SYNTHESIS AND COMPARISON OF PEG-IBUPROFEN AND PEG-KETOPROFEN PRODRUGS BY IN VITRO AND IN VIVO EVALUATION

Pain is an unpleasant sensation experienced by all individuals and classified as acute and chronic pain. NSAID’s were most widely used for treatment of Analgesia and Inflammation. Ibuprofen, Ketoprofen, Polyethylene glycol 1500 & PEG 6000 were used as drug carriers and Glycine was used as spacer to link the drugs through ester linkage. Ibuprofen and Ketoprofen belong to propionic acid derivatives of Anti-inflammatory drugs and are non-selective COX inhibitors. PEG 1500/PEG6000-Ibuprofen/Ketoprofen and PEG 1500/PEG 6000-Glycine-Ibuprofen/Ketoprofen were synthesized and are subjected to In Vitro dissolution studies which revealed that the drug release was higher at 7.2 pH rather than at 1.2 pH. The results of In Vivo evaluation studies of both synthesized prodrugs revealed that these prodrugs retained their Analgesic activity by hot plate method and acetic acid method, Anti-inflammatory activity by paw edema method and cotton pellet method. Both the prodrugs had exhibited good ulcer protective activity when compared to parent drugs. Keywords: Prodrugs, Polyethylene Glycol 1500, Poly Ethylene Glycol 6000, Ibuprofen, Ketoprofen

DEVELOPMENT OF NANOEMULSION TO IMPROVE THE OCULAR BIOAVAILABILITY AND PATIENT COMPLIANCE IN POSTOPERATIVE TREATMENT USING INDOMETHACIN

Objective: To develop a new cationic nanoemulsion (NE) for ophthalmic delivery of indomethacin (IND) to improve the permeability and retention time of formulations, thereby improving the drug's ocular bioavailability. Methods: Based on the solubility profile of indomethacin in various solvents, captex 8000 was selected as oil phase, span 20 as a surfactant and tween 20 as co-surfactant to construct pseudo ternary phase diagrams and nanoemulsion region was recognized. Sonication was used as the method of NE preparation. Optimization was done using 32 factorial designs by considering the oil and the ratio of surfactant to co-surfactant (Smix) quantities as independent variables and evaluated for different physicochemical properties. Ex vivo transcorneal permeability was studied using bovine cornea, the In vivo drug pharmacokinetics of optimized NE and marketed formulation were assessed in rabbit aqueous humor and also in plasma. Results: The mean globule size, zeta potential, viscosity, refractive index, pH, surface tension and the osmolarity values for the prepared indomethacin nanoemulsions (IND-NEs) were found between 129.8±1.1 to 191.4±1.6 nm,+13.20±4.6 to+23.45±4.82, 15.3±0.1 to 32.7±0.0 mPas, 1.346±0.007 to 1.386±0.005, 5.5±0.4 to 6.9±0.9, 32.0±2.6 to 52.3±3.4 mN/m and 303-395 mOsm/l respectively and all these values found to be falling under the recommended values for ophthalmic use. From the In vitro release studies, it was found that the IND-NEs exhibited sustained drug release with 67.91±2.01 to 95.90±1.93 % drug release at 24h when compared to the drug solution which showed 99.81±5.21 % drug release within 2h. The Ex vivo drug permeation through the corneal membrane at 4h from the optimized NE and drug solution was found to be 524±1.5 µg/cm2 and 175±2.6 µg/cm2 respectively. Further, the optimized NE was found to be nonirritant with the lowest ocular irritation potential (Iirr) of 1 towards the rabbit's eyes. The area under the drug concentration vs. time curve for 24h (AUC (0–24h)) for optimized NE and the marketed formulation was found to be 1514.99 ng/ml/h and 974.14 ng/ml/h in aqueous humour; 2266.83 ng/ml/h and 778.15 ng/ml/h in plasma respectively. Conclusion: Due to its improved corneal absorption and prolonged drug release along with less systemic absorption, the optimized NE offers an effective postoperative treatment with increased ocular bioavailability and improved patient compliance with a decrease in the number of installations per day and a decrease or disappearance of systemic side effects of IND

