Fabrication of long-acting insulin formulation based on poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) nanoparticles: preparation,optimization, characterization,and in vitro evaluation

The purpose of this research was the fabrication, statistical optimization, and in vitro characterization of insulin-loaded poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) nanoparticles (INS-PHBV-NPs). Nanopar-ticles were successfully developed by double emulsification solvent evaporation method. The NPs were characterized for particle size, entrapment efficiency (EE%), and polydispersity index (PDI). The NPs also were characterized by scanning electron microscopy (SEM), Fourier transformed infrared spectroscopy (FTIR), X-ray diffraction (XRD), differential scanning calorimetry (DSC), and circular dichroism (CD). The optimum conditions were found to be 1.6% polyvinyl alcohol (PVA), 0.9% of PHBV, and 15?mg/ml of insulin with the aid of the Box–Behnken experimental design results. The optimized NPs showed spherical shape with particle size of 250.21?±?11.37?nm, PDI of 0.12?±?0.01, and with EE% of 90.12?±?2.10%. In vitro drug release pattern followed Korsmeyer–Peppas model and exhibited an initial burst release of 19% with extended drug release of 63.2% from optimized NPs within 27?d. In conclusion, these results suggest that INS-PHBV-NPs could be a promising candidate for designing an injectable sustained release formulation for insulin.     

Polymeric ethosomal gel loaded with nimodipine: Optimisation,pharmacokinetic and histopathological analysis

This study was performed with the main objective of formulating and evaluating the potential of ethosomesl gel (Etho gel) to deliver nimodipine (NiM) for cardiovascular disease, a potent water insoluble anti-hypertensive drug via skin to reach the deeper layers of skin. The Box-Behnken design (BBD) was used to optimize the NiM-Eth to determine the impact of the independent and depended variables. The effectiveness of drug entrapment, vesicle size, and cumulative drug release were assessed for the NiM loaded ethosomes and NiM-Eth gel using carbopol 934 as a gelling agent. Fourier transform infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC), Power X-ray diffraction (PXRD), and scanning electron microscopy (SEM) analysis were performed and analysed their physicochemical characters. Rat abdomen skin was used to investigate drug permeability and deposition. As compared to marketed products, NiM-Eth gel produced an improved drug permeability in ex vivo experiments. The mean AUC₀ to AUC_0-∞ of NiM-Eth gel when compared to oral formulation (Nymalize oral preparation) was found to be increased from 4.1 to 5.9 folds which was found to be resulted from first pass effect. Histophatlogical findings revealed that the maximum amount of NiM penetrated the stratum corneum of the skin and create drug depots in the deep layer. In summary, it can be said that NiM might be successfully prepared in NiM-Eth gel for transdermal drug 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.     

Application of quality by design (QbD) to formulation and processing of naproxen pellets by extrusion–spheronization

Abstract

The aim of this research was to apply quality by design (QbD) to the development of naproxen loaded core pellets which can be used as the potential core for colon-specific pellets. In the early stages of this study, prior knowledge and preliminary studies were systematically incorporated into the risk assessment using failure mode and effect analysis (FMEA) and fishbone diagram. Then Plackett–Burman design was used to screen eight potential high risk factors (spheronization speed, spheronization time, extrusion speed, drying method, CCMC-Na concentration, lactose concentration, water concentration and Tween 80 concentration) obtained from the above risk assessment. It was discovered that out of the eight potential high risk factors only three factors (spheronization speed, extrusion speed and CCMC-Na concentration) had significant effects on the quality of the pellets. This allowed the use of Box–Behnken design (BBD) to fully elucidate the relationship between the variables and critical quality attribute (CQA). Finally, the final control space was established within which the quality of the pellets can meet the requirement of colon-specific drug delivery system. This study demonstrated that naproxen loaded core pellets were successfully designed using QbD principle.     

