Development of novel sustained release matrix pellets of betahistine dihydrochloride: effect of lipophilic surfactants and co-surfactants

Sustained release matrix pellets of the freely water soluble drug, betahistine dihydrochloride (BH), were prepared using freeze pelletization technique. Different waxes and lipids (cetyl alcohol, beeswax, glyceryl tripalmitate (GTP) and glyceryl tristearate) were evaluated for the preparation of matrix pellets. A D-optimal design was employed for the optimization and to explore the effect of drug loading (X₁), concentration of lipophilic surfactant (X₂), concentration of co-surfactant (X₃) and wax type (X₄) on the release extent of the drug from matrix pellets. The entrapment efficiency (Y₁), pellet diameter (Y₂), and the percentage drug released at given times were selected as dependent variables. Results revealed a significant impact of all independent variables on drug release from the formulated pellets. The lipophilic surfactant significantly increased both the entrapment efficiency and the in vitro drug release and significantly decreased the pellet size. The optimized BH-loaded pellets were composed of 19.95% drug loading, 9.95% Span^® 80 (surfactant), 0.25% Capmul^® (co-surfactant) using glyceryl tripalmitate as a matrix former. The release profiles of the drug from hard gelatin capsule containing optimized pellets equivalent to 32?mg BH was similar to that of target release model for once-daily administration based on similarity factor. It could be concluded that a promising once-daily capsule containing sustained release pellets of BH was successfully designed.     

Iron oxide induced enhancement of mucoadhesive potential of Eudragit RLPO: formulation,evaluation and optimization of mucoadhesive drug delivery system

Objectives: The objective of the study was to investigate the effect of iron oxide in the development of mucoadhesive tablets of cinnarizine using Eudragit RLPO polymer. A simplex lattice design was employed for optimizing the drug delivery system.

Methods: Different concentrations of Eudragit RLPO (X₁), iron oxide (X₂) and PVP K 30 (X₃) were taken as independent variables and mucoadhesive strength, t_50%, t_90%, MDT and tablet tensile strength were the selected response variables. Contour and 3D plots were drawn to portray the relationship between independent and response variables. Ex vivo studies were performed for the determination of mucoadhesive strength of formulated tablets employing texture analyzer. ATR-FTR, DSC and zeta potential determination were conducted for drug-excipient and ionic interaction studies.

Results: Friability, hardness and tensile strength of mucoadhesive tablet formulation were found to be 0.42 ± 0.21%, 3.93 ± 1.57 kg/cm² and 0.65 ± 0.26 mN/m², respectively. Mucoadhesive strength was found to be ranging between 5.75 ± 4.41 and 42.85 ± 3.94 g. Value of release exponent (n) was found to be 0.65 ± 0.22, indicating anomalous drug release behavior from the formulations. Numerical optimization using the desirability approach was employed for developing optimized formulation by setting constraints of the dependent and independent variables. The mucoadhesive tablet formulation composition consisting of 8.58% w/w Eudragit RLPO, 7.02% w/w iron oxide and 7.26% w/w PVP K 30 fulfilled maximum requirements of an optimum formulation with better regulation of the selected constraints.

Conclusions: Eudragit RLPO and iron oxide combination showed high level potential for fabricating gastroretentive as well as mucoadhesive drug delivery systems.     

Preparation and characterization of metformin hydrochloride loaded-Eudragit®RSPO and Eudragit®RSPO/PLGA nanoparticles

The aim of the present study was to develop and characterize metformin HCl-loaded nanoparticle formulations. Nanoparticles were prepared by the nanoprecipitation method using both a single polymer (Eudragit^®RSPO) and a polymer mixture (Eudragit/PLGA). The mean particle size ranged from 268.8 to 288?nm and the nanoparticle surface was positively charged (9.72 to 10.1 mV). The highest encapsulation efficiency was observed when Eudragit®RSPO was used. All formulations showed highly reproducible drug release profiles and the in vitro drug release in phosphate buffer (pH?=?6.8) ranged from 92 to 100% in 12?h. These results suggest that Eudragit^®RSPO or Eudragit/PLGA nanoparticles might represent a promising sustained-release oral formulation for metformin HCl, reducing the necessity of repeated administrations of high doses to maintain effective plasma concentrations, and thus, increasing patient compliance and reducing the incidence of side-effects.     

