Capmul MCM Research Articles

Quality by Design Approach for Developing Lipid-Based Nanoformulations of Gliclazide to Improve Oral Bioavailability and Anti-Diabetic Activity.

The aim of the current investigation was to generate a self-nanoemulsifying drug delivery system (SNEDDS) of gliclazide (GCZ) to address the poor solubility and bioavailability. Ternary phase diagram was created with Capmul MCM C8 NF (oil), Cremophor RH 40 (surfactant), and Transcutol HP (co-surfactant) to distinguish the self-emulsifying region. A D-optimal design was employed with three variables, such as oil, surfactant, and co-surfactant, for further optimization of liquid (L)-SNEDDS. GCZ-loaded L-SNEDDs were analyzed for globule size, polydispersity index (PDI), and solubility. In vitro dissolution of optimized L-SNEDDS exhibited (F5) faster drug release (97.84%) within 30min as compared to plain drug (15.99%). The optimized L-SNEDDS was converted to solid (S)-SNEDDS as a self-nanoemulsifying powder (SNEP) and pellets by extrusion-spheronization. Optimized S-SNEDDS were characterized using Fourier-transform infrared spectroscopy (FTIR), X-ray diffractometry (XRD), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). In vitro dissolution of SNEP (S3) and pellet were 90.54 and 73.76%, respectively, at 30min. In vivo studies showed a twofold rise in bioavailability through SNEDDS with a significant decline in blood glucose levels compared to plain drug suspension suggesting a lipid-based system as an alternative approach for treating diabetes.

Solubilization of vardenafil HCl in lipid-based formulations enhances its oral bioavailability in vivo: A comparative study using Tween - 20 and Cremophor - EL

The aim of the present investigation was to develop and characterize a promising oral drug delivery system for vardenafil HCl trihydrate (VDN), a poorly soluble drug. For this, self-microemulsifying drug delivery system (SMEDDS) was prepared. Capmul MCM C8 showing highest solubilization capacity was selected as oil. Self-microemulsifying capacity of two surfactants viz. Cremophor EL and Tween 20 were compared for the selected oil phase. Comparing the size of the reconstituted emulsions obtained by small angle neutron scattering (SANS) and Cryo-TEM with that from dynamic light scattering (DLS), it was found that actual core size of oil globule was much smaller than the hydrodynamic diameter. Owing to more number of carbons, Cremophor EL based system was more viscous than Tween 20 VDN SMEDDS. In vitro dissolution and ex vivo permeation study showed superior performance of SMEDDS over drug suspension. In vitro toxicity study using MTT dye on CaCO2 cell line indicated safety of the drug and formulation. Endocytosis and perinuclear localization of SMEDDS system was qualitatively confirmed by cellular uptake study using Coumarin 6 fluorescent dye. In vivo performance was assessed by cryo-sectioning of intestinal tissue and pharmacokinetics. Compared to Cremophor-EL VDN SMEDDS, Tween 20 VDN SMEDDS showed 2.8-fold increase in bioavailability owing to smaller globule size, enhanced dissolution and permeation ability. The encouraging results of SMEDDS suggests its potential application for oral delivery of VDN for treatment of erectile dysfunction.

Curcumin-loaded lipid-hybridized cellulose nanofiber film ameliorates imiquimod-induced psoriasis-like dermatitis in mice