PLGA nanoparticles for intravitreal peptide delivery: statistical optimization,characterization and toxicity evaluation

Abstract

Frequent intravitreal injections are currently used to overcome the ocular barriers and provide sufficient drug to the posterior eye segment. However, intravitreal injections have been associated with a number of complications and high treatment costs. To overcome these limitations, peptide-loaded poly(d,l-lactic-co-glycolic acid) nanoparticles (PLGA NPs) were developed using the nanoprecipitation technique and were optimized via Box–Behnken Design (BBD) and Response Surface Methodology (RSM). Developed NPs were evaluated for potential toxicity and cell apoptosis using the zebrafish embryo toxicity (ZET) model with titanium dioxide NPs and ethanol (1% v/v) serving as positive controls. Developed NPs had a size of 75.6–153.8?nm, a polydispersity index between 0.11 and 0.25 and a zeta potential of ?9.4 to ?46.0?mV. Loaded peptide was found to be stable under various experimental conditions tested. BBD and RSM were validated through the characterization of optimized formulations. Survival and hatching rates of NP-treated zebrafish 0–144?h post-fertilization were found to be normal with no significant malformations. Cellular apoptosis studies also endorsed the non-cytotoxic nature of the NPs. The overall results indicate that optimized PLGA nanoparticles could be a promising platform for efficient peptide delivery to the posterior segment of the eye.     

A quality by design (QbD) case study on enteric-coated pellets: Screening of critical variables and establishment of design space at laboratory scale

The study aims to prepare naproxen enteric-coated pellets (NAP-ECPs) by fluid-bed coating using QbD principle. Risk assessment was firstly performed by using failure mode and effect analysis (FMEA) methodology. A Plackett–Burman design was then used for assessment of the most important variables affecting enteric-coated pellets characteristics. A Box–Behnken design was subsequently used for investigating the main, interactive, and quadratic effects of these variables on the response. By FMEA we discovered that eight factors should be considered to be high/important risk variables as compared with others. The responses of acid resistance and cumulative drug release were taken as critical quality attributes (CQAs). Pareto ranking analyses indicated that the coating weight gain (X₇), triethyl citrate percentage (X₁) and glycerol monostearate percentage (X₂) were the most significant factors affecting the selected responses out of the eight high-risk variables. Optimization with response surface method (RSM) further fully clarified the relationship between X₇, X₁, X₂ and CQAs, and design space was established based on the constraints set on the responses. Due to the extreme coincidence of the predicted value generated by model with the observed value, the accuracy and robustness of the model were confirmed. It could be concluded that a promising NAP-ECPs was successfully designed using QbD approach in a laboratory scale.     

Improved pharmacokinetics and antihyperlipidemic efficacy of rosuvastatin-loaded nanostructured lipid carriers

In the present study, rosuvastatin calcium-loaded nanostructured lipid carriers were developed and optimized for improved efficacy. The ROS-Ca-loaded NLC was prepared using melt emulsification ultrasonication technique and optimized by Box–Behnken statistical design. The optimized NLC composed of glyceryl monostearate (solid lipid) and capmul MCM EP (liquid lipid) as lipid phase (3% w/v), poloxamer 188 (1%) and tween 80 (1%) as surfactant. The mean particle size, polydispersity index (PDI), zeta potential (ζ) and entrapment efficiency (%) of optimized NLC formulation was observed to be 150.3?±?4.67?nm, 0.175?±?0.022, ?32.9?±?1.36?mV and 84.95?±?5.63%, respectively. NLC formulation showed better in vitro release in simulated intestinal fluid (pH 6.8) than API suspension. Confocal laser scanning showed deeper permeation of formulation across rat intestine compared to rhodamine B dye solution. Pharmacokinetic study on female albino Wistar rats showed 5.4-fold increase in relative bioavailability with NLC compared to API suspension. Optimized NLC formulation also showed significant (p?<?0.01) lipid lowering effect in hyperlipidemic rats. Therefore, NLC represents a great potential for improved efficacy of ROS-Ca after oral administration.     