Blends of hydrophobic and swelling agents in the swelling layer in the preparation of delayed-release pellets of a hydrophilic drug with low MW: Physicochemical characterizations and in-vivo evaluations

In this study, a hydrophobic material, ethylcellulose, which was used as its aqueous suspension Surelease^®, was combined with a swelling agent as the swelling layer to prepare delayed-release pellets for Danshensu, which is a hydrophilic drug with low MW. A rupturable, delayed-release pellet consists of a drug core, a swelling layer containing a swelling agent (cross-linked sodium carboxymethyl cellulose) with a hydrophobic agent (Surelease^®), and a controlled layer composed by an insoluble, water-permeable polymeric coating (aqueous ethylcellulose dispersions) was developed in a fluidised bed. Results showed that blending Surelease^® into the swelling layer could effectively extend the release of Danshensu from the pellets, which may be attributed to the slowed swelling rate by reduction of water penetration and improvement of mechanical integrity of the swelling layer. Drug in the delayed pellets showed sustained release in beagle dogs after oral administration with comparable in-vivo exposure to the uncoated drug pellets. In conclusion, blends of hydrophobic and swelling agents in the swelling layer in double-membrane pellets could achieve a delayed drug-release profile in vitro, as well as delayed and sustained absorption in vivo for highly soluble, low-MW drug. The present study highlighted the potential use of a delayed-release system for other hydrophilic, low-MW drugs to meet the formulation requirements for chronopharmacological diseases.     

Novel non-ionic surfactant proniosomes for transdermal delivery of lacidipine: optimization using 23 factorial design and in vivo evaluation in rabbits

Abstract

Context: Proniosomes offer a versatile vesicle drug delivery concept with potential for delivery of drugs via transdermal route.

Objectives: To develop proniosomal gel using cremophor RH 40 as non-ionic surfactant containing the antihypertensive drug lacidipine for transdermal delivery so as to avoid its extensive first pass metabolism and to improve its permeation through the skin.

Materials and methods: Proniosomes containing 1% lacidipine were prepared by the coacervation phase separation method, characterized, and optimized using a 2³ full factorial design to define the optimum conditions to produce proniosomes with high entrapment efficiency, minimal vesicle size, and high-percentage release efficiency. The amount of cholesterol (X₁), the amount of soya lecithin (X₂), and the amount of cremophor RH 40 (X₃) were selected as three independent variables.

Results and discussion: The system F4 was found to fulfill the maximum requisite of an optimum system because it had minimum vesicle size, maximum EE, maximum release efficiency, and maximum desirability. The optimized system (F4) was then converted to proniosomal gel using carbopol 940 (1% w/w). In vitro permeation through excised rabbit skin study revealed higher flux (6.48?±?0.45) for lacidipine from the optimized proniosomal gel when compared with the corresponding emulgel (3.04?±?0.13) mg/cm²/h. The optimized formulation was evaluated for its bioavailability compared with commercial product. Statistical analysis revealed significant increase in AUC (0???α) 464.17?±?113.15?ng h/ml compared with 209.02?±?47.35?ng h/ml for commercial tablet. Skin irritancy and histopathological investigation of rat skin revealed its safety.

Conclusions: Cremophor RH 40 proniosomal gel could be considered as very promising nanocarriers for transdermal delivery of lacidipine.     

硝苯地平胃漂浮型延迟缓释微丸的制备

目的:制备硝苯地平胃漂浮型延迟缓释微丸并考察其体外漂浮行为.方法:挤出滚圆法制备漂浮型空白丸芯,空白丸芯上药法制备载药丸芯,分别以Surelease水分散体和Eudragit L30D-55为包衣材料,进行流化床包衣.采用正交试验设计对处方进行优化.结果:模拟人体胃肠道条件下溶出,自制漂浮型微丸在人工胃液中6 h累计释放小于10%,换人工肠液后12 h释放完全,体外漂浮10 h以上. 结论:自制微丸达到了漂浮和延迟缓释的效果.     

