Enhanced oral bioavailability of lurasidone by self-nanoemulsifying drug delivery system in fasted state

Objective: The purpose of this work was to develop a new formulation to enhance the bioavailability and reduce the food effect of lurasidone using self-nanoemulsifying drug delivery systems (SNEDDSs).

Methods: The formulation of lurasidone-SNEDDS was selected by the solubility and pseudo-ternary phase diagram studies. The prepared lurasidone-SNEDDS formulations were characterized for self-emulsification time, effect of pH and robustness to dilution, droplet size analysis, zeta potential and in vitro drug release. Lurasidone-SNEDDSs were administered to beagle dogs in fed and fasted state and their pharmacokinetics were compared to commercial available tablet as a control.

Results: The result showed lurasidone-SNEDDS was successfully prepared using Capmul MCM, Tween 80 and glycerol as oil phase, surfactant and co-surfactant, respectively. In vitro drug release studies indicated that the lurasidone-SNEDDS showed improved drug release profiles and the release behavior was not affected by the medium pH with total drug release of over 90% within 5?min. Pharmacokinetic study showed that the AUC_(0–∞) and C_max for lurasidone-SNEDDS are similar in the fasted and fed state, indicating essentially there is no food effect on the drug absorption.

Conclusion: It was concluded that enhanced bioavailability and no food effect of lurasidone had been achieved by using SNEDDS.     

Impact of various solid carriers and spray drying on pre/post compression properties of solid SNEDDS loaded with glimepiride: in vitro-ex vivo evaluation and cytotoxicity assessment

Development of self-nanoemulsifying drug delivery systems (SNEDDS) of glimepiride is reported with the aim to achieve its oral delivery. Lauroglycol FCC, Tween-80, and ethanol were used as oil, surfactant, and co-surfactant, respectively as independent variables. The optimized composition of SNEDDS formulation (F1) was 10% v/v Lauroglycol FCC, 45% v/v Tween 80, 45% v/v ethanol, and 0.005% w/v glimepiride. Further, the optimized liquid SNEDDS were solidified through spray drying using various hydrophilic and hydrophobic carriers. Among the various carriers, Aerosil 200 was found to provide desirable flow, compression, dissolution, and diffusion. Both, liquid and solid-SNEDDS have shown release of more than 90% within 10?min. Results of permeation studies performed on Caco-2 cell showed that optimized SNEDDS exhibited 1.54 times higher drug permeation amount and 0.57 times lower drug excretion amount than that of market tablets at 4?hours (p?p?>?.05, i.e. 0.74). The formulation was found stable with temperature variation and freeze thaw cycles in terms of droplet size, zeta potential, drug precipitation and phase separation. Crystalline glimepiride was observed in amorphous state in solid SNEDDS when characterized through DSC, PXRD, and FT-IR studies. The study revealed successful formulation of SNEDDS for glimepiride.     

Nanosuspension of efavirenz for improved oral bioavailability: formulation optimization,in vitro,in situ and in vivo evaluation

Context: Nanosuspensions (NSs) of poorly water-soluble drugs are known to increase the oral bioavailability.

Objectives: The purpose of this study was to develop NS of efavirenz (EFV) and to investigate its potential in enhancing the oral bioavailability of EFV.

Materials and methods: EFV NS was prepared using the media milling technique. The Box–Behnken design was used for optimization of the factors affecting EFV NS. Sodium lauryl sulfate and PVP K30 were used to stabilize the NS. Freeze-dried NS was completely re-dispersed with double-distilled filtered water.

Results: Mean particle size and zeta potential of the optimized NS were found to be 320.4?±?3.62?nm and –32.8?±?0.4 mV, respectively. X-ray diffraction and differential scanning calorimetric analysis indicated no phase transitions. Rate and extent of drug dissolution in the dissolution medium for NS was significantly higher compared to marketed formulation. The parallel artificial membrane permeability assay revealed that NS successfully enhanced the permeation of EFV. Results of in situ absorption studies showed a significant difference in absorption parameters such as K_a, t_1/2 and uptake percentages between lyophilized NS and marketed formulation of EFV. Oral bioavailability of EFV in rabbits resulting from NS was increased by 2.19-fold compared to the marketed formulation.

Conclusion: Thus, it can be concluded that NS formulation of EFV can provide improved oral bioavailability due to enhanced solubility, dissolution velocity, permeability and hence absorption.     

