Physicochemical characterization of tacrolimus-loaded solid dispersion with sodium carboxylmethyl cellulose and sodium lauryl sulfate

To develop a novel tacrolimus-loaded solid dispersion with improved solubility, various solid dispersions were prepared with various ratios of water, sodium lauryl sulfate, citric acid and carboxylmethylcellulose-Na using spray drying technique. The physicochemical properties of solid dispersions were investigated using scanning electron microscopy, differential scanning calorimetery and powder X-ray diffraction. Furthermore, their solubility and dissolution were evaluated compared to drug powder. The solid dispersion at the tacrolimus/CMC-Na/sodium lauryl sulfate/citric acid ratio of 3/24/3/0.2 significantly improved the drug solubility and dissolution compared to powder. The scanning electron microscopy result suggested that carriers might be attached to the surface of drug in this solid dispersion. Unlike traditional solid dispersion systems, the crystal form of drug in this solid dispersion could not be converted to amorphous form, which was confirmed by the analysis of DSC and powder X-ray diffraction. Thus, the solid dispersion system with water, sodium lauryl sulfate, citric acid and CMC-Na should be a potential candidate for delivering a poorly water-soluble tacrolimus with enhanced solubility and no convertible crystalline.     

环孢素A植入微球的制备

目的制备长效环孢素A微球。方法以聚乳酸为基质,采用乳化-挥发法制备,正交设计优化制备工艺。结果优选制备工艺的重复性良好,环孢素A微球平均粒径为(84.6±3.4)μm,跨距为(0.68±0.13)μm,载药量为20.1%±1.2%,包封率为92.6%±2.7%。结论该处方和制备工艺合理可行。     

液相中制备尼群地平的固体分散体缓释微球液相中制备尼群地平的固体分散体缓释微球

目的在液相中制备尼群地平的固体分散体缓释微球并研究其影响因素。方法采用球晶造粒技术与溶剂沉积法相结合的方法,以滑石粉为固体分散体载体,Eudragit RS PO 为阻滞剂,在液相中一步制备尼群地平的固体分散体微球.考察了微球的收率、粉体性质及影响微球成形和释放速度的因素。结果采用该方法制备的尼群地平缓释微球圆整、均匀,粒径在280～900 μm的微球收率可达70%以上,堆密度在0.7 kg·L^-1左右,药物的包封率可达95%以上,微球的成形主要受溶剂系统中液体架桥剂量和不良溶剂中乳化剂的影响,药物从微球中的释放速度可通过调节处方中阻滞剂和分散剂的量的比例控制。结论本方法适用于难溶性药物制备缓释微球。     

HPLC法测定环胞素A微球中环胞素A的含量

目的测定环胞素A微球中环胞素A的含量。方法采用高效液相色谱法,色谱柱为C18柱（150mm×4．6mm,5μm）,流动相为乙腈-甲醇-水（54：23：23）,检测波长：213nm。结果环胞素A在5-80μg/ml范围内呈线性,平均回收率为99．6％,RSD=1．12％（n=9）。结论本方法简便、灵敏、准确,可用于环胞素A微球的质量控制。     

Incorporation of cyclosporin A in solid lipid nanoparticles (SLN)

The cyclic undecapeptide cyclosporin A (CyA) a potent immunosuppressive drug used in many therapies, is extremely hydrophobic. Commercial products employ solubilising agents to improve gastrointestinal absorption. In the present study CyA solid lipid nanoparticles (SLN) are prepared from warm o/w microemulsion, dispersed in cold water. The matrix chiefly consists of stearic acid, phosphatidylcholine and taurocholate; up to 13% of CyA can be incorporated. The average diameter of CyA-loaded SLNs is below 300 nm and transmission electron microscopy (TEM) analysis shows them to be spherical. In vitro release of CyA from SLNs is low. CyA-loaded SLNs can be proposed for most administration routes, in particular for the duodenal route.     

安乃近滴液在正常人体内的生物利用度

目的：对６例健康志愿者服用１ｇ安乃近滴液和１ｇ安乃近片剂的生物利用度进行比较。方法：采用高效液相色谱法测定受试者体内安乃近的活性代谢产物,４甲氨基安替比林（ＭＡＡ）血浆浓度,并计算药物动力学参数。结果：其ＭＡＡ在血浆中的达峰时间（ＴＰ）：滴液组平均为１．０８±０．２５ｈ,片剂组平均为１．３６±０．１３ｈ,Ｐ＜０．０５。其相对生物利用度（Ｆ＝ＡＵＣ滴剂／ＡＵＣ片剂）为１．３±０