Ultrahigh verapamil-loaded controlled release polymeric beads using superamphiphobic substrate: D-optimal statistical design,in vitro and in vivo performance

Controlled-release multiparticulate systems of hydrophilic drugs usually suffer from poor encapsulation and rapid-release rate. In the present study, ultra-high loaded controlled release polymeric beads containing verapamil hydrochloride (VP) as hydrophilic model drug were efficiently prepared using superamphiphobic substrates aiming to improve patient compliance by reducing dosing frequency. Superamphiphobic substrates were fabricated using clean aluminum sheets etched with ammonia solution and were treated with 1.5% (w/v) perfluorodecyltriethoxysilane (PFDTS) alcoholic solution. The effect of the main polymer type (lactide/glycolide (PLGA) 5004A, PLGA 5010, and polycaprolactone (PCL)), copolymer (Eudragit RS100) content together with the effect of drug load on encapsulation efficiency (EE%) and in vitro drug release was statistically studied and optimized via D-optimal statistical design. In vivo pharmacokinetic study was carried out to compare the optimized system relative to the market product (Isoptin^®). Results revealed that superamphiphobic substrates were successfully prepared showing a rough micro-sized hierarchical structured surface upon observing with scanning electron microscope and were confirmed by high contact angles of 151.60?±?2.42 and 142.80°±05.23° for water and olive oil, respectively. The fabricated VP-loaded beads showed extremely high encapsulation efficiency exceeding 92.31% w/w. All the prepared systems exhibited a controlled release behavior with Q12?h ranging between 5.46 and 95.90%w/w. The optimized VP-loaded system composed of 150?mg (1.5% w/v) PCL without Eudragit RS100 together with 160?mg VP showed 2.7-folds mean residence time compared to the market product allowing once daily administration instead of three times per day.     

Zero-order release and bioavailability enhancement of poorly water soluble Vinpocetine from self-nanoemulsifying osmotic pump tablet

Abstract

Solid self-nanoemulsifying (S-SNEDDS) asymmetrically coated osmotic tablets of the poorly water-soluble drug Vinpocetine (VNP) were designed. The aim was to control the release of VNP by the osmotic technology taking advantage of the solubility and bioavailability-enhancing capacity of S-SNEDDS. Liquid SNEDDS loaded with 2.5?mg VNP composed of Maisine? 35-1, Transcutol^® HP, and Cremophor^® EL was adsorbed on the solid carrier Aeroperl^®. S-SNEDDS was mixed with the osmotic tablet excipients (sodium chloride, Avicel^®, HPMC-K4M, PVP-K30, and Lubripharm^®), then directly compressed to form the core tablet. The tablets were dip coated and mechanically drilled. A 3²*2¹ full factorial design was adopted. The independent variables were: type of coating material (X₁), concentration of coating solution (X₂), and number of drills (X₃). The dependent variables included % release at 2?h (Y₁), at 4?h (Y₂), and at 8?h (Y₃). The in vivo performance of the optimum formula was assessed in rabbits. Zero-order VNP release was obtained by the single drilled 1.5% Opadry^® CA coated osmotic tablets and twofold increase in VNP bioavailability was achieved. The combination of SNEDDS and osmotic pump tablet system was successful in enhancing the solubility and absorption of VNP as well as controlling its release.     

Dissolution stability studies of suspensions of prolonged-release diclofenac microcapsules prepared by the Wurster process: I. Eudragit-based formulation and possible drug-excipient interaction

The aim was to evaluate possible interaction in solid and liquid state of the drug with formulation excipients consequent to very fast drug release of diclofenac-Eudragit® prolonged release microcapsules. The microcapsules were prepared by drug layering on calcium carbonate cores and coated with Eudragit® RS 30D and L30D-55 as previously reported. Suspension of the microcapsules was prepared using microcrystalline cellulose/sodium carboxymethyl cellulose (Avicel® CL-611) as medium. In vitro dissolution testing of the suspension was done, and, based on the dissolution results, possible interaction between diclofenac and Eudragit and Avicel in the medium was studied. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) analyses were performed using 1:1 binary, 1:1:1 ternary mixtures and a ratio equivalent to that in the formulation. The mixtures were prepared by mixing the dispersions—Eudragit RS 30D or L30D-55 with the drug or other components, followed by drying at 60°C for 48?h. Dry mixing was done using the powder equivalents of the polymers, Eudragit RS PO and L100-55, Avicel and calcium carbonate. In vitro dissolution of the suspended microcapsules showed a very fast release after 48?h (T₅₀?=?<1?h) compared to the solid microcapsules (T₅₀?=?6?h). DSC curves of the formulation components or microcapsules did not show the characteristic endothermic peak of diclofenac at 287°C. Powder X-ray diffraction of the binary or ternary mixtures of diclofenac and Eudragit polymers indicated reduction, shift or modification of the crystalline peaks of the drug or excipients at 2θ of 12° and 18°, suggestive of interaction. Some changes in drug peak characteristics at 18° and 23° were observed for Avicel/drug mixture, though not significant. The DSC curves of the binary mixture of diclofenac co-dried with liquid forms of Eudragit (i.e. RS 30D or L30D-55) revealed greater interaction compared to the curves of drug and powdered forms of Eudragit (RS PO or L100-55). This was depicted by greater shift in fusion points of the mixtures relative to the drug. However, comparing the RS and L-type Eudragit, the latter generally showed greater interaction with the drug. Interaction between diclofenac and L-type Eudragit polymers can occur in liquid formulations.     

