Intranasal delivery of Clozapine using nanoemulsion-based in-situ gels: An approach for bioavailability enhancement

Limited solubility and hepatic first-pass metabolism are the main causes of low bioavailability of anti-schizophrenic drug, Clozapine (CZP). The objective of the study was to develop and validate nanoemulsion (NE) based in-situ gel of CZP for intranasal administration as an approach for bioavailability enhancement. Solubility of CZP was initially investigated in different oils, surfactants and co-surfactants, then pseudoternary phase diagrams were constructed to select the optimized ratio of oil, surfactant and co-surfactant. Clear and transparent NE formulations were characterized in terms of droplet size, viscosity, solubilization capacity, transmission electron microscopy, in-vitro drug release and compatibility studies. Selected NEs were incorporated into different in-situ gel bases using combination of two thermosensitive polymers; Pluronic® F-127 (PF127) and F-68 (PF68). NE-based gels (NG) were investigated for gelation temperature, viscosity, gel strength, spreadability and stability. Moreover, selected NGs were evaluated for ex-vivo permeation, mucoadhesive strength and nasal ciliotoxicity. Peppermint oil, tween 80 and transcutol P were chosen for NE preparation owing to their maximum CZP solubilization. Clear NE points extrapolated from tween 80:transcutol P (1:1) phase diagram and passed dispersibility and stability tests, demonstrated globule size of 67.99 to 354.96 nm and zeta potential of −12.4 to −3.11 mV with enhanced in-vitro CZP release (>90% in some formulations). After incorporation of the selected N3 and N9 formulations of oil:Smix of 1:7 and 2:7, respectively to a mixture of PF127 and PF68 (20:2% w/w), the resultant NG formulations exhibited optimum gelation temperature and viscosity with enhanced CZP permeation and retention through sheep nasal mucosa. Ciliotoxicity examinations of the optimum NGs displayed no inflammation or damage of the lining epithelium and the underlying cells of the nasal mucosa. In conclusion, NE-based gels may be a promising dosage form of CZP for schizophrenia treatment.     

Formulation development of ambroxol hydrochloride soft gel with application of statistical experimental design and response surface methodology

The purpose of present work was to develop ambroxol hydrochloride soft gel formulation with the application of statistical experimental design and response surface methodology (RSM). A two-factor, three-level (3(2)) full factorial design of experiment with RSM was run to evaluate the main and interaction effect of two independent formulation variables that included the amount of low-acetylated gellan gum and sodium citrate. The dependent variables included viscosity (Y(1)), amount of drug release at 10 min (Y(2)) and 30 min (Y(3)), and gelation time (Y(4)). In order to obtain a formulation having the maximum amount of drug release at 10 min and minimum gelation time, RSM optimization was used. The prepared formulations were evaluated for pH, viscosity, rheological properties, gelation time, drug content, in vitro drug release, appearance, and taste. All the formulations showed a gelation time in the range of 6 to 48 min. The drug content in all the formulations was within limit (99.6 ± 1.56%). The viscosity of all the formulations was found in the range of 1872-12,182 cP. Dissolution studies of the formulations showed drug release in the range of 40.56-72.46% within 10 min and 80.2-100.5% within 30 min. Human evaluation tests revealed that all the gels possessed acceptable characteristics. This study showed that the soft gel formulation GA5, containing 0.3% of gellan gum and 0.4% of sodium citrate, has potential use as an immediate release soft gel for oral drug delivery. LAY ABSTRACT: The objective of this investigation was to develop a new, immediate-release, soft gel dosage form for ambroxol hydrochloride, an oral expectorant and mucolytic agent. This novel soft gel dosage form needs to be suitable for pediatric and geriatric patients as well as patients with dysphagia. A statistical technique was used for optimization of the gel formulation. The methodology, called a design of experiment with response surface methodology, evaluated several independent formulation variables, including the amount of two ingredients, low-acetylated gellan gum and sodium citrate. Their effects were studied by comparing physical properties of the gel such as viscosity, amount of drug release at 10 and 30 min, and gelation time. The final optimized formulation (0.3% of gellan gum and 0.4% of sodium citrate) was chosen to maximize the amount of drug release at 10 min, minimize gelation time, and optimize viscosity in a reasonable range. After this optimization exercise, the prepared ambroxol hydrochloride soft gel formulations were evaluated for pH, viscosity, rheological properties, gelation time, drug content, in vitro drug release, appearance, and taste. Human evaluation tests revealed that all the gels possessed acceptable organoleptic characteristics.     

