Development and evaluation of clozapine intranasal mucoadhesive in situ gels for brain targeting

Blood brain barrier, poor solubility and low bioavailability (<27%) due to hepatic metabolism are major constraints of clozapine (CZP) oral tablets for their clinical application in the treatment of psychosis. Therefore, the study aims to develop pluronic based thermosensitive mucoadhesive in situ gel of clozapine for brain targeting through intranasal olfactory pathway. The objective of the present study was to develop an aqueous and oil based thermosensitive mucoadhesive in situ gel of clozapine for intranasal delivery and to evaluate the gels for in vitro characterization and ex vivo permeation in comparison to drug solution. The aqueous and oil based in situ gel systems were developed by cold method using water and oleic acid as solvents respectively. Combination of Pluronic F-127 and F-68 (20:2) were used as thermosensitive gelling agents.  Labrasol and Transcutol P at 1:1 ratio were employed as co solvents for the solubilisation of drug. The prepared in situ gels were evaluated for clarity, gelation temperature (Tsol-gel), gelation time (GT), gel strength (GS), pH, viscosity, mucoadhesive strength and ex vivo drug permeation studies. The effect of mucoadhesive agents like Chitosan, Sodium-β- glycerophosphate and Polyox WSR303 on gelation temperature (Tsol-gel) and drug permeation was also evaluated. The optimized aqueous in situ gel with 0.5% chitosan (Fa15) showed viscosity 554.66±8.73cP at 31oC; mucoadhesive strength 5114.91±107.37dynes/cm2, gelation temperature (Tsol-gel) 29.6±1.7 oC and gelation time (GT) 69±5 sec. The flux was found to be 243.46 µg/cm2/hr which was significantly high (p<0.0001) compared to drug solution and the enhancement ratio(ER) was found to be 2.28 folds to the drug solution whereas the oil gel showed flux of 190.34 µg/cm2/hr and enhancement ratio was found to be1.64 folds to the drug solution. The results indicated that the hydrogels are potential carriers than oil gels for delivery of clozapine via intranasal route. Keywords: Clozapine, in situ gels, nasal drug delivery, olfactory pathway, brain targeting, psychosi

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

Formulation, Characterization, In-vitro Evaluation and Ex-Vivo Studies of Doxepin Loaded Self Micro Emulsifying Drug Delivery system

The objective of the present study was to develop a novel Self Micro emulsifying drug delivery system (SMEDDS) of Doxepin to increase the oral bioavailability by escaping metabolism from the effect of the CYP450 enzyme, and evaluate its stability, drug release by In-vitro and Ex-vivo drug permeation studies. The solubility of Doxepin in oils, surfactants and co-surfactants was determined. Pseudo ternary phase diagrams were constructed for oil, Smix and water to identify the microemulsion forming region. The optimized SMEDDS formulation was composed of Oleicacid, Tween, PEG, Drug in ratios of 25:60:15:5.The SMEDDS were evaluated for self-micro emulsification time, PDI, Zeta potential, globule size, drug content. Optimized formulation (F6) was showed globule size of 37.1nm, PDI 0.21, zeta potential-22.3mv and drug content of 98.21%. Invitro drug release studies were carried out in 0.1N HCL for 2hrs followed by pH 6.8 phosphate buffer for 10 hrs using dialysis bag method. Optimized formulation F6 converted to solid SMEDDS by physical adsorption technique Neusilin US2 as carrier. Ex-vivo permeation studies were performed for the optimized solid formulation (F6-S) and drug suspension using normal sac method.The percentage drug release of optimized formulation was significantly high when compared to drug suspension. Through this we can conclude that bioavailability of formulation of doxepin could be enhanced significantly by formulating into solid SMEDDS or liquid SMEDDS. Keywords: Self Micro emulsifying drug delivery system, Pseudo ternary phase diagram, Doxepin, Ex-vivo permeation