ANTIINFLAMMATORY AND ANTIOXIDANT ACTIVITIES OF 2-AMINO-N-(SUBSTITUTED ALKYL) BENZOXAZOLE-5-CARBOXAMIDE DERIVATIVES

Objective: In continuation of the work on Benzoxazoles present work deals with the synthesis,characterization and evaluation of 2-Amino-N-(substituted alkyl) benzoxazole-5- carboxamides for anti-inflammatory and antioxidant activities. Methods: Synthetic methodology of benzoxazoles from 4-carbomethoxynitrophenol.Evaluation of compounds for anti-inflammatory activity by carragenean induced rat paw odema method and antioxidant activity by DPPH method. Results: Among them compounds Vc(R=ethyl), Ve(R=propyl) and Vg (R=diisopropyl) V g (R=propyl) were found to be potent compounds. Compound Vf (R=isopropyl) showed comparatively more percentage of free radical scavenging activity with IC 50 of 4.65 when compared with the standard ascorbic acid. Conclusion: Vf is considered to be the dual anti-inflammatory and antioxidant agent

Synthesis, anti-inflammatory and analgesic activity of 4-(substituted benzylamino)-5-substituted phenyl-3-amino-1,2,4-triazole derivatives

A novel series of 4-(substituted benzylamino)-5-substituted phenyl-3-amino-1, 2, 4-triazole derivatives were synthesized by reaction of 5-substituted phenyl-3,4-diamino-1,2,4-triazole with different aromatic aldehydes. The structures of the compounds were synthesized and characterised by elemental analysis, 1H NMR, Mass and IR Spectra. The title compounds were investigated for anti-inflammatory and analgesic activities using carrageenan induced rat paw edema and acetic induced writhing test, respectively. All the test compounds exhibited significant activity, compounds IVg, IVh and IVb showed more potent anti-inflammatory activity when compared with standard (Ibuprofen). All the test compounds were significantly (p < 0.05) reduced writhings induced by the acetic acid in mice.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Synthesis, anti-inflammatory and analgesic activity of 4-(substituted benzylamino)-5-substituted phenyl-3-amino-1,2,4-triazole derivatives

A novel series of 4-(substituted benzylamino)-5-substituted phenyl-3-amino-1, 2, 4-triazole derivatives were synthesized by reaction of 5-substituted phenyl-3,4-diamino-1,2,4-triazole with different aromatic aldehydes. The structures of the compounds were synthesized and characterised by elemental analysis, 1H NMR, Mass and IR Spectra. The title compounds were investigated for anti-inflammatory and analgesic activities using carrageenan induced rat paw edema and acetic induced writhing test, respectively. All the test compounds exhibited significant activity, compounds IVg, IVh and IVb showed more potent anti-inflammatory activity when compared with standard (Ibuprofen). All the test compounds were significantly (p < 0.05) reduced writhings induced by the acetic acid in mice.Colegio de Farmacéuticos de la Provincia de Buenos Aire

SYNTHESIS OF PRODRUGS OF MEFENAMIC ACID AND THEIR IN VIVO EVALUATION

Objective: The purpose of the study was to synthesize prodrugs of mefenamic acid, to be used as Anti inflammatory drug with fewer adverse effects. Methods: The drug was covalently bonded to PEG 1500 (polyethylene glycol) and PEG 6000 as such and with a linker glycine. The prodrugs were characterized by FT-I.R and N.M.R. For the drug release studies, all the prodrugs were subjected to pH 1.2 and pH 7.2. For the anti inflammatory activity, Carrageenan induced rat paw edema method was followed and for Ulcer protecting activity, Pylorus ligation method was used, the prodrugs were administered to male Sprague-Dawley rats. Results: The results suggested that the prodrugs of mefenamic acid, the drug release was higher at pH 7.2 than at pH 1.2. The result obtained for anti inflammatory activity was comparable to the standard drug of mefenamic acid. For ulcers, the prodrugs were found to possess Ulcer curing property higher than the standard drug. Conclusion: The prodrugs thus synthesized possess anti inflammatory activity as well as good ulcer protecting activity, can be used instead of standard drug

Synthesis, anti-inflammatory and analgesic activity of 4-(substituted benzylamino)-5-substituted phenyl-3-amino-1,2,4-triazole derivatives