Nasal in-situ gels for delivery of rasagiline mesylate: improvement in bioavailability and brain localization

Abstract

Intranasal thermosensitive gel for rasagiline mesylate (RM) was developed for effective treatment of Parkinson’s disease. Intranasal gels were prepared by combination of poloxamer 407 and poloxamer 188 (1:1) with mucoadhesive polymers (carbopol 934?P and chitosan). The formulations were evaluated for sol–gel transition temperature, in-vitro drug release and in-vivo mucociliary transit time. Further, optimal intranasal gel formulations were tested for in-vivo pharmacokinetic behavior, nasal toxicity studies and brain uptake studies. It was found that optimal formulations had acceptable gelation temperature (28–33?°C) and adequate in-vitro drug release profile. Pharmacokinetic study in rabbits showed significant (p?<?0.05) improvement in bioavailability (four- to six-folds) of the drug from intranasal gels than oral solution. Chronic exposure studies in Wistar rats showed that these intranasal gels were non-irritant and non-toxic to rat nasal mucosa. Estimation of RM in rat brain tissue showed significant (p?<?0.01) improvement in uptake of RM form intranasal gel formulations than nasal solution.     

Formulation development of novel in situ nanoemulgel (NEG) of ketoprofen for the treatment of periodontitis

The aim of the present study was to formulate and evaluate in situ gelling syringeable nanoemulgels (NEGs) of ketoprofen for periodontal delivery. Application of 3-factor 3-level design was employed using the Box–Behnken experimental design for the optimization of nanoemulsion using three independent variables such as percent concentration (v/v) of oil (X₁), S_mix (mixture of surfactant and cosurfactant) (X₂) and water (X₃); while the particle size (nm) (Y₁), polydispersity index (Y₂) and zeta potential (mV) (Y₃) were used as dependent variables. The NEG was evaluated based on their drug content, pH measurement, mucoadhesion on the goat buccal mucosa, syringeability and inverted sol-gel transition temperature. The drug release data were analyzed for curve fitting based on the Korsmeyer–Peppas law, and the n-values of optimized A5 and A8 formulations were found 0.3721 and 0.3932, respectively, confirmed that both the formulations followed pseudo Fickian diffusion (n?<?0.43). The formulation A8 with the optimal drug release was identified as the best NEG formulation. Results of rheological, mucoadhesion and syringeability studies showed the suitability of desired sol-gel property for periodontal drug delivery. The Herschel–Bulkley model was the best fit model to explain the flow behavior of optimized formulation. Using the HET-CAM method, significantly lower in vitro toxicity was indicated the suitability of developed NEG for intra-pocket delivery.     

Polymer based solutions of bupranolol hydrochloride for intranasal systemic delivery

The present study was aimed at developing intranasal polymer based solutions as alternative route for systemic delivery of Bupranolol hydrochloride (BPH). It is a potent β-blocker drug which upon oral administration undergoes extremely high hepatic first-pass metabolism (>90% in humans). The polymeric solutions were prepared using varying concentrations of polymers like sodium alginate, chitosan, sodium carboxymethylcellulose, methylcellulose (MC), polyvinyl alcohol, carbopol, hydroxypropyl MC, and hydroxypropyl cellulose. The prepared formulations were evaluated in terms of pH of the solution, angular viscosity, drug content, gel strength, gelation temperature, in vitro drug release, in vivo pharmacodynamic studies, histopathological, and stability studies. Except MC based solutions, a biphasic pattern of drug release was obtained in all other cases. Nasal administration of selected batches of polymeric solutions were found to be nontoxic and were able to improve drug bioavailability when compared to oral, nasal, and intravenous solution administrations of BPH.     

pH-Induced In Situ Gel for Periodontal Anesthesia

A pH mediated in situ gelling system was developed using prilocaine hydrochloride for periodontal anesthesia using combination of chitosan and hydroxypropylmethylcellulose. The gel so developed can be used as anaesthetic in lengthy dental surgery. The gel was evaluated for many parameters like gelation pH, viscosity, physicochemical properties, in vitro release, sterility and stability. Gel with chitosan (0.25% w/v) and hydroxypropylmethylcellulose (0.25% w/v) was found to have good gelation near pH 7.4 (pH of mucous) with prolonged action.     

