Development and evaluation of self-microemulsifying liquid and granule formulations of Brucea javanica oil

The aim of this study was to develop and characterize a self-microemulsifying drug delivery system (SMEDDS) of Brucea javanica oil (BJO) and transform the liquid formulation into solid granules. Solubility studies of BJO and pseudo-ternary phase diagrams were used to identify the most efficient self-emulsification region. A methyl thiazolyl tetrazolium (MTT) assay was performed to identify cell apoptosis. Antitumor activity studies were also employed to evaluate the BJO SMEDDS. The optimized BJO SMEDDS in liquid and granule formulations rapidly formed fine oil-in-water microemulsions with particle sizes <50 nm. Additionally, the MTT assay demonstrated that BJO SMEDDS had a significant effect on cancer cells, and antitumor activity studies showed remarkable inhibition of S180 tumors. The BJO SMEDDS, optimized to have good characteristics, was successfully transformed into solid granules by adsorbing onto crospovidone. The studies of the release of the BJO SMEDDS of liquid and granules in vitro suggested that the release of BJO was enhanced by the SMEDDS. These studies revealed that the new self-microemulsifying systems of liquid and granule forms might be promising strategies for the oral delivery of the poorly water-soluble drug BJO.     

Characterization and evaluation of self-microemulsifying sustained-release pellet formulation of puerarin for oral delivery

The present study aims to develop self-microemulsifying drug delivery systems (SMEDDS) in sustained-release pellets of puerarin to enhance the oral bioavailability of puerarin. The performances of puerarin-SMEDDS including oils, emulsifiers, and co-emulsifiers were evaluated. Pseudo-ternary phase diagrams shows that the optimized formulation consisted of castor oil as the oil phase, Cremophor EL as the emulsifier, and 1,2-propanediol as the co-emulsifier. SMEDDS sustained-release pellets were prepared via extrusion-spheronization. The particle size distributions of the formulations were determined using transmission electron microscopy and scanning electronic microscopy. The mean particle size was 50 ± 8 nm. The pharmacokinetics and bioavailability of the puerarin-SMEDDS sustained-release pellets and puerarin tablets were evaluated and compared in beagle dogs. The absolute bioavailability of the puerarin-SMEDDS sustained-release pellets was enhanced by approximately 2.6-fold compared with that of the puerarin tablet. The relative bioavailability (F(rel)) of the SMEDDS pellets was 259.7% compared with the tablet group. The results demonstrated that the puerarin-SMEDDS sustained-release pellets had a sustained-release effect, and could remarkably improve the oral bioavailability of puerarin.     

Development of shellac-coated sustained release pellet formulations

Shellac is an important coating material for food products. Since the introduction of aqueous ammoniacal solutions it also regained importance for pharmaceutical applications. Because of the comparatively high dissolution pH of this material, further additives are required if shellac is used as enteric coating material. However, this dissolution behaviour of shellac may be of interest for sustained release or colon targeting applications. In the present study different subcoats containing calcium chloride, citric acid or Eudragit^® E, respectively, were applied to immediate release theophylline pellets which were subsequently coated with shellac. Drug release from the resulting pellet formulations was measured. The mechanism of interaction between the modifying subcoat ingredients and the shellac coating was investigated using FT-IR spectroscopy. All formulations with modifying subcoat prolonged drug release. Whereas the effect of calcium chloride was a result of ionic interactions with shellac, the effect of citric acid was a reduction of the degree of dissociation of shellac. The influence of Eudragit^® E can be explained by the solubility characteristics of this basic polymer. The application of modifying subcoats is an easy and effective means to achieve sustained release from shellac-coated dosage forms. The choice of a suitable substance and the adjustment of its concentration allow tailor made sustained release profiles.     