Development and characterization of colon specific drug delivery system bearing 5-ASA and camylofine dihydrochloride for the treatment of ulcerative colitis

The treatment of ulcerative colitis (inflammatory bowel disease, IBD) has been achieved by using colon specific drug delivery system bearing 5-ASA and Camylofine dihydrochloride. Chitosan microspheres were prepared separately for both the drugs using emulsion method followed by enteric coating with Eudragit^®S-100. The in vitro drug release was investigated in different simulated GIT medium. The drug release in PBS (pH7.4) and simulated gastric fluid has shown almost similar pattern and rate, whereas a significant increase in drug release (70.3?±?1.36 and 72.5?±?1.33% of 5-ASA and Camylofine, respectively) was observed in medium containing 3% rat caecal matter, after 24?h. In control study, 57.1?±?1.13% of 5-ASA and 59.2?±?1.2% of Camylofine release was observed in 24?h. For enzyme induction, rats were orally administered with 1?mL of 1% w/v dispersion of chitosan for 5 days and release rate studies were conducted in SCF with 3% w/v of caecal matter. An enhanced drug release (i.e., 92.3?±?3.81 and 95.5?±?3.52% 5-ASA and Camylofine, respectively) was observed after 24?h in dissolution medium containing 3% caecal content obtained from enzyme induced animals. In vivo data showed that microspheres delivered most of its drug load (76.55?±?2.13%) to the colon after 9?h, which reflects its targeting potential to the colon. It is concluded that orally administered microspheres of both drugs can be used together for the specific delivery of drug to the colon and reduce symptoms of ulcerative colitis.     

Eudragit®: a technology evaluation

Introduction: Eudragit is the brand name for a diverse range of polymethacrylate-based copolymers. It includes anionic, cationic, and neutral copolymers based on methacrylic acid and methacrylic/acrylic esters or their derivatives.

Areas covered: In this review, the physicochemical characteristics and applications of different grades of Eudragit in colon-specific/enteric-coated/sustained release drug delivery and taste masking have been addressed.

Expert opinion: Eudragits are amorphous polymers having glass transition temperatures between 9 to > 150^oC. Eudragits are non-biodegradable, nonabsorbable, and nontoxic. Anionic Eudragit L dissolves at pH > 6 and is used for enteric coating, while Eudragit S, soluble at pH > 7 is used for colon targeting. Studies in human volunteers have confirmed that pH drops from 7.0 at terminal ileum to 6.0 at ascending colon, and Eudragit S based systems sometimes fail to release the drug. To overcome the shortcoming, combination of Eudragit S and Eudragit L which ensures drug release at pH < 7 has been advocated. Eudragit RL and RS, having quaternary ammonium groups, are water insoluble, but swellable/permeable polymers which are suitable for the sustained release film coating applications. Cationic Eudragit E, insoluble at pH ≥ 5, can prevent drug release in saliva and finds application in taste masking.     

