Ocular bioanalysis of moxifloxacin and ketorolac tromethamine in rabbit lacrimal matrix using liquid chromatography-tandem mass spectrometry.

Aim: The fixed-dose combination of moxifloxacin (MOXI) and ketorolac tromethamine (KTR) is widely used for the treatment of bacterial keratitis. Thus, a new LC-MS/MS method was developed to determine MOXI and KTR in lacrimal fluid. Methods: Bioanalysis was performed using a Shimadzu 8050 LC-MS/MS in electrospray ionization-positive mode and the method was validated per US FDA guidelines. Isocratic separation was performed with a Waters Symmetry C18 column using methanol and 0.1% formic acid containing deionized water (85:15, v/v). Results & conclusion: An easy, quick and selective method was established and applied to assess the ocular pharmacokinetic profile of a commercially available formulation containing MOXI and KTR. Based on the pharmacokinetic data, this work describes pharmacokinetics-based dosage regimen calculations and their clinical significance.

HPV Lesions and Other Issues in the Oral Cavity Treatment and Removal without Pain.

Due to different oral and dental conditions, oral mucosa lesions such as those caused by the human papilloma virus and temporomandibular joint pathologies often have to be treated by surgical, ablative or extractive procedures. The treatment and control of pain and inflammation during these procedures is essential to guarantee the patient's well-being. For the foregoing reason, a hydrogel based on sodium alginate and hyaluronic acid containing 2% of ketorolac tromethamine has been developed. We characterized it physically, mechanically and morphologically. The rheological results suggest that the formulation can be easily and gently applied. Ex vivo permeation studies show that Ketorolac Tromethamine is able to penetrate through the buccal and sublingual mucosae, in addition to being retained in the mucosae's structure. Through an in vitro test, we were able to evaluate the role that saliva plays in the bioavailability of the drug, observing that more than half of the applied dose is eliminated in an hour. The histological and cytotoxic studies performed on pigs in vivo showed the excellent safety profile of the formulation, as well as its high tolerability. In parallel, a biomimetic artificial membrane (PermeaPad®) was evaluated, and it showed a high degree of correlation with the oral and sublingual mucosa.

Eudragit RL100 Based Moxifloxacin Hydrochloride and Ketorolac Tromethamine Combination Nanoparticulate System for Ocular Drug Delivery.

BACKGROUND: Bacterial conjunctivitis is a serious ocular infection if left untreated. It is caused by several species of bacteria like Pseudomonas, Staphylococcus and Mycobacterium. OBJECTIVE: The present investigation explores the development and characterization of moxifloxacin hydrochloride and ketorolac tromethamine combination loaded Eudragit RL 100 nanosuspension for ocular drug delivery in order to overcome the problems associated with conventional dosage forms. METHODS: The nanosuspension prepared by nanoprecipitation technique showed successful entrapment of both water-soluble drugs in the polymer matrix indicated by their % entrapment efficiencies. RESULTS: Formulations showed a mean particle size <200 nm with narrow size distribution and positive surface charge due to the presence of quaternary ammonium groups of Eudragit RL100. FTIR study revealed compatibility among the components, while a reduction in the crystallinity of formulation was observed in the PXRD study. The release of both the drugs was found to be sustained in nanosuspension as compared to commercial eyedrops. Ex vivo studies showed increased transcorneal permeation of drugs from nanosuspension, where approximately 2.5-fold and 2-fold increase in the permeation was observed for moxifloxacin hydrochloride and ketorolac tromethamine, respectively. The formulation was stable at 4°C and room temperature. CONCLUSION: Due to their sustained release, positive surface charge and higher transcorneal permeation, this will be a promising ocular drug delivery.

Design, development and characterization of ketorolac tromethamine polymeric nanosuspension.

Aim: At present, various ophthalmic formulations show low bioavailability. The rationale of present work was to design and develop stable ketorolac tromethamine nanosuspension with sustained effect and greater permeability for ocular drug delivery and increased ocular residence. Materials & methods: Formulations were designed by using central composite design, developed by combined nanoprecipitation and probe sonication method. Results & discussion: Nanosuspensions depicted the size range of the particles in between 199 and 441 nm with slight reduction in crystallinity of drug. In vitro drug release revealed that higher % entrapment efficiency of drug in nanosuspension delays the drug release. Conclusion: Eudragit RL-100-based nanosuspension increases viscosity and avoids problems like drug loss from precorneal surface and rapid drainage through nasolacrimal areas.

Confocal Raman spectroscopy: Evaluation of a non-invasive technique for the detection of topically applied ketorolac tromethamine in vitro and in vivo.