Cellulose nanofiber (CNF) is an attractive biomaterial given its film-forming properties, excellent mechanical properties and biocompatibility. Herein, CNF film was prepared as a topical drug delivery system by hybridizing curcumin (Cur)-loaded nanostructured lipid carriers (NLCs). NLCs with a mean diameter of ≈500 nm were fabricated by using a solvent diffusion method. The lipid composition of the NLCs was optimized based on the efficiency of Cur delivery to the artificial skin and mechanical strength of the developed films, where a composition containing shea butter and Capmul MCM EP exhibited the highest values of 233.2 ± 96.6 μg/cm2/mg and 4.86 ± 0.14 MPa, respectively. The Cur-loaded lipid-hybridized CNF (lipid@CNF) films with a smooth rather than particle-embedded surface were obtained by vacuum filtration of the NLCs and CNF mixture, which were confirmed by TEM, SEM, AFM, XPS, and FTIR analyses. The Cur-loaded lipid@CNF films exhibited more than 2.0-fold increases in Cur deposition to the epidermis of imiquimod (IMQ)-induced psoriatic mouse compared with the films without lipids, which potentially resulted from the amorphous state of Cur observed in the DSC and PXRD analyses and the permeation-enhancing effect of lipids. The in vivo anti-psoriatic efficacy test revealed that the Cur-loaded lipid@CNF films ameliorated the psoriatic skin symptoms in IMQ-induced mice, reducing the pro-inflammatory cytokine levels in the skin almost comparable to a commercially available topical corticosteroid cream. These results could be attributed to the enhanced Cur deposition along with the skin hydration effect of the films. These findings suggest that the developed CNF films can be used as a promising topical drug delivery system for psoriasis therapy.

QBD-based systematic development of Bosentan SNEDDS: Formulation, characterization and pharmacokinetic assessment

The aim of this study was to develop self-nanoemulsifying drug delivery system (SNEDDS) of bosentan using quality by design (QBD) approach with better bioavailability. The major component of the formulation vis-à-vis lipid (Capmul MCM), surfactant (LABRASOL) and co-surfactant (PEG 600) were selected on the basis of saturation solubility. Mixture of LABRASOL and PEG 600 in the ratio of 1:1 showed better nano emulsifying region as depicted by pseudo ternary phase diagram. The optimum mixture of Capmul MCM, LABRASOL and PEG 600 were selected by using response surface method (RSM) with central composite design (CCD). Pharmacokinetic study was conducted to determine various critical parameters. The optimized formulation showed 98.5% drug release in 15 min, globule size of 62.5 nm, emulsification time of 12 s and PDI of 0.146. TEM study revealed the drug entrapment within the oil globules of nano size range. Pharmacokinetic study of optimized formulation indicated faster dissolution and absorption which was evidenced from significantly higher Cmax, larger AUC and lower Tmax than pure drug bosentan. Thus the present study confirms potential of SNEDDS in enhancing the oral bioavailability of bosentan.

INVESTIGATING THE POTENTIAL OF AN ANTIDEPRESSANT INTRANASAL MUCOADHESIVE MICROEMULSION

Objective: The main aim of this study was to formulate, develop and optimized a duloxetine hydrochloride (dlx-hcl) loaded mucoadhesive microemulsion intended for intranasal administration.Methods: Established on solubility studies capmul mcm, transcutol-p, labrasol were used as oil, co-surfactant and surfactant respectively. The optimized mucoadhesive microemulsion prepared using water titration method was further characterized for particle size, polydispersity index, zeta potential and conductivity measurements followed by drug content, nasal cilio toxicity and biochemical estimation of the selected formulation.Results: All physicochemical parameters conducted, proved that dlx-hcl microemulsion was appropriate for nasal delivery. Chitosan, used as mucoadhesive polymer demonstrated enhanced retention time of the microemulsion in nasal mucosa with no signs of toxicity and epithelial damage. The particle size and zeta potential were found to be of 200 nm and-15 mV respectively considering the formulation safe for nasal delivery.Conclusion: This formulation strategy can be used as an effective targeting technique for the drugs having low bioavailability and poor brain penetration along with an effective method for the treatment long-term disease like depression.