Self-emulsifying drug delivery system for enhanced solubility of asenapine maleate: design,characterization, in vitro,ex vivo and in vivo appraisal

Self-emulsifying drug delivery systems (SES) were developed to improve oral bioavailability of asenapine maleate (ASM), an antipsychotic drug with challenging amphiphobic nature and extensive pre-systemic metabolism. ASM-SES was prepared by choosing the proportion of oil, surfactant, co-surfactant from constructed phase diagram. The in vitro and ex vivo evaluation was done. In vivo evaluation was done through pharmacokinetic and pharmacodynamic studies. Role of lymphatic absorption was studied by lymphatic absorption inhibition study. A formulation consisting of 9.9%, 59.4%, 29.7% and 1% of oil, surfactant, co-surfactant, and drug respectively was considered as optimized formulation. After various evaluation test, the globule size and zeta potential for optimized formulation (SES₄) were found to be 137.9?nm and ?28.8?mV respectively. A maximum of 99.64?±?0.16% of ASM was released from SES₄ in 60?minutes of time. The flux (ex vivo study) increased by 2.33 folds, which prove the enhanced release and permeation of ASM when loaded into SES. The animals administered with SES₄ showed higher activity and good pharmacodynamic response than the control and ASM-Suspension, which may be due to the greater availability of the drug. The maximum pharmacodynamic response was observed at the t_max determined by Pharmacokinetic studies. The bioavailability increased by 1.64 folds with 16.55?±?3.11% as extend of lymphatic absorption (r?=?0.9732). Good in vitro in vivo correlation was observed. ASM-SES is a novel approach to effectively deliver ASM and improve the oral bioavailability.     

Single non-ionic surfactant based self-nanoemulsifying drug delivery systems: formulation,characterization, cytotoxicity and permeability enhancement study

Single non-ionic surfactant based self-nanoemulsifying drug delivery system (SNEDDS) was formulated and characterised for poor water soluble drug, Atorvastatin calcium. Capmul MCM oil showing highest solubility for Atorvastatin calcium was selected as oil phase. Self-nanoemulsifying capacity of Cremophor RH 40, Cremophor EL, Tween 20, Tween 60, Tween 80 and Labrasol were tested for the selected oil. In vitro dissolution studies were performed and were characterized by t85% and dissolution efficiency (DE). Cytotoxicity of the formulations and permeation enhancement of the drug across caco-2 cell monolayer was assessed. Capmul MCM was found to be better nanoemulsified in decreasing order of Cremophor RH 40 > Cremophor EL > Tween 20 > Tween 60 > Tween 80. Values of droplet size (range 11–83 nm), polydispersity index (range 0.07–0.65); zeta potential (range ?3.97 to ?19.0) and cloud point (60–85°C) before and after drug loading proves the uniformity and stability of the formulations. SNEDDS formulated with Tween 20 surfactant showed enhanced dissolution with t85% and DE values at 10 min and 78.70, respectively. None of the formulation showed cytotoxicity at the concentration tested. Tween 20 based SNEDDS enhanced permeation of the drug as compared with pure drug across cell lines. It can be concluded that SNEDDS can be formulated by using single non-ionic surfactant system for enhance dissolution and absorption of poorly soluble drug, Atorvastatin calcium.     

Development and assessment of stable formulations containing two herbal antimicrobials: Allium sativum L. and Eruca sativa miller seed oils

Abstract

Context: Garlic oil and Eruca oil have been reported to have excellent antimicrobial activity. However, the exact knowledge of their required hydrophilic–lipophilic balance (rHLB) values to facilitate their emulsification are still not reported in the literature.

Objective: The objective of this study is to determine rHLB values of Garlic and Eruca oils to formulate an elegant stable cream formulation enriched with both oils.

Materials and methods: Emulsions of both oils were prepared by the bottle method using water, Tween 80 and Span 80. Formulated emulsions were evaluated for creaming index (CI), droplet size, and turbidity to determine rHLB. Utilizing determined rHLB, creams were formulated using a combination of two surfactants, Span 60:Brij 58 (1:2.333) at three different concentrations (2, 4, and 6%).

Results: rHLB of Garlic oil and Eruca oil was determined to be 7.92?±?0.27 and 9.76?±?0.32, respectively. Stable cream (F1) developed with 2% surfactant blend showed elegant rheological properties, the best antimicrobial activity against Staphyococcus aureus ATCC29737, Escherichia coli ATCC25299 S. aureus (MRSA), Malassezia fufur AUMC No. 5173 with no skin irritation. In addition, its texture parameters and pH were found to be consistent over 12 months at 25?±?1?°C and 60% relative humidity.

