Pharmacokinetics, bioavailability and plasma protein binding of tolfenamic acid in rainbow trout (Oncorhynchus mykiss).

BACKGROUND: Although research on the mechanism and control of pain and inflammation in fish has increased in recent years, the use of analgesic drugs is limited due to the lack of pharmacological information about analgesic drugs. Tolfenamic acid is a non-steroidal anti-inflammatory drug and can be used in fish due to its low side effect profile and superior pharmacokinetic properties. OBJECTIVES: The pharmacokinetics, bioavailability and plasma protein binding of tolfenamic acid were investigated following single intravascular (IV), intramuscular (IM) and oral administration of 2 mg/kg in rainbow trout at 13 ± 0.5°C. METHODS: The experiment was carried out on a total of 234 rainbow trout (Oncorhynchus mykiss). Tolfenamic acid was administered to fish via IV, IM and oral route at a dose of 2 mg/kg. Blood samples were taken at 13 different sampling times until the 72 h after drug administration. The plasma concentrations of tolfenamic acid were quantified using high pressure liquid chromatography-ultraviolet (UV) and pharmacokinetic parameters were assessed using non-compartmental analysis. RESULTS: The elimination half-life (t1/2ʎz) of tolfenamic acid for IV, IM and oral routes was 3.47, 6.75 and 9.19 h, respectively. For the IV route, the volume of distribution at a steady state and total body clearance of tolfenamic acid were 0.09 L/kg and 0.03 L/h/kg, respectively. The peak plasma concentration and bioavailability for IM and oral administration were 8.82 and 1.24 µg/mL, and 78.45% and 21.48%, respectively. The mean plasma protein binding ratio of tolfenamic acid in rainbow trout was 99.48% and was not concentration dependent. CONCLUSIONS: While IM route, which exhibits both the high plasma concentration and bioavailability, can be used in rainbow trout, oral route is not recommended due to low plasma concentration and bioavailability. However, there is a need to demonstrate the pharmacodynamic activity of tolfenamic acid in rainbow trout.

Microchannel-embedded implantable device with fibrosis suppression for prolonged controlled drug delivery.

For the prolonged, controlled delivery of systemic drugs, we propose an implantable drug-delivery chip (DDC) embedded with pairs of a microchannel and drug-reservoir serving as a drug diffusion barrier and depot, respectively. We pursued a DDC for dual drugs: a main-purpose drug, diclofenac (DF), for systemic exposure, and an antifibrotic drug, tranilast (TR), for local delivery. Thus, the problematic fibrotic tissue formation around the implanted device could be diminished, thereby less hindrance in systemic exposure of DF released from the DDC. First, we separately prepared DDCs for DF or TR delivery, and sought to find a proper microchannel length for a rapid onset and sustained pattern of drug release, as well as the required drug dose. Then, two distinct DDCs for DF and TR delivery, respectively, were assembled to produce a Dual_DDC for the concurrent delivery of DF and TR. When the Dual_DDC was implanted in living rats, the DF concentration in blood plasma did not drop significantly in the later periods after implantation relative to that in the early periods before fibrotic tissue formation. When the Dual_DDC was implanted without TR, there was a significant decrease in the blood plasma DF concentration as the time elapsed after implantation. Biopsied tissues around the Dual_DDC exhibited a significant decrease in the fibrotic capsule thickness and collagen density relative to the Dual_DDC without TR, owing to the effect of the local, sustained release of the TR.

Quantification of field-incurred residues of cyantraniliprole and IN-J9Z38 in cabbage/soil using QuEChERS/HPLC-PDA and dietary risk assessment.

Cyantraniliprole is an anthranilic diamide insecticide used for the effective management of diamondback moth in cabbage. Dietary risk assessment of pesticides in food is a major concern now. This study developed a QuEChERS/HPLC-PDA-based highly efficient and reliable method, registering 89.80-100.11% recoveries of cyantraniliprole and its metabolite IN-J9Z38 from cabbage and soil with a relative standard deviation of 0.43-5.77%. Field experiment was conducted to study the residue dissipation of cyantraniliprole in cabbage and soil. Two foliar treatments of 10.26% formulation (Benevia) at 60 (T1 ) and 120 (T2 ) gram active ingredient/hectare were applied. The dissipation half-lives of cyantraniliprole in cabbage and soil were determined to be 3.5-4.2 and 3.8-5.3 days at T1 and 3.9-4.8 and 4.1-4.7 days at T2 , respectively. The maximum concentrations of IN-J9Z38 at T1 and T2 were 0.819 and 1.061 mg/kg, respectively, on the fifth day. A risk quotient value of <1 indicates no dietary risk to the consumers. The residues in the harvested cabbage were below the tolerance level of 2.0 mg/kg established by the regulatory body in India.