Formulation and Evaluation of Curcumin Gel for Topical Application

The aim of the present investigation was to develop and study topical gel delivery of curcumin for its anti-inflammatory effects. Carbopol 934P (CRB) and hydroxypropylcellulose (HPC) were used for the preparation of gels. The penetration enhancing effect of menthol (0–12.5% w/w) on the percutaneous flux of curcumin through the excised rat epidermis from 2% w/w CRB and HPC gel system was investigated. All the prepared gel formulations were evaluated for various properties such as compatibility, drug content, viscosity, in vitro skin permeation, and anti-inflammatory effect. The drug and polymers compatibility was confirmed by Differential scanning calorimetry and infrared spectroscopy. The percutaneous flux and enhancement ratio of curcumin across rat epidermis was enhanced markedly by the addition of menthol to both types of gel formulations. Both types of developed topical gel formulations were free of skin irritation. In anti-inflammatory studies done by carrageenan induced rat paw oedema method in wistar albino rats, anti-inflammatory effect of CRB, HPC and standard gel formulations were significantly different from control group (P < 0.05) whereas this effect was not significantly different for CRB and HPC gels formulations to that of standard (diclofenac gel) formulation (P > 0.05). CRB gel showed better % inhibition of inflammation as compared to HPC gel.     

Thermosensitive hydrogel containing sertaconazole loaded nanostructured lipid carriers for potential treatment of fungal keratitis

This study was conducted to develop an in situ thermosensitive gel containing sertaconazole-loaded nanostructured lipid carriers (NLCs) for prolonged ocular drug delivery. To this end, sertaconazole-loaded NLCs (sertaconazole-NLCs) were prepared by emulsification solvent-diffusion method and the effects of different formulation variables were assessed using the fractional factorial design. Then, optimized sertaconazole-NLCs were incorporated into the pluronic F127 (PF127)/hydroxy propylmethylcellulose (HPMC) K4M hydrogel. The formulations were examined for pH, gelation temperature, rheological properties, in vitro permeation studies, and anti-fungal activity. The optimized sertaconazole-NLCs showed a mean particle size of 272.40?nm, encapsulation efficiency of 89.97%, zeta potential of 12.9?mV, and polydispersity index of 0.31. All the in situ formulations had acceptable pH, ranging from 5.89 to 6.28. The gelation temperature of the optimized formulation was 35.1?°C after dilution with simulated tear fluid (STF). Sertaconazole-NLCs showed a higher antifungal activity and permeation through the bovine cornea compared to the free drug and the in situ gel formulation. The cornea penetration of sertaconazole for the in situ gel of NLCs was also comparable to that for free drug. The obtained results indicated that the prepared nanocomposite system may have potential for treatment of fungal keratitis.     

Formulation development of smart gel periodontal drug delivery system for local delivery of chemotherapeutic agents with application of experimental design

Smart gel periodontal drug delivery systems (SGPDDS) containing gellan gum (0.1–0.8% w/v), lutrol F127 (14, 16, and 18% w/v), and ornidazole (1% w/v) were designed for the treatment of periodontal diseases. Each formulation was characterized in terms of in vitro gelling capacity, viscosity, rheology, content uniformity, in vitro drug release, and syringeability. In vitro gelation time and the nature of the gel formed in simulated saliva for prepared formulations showed polymeric concentration dependency. Drug release data from all formulations was fitted to different kinetic models and the Korsemeyer-Peppas model was the best fit model. Drug release was significantly decreased as the concentration of each polymer component was increased. Increasing the concentration of each polymeric component significantly increased viscosity, syringeability, and time for 50%, 70%, and 90% drug release. In conclusion, the formulations described offer a wide range of physical and drug release characteristics. The formulation containing 0.8% w/v of gellan gum and 16% w/v of lutrol F127 exhibited superior physical characteristics.     