多替拉韦自微乳化释药系统的制备与大鼠药动学评价

目的 制备多替拉韦自微乳化释药系统（DTG-SMEDDSs）,并对其在大鼠体内的药动学行为进行评价。方法 2021年6月至2023年3月通过测定多替拉韦（DTG）在不同种类油、乳化剂和助乳化剂中的平衡溶解度、辅料配伍相容性实验来确定DTG-SMEDDSs的处方组成,根据伪三元相图初步确定各辅料的用量范围,评价DTG-SMEDDSs的热力学稳定性以及在不同稀释倍速中的稳定性,通过透射电镜观察到DTG-SMEDDSs形成乳液的微观形态,考察DTG-SMEDDSs的体外药物溶出速率,通过大鼠口服给药比较DTG混悬剂与DTG-SMEDDSs的大鼠体内药动学特征。结果 平衡溶解度和辅料配伍相容性实验确定选择单亚油酸甘油酯（Maisine）作为油相,吐温80作为乳化剂,二乙二醇单乙基醚（Transcutol HP）作为助乳化剂,其配比为30∶35∶35,制备的DTG-SMEDDSs具有良好的热力学稳定性及稀释稳定性,其自乳化形成的微乳呈类球形;DTG-SMEDDSs中的药物在10 min内基本完全溶出,其溶出速率显著快于DTG原料药;大鼠体内药动学结果显示,大鼠口服DTG-SMEDDSs后的达峰浓...     

Development of topical functionalized formulations added with propolis extract: stability, cutaneous absorption and in vivo studies

Propolis, which is a natural product widely consumed in the folk medicine, is a serious candidate to be applied topically due to its outstanding antioxidant properties. So, the purpose of this study was to develop stable topical formulations added with propolis extract in an attempt to prevent and/or treat the diseases occurring in skin caused by UV radiation. The antioxidant activity using a chemiluminescent method was used to evaluate the functional stability and the permeation/retention in skin of these formulations. In the long-term stability study, the formulations were stored at 25+/-2 degrees C/AH and at 40+/-2 degrees C/70% RH for 360 days. It was found in this study, that the formulations prepared with Polawax showed functional and physical stability in the period of study. In addition, this formulation presented good results in the percutaneous study, allowing the antioxidant compounds present in the propolis extract to reach lower layers in pig ear skin and in the whole hairless mice skin (retention=0.12 and 0.13 microL of propolis/g of skin, respectively). In the in vivo study, it was also suggested that this formulation may be effective in protecting skin from UVB photodamage, nevertheless other assays need to be done in order to have a complete understanding of the protective effect of formulations added with propolis extract.     

The dissolution rate and bioavailability of hydrochlorothiazide in pellet formulations

The influence of non-active ingredients in the manufacture of pellets on in-vitro dissolution rate and on bioavailability of hydrochlorothiazide has been studied. Pellets were formulated using either microcrystalline cellulose or microcrystalline cellulose-carboxymethylcellulose sodium blends as matrix, and hydrochlorothiazide as the active ingredient. In-vitro drug release from the different pellet formulations was retarded in comparison to a conventional tablet formulation and was dependent on the nature of the non-active ingredient and, for the microcrystalline cellulose-carboxymethylcellulose sodium blend, of the dissolution medium. In-vivo bioavailability of both pellet formulations was low compared with that of the conventional tablet and the plasma concentration-time profiles did not suggest slow release.     

Development and evaluation of nasal formulations of ketorolac

Ketorolac tromethamine is a potent non-narcotic analgesic with moderate anti-inflammatory activity. Clinical studies indicate that ketorolac has a single dose efficacy greater than morphine for postoperative pain and has excellent applicability in the emergency treatment of pain. Due to incomplete oral absorption of ketorolac, several approaches have been tried to develop a nonoral formulation in addition to injections, especially for the treatment of migraine headache. The aim of our study was to develop a nasal formulation of ketorolac with a dose equivalent to the oral formulation. A series of spray and lyophilized powder formulations of ketorolac were administered into the nasal cavity of rabbits, and their pharmacokinetics profiles were assessed. The spray and powder formulations were compared through their pharmacokinetics parameters and absolute bioavailability. Drug plasma concentration was determined using solid phase extraction, followed by an HPLC analysis. Nasal spray formulations were significantly better absorbed than powder formulations. A nasal spray formulation of ketorolac tromethamine showed the highest absorption with an absolute bioavailability of 91%. Within 30 min of administration, the plasma concentration was comparable to that resulting from an intravenous injection. The absolute bioavailability of a solution of ketorolac acid was 70%. Apparently, the dissolution of ketorolac acid into the mucous layer limits its absorption. There were no significant differences in absorption between different powder formulations. Even the reduction of particle size from 123 θ m to 63 θ m did not indicate better absorption of ketorolac tromethamine from powder formulations. Interestingly, the absolute bioavailability of ketorolac tromethamine from a powder formulation is only 38%, indicating that the drug may not be totally released from the polymer matrix before it is removed from nasal epithelium by mucociliary clearance.     

