Optimized preparation, characterization and biodistribution in heart of breviscapine lipid emulsion

Breviscapine is a Traditional Chinese Medicine treating cardiovascular diseases by promoting blood circulation and removing blood stasis. The major active component of breviscapine has low aqueous solubility, poor chemical stability, short biological half-life and rapid elimination rate from the plasma. The use of a lipid emulsion formulation containing breviscapine might improve chemical stability, increase drug loading, exhibit sustained release profile. In the present study, we developed an optimized formulation and technological method for the preparation of sterile and stable breviscapine lipid emulsion (Bre-LE) for intravenous infusion. The average particle size, polydispersity index, zeta potential, stability constant (K(s)) value and content of final product were (225.3±8.8) nm, 0.221±0.020, (-29.6±1.5) mV, (24.3±2.9)% and (94.5±0.6)% respectively (n=3). The results of in vitro release experiment suggest that lipid emulsion as breviscapine carrier showed a desirable sustained release profile. Dilution stability and long-term stability were also researched in the present paper. The results show the carrier could protect drug from degradation after dilution by phosphate buffered saline and fetal calf serum. And Bre-LE was stable for up to 6 months at room temperature storage condition. The biodistribution of drug in heart of mice increased dramatically after encapsulation into lipid emulsion which was beneficial to heart disease therapy.     

Magnetic‐targeted pH‐responsive drug delivery system via layer‐by‐layer self‐assembly of polyelectrolytes onto drug‐containing emulsion droplets and its controlled release

Novel magnetic‐targeted pH‐responsive drug delivery system have been designed by the layer‐by‐layer self‐ assembly of the polyelectrolytes (oligochitosan as the polycation and sodium alginate as the polyanion) via the electrostatic interaction with the oil‐in‐water type hybrid emulsion droplets containing the superparamagnetic ferroferric oxide nanoparticles and drug molecules [dipyridamole (DIP)] as cores. Here the drug molecules were directly encapsulated into the interior of droplets without etching the templates and refilling with the desired guest molecules. The drug‐delivery system showed high encapsulation efficiency of drugs and drug‐loading capacity. The cumulative release ratio of dipyridamole from the oligochitosan/sodium alginate multilayer‐encapsulated magnetic hybrid emulsion droplets (DIP/Fe₃O₄‐OA/OA)@(OCS/SAL)₄ was up to almost 100% after 31 h at pH 1.8. However, the cumulative release ratio was only 3.3% at pH 7.4 even after 48 h. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Methods for the preparation of doxycycline-loaded phb micro- and nano-spheres

Natural and synthetic biodegradable polymers have been investigated for controlled drug release. Poly(3-hydroxybutyrate) can be produced by bacteria and is remarkable for this application due to its excellent biocompatibility and biodegradability. The objective of this work was to study different drug-entrapment and emulsification methods for the obtaining of doxycycline-loaded PHB micro- and nano-spheres. The micro-/nano-particles were prepared by polymer precipitation via dialysis, simple emulsion (O/W) or multiple emulsion (W₁/O/W₂) applying solvent evaporation in the last two cases. This was carried out either by ultrasonication, dripping and/or high speed stirring. Different processing conditions were varied in order to evaluate their influence on morphology, size, and drug entrapment capabilities. The highest drug loading was obtained by single emulsion with high speed stirring. In the case of multiple emulsion, the combination of ultrasound with high speed stirring resulted in the most elevate process yield and drug loading capability.     

Encapsulation of doxorubicin in magnetic‐polymer hybrid colloidal particles of Eudragit E100 and their hyperthermia and drug release studies

Water‐soluble magnetite Fe₃O₄ nanoparticles were synthesized by coprecipitation that exhibit spherical morphology and superparamagnetic behavior with a saturation magnetization of 46 emu/g. These nanoparticles were coated with amino methacrylate copolymer (Eudragit E100) along with encapsulation of Doxorubicin drug under the action of sonication via a double emulsion solvent evaporation method. The prepared magnetic colloids were evaluated for particle size, surface morphology, surface charge, drug loading capacity, and entrapment efficiency. The drug release studies indicated the sustained release of drug of 92% in 24 hours at physiological pH of 7.4 and drug release kinetics followed first order. The prepared nanoparticles and their colloids were also investigated for magnetic hyperthermia and specific absorption rate values were found to be 2.41, 2.71, and 4.28 W/g at 259, 327, and 518 kHz, respectively. The developed magnetic colloids have the potential to perform controlled hyperthermia and drug release to the target sites.     