Discussion: The lowest CI, smallest droplet size, and highest turbidity were obtained at the optimum surfactant concentration in the prepared emulsions. Increasing surfactant blend concentration in cream formulations leads to increasing viscosity and consequently decreasing antimicrobial activity.

Conclusion: Determination of the rHLB of Garlic and Eruca oils allows the ease of preparation of stable, consistent, and non-irritant cream.     

Preparation and characterization of self nano-emulsifying drug delivery system (SNEDDS) for oral delivery of heparin using hydrophobic complexation by cationic polymer of β-cyclodextrin

Objective: The aim of this study was the preparation of a self nano-emulsifying drug delivery system (SNEDDS) for oral delivery of heparin.

Significance: Preparation of hydrophobic complexes between heparin as the hydrophilic macromolecule and cationic polymer of β-cyclodextrin (CPβCD) was considered for preparation of orally administered SNEDDS in which the drug incorporated in internal oil phase of O/W nano-droplets.

Methods: Hydrophobic complexes of heparin-CPβCD were prepared by electrostatic interaction. The lipophilic feature of complexes was characterized by determining their partition co-efficients. SNEDDS prototypes were prepared by mixing liquid paraffin, Tween 80, propylene glycol and ethanol, diluted 1:100 in an aqueous medium. Central composite response surface methodology was applied for statistical optimization. Independent variables were the amount of liquid paraffin and the amount of Tween 80, while responses were size and poly dispersity index (PdI). Optimized SNEDDS were studied morphologically using transmission electron microscopy (TEM). In vitro release of heparin was studied in the simulated gastric and simulated intestinal media.

Results: The data revealed that in molar ratio 1:3 (heparin:CPβCD), the n-octanol recovery was maximized and reached 67.6?±?11.86%. Size, PdI, zeta potential, EE% in gastric medium and EE% in intestinal medium for optimized nano-droplets were reported as 307?±?30.51?nm, 0.236?±?0.02,?+2.1?±?0.66?mV, 90.2?±?0.04 and 96.1?±?0.73%, respectively. Microscopic images revealed spherical nano-droplets. The obtained data revealed no burst release of heparin from nano-droplets.

Conclusions: The obtained results indicate that SNEDDS could be regarded as a good candidate for oral delivery of heparin as the hydrophilic macromolecule.     

A combination of complexation and self-nanoemulsifying drug delivery system for enhancing oral bioavailability and anticancer efficacy of curcumin

Abstract

Objective: Curcumin, the golden spice from Indian saffron, has shown chemoprotective action against many types of cancer including breast cancer. However, poor oral bioavailability is the major hurdle in its clinical application. In the recent years, self-nanoemulsifying drug delivery system (SNEDDS) has emerged as a promising tool to improve the oral absorption and enhancing the bioavailability of poorly water-soluble drugs. In this context, complexation with lipid carriers like phospholipid has also shown the tremendous potential to improve the solubility and therapeutic efficacy of certain drugs with poor oral bioavailability.

Methods: In the present investigation, a systematic combination of both the approaches is utilized to prepare the phospholipid complex of curcumin and facilitate its incorporation into SNEDDS. The combined use of both the approaches has been explored for the first time to enhance the oral bioavailability and in turn increase the anticancer activity of curcumin.

Results: As evident from the pharmacokinetic studies and in situ single pass intestinal perfusion studies in Sprague–Dawley rats, the optimized SNEDDS of curcumin–phospholipid complex has shown enhanced oral absorption and bioavailability of curcumin. The cytotoxicity study in metastatic breast carcinoma cell line has shown the enhancement of cytotoxic action by 38.7%. The primary tumor growth reduction by 58.9% as compared with the control group in 4T1 tumor-bearing BALB/c mice further supported the theory of enhancement of anticancer activity of curcumin in SNEDDS.

Conclusion: The developed formulation can be a potential and safe carrier for the oral delivery of curcumin.     