The use of response surface methodology for the formulation and optimization of salbutamol sulfate hydrophilic matrix sustained release tablets

The objective of this study was to develop a hydrophilic matrix formulation with in vitro release characteristics similar to Asthalin^® tablets and that would sustain the release of salbutamol sulfate over a 12-h period. A central composite design was used as the framework for manufacturing formulations that may be used to understand the relationships between polymer levels and in vitro release characteristics. Tablets were manufactured using wet granulation with Surelease^® as the granulating fluid and different levels of Methocel^® K100M, xanthan gum, and Carbopol^® 974P as matrix-forming materials. In vitro dissolution testing was conducted using USP Apparatus 3 and samples were analyzed using a validated reversed-phase HPLC method. The results revealed that the levels and types of polymers had a significant impact on the rate of drug release from these formulations and that it was possible to optimize the levels of matrix-forming polymers to achieve the desired release characteristics. Statistical design and response surface methodology have been successfully used to understand and optimize formulation factors and interactions that impact the in vitro release characteristics of salbutamol sulfate from a potential multisource sustained release dosage form.     

Emodin inhibits ATP-induced IL-1β secretion,ROS production and phagocytosis attenuation in rat peritoneal macrophages via antagonizing P2X7 receptor

Context: Previous in vitro studies have demonstrated that emodin (1,3,8-trihydroxy-6-methyl-anthraquinone), an anthraquinone derivative from the rhizome of Rheum palmatum L., can inhibit the activation of P2X₇ receptors (P2X₇R) as a potential antagonist. However, the effects of emodin on P2X₇R-related inflammatory processes remain unclear.

Objective: This study aimed to investigate the effects of emodin on different inflammation responses of macrophages induced by ATP, the natural ligand of P2X₇R.

Materials and methods: Rat peritoneal macrophages were treated with millimolar ATP and emodin (0.1, 0.3,?1,?3,?10?µM) or brilliant blue G (BBG, 0.1,?1,?10?µM). Cytosolic Ca²⁺ concentration ([Ca²⁺]_c) was detected by fluorescent Ca²⁺ imaging. Interleukin-1β (IL-1β) release was measured by rat IL-1β ELISA kits. Reactive oxygen species (ROS) generation was examined by dihydroethidium (DHE) fluorescent staining. Phagocytic activity was tested by neutral red uptake assay.

Results: We found that the [Ca²⁺]_c increase evoked by ATP (5?mM) was inhibited by emodin, in a dose-dependent manner with IC₅₀ of 0.5?μM. Furthermore, emodin reduced the IL-1β release induced by ATP (2?mM) in lipopolysaccharide (LPS)-activated macrophages, with an IC₅₀ of 1.6?μM. Emodin also strongly suppressed the ROS production and phagocytosis attenuation triggered by ATP (1?mM), with IC₅₀ values of 1?μM and 0.7?μM, respectively. Besides, BBG, a specific antagonist of P2X₇R, exhibited similar suppressive effects on these inflammation responses.

Conclusion: These results showed the inhibitory effects of emodin on ATP-induced [Ca²⁺]_c increase, IL-1β release, ROS production and phagocytosis attenuation in rat peritoneal macrophages, by inhibiting the activation of P2X₇R.     

星点设计法优化盐酸小檗碱树脂复合胃黏附给药系统的研究

本文以离子交换树脂(IER)作为载体吸附盐酸小檗碱，通过包衣将其制成胃黏附微囊，并以胃黏附微囊的载药量，胃滞留时间和体外释药时间作为评价指标，对处方进行优化。考察不同型号载体与不同浓度、温度和pH值的药物溶液对IER载药量的影响；以卡伯姆934与IER的比例(X₁)、丙烯酸树脂(Eudragit)与IER的比例(X₂)、Eudragit RL与Eudragit RS的比例(X₃)为自变量，以制剂累计释放量85%的时间点(Y₁)、制剂在大鼠胃体外黏附滞留百分比(Y₂)为因变量，通过星点设计—效应面法优化胃黏附包衣处方。优化后载药工艺为在37 ℃、pH 5左右条件下，用IRP88离子交换树脂对1.0 mg·mL^-1盐酸小檗碱溶液载药；优化后的包衣液组成为X₁=0.75、 X₂=0.9、 X₃=0.6，所得制剂单位质量载药量高，可在300 min左右达到累计释放总量的85%，同时在所设计条件范围内胃黏附作用最强。     

Comparison of novel granulated pellet-containing tablets and traditional pellet-containing tablets by artificial neural networks