Toxicological evaluation of pH-sensitive nanoparticles of curcumin: Acute,sub-acute and genotoxicity studies

Research in nanotoxicology is still in nascent stages. This hampers the design of appropriate regulatory policies for these beneficial nano-drug delivery systems thus affecting their routine employment as therapeutics. Establishing the entire toxicological profile is thus indispensable for proving the human safety of nanocarriers, which was the primary objective of the current investigation. The developed curcumin loaded polymeric nanoparticles of Eudragit® S100 were subjected to various toxicological evaluations which included acute-toxicity study, sub-acute-toxicity study (28 days) and various genotoxicity studies like in vivo Micronucleus assay, in vivo Chromosomal Aberration assay and in vivo Comet assay. The formulation was found to be non-toxic at the dose equivalent to 2000 mg/kg of body weight of curcumin in the acute-toxicity study. Sub-acute-toxicity study proved the safety of the formulation for prolonged administration at the commonly used therapeutic dose of 100 mg/kg of body weight of curcumin and at twice the therapeutic dose. Genotoxicity studies proved the cellular safety of the developed formulation at the therapeutic dose, and even at doses equivalent to thrice the therapeutic dose. Thus the developed curcumin loaded polymeric nanoparticles of Eudragit® S100 were found to be safe for oral administration for a short as well as a prolonged duration.     

Development of stable liquid formulations for adenovirus-based vaccines

We have evaluated the stability profiles of adenovirus type-5 (Ad5)-based vaccine formulations to identify liquid formulations that are stable during long-term storage at 4 degrees C. By identifying the major physiochemical inactivation pathway(s) during storage, formulations of Ad5 were designed with specific pharmaceutical excipients leading to greatly enhanced stability. For example, results indicate that Ad5 is stabilized by non-ionic surfactants and cryoprotectants as well as excipients known to inhibit free-radical oxidation. A non-ionic surfactant is necessary to prevent adsorption of adenovirus to glass surfaces during storage, and a cryoprotectant is needed to prevent freeze-thaw-induced virus inactivation. In a base formulation (A105) containing sucrose as the cryoprotectant and polysorbate-80 as the non-ionic surfactant, metal-ion catalyzed free-radical oxidation is an important mechanism of Ad5 inactivation. The free-radical oxidation inhibitors ethanol and histidine, combined with the metal-ion chelator ethylenediaminetetraacetic acid (EDTA), were determined to be effective stabilizers of Ad5. Arrhenius plots of stability data are consistent with a first-order inactivation mechanism with apparent activation energies for virus inactivation of 26.5 +/- 0.9 and 28.7 +/- 0.6 kcal/mol in the absence and presence of free-radical oxidation inhibitors, respectively. Optimization of formulation pH, as well as the EDTA and ethanol concentrations, allowed for the identification of formulations that further enhanced long-term storage stability. For example, Ad5 in an optimized liquid formulation (A195) lost <0.1 logs of infectivity after 24 months of storage at 4 degrees C. The immunogenicity of a recombinant Ad5-based human immunodeficiency virus (HIV) vaccine candidate expressing HIV-1 gag (MRKAd5gag) formulated in A195, was shown to be equivalent to the same vaccine formulated in A105. Therefore, the use of EDTA, ethanol, and histidine did not significantly alter the immunogenicity of the vaccine in mice. The identification of 4 degrees C stable liquid formulations should significantly enhance the utility of Ad5 as a vector for vaccines and gene therapy.     