Development and evaluation of nanosized niosomal dispersion for oral delivery of Ganciclovir

Encapsulation of Ganciclovir in lipophilic vesicular structure may be expected to enhance the oral absorption and prolong the existence of the drug in the systemic circulation. So the purpose of the present study was to improve the oral bioavailability of Ganciclovir by preparing nanosized niosomal dispersion. Niosomes were prepared from Span40, Span60, and Cholesterol in the molar ratio of 1:1, 2:1, 3:1, and 3:2 using reverse evaporation method. The developed niosomal dispersions were characterized for entrapment efficiency, size, shape, in vitro drug release, release kinetic study, and in vivo performance. Optimized formulation (NG8; Span60:Cholesterol 3:2 molar ratio) has shown a significantly high encapsulation of Ganciclovir (89?±?2.13%) with vesicle size of 144?±?3.47?nm (polydispersity index [PDI]?=?0.08). The in vitro release study signifies sustained release profile of niosomal dispersions. Release profile of prepared formulations have shown that more than 85.2?±?0.015% drug was released in 24?h with zero-order release kinetics. The results obtained also revealed that the types of surfactant and Cholesterol content ratio altered the entrapment efficiency, size, and drug release rate from niosomes. In vivo study on rats reveals five-time increment in bioavailability of Ganciclovir after oral administration of optimized formulation (NG8) as compared with tablet. The effective drug concentration (>0.69 µg/mL in plasma) was also maintained for at least 8?h on administration of the niosomal formulation. In conclusion, niosomes can be proposed as a potential oral delivery system for the effective delivery of Ganciclovir.     

Fabrication of solid lipid nanoparticles of lurasidone HCl for oral delivery: optimization,in vitro characterization,cell line studies and in vivo efficacy in schizophrenia

Objective: The aim of the present investigation was to investigate the efficacy of solid lipid nanoparticles (SLNs) to enhance the absorption and bioavailability of lurasidone hydrochloride (LH) following oral administration.

Methods: The LH loaded SLNs (LH-SLNs) were prepared by high pressure homogenization (HPH) method, optimized using box Behnken design and evaluated for particle size (PS), entrapment efficiency (EE), morphology, FTIR, DSC, XRD, in vitro release, ex vivo permeation, transport studies across Caco-2 cell line and in vivo pharmacokinetic and pharmacodynamic studies.

Results: The LH-SLNs had PS of 139.8?±?5.5?nm, EE of 79.10?±?2.50% and zeta potential of ?30.8?±?3.5?mV. TEM images showed that LH-SLNs had a uniform size distribution and spherical shape. The in vitro release from LH-SLNs followed the Higuchi model. The ex vivo permeability study demonstrated enhanced drug permeation from LH-SLNs (>90%) through rat intestine as compared to LH-suspension. The SLNs were found to be taken up by energy dependent, endocytic mechanism which was mediated by clathrin/caveolae-mediated endocytosis across Caco-2 cell line. The pharmacokinetic results showed that oral bioavailability of LH was improved over 5.16-fold after incorporation into SLNs as compared to LH-suspension. The pharmacodynamic study proved the antipsychotic potential of LH-SLNs in the treatment of schizophrenia.

Conclusion: It was concluded that oral administration of LH-SLNs in rats improved the bioavailability of LH via lymphatic uptake along with improved therapeutic effect in MK-801 induced schizophrenia model in rats.     

Development of phyllanthin-loaded self-microemulsifying drug delivery system for oral bioavailability enhancement

Phyllanthin, a poorly water-soluble herbal active component from Phyllanthus amarus, exhibited a low oral bioavailability. This study aims at formulating self-microemulsifying drug delivery systems (SMEDDS) containing phyllanthin and evaluating their in-vitro and in-vivo performances. Excipient screening was carried out to select oil, surfactant and co-surfactant. Formulation development was based on pseudo-ternary phase diagrams and characteristics of resultant microemulsions. Influences of dilution, pH of media and phyllanthin content on droplet size of the resultant emulsions were studied. The optimized phyllanthin-loaded SMEDDS formulation (phy-SMEDDS) and the resultant microemulsions were characterized by viscosity, self-emulsification performance, stability, morphology, droplet size, polydispersity index and zeta potential. In-vitro dissolution and oral bioavailability in rats of phy-SMEDDS were studied and compared with those of plain phyllanthin. Phy-SMEDDS consisted of phyllanthin/Capryol 90/Cremophor RH 40/Transcutol P (1.38:39.45:44.38:14.79) in % w/w. Phy-SMEDDS could be emulsified completely within 6?min and formed fine microemulsions, with average droplet range of 27–42?nm. Phy-SMEDDS was robust to dilution and pH of dilution media while the resultant emulsion showed no phase separation or drug precipitation after 8?h dilution. The release of phyllanthin from phy-SMEDDS capsule was significantly faster than that of plain phyllanthin capsule irrespective of pH of dissolution media. Phy-SMEDDS was found to be stable for at least 6 months under accelerated condition. Oral absorption of phyllanthin in rats was significantly enhanced by SMEDDS as compared with plain phyllanthin. Our study indicated that SMEDDS for oral delivery of phyllanthin could be an option to enhance its bioavailability.     