DEVELOPMENT AND IN VIVO EVALUATION LOVASTATIN BY SELF-NANOEMULSIFYING DRUG DELIVERY SYSTEM

In the present investigation, self-nanoemulsifying drug delivery system (SNEDDS), of Lovastatin is being formulated to increase the solubility and bioavailability. The optimized Lovastatin SNEDDS formulation (F8) has a composition of Acrysol EL 135 as oil phase, Lauro glycol 90 and Capmul MCM as surfactant and co-surfactant respectively. Formulation F8 was found to be best formulation based on evaluation parameters. No drug precipitation or phase separation was observed in the optimized formulation. The particle size of the optimized formulation was found to be 4.9 nm & Z-Average of 71.5 nm indicating all the particles were in the nanometer range. The zeta potential of the optimized SNEDDS formulation was found to be -13.7 mV which comply with the requirement of the zeta potential for stability. Furthermore, pharmacokinetic studies in rats indicated that compared to the pure drug, the optimized SMEDDS formulation significantly improved the oral bioavailability of Lovastatin. Therefore, from our results the study suggests that the Lovastatin loaded self-nanoemulsifying formulation has a great potential for clinical application.

Pediatric oral formulation of dendrimer-N-acetyl-l-cysteine conjugates for the treatment of neuroinflammation

N-Acetyl-l-cysteine (NAC) commonly used as an antidote in acetaminophen poisoning has shown promise in the treatment of neurological disorders such as cerebral palsy (CP). However, NAC suffers from drawbacks such as poor oral bioavailability and suboptimal blood-brain-barrier (BBB) permeability limiting its clinical success. It was previously demonstrated that intravenous administration of dendrimer-NAC (D-NAC) conjugates have shown significant promise in the targeted treatment of neuroinflammation, in multiple preclinical models. Development of an oral formulation of D-NAC may open new administrative routes for this compound. Here, we report the gastrointestinal stability, in vitro transepithelial permeability, and in vivo oral absorption and pharmacokinetics in rats of a pediatric formulation of D-NAC containing Capmul MCM (glycerol monocaprylate) as a penetration enhancer. D-NAC was stable for 6 h in all five simulated gastrointestinal fluids with no signs of chemical degradation. The apparent permeability (Papp) of D-NAC increased 9-fold in the formulation containing Capmul. The area under the curve [AUC]0-∞ of D-NAC with Capmul increased by 47% when compared to D-NAC alone. These results indicate that an oral pediatric formulation containing D-NAC and Capmul can be an effective option for the treatment of neuroinflammation.

Ameliorating the in vivo antimalarial efficacy of artemether using nanostructured lipid carriers

Cerebral malaria (CM) is a fatal neurological complication of Plasmodium falciparum infection that affects children (below five years old) in sub-Saharan Africa and adults in South-East Asia each year having the fatality rate of 10–25%. The survivors of CM also have high risk of long term neurological or cognitive deficits. The objective of the present investigation was to develop optimised nanostructured lipid carriers (NLCs) of artemether (ARM) for enhanced anti-malarial efficacy of ARM. NLCs of ARM were prepared by a combination of high speed homogenisation (HSH) and probe sonication techniques. Preliminary solubility studies for ARM showed highest solubility in trimyristin (solid lipid), capmul MCM NF (liquid lipid) and polysorbate 80 (surfactant). Trimyristin and capmul showed superior miscibility at a ratio of 70:30.The optimised NLC formulation has the particle size (PS) of: 48.59 ± 3.67 nm, zeta potential (ZP) of: −32 ± 1.63 mV and entrapment efficiency (EE) of: 91 ± 3.62%. In vitro cell line (human embryonic kidney fibroblast cell line (HEK 293 T)) cytotoxicity studies showed that prepared formulation was non-toxic. The results of in vivo studies in CM induced mice prevented the recrudescence of parasite after administration of NLCs of ARM. Additionally, NLCs of ARM showed better parasite clearance, higher survival (60%) in comparison to ARM solution (40%). Also it was observed that lesser entrapment of Evans blue stain (prepared in PBS as solution) in the NLCs of ARM treated brains of C57BL/6 mice than ARM solution treated mice. Hence NLCs of ARM may be a better alternative for improving therapeutic efficacy than ARM solution.