Role of the Abcg2 transporter in plasma levels and tissue accumulation of the anti-inflammatory tolfenamic acid in mice.

The Breast Cancer Resistance Protein (BCRP/ABCG2) is an ATP-binding cassette efflux transporter that is expressed in the apical membrane of cells from relevant tissues involved in drug pharmacokinetics such as liver, intestine, kidney, testis, brain and mammary gland, among others. Tolfenamic acid is an anti-inflammatory drug used as an analgesic and antipyretic in humans and animals. Recently, tolfenamic acid has been repurposed as an antitumoral drug and for use in chronic human diseases such as Alzheimer. The aim of this work was to study whether tolfenamic acid is an in vitro Abcg2 substrate, and to investigate the potential role of Abcg2 in plasma exposure, secretion into milk and tissue accumulation of this drug. Using in vitro transepithelial assays with cells transduced with Abcg2, we showed that tolfenamic acid is an in vitro substrate of Abcg2. The in vivo effect of this transporter was tested using wild-type and Abcg2-/- mice, showing that after oral and intravenous administration of tolfenamic acid, its area under the plasma concentration-time curve in Abcg2-/- mice was between 1.7 and 1.8-fold higher compared to wild-type mice. Abcg2-/- mice also showed higher liver and testis accumulation of tolfenamic acid after intravenous administration. In this study, we demonstrate that tolfenamic acid is transported in vitro by Abcg2 and that its plasma levels as well as its tissue distribution are affected by Abcg2, with potential pharmacological and toxicological consequences.

The Discovery of Novel ACA Derivatives as Specific TRPM2 Inhibitors that Reduce Ischemic Injury Both In Vitro and In Vivo.

The transient receptor potential melastatin 2 (TRPM2) channel is associated with ischemia/reperfusion injury, inflammation, cancer, and neurodegenerative diseases. However, the limit of specific inhibitors impedes the development of TRPM2-targeted therapeutic agents. To discover more potent and selective TRPM2 inhibitors, 59 N-(p-amylcinnamoyl) anthranilic acid (ACA) derivatives were synthesized and evaluated using calcium imaging and electrophysiology approaches. Systematic structure-activity relationship studies resulted in some potent compounds inhibiting the TRPM2 channel with sub-micromolar half-maximal inhibitory concentration values. Among them, the preferred compound A23 exhibited TRPM2 selectivity over TRPM8 and TRPV1 channels as well as phospholipase A2 and showed neuroprotective activity in vitro. Following pharmacokinetic studies, A23 was further evaluated in a transient middle cerebral artery occlusion model in vivo, which significantly reduced cerebral infarction. These data indicate that A23 might serve as a useful tool for TRPM2-related research as well as a lead compound for the development of therapeutic agents for ischemic injury.

Pharmacokinetics of tolfenamic acid after different administration routes in geese (Anser cygnoides).

The pharmacokinetics and bioavailability of tolfenamic acid were determined in geese (Anser cygnoides) following intravenous (IV), intramuscular (IM), subcutaneous (SC), and oral administrations at 2 mg/kg dose. In this study, eight healthy geese (3.5 ± 0.5 kg) were used. The study was performed in four periods according to a crossover design with a 15-day washout period between two administrations. The plasma concentrations of tolfenamic acid were analyzed using HPLC-UV, and pharmacokinetic parameters were calculated by noncompartmental analysis. The elimination half-life was 1.73, 2.51, 2.34, and 2.31 hr for IV, IM, SC, and oral routes, respectively. The volume of distribution at steady state and total clearance after IV administration were 0.25 L/kg and 0.16 L hr-1  kg-1 , respectively. The peak plasma concentrations of tolfenamic acid after IM, SC, and oral administrations were 4.89, 2.94, and 2.92 µg/ml at 0.25, 0.75, and 1 hr, respectively. The bioavailability was 87.91, 77.87, and 76.03% for the IM, SC, and oral routes, respectively. Tolfenamic acid, which exhibits the good bioavailability and plasma concentration following IM, SC, and oral administrations at 2 mg/kg dose, may be useful in the treatment of inflammatory disease conditions in geese.

