Development of Nanonized Nitrendipine and Its Transformation into Nanoparticulate Oral Fast Dissolving Drug Delivery System.

The present research focuses on the development of a nanoparticulate (nanocrystals-loaded) rapidly dissolving (orodispersible) tablet with improved solubility and bioavailability. The nanosuspension (NS) was prepared by antisolvent sonoprecipitation technique and the optimized NS was lyophilized to obtain nanocrystals (NCs), which were evaluated for various parameters. The nitrendipine (NIT) nanoparticulate orodispersible tablet (N-ODT) was prepared by direct compression method. The optimized N-ODT was evaluated for pre and post compression characteristics, in vivo pharmacokinetic and stability profile. The optimized NS showed a particle size of 505.74 ± 15.48 nm with a polydispersity index (PDI) of 0.083 ± 0.006. The % NIT content in the NCs was found to be 78.4 ± 2.3%. The saturation solubility of NIT was increased remarkably (26.14 times) in comparison to plain NIT, post NCs development. The DSC and p-XRD analysis of NCs revealed the perseverance of the integrity and crystallinity of NIT on lyophilization. The results of micromeritic studies revealed the good flow-ability and compressibility of NCs blend. All the post-compression properties of N-ODT were observed within the standard intended limit. The dispersion, wetting, and disintegration time of the optimized batch of N-ODT was found to be 39 ± 1.13 s, 44.66 ± 1.52 s, and 33.91 ± 0.94 s respectively. The in vitro dissolution study displayed 100.28 ± 2.64% and 100.61 ± 3.3% of NIT released from NCs (in 8 min) and N-ODT (in 6 min) respectively, while conventional NIT tablet took 30 min to release 99.94 ± 1.57% of NIT. The in vivo pharmacokinetic study in rabbits demonstrated significantly (p < 0.05) higher bioavailability of NIT on release from N-ODT than the conventional NIT tablet. Thus, N-ODT could be a promising tool for improving the solubility and bioavailability of NIT and to treat cardiovascular diseases effectively.

Development and optimization of nanoemulsion based gel for enhanced transdermal delivery of nitrendipine using box-behnken statistical design.

Objective: The purpose of present research was to develop and statistically optimize nitrendipine nanoemulsion gel for transdermal delivery using box-behnken statistical design.Method: The nanoemulsion formulations bearing nitrendipine were prepared by application of ternary phase diagram and spontaneous emulsification method. Box-behnken design was employed for the optimization of nitrendipine loaded nanoemulsion. The independent variables were oil, surfactant and co-surfactant while globule size, drug content and zeta potential were dependent variables. The optimized nanoemulsion formulation was incorporated into gel and evaluated for in-vitro release, ex-vivo permeation studies, confocal laser scanning microscopy, skin irritation and histopathological studies.Results: The optimized formulation through box-behnken statistical design showed globule size of 20.43 ± 1.50 nm, drug content of 97.05 ± 1.77% and zeta potential of -15.45 ± 0.35 mV. The ex-vivo study confirmed the enhanced delivery of nitrendipine from nanoemulsion gel than compare to drug solution by virtue of better permeation and solubility. Nanoemulsion gel was proved significantly superior by confocal laser scanning microscopy for satisfactory permeation and distribution of gel, deep into the rat skin. The optimized gel was found with no allergic dermal effects and was proved safe by histopathological studies for transdermal application.Conclusions: Results reveals that developed nitrendipine nanoemulsion gel overcomes the limitation of low penetration and accentuate permeation through albino Wistar rat skin. It was concluded that nanoemulsion gel could be utilized as a potential carrier for transdermal delivery of nitrendipine.

Preparation of starch macrocellular foam for increasing the dissolution rate of poorly water-soluble drugs.

Starch macrocellular foam (SMF), a novel natural bio-matrix material, was prepared by the hard template method in order to improve the dissolution rate and oral bioavailability of poorly water-soluble drugs. Nitrendipine (NDP) was chosen as a model drug and was loaded into SMF by the solvent evaporation method. SMF and the loaded SMF samples (NDP-SMF) were characterized by scanning electron microscopy, differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy. In vitro drug release studies showed that SMF significantly increased the dissolution rate of NDP. In vivo studies showed that the NDP-SMF tablets clearly increased the oral bioavailability of NDP in comparison with the reference commercial tablets. All the results obtained demonstrated that SMF was a promising carrier for the oral delivery of poor water-soluble drugs.