Enhanced Oral Bioavailability and Anticoagulant Activity of Dabigatran Etexilate by Self-Micro Emulsifying Drug Delivery System: Systematic Development, In vitro, Ex vivo and In vivo Evaluation

Dabigatran etexilate (DE), a prodrug of Dabigatran, is a potent, oral, reversible and direct thrombin inhibitor with low oral bioavailability due to active efflux by intestinal P-glycoprotein receptors. No lipid based oral formulation is marketed for DE till date. Hence, we formulated and evaluated self-micro emulsifying drug delivery system (SMEDDS), by using P-gp modulator excipients to tackle this issue and elevate the systemic availability of DE. The SMEDDS were developed using Capmul MCM C8, Cremophor EL and Transcutol HP as oil, surfactant and co-surfactant respectively. The formulation was optimized using statistical D-optimal design. The globule size of 73.24 nm with 0.085 PDI was achieved upon spontaneous emulsification with >99% Transmittance at 250 times dilution and discrete globules were observed under TEM. The in vitro and ex vivo drug release from DE-SMEDDS was found to be significantly higher in comparison to that from plain drug suspension. The DE-SMEDDS was observed to be non-cytotoxic and safe when assessed by MTT assay on Caco-2 cells. Moreover, a deeper penetration in the Caco-2 cells was observed with DE-SMEDDS when assessed using confocal laser scanning microscopy. Flow-cytometric studies also revealed greater uptake of fluorescent probe in Caco-2 cell-lines from the DE-SMEDDS when compared with drug suspension. Furthermore, the AUC0→t of DE from the optimized DE-SMEDDS formulation was found to be 2.5 times higher and relative bioavailability was enhanced by 3.36 folds than that from drug suspension on oral administration to rats. Moreover, DE SMEDDS exhibited higher anticoagulant activity than drug suspension, further indicating better bioavailability.

Development and Optimization of Piroxicam-loaded Solid Self-micro emulsifying Drug Delivery System

The aim of present study was to formulate and evaluate self-microemulsifying drug delivery system containing piroxicam and to use the ability of porous magnesium alumina metasilicate as a solid carrier for self-micro emulsifying drug delivery system. It was developed to resolve the problems of piroxicam such as low water solubility, low bioavailability and gastrointestinal irritation. Self-micro emulsifying drug delivery system containing varying proportions of Capmul MCM, Cremophor EL and Transcutol-P were prepared and optimized using response surface methodology of Design-Expert® software version 10 stat-ease. Liquid self-microemulsifying drug delivery systems were subjected to in vitro evaluation, including self-emulsification efficiency study, droplet size, zeta potential measurement and in vitro drug release studies. Solid self-micro emulsifying drug delivery system was prepared by adding liquid self-micro emulsifying drug delivery system with Neusilin US2 and filled in hard gelatin capsule. The optimized formulation consists of 28.26 % of Capmul MCM, 44.16 % of Cremophor EL and 27.58 % of Transcutol-P. The results showed that the drug release profile of piroxicam from the self-microemulsifying drug delivery formulations was higher than the pure piroxicam powder. The release of piroxicam was rapid and complete. Solid self-micro emulsifying drug delivery systems after filled in hard gelatin capsule, predicted to be a promising technique to deliver a liquid formulation in solid dosage form.

Self-nanoemulsifying Drug Delivery System of Mebendazole for Treatment of Lymphatic Filariasis

Lipid-based self-nanoemulsifying drug delivery system was explored to improve the oral bioavailability and target specificity of mebendazole for treatment of lymphatic worm infestations. Ternary phase diagrams were constructed to select suitable oil-surfactant mixture. Liquid self-nanoemulsifying drug delivery system consisting of Capmul MCM L8, Chromophore RH40 and tocopherol polyethylene glycol succinates a pre-concentrate was systematically optimized using 32 full factorial designs. β-cyclodextrin-based nanosponges were used to prepare solid self-nanoemulsifying drug delivery system. Characterization of liquid self-nanoemulsifying drug delivery system was carried out using percent transmission, globule size, zeta potential, polydispersity index and drug content. Globule size in the range of 50-90 nm and zeta potential of –5 to –12 mV was obtained, which co-related well with percent transmission. Powder X-ray diffraction, differential scanning calorimetry and scanning electron microscope of solid self-nanoemulsifying drug delivery system indicated the presence of mebendazole as a molecular dispersion. Ex vivo studies showed nearly five-fold increase in the flux. In vivo studies showed two-fold increase in bioavailability. Significant enhancement in drug dissolution and saturation solubility from solid self-nanoemulsifying drug delivery system resulted in an increase in the bioavailability. Besides this, greater surface area, improved release, P-gp modulation potential of excipients and lymphatic bypass via Peyer’s patches protected drug from hepatic first pass metabolism all of which would contribute to the observed improved bioavailability. Lymphatic transport of drug could achieve target specificity in lymphatic filariasis.