Preparation and Characterization of Poly (D,L-Lactide-co-Glycolide) (PLGA) Nanoparticles Loaded with Linamarin for Controlled Drug Release

Poly (D,L-lactide-co-glycolide) nanoparticles loaded with linamarin as a model drug were successfully prepared using the double emulsion solvent evaporation technique. The physicochemical characterization of the formulated nanoparticles revealed that they were spherical, nonaggregated, and negatively charged, with good drug encapsulation efficiencies (>50%) and average particle sizes <200 nm. Interestingly, all the nanoparticles exhibited dibasic release profiles with a starting burst release within the first 8 h, followed by a controlled release phase lasting four days. Thus, linamarin-loaded nanoparticles indicate a promising candidate for controlled drug release applications.     

Formulation of pH-sensitive aminated chitosan–gelatin crosslinked hydrogel for oral drug delivery

The objective of this study is to develop efficient pH-sensitive hydrogel based on aminated chitosan (AmCs) and gelatin (Gel) biopolymers for oral drug delivery. Herein, AmCs was chemically crosslinked with gelatin (Gel) biopolymer with different ratios, while their structures, thermal profiles and morphological properties were investigated by FTIR, TGA and SEM characterization tools, respectively. Moreover, gel-content, crosslinking density and rheological analysis were also performed. The results clarified that the developed AmCs-Gel crosslinked hydrogel displayed variable pH-sensitive swelling profiles. By increasing AmCs ratio, the swelling ratio was boosted at pH 1.2 and declined at pH 7.4. Besides, by increasing gelatin ratio in the hydrogel matrix, the loading efficiency of Oseltamivir phosphate (as a model of drug) was augmented and reached maximum value of 79.0% by AmCs-Gel (2:3) crosslinked hydrogel. The in vitro drug release profiles were investigated for 6 h in simulated gastric fluid [SGF; pH 1.2] and simulated colon fluid [SCF; pH 7.4]. Variable release profiles were realized depending on variation of AmCs and Gel ratios in the crosslinked hydrogel matrix. Finally, the formulated smart crosslinked AmCs-Gel hydrogels demonstrated acceptable biodegradability with no cellular toxicity, suggesting their applicability as pH-sensitive oral drug carriers.     

Preparation of poly(butylene-co-ε-caprolactone carbonate) and their use as drug carriers for a controlled delivery system

Poly(butylene-co-ε-caprolactone carbonate) (PBCCL) was successfully synthesized via terpolymerization of carbon dioxide, 1,2-butylene oxide (BO), and ε-caprolactone (ε-CL). ε-CL was inserted into the backbone of BO-CO₂. The glass transition temperature (T_g) and the decomposition temperature (T_d) of PBCCL were much higher than those of poly(butylene carbonate) (PBC). The degradation rate of PBCCL was higher than that of PBC in a pH 7.4 phosphate-buffered solution. ε-CL offered an ester structural unit that gave the terpolymers remarkable degradability. PBC and PBCCL microcapsules containing a hydrophilic antibiotic drug pazufloxacin mesilate (PZFX) were elaborated by solvent evaporation method based on the formation of double W/O/W emulsion. Microcapsules were characterized in terms of the morphology, size, amount of encapsulated, and encapsulation efficiency. The results showed that the microcapsules had smooth and spherical surfaces, and the mean diameter of the microcapsules was in the range of 0.5–1 μm. Of all, 87.90% drug encapsulation efficiency has been achieved for microcapsules of 38.21% drug loading. In vitro drug release of these microcapsules was performed in a pH 7.4 phosphate-buffered solution. The release profiles were investigated from the measurement of PZFX presented in the release medium at various intervals. The release profiles of PZFX from PBC and PBCL microcapsules were found to be biphasic with a burst release followed by a gradual release phase. The release rate of PZFX from the microcapsules increased with increasing the content of ε-CL inserted into the copolymers. It showed that the release profiles of PZFX were highly polymer-dependent. © 2007 Wiley Periodicals, Inc. JPolym Sci Part A: Polym Chem 45: 2152–2160, 2007     