Current information about the pharmacokinetics of an ocular drug can only be achieved by invasive sampling. However, confocal Raman spectroscopy bears the potential to quantify drug concentrations non-invasively. In this project, we evaluated the detection and quantification of ocular ketorolac tromethamine levels with confocal Raman spectroscopy after topical administration. Confocal Raman spectroscopy and high-performance liquid chromatography (HPLC) were compared in terms of sensitivity of detection. Enucleated pig eyes were treated with different concentrations of ketorolac. Hereafter, ketorolac concentrations in the aqueous humor of pig eyes were analyzed by confocal Raman spectroscopy and HPLC. Subsequently, twelve rabbits were treated with Acular™ for four weeks. At several time points, ketorolac concentrations in aqueous humor of the rabbits were measured by confocal Raman spectroscopy followed by drawing an aqueous humor sample for HPLC analysis. In ketorolac treated pig eyes, both ex vivo Raman spectroscopy as well as HPLC were able to detect ketorolac in a broad concentration range. However, in vivo confocal Raman spectroscopy in rabbits was unable to detect ketorolac in contrast to HPLC. To conclude, confocal Raman spectroscopy has the capacity to detect ketorolac tromethamine in vitro, but currently lacks sensitivity for in vivo detection.

Sustained release of ketorolac tromethamine from poloxamer 407/cellulose nanofibrils graft nanocollagen based ophthalmic formulations.

There has been extensive utilization of poloxamer 407 (PM) for the delivery of various ophthalmic drugs aimed at efficient ophthalmic drug delivery approach for longer precorneal residence time along with acceptable bioavailability of drugs. We have studied the effect of nanocellulose grafted collagen (CGC) on the performance of in situ gels based on PM for the controlled in vitro release of Ketorolac Tromethamine (KT). CGC has shown great influence evident by the reduction in PM critical gelation concentration, increased gel strength, and prolonged the release of loaded drugs compared with the virgin PM gel. The engineered nanocomposite formulations established an anomalous diffusion mechanism along with a Fickian diffusion controlled drug release for 1.5 & 1.75 w/v% CGC reinforced PM. Hence, the synthesized in situ nanocomposites are potential candidates for ophthalmic drug delivery system.

Synthesis of methylcellulose/cellulose nano-crystals nanocomposites: Material properties and study of sustained release of ketorolac tromethamine.

Non-toxic nanocomposites based bio-films obtained from methylcellulose (MC) can reduce environmental problems associated with synthetic polymers. A new facile route for the isolation of cellulose nano-crystals (CNC) from jute waste is successfully utilized here. The fabrication of CNC reinforced MC nanocomposites by film casting technique and the studies of the effect of CNC on the properties of the MC based nanocomposites have been reported. The synthesized nanocomposites have shown improved UV resistance, mechanical, barrier, and thermal properties. FTIR results established the physicochemical compatibility between the drug, MC and CNC in nanocomposites. In vitro permeation studies performed by using Franz diffusion cell revealed diffusion mediated sustained drug release from the devices due to the presence of interaction between MC and CNC through H-bonding, electrostatic interaction between the hydrophilic polymer/CNC chains with the drug and the formation of tortuous path. The nanocomposites can be used for edible packaging and transdermal drug delivery.

Nanostructured SBA-15 host applied in ketorolac tromethamine release system.

The ordered mesoporous silica SBA-15 has been applied in studies of ketorolac tromethamine adsorption and release. The SBA-15 materials with hexagonal and regular structure were obtained using a triblock copolymer Pluronic P123 as a template and TEOS as a silica source. Ketorolac tromethamine was adsorbed into SBA-15 silica nanochannels using ethanol as solvent. The physicochemical and textural properties of SBA-15 and ketorolac tromethamine/SBA-15 were characterized by X-ray diffraction, thermogravimetric analysis, transmission electron microscopy, fourier transform infrared spectroscopy and BET surface studies. Drug release was evaluated by soaking the loaded silica mesoporous material into a solution of HCl (0.1 N) at initial time (0-2 h) and buffer pH 7 at high times at 37 °C under continuous stirring. Oral commercial Keto tablets (Dolten®) and Keto solution (Keto power) were study for the contrast. Release studies were performed in order to evaluate the required therapeutic efficacy. SBA-15 provides significant improvement in the controlled release of ketorolac tromethamine. Release profile of KETO from SBA-15/KETO and control releases.

Developing Transdermal Applications of Ketorolac Tromethamine Entrapped in Stimuli Sensitive Block Copolymer Hydrogels.

