and X-ray diffraction analysis showed that ibuprofen remained in an amorphous or dissolved state in the extrudates containing drug up to 35%, whereas theophylline was dispersed in the polymer matrix. The increase in amounts of ibuprofen or theophylline in the hot-melt extrudates resulted in the increase in the drug release rates. Theophylline release rate in hot-melt extruded matrices decreased as the extrusion temperature increased. In contrast, a higher processing temperature caused the higher ibuprofen release. This was a clear indication of the plasticizing effect of ibuprofen on Kollidon SR and a result from water uptake. Theophylline release rate from hot-melt extrudates decreased with increasing triethyl citrate (TEC) level because of the formation of a denser matrix. By adding of Klucel LF as a water-soluble additive to the hot-melt extruded matrices, an increase in ibuprofen and theophylline release rates was obtained.

An alternative topical treatment of osteoarthritis of the knee with cutaneous diclofenac solution.

BACKGROUND: Osteoarthritis (OA) is the most common chronic degenerative disease, which is characterised by the destruction of the articular cartilage and subchondral bone. The current treatment of OA is based primarily on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics. There are disadvantages to routinely using NSAIDs in OA. Topical NSAIDs represent a potentially important advance in this regard as they may be significantly safer than oral NSAIDs. Cutaneous diclofenac solution (Pennsaid) was developed for the treatment of symptomatic OA of the knee and contains diclofenac sodium as an active ingredient and dimethyl sulfoxide (DMSO), a penetration enhancer. OBJECTIVE: To review: i) dermal drug application; ii) the treatment of OA with systemic and topical NSAID therapies; and iii) the clinical efficiency of Pennsaid on the topical treatment of OA of the knee. METHODS: A literature search was carried out on skin, topical drug delivery, treatment of OA and assessment of published clinical studies with Pennsaid. RESULTS AND DISCUSSION: The clinical studies showed that applying the topical diclofenac solution (Pennsaid) to a painful knee with primary OA could provide symptom relief equivalent to oral diclofenac with minimal systemic side effects; however, studies are needed that compare the effectiveness of Pennsaid with different topical forms of diclofenac.

The absorption of (99m)Tc-alendronate given by rectal route in rabbits.

Alendronate sodium (ALD) is a bisphosphonate medication used in the treatment and prevention of osteoporosis. Absorption of ALD as oral formulation is very poor (0.5%-1%). Its bioavailability can decrease with food effect. It has some gastrointestinal adverse effects such as gastritis, gastric ulcer, and esophagitis. The aim of this study was to develop a rectal formulation of ALD as an alternative to oral route and to investigate the absorption of it by using gamma scintigraphy. For this reason, ALD was labeled with Technetium-99m ((99m)Tc) by direct method. The radiochemical characterization of the (99m)Tc-ALD was carried out by paper chromatography, thin layer chromatography, and electrophoresis methods. The labeling efficiency of (99m)Tc-ALD was found 99% without significant changes until 6 h postlabeling at room temperature. The rectal suppositories containing (99m)Tc-ALD were prepared by fusion method using polyethylene glycol (PEG) 1500. The (99m)Tc-labeled ALD suppositories were administrated to rabbits by rectal route. Serial scintigrams over all bodies of the rabbits were obtained at different time intervals using a gamma camera. We found that the rectal absorption of (99m)Tc-ALD from suppository formulation was possible. According to our results, this formulation of ALD can be suggested for the therapy of osteoporosis as an alternative route.

Comparison of different water/oil microemulsions containing diclofenac sodium: preparation, characterization, release rate, and skin irritation studies.

The aim of the present study was to make a comparison of the in vitro release rate of diclofenac sodium (DS) from microemulsion (M) vehicles containing soybean oil, nonionic surfactants (Brij 58 and Span 80), and different alcohols (ethanol [E], isopropyl alcohol [I], and propanol [P]) as cosurfactant. The optimum surfactant:cosurfactant (S:CoS) weight ratios and microemulsion areas were detected by the aid of phase diagrams. Three microemulsion formulations were selected, and their physicochemical properties were examined for the pH, viscosity, and conductivity. According to the release rate of DS, M prepared with P showed the significantly highest flux value (0.059 +/- 0.018 mg/cm(2)/h) among all formulations (P < .05). The conductivity results showed that DS-loaded microemulsions have higher conductivity values (18.8-20.2 microsiemens/cm) than unloaded formulations (16.9-17.9 microsiemens/cm), and loading DS into the formulation had no negative effect on system stability. Moreover, viscosity measurements were examined as a function of shear rate, and Newtonian fluid characterization was observed for each microemulsion system. All formulations had appropriate observed pH values varying from 6.70 to 6.85 for topical application. A skin irritation study was performed with microemulsions on human volunteers, and no visible reaction was observed with any of the formulations. In conclusion, M prepared with P may be a more appropriate formulation than the other 2 formulations studied as drug carrier for topical application.

Transdermal delivery of diclofenac sodium through rat skin from various formulations.