5-FU-induced cardiac toxicity--an underestimated problem in radiooncology?

BACKGROUND: 5-Fluorouracil (5-FU) is an antimetabolite, which is frequently used as chemotherapeutic agent for combined chemoradiotherapy. The purpose of this study was to present the clinical course of three patients who developed severe cardiac toxicity by 5-FU and to give a review of the literature on the cardiotoxic potential of 5-FU. RESULTS: Cardiotoxicity is a rare, but relevant side effect of fluoropyrimidines. It comprehends a wide spectrum of side effects, from electrocardiogram changes (69% of cardiac events) to myocardial infarction (22%) and cardiogenic shock (1%).In this case series three patients with cardiotoxic events during chemoradiotherapy including 5-FU, the reaction's characteristics and their influence on further therapy are described. Two of the patients could not be treated with 5-FU any more because they had developed a myocardial ischemia, which was most likely caused by fluorouracil. Another patient, who complained about typical angina pectoris during 5-FU-infusion and had a new left anterior hemiblock, was reexposed with prophylactic administration of nitrendipine. CONCLUSION: Cardiotoxicity caused by 5-FU is an underestimated problem in radiooncology. Especially patients without history of cardiac disease are often treated as out-patients and therefore without cardiac monitoring. Consequently asymptomatic and symptomatic cardiac events may be overlooked. The benefit of prophylactic agents remains unclear, so close cardiac monitoring is the most established method to prevent manifest cardiotoxic events.

Anti-arrhythmic and hemodynamic effects of oxy nifedipine, oxy nimodipine, oxy nitrendipine and oxy nisoldipine.

Our previous studies have established cardio-protective effects of furnidipine and its active metabolites. We therefore decided to compare the influence of oral and intravenous administration of furnidipine, nifedipine, nitrendipine and nimodipine to examine their effects on hemodynamics and arrhythmias. Since dihydropyridines are oxidatively metabolized in the body and the oxidized metabolites are among the final products, we studied the influence of four oxidized dihydropyridines (oxy nifedipine, oxy nimodipine, oxy nitrendipine and oxy nisoldipine) on the same parameters. In vivo model of ischemia- and reperfusion-induced arrhythmias of rats was used. Dihydropyridines were administered 5 mg/kg orally (24 and 1 h before ischemia) or 5 µg/kg intravenously (10 min before ischemia). 20 mg/kg of the oxidized dihydropyridines was given orally (24 and 1 h before ischemia). The dihydropyridines exhibited significant anti-arrhythmic actions after both forms of administration but their influence on blood pressure was differential and contrasting and depended on route of administration. The oxidized dihydropyridines imparted strong protection against lethal arrhythmias while exerting differential influences on blood pressure with oxy nifedipine and oxy nisoldipine being hypertensive and oxy nitrendipine being most normotensive. The differential effects observed with the dihydropyridines after the two routes of administration lend strength to the hypothesis that their metabolites may have a significant role in mediating the actions of the parent drug. The strong anti-arrhythmic action of the oxidized dihydropyridines along with their differential effect on blood pressure could indicate their potential use as cardio-protective drugs in certain groups of patients.

The development of a novel dry powder inhaler.

A novel active and multi-dose dry powder inhaler (DPI) was developed and evaluated to deliver a small quantity (100-500 µg) of pure drug without any excipient. This dry powder inhaler utilized two compressed air flows to dispense and deliver drug powder: the primary flow aerosolizes the drug powder from its pocket and the secondary flow further disperses the aerosol. In vitro tests by Anderson Cascade Impactor (ACI) indicated that the fine particle fraction (FPF) (<4.7 µm) of drug delivery could reach over a range of 50-70% (w/w). Emitted dose tests showed that delivery efficiency was above 85% and its relative standard deviation (RSD) was under 10%. Confocal microscopy was used to confirm the deposition of fluorescently labeled spray-dried powder in rabbit lungs. Also, a chromatographic method was used to quantify drug deposition. The results of animal tests showed that 57% of aerosol deposited in the rabbit lung and 24% deposited in its trachea. All the results implied that this novel active dry powder inhaler could efficiently deliver a small quantity of fine drug particles into the lung with quite high fine particle fraction.