Formulation and evaluation of anti-rheumatic dexibuprofen transdermal patches: a quality-by-design approach

Dexibuprofen (DXIBN) transdermal patches were formulated using various concentrations of selected polymeric excipients (matrix material; ethyl cellulose and polyvinylpyrrolidone, plasticizer (di-N-butyl phthalate), and a conventional permeation enhancer (almond oil)). Initial patch formulations were evaluated for their physiochemical properties (thickness, moisture uptake, final moisture content, and DXIBN content). Also, impact of patch components on resulting tensile strength and in vitro permeation were used to predict an optimal patch formulation using a quality-by-design (QbD) approach, which was subsequently evaluated and further compared with a commercial oral tablet dosage form for in vitro and in vivo release (rabbit model). Initially formulated patches demonstrated uniform thickness (0.44?±?0.02?cm), relatively low moisture uptake (7.87?±?1.11 w/w %), and highly acceptable drug loading values (100.0?±?0.026%). The tensile strength of patches increased significantly with matrix polymer concentration and to a lesser degree with increase in plasticizer and permeation enhancer content, although these affected the permeation of DXIBN. Predicted properties (tensile strength and DXIBN steady-state flux) for the QbD-optimized formulation were in close agreement to experimental results. The QbD optimal patch formulation behavior differed significantly from the commercial tablet formulation in vivo. Such model-based predictions (QbD approach) will reduce cost and time in formulation development sciences.     

Multiple response optimisation of processing and formulation parameters of pH sensitive sustained release pellets of capecitabine for targeting colon

Purpose: To optimise the Eudragit/Surelease^®-coated pH-sensitive pellets for controlled and target drug delivery to the colon tissue and to avoid frequent high dosing and associated side effects which restrict its use in the colorectal-cancer therapy.

Methods: The pellets were prepared using extrusion-spheronisation technique. Box–Behnken and 3² full factorial designs were applied to optimise the process parameters [extruder sieve size, spheroniser-speed, and spheroniser-time] and the coating levels [%w/v of Eudragit S100/Eudragit-L100 and Surelease^®], respectively, to achieve the smooth optimised size pellets with sustained drug delivery without prior drug release in upper gastrointestinal tract (GIT).

Results: The design proposed the optimised batch by selecting independent variables at; extruder sieve size (X₁?=?1?mm), spheroniser speed (X₂?=?900 revolutions per minute, rpm), and spheroniser time (X₃?=?15?min) to achieve pellet size of 0.96?mm, aspect ratio of 0.98, and roundness 97.42%. The 16%w/v coating strength of Surelease^® and 13%w/v coating strength of Eudragit showed pH-dependent sustained release up to 22.35?h (t_99%). The organ distribution study showed the absence of the drug in the upper part of GIT tissue and the presence of high level of capecitabine in the caecum and colon tissue. Thus, the presence of Eudragit coat prevent the release of drug in stomach and the inner Surelease^® coat showed sustained drug release in the colon tissue.

Conclusion: The study demonstrates the potential of optimised Eudragit/Surelease^®-coated capecitabine-pellets for effective colon-targeted delivery system to avoid frequent high dosing and associated systemic side effects of drug.     

Catechin-loaded Eudragit microparticles for the management of diabetes: formulation,characterization and in vivo evaluation of antidiabetic efficacy

Catechin (CT) is natural molecule proved for antidiabetic activity. Clinical application of CT is highly restricted because of its low bioavailability and ineffectiveness in in vivo conditions. Therefore, the main objective of the present investigation was to formulate CT-loaded Eudragit RS 100 microparticles and evaluated for its potential against diabetes. CT microparticles showing highest entrapment efficiency of 92.3?±?6.5% and higher percentage yield of 63.46?±?4.3% was selected as optimised formulation. CT microparticles treated rats showed significantly lower blood glucose, cholesterol, LDL, free fatty acid and triglyceride concentrations in comparison to pristine CT-treated rats. The glucose and lipid profiles of microparticle formulation were akin to normal rats. Moreover, CT microparticles did not produce obesity even after 60 days which is a comment side effect of antidiabetic drugs. These results indicate that the CT microparticles can be applied as potential and safe carrier for the treatment of diabetes.     