The aim of this study was to evaluate and compare the in vitro and in vivo transdermal potential of w/o microemulsion (M) and gel (G) bases for diclofenac sodium (DS). The effect of dimethyl sulfoxide (DMSO) as a penetration enhancer was also examined when it was added to the M formulation. To study the in vitro potential of these formulations, permeation studies were performed with Franz diffusion cells using excised dorsal rat skin. To investigate their in vivo performance, a carrageenan-induced rat paw edema model was used. The commercial formulation of DS (C) was used as a reference formulation. The results of the in vitro permeation studies and the paw edema tests were analyzed by repeated-measures analysis of variance. The in vitro permeation studies found that M was superior to G and C and that adding DMSO to M increased the permeation rate. The permeability coefficients (Kp) of DS from M and M+DMSO were higher (Kp = 4.9 x 10(-3) +/- 3.6 x 10(-4) cm/h and 5.3 x 10(-3) +/- 1.2 x 10(-3) cm/h, respectively) than the Kp of DS from C (Kp = 2.7 x 10(-3) +/- 7.3 x 10(-4) cm/h) and G (Kp = 4.5 x 10(-3) +/- 4.5 x 10(-5) cm/h). In the paw edema test, M showed the best permeation and effectiveness, and M+DMSO had nearly the same effect as M. The in vitro and in vivo studies showed that M could be a new, alternative dosage form for effective therapy.

Dissolution characteristics of megaloporous tablets prepared with two kinds of matrix granules.

The purpose of this study is to obtain a drug release at a constant rate with a megaloporous tablet, which was prepared with a simple formulation. These tablets were prepared with two kinds of granules. One of them is the restraining-phase matrix granule (RMG) and it controls the release rate of the drug. The other one is the soluble housing-phase matrix granule (HMG) and controls liquid penetration into the system. Eudragit RL 100 and Eudragit L 100 polymers were used to constitute the restraining and housing matrix phases, respectively. The effect of the amount of Eudragit RL 100 in the RMG was investigated and decreasing of amount of Eudragit RL 100 in the RMG increased the drug release rate. The tablets were prepared with compaction pressures of 188, 377, 1884 and 7540 kg/cm(2) and it was observed that the compaction forces ranging from 377 to 7540 kg/cm(2) did not influence drug release. The effect of the size of the matrices was demonstrated and it was found that the drug release rate increased with decreasing of the size of the tablets. The impact of the dosage to the dissolution rates was also investigated using two different amounts of drug. Therefore, the tablets were designed with two different dosages to use once or twice a day at the dosage interval of every 12 or 24 h, respectively. The release kinetic of the best formulation (4K) of the study was evaluated with the goodness-of-fit analysis and it was seen that the target profile was nearly achieved. This study suggests using megaloporous tablets in therapy, which could be prepared with a simple and cheap way similarly to conventional tablets to obtain a constant drug release.

Preparation of arsenic trioxide-loaded microemulsion and its enhanced cytotoxicity on MCF-7 breast carcinoma cell line.

In this study, an injectable microemulsion of arsenic trioxide (As2O3-M) was prepared for intratumoral injection and the suppressive effect of As2O3-loaded microemulsion on human breast cancer cells MCF-7 was compared with those of a solution of the drug. Microemulsion was made up of soybean oil as oil phase, a mixture of Brij 58 and Span 80 as surfactants, absolute ethanol as cosurfactant, and bidistilled water containing As2O3 solution as the aqueous phase. Microemulsion formulation contains 5 x 10(-6) M As2O3. The pH of As2O3-M was adjusted to 7.35 +/- 0.1 and the physicochemical stability of the formulation was observed. The particle size distribution and zeta potential of As2O3-M were measured by Zetasizer 3000 HSA. The mean droplet diameters of As2O3-M were determined as 8.6 +/- 0.4 nm. As2O3-M exhibited 13.1 +/- 0.9 mV zeta potential. The formulation was physically stable for 12 months at room temperature when kept in ampule forms, as well as after autoclaving at 110 degrees C for 30 min. The antitumor effects of As2O3-M were examined on human breast cancer cells MCF-7. It was clearly demonstrated that As2O3-M had a significant cytotoxic effect on breast cancer cell lines, and the cytotoxic effect of As2O3-M was significantly more than that of regular As2O3 solutions. Even approximately 3000 times diluted microemulsion formulation loaded with 5 x 10(-6) M As2O3 showed a cytotoxic effect. As a result, this diluted concentration (approximately 1.6 x 10(-9) M) was found 1000 times more effective than regular As2O3 solutions (5 x 10(-6) M). According to the in vitro cytotoxicity studies, we concluded that when As2O3 was incorporated into the microemulsion (As2O3-M), which is a new drug carrier system, it suppresses tumor cell growth on multiple tumor lines. These results indicate that As2O3-M may exert a low cytotoxic effect on normal cells and may be effective as an antitumor agent that induces apoptosis.