A novel surface modified nitrendipine nanocrystals with enhancement of bioavailability and stability.

In this study, chitosan, a cationic polymer with positive charge, was introduced to modify the nanocrystals of nitrendipine with negative charge. The nanocrystals were prepared via precipitation-high pressure homogenization method. Then the nanocrystals were dispersed into chitosan solution, and the free chitosan was removed by centrifugation to obtain the chitosan modified nanocrystals, which remained the same particle size. However, the zeta-potential changed to positive after modification. The physical stability of the chitosan modified nanocrystals was remarkably improved under ambient conditions. During the in vitro dissolution test, the modified nanocrystals showed a certain degree of slow-release property. In the in vivo study, the C(max) of nitrendipine remained the same, however, the T(max) delayed from 0.75 h to 1.5 h with the chitosan modified nanocrystals. The surface modification by chitosan improved the bioavailability compared with the initial nanocrystals, which had demonstrated significant improvement of bioavailability compared to the traditional coarse powder form. Based on the experimental results, modification of the nanocrystals with certain polymer was supposed to be a good method to control the in vitro and in vivo behaviors of the nanocrystals, which could further increase the bioavailability of the water insoluble drug.

Nitrendipine nanocrystals: its preparation, characterization, and in vitro-in vivo evaluation.

The present investigation was undertaken with the objective of developing a solid formulation containing nitrendipine nanocrystals for oral delivery. Nitrendipine nanocrystals were prepared using a tandem precipitation-homogenization process. Then, spray drying, a cost-effective method very popular in industrial situations, was employed to convert the nanocrystals into a solid form. The parameters of the preparation process were investigated and optimized. The optimal process was as follows: firstly, nitrendipine/acetone solution (100 mg/ml) was added to a polyvinyl alcohol solution (1 mg/ml) at 10°C, then the pre-suspension was homogenized for 20 cycles at 1,000 bar. Both differential scanning calorimetry and X-ray diffraction analysis indicated that nitrendipine was present in crystalline form. The in vitro dissolution rate of the nanocrystals was significantly increased compared with the physical mixture and commercial tablet. The in vivo testing demonstrated that the C(max) of the nanocrystals was approximately 15-fold and 10-fold greater than that of physical mixture and commercial tablet, respectively. In addition, the AUC(0→24) of the nanocrystals was approximately 41-fold and 10-fold greater than that of physical mixture and commercial tablet, respectively.

Differences in crystallization rate of nitrendipine enantiomers in amorphous solid dispersions with HPMC and HPMCP.

To clarify the contribution of drug-polymer interaction to the physical stability of amorphous solid dispersions, we studied the crystallization rates of nitrendipine (NTR) enantiomers with identical physicochemical properties in the presence of hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate (HPMCP) and polyvinylpyrrolidone (PVP). The overall crystallization rate at 60°C and the nucleation rate at 50-70°C of (+)-NTR were lower than those of (-)-NTR in the presence of 10-20% HPMC or HPMCP. In contrast, similar crystallization profiles were observed for the NTR enantiomers in solid dispersions containing PVP. The similar glass transition temperatures for solid dispersions of (-)-NTR and (+)-NTR suggested that the molecular mobility of the amorphous matrix did not differ between the enantiomers. These results indicate that the interaction between the NTR enantiomers and HPMC or HPMCP is stereoselective, and that differences in the stereoselective interaction create differences in physical stability between (-)-NTR and (+)-NTR at 50-70°C. However, no difference in physical stability between the enantiomers was obvious at 40°C. Loss of the difference in physical stability between the NTR enantiomers suggests that the stereoselective interaction between NTR and the polymers may not contribute significantly to the physical stabilization of amorphous NTR at 40°C.

Ultra-performance liquid chromatography-tandem mass spectrometry method for the determination of nitrendipine in dog plasma and its application to a pharmacokinetic study of a solid self-emulsifying pellet formulation.