Abstract

Novel granulated pellets technique was adopted to prepare granulated pellet-containing tablets (GPCT). GPCT and traditional pellet-containing tablets (PCT) were prepared according to 29 formulations devised by the Design Expert 7.0, with doxycycline hydrochloride as model drug, blends of Eudragit FS 30D and Eudragit L 30D-55 as coating materials, for the comparison study to confirm the superiority of GPCT during compaction. Eudragit FS 30D content, coating weight gain, tablet hardness and pellet size were chosen as influential factors to investigate the properties and drug release behavior of tablets. The correlation coefficients between the experimental values and the predicted values by artificial neural networks (ANNs) for PCT and GPCT were 0.9474 and 0.9843, respectively, indicating the excellent prediction of ANNs. The similarity factors (f₂) for release profiles of GPCT and the corresponding original pellets were higher than those of PCT, suggesting that the excipient layer of granulated pellets absorbed the compressing force and protected the integrity of coating films during compaction.     

Design,in vitro release characterization and pharmacokinetics of novel controlled release pellets containing levodropropizine

Abstract

This study was performed to investigate the in vitro release characteristics of levodropropizine (LDP) from novel dual-coated sustained release (SR) pellets, and evaluate the pharmacokinetics of a novel controlled release (CR) preparation composed of the dual-coated SR pellets and immediate release (IR) LDP pellets. The dual-coated SR pellets composed of a drug-loaded nonpareil core, a sub-coating layer (HPMC 6cps) and an SR-coating layer (Aquacoat® ECD, Eudragit® RS 30D or Kollicoat® SR 30D) were prepared by a bottom-spray fluidized bed-coating method. The drug release from the dual-coated SR pellets coated with Aquacoat® ECD followed a zero-order profile in water, and the drug release was not affected by the coating level of the sub-coating layer and stable under the accelerated storage condition (40?°C, 75% RH) for 6 months. The CR preparation showed significantly decreased values of maximum drug concentration (C_max) and elimination rate (K) than the reference product (LEVOTUS® SYR) but the similar bioavailability (F?=?95.43%). The novel CR preparation presents promising delivery of LDP with an immediate and sustained release manner, with similar clinical effect as the commercial IR product.     

Formulation and in vitro evaluation of a PEGylated microscopic lipospheres delivery system for ceftriaxone sodium

The aim of this study was to formulate and evaluate in vitro, ceftriaxone sodium lipospheres dispersions for oral administration. Ceftriaxone sodium lipospheres were prepared by melt-emulsification using 30%w/w Phospholipon^® 90H in Softisan^® 154 as the lipid matrix containing increasing quantities of PEG 4000 (10, 20, 30, and 40%w/w). Characterization based on particle size, particle morphology, encapsulation efficiency, loading capacity and pH were carried out on the lipospheres. Microbiological studies of the ceftriaxone sodium-loaded lipospheres were performed using Escherichia coli as the model organism. In vitro permeation of ceftriaxone sodium from the lipospheres through artificial membrane (0.22?μm pore size) was carried out using Franz cell and simulated intestinal fluid (SIF) without pancreatin as acceptor medium. Photomicrographs revealed spherical particles within a micrometer range with minimal growth after 1 month (Maximum size?=?64.76?±?3.81?μm). Microbiological studies indicated that lipospheres formulated with 20%w/w of PEG 4000 containing 2%w/w or 3%w/w of ceftriaxone sodium gave significantly (p?<?0.05) higher inhibition zone diameter than those with 30%w/w or 40%w/w of PEG 4000. The result also indicated that lipospheres with 10%w/w PEG 4000 resulted in significantly higher encapsulation efficiency (p?<?0.05) while those with 30%w/w gave the least, while the loading capacity values ranged from 3.22?mg of ceftriaxone sodium/100?mg of lipid to 6.36?mg of ceftriaxone sodium/100?mg of lipid. Permeation coefficient values varied and ranged from 8.55?×?10^?7 cm/s to 2.08?×?10^?6 cm/s depending on the concentration of PEG 4000. The result of this study gave insight that the issue of ceftriaxone stability in oral formulation could be adequately addressed by tactical engineering of lipid drug delivery systems such as lipospheres.     