Formulation optimization and the absorption mechanisms of nanoemulsion in improving baicalin oral exposure

Objective: The aim of this study was to optimize baicalin nanoemulsion, clarify the absorption mechanisms of nanoemulsion improving the exposure of baicalin, and assess the potential of employing nanoemulsion as nanosystem for insoluble drugs.

Significance: A novel nanoemulsion formulation was successfully prepared to enhance oral exposure of baicalin.

Methods: Pseudo-ternary phase diagrams were utilized to evaluate nanoemulsion area. Physicochemical properties of optimal nanoemulsion formulation were investigated. The exposure of baicalin from the nanoemulsion was compared with baicalin suspension. The in situ single-pass intestine perfusion (SPIP) method and chylomicron-blocked rat model were used to study the absorption mechanisms of nanoemulsion.

Results: Baicalin nanoemulsion was nearly spherical in shape with the average droplet size of 58.43?nm, and the zeta potential was –8.18?±?1.2?mV. The stability test showed that baicalin nanoemulsion was very stable. Pharmacokinetic study indicated that baicalin nanoemulsion showed 14.56-fold improvement in exposure in comparison to baicalin suspension. The results of SPIP and chylomicron flow blocking study showed that intestinal absorption and lymphatic transport process contributed to its systemic exposure.

Conclusions: Based on the results, optimal nanoemulsion might be promising nanosystems for oral delivery of baicalin to satisfy clinical requirements.     

Development and in vitro–in vivo evaluation of a water-in-oil microemulsion formulation for the oral delivery of troxerutin

Objective: The main objective of this study was to develop and evaluate a W/O microemulsion formulation of troxerutin to improve its oral bioavailability.

Methods: The W/O microemulsion was optimized using a pseudo-ternary phase diagram and evaluated for physical properties. In vitro MDCK cell permeability studies were carried out to evaluate the permeability enhancement effect of microemulsion, and in vivo absorption of troxerutin microemulsion in the intestine was compared with that of solution after single-dose administration (56.7?mg/kg) in male Wistar rats.

Results: The optimal formulation consisted of lecithin, ethanol, isopropyl myristate and water (23.30/11.67/52.45/12.59 w/w) was physicochemical stable and the mean droplet size was about 50.20?nm. In vitro study, the troxerutin-loaded microemulsion showed higher intestinal membrane permeability across MDCK monolayer when compared with the control solution. The W/O microemulsion can significantly promote the intestinal absorption of troxerutin in rats in vivo, and the relative bioavailability of the microemulsion was about 205.55% compared to control solution.

Conclusion: These results suggest that novel W/O microemulsion could be used as an effective formulation for improving the oral bioavailability of troxerutin.     

Design,characterization, and evaluation of intranasal delivery of ropinirole-loaded mucoadhesive nanoparticles for brain targeting

Context: Parkinson disease (PD) is a common, progressive neurodegenerative disorder, characterized by marked depletion of striatal dopamine and degeneration of dopaminergic neurons in the substantia nigra.

Objective: The purpose of the present study was to investigate the possibility of targeting an anti-Parkinson’s drug ropinirole (RH) to the brain using polymeric nanoparticles.

Materials and methods: Ropinirole hydrochloride (RH)-loaded chitosan nanoparticles (CSNPs) were prepared by an ionic gelation method. The RH-CSNPs were characterized for particle size, polydispersity index (PDI), zeta potential, loading capacity, entrapment efficiency in vitro release study, and in vivo distribution after intranasal administration.

Results and discussion: The RH-CSNPs showed sustained release profiles for up to 18?h. The RH concentrations (% Radioactivity/g) in the brain following intranasal administration (i.n.) of RH-CSNPs were found to be significantly higher at all the time points compared with RH solution. The concentration of RH was highest in the liver (7.210?±?0.52), followed by kidneys (6.862?±?0.62), intestine (4.862?±?0.45), and lungs (4.640?±?0.92) in rats following i.n. administration of RH-CSNPs. Gamma scintigraphy imaging in rats was performed to ascertain the localization of drug in the brain following intranasal administration of formulations. The brain/blood ratios obtained (0.251?±?0.09 and 0.386?±?0.57 of RH (i.n.) and RH-CSNPs (i.n.), respectively) at 0.5?h are indicative of direct nose to brain transport, bypassing the blood–brain barrier (BBB).