玳玳黄酮自微乳化微丸含量测定及HPLC特征图谱分析

目的:建立玳玳黄酮自微乳化微丸中柚皮苷、新橙皮苷HPLC含量测定方法和HPLC特征图谱,为玳玳黄酮自微乳化微丸的质量控制提供有效的方法。方法:含量测定采用Agilent-C18色谱柱(250 mm×4.6 mm,5μm),流动相为乙腈-0.1%磷酸水溶液(22∶78),流速为1.0 mL.min-1,柱温为室温。HPLC特征图谱测定采用250-4 Lichrocart C18色谱柱(250 mm×4.0mm,5μm),流动相为甲醇-乙腈-0.1%的磷酸水溶液,梯度洗脱,流速1.0 mL.min-1,柱温30℃。检测波长均为283 nm。结果:柚皮苷浓度在4.48～17.92μg.mL-1范围内线性关系良好(r=0.9998),平均加样回收率为97.5%(RSD=1.0%);新橙皮苷浓度在5.92～23.68μg.mL-1范围内线性关系良好(r=0.9997),平均加样回收率为98.8%(RSD=0.82%)。在此条件下所建立的特征图谱中各成分得到有效分离,各批玳玳黄酮自微乳化微丸的相似度在0.900～1.000间。结论:HPLC法同时测定玳玳黄酮自微乳化微丸中柚皮苷和新橙皮苷含量的方法简便、准确,建立的HPLC特征图谱可用于评价微丸的物质组成及有效物质群的质量变化,可作为玳玳黄酮自微乳化微丸质量控制的依据。     

苦参碱固体自微乳制剂的制备及其评价

目的 制备苦参碱固体自微乳颗粒,并对其进行质量评价.方法 通过固体吸附材料的优选,制备了苦参碱固体自微乳颗粒,建立了HPLC法测定颗粒中苦参碱及其体外溶出度的方法;对溶解后微乳的类型、pH值、Zeta电位、粒径进行研究.结果 选择微粉硅胶与甘露醇质量比2∶1为固体吸附材料,每克苦参碱微乳液需加微粉硅胶0.42 g,微晶纤维素0.21 g,50℃恒温干燥后成淡黄色的苦参碱自微乳颗粒,遇水快速形成澄明的液体,平均粒径79 nm,pH值为7.95,Zeta电位-1.34 mV,载药量23.51 mg/g,45 min内累积溶出94.2％以上.结论 苦参碱固体自微乳的制备工艺简单,制剂稳定,可为水难溶性药物的开发提供一个新方法、新思路.     

脂质制剂体外动态肠吸收模型的建立及评价

根据脂质制剂肠消化吸收的特性,本文在体外脂解模型基础上,引入肠吸收评价方法,建立了一种用于筛选评价脂质制剂的新型体外动态肠吸收模型,包括肠消化和肠组织培养两大体系。探究模型重要参数(Ca2+、葡萄糖、K+)的影响,发现Ca2+浓度的增加能显著增强脂质制剂的肠消化;葡萄糖浓度的递增能显著减慢肠组织活性衰减;K+虽能维持肠组织的活性,但其浓度变化对肠组织活性衰减并无显著性影响;最终选择Ca2+10 mmol.L-1、葡萄糖15 mmol.L?1和K+5.5 mmol.L-1为模型参数。利用该模型评价TypeⅠ脂质制剂得到的体外吸收曲线与大鼠体内吸收曲线呈现极显著的点对点相关性(r=0.995 6,P<0.01)。本模型可望应用于脂质制剂的筛选、评价及预测。     

Development and in vitro evaluation of topically applied cinnamic acid formulations