Identification of an Orally Bioavailable,Brain-Penetrant Compound with Selectivity for the Cannabinoid Type 2 Receptor

Modulation of the endocannabinoid system (ECS) is of great interest for its therapeutic relevance in several pathophysiological processes. The CB2 subtype is largely localized to immune effectors, including microglia within the central nervous system, where it promotes anti-inflammation. Recently, a rational drug design toward precise modulation of the CB2 active site revealed the novelty of Pyrrolo[2,1-c][1,4]benzodiazepines tricyclic chemotype with a high conformational similarity in comparison to the existing leads. These compounds are structurally unique, confirming their chemotype novelty. In our continuing search for new chemotypes as selective CB2 regulatory molecules, following SAR approaches, a total of 17 selected (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs were synthesized and tested for their ability to bind to the CB1 and CB2 receptor orthosteric sites. A competitive [³H]CP-55,940 binding screen revealed five compounds that exhibited >60% displacement at 10 μM concentration. Further concentration-response analysis revealed two compounds, 4k and 4q, as potent and selective CB2 ligands with sub-micromolar activities (K_i = 146 nM and 137 nM, respectively). In order to support the potential efficacy and safety of the analogs, the oral and intravenous pharmacokinetic properties of compound 4k were sought. Compound 4k was orally bioavailable, reaching maximum brain concentrations of 602 ± 162 ng/g (p.o.) with an elimination half-life of 22.9 ± 3.73 h. Whether administered via the oral or intravenous route, the elimination half-lives ranged between 9.3 and 16.7 h in the liver and kidneys. These compounds represent novel chemotypes, which can be further optimized for improved affinity and selectivity toward the CB2 receptor.     

Sodium alginate/HPMC/liquid paraffin emulsified (o/w) gel beads,by factorial design approach; and in vitro analysis

The present study involved development of a novel sodium alginate (SA)/HPMC/light liquid paraffin emulsified (o/w) gel beads containing Diclofenac sodium (DS) as an active pharmaceutical ingredient and its site specific delivery by using hard gelatin capsule fabricated by enteric coated Eudragit L-100 polymer. Emulsified gel beads were formulated by 3-level factorial design, ionic gelatin method. The obtained beads were characterized by Fourier transform infrared, X-ray diffraction and Field emission scanning electron microscope analysis. The variables such as SA (X₁), HPMC (X₂), were optimized for drug loading and in vitro drug release with the help of response surface methodology (RSM). The RSM analysis predicted that SA was significant for both drug loading (p = 0.0005) and drug release (p = 0.0041). HPMC was only significant for drug release (p = 0.0154). The cross-product contribution (2FI) and quadratic model were found to be adequate and statistically accurate with correlation value (R²) of 0.9054 and 0.9450 to predict the drug loading and drug release respectively. An increase in concentration of HPMC and SA decreases the drug loading as well as the drug release. The obtained optimum values of drug loading and DS released were 7.43 % and 85.54 % respectively, which were well in agreement with the predicted value by RSM.     

Formulation of Quaternized Aminated Chitosan Nanoparticles for Efficient Encapsulation and Slow Release of Curcumin

An effective drug nanocarrier was developed on the basis of a quaternized aminated chitosan (Q-AmCs) derivative for the efficient encapsulation and slow release of the curcumin (Cur)-drug. A simple ionic gelation method was conducted to formulate Q-AmCs nanoparticles (NPs), using different ratios of sodium tripolyphosphate (TPP) as an ionic crosslinker. Various characterization tools were employed to investigate the structure, surface morphology, and thermal properties of the formulated nanoparticles. The formulated Q-AmCs NPs displayed a smaller particle size of 162 ± 9.10 nm, and higher surface positive charges, with a maximum potential of +48.3 mV, compared to native aminated chitosan (AmCs) NPs (231 ± 7.14 nm, +32.8 mV). The Cur-drug encapsulation efficiency was greatly improved and reached a maximum value of 94.4 ± 0.91%, compared to 75.0 ± 1.13% for AmCs NPs. Moreover, the in vitro Cur-release profile was investigated under the conditions of simulated gastric fluid [SGF; pH 1.2] and simulated colon fluid [SCF; pH 7.4]. For Q-AmCs NPs, the Cur-release rate was meaningfully decreased, and recorded a cumulative release value of 54.0% at pH 7.4, compared to 73.0% for AmCs NPs. The formulated nanoparticles exhibited acceptable biocompatibility and biodegradability. These findings emphasize that Q-AmCs NPs have an outstanding potential for the delivery and slow release of anticancer drugs.     