A rapid, sensitive and selective ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantitative determination of nitrendipine (NTD, CAS 39562-70-4) in dog plasma. Using propranolol hydrochloride (CAS 318-98-9) as an internal standard (IS), plasma samples pretreatment adopted a simple liquid-liquid extraction process with diethyl ether. Separation was carried out by a gradient elution on an Acquity UPLC BEH C18 column with a mobile phase consisting of water (containing 0.1% formic acid) and acetonitrile. Detection was performed by a triple-quadrupole mass spectrometry with positive electrospray ionization (ESI) as source ionization in multiple-reaction monitoring (MRM) mode at m/z 361.0 --> 315.0 for NTD and m/z 260.2 --> 116.0 for IS. The method demonstrated good linearity at the concentrations ranged from 0.1-200 ng/mL and the lower limit of quantification (LLOQ) of NTD was 0.1 ng/mL. The intra- and inter-day relative standard deviations (RSD) were less than 10%. The mean extraction recoveries of NTD and IS were 90.2% and 82.4%, respectively. Finally, the method was successfully applied to a pharmacokinetic study of home-made solid self-emulsifying pellets and conventional NTD tablets in beagle dogs following a single oral administration.

Effect of crystal size on the in vitro dissolution and oral absorption of nitrendipine in rats.

PURPOSE: To investigate the effect of crystal size on the dissolution and oral absorption of nitrendipine, a poorly soluble drug, in rats. METHODS: Five types of nitrendipine crystal suspensions with different particle sizes (200 nm, 620 nm, 2.7 microm, 4.1 microm, 20.2 microm) were prepared either by the precipitation-ultrasonication or the anti-solvent precipitation method. The simulated intestinal fluid in the fasted state (FaSSIF) was selected as the dissolution medium, and the dissolution behaviors of different nitrendipine crystals were simulated based on a Noyes-Whitney type equation. The in vivo absorption and the absolute bioavailability of the different nitrendipine crystals were evaluated in Wistar rats. RESULTS: The dissolution rate of nitrendipine was significantly increased by a reduction in particle size. The dissolution test in FaSSIF could discriminate between the differences in the dissolution rates of the different particle sizes, and the simulated results were in agreement with the observed dissolution curves. From the simulated T(50%) values (50% dissolution time), the dissolution rates of crystals with particle sizes of 200 nm, 620 nm, 2.7 microm, 4.1 microm and 20.2 microm were calculated to be 5.1 x 10(4), 1.0 x 10(4), 237, 64 and 11-fold greater than that of the raw crystals and resulted in absolute bioavailability of 61.4% 51.5%, 29.4%, 26.7%, 24.7%, respectively. The reduction in the drug particle size correlated well with incremental improvements in oral absorption. A good linear relationship was observed between the Log (T(50%)) and the absolute bioavailability of nitrendipine. CONCLUSIONS: The dissolution rate and the oral bioavailability of nitrendipine were significantly affected by the crystal size, and the oral bioavailability could be improved significantly by preparing it as nanocrystals. FaSSIF can be used to predict differences in oral absorption of crystals with different particle sizes.

Morbidity and mortality on combination versus monotherapy: a posthoc analysis of the Systolic Hypertension in Europe trial.

BACKGROUND: The current literature supports the immediate use of combinations of antihypertensive drugs in terms of ease of use and adherence, but the key issue whether combination therapy is more effective than monotherapy in the prevention of cardiovascular complications remains unproven. METHODS: We analysed the double-blind (median follow-up 2.0 years) and open follow-up (6.0 years) phases of the Systolic Hypertension in Europe trial. Patients were 60 years or more with an entry systolic/diastolic blood pressure (BP) of 160-219/less than 95 mmHg. Antihypertensive treatment started immediately after randomization in the active-treatment group, but only after completion of the double-blind trial in control patients. Treatment consisted of nitrendipine (10-40 mg/day) with the possible addition of enalapril (5-20 mg/day). We adjusted our analyses for sex, age, history of cardiovascular complications, baseline systolic BP and previous antihypertensive treatment. RESULTS: During the double-blind trial, adding enalapril to nitrendipine (n = 515), compared with the equivalent combination of placebos (n = 559), decreased systolic BP by a further 9.5 mmHg and reduced all cardiovascular events by 51% (P = 0.0035) and heart failure by 66% (P = 0.032), with similar trends for stroke (-51%; P = 0.066) and cardiac events (-44%; P = 0.075). Over the whole duration of follow-up, combination therapy (n = 871), compared with nitrendipine monotherapy (n = 1552), decreased systolic BP by 3.1 mmHg and reduced total mortality (-32%; P = 0.023), with similar trends for all cardiovascular events (-23%; P = 0.081) and stroke (-42%; P = 0.054). CONCLUSION: Despite the limitations of a posthoc analysis, but congruent with the stronger BP reduction, our results suggest that combination therapy with nitrendipine plus enalapril might improve outcome over and beyond the benefits seen with nitrendipine monotherapy.