Pharmacokinetics of tolfenamic acid in goats after different administration routes.

The aim of this study was to determine the pharmacokinetics and bioavailability of tolfenamic acid in goats after intravenous (IV), intramuscular (IM), subcutaneous (SC), and oral (PO) administrations at 2 mg/kg dose. In this study, eight clinically healthy goats were used. The study comprised four periods, according to a crossover design with at least a 15-day washout period between treatments. Plasma concentrations of tolfenamic acid were determined by HPLC-UV, and the pharmacokinetic parameters were estimated using a non-compartmental method. Following IV administration, terminal elimination half-life, volume of distribution at steady state, and total clearance were 1.60 h, 0.37 L/kg, and 0.27 L/h/kg, respectively. The mean peak plasma concentration following IM, SC, and PO administrations was 1.77, 1.22, and 0.30 µg/ml, respectively. The mean bioavailability following IM, SC, and PO administrations was 64.46, 55.43, and 19.46%, respectively. The PO route, which exhibits both the low plasma concentration and bioavailability, is not recommended in goats. The IV, IM, and SC routes, which show comparable pharmacokinetic profiles, may be proposed for use in goats. However, the multi-dose and pharmacodynamic studies are necessary to establish more accurately its safety and efficacy in the goat.

Prolonged Distribution of Tranilast in the Eyes after Topical Application onto Eyelid Skin.

Tranilast, a lipophilic drug with various ophthalmic applications, was used as a model drug to establish the possibility of delivering lipophilic drugs through the eyelid skin. Pharmacokinetics and tissue distribution studies were conducted employing three application methods (topical application onto eyelid skin, eye drops, and intravenous injection in rats) to broaden the significance of delivering drugs through the eyelids. A two-compartment open model analysis was used for intravenous route while a non-compartmental evaluation was used for topical applications to estimate the pharmacokinetic parameters. Eyelid skin application, eye drops, and intravenous administration had mean residence times (MRTs) of 8.07, 1.79, and 3.25 h in the eyeball and 10.8, 1.29, and 2.97 h in the conjunctiva, correspondingly. In the eyeball, topical application of tranilast onto the eyelids corresponded to a 4.5- and 2.5-fold higher MRT compared with eye drops and intravenous administration, respectively. An 8.4- or 3.6-fold higher MRT was observed in the conjunctiva after topical application compared with eye drops or intravenous administration, respectively. This indicated a gradual penetration of tranilast into the eyeball and conjunctiva, subsequently a slow elimination from these target tissues.

Effect of dose on the intravenous pharmacokinetics of tolfenamic acid in goats.

The objective of this study was to determine the pharmacokinetics of tolfenamic acid (TA) following intravenous (IV) administration at doses of 2 and 4 mg/kg in goats. In this study, six healthy goats were used. TA was administered intravenously to each goat at 2 and 4 mg/kg doses in a cross-over pharmacokinetic design with a 15-day washout period. Plasma concentrations of TA were analyzed using the high performance liquid chromatography with ultraviolet detector, and pharmacokinetic parameters were assigned by noncompartmental analysis. Following IV administration at dose of 2 mg/kg, area under the concentration-time curve (AUC0-∞ ), elimination half-life (t1/2ʎz ), total clearance (ClT ) and volume of distribution at steady state (Vdss ) were 6.64 ± 0.81 hr* µg/ml, 1.57 ± 0.14 hr, 0.30 ± 0.04 L h-1  kg-1 and 0.40 ± 0.05 L/kg, respectively. After the administration of TA at a dose of 4 mg/kg showed prolonged t1/2ʎz , increased dose-normalized AUC0-∞ , and decreased ClT . In goats, TA at 4 mg/kg dose can be administered wider dose intervals compared to the 2 mg/kg dose. However, further studies are needed to determine the effect of different doses on the clinical efficacy of TA in goats.