PURPOSE: In order to obtain dermal vehicles of ketorolac tromethamine (KT) for the local treatment of inflammation and restrict undesirable side effects of systemic levels hydrogels (HGs) of poloxamer and carbomer were developed. METHODS: KT poloxamer based HG (KT-P407-HG) and KT carbomer based HG (KT-C940-HG) were elaborated and characterized in terms of swelling, degradation, porosity, rheology, stability, in vitro release, ex vivo permeation and distribution skin layers. Finally, in vivo anti-inflammatory efficacy and skin tolerance were also assessed. RESULTS: HGs were transparent and kept stable after 3 months exhibiting biocompatible near neutral pH values. Rheological patterns fitted to Herschel-Bulkley for KT-C940-HG and Newton for KT-P407-HG due to its low viscosity at 25°C. Rapid release profiles were observed through first order kinetics. Following the surface the highest concentration of KT from C940-HG was found in the epidermis and the stratum corneum for P407-HG. Relevant anti-inflammatory efficacy of KT-P407-HG revealed enough ability to provide sufficient bioavailability KT to reach easily the site of action. The application of developed formulations in volunteers did not induce any visual skin irritation. CONCLUSIONS: KT-P407-HG was proposed as suitable formulation for anti-inflammatory local treatment without theoretical systemic side effect.

Ketoroloac tromethamine loaded nanodispersion incorporated into thermosensitive in situ gel for prolonged ocular delivery.

The present study was designed to improve the ocular availability of ketorolac tromethamine and to prolong its precorneal residence time for the treatment of postoperative ocular inflammation. Ketorolac tromethamine nanodispersions were successfully prepared by nanoprecipitation method using Eudragit(®) RL100. These nanodispersions were characterized in terms of particle size, zeta potential, entrapment efficiency and in vitro release. Consequently, the optimum nanodispersion was incorporated into thermosensitive in situ gel. The optimum gelling capacity was obtained by 20% Pluronic(®) F-127 and 14% Pluronic(®) F-127/1.5% HPMC K4m. The gelling temperature and gelation time of the in situ gels increased by decreasing the concentration of Pluronic(®) F-127. The mucoadhesive strength was significantly improved by the addition of HPMC. Incorporation of ketorolac tromethamine loaded nanodispersions into in situ gel bases sustained the release of ketorolac tromethamine, improved its ocular availability and prolonged its residence time without causing irritation to eye.

Formulation and corneal permeation of ketorolac tromethamine-loaded chitosan nanoparticles.

The aim of this work was to formulate chitosan (CS)-based nanoparticles (NPs) loaded with ketorolac tromethamine (KT) intended for topical ocular delivery. NPs were prepared using ionic gelation method incorporating tri-polyphosphate (TPP) as cross-linker. Following the preparation, the composition of the system was optimized in terms of their particle size, zeta potential, entrapment efficiency (EE) and morphology, as well as performing structural characterization studies using Fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). The data suggested that the size of the NPs was affected by CS/TPP ratio where the diameter of the NPs ranged from 108.0 ± 2.4 nm to 257.2 ± 18.6 nm. A correlation between drug EE and the corresponding drug concentration added to the formulation was observed, where the EE of the NPs increased with increasing drug concentration, for up to 10 mg/mL. FT-IR and DSC revealed that KT was dispersed within the NPs where the phosphate groups of TPP were associated with the ammonium groups of CS. The in vitro release profile of KT from CS NPs showed significant differences (p < 0.05) compared to KT solution. Furthermore, mucoadhesion studies revealed adhesive properties of the formulated NPs. The KT-loaded NPs were found to be stable when stored at different storage conditions for a period of 3 months. The ex vivo corneal permeation studies performed on excised porcine eye balls confirmed the ability of NPs in retaining the drug on the eye surface for a relatively longer time. These results demonstrate the potential of CS-based NPs for the ocular delivery of KT.

Studies on methylcellulose/pectin/montmorillonite nanocomposite films and their application possibilities.

Films based on methylcellulose (MC) and pectin (PEC) of different ratios were prepared. MC/PEC (90:10) (MP10) gave the best results in terms of mechanical properties. Sodium montmorillonite (MMT) (1, 3 and 5 wt%) was incorporated in the MP10 matrix. The resulting films were characterized by X-ray diffraction and transmission electron microscopy, and it was found that nanocomposites were intercalated in nature. Mechanical studies established that addition of 3 wt% MMT gave best results in terms of mechanical properties. However, thermo-gravimetric and dynamic mechanical analysis proved that decomposition and glass transition temperature increased with increasing MMT concentration from 1 to 5 wt%. It was also observed that moisture absorption and water vapor permeability studies gave best result in the case of 3 wt% MMT. Optical clarity of the nanocomposite films was not much affected with loading of MMT. In vitro drug release studies showed that MC/PEC/MMT based films can be used for controlled transdermal drug delivery applications.

pH-sensitive interpenetrating polymer network microspheres of poly(vinyl alcohol) and carboxymethyl cellulose for controlled release of the nonsteroidal anti-inflammatory drug ketorolac tromethamine.