Curcumin-phospholipid complex: Preparation, therapeutic evaluation and pharmacokinetic study in rats

A novel formulation of curcumin in combination with the phospholipids was developed to overcome the limitation of absorption and to investigate the protective effect of curcumin–phospholipid complex on carbon tetrachloride induced acute liver damage in rats. The antioxidant activity of curcumin–phospholipid complex (equivalent of curcumin 100 and 200 mg/kg body weight) and free curcumin (100 and 200 mg/kg body weight) was evaluated by measuring various enzymes in oxidative stress condition. Curcumin–phospholipid complex significantly protected the liver by restoring the enzyme levels of liver glutathione system and that of superoxide dismutase, catalase and thiobarbituric acid reactive substances with respect to carbon tetrachloride treated group (P < 0.05 and <0.01). The complex provided better protection to rat liver than free curcumin at same doses. Serum concentration of curcumin obtained from the complex (equivalent to 1.0 g/kg of curcumin) was higher (C_max 1.2 μg/ml) than pure curcumin (1.0 g/kg) (C_max 0.5 μg/ml) and the complex maintained effective concentration of curcumin for a longer period of time in rat serum. The result proved that curcumin–phospholipid complex has better hepatoprotective activity, owe to its superior antioxidant property, than free curcumin at the same dose level.     

Box-Behnken试验设计优选淫羊藿饮片中淫羊藿苷及总黄酮提取工艺

摘 要 目的： 建立淫羊藿饮片醇提生产工艺。方法: 采用Box Behnken试验设计结合效应面法对各工艺参数进行优选,HPLC色谱法和紫外可见分光光度法联合定量评价。结果: 淫羊藿生产最佳提取工艺为：加入15倍量70%乙醇,提取150 min。结论: Box Behnken试验设计适合对因素的水平范围进行合理筛选,该工艺稳定,可行性强。     

Long circulation nanostructured lipid carriers for gambogenic acid: formulation design,characterization, and pharmacokinetic

1.?GNA-PEG-NLC and GNA-NLC were prepared by emulsification and low-temperature solidification methods. The optimized GNA-PEG-NLC and GNA-NLC were not only found to have small mean size (146.33?±?2.11 and 144.07?±?1.44) nm, high Zeta potential (?25.10?±?1.35 and ?28.03?±?0.29) mV, but also great entrapment efficiency (79.07?±?1.11 and 84.65?±?0.98%). TEM proved that particles were nearly spherical with smooth surface shape. Furthermore, in vitro release revealed a burst release initially, followed by a sustained profiles up to 48?h, and the cumulative drug release of GNA-PEG-NLC and GNA-NLC was 65.90?±?2.34% and 69.25?±?1.77%, respectively.

2.?In pharmacokinetic, GNA-PEG-NLC exhibited prolonged MRT and higher AUC values compared with GNA-NLC and GNA solution. Moreover, the tissue distribution demonstrated a high uptake of GNA-PEG-NLC in stomach.

3.?These results indicated that PEG-NLC is a promising delivery system for GNA, which could prolong drug circulation time in body and thus improved its bioavailability.     

Preparation,statistical optimisation and in vitro characterisation of poly (3-hydroxybutyrate-co-3-hydroxyvalerate)/poly (lactic-co-glycolic acid) blend nanoparticles for prolonged delivery of teriparatide

The purpose of this study was the preparation, optimisation and in vitro characterisation of PHBV and PLGA blend nanoparticles (NPs) for prolonged delivery of Teriparatide. Double emulsion solvent evaporation technique was employed for the fabrication of NPs. The nanoformulation was optimised using the Box–Behnken methodology. The morphological properties of NPs were assessed by both SEM and transmission electron microscopy (TEM). Encapsulation of Teriparatide within the NPs and lacking of chemical bonds between drug and copolymers were proved by XRPD, FTIR and DSC. The structural stability of Teriparatide after processing was confirmed by fluorescence spectrometry. The average size of optimised NPs was 250.0?nm with entrapment efficiency (EE) of 89.5% and drug loading (DL) of 5.0%. Teriparatide release from optimised NPs led to 64.4% release over 30 days and it showed a diffusion-based mechanism. Based on the favourable results, PHBV/PLGA blend NPs could be a promising candidate for designing a controlled release formulation of Teriparatide.     