Pharmacokinetics of tolfenamic acid in green sea turtles (Chelonia mydas) after intravenous and intramuscular administration.

The present study aimed to evaluate the pharmacokinetic features of tolfenamic acid (TA) in green sea turtles, Chelonia mydas. Green sea turtles were administered single either intravenous (i.v.) or intramuscular (i.m.) injection of TA, at a dose of 4 mg/kg body weight (b.w.). Blood samples were collected at preassigned times up to 168 hr. The plasma concentrations of TA were measured using a validated liquid chromatography tandem mass spectrometry method. Tolfenamic acid plasma concentrations were quantifiable for up to 168 hr after i.v. and i.m. administration. The concentration of TA in the experimental green sea turtles with respect to time was pharmacokinetically analyzed using a noncompartment model. The Cmax values of TA were 55.01 ± 8.34 µg/ml following i.m. administration. The elimination half-life values were 32.76 ± 4.68 hr and 53.69 ± 3.38 hr after i.v. and i.m. administration, respectively. The absolute i.m. bioavailability was 72.02 ± 10.23%, and the average binding percentage of TA to plasma protein was 19.43 ± 6.75%. Based on the pharmacokinetic data, the i.m. administration of TA at a dosage of 4 mg/kg b.w. might be sufficient to produce a long-lasting anti-inflammatory effect (7 days) for green sea turtles. However, further studies are needed to determine the clinical efficacy of TA for treatment of inflammatory disease after single and multiple dosages.

Synthesis and evaluation of novel radioiodinated anthranilate derivatives for in vivo imaging of vascular endothelial growth factor receptor with single-photon emission computed tomography.

OBJECTIVE: Angiogenesis facilitates tumor survival and promotes malignancy. The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) tyrosine kinase (TK) signaling pathway is a key factor mediating angiogenesis, suggesting that this pathway may be a target for diagnosis and therapy. In this study, we aimed to develop small molecule radioiodinated probes applicable for in vivo VEGFR imaging considering the versatility and usefulness of single-photon emission computed tomography (SPECT). METHODS: We designed and synthesized four radioiodinated anthranilate compounds (6a-d) based on the structure of an anticancer drug targeting VEGFR-TK. The inhibitory potencies of corresponding cold compounds 4a-d and in vitro stability of compounds 6a-d were assessed by cellular proliferation inhibition assays and radio thin-layer chromatography after incubation in neutral solution. In vivo biodistributions were evaluated by determining radioactivity in tissues of interest after intravenous injection of test compounds in tumor-bearing mice. In vitro and in vivo blocking experiments using a selective VEGFR-TK inhibitor and SPECT/computed tomography (CT) imaging were performed in tumor-bearing mice. RESULTS: The radioiodinated compounds 6a-d were obtained with more than 68.0% radiochemical yield and more than 95% radiochemical purity. Because compounds 4a-d showed high inhibitory potencies and compounds 6c and 6d showed high in vitro stability, 6c ([125I]m-NPAM) and 6d ([125I]p-NPAM) were further evaluated. Analysis of the in vivo biodistribution revealed a tumor to blood radioactivity ratio of greater than 4 at 24 h after [125I]p-NPAM administration. Accumulation of radioactivity in cultured tumor cells and tumor xenografts after [125I]p-NPAM administration was significantly blocked by inhibitor pretreatment. Tumors were clearly imaged at 24 h after [125I]p-NPAM injection with SPECT/CT in comparison to that in inhibitor-pretreated tumor-bearing mice. CONCLUSION: [125I]p-NPAM may have potential applications as a lead compound for future development of a clinically usable VEGFR imaging probe for SPECT.

Phototoxic risk assessment of dermally-applied chemicals with structural variety based on photoreactivity and skin deposition.

