Design of experiment approach in development of febuxostat nanocrystal: Application of Soluplus® as stabilizer

Febuxostat (FBX) is a drug able to inhibit xanthine oxidase and reduce uric acid production commonly used for the treatment of hyperuricemia in subjects suffering from gout. Several studies have also been directed at its use as anti-cancer drug during the last years, opening a window for its off-label use. In the present study, an optimized formulation in terms of vesicle size and drug release, obtained by encapsulation of FBX into the emulsomes (FBX-EMLs), was evaluated for its cytotoxic potential in human colorectal carcinoma (HCT 116) cells. The optimized FBX-EMLs formula had an improved half maximal inhibitory concentration (IC50), about 4-fold lower, compared to the free drug. The cell cycle analysis showed a significant inhibition of the HCT 116 cells proliferation following FBX-EMLs treatment compared to all the other conditions, with a higher number of cells accumulating on G2/M and pre-G1 phases, paralleled by a significant reduction of cells in G0/G1 and S phases. The optimized formula was also able to significantly increase the percentage of cell population in both early and late stages of apoptosis, characterized by a higher intracellular caspase-3 concentration, as well as percentage of necrotic cells. Lastly, the FBX ability to decrease the mitochondrial membrane potential was enhanced when the drug was delivered into the EMLs. In conclusion, the new formulation of FBX into EMLs improved all the parameters related to the anti-proliferative activity and the toxic potential of the drug towards colorectal cancer cells.

https://www.mdpi.com/1999-4923/12/10/956/pdf

The Encapsulation of Febuxostat into Emulsomes Strongly Enhances the Cytotoxic Potential of the Drug on HCT 116 Colon Cancer Cells.

The goal of the present investigation is to formulate febuxostat (FXT) self-nanoemulsifying delivery systems (liquid SNEDDS, solid SNEDDS, and pellet) to ameliorate the solubility and bioavailability. To determine the self-nanoemulsifying region, ternary plot was constructed utilizing Capmul MCM C8 NF® as an oil phase, Labrasol® as principal surfactant, and Transcutol HP® being the co-surfactant. Liquid SNEDDS (L-SNEDDS) were characterized by evaluating droplet size, zeta potential, % transmission, and for thermodynamic stability. In vitro dissolution study of FXT loaded L-SNEDDS (batch F7) showed increased dissolution (about 48.54 ± 0.43% in 0.1 N HCl while 86.44 ± 0.16% in phosphate buffer pH 7.4 within 30 min) compared to plain drug (19.65 ± 2.95% in 0.1 N HCl while about 17.61 ± 2.63% in phosphate buffer pH 7.4 within 30 min). Single pass intestinal permeability studies revealed fourfold increase in the intestinal permeability of F7 compared to plain drug. So, for commercial aspects, F7 was further transformed into solid SNEDDS (S-SNEDDS) as readily nanoemulsifying powder form (SNEP) as well as pellets prepared by application of extruder spheronizer. The developed formulation was found superior to pure FXT with enhanced oral bioavailability and anti-gout activity (with reduced uric acid levels), signifying a lipidic system being an efficacious substitute for gout treatment.

Quality by Design Approach for the Development of Self-Emulsifying Systems for Oral Delivery of Febuxostat: Pharmacokinetic and Pharmacodynamic Evaluation

Gout is the most familiar inflammatory arthritis condition caused by the elevation of uric acid in the bloodstream. Febuxostat (FBX) is the latest drug approved by the United States Food and Drug Administration (US FDA) for the treatment of gout and hyperuricemia. FBX is characterized by low solubility resulting in poor gastrointestinal bioavailability. This study aimed at improving the oral bioavailability of FBX by its incorporation into self-nanoemulsifying delivery systems (SNEDS) with minimum globule size and maximum stability index. The SNEDS-incorporated FBX was loaded into a carrier substrate with a large surface area and lyophilized with other excipients to produce a fluffy, porous-like structure tablet for the transmucosal delivery of FBX. The solubility of FBX was studied in various oils, surfactants, and cosurfactants. Extreme vertices design was utilized to optimize FBX-SNEDS, and subsequently loaded into lyophilized tablets along with suitable excipients. The percentages of the main tablet excipients were optimized using a Box-Behnken design to develop self-nanoemulsifying lyophilized tablets (SNELTs) with minimum disintegration time and maximum drug release. The pharmacokinetics parameters of the optimized FBX-SNELTs were tested in healthy human volunteers in comparison with the marketed FBX tablets. The results revealed that the optimized FBX-SNELTs increased the maximum plasma concentration (Cmax) and decreased the time to reach Cmax (Tmax) with a large area under the curve (AUC) as a result of the enhanced relative oral bioavailability of 146.4%. The significant enhancement of FBX bioavailability is expected to lead to reduced side effects and frequency of administration during the treatment of gout.