Preparation,characterization and anticancer therapeutic efficacy of cisplatin-loaded niosomes

This study developed a carrier for anticancer drug, cisplatin. Cisplatin-loaded niosomes (CP-NMs) were prepared under optimized conditions with Span 40 and cholesterol as the excipients, and then lyophilized and characterized. Their anticancer efficacy was tested in rabbits bearing VX2 sarcoma. The obtained spherical-looking vesicles showed a diameter of 7.73?±?1.49?µm with a zeta-potential of 0?mV. The entrapment efficiency was 76.93?±?2.67%, and drug loading 2.96?±?0.10%. In vitro release tests gave a t_50% of 8.36?h. The rabbits locally injected with the CP-NMs gave significantly superior results of inhibition of tumour growth, much lower mortality and improved results of body weight change and inhibition of tumour metastasis to inguinal lymph nodes and liver compared to those treated in the same way with the drug solution. The inspiring anticancer results indicated that the CP-NMs might be developed as an effective anticancer preparation with low toxicity.     

Aprotinin revisited: formulation,characterization, biodistribution and therapeutic potential of new aprotinin microemulsion in acute pancreatitis

The aim of this study was to develop aprotinin-loaded microemulsion (M_A) for intravenous administration and evaluate the biodistribution and therapeutic potential of developed formulation in acute pancreatitis models in rats. Phase diagrams were constructed to identify microemulsion region and the optimal microemulsion was evaluated for physicochemical properties and treatment effect in rats, and comparisons made with the solution of aprotinin (S_A). To evaluate the biodistribution of the drug by gamma scintigraphy aprotinin was radiolabeled with ^99mTc radionuclide. Mild and severe acute pancreatitis was induced in rats by subcutaneous injections of cerulein and introductal infusion of 3% sodium taurocholate into the bile-pancreatic duct, respectively. In addition, serum amylase and pancreatic tissue myeloperoxidase activities were measured to evaluate the pancreatic damage. According to gamma scintigraphy and biodistribution studies, accumulation times and distribution of ^99mTc-M_A and S_A were different. While M_A was highly uptake by reticuloendothelial system, S_A was mostly excreted by kidneys and bladder. Compared with the mild acute pancreatitis group, treatment with M_A significantly decreased the serum amylase activity and pancreas myeloperoxidase activity. Furthermore, the protease inhibitor molecule aprotinin has therapeutic potential in acute pancreatitis. Finally, M_A may be suggested as a promising alternative for treatment of acute pancreatitis.     

Lofepramine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness

Lofepramine is a tricyclic antidepressant that is structurally similar to imipramine and is extensively metabolised to desipramine. In the absence of other major pharmacological effects it appears that its antidepressant activity stems from the facilitation of noradrenergic neurotransmission by uptake inhibition, and possibly by the additional facilitation of serotoninergic neurotransmission. The overall therapeutic efficacy of lofepramine is comparable to that of imipramine, amitriptyline, clomipramine, maprotiline and mianserin in patients with depression of varying severity, and coexisting anxiety. Dry mouth is the most commonly reported side effect of usual therapeutic doses of lofepramine, but the incidence of this and other anticholinergic side effects is less among patients treated with lofepramine than with imipramine. Lofepramine has not been associated with adverse effects on cardiac function even in cases of attempted suicide by overdose. Thus, providing its apparent favourable side effect profile is confirmed in practice, lofepramine may be a valuable alternative for treatment of the depressed patient where a tricyclic is indicated.     

Fluvoxamine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness

Fluvoxamine is a new antidepressant which potently and specifically inhibits neuronal reuptake of serotonin. In the absence of other major pharmacological effects it appears that its antidepressant activity stems from facilitation of serotoninergic neurotransmission as a result of reuptake inhibition. Studies suggest that fluvoxamine has overall therapeutic efficacy comparable with that of imipramine and clomipramine in depressive illness. It causes fewer anticholinergic-type and cardiovascular side effects than the tricyclic antidepressants but it is associated with a higher incidence of nausea and vomiting. Elderly patients also respond well to fluvoxamine. Studies are now required to compare fluvoxamine with other second generation antidepressants and to establish whether some types of depressive illness respond more readily to fluvoxamine than other agents. Thus, in patients with depressive illness, fluvoxamine offers a suitable alternative to tricyclic antidepressants and may be especially valuable in patients with concomitant cardiovascular disease, and those unresponsive to or unable to tolerate tricyclic antidepressants.