Formulation and evaluation of monolithic matrix polymer films for transdermal delivery of nitrendipine.

The objective of the present work was to develop a suitable transdermal drug delivery system for nitrendipine. Polymeric films of nitrendipine were prepared by the film casting technique (glass ring) on mercury substrate. They were evaluated for physicochemical parameters, in vitro release and ex vivo permeation (heat separated human epidermis). Release of the drug from the films followed anomalous transport (0.5 < n < 1).Polymeric combination containing Eudragit RL 100:PVP K 30 in a 4:6 ratio showed the best results. Maximum drug release and skin permeability coefficient in 48 h were 85.8% and 0.0142 cm h(-1), respectively, in formulation C3 (Eudragit RL 100/Plasdone S 630; 4:6) and 88.0% and 0.0155 cm h(-1), respectively, in formulation, D3 (Eudragit RL 100/PVP K 30; 4:6). FTIR and TLC studies indicated no drug and polymer interaction.

Design, development, physicochemical, in vitro and in vivo evaluation of monolithic matrix type transdermal patches containing nitrendipine.

The matrix type transdermal drug delivery systems (patches) of Nitrendipine were prepared by film casting technique. The patches were characterized for physical, in vitro release studies and ex-vivo permeation studies (human cadaver skin). On the basis of in vitro drug release and skin permeation performance, formulation B3 was found to be better than the other formulations and it was selected as the optimized formulation. The final optimized formulation (B3) was subjected to skin irritation, pharmacokinetic, pharmacodynamic and stability studies. The maximum percentage drug release in 48 hours was 94.67 +/- 3.25 for B3 and 91.43 +/- 2.106 for A2 formulation. Again formulation B3 (0.0627 mg/cm2/h) and A2 (0.0566 mg/cm2/h) showed maximum skin flux in the respective series. Patches prepared with Plasdone S-630 were more flexible as compared to PVP K 30 containing patches. Patches prepared with PVP K 30 showed drug release and skin permeation at higher percentage as compared to those containing Plasdone S-630. The interaction studies carried out by comparing the results of ultraviolet, infrared, TLC and DSC analyses for the pure drug, medicated and placebo formulations indicated no chemical interaction between the drug and excipients. The TDDS was found to be free of any skin irritation as suggested by skin irritation score of 1.16 (< 2.00) under Draize score test.

Effectiveness and tolerability of fixed-dose combination enalapril plus nitrendipine in hypertensive patients: results of the 3-month observational, post-marketing, multicentre, prospective CENIT study.