Properties of bioadhesive ketoprofen liquid suppositories: preparation,determination of gelation temperature,viscosity studies and evaluation of mechanical properties using texture analyzer by 4 × 4 factorial design

Abstract

Context: Development and evaluation of thermosensitive and bioadhesive liquid suppositories containing ketoprofen (KP).

Objective: This study was conducted to develope thermosensitive and bioadhesive liquid suppositories containing KP using poloxamer and different bioadhesive polymers and to investigate their gelation temperature, viscosity and mechanical properties.

Materials and methods: Bioadhesive liquid suppositories were prepared by the cold method using poloxamer 407 (P 407), Poloxamer 188 (P 188) and various amounts of different bioadhesive polymers. Their gelation temperatures, viscosity values and mechanical properties were determined using texture analyzer by 4?×?4 factorial design.

Results: It was seen that in presence of KP, gelation temperature of formulation P 407/P 188 (4/20%) significantly decreased from 64 to 37.1?°C. It is to be noted that addition of increasing concentrations of bioadhesive polymers lowered gelation temperature and its decrease was highest with addition of Carbopol 934 P (C). Results of texture profile analysis (TPA) showed that formulations containing C have significantly higher hardness and adhesiveness values than other bioadhesive formulations. According to TPA, gel structure of liquid suppository formulation F5, containing P 407/P 188/KP/C (4/20/2.5/0.8%), exhibited the greatest hardness, compressibilty, adhesiveness and besides greatest viscosity.

Discussion and conclusion: According to mechanical properties and viscosity values, it was concluded that F5 could be a promising formulation.     

Formulation and evaluation of novel controlled release of topical pluronic lecithin organogel of mefenamic acid

In the present study, pluronic lecithin based organogels (PLO gels) were formulated as topical carrier for controlled delivery of mefenamic acid. Ten organogel formulations were prepared by a method employing lecithin as lipophilic phase and pluronic F-127 as hydrophilic phase in varying concentrations to study various parameters using in vitro diffusion study and in vivo studies. All formulations were found to be off-white, homogenous, and reluctant to be washed easily and have pH value within the range of 5.56–5.80 which is nonirritant. Polymer concentration increased in formulations of F1 to F5 (lecithin) and F6 to F10 (pluronic) resulted in decrease of the gelation temperature, increase of viscosity and reduction of spreadability of gels having polymer tendency to form rigid 3D network. Organogels with higher viscosity were found to be more stable and retard the drug release from the gel. The formulations of F2 and F3 were selected for kinetic studies and stability studies, as they found to have all physical parameters within acceptable limits, highest percent drug content and exhibited highest drug release in eight hours. The order of drug release from various formulations was found to be F2?>?F3?>?F10?>?F4?>?F1?>?F9?>?F8?>?F5?>?F7?>?F6. The optimized formulation F2 was found to follow zero order rate kinetics showing controlled release of the drug from the formulations. In vivo anti-inflammatory activity of optimized mefenamic acid organogel (F2) against a standard marketed preparation (Volini gel) was found satisfactory and significant.     

The influence of the degree of esterification on the release characteristics of in situ gelling pectin formulations for oral sustained delivery of paracetamol

The aim of this study was to examine the effect of a change of the degree of esterification of pectin on the in situ gelation and release characteristics of 1.5% (w/v) pectin solutions over a wide pH range. Formulations of pectin with degrees of esterification of 9% (DE9) and 31% (DE31) containing complexed calcium ions formed gels in vitro at pH 1.2 as a consequence of cross-linking of the pectin chains by free calcium ions released from the complex. In vitro release of paracetamol from these gels was diffusion controlled. A sustained release of paracetamol was observed following oral administration of pectin DE9 and DE31 formulations to gastric acidity-controlled rats at pH 2.5 but only with DE9 formulations at pH 5.5. Examination of the stomach contents confirmed effective in situ gelation of pectin DE9 formulations at a gastric pH of 6 but there was no evidence of the gelation of pectin DE31 formulations at this pH.     