Determination of the anxiolytic agent 8-chloro-6-(2-chlorophenyl)-4H-imidazo-[1,5-alpha] [1,4]-benzodiazepine-3-carboxamide in whole blood, plasma or urine by high-performance liquid chromatography

A rapid, sensitive and specific high-performance liquid chromatographic (HPLC) assay was developed for the determination of 8-chloro-6-(2-chlorophenyl)-4H-imidazo-[1,5-alpha]-[1,4]-benzodiazepine-3-carboxamide [I] and its 4-hydroxy metabolite, 8-chloro-6-(2-chlorophenyl)-4-hydroxy-4H-imidazo-[1,5-alpha] [1,4]-benzodiazepine-3-carboxamide [II] in whole blood, plasma or urine. The assay for both compounds involves extraction into diethyl ether-methylene chloride (70:30) from blood, plasma, or urine buffered to pH 9.0. The overall recoveries of [I] and [II] are 92.0 +/- 5.4% (S.D.) and 90.3 +/- 4.9% (S.D.), respectively. The sensitivity limit of detection is 50 ng/ml of blood, plasma, or urine using a UV detector at 254 nm. The HPLC assay was used to monitor the blood concentration-time fall-off profiles, and urinary excretion profiles in the dog following single 1 mg/kg intravenous and 5 mg/kg oral doses, and following multiple oral doses of 100 mg/kg/day of compound [I].     

Citric acid-loaded W1/O/W2 multiple emulsions efficiently remove colonic ammonia both in vitro and in vivo

Hepatic encephalopathy (HE) is a neuropsychiatric disorder caused by chronic and acute liver diseases. It is believed that ammonia played an important role on the pathogenesis of the disease. Herein, acid-loaded water-in-oil-in-water (W₁/O/W₂) multiple emulsions with over 95% encapsulation efficiency were prepared and used to absorb colonic ammonia. The study of citric acid release from W₁ to W₂ in bulk deionized water indicated that only 17% acid released in 8 hours, which proved the stability of the multiple emulsions and hence prevented the intestine from being irritated by acid burst release. In vitro, the W₁/O/W₂ emulsion could remove around 90% ammonia in 1.5 hours from either the 3 mmol/L ammonia solution or the artificial colonic fluid with 1 and 0.5 mmol/L ammonia without acidifying the artificial colonic fluid. In vivo, compared with lactulose, W₁/O/W₂ emulsions could efficiently reduce the blood ammonia to the similar level in the rat models with HE without increasing the water content in feces. All these results indicated a potential application of W₁/O/W₂ multiple emulsions for the treatment of HE.     

Ligation of the quinolone antibacterial agent pipemidic acid to Keggin polyoxotungstates

Three new drug molecules modifying Keggin polyoxometallate compounds have been synthesized under hydrothermal conditions and structurally characterized by routine techniques. Single-crystal X-ray diffraction analysis shows that compound 1 is constructed by a Keggin cluster and two [Cu(PPA)₂] drug complexes, formulated as [Cu(PPA)₂]₂·[PW₁₂O₄₀]·6H₂O. Compound 2 consists of a Cd substituted Keggin cluster [PW₁₁CdO₃₉] and five isolated HPPA drug molecules, formulated as [HPPA]₅·[PW₁₁CdO₃₉]·2H₂O. Compound 3 consists of a full oxidised Keggin [PW₁₂O₄₀] cluster and three isolated HPPA drug molecules, formulated as [HPPA]₃·[PW₁₂O₄₀]·2H₂O. Additionally, the antitumor activity of the three new compounds and their parent components in vitro were studied by a MTT experiment. The results show that introduction of TM-PPA/PPA into the polyoxoanion surface could increase their antitumor activity and make the compounds penetrate into the cells easily. Furthermore, the antitumor activity of the compounds can be modulated by their different structures.     