Combined use of photochemical and pharmacokinetic (PK) data for phototoxic risk assessment was previously proposed, and the system provided reliable phototoxic risk predictions of chemicals in same chemical series. This study aimed to verify the feasibility of the screening system for phototoxic risk assessment on dermally-applied chemicals with wide structural diversity, as a first attempt. Photochemical properties of test chemicals, 2-acetonaphthalene, 4'-methylbenzylidene camphor, 6-methylcoumarin, methyl N-methylanthranilate, and sulisobenzone, were evaluated in terms of UV absorption and reactive oxygen species (ROS) generation, and PK profiles of the test chemicals in rat skin were characterized after dermal co-application. All test chemicals showed strong UVA/B absorption with molar extinction coefficients of over 3000 M-1⋅cm-1, and irradiated 2-acetonaphthalene, 6-methylcoumarin, and methyl N-methylanthranilate exhibited significant ROS generation. Dermally-applied 2-acetonaphthalene and 4'-methylbenzylidene camphor indicated high and long-lasting skin deposition compared with the other test chemicals. Based on the photochemical and PK data, 2-acetonaphthalene was predicted to have potent phototoxic risk. The predicted phototoxic risk of the test chemicals by integration of obtained data was mostly consistent with their in vivo phototoxicity observed in rat skin. The screening strategy employing photochemical and PK data would have high prediction capacity and wide applicability for photosafety evaluation of chemicals.

Pharmacokinetics of tolfenamic acid in Hawksbill turtles (Eretmochelys imbricata) after single intravenous and intramuscular administration.

To the best of our knowledge, limited pharmacokinetic information to establish suitable therapeutic plans is available for Hawksbill turtles. Therefore, the present study aimed to assess the pharmacokinetic features of tolfenamic acid (TA) in Hawksbill turtles, Eretmochelys imbricata, after single intravenous (i.v.) and intramuscular (i.m.) administration at dosage 4 mg/kg body weight (b.w.). The study (parallel design) used 10 Hawksbill turtles randomly divided into equal groups. Blood samples were collected at assigned times up to 144 hr. The concentrations of TA in plasma were quantified by a validated liquid chromatography tandem mass spectrometry (LC-ESI-MS/MS). The concentration of TA in the experimental turtles with respect to time was pharmacokinetically analyzed using a noncompartment model. The Cmax values of TA were 89.33 ± 6.99 µg/ml following i.m. administration. The elimination half-life values were 38.92 ± 6.31 hr and 41.09 ± 9.32 hr after i.v. and i.m. administration, respectively. The absolute i.m. bioavailability was 94.46%, and the average binding percentage of TA to plasma protein was 31.39%. TA demonstrated a long half-life and high bioavailability following i.m. administration. Therefore, the i.m. administration is recommended for use in clinical practice because it is both easier to perform and provides similar plasma concentrations to the i.v. administration. However, further studies are needed to determine the clinical efficacy of TA for treatment of inflammatory disease after single and multiple dosages.

Pharmacokinetics of tolfenamic acid in red-eared slider turtles (Trachemys scripta elegans).

OBJECTIVE: To determine the pharmacokinetics of tolfenamic acid (TA) after different routes of administration [intravenous (IV) and intramuscular (IM), 2 mg kg-1] and doses (IV, 2 and 4 mg kg-1) in red-eared slider turtles (Trachemys scripta elegans). STUDY DESIGN: Randomized experimental trial. ANIMALS: Sixteen healthy red-eared slider turtles. METHODS: Turtles were randomly assigned to two groups (n = 8 each). Group 1 received TA at a dose of 2 mg kg-1 IV and then IM, after a washout period of 30 days. Group 2 received 4 mg kg-1 TA IV. A noncompartmental analysis was used to calculate pharmacokinetic variables. RESULTS: No local and/or systemic adverse drug effects were observed in any turtle. Elimination half-life and mean residence time following IM administration at 2 mg kg-1 were significantly longer than those following IV administration. The bioavailability following IM administration was complete. The area under the plasma concentration-time curve, elimination half-life, mean residence time and total clearance were significantly different between the dose groups. CONCLUSIONS AND CLINICAL RELEVANCE: The absence of adverse reactions in the turtles of the study of TA along with the favourable pharmacokinetic properties (the long half-life and the complete bioavailability) of TA administered at the single doses of 2 and 4 mg kg-1 suggest the possibility of its effective use in turtles. However, further studies are required to establish a multiple dosage regimen of TA and to evaluate the clinical efficacy of administering TA.

In silico study of the mechanism of action, pharmacokinetic and toxicological properties of some N-methylanthranilates and their analogs.