Formulation and optimization of nanoemulsion using antifungal lipid and surfactant for accentuated topical delivery of Amphotericin B

The objective of the study was to develop, optimize and evaluate a nanoemulsion (NE) of Amphotericin B (AmB) using excipients with inherent antifungal activities (Candida albicans and Aspergillus niger) for topical delivery. AmB-loaded NE was prepared using Capmul PG8 (CPG8), labrasol and polyethylene glycol-400 by spontaneous titration method and evaluated for mean particle size, polydispersity index, zeta potential and zone of inhibition (ZOI). NE6 composed of CPG8 (15%w/w), S_mix (24%w/w) and water (61%w/w) was finally selected as optimized NE. AmB-NE6 was studied for improved in vitro release, ex vivo skin permeation and deposition using the Franz diffusion cell across the rat skin followed with drug penetration using confocal laser scanning microscopy (CLSM) as compared to drug solution (DS) and commercial Fungisome^®. The results of in vitro studies exhibited the maximum ZOI value of NE6 as 19.1?±?1.4 and 22.8?±?2.0?mm against A. niger and C. albicans, respectively, along with desired globular size (49.5?±?1.5?nm), zeta potential (?24.59?mV) and spherical morphology. AmB-NE6 revealed slow and sustained release of AmB as compared to DS in buffer solution (pH 7.4). Furthermore, AmB-NE6 elicited the highest flux rate (22.88?±?1.7?μg/cm²/h) as compared to DS (2.7?±?0.02?μg/cm²/h) and Fungisome^® (11.5?±?1.0?μg/cm²/h). Moreover, the enhancement ratio and drug deposition were found to be highest in AmB-NE6 than DS across the stratum corneum barrier. Finally, CLSM results corroborated enhanced penetration of the AmB-NE6 across the skin as compared to Fungisome^® and DS suggesting an efficient, stable and sustained topical delivery.     

Lipid Based nanoformulation of lycopene improves oral delivery: formulation optimization,ex vivo assessment and its efficacy against breast cancer

This study aims at developing an optimised nanostructured lipid carrier (NLC) of lycopene for efficient absorption following oral administration. The optimised formulation showed an average particle size of 121.9?±?3.66?nm, polydispersity index (PDI) 0.370?±?0.97 and zeta potential ?29.0?±?0.83?mV. Encapsulation Efficiency (% EE) and drug loading (% DL) was found to be 84.50%?±?4.38 and 9.54%?±?2.65, respectively. In vitro release studies demonstrated the burst release within 4–9?h followed by sustained release over 48?h. The IC₅₀ value of lycopene extract and optimised NLC for ABTS^+? were found to be 172.37?μg Trolox equivalent and 184.17?μg Trolox equivalent whereas, for DPPH^?, 117.76?μg Trolox equivalent and 143.08?μg Trolox equivalent respectively. Ex vivo studies and MTT assay revealed that the NLC had better permeation and cause sufficiently more cytotoxicity as compared to drug extract due to higher bioavailability and greater penetration.     

Development and in Vitro-in Vivo Evaluation of a Multiparticulate Sustained Release Formulation of Diltiazem

Purpose. To develop and evaluate the in vitro/in vivo performance of diltiazem sustained release pellets that were prepared by the Wurster column process. Methods. Pellets containing diltiazem were prepared by spraying a slurry of micronized diltiazem hydrochloride, pharmaceutical glaze and alcohol onto an appropriate mesh fraction of nonpareil seeds using the Wurster column. A two-step drug layering process was used to increase drug loading from 60% to 75%. The oven-dried diltiazem basic pellets were coated with eth-ylcellulose/dibutyl sebacate coating solution to yield diltiazem sustained release pellets. An open, randomized Latin square, three-way crossover clinical study was used to evaluate the in vivo performance of the coated product. Results. Altering the mesh fraction of the starting nonpareil seeds for this layering process was found to affect the release characteristics of drug from the pellets. An oven-drying step was required to stabilize the diltiazem basic pellets. The thicker the drug loading layer the longer the oven drying is needed to stabilize the pellets. The diltiazem sustained release pellets produced by these methods displayed sustained release dissolution profiles both in vitro and in vivo. Diltiazem basic pellets coated with a 0.6% ethylcellulose/dibutyl sebacate coating showed a different rate of absorption (lower C _max and higherT _max) and the same extent of absorption as compared to Cardizem^® tablets. Conclusions. Clinical data confirmed that this formulation approach is an effective means to produce a diltiazem sustained release product.