In this study, we aimed to produce pH-sensitive microspheres for the controlled release of the nonsteroidal anti-inflammatory drug, ketorolac tromethamine (KT). For this purpose, an interpenetrating polymer network (IPN) of microspheres of poly(vinyl alcohol) (PVA)/sodium carboxymethyl cellulose (NaCMC) were prepared, based on different formulations using glutaraldehyde (GA) (0.66 M) and hydrochloric acid (HCl) (3%, v/v). The preparation conditions of the microspheres were optimized by considering the percentage of entrapment efficiency and swelling capacity of the microspheres, and their release data. The effects of PVA and NaCMC ratio on the release of KT for over a period of 6 h, at three pH values (1.2, 6.8, and 7.4), have been discussed.

Sunlight-driven photocatalytic degradation of non-steroidal anti-inflammatory drug based on TiO2 quantum dots.

This paper reports the facile synthesis, characterization and solar-light driven photocatalytic degradation of TiO2 quantum dots (QDs). The TiO2 QDs were synthesized by a facile ultrasonic-assisted hydrothermal process and characterized in terms of their structural, morphological, optical and photocatalytic properties. The detailed studies confirmed that the prepared QDs are well-crystalline, grown in high density and exhibiting good optical properties. Further, the prepared QDs were efficiently used as effective photocatalyst for the sun-light driven photocatalytic degradation of ketorolac tromethamine, a well-known non-steroidal anti-inflammatory drug (NSAID). To optimize the photocatalytic degradation conditions, various dose-dependent, pH-dependent, and initial drug-concentration dependent experiments were performed. The detailed solar-light driven photocatalytic experiments revealed that ∼99% photodegradation of ketorolac tromethamine drug solution (10 mg L(-1)) was observed with optimized amount of TiO2 QDs and pH (0.5 g L(-1) and 4.4, respectively) under solar-light irradiations. The observed results demonstrate that simply synthesized TiO2 QDs can efficiently be used for the solar-light driven photocatalytic degradation of harmful drugs and chemicals.

Formulation and pharmacokinetics of colon-specific double-compression coated mini-tablets: Chronopharmaceutical delivery of ketorolac tromethamine.

The present study is designed and significantly planned to study the effect of double-compression coating on core mini-tablets to attain the chronopharmaceutical delivery of ketorolac tromethamine to colon. Double-compression coated tablets were prepared based on time-controlled hydroxypropyl methylcellulose K100M inner compression coat and pH-sensitive Eudragit S100 outer compression coat. From the in vitro drug release studies, F6 tablets was considered as the optimized formulation, which retarded the drug release in stomach and small intestine (3.51 ± 0.15% in 5h) and progressively released to colon (99.82 ± 0.69% in 24h). The release process followed supercase-II transport with zero order release kinetics. Similarity factor calculated from stability studies was found to be 84.73. From the pharmacokinetic evaluation, the immediate release core mini-tablets reached peak plasma concentration (Cmax of 4532.68 ± 28.14 ng/ml) at 2h Tmax and colon targeted tablets showed Cmax=3782.29 ± 17.83 ng/ml at 12h Tmax. The area under the curve and mean resident time of core mini-tablets were found to be 11,278.26 ± 132.67 ng-h/ml and 3.68 h respectively while 17,324.48 ± 56.32 ng-h/ml and 10.39 h for compression coated tablets. Hence the development of double-compression coated tablets is a promising way to gain the chronopharmaceutical delivery of ketorolac tromethamine to colon.

Nasal delivery of analgesic ketorolac tromethamine thermo- and ion-sensitive in situ hydrogels.