Investigating the Potential of Transmucosal Delivery of Febuxostat from Oral Lyophilized Tablets Loaded with a Self-Nanoemulsifying Delivery System

Metronidazole has the potential to produce local stomach specific action in order to treat Helicobacter pylori induced peptic ulcer disease. The current project executes the development of osmotically controlled bioadhesive metronidazole loaded effervescent floating tablets with optimized floating and swelling behavior. Direct compression technique was used to prepare the tablets. The designed formulations exhibited physico-chemical properties within acceptable optimum limits as per pharmacopeial requirements. The results of tablet floating studies revealed that all formulations, except F1 and F5, had good buoyancy characteristics (TFT > 12 h except F2 and F8 with TFT of 6 h). Formulation F2 containing guar gum in higher concentration with carbopol and formulation F8 containing guar gum in 50% decreased concentration in combination with HPMC and carbopol had enhanced FLT appreciably, with least TFT as compared to formulations F3, F4, and F6 (ANOVA; p ≤ 0.05). Formulation batches of F3, F4, and F6 exhibited appreciable FLT as well as TFT and were optimized formulations. Out of the above mentioned optimized batches, F4 and F6 formulations showed low FLT (4 and 5 s respectively). The results of the swelling study indicated a proportionate increase in the swelling index with increase in time. A significantly higher swelling ratio was found with formulation F6 and F4 compared with that of F7 and F8 (ANOVA; p ≤ 0.05). Additionally, the impact of pH change, agitational intensity, as well as increasing concentration of NaCl was investigated on drug release. It was observed that agitational intensity had no effect on drug release rate while increasing concentration of NaCl produced an increased drug release from the dosage form as compared to the drug release exhibited by the formulations in the absence of NaCl. Overall, this project could have valuable contribution in the fabrication of metronidazole loaded effervescent floating tablets. Gastro-retentive systems are expected to enhance local stomach specific action of anti H. pylori agents based on their buoyancy and swelling behavior.

/pdf/metronidazole-based-floating-bioadhesive-drug-delivery-14wwwf0g.pdf

Metronidazole Based Floating Bioadhesive Drug Delivery System for Potential Eradication of H. pylori: Preparation and In Vitro Characterization

The present investigation deals with the formulation and evaluation of sodium alginate and pectin based In situ gel of Losartan Potassium. Sodium alginate and guar gum were used as a polymer and CaCO3 was used as a crosslinking agent. The formulation of gel depends upon factors like temperature modulation, pH changes, presence of ions and ultra-violet irradiation, from which drug gets released in sustained and controlled manner. The objective of this study was to develop a novel in- situ gel. The system utilizes polymers that exhibit sol-to-gel phase transition due to change in specific Physico-chemical parameters. In-situ gel was formed at a biological pH. In vitro release studies were conducted in simulated gastric fluid and cumulative amount of drug release was analyzed by spectrophotometry. From designed set of experiments, it was evident that formulation containing 2% of sodium alginate and 1.5% of Guar gum control the release of drug for longer duration. The in-situ gel exhibited the expected, viscosity, drug content, pH, in vitro gelling capacity, in vitro floating ability and sustained drug release. The drug release from the in situ gels follows the Fickian diffusion type of release.

/pdf/formulation-and-evaluation-of-floating-in-situ-gelling-5grnk1953d.pdf

Formulation and evaluation of floating in situ gelling system of losartan potassium

Febuxostat is a urate lowering drug, an inhibitor of xanthine oxidase used in the treatment of hyperuricemia and chronic gout. The drug shows dissolution-rate limited absorption, there by poor and variable bioavailability. It needs enhancement in bioavailability to derive maximum therapeutic efficacy. The main objective of   the   present research work is to enhance the solubility and dissolution rate of Febuxostat by preparing the Spherical agglomerates. Spherical agglomerates were prepared by the quasi emulsion solvent diffusion method. N, N-dimethyl form amide, chloroform and water were selected as good solvent, bridging liquid and poor solvents respectively. Polyethylene glycol, Poloxomer- F68 and Polyvinyl alcohol were used as a carrier. Among all the formulations prepared, spherical agglomerates prepared with Febuxostat and Poloxomer- F68 in 1:1 ratio showed highest drug release in 60 minutes. Spherical agglomerates prepared with Febuxostat and Poloxomer- F68 in 1:1 ratio was used in the preparation of orodispersible tablets. To study the influence of  superdisintegrants on performance of  Febuxostat Orodispersible Tablets, a set of three formulations (K1, K2, K3) were prepared using three superdisintegrants sodium starch glycolate, Croscarmalose sodium and Crospovidone . The orodispersible tablets of Febuxostat prepared with Crospovidone showed rapid drug release when compared to pure drug and other tablet formulations.

/pdf/formulation-and-evaluation-of-poorly-soluble-febuxostat-43im4u32bb.pdf

L. Srinivas

Papers

Formulation and evaluation of floating in situ gelling system of losartan potassium

Formulation and Evaluation of Poorly Soluble Febuxostat Orodispersable Tablet