Hexanoate-Cucurbit[7]uril: Highly Soluble with Controlled Release Ability

Current drug delivery systems gain more functions with increased complexity. With the idea of less is more, we synthesized hexanoate-cucurbit[7]uril (CB[7]C₅COONa) with multiple promising features for drug delivery. The hexanoate group integrates multiple functions. It endows CB[7]C₅COONa extremely high solubility of over 600 mg mL⁻¹ and well-defined pH-controlled release ability without sacrificing on the high binding affinity of CB[7] cavity. Based on the pH-controlled release ability, CB[7]C₅COONa can be used for controlling the bioactivity of drug molecules. We anticipate that the strategy of function integration would be useful for the design of simple yet powerful drug delivery systems.     

Controlled release of amoxicillin from bacterial cellulose membranes

Bacterial cellulose (BC), a natural polymer with unique physical and mechanical properties, has several applications in the biomedical field, including drug loading and controlled drug delivery. For this study, a Box-Behnken experimental design was employed as a statistical tool to optimize the release of a model drug, amoxicillin, from BC membranes. Independent variables studied were the concentration of the drug (X₁), the concentration of glycerol (X₂) and the concentration of a permeation enhancer (X₃). From the variables studied, drug concentration had the highest effect on drug release. Among the other independent variables, th linear and quadratic X₂ terms, the linear X₃ term and the interaction term X₂X₃ were found to affect the release of amoxicillin from bacterial cellulose membranes.

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Modulation of the physicochemical state of interior agents to prepare controlled release liposomes

To prepare controlled release liposomes, freeze-drying of double emulsions (FDE) was employed to entrap a model drug, topotecan, which has been reported to tend to leak rapidly from vesicles. In addition, hydrogenated soy phosphatidylcholine (HSPC), N-(carbonyl-methoxypolyethyleneglycol2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (PEG-PE), and cholesterol (3:1:1, mass ratio) were used as the vesicle lipid. Different inner aqueous phases (W1) containing topotecan together with a variety of chemicals, such as citrate, sulfate, and divalent copper ions, were used to prepare W1/O/W2 double emulsions, which were then freeze-dried to obtain dry products. Upon rehydration, the dry products formed topotecan-entrapping unilamelar liposomes with an encapsulation efficiency of 80% and a mean diameter of less than 200 nm. The in vitro release experiments demonstrated that the drug release of topotecan-entrapping FDE liposomes could be successfully controlled through altering the state of the incorporated drug by means of protonation, precipitation, or forming a transition metal-complex. Specifically, the formulation of 300 mM CuSO₄ had a drug release half-life of 36 h. This novel method is a promising way to prepare controlled release liposomes that are more suitable for therapeutic application. In addition, the liposome formation mechanism was discussed based on micrographs and the size of the double emulsions and vesicles, as well as the small angle X-ray scattering pattern and transmission electron microscopy images.     

Stealth Liposomes (PEGylated) Containing an Anticancer Drug Camptothecin: In Vitro Characterization and In Vivo Pharmacokinetic and Tissue Distribution Study

Numerous attempts to overcome the poor water solubility of cam ptothecin (CPT) by various nano drug delivery systems are described in various sources in the literature. However, the results of these approaches may be hampered by the incomplete separation of free CPT from the formulations, and this issue has not been investigated in detail. This study aimed to promote the solubility and continuous delivery of CPT by developing long-lasting liposomes using various weights (M.W. 2000 and 5000 Daltons) of the hydrophilic polymer polyethylene glycol (PEG). Conventional and PEGylated liposomes containing CPT were formulated via the lipid film hydration method (solvent evaporation) using a rotary flash evaporator after optimising various formulation parameters. The following physicochemical characteristics were investigated: surface morphology, particle size, encapsulation efficiency, in vitro release, and formulation stability. Different molecular weights of PEG were used to improve the encapsulation efficiency and particle size. The stealth liposomes prepared with PEG₅₀₀₀ were discrete in shape and with a higher encapsulation efficiency (83 ± 0.4%) and a prolonged rate of drug release (32.2% in 9 h) compared with conventional liposomes (64.8 ± 0.8% and 52.4%, respectively) and stealth liposomes containing PEG₂₀₀₀ (79.00 ± 0.4% and 45.3%, respectively). Furthermore, the stealth liposomes prepared with PEG₅₀₀₀ were highly stable at refrigeration temperature. Significant changes were observed using various pharmacokinetic parameters (mean residence time (MRT), half-life, elimination rate, volume of distribution, clearance, and area under the curve) of stealth liposomes containing PEG₂₀₀₀ and PEG₅₀₀₀ compared with conventional liposomes. The stealth liposomes prepared with PEG₅₀₀₀ showed promising results with a slow rate of release over a long period compared with conventional liposomes and liposomes prepared with PEG₂₀₀₀, with altered tissue distribution and pharmacokinetic parameters.     