The in silico evaluation for the three previously synthesized compounds (Methyl (MMA), propyl (PMA) and isopropyl (IMA) N-methylanthranilate), MMA and IMA originally found in the leaf essential oil of Choisya ternata, provided a very good confirmation for the in vivo pharmacological results obtained with such compounds for a number of pharmacological targets. This manuscript dealt with their assessment in six pharmacological targets to understanding anti-inflammatory, antinociceptive, anxiolytic, antidepressant and anti-allergic activities using docking molecular as well as their pharmacokinetics and toxicological parameters prediction. The compound IMA seems to be the best one when all the combined parameters are put together. Interestingly this compound presented the best in vivo profile in previous studies by the group. Derivatives of the three original molecules were proposed. Overall the second modification (5-[2-(methoxycarbonyl)anilino]pentanoic acid, 5-[2-(propoxycarbonyl)anilino]pentanoic acid and 5-(2-{[(propan-2-yl)oxy]carbonyl}anilino)pentanoic acid) of all three original molecules was the one that achieved highest score in molecular docking and a better combination of the other parameters. Further research as in the obtaining of such derivatives via synthesis and their in vivo testing to confirm their higher pharmacological potential is currently on the way.

Distribution of methyl and isopropyl N-methylanthranilates and their metabolites in organs of rats treated with these two essential-oil constituents.

Two volatile alkaloids, methyl (MMA) and isopropyl N-methylanthranilates (IMA), identified in the essential oil of Choisya ternata Kunth (Rutaceae), have been proven to possess polypharmacological properties (antinociceptive, anti-inflammatory, gastro-, hepato-, nephroprotective activities, anxiolytic and antidepressant properties, and likewise an effect on diazepam-induced sleep). In the continuation of our investigation of their urinary-metabolite profiles, we performed GC-MS analyses of the diethyl-ether extracts of selected tissues (liver, kidneys, heart, brain, lungs, quadriceps femoris muscle, and spleen) of rats intraperitoneally treated with MMA or IMA (2 g kg-1). Organ-metabolite profiles of MMA and IMA were qualitatively mutually analogous (varying only in the alcohol moiety of the metabolites), and generally analogous to their urinary-metabolite profiles. The greatest diversity and the highest overall amount of anthranilate metabolites was found in the hepatic tissue. The principal anthranilate-related compounds in the organs of rats treated with MMA, among 12 detected, were the products of ester hydrolysis, N-methylanthranilic and anthranilic acids. In the tissues of IMA-treated rats, among 16 compounds, the most abundant ones were the unmetabolized IMA and N-methylanthranilic acid. A collection of the compositional data regarding the anthranilate-related metabolites was statistically treated by multivariate statistical analysis that provided a better insight into the possible biotransformation pathways.

Pharmacokinetics and bioavailability of tolfenamic acid in sheep.

The pharmacokinetics, bioavailability, and tolerability of tolfenamic acid (TA) were determined after treating sheep with TA via different routes and doses. This crossover study was carried out with a washout period of 15 days. In the study, 16 clinically healthy sheep were randomly assigned to two equal groups. In the first group (n = 8), animals received TA by intravenous (IV), intramuscular (IM), subcutaneous (SC), or oral (OR) routes at 2 mg/kg. In the second group (n = 8), TA was administered intravenously to each sheep at 2, 4, 8, and 16 mg/kg. Plasma samples were analyzed with a high-performance liquid chromatography assay. Noncompartmental pharmacokinetic analyses were used to evaluate the data. The area under the concentration-time curves (AUC0-∞ ), elimination half-life (t1/2ʎz ), and the mean residence time (MRT) significantly differed among the administration routes at 2 mg/kg of TA. Following IM, SC, and OR administrations, TA demonstrated different peak concentrations (Cmax ) and time to reach Cmax (Tmax ), with a bioavailability of 163%, 127%, and 107%, respectively. The dose-normalized AUC0-∞ revealed a significant difference among the dose groups; however, the relationship between dose and AUC0-∞ was linear. Both t1/2ʎz and MRT increased depending on the dose. Although the total clearance (ClT ) decreased depending on dose, the volume of distribution at steady-state (Vss ) increased. Tolfenamic acid indicated a long half-life and high bioavailability following IM, SC, and OR administrations at 2 mg/kg. TA exhibited linear kinetics and was well tolerated by the animals, except at 16 mg/kg. Thus, TA may be used in different routes and doses (≤8 mg/kg) in sheep; however, further studies are needed to determine the clinical efficacy of TA during the inflammatory and painful conditions and the pharmacokinetics and safety of repeated administration in sheep.