温敏型姜黄素鼻用原位凝胶增强脑靶向性

目的：制备温度敏感型的姜黄素鼻用凝胶制剂,以提高姜黄素的脑部生物利用度。方法：通过粘度实验进行原位凝胶制剂的处方筛选,以胶凝时间、胶凝温度等为指标,优化处方;采用透析袋法考察原位凝胶的体外释放：以大鼠为模型,考察姜黄素原位凝胶的脑靶向性及脑内分布．并与其静脉注射剂相比较。结果：姜黄素原位凝胶剂优化处方具有最短的胶凝时间,可以长时间粘附在鼻腔粘膜上：释放行为属于Fickian扩散机制;姜黄素脑内分布试验表明,原位凝胶在大脑、小脑、海马、嗅球中的药物靶向效率（DTE）分别为静脉给药的1.82、2．05、2．07、1．51倍,说明原位凝胶给药显著增强了姜黄素的脑靶向性。结论：制备的姜黄素原位凝胶剂具有温度敏感的特点．并显著提高了姜黄素的脑靶向性。     

Dual controlled release, in situ gelling periodontal sol of metronidazole benzoate and serratiopeptidase: statistical optimization and mechanistic evaluation

In situ gelling syringeable periodontal sol capable of dual controlled delivery of metronidazole benzoate and serratiopeptidase was designed based on 2(3) factorial design with drug, poloxamer 407 and aerosil as independent variables and sol gel transition characteristics, %CDR(48h) and palatability as responses. The sols had agreeable taste, were mucoadhesive, syringeable and inverted into gels at periodontal cavity temperature. F8 with optimal drug release was identified as the best formulation. The dispersion characteristics of poloxamer significantly affected the pharmacotechnical properties of the in situ gelling systems. Extra design checkpoint generated using Design Expert software 8.02 (Stat-Ease, USA) validated the experimental design. Thus a thermoreversible, in situ gelling and syringeable periodontal sol with acceptable taste characteristics that offered controlled release of metronidazole benzoate and serratiopeptidase was developed for application into the periodontal pocket. The developed optimized sol was satisfactory in terms of taste, syringeability, palatability and incorporation of serratiopeptidase as anti-inflammatory agent, has the potential of developing a therapeutically efficacious system for treatment of periodontal inflammatory anaerobic infections.     

温控型胰岛素液体肛门栓药剂学研究

目的 温控型胰岛素液体肛门栓药剂学性质的研究。 方法 采用正交试验法,以形成凝胶时间、胶凝强度、生物黏附力、黏度、胶凝温度作为评价指标,对处方中的泊洛沙姆407和泊洛沙姆188的比例、壳聚糖质量分数和pH值3个因素进行考察,确定最优处方工艺;测定最优处方液体栓剂的胶凝强度、生物黏附力、黏度、胶凝温度。 结果 泊洛沙姆407:泊洛沙姆188(15:25),壳聚糖质量分数0.4%,pH值为5±0.2。 结论 经验证结果良好,液体栓剂强度及生物黏附力良好。     

Preparation of curcumin self-micelle solid dispersion with enhanced bioavailability and cytotoxic activity by mechanochemistry

An amorphous solid dispersion (SD) of curcumin (Cur) with disodium glycyrrhizin (Na₂GA) was prepared by mechanical ball milling. Curcumin loaded micelles were self-formed by Na₂GA when SD dissolved in water. The physical properties of Cur SD in solid state were characterized by differential scanning calorimetry, X-ray diffraction studies, and scanning electron microscope. The characteristics of the sample solutions were analyzed by reverse phase HPLC, UV–visible spectroscopy, ¹H NMR spectroscopy, gel permeation LC, and transmission electron microscopy. In vitro cytotoxic tests demonstrated that Cur SD induced higher cytotoxicity against glioblastoma U-87?MG cells than free Cur. Besides, an improvement of membrane permeability of Cur SD was confirmed by parallel artificial membrane permeability assay. Further pharmacokinetic study of this SD formulation in rat showed a significant ～19-fold increase of bioavailability as comparing to free Cur. Thus, Cur SD provide a more potent and efficacious formulation for Cur oral delivery.     

Evaluation of mesoporous silica particles as drug carriers in hydrogels

Mesoporous silica particles have recently been used in the preparation of solid oral as well as dermal pharmaceutical formulations. In this work, the use of mesoporous silica of different particle size, pore size and pore volume as carrier for curcumin in hydrogels for dermal use was investigated. Oil absorption capacity of the silica, in vitro release of curcumin from formulations and chemical stability of curcumin during three months storage were evaluated. It was found that the silica particles did not alter in vitro release of curcumin compared to an emulsion. Furthermore, curcumin was found to exhibit similar or inferior stability in hydrogels containing mesoporous silica opposed to emulsions.     