The aim of this study was to formulate microcapsulated cinnamic acid (CN) formulations in w/o and o/w emulsions and to compare their release profiles with w/o, o/w and w/o/w emulsions without microcapsules through cellulose acetate, cellulose nitrate membranes and excised rat skin. The experimental design approach was used for understanding the influence of different formulation factors on release characteristics and to optimise most accurate formulating parameters. The data obtained in this study were subjected to statistical analysis by a repeated measures ANOVA, following Bonferroni multiple comparisons test. A significantly different release was observed due to the core:wall ratio of microcapsules. Emulsions containing microcapsules with 2:1 core:wall ratio were found to be ideal according to the factorial design, dissolution and diffusion studies. The type of emulsion was found to be a very important factor affecting the release profile of CN. The results described in this study indicate that microencapsulation of CN in w/o emulsion could be suggested as an effective carrier for CN to achieve sustained release and to protect the drug. Moreover, w/o/w emulsions were also useful carriers for prolonged release by encapsulating the substances in their internal aqueous phase and they also protect drugs and their preparation and application are easy. By the way, in the case of o/w emulsion any significant difference was observed. The type of the membrane also affected release. According to the release results, rat skin was found to be significantly different from the synthetic membranes.     

Stability-indicating HPTLC determination of curcumin in bulk drug and pharmaceutical formulations

A simple, selective, precise and stability-indicating high-performance thin-layer chromatographic method of analysis of curcumin both as a bulk drug and in formulations was developed and validated. The method employed TLC aluminium plates precoated with silica gel 60 F-254 as the stationary phase. The solvent system consisted of chloroform:methanol (9.25:0.75 v/v). This system was found to give compact spots for curcumin (R(f) value of 0.48 +/- 0.02). Densitometric analysis of curcumin was carried out in the absorbance mode at 430 nm. The linear regression analysis data for the calibration plots showed good linear relationship with r = 0.996 and 0.994 with respect to peak height and peak area, respectively, in the concentration range 50-300 ng per spot. The mean value +/- S.D. of slope and intercept were 1.08 +/- 0.01, 51.93 +/- 0.54 and 8.39 +/- 0.21, 311.55 +/ -3.23 with respect to peak height and area, respectively. The method was validated for precision, recovery and robustness. The limits of detection and quantitation were 8 and 25 ng per spot, respectively. Curcumin was subjected to acid and alkali hydrolysis, oxidation and photodegradation. The drug undergoes degradation under acidic, basic, light and oxidation conditions. This indicates that the drug is susceptible to acid, base hydrolysis, oxidation and photo oxidation. Statistical analysis proves that the method is repeatable, selective and accurate for the estimation of said drug. As the method could effectively separate the drug from its degradation product, it can be employed as a stability-indicating one.     

Percutaneous absorption of non-steroidal anti-inflammatory drugs from in situ gelling xyloglucan formulations in rats

The potential of gels formed in situ by dilute aqueous solutions of a xyloglucan polysaccharide derived from tamarind seed as sustained release vehicles for percutaneous administration of non-steroidal anti-inflammatory drugs has been assessed by in vitro and in vivo studies. Chilled aqueous solutions of xyloglucan that had been partially degraded by beta-galactosidase formed gels at concentrations of 1-2% w/w when warmed to 37 degrees C. The in vitro release of ibuprofen and ketoprofen at pH 7.4 from the enzyme degraded xyloglucan gels and the subsequent permeation of these fully ionized drugs through cellulose membranes followed root-time kinetics over a period of 12 h after an initial lag period. Diffusion coefficients were appreciably higher when the drugs were released from 1.5% w/w xyloglucan gels than when released from 25% w/w Pluronic F127 gels formed in situ under identical conditions. The difference in release rates was attributed to differences in the structure of the gels. The permeation rate of ibuprofen through excised skin was higher than that of ketoprofen when released from both gels, but of similar magnitude through cellulose membranes. Plasma concentrations of ibuprofen and ketoprofen from gels formed in situ following topical application of chilled aqueous solutions of xyloglucan and Pluronic F127 to the abdominal skin of rats were compared. The bioavailabilities of ibuprofen and ketoprofen were significantly higher when released from xyloglucan gels compared to Pluronic F127 gels. Occlusive dressing techniques had a greater enhancing effect on the bioavailability of ibuprofen when released from Pluronic gels.     

