Mihir Raval

Formulation and development of a self-nanoemulsifying drug delivery system of irbesartan.

Irbesartan (IRB) is an angiotensin II receptor blocker antihypertensive agent. The aim of the present investigation was to develop a self-nanoemulsifying drug delivery system (SNEDDS) to enhance the oral bioavailability of poorly water-soluble IRB. The solubility of IRB in various oils was determined to identify the oil phase of SNEDDS. Various surfactants and co-surfactants were screened for their ability to emulsify the selected oil. Pseudoternary phase diagrams were constructed to identify the efficient self-emulsifying region. The optimized SNEDDS formulation contained IRB (75 mg), Cremophor® EL (43.33%), Carbitol® (21.67%) and Capryol® 90 (32%). SNEDDS was further evaluated for its percentage transmittance, emulsification time, drug content, phase separation, dilution, droplet size and zeta potential. The optimized formulation of IRB-loaded SNEDDS exhibited complete in vitro drug release in 15 min as compared with the plain drug, which had a limited dissolution rate. It was also compared with the pure drug solution by oral administration in male Wister rats. The in vivo study exhibited a 7.5-fold increase in the oral bioavailability of IRB from SNEDDS compared with the pure drug solution. These results suggest the potential use of SNEDDS to improve dissolution and oral bioavailability of poorly water-soluble IRB.

Design and development of a self-nanoemulsifying drug delivery system for telmisartan for oral drug delivery

Background and Aim: Telmisartan (TEL) is an angiotensin II receptor blocker (ARB) antihypertensive agent. The aim of the present investigation was to develop a self-nanoemulsifying drug delivery system (SNEDDS) to enhance the oral bioavailability of poorly water soluble TEL. Materials and Methods: The solubility of TEL in various oils was determined to identify the oil phase of a SNEDDS. Various surfactants and co-surfactants were screened for their ability to emulsify the selected oil. Pseudoternary phase diagrams were constructed to identify the efficient self-emulsifying region. A SNEDDS was further evaluated for its percentage transmittance, emulsification time, drug content, phase separation, dilution, droplet size, zeta potential, pH, refractive index, and viscosity. Results: The developed SNEDDS formulation contained TEL (20 mg), Tween® 20 (43.33%w/w), Carbitol® (21.67%w/w), and Acrysol® EL 135 (32%w/w). The optimized formulation of the TEL-loaded SNEDDS exhibited a complete in vitro drug release in 15 min as compared with the plain drug, which had a limited dissolution rate. It was also compared with the pure drug suspension by oral administration in male Wister rats. The in vivo study exhibited a 7.5-fold increase in the oral bioavailability of TEL from the SNEDDS compared with the pure drug suspension. Conclusions: These results suggest the potential use of the SNEDDS to improve the dissolution and oral bioavailability of poorly water soluble TEL.

Influence of polymers/excipients on development of agglomerated crystals of secnidazole by crystallo-co-agglomeration technique to improve processability

Background: Direct tabletting is a need of Pharmaceutical industries. Poor mechanical properties of drug particles require wet granulation which is uneconomical, laborious, and tedious. Objective: Objective of this work was to study influence of various polymers/excipients on formation of directly compressible Crystallo-co-agglomerates (CCA) of water soluble drug Secnidazole (hydroxy-2-propyl)-1-methyl-2-nitro-5-imidazole), an antimicrobial agent. Method: Acetone-petroleum ether system was used to develop CCA of drug in the presence of polymers/excipients. Clarity of the supernatant was considered an endpoint for completion of agglomeration. The prepared CCA were subjected for topographic, micromeritic, mechanical, compressional, and drug release properties. Results: The process yielded ~92 to 98% wt/wt CCA containing secnidazole with the diameter between 0.2 and 0.7 mm. CCA showed excellent flow, packability, compatibility, and crushing strength. Heckel plot showed lower σ0 and higher tensile strength with lower elastic recovery (0.55–1.28%) of CCA. Dissolution profile of CCA was improved. Differential scanning calorimetry , fourier transform infra-red, and x-ray diffractometry results showed absence of drug–excipient interaction. Discussion: Matrix beads were generated with uniform dispersion of crystallized drug. Excellent flow, packability, and compactability were due to sphericity of agglomerates. Higher crushing strength of CCA was an indication of good handling qualities. Lower σ 0, higher tensile strength, and lower elastic recovery indicated excellent compressibility of agglomerates. Improvement in dissolution profile was due to porous nature of CCA. Conclusion: Excipients and polymers can play a key role to prepare CCA, an excellent alternative to wet granulation process to prepare particles for direct compression.

Solubility of aceclofenac in polyamidoamine dendrimer solutions.