Ketorolac tromethamine (KT) was potent to treat moderate to moderately severe pains. However, KT solutions for nasal delivery lost quickly from the nasal route. Thermo- and ion-sensitive in-situ hydrogels (ISGs) are appropriate for nasal drug delivery because the intranasal temperature maintains ∼37 °C and nasal fluids consist of plentiful cations. In this study, a novel nasal thermo- and ion-sensitive ISG of KT was prepared with thermo-sensitive poloxamer 407 (P407) and ion-sensitive deacetylated gellan gum (DGG). The optimal formulation of the KT ISG consisted of 3% (w/v) DGG and 18% (w/v) P407 and its viscosity was up to 7.63 Pas at 37 °C. Furthermore, penetration enhancers and bacterial inhibitors were added and their fractions in the ISG were optimized based on transmucosal efficiencies and toxicity on toad pili. Sulfobutyl ether-ß-cyclodextrin of 2.5% (w/v) and chlorobutanol of 0.5% (w/v) were chosen as the penetration enhancer and the bacterial inhibitor, respectively. The Fick's diffusion and dissolution of KT could drive it continuous release from the dually sensitive ISG according to the in vitro investigation. Two methods, writhing frequencies induced by acetic acid and latency time of tails retracting from hot water, were used to evaluate the pharmacodynamics of the KT ISG on the mouse models. The writhing frequencies significantly decreased and the latency time of tail retracting was obviously prolonged (p<0.05) for the KT ISG compared to the control. The thermo- and ion-sensitive KT ISG had appropriate gelation temperature, sustained drug release, improved intranasal absorption, obvious pharmacodynamic effect, and negligible nasal ciliotoxicity. It is a promising intranasal analgesic formulation.

Preclinical evaluation of dual action intranasal formulation intended for postoperative/cancer associated therapies.

Granisetron hydrochloride is a potent antiemetic yet experiencing first pass metabolism. Ketorolac tromethamine is a potent analgesic NSAID that is known to cause gastrointestinal complications. The purpose of this study is to prepare combined in situ nasal copolymer thermal gel combining both drugs for the management of postoperative and cancer associated nausea, vomiting and pain while avoiding the problems associated with their therapy. In situ gelling nasal formulations with/without different mucoadhesive polymers were prepared and evaluated. Viscosity of different formulations was measured and correlated to in-vitro drug release. Selected formulae were evaluated for in-vivo mucociliary transit time. Based on in-vitro release pattern and mucociliary transit time, the selected formula F4 was evaluated for chemical and thermal anti-nociception activity in rats following intranasal or intraperitoneal administration. Only the intra-nasal administration of the selected formulation F4 showed significant analgesia against chemical nociception during both the early and late phases. Also, intranasal administration of the selected formulation F4 showed significant analgesia against thermal nociception. F4 intranasal formulation may offer higher therapeutic value than oral administration as it may not only avoid granisetron first pass metabolism but may also minimize ketorolac gastrointestinal adverse effects as well.

Effect of methyl cellulose on gelation behavior and drug release from poloxamer based ophthalmic formulations.

The effect of weight average molecular weight (Mw) of methyl cellulose (MC) on the gelation behavior of Poloxamer 407 (PM) and in vitro release of Ketorolac Tromethamine (KT) from different ophthalmic formulations based on PM is examined. A drop of gelation temperature of PM is observed using MC of various M(w) by test tube tilting method, UV-vis spectroscopy, viscometry and rheometry. It is also observed that the viscosity and gel strength of all the formulations are increased with the increase in Mw of MC. PM with highest Mw of MC provides best drug release property among all the formulations. It is evident from this investigation that there is a distinct effect of M(w) of MC on the gelation behavior of PM as well as on the drug release profile of KT from PM-MC based ophthalmic formulations.

Enhancement in bioavailability of ketorolac tromethamine via intranasal in situ hydrogel based on poloxamer 407 and carrageenan.

The objective of this study was to construct a new in situ gel system based on the combination of poloxamer 407 and carrageenan (carrageenan-poloxamer 407 hydrogel, CPH) for intranasal delivery of ketorolac tromethamine. CPH showed potassium ion concentration - dependent erosion characteristics which ensured slow erosion in aqueous environment containing potassium ion at the physiological level. Loading with ketorolac tromethamine influenced erosion, drug release and thermosensitive properties of CPH. CPH containing 15% ketorolac tromethamine showed suitable gelation temperature (near 35°C) and in vitro sustained release profiles. Pharmacokinetic study of intranasal CPH containing 15% ketorolac tromethamine in rats demonstrated enhanced absolute bioavailability (68.8 ± 23.3%) and prolonged mean residence time (8.8 ± 3.5h) in comparison with the intranasal solution group (24.8 ± 13.8%, 3.9 ± 0.6h). Nasal ciliotoxicity evaluation on an in situ toad palate model preliminarily showed the safety of CPH for intranasal use. All results suggested the potential of CPH as a new sustained - release platform for the intranasal delivery of ketorolac tromethamine.