BACKGROUND AND OBJECTIVE: Monotherapy with any class of antihypertensive drug effectively controls blood pressure (BP) in only about 50% of patients. Consequently, the majority of patients with hypertension require combined therapy with two or more medications. This study aimed to evaluate the effectiveness (systolic BP [SBP]/diastolic BP [DBP] control) and tolerability of the fixed-dose combination enalapril/nitrendipine 10 mg/20 mg administered as a single daily dose in hypertensive patients. METHODS: This was a post-authorization, multicentre, prospective, observational study conducted in primary care with a 3-month follow-up. Patients throughout Spain with uncontrolled hypertension (> or =140/90 mmHg for patients without diabetes mellitus, or > or =130/85 mmHg for patients with diabetes) on monotherapy or with any combination other than enalapril + nitrendipine, or who were unable to tolerate their previous antihypertensive therapy, were recruited. Change from previous to study treatment was according to usual clinical practice. BP was measured once after 5 minutes of rest in the sitting position. Therapeutic response was defined as follows: 'controlled' meant controlled BP (<140/90 mmHg for nondiabetic patients, or <130/85 mmHg for diabetic patients); 'response' meant controlled BP, or a decrease in SBP of > or =20 mmHg and in DBP of > or =10 mmHg. The main laboratory test parameters were documented at baseline and after 3 months. Patients aged >65 years, with diabetes, with isolated systolic hypertension (ISH; SBP > or =140 mmHg for patients without diabetes, SBP > or =130 mmHg for patients with diabetes) and who were obese (body mass index [BMI] > or =30 kg/m2) were analysed separately. RESULTS: Of 6537 patients included, 5010 and 6354 patients were assessed in effectiveness and tolerability analyses, respectively. In the tolerability analysis population, there were 3023 men (47.6%) and 3321 women (52.4%). The mean (+/- SD) age of the tolerability analysis group was 62.8 (+/- 10.7) years. A total of 71.1% of the patients presented at least one clinical cardiovascular risk factor other than hypertension, with the most frequent being dyslipidaemia (42.3%), obesity (29.2%) and diabetes (23.9%). After 3 months of treatment, SBP and DBP showed mean (+/- SD) decreases of 26.5 (+/- 14.4) mmHg and 14.9 (+/- 9.0) mmHg, respectively, and 73.0% of patients responded to treatment while 40.9% achieved BP control (70.8%/36.1% in 2658 patients aged >65 years; 61.7%/46.8% in 1521 patients with diabetes; 55.3%/44.2% in 731 patients with ISH; 72.0%/36.4% in 1762 obese patients). Adverse events were reported in 10.8% of patients (n = 689). During the follow-up period, ten patients died and seven patients had serious adverse events; in no case was a causal relationship attributed to the study product. CONCLUSIONS: The rate of SBP/DBP control achieved demonstrates the effectiveness of the fixed-dose enalapril/nitrendipine 10 mg/20 mg combination administered as a single daily dose in patients with essential hypertension not adequately controlled with monotherapy or with any combination other than enalapril + nitrendipine. The proportion and type of adverse events reported were as expected and have already been described for both components of the enalapril/nitrendipine 10 mg/20 mg combination. These results confirm the effectiveness of a strategy based on a fixed-dose enalapril/nitrendipine 10 mg/20 mg combination in reducing BP and achieving BP control goals.

Development and evaluation of nitrendipine nanoemulsion for intranasal delivery.

The clinical efficacy of Nitrendipine (NDP), a potent antihypertensive molecule, is limited due to its low oral bioavailability (10% to 20%) resulting from its extensive first-pass metabolism. The purpose of the present investigation was to enhance the bioavailability of NDP through formulating a nanoemulsion for its intranasal delivery. A Caproyl 90 based nanoemulsion sytem with Tween 80 as the surfactant, Transcutol P and Solutol HS-15 as solubiliser and cosurfactant respectively, was developed. A single isotropic region, which is considered as a bicontinuous nanoemulsion, was identified in the pseudo-ternary phase diagrams developed at various Tween 80: Transcutol P: Solutol HS-15 ratios. NDP was solubilized in a system consisting of Tween 80: Transcutol P: Solutol HS-15 at 1:2:1 weight ratio. The developed nanoemulsion was safe for nasal administration as confirmed by nasal histopathlogy studies with the mean globule size of 98.50 nm. The drug content per actuation was found to be 99.58 +/- 0.05%, with no significant changes over a period of one month. In vivo absorption studies revealed that NDP absorption from the nanoemulsion had a rapid onset of action and a relative bioavailability of 60.44%, significantly greater than the marketed oral tablets.

Development of SLN and NLC enriched hydrogels for transdermal delivery of nitrendipine: in vitro and in vivo characteristics.