In the present study we investigated the effect of polyamidoamine (PAMAM) dendrimers on the aqueous solubility of aceclofenac. The aqueous solubility of aceclofenac was measured in the presence of dendrimers in distilled water. The effect of variables, such as pH condition, concentration, temperature and generation (molecule size) of dendrimer, has been investigated. Results showed that the solubility of aceclofenac in the dendrimer solutions was proportional to dendrimer concentration. The order in which the dendrimers increased the solubility at a constant pH condition was G3 > G0. The influence of dendrimer solution pH on the solubility enhancement of aceclofenac suggests that it involves an electrostatic interaction between the carboxyl group of the aceclofenac molecule and the amine groups of the dendrimer molecule. The solubility of aceclofenac was inversely proportional to the temperature of dendrimer solution.Different generation (G0 and G3) PAMAM dendrimers have the potential to significantly enhance the solubility of poor water-soluble drugs.

Development of the UV spectrophotometric method of Olmesartan medoxomil in bulk drug and pharmaceutical formulation and stress degradation studies

A simple, sensitive, specific, spectrophotometric method was developed for the detection of Olmesartan medoxomil (OLM) in bulk and pharmaceutical formulations. The optimum conditions for the analysis of the drug were established. OLM was subjected to stress degradation under different conditions recommended by the International Conference on Harmonization (ICH). The samples so generated were used for degradation studies using the developed method. The λmax of the OLM was found to be 257 nm. The method exhibited high sensitivity, with linearity, in the 2 to 20 μg/ml range. The lower limit of detection and the limit of quantification were found to be 1.012 μg/ml and 3.036 μg/ml, respectively. All the calibration curves demonstrated a linear relationship between the absorbance and concentration, with the correlation coefficient higher than 0.99. The regression equation of the curve was Y = 0.0579x + 0.0006. The precision of the method was found to be 40.043 ± 0.067 against the label claim of 40 mg. The percentage recovery was found to be 101.32 ± 0.452. The sample solution was stable for up to two hours. Hence, it could be concluded that the proposed method would be suitable for the analysis of OLM in bulk and pharmaceutical formulations.

Development of loteprednol etabonate-loaded cationic nanoemulsified in-situ ophthalmic gel for sustained delivery and enhanced ocular bioavailability

Abstract A novel cationic nanoemulsified in-situ ophthalmic gel of loteprednol etabonate (LE) was developed to improve the permeability and retention time of formulations for overall improvement of drug’s ocular bioavability. Capryol 90 (oil phase), tween 80 (surfactant) and transcutol P (cosurfactant) was selected as formulation excipients to construct pseudoternary phase diagrams and nanoemulsion region was recognized from diagrams. Spontaneous emulsification method was used to manufacture LE nanoemulsion and it was optimized using 32 factorial design by considering the amount of oil and the ratio of surfactant to cosurfactant (Smix) as independent variables and evaluated for various physicochemical properties. Optimized NE was dispersed in Poloxamer 407 and 188 solution to form nanoemulsified sols that were predictable to transform into in-situ gels at corneal temperature. Drug pharmacokinetics of sterilized optimized in situ NE gel, NE-ISG2 [0.69% w/w Capryol 90, 0.99%w/w Smix (3:1), 13% Poloxamer 407, 4% w/w Poloxamer 188] and marketed formulation were assessed in rabbit aqueous humor. The in-situ gels were clear, shear thinning in nature and displayed zero-order drug release kinetics. NE-ISG2 showed the minimum ocular irritation potential and significantly (p < 0.01) higher Cmax and AUC(0–10 h), delayed Tmax, extended mean residence time and improved (2.54-fold times) bioavailability compared to marketed formulation.

Quality by design approach for oral bioavailability enhancement of Irbesartan by self-nanoemulsifying tablets

Abstract The present investigation was aimed to develop self-nanoemulsifying tablets (SNETs) as novel nanosized solid oral dosage forms for Irbesartan (IRB). In the first part of the investigation, IRB-loaded self-nanoemulsifying drug delivery systems (SNEDDS) were developed using Capryol 90 – Cremophor RH40 – Transcutol P as three component (oil – surfactant – cosurfactant) SNEDDS system. On the basis of ternary phase diagram IRB-loaded SNEDDS were optimized by using Design of Experiments (DoE) and Principal component analysis (PCA) with amount of oil and surfactant: cosurfactant ratio (Km) as factors. The optimized batch of IRB-loaded SNEDDS comprised of 31.62% w/w of Capryol 90 as oil phase, 49.90% w/w Cremophor RH40 as surfactant and 18.48% w/w of Transcutol P as cosurfactant exemplified a mean globule size as 23.94 nm. Further, with an aim to provide enhanced patient compliance the optimized batch of liquid SNEDDS was transformed into SNETs by liquisolid compaction technique. Solid state characterization of IRB-loaded liquisolid mixtures revealed a decrease in the magnitude of crystallinity of IRB. The results of in vitro drug release study of optimized batch of IRB-loaded SNET illustrated a remarkable improvement in the dissolution rate as compared to marketed tablets (Avapro® 75). The results of in vivo pharmacokinetic study on Wister rats revealed 1.78-fold enhancement in oral bioavailability for IRB-loaded SNETs against marketed tablets. The present study proposed SNEDDS as one of the suitable approach for developing nanosized solid oral dosage forms of poorly water soluble drugs like Irbesartan.