A novel series of 4-(substituted benzylamino)-5-substituted phenyl-3-amino-1, 2, 4-triazole derivatives were synthesized by reaction of 5-substituted phenyl-3,4-diamino-1,2,4-triazole with different aromatic aldehydes. The structures of the compounds were synthesized and characterised by elemental analysis, 1H NMR, Mass and IR Spectra. The title compounds were investigated for anti-inflammatory and analgesic activities using carrageenan induced rat paw edema and acetic induced writhing test, respectively. All the test compounds exhibited significant activity, compounds IVg, IVh and IVb showed more potent anti-inflammatory activity when compared with standard (Ibuprofen). All the test compounds were significantly (p < 0.05) reduced writhings induced by the acetic acid in mice.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Enantiomeric separation and determination of stereospecific drug release from marketed racemic omeprazole products by chiral HPLC

The objective of carrying out this research work was to investigate the effect of chirality on stereospecific dissolution of omeprazole enantiomers from various marketed racemic omeprazole products. Omeprazole is used for the treatment of gastro-duodenal ulcers and symptomatic gastro-oesophageal reflux. Dissolution of various marketed products was performed using USP type I apparatus in 0.1 N HCl for 2 h and in pH 6.8 phosphate buffer for 1 h at 100 rpm. The separation of enantiomers was done using a chiral HPLC method on CHIRAL AGP column (100 x 4.6 mm i.d.). The wavelength for UV detection was set at 210 nm. The mobile phase was 10 mM phosphate buffer with 5 % acetonitrile adjusted to pH 6.5 at a flow rate of 0.9 ml min-1 with an injector valve fitted to a 50 μL volume sample loop. The retention times for R and S enantiomers of omeprazole were 5 and 7.5 min, respectively. The dissolution of S enantiomer of Ocid-20 and Omee was found to be significantly more compared to their R enantiomer at 5 and 10 min dissolution time points after which there was no stereospecific discrimination in the dissolution. From the S/R ratios of different racemic omeprazole marketed products it was concluded that at 5 and 10 min dissolution time points there was a stereospecific drug release between the S and R enantiomers with the brands Ocid-20 and Omee (p 0.05).Colegio de Farmacéuticos de la Provincia de Buenos Aire

Stereospecific dissolution of inclusion complexes of amlodipine base and its besylate enantiomers with hydroxypropyl-β-cyclodextrin

The objective of this work was the preparation of inclusion complexes of amlodipine base and its besylate salt with hydroxy propyl-β-cyclodextrin (HPBC) to improve the dissolution and to investigate the stereospecific dissolution of amlodipine enantiomers. The prepared inclusion complexes were characterized by FTIR and DSC. Significant improvement in the dissolution was found with S and R enantiomers of amlodipine base where as no improvement was found with enantiomers of amlodipine besylate (p > 0.05) after complexation with HPBC. This indicates the formation of inclusion complexes with only enantiomers of amlodipine base (p 0.05). Stereospecific dissolution was observed with pure enantiomers of amlodipine base when its inclusion complexes were prepared by solvent evaporation method with l:1 and 1:2 molar ratios but not with 1:3 molar ratio.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Effect of Ashwagandha and Aloe vera pretreatment on intestinal transport of buspirone across rat intestine

The transport of buspirone across rat intestine (duodenum, jejunum, ileum and colon) was studied by using the non-everted sac method. Rats were pretreated with ashwagandha (Withania somnifera) and Aloe vera juice for 7 days. The rats were sacrificed by using anesthetic ether, the intestinal segments were isolated and used for the studies. The probe drug (buspirone) solution was placed in the isolated intestinal sac. Samples were collected at preset time points and replaced with fresh buffer. The drug content in the samples was estimated using high performance liquid chromatography method. Control experiments were also performed. The results reveal that there was a significant (p < 0.05) difference compared to control, in the transport of buspirone from the intestinal sacs which were pretreated with ashwagandha and Aloe vera juice. It suggests that both ashwagandha and Aloe vera might be acting by inhibiting the transporters and enzymes which are responsible for transport/metabolism of buspirone.Colegio de Farmacéuticos de la Provincia de Buenos Aire