Conclusion: The novel formulation showed the superiority of nose to brain delivery of RH using mucoadhesive nanoparticles compared with other delivery routes reported earlier.     

Self-nanoemulsifying drug-delivery system for improved oral bioavailability of rosuvastatin using natural oil antihyperlipdemic

Aim: The aim is improving the antihyperlipidemic activity of Rosuvastatin Calcium (Rs) through improving its solubility using self-nanoemulsifying drug delivery system (SNEDDS) containing natural oil full of unsaturated fatty acid and omega 3.

Methods: A 7?×?3² full factorial design was adopted for optimization of oil ratio, Surfactant: Co-surfactant (S:CoS) ratio and oil:S/CoS ratio. Ternary phase diagrams were constructed for optimizing the system with drug loading (10 and 20%). The optimized SNEDD systems were evaluated according to their physical evaluation and drug release. Furthermore, the anti-hyperlipidemia efficacy was compared with commercially marketed product on rates followed by clinical study.

Results: The system containing Tween 80:PEG 400 (3:1) and olive oil:garlic oil (1:1) as an oily phase has droplet size less than 100?nm, ZP (+23.43?±?2.58?mV), PDI (<0.02) and cloud point (>90?°C). In vitro drug release studies showed remarkable enhancement of the Rs release from Rs-SNEDDS. The antihyperlipidemic effect of Rs-SNEDDS is greater than that of the commercial tablets and the pure drug on rates and in hyperlipidemic patients.

Conclusion: Rs-SNEDDS is a promising drug delivery system for improving the drug solubility and antihyperlipidemic effect using natural oils as (olive oil and garlic oil).     

Determination of required hydrophilic–lipophilic balance of citronella oil and development of stable cream formulation

Context: Citronella oil is reported to have excellent mosquito-repellent activity. To develop a stable cream formulation (emulsion), its hydrophilic–lipophilic balance (HLB) value is important.

Objective: To determine required hydrophilic–lipophilic balance (rHLB) value of citronella oil and to develop stable cream formulation.

Materials and Methods: Emulsions of citronella oil were prepared by phase inversion temperature technique using water, Tween 80 and Span 80. A first series of 11 emulsions with HLB values ranging from 5.0 to 15.0 and a second series of eight emulsions with smaller interval in HLB values from 11.0 to 13.8 were prepared. Emulsions were evaluated for creaming index, droplet size and turbidity to determine rHLB. Utilizing determined rHLB, citronella oil cream was formulated and evaluated for different texture parameters. rHLB of light liquid paraffin was also determined for validation of methodology.

Results: rHLB of light liquid paraffin and citronella oil was determined to be 11.80 and 12.60, respectively. Stable citronella oil cream was developed with 10% emulsifier blend. Texture parameters were found to be consistent over the entire storage period.

Discussion: Creaming index, droplet diameter, percent increase in droplet diameter and turbidity are the established parameters to determine rHLB and to develop stable emulsion. Emulsions with optimum emulsifier concentration resulted in less percentage creaming index, smallest droplet, less percentage increase in droplet diameter and highest turbidity. Texture properties evaluation ensures the stability of the developed cream.

Conclusion: rHLB value of citronella oil was found 12.6 and a stable cream was formulated utilizing determined rHLB.     

Pharmacokinetic and pharmacodynamic studies of nisoldipine-loaded solid lipid nanoparticles developed by central composite design

Abstract

Objective: Nisoldipine (ND) is a potential antihypertensive drug with low oral bioavailability. The aim was to develop an optimal formulation of ND-loaded solid lipid nanoparticles (ND-SLNs) for improved oral bioavailability and pharmacodynamic effect by using a two-factor, three-level central composite design. Glyceryl trimyristate (Dynasan 114) and egg lecithin were selected as independent variables. Particle size (Y₁), PDI (Y₂) and entrapment efficiency (EE) (Y₃) of SLNs were selected as dependent response variables.