Thermoreversible mucoadhesive ophthalmic in situ hydrogel: Design and optimization using a combination of polymers

The purpose of the study was to develop an optimized thermoreversible in situ gelling ophthalmic drug delivery system based on Pluronic F 127, containing moxifloxacin hydrochloride as a model drug. A 3(2) full factorial design was employed with two polymers: Pluronic F 68 and Gelrite as independent variables used in combination with Pluronic F 127. Gelation temperature, gel strength, bioadhesion force, viscosity and in vitro drug release after 1 and 10 h were selected as dependent variables. Pluronic F 68 loading with Pluronic F 127 was found to have a significant effect on gelation temperature of the formulation and to be of importance for gel formation at temperatures 33-36 °C. Gelrite loading showed a positive effect on bioadhesion force and gel strength and was also found helpful in controling the release rate of the drug. The quadratic mathematical model developed is applicable to predicting formulations with desired gelation temperature, gel strength, bioadhesion force and drug release properties.     

载姜黄素的透明质酸-熊果酸-硫辛酸交联纳米粒的制备及其体外抗肿瘤活性

目的 制备载姜黄素的透明质酸-熊果酸-硫辛酸交联纳米粒（Cur/cLA-HU NPs）,并进行体外抗肿瘤活性评价。方法 以载药量、包封率为指标,采用超声法,通过单因素考察优化Cur/cLA-HU NPs的制备工艺,并对Cur/cLA-HU NPs的粒径、Zeta电位、形态和体外释药情况进行评价。通过荧光倒置显微镜分析HepG2细胞对Cur/cLA-HU NPs的摄取,以MTT法考察Cur/cLA-HU NPs对HepG2细胞的毒性。结果 最佳载药工艺为：以甲醇为药物姜黄素有机溶剂,以药质比4∶10进行投料,超声于100 W下次数为3次,每次处理3 min,超声程序设置为开2 s、停4 s。Cur/cLA-HU NPs的包封率为（87.91±1.51）%,载药量为（16.64±0.45）%,粒径为（172.3±2.57）nm,PDI为（0.174±0.021）,分散均匀,Zeta电位为（−35.3±2.12）mV。Cur/cLA-HU NPs具有还原响应性,释放药物的快慢受到GSH浓度的影响;靶向肿瘤细胞,且被细胞快速摄取;对HepG2人肝癌细胞增殖具有明显抑制作用。结论 Cur/cLA-HU NPs载药量和包封率高,其体外抗肿瘤活性稍优于姜黄素,具有肿瘤靶向性。     

Development of loteprednol etabonate-loaded cationic nanoemulsified in-situ ophthalmic gel for sustained delivery and enhanced ocular bioavailability

A novel cationic nanoemulsified in-situ ophthalmic gel of loteprednol etabonate (LE) was developed to improve the permeability and retention time of formulations for overall improvement of drug’s ocular bioavability. Capryol 90 (oil phase), tween 80 (surfactant) and transcutol P (cosurfactant) was selected as formulation excipients to construct pseudoternary phase diagrams and nanoemulsion region was recognized from diagrams. Spontaneous emulsification method was used to manufacture LE nanoemulsion and it was optimized using 3² factorial design by considering the amount of oil and the ratio of surfactant to cosurfactant (S_mix) as independent variables and evaluated for various physicochemical properties. Optimized NE was dispersed in Poloxamer 407 and 188 solution to form nanoemulsified sols that were predictable to transform into in-situ gels at corneal temperature. Drug pharmacokinetics of sterilized optimized in situ NE gel, NE-ISG2 [0.69% w/w Capryol 90, 0.99%w/w S_mix (3:1), 13% Poloxamer 407, 4% w/w Poloxamer 188] and marketed formulation were assessed in rabbit aqueous humor. The in-situ gels were clear, shear thinning in nature and displayed zero-order drug release kinetics. NE-ISG2 showed the minimum ocular irritation potential and significantly (p?<?0.01) higher C_max and AUC_(0–10?h), delayed T_max, extended mean residence time and improved (2.54-fold times) bioavailability compared to marketed formulation.