The purpose of this research was to investigate novel particulate carrier systems such as solid lipid nanoparticles (SLN) and nanostructured lipid carrier (NLC) for transdermal delivery of nitrendipine (NDP). For this investigation, four different gel-forming agents were selected for hydrogel preparation. Aqueous dispersions of lipid nanoparticles made from trimyristin (TM) were prepared by hot homogenization technique followed by sonication and then incorporated into the freshly prepared hydrogels. The particle size was analyzed by photon correlation spectroscopy (PCS) using Malvern zetasizer, which shows that for all the tested formulations, more than 50% of the particles were below 250 nm after 90 days of storage at room temperature. DSC analysis was performed to characterize the state of drug and lipid modification. Shape and surface morphology were determined by scanning electron microscope (SEM) and transmission electron microscope (TEM), which revealed fairly spherical shape of the formulations. The antihypertensive activity of the gels in comparison with that of oral NDP was studied using desoxy corticosterone acetate (DOCA)-induced hypertensive rats. It was observed that both carbopol SLN (A1) and carbopol NLC (B1) gels significantly controlled hypertension from the first hour (p < .05). The developed gels increased the efficacy of NDP for the therapy of hypertension. Both the SLN and NLC dispersions and the gels enriched with SLN and NLC possessed a sustained drug release over a period of 24 h, but the sustained effect was more pronounced with the SLN and the NLC gel formulations. Further, they were evaluated for zeta potential, entrapment efficiency, in vitro release, ex vivo permeation, and skin irritation studies.

The effect of penetration enhancers on permeation kinetics of nitrendipine in two different skin models.

The purpose of this research was to evaluate the effect of penetration enhancers on permeation kinetics of nitrendipine (NTP) through two different skin models. The permeation profile and related kinetics parameters such as activity parameter, diffusion parameter, lag time, relative activity parameter and relative diffusion parameter of NTP was determined in presence of some novel and widely accepted permeation enhancers. Among all the more pronounced enhancing effect was obtained with oleic acid (OA) as it presented the highest permeability coefficient. The enhancement was found to be increased in the following order: Dimethyl sulphoxide (DMSO)

Development of nitrendipine controlled release formulations based on SLN and NLC for topical delivery: in vitro and ex vivo characterization.

The aim of the investigation is to develop solid lipid nanoparticles (SLN) and nano-structured lipid carrier (NLC) as carriers for topical delivery of nitrendipine (NDP). NDP-loaded SLN and NLC were prepared by hot homogenization technique followed by sonication, and they were characterized for particle size, zeta potential, entrapment efficiency, stability, and in vitro release profiles. Also the percutaneous permeation of NDPSLN A, NDPSLN B, and NDPNLC were investigated in abdominal rat skin using modified Franz diffusion cells. The steady state flux, permeation coefficient, and lag time of NDP were estimated over 24 h and compared with that of control (NDP solution). The particle size was analyzed by photon correlation spectroscopy (PCS) using Malvern zeta sizer, which shows that the NDPSLN A, NDPSLN B, and NDPNLC were in the range of 124-300 nm during 90 days of storage at room temperature. For all the tested formulations (NDPSLN A, NDPSLN B, and NDPNLC), the entrapment efficiency was higher than 75% after 90 days of storage. The cumulative percentage of drug release at 24 h was found to be 26.21, 30.81, and 37.52 for NDPSLN A, NDPSLN B, and NDPNLC, respectively. The results obtained from in vitro release profiles also indicated the use of these lipid nanoparticles as modified release formulations for lipophilic drug over a period of 24 h. The data obtained from in vitro release from NDPSLN A, NDPSLN B, and NDPNLC were fitted to various kinetic models. High correlation was obtained in Higuchi and Weibull model. The release pattern of drug is analyzed and found to follow Weibull and Higuchi equations. The permeation profiles were obtained for all formulations: NDPSLN A, NDPSLN B, and NDPNLC. Of all the three formulations, NDPNLC provided the greatest enhancement for NDP flux (21.485 +/- 2.82 microg/h/cm(2)), which was fourfold over control (4.881 +/- 0.96 microg/h/cm(2)). The flux obtained with NDPSLN B (16.983 +/- 2.91 microg/h/cm(2)) and NDPNLC (21.485 +/- 2.82 microg/h/cm(2)) meets the required flux (16.85 microg/h/cm(2)).