Methods: The ND-SLNs were prepared by hot homogenization followed by ultrasonication. The size, PDI, zeta potential, EE, assay, in vitro release and morphology of ND-SLNs were characterized. Further, the pharmacokinetic (PK) and pharmacodynamic behavior of ND-SLNs was evaluated in male Wistar rats.

Results: The optimal ND-SLN formulation had particle size of 104.4?±?2.13?nm, PDI of 0.241?±?0.02 and EE of 89.84?±?0.52%. The differential scanning calorimetry and X-ray diffraction analyses indicated that the drug incorporated into ND-SLNs was in amorphous form. The morphology of ND-SLNs was found to be nearly spherical by scanning electron microscopy. The optimized formulation was stable at refrigerated and room temperature for 3 months. PK studies showed that 2.17-fold increase in oral bioavailability when compared with a drug suspension. In pharmacodynamic studies, a significant reduction in the systolic blood pressure was observed, which sustained for a period of 36?h when compared with a controlled suspension.

Conclusion: Taken together, the results conclusively demonstrated that the developed optimal ND-SLNs caused significant enhancement in oral bioavailability along with pharmacodynamic effect.     

Preparation and evaluation of optimized zolmitriptan niosomal emulgel

Objective: Novel niosomal formulation may be successfully applied to treat a systemic disease such as migraine through transdermal drug delivery system (TDDS), moreover, the treatment of topical diseases such as mycotic infections by targeting and localizing the drug to the stratum corneum. The current study aims to formulate zolmitriptan (Zt) in niosomal vesicles to potentiate its transdermal effect.

Significance: The development of a promising niosomal formulation will push the scaling up of pharmaceutical industry in this field.

Methods: Design- Expert 10 was used to design twelve formulations using Box-Behnken. Zt loaded niosomes were prepared by the thin film hydration method using Span 60(S 60), Span 80(S 80) along with cholesterol(Ch) at three different levels. The optimized formulation (F11) was formulated in Emulgel (1:1 emulsion/gel ratio).

Results: The vesicles revealed vesicle size (VS) ranging from 133.1 to 851.3?nm, zeta potential (ZP) ?43.8 to ?82.8?mV, entrapment efficiency (EE%) from 66.7 to 88.7%, and Zt release after 4?h up to 67%. Optimized niosomal formulation (F11) depicted the smallest VS (133.1?nm), highest EE (88.7%), high ZP (?80.6?mV) and satisfactory release after 4?h (61.5%). There was a significant difference (p <.05) in drug permeation after 8?h for niosomal F11(460.98?ug/cm²) and niosomal F11 loaded Emulgel (336.92?ug/cm²) compared to plain Zt loaded emulgel (160.83?ug/cm²). Niosomal F11 loaded emulgel showed thixotropic behavior of rapid recovery, significant bioavailability and pharmacokinetic parameters as compared to the plain Zt-loaded Emulgel.

Conclusion: Optimized F11 represents a promising formulation for transdermal drug delivery system to treat both topical and systemic diseases.     

Optimization of self nanoemulsifying drug delivery system for poorly water-soluble drug using response surface methodology

There is an increasing interest on self-nanoemulsifying drug delivery system (SNEDDS) for oral delivery of poorly water-soluble drugs. However, development of SNEDDS is often driven by empiric, pseudo-ternary diagrams and solubility of drugs, and it is lacking a systematic approach for evaluating impact of excipients on the performance of formulations as well as the fate of drug. The aim of this study was to rationalize the SNEDDS development procedure and to get a better understanding on the role of excipients on the SNEDDS. The formulations consist of soybean oil or rapeseed oil, Cremophor^® RH40, Maisine? 35-1 and ethanol. Response surface methodology (RSM) was used in the development of SNEDDS. Significant advantages of RSM were found in reducing the work load and determining the impact of excipients on formulation characteristics. The most significant factor in influencing droplet size was the co-surfactant Maisine? 35-1, the droplet size increased with increasing concentration of Maisine? 35-1. It suggests that Maisine? 35-1 has double functions in the SNEDDS; it functions as co-surfactant to improve the emulsification of oil, meanwhile it also works as the oil phase and results in larger droplets. A significant reduction in droplet size was interestingly observed when fenofibrate was loaded in the vehicles, probably due to the surface activity of fenofibrate, promoting the self-emulsifying process. It was evident that drug precipitation during lipolysis was not affected by the level of co-solvent ethanol in the formulation, while it had pronounced impact on drug solubilization during the initial dispersion stage.