Control of prolonged drug release and compression properties of ibuprofen microspheres with acrylic polymer, eudragit RS, by changing their intraparticle porosity [corrected]

Prolonged-release spherical micro-matrices of ibuprofen with Eudragit RS were prepared using a novel emulsion-solvent diffusion method. Those particles were termed "microspheres" due to their characteristic sponge-like texture and unique dissolution and compression properties unlike conventional microcapsules or microspheres. The internal porosity of microspheres could be easily controlled by changing the concentration of the drug and the polymer in the emulsion droplet (ethanol). With lower concentration of ibuprofen in the ethanol, the resultant microspheres had a higher porosity, about 50%. The drug release rate from the microspheres was interpreted by the Higuchi model of spherical matrices, which depended only on their internal porosity of the microspheres when size distribution and drug content were the same. The tortuosities in the microspheres were found to be almost constant (3-4) irrespective of porosity, suggesting the same internal texture. Microsphere compressibility was much improved over the physical mixture of the drug and polymer owing to the plastic deformation of their sponge-like structure. The more porous microspheres produced stronger tablets [corrected].     

聚乳酸包载5-氟尿嘧啶靶向超微粒子对人胃癌转移瘤的靶向性和控制释放研究

使用w／o／w复乳法制备聚乳酸载5-氟尿嘧啶超微粒子,使用透射电镜、激光粒度仪和紫外分光光度计对超微粒子进行表征,并考察其体外释药性质。将^99mTc标记的连有VEGF121单克隆抗体的超微粒子通过尾静脉注射到SCID裸鼠体内,观察它对胃癌转移瘤的靶向效果和治疗效果。结果显示超微粒子成圆球形,平均粒径为195.2nm,多分散系数为0.148,靶向载药超微粒子的载药率为8．23％,包封率为24．71％。聚乳酸载5-Fu超微粒子在PBS缓冲溶液中具有较好的控释效果,累积释放量Q与时间平方根t^1/2基本呈线性关系．尾静脉注射靶向超微粒子两小时以后可看到大部分超微粒子集中到肿瘤部位。在所有的实验组中,含5-Fu靶向载药超微粒子组的疗效最好,说明本靶向载药超微粒子具有抑制肿瘤的血管生成并在肿瘤组织释放化疗药物抑制肿瘤生长的双重作用。     

pH- and H2O2-sensitive drug delivery system based on sodium xanthate: Dual-responsive supramolecular vesicles from one functional group

Nano-drug delivery systems with multiple stimulus-responsive capabilities have superior response performance and efficient drug release. Nevertheless, it is sophisticated to construct multiple stimulus-responsive systems where the two or more functional groups need to be introduced simultaneously. Xanthate, one functional group with pH and H₂O₂ stimulus responsiveness, has significant potential applications for building dual-responsive drug delivery system. Herein, we present a novel dual stimuli-responsive supramolecular drug delivery system by using sodium xanthate derivative (SXD) as guest molecule and quaternary ammonium capped pillar[5]arene (QAP5) as host molecule through host-guest interaction on the basis of electrostatic interaction. The amphiphile QAP5?SXD could self-assemble into vesicles to efficiently load the anti-cancer drug DOX. The experimental results showed that QAP5?SXD nanoparticles could achieve efficient drug delivery and controlled release in the tumor microenvironment. Cytotoxicity experiments proved that DOX@QAP5?SXD nanoparticles could significantly improve the anticancer efficiency of free DOX on cancer cells. The present study provides an efficient strategy to develop supramolecular nanocarriers with dual-responsiveness in one functional group for controlled drug release.