Development of self-microemulsifying drug delivery system for oral delivery of poorly water-soluble nutraceuticals

The objective of the study was to develop a self-microemulsifying drug delivery system (SMEDDS), also known as microemulsion preconcentrate, for oral delivery of five poorly water-soluble nutraceuticals or bioactive agents, namely, vitamin A, vitamin K2, coenzyme Q10, quercetin and trans-resveratrol. The SMEDDS contained a 1:1 mixture (w/w) of Capmul MCM NF (a medium chain monoglyceride) and Captex 355 EP/NF (a medium chain triglyceride) as the hydrophobic lipid and Tween 80 (polysorbate 80) as the hydrophilic surfactant. The lipid and surfactant were mixed at 50:50 w/w ratio. All three of the SMEDDS components have GRAS or safe food additive status. The solubility of nutraceuticals was determined in Capmul MCM, Captex 355, Tween 80, and the SMEDDS (microemulsion preconcentrate mixture). The solubility values of vitamin A palmitate, vitamin K2, coenzyme Q10, quercetin, and trans-resveratrol per g of SMEDDS were, respectively, 500, 12, 8, 56, and 87 mg. Appropriate formulations of nutraceuticals were prepared and filled into hard gelatin capsules. They were then subjected to in vitro dispersion testing using 250 mL of 0.01 N HCl in USP dissolution apparatus II. The dispersion test showed that all SMEDDS containing nutraceuticals dispersed spontaneously to form microemulsions after disintegration of capsule shells with globule size in the range of 25 to 200 nm. From all formulations, except that of vitamin K2, >80–90% nutraceuticals dispersed in 5–10 min and there was no precipitation of compounds during the test period of 120 min. Some variation in dispersion of vitamin K2 was observed due to the nature of the material used (vitamin K2 pre-adsorbed onto calcium phosphate). The present report provides a simple and organic cosolvent-free lipid-based SMEDDS for the oral delivery of poorly water-soluble nutraceuticals. Although a 50:50 w/w mixture of lipid to surfactant was used, the lipid content may be increased to 70:30 without compromising the formation of microemulsion.

Oral bioavailability enhancement of raloxifene by developing microemulsion using D-optimal mixture design: optimization and in-vivo pharmacokinetic study

The objective of this work was to utilize a potential of microemulsion for the improvement in oral bioavailability of raloxifene hydrochloride, a BCS class-II drug with 2% bioavailability. Drug-loaded microemulsion was prepared by water titration method using Capmul MCM C8, Tween 20, and Polyethylene glycol 400 as oil, surfactant, and co-surfactant respectively. The pseudo-ternary phase diagram was constructed between oil and surfactants mixture to obtain appropriate components and their concentration ranges that result in large existence area of microemulsion. D-optimal mixture design was utilized as a statistical tool for optimization of microemulsion considering oil, Smix, and water as independent variables with percentage transmittance and globule size as dependent variables. The optimized formulation showed 100 ± 0.1% transmittance and 17.85 ± 2.78 nm globule size which was identically equal with the predicted values of dependent variables given by the design expert software. The optimized microemulsion showed pronounced enhancement in release rate compared to plain drug suspension following diffusion controlled release mechanism by the Higuchi model. The formulation showed zeta potential of value −5.88 ± 1.14 mV that imparts good stability to drug loaded microemulsion dispersion. Surface morphology study with transmission electron microscope showed discrete spherical nano sized globules with smooth surface. In-vivo pharmacokinetic study of optimized microemulsion formulation in Wistar rats showed 4.29-fold enhancements in bioavailability. Stability study showed adequate results for various parameters checked up to six months. These results reveal the potential of microemulsion for significant improvement in oral bioavailability of poorly soluble raloxifene hydrochloride.