Addition of Cationic Surfactants to Lipid-Based Formulations of Poorly Water-Soluble Acidic Drugs Alters the Phase Distribution and the Solid-State Form of the Precipitate Upon In Vitro Lipolysis.

It has been previously shown that the interaction of some weakly basic drugs with oppositely charged fatty acids during digestion can influence the solid-state form of the drug if it precipitates. The present study hypothesized the opposite effect for weakly acidic drugs. Tolfenamic acid (TA) and an oppositely charged cationic surfactant, didodecyldimethylammonium bromide (DDAB) were combined in a model medium chain lipid formulation. The phase distribution upon in vitro lipolysis was determined using HPLC and the solid-state form of precipitated TA was determined using X-ray diffraction and crossed polarized light microscopy. TA precipitated in a different polymorphic crystalline form to the starting reference material in the absence of DDAB but precipitated in an amorphous form when DDAB was included in the same formulation. The solubility of TA upon dispersion and digestion of the formulation was considerably higher in the presence of DDAB. The findings point to ionic interactions between TA and DDAB as the reason for the improved drug solubility throughout digestion, and precipitation of drug in an amorphous salt form, analogous to what has been observed in the past for some poorly water-soluble weakly basic drugs with anionic co-formers.

Tolfenamic Acid.

Tolfenamic acid (TA) is a nonsteroidal antiinflammatory drug and belongs to the group of fenamates. It is used as a potent pain reliever in the treatment of acute migraine attacks, and disorders like dysmenorrhea, rheumatoid, and osteoarthritis. TA has shown excellent in vitro antibacterial activity against certain ATCC strains of bacteria when complexed with bismuth(III). It has also been reported to block pathological processes associated with Alzheimer's disease. In the recent past, TA has also been used as a novel anticancer agent for the treatment of various cancers. In view of the clinical importance of TA, a comprehensive review of the physical and pharmaceutical properties and details of the various analytical methods used for the assay of the drug in pharmaceutical and biological systems has been made. The methods reviewed include identification tests and titrimetric, spectrophotometric, chromatographic, electrochemical, thermal, microscopic, enzymatic, and solid-state techniques. Along with the analytical profile, the stability and degradation of TA, its pharmacology and pharmacokinetics, dosage forms and dose, adverse effects and toxicity, and interactions have been discussed.

Enhanced biopharmaceutical effects of tranilast on experimental colitis model with use of self-micellizing solid dispersion technology.

The present study aimed to clarify the applicability of a self-micellizing solid dispersion of tranilast (SMSD/TL) to the treatment of inflammatory bowel diseases (IBD) using an experimental colitis model. SMSD/TL with several loading amounts ranging from 10 to 50% was prepared using a wet-milling system. The physicochemical properties of SMSD/TL were evaluated in terms of the dissolution behavior, morphology, and particle size distribution. Animal studies were conducted to evaluate oral bioavailability in rats and anti-inflammatory effects in a rat model of chemically induced colitis. SMSD/TL with drug loading of 15% (SMSD/TL15) showed enhanced dissolution behavior at pH 1.2, compared with other tested other formulations. After the dispersion of SMSD/TL15 in deionized water, fine micelles formed with an average diameter of 137 nm. SMSD/TL15 (10 mg-TL/kg) exhibited about 147- and 34-fold greater value for Cmax and the area under the curve of plasma concentration vs. time than crystalline TL, respectively. Although the anti-inflammatory effect on the colitis model was very limited in the crystalline TL (2 mg/kg) group, inflammatory events, such as myeloperoxidase activity and thickening of the submucosa in colon tissues, were significantly suppressed in the SMSD/TL15 (2 mg-TL/kg) group. Based on these findings, SMSD/TL might be a more efficacious dosage option for improved IBD treatment.