Formulation and evaluation of sustained release enteric-coated pellets of budesonide for intestinal delivery.

Introduction: The aim of present work was to develop intestinal-targeted pellets of Budesonide, a potent glucocorticoid, used for the treatment of ulcerative colitis and Crohns disease by extrusion and spheronization method. Current available oral formulations of Budesonide have low efficacy because of the premature drug release in the upper part of the gastrointestinal tract. In this study, a pH-controlled intestinal-targeted pellet of budesonide was established using 32 full factorial design by giving an enteric coating with Eudragit S100. Materials and Methods: Budesonide-sustained release pellets were prepared by extruder and spheronization technique using a combination of water-soluble and permeable polymers by applying 32 full factorial design. The pellets were coated by spray coating technique using Eudragit S100 as an enteric polymer. The pellets were characterized for its flowability, sphericity, friability, and in vitro drug release. Release behaviour was studied in different pH media. The release profile was studied for the mechanism of drug release. Result: The optimized formulation showed negligible drug release in the stomach followed by release for 12 h in the intestinal pH. Differential scanning calorimetry and Fourier Transform Infrared Spectroscopy studies indicated no interaction between drug and polymer. Scanning Electron Microscopy image of coated pellets suggested a uniform and smooth coat over the surface of pellets. Accelerated stability studies showed a stable nature of drug in the formulation. All evaluation parameter showed that pellets were good in spherocity and flowability. Conclusion: Sustained release pellets of Budesonide could be prepared by extrusion and spheronization which released the drug in intestinal pH for an intestine to treat inflammatory bowel disease. A ratio of polymer combination could be decided using a full factorial design.

Influence of excipients and processing conditions on the development of agglomerates of racecadotril by crystallo-co-agglomeration

Purpose: The purpose of the present investigation was to improve the flow and mechanical properties of racecadotril by a crystallo-co-agglomeration (CCA) technique. Direct tableting is a requirement of pharmaceutical industries. Poor mechanical properties of crystalline drug particles require wet granulation which is uneconomical, laborious, and tedious. Materials and Methods: The objective of this work was to study the influence of various polymers/excipients and processing conditions on the formation of directly compressible agglomerates of the water-insoluble drug, racecadotril, an antidiarrheal agent. The agglomerates of racecadotril were prepared using dichloromethane (DCM)–water as the crystallization system. DCM acted as a good solvent for racecadotril as well as a bridging liquid for the agglomeration of the crystallized drug and water as the nonsolvent. The prepared agglomerates were tested for micromeritic and mechanical properties. Results: The process yielded ~90 to 96% wt/ wt spherical agglomerates containing racecadotril with the diameter between 299 and 521 μ. A higher rotational speed of crystallization system reduces the size of the agglomerates and disturbs the sphericity. Spherical agglomerates were generated with a uniform dispersion of the crystallized drug. CCA showed excellent flowability and crushing strength. Conclusion: Excipients and processing conditions can play a key role in preparing spherical agglomerates of racecadotril by CCA, an excellent alternative to the wet granulation process to prepare intermediates for direct compression.

Formulation and Development of Self-Nanoemulsifying Granules of Olmesartan Medoxomil for Bioavailability Enhancement

The present investigation was aimed to formulate self-nanoemulsifying granules (SNEGs) of poorly water soluble drug, Olmesartan Medoxomil (OLM) to improve its solubility and oral bioavailability. Acconon sorb 20, Tween 80, and Carbitol were selected as oil, surfactant and cosurfactant, respectively for the development of liquid self-nanoemulsifying system (L-SNEDDS), which subsequently adsorbed on a carrier (Aerosil 200) to develop SNEGs. The results of in vitro and in vivo study of OLM-SNEGs revealed remarkable improvement compared to pure OLM. The present study proposed SNEGs as one of the suitable approach for developing nanosized solid oral dosage forms of OLM.