Design, Optimization and Evaluation of Repaglinide Self-Nanoemulsifying Drug Delivery for Enhanced Solubility

The aim of study was to develop self-nanoemulsifying systems of poorly water-soluble drug repaglinide, which is an antidiabetic drug in the class of medications known as meglitinides. Solubility of repaglinide in oily phases and surfactants was determined to identify components of self-nanoemulsifying drug delivery system (SNEDDS). Surfactants and oil was selected based on solubility studies were further screened for their efficiency in formulation. Acrysol K 150, Kolliphor EL and Capmul MCM were selected as oil, surfactant and co-surfactant respectively. Formulation F8 was found to be optimized formulation on the basis of in vitro dissolution studies, particle size and zeta potential. The optimized formulation was then subjected to stability studies and was found to be stable after 6 months. Thus, SNEDDS were found to be influential in improving the release performance of repaglinide, indicating their potential to improve the solubility and oral bioavailability of repaglinide.

Effect of different polysorbates on development of self-microemulsifying drug delivery systems using medium chain lipids

The primary objective of this study was to develop lipid-based self-microemulsifying drug delivery systems (SMEDDS) without using any organic cosolvents that would spontaneously form microemulsions upon dilution with water. Cosolvents were avoided to prevent possible precipitation of drug upon dilution and other stability issues. Different polysorbates, namely, Tween 20, Tween 40, Tween 60, and Tween 80, were used as surfactants, and Captex 355 EP/NF (glycerol tricaprylate/caprate) or its 1:1 mixture with Capmul MCM NF (glycerol monocaprylocaprate) were used as lipids. Captex 355-Tween-water ternary phase diagrams showed that oil-in-water microemulsions were formed only when the surfactant content was high (80–90%) and the lipid content low (10–20%). Thus, mixtures of Tweens with Captex 355 alone were not suitable to prepare SMEDDS with substantial lipid contents. However, when Captex 355 was replaced with the 1:1 mixture of Captex 355 and Capmul MCM, clear isotropic microemulsion regions in phase diagrams with sizes in the increasing order of Tween 20 < Tween 40 < Tween 60 < Tween 80 were obtained. Tween 80 had the most profound effect among all surfactants as microemulsions were formed with lipid to surfactant ratios as high as 7:3, which may be attributed to the presence of double bond in its side chain that increased the curvature of surfactant layer. Thus, lipid-surfactant mixtures containing 1:1 mixture of medium chain triglyceride (Captex 355) and monoglyceride (Capmul MCM) and as low as 30% Tween 80 were identified as organic cosolvent-free systems for the preparation of SMEDDS. Formulations with a model drug, probucol, dispersed spontaneously and rapidly upon dilution with water to form microemulsions without any drug precipitation.

Development and evaluation of camptothecin loaded polymer stabilized nanoemulsion: Targeting potential in 4T1-breast tumour xenograft model

