Design of multicomponent indomethacin-paracetamol and famotidine loaded nanoparticles for sustained and effective anti-inflammatory therapy.

Indomethacin is one of the nonsteroidal anti-inflammatory drugs (NSAIDs) that are widely prescribed drug for pain and inflammation. However, its notoriety of causing gastrointestinal effect, low water solubility, and its short half-life would affect patient compliance and its oral absorption and accordingly justify the need to develop a formula with a controlled and sustained release manner in combination with anti-ulcer drugs. Herein, we synthesized indomethacin-paracetamol co-drug loaded in nanoemulsion and encapsulated in famotiditine loaded polycaprolactone (PCL) nanoparticles. The synthesis of the co-drug was achieved by the formation of a hydrolyzable ester between the indomethacin and paracetamol. The synthesized co-drug was preloading in nanoemulsion (Co-NE), which encapsulated into famotidine PCL nanoparticles utilizing the nanoprecipitation approach. The developed nanosystem showed hydrodynamic size less than 200 nm and the zeta potential value above -30 mV. TEM images confirmed the morphological structure of the formed nanoemulsion and the loaded PCL nanoparticles. Stability studies revealed that the developed nanosystem was stable at different temperatures and pHs over 1 month. Moreover, improvement of the solubilities of these three drugs leading to have a controlled-release multicomponent system of both co-drug and famotidine over 3 days. This multicomponent nanoparticle might be a potential platform to overcome the obstacles of NSAIDs, synergize drugs with different mechanisms of actions by co-encapsulating a small-sized nanoemulsion into PCL nanoparticles for reaching the goal of effective anti-inflammatory therapy.

RP-HPLC Method Development and Validation of Synthesized Codrug in Combination with Indomethacin, Paracetamol, and Famotidine.

BACKGROUND: Indomethacin is considered a potent nonsteroidal anti-inflammatory drug that could be combined with Paracetamol to have superior and synergist activity to manage pain and inflammation. To reduce the gastric side effect, they could be combined with Famotidine. Methodology. A codrug of Indomethacin and Paracetamol was synthesized and combined in solution with Famotidine. The quantification of the pharmaceutically active ingredients is pivotal in the development of pharmaceutical formulations. Therefore, a novel reverse-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated according to the International Council for Harmonization (ICH) Q2R1 guidelines. A reverse phase C18 column with a mobile phase acetonitrile: sodium acetate buffer 60 : 40 at a flow rate of 1.4 mL/min and pH 5 was utilized. RESULTS: The developed method showed good separation of the four tested drugs with a linear range of 0.01-0.1 mg/mL (R 2 > 0.99). The LODs for FAM, PAR, IND, and codrug were 3.076 × 10-9, 3.868 × 10-10, 1.066 × 10-9, and 4.402 × 10-9 mg/mL respectively. While the LOQs were 9.322 × 10-9, 1.172 × 10-10, 3.232 × 10-9, and 1.334 × 10-8 mg/mL, respectively. Furthermore, the method was precise, accurate, selective, and robust with values of relative standard deviation (RSD) less than 2%. Moreover, the developed method was applied to study the in vitro hydrolysis and conversion of codrug into Indomethacin and Paracetamol. CONCLUSION: The codrug of Indomethacin and Paracetamol was successfully synthesized for the first time. Moreover, the developed analytical method, to our knowledge, is the first of its kind to simultaneously quantify four solutions containing the following active ingredients of codrug, Indomethacin, Paracetamol, and Famotidine mixture with added pharmaceutical inactive ingredients in one HPLC run.

Pharmacodynamic testing and new validated HPLC method to assess the interchangeability between multi-source orlistat capsules.

BACKGROUND: Orlistat is an irreversible inhibitor of the lipase enzyme that prevents trigylcerides from being digested, thereby inhibiting triglyceride hydrolysis and absorption. The resultant reduced calorie uptake enables a positive effect on weight control. Systemic absorption of the drug is, therefore, not necessary for its mode of action. An alternative in vitro study (pharmacodynamic) has been introduced for this drug, as in vivo bioavailability studies are irrelevant with regard to the achievement of the product's intended purposes. OBJECTIVES: To develop a new validated high-performance liquid chromatography (HPLC) method for the analysis of orlistat and to assess the potency and equivalence of three orlistat formulations using the pharmacodynamic method as a surrogate indicator of pharmaceutical interchangeability. METHODS: A new HPLC method was developed for the analysis and for the dissolution studies of orlistat in capsules. Pancreatic lipase activity was measured for three different capsule products: Orlislim®, Slimcare®, and Xenical®, G1, G2, and the brand, respectively. Porcine pancreatic lipase and p-nitrophenyl butyrate (PNPB) were placed in a pH 7.4 reaction buffer at 37°C, and substrate hydrolysis was monitored by measuring absorbance changes at 410 nm; this was repeated on six capsules of each product. The inhibition was expressed by the concentration of product, which inhibited 50% of the activity of pancreatic lipase (IC50). RESULTS: The new analytical method was suitable for orlistat analysis. Values of IC50 from regression lines and equations were 6.14, 8.43, and 7.80 µg/mL for Orlislim®, Xenical®, and Slimcare®, respectively. CONCLUSION: Pharmacodynamic studies of lipase inhibition could be used to support in vitro dissolution, which demonstrates interchangeability between generic and branded orlistat capsules. Moreover, it could be suggested as an alternative tool to bioequivalence studies for orlistat oral products.