Effect of curcumin on glucose absorption: an experimental study on albino rats

Curcumin derived from the rhizome Curcuma longa is one of the primary ingredient in turmeric. Turmeric is used frequently as food additive in Asia, specially the Indian subcontinent. The daily intake of turmeric in the diet may therefore expose the gut to curcumin and affect its physiological functions, including the absorption of nutrients from small intestine. However, no published reports are available on the effect curcumin on absorption of nutrients from small intestine. To explore this possibility, transport of glucose from small intestine was studied in adult albino rats following feeding the animals curcumin intragastrically for five consecutive days. The controls were fed simultaneously, the vehicular fluid intragastrically in the identical volume. Transport of glucose from small intestine was studied using everted sac technique of Wilson and Wiseman (1954) on animals fasted for 16-20 hrs. Everted sacs were prepared from both jejunal and ileal portion of small intestine. Observations showed a significant increase in glucose transport from jejunal and upper ileal portion of small intestine suggesting that curcumin does influence the transport of nutrients from the gut.     

Optimization and in situ intestinal absorption of self-microemulsifying drug delivery system of oridonin

The objective of this study was to optimize and characterize an oridonin self-microemulsifying drug delivery system (SMEDDS) formulation. A central composite design (CCD) was used to investigate the influence of factors (oil percentage and surfactant to co-surfactant ratio (Sur/Co-s ratio)) on the responses including droplet size, polydispersity, equilibrium solubility and in situ intestine absorption rate. Furthermore, the desirability function approach was applied to obtain the best compromise among the multiple responses. It was found that oil percentage played a significant role on the droplet size and polydispersity. The drug equilibrium solubility was mainly contributed to oil percentage and less to Sur/Co-s ratio. The in situ intestinal absorption was influenced by both of the two factors, whereas the oil percentage played a more important role in absorption. The practical response values under the optimized formulation were in good accordance with the predicted values. Our results demonstrate CCD is of value in optimizing the SMEDDS formulation and understanding the effects of formulation compositions on SMEDDS properties.     

Preparation and evaluation of celecoxib-loaded microcapsules with self-microemulsifying core

The purpose of this study was to prepare alginate microcapsules with a self-microemulsifying system (SMES) containing celecoxib in the core. An Inotech IE-50 R encapsulator equipped with a concentric nozzle was used to prepare the microcapsules. The encapsulated SMES was shown to increase celecoxib solubility over that of the pure drug more than 400-fold. Microcapsules prepared with a high SMES:celecoxib ratio exhibited distinct core vesicles containing liquid SMES. By modifying the SMES and including an additional chitosan coating, drug loading in the range from 12–40% could be achieved with the degree of encapsulation ranging from 60–82%. Alginate microcapsules loaded with SMES and celecoxib showed increased dissolution rate of celecoxib over that of alginate microcapsules loaded with celecoxib or of the celecoxib alone. Compared to the previous report, drug loading capacity was significantly improved, enabling the formulation of dosage forms which are of suitable size for peroral application.     

Preparation and evaluation of self-microemulsifying drug delivery system of oridonin

The objective of this study was to develop self-microemulsifying drug delivery system (SMEDDS) to enhance the oral bioavailability of the poorly water-soluble drug, oridonin. The influence of the oil, surfactant and co-surfactant types on the drug solubility and their ratios on forming efficient and stable SMEDDS were investigated in detail. The SMEDDS were characterized by morphological observation, droplet size and zeta-potential determination, cloud point measurement and in vitro release study. The optimum formulation consisted of 30% mixture of Maisine 35-1 and Labrafac CC (1:1), 46.7% Cremopher EL, and 23.3% Transcutol P. Invitro release test showed a complete release of oridonin from SMEDDS in an approximately 12h. The absorption of oridonin from SMEDDS showed a 2.2-fold increase in relative bioavailability compared with that of the suspension. Our studies demonstrated the promising use of SMEDDS for the delivery of oridonin by the oral route.