Targeted delivery of anticancer agents is poised to improve cancer therapy, for which polymers can serve as targeting ligands or nanocarriers for chemotherapeutic agents. In this study, we have developed and evaluated the efficacy of a camptothecin (CPT)-loaded polymer stabilized nanoemulsion (PSNE) for the passive targeted delivery to breast cancer. Based on the pseudo-ternary phase diagrams, PSNEs were developed using capmul MCM:poloxamer 407 (4:1), solutol HS 15:simulsol P23 (1:2) and water. CPT polymer mixture was developed by solvent evaporation technique. The PSNEs were characterized for droplet size distribution, plasma protein adsorption, drug release, in-vivo targeting potential, hemolytic potential, cytotoxicity, genotoxicity, in-vivo biodistribution and CPT lactone ring stability. The developed PSNEs showed uniform droplet distribution, extended drug release (76.59±6.12% at 24h), acceptable hemolytic potential, significant cytotoxicity (IC50=176±4.3ng/mL) and genotoxicity against MCF-7 cancer cells but low DNA damage potential in human peripheral blood lymphocytes. The efficiency of PSNEs for the targeted delivery of CPT into the tumour regions was documented in 4T1-breast tumour xenografted BALB/c mice. In-vivo biodistribution study shows that 7105.84±568.46ng/g of CPT was passively targeted from PSNE to breast cancer tissue. About 80% of the lactone form was stable for 24h. Taken together, our study provides a promising strategy for developing PSNE-targeted drug delivery system for the breast cancer therapy.

Ultrasonically tailored, chemically engineered and “QbD” enabled fabrication of agomelatine nanoemulsion; optimization, characterization, ex-vivo permeation and stability study

The objective of present study was to develop a nanoemulsion formulation of agomelatine (BCS class II drug) for the solubility enhancement. Capmul MCM, Tween 80 and PEG-400 were selected as oil, surfactant and co-surfactant respectively. The high energy ultrasonication method was used for the preparation of nanoemulsion. Three-factor three-level central composite design was employed to get the best formulation. The independent variables selected for the optimization were % oil, %Smix and sonication time (second). Based on the constraints applied to independent and dependent variables, the optimized formulation was selected with 2% oil, 10% Smix and 45s sonication time. The experimental values for dependent variables such as hydrodynamic diameter (nm), % transmittance and % CDR were found to be 73.72±2.53nm, 98.2±0.42%, 84.71±4.05% respectively. TEM and AFM−assisted morphological characterization of optimized Ago-NE was done and it was found with a spherical shape. The PDI, Zeta potential and the refractive index of optimized Ago-NE were found to be 0.137±0.016, −7.40±0.12mV and 1.423±0.045 respectively. The viscosity, pH and drug content of optimized Ago-NE were found as 25.12±0.67cP, 6.4±0.17 and 97.83±1.03% respectively. The ex-vivo permeation profile of optimized Ago-NE and agomelatine suspension through goat nasal mucosa were compared till 12h and % cumulative drug permeated was found to be 90% and 40% respectively. The higher drug permeation profile of optimized Ago-NE confirmed that the solubility of agomelatine has been improved.

FORMULATION AND OPTIMIZATION OF CELECOXIB NANOEMULGEL

Objective: The main objective of this experiment was to prepare and optimized celecoxib nanoemulgel. This formulation can be used for acuterheumatoid arthritis patients.Methods: Celecoxib is a poorly water soluble drug. We prepared celecoxib nanoemulgel to improve intrinsic solubility of celecoxib and enhancedeeper permeation throughout the skin. After several screening, the combination of acetonitrile, triacetin, campul 908P was considered for oil phase;acconon MC8-2EP as surfactant, and capmul MCM C-10 as a co-surfactant accordingly. As per Box-Behnken surface design model, optimization wasdone for all the 13 formulations.Results: Based on pseudo ternary plot, it was found that 4:1 Smix ratio was optimum and possessed maximum drug solubility. Further, screeningshown, 0.25-0.75% carbopol-940 can be a stable candidate for hydrogel preparation. Prepared nanoemulsions and hydrogels were admixed to preparenanoemulgel. Based on overlay plot, EG14* formulation was consider as optimum one, and various evaluation parameters were performed along withother formulations. Using Franz diffusion cell, in-vitro diffusion studies was performed. Almost all the formulations produces good qualitative drugrelease profile. The EG14* shown 95.50% drug release after 12th hrs with standard Higuchi plot (R2 value 0.9989). The optimum viscosity was foundto be 521±0.81 mPas at 100 rpm. The appearance of the formulations was milky, yellowish white with expectable pH ranged from 5.8 to 6.7. Theoptimized formulation has good spreadability coefficient, good ex-vivo diffusion enhancement factor (3.03) as compare to marketed gel. Mostly, ourformulations have less skin irritation and higher anti-inflammatory activity (92.56% of inhibition of paw edema for EG14*).Conclusion: From the thermodynamic studies, it was confirmed that EG14* maintained excellent stability profile in various heating-cooling cycle,centrifugation, and freeze-thaw cycle condition. Hence, it can be conclude that, our formulation, can be consider for pilot scale up.

Self-Emulsifying Formulation of Indomethacin with Improved Dissolution and Oral Absorption

The objective of the present study was to enhance the solubility, dissolution and hence anti-inflammatory activity of poorly soluble drug indomethacin (IMN) by formulating into self emulsifying systems. Self emulsifying formulations were prepared using capmul MCM as oil, tween 80 as surfactant, transcutol P as cosurfactant. Fourier transform infrared spectroscopy and differential scanning calorimetry studies were conducted to know the interaction between drug and excipients. Pseudo ternary phase diagrams were constructed using surfactant and cosurfactant in 1:1 to 1:4 and 2:1 to 4:1 to know the efficient self emulsification region. The formulations were evaluated for their particle size, zeta potential, refractive index, viscosity and cloud point. In vitro dissolution studies were conducted in one part of pH 7.2 phosphate buffer and four parts of water. The pharmacokinetic parameters were analysed by Win Nonlin software. The self emulsification was higher with the ratios 2:1, 3:1 and 1:2 of surfactant and co surfactant and the IMN formulations were prepared. The formulations were stable at different pH and dilutions. The globule size was in the range of 184.1 nm to 340.5 nm, as the ratio of oil, surfactant and cosurfactant mixture has varied effects on the size of globule. The negative charge on the globules of all formulations attributes their stability. The optimized formulation showed better release as compared to marketed product. The AUC of the optimised Self-Emulsifying Drug Delivery System was significantly higher than the marketed product. Thus, from the present research, self emulsifying systems of IMN provide a useful alternative to enhance dissolution and hence anti inflammatory activity.

Development and in vitro characterization of self-emulsifying drug delivery system (SEDDS) for oral opioid peptide delivery

Aim: In this study, self-emulsifying drug delivery system (SEDDS) for oral delivery of opioid peptide dalargin were developed and characterized in vitro.Methods: Dalargin lipophilicity was increased by O-esterification of tyrosine OH group, hydrophobic ion pairing, or a combination thereof. Distribution coefficients (log D) of lipidized dalargin derivatives were determined. Then, dalargin was incorporated in chosen SEDDS, namely SEDDS-1, composed of 50% Capmul 907, 40% Cremophor EL, and 10% propylene glycol and comparatively more lipophilic SEDDS-2 composed of 30% Captex 8000, 30% Capmul MCM, 30% Cremophor EL, and 10% propylene glycol. Additionally, SEDDS were characterized regarding droplet size, polydispersity index (PDI), cloudy point, physical stability and stability against pancreatic lipase. Furthermore, mucus permeating properties of SEDDS and their ability to protect the incorporated dalargin against proteolysis by trypsin, α-chymotrypsin, elastase, simulated gastric fluid (SGF), and simulated intestinal fluid (SIF) were evaluated.Results: The highest dalargin drug payload of 4.57% in SEDDS-2 was achieved when dalargin palmitate (pDAL) was ion paired with sodium dodecyl sulfate (SDS) in molar ratio 1:1. Moreover, SEDDS-1 and SEDDS-2 had a narrow droplet size distribution with average droplet sizes of 42.1 and 33.1 nm with PDI of 0.042 and 0.034, respectively. Lipolysis study showed that within 30 min 78.5% of SEDDS-1 and 92.1% of SEDDS-2 were digested. In addition, both SEDDS exhibited mucus permeating properties as well as a protective effect against enzymatic degradation by trypsin, α-chymotrypsin, elastase, SGF and SIF.Conclusion: The results of this study suggest that the developed SEDDS could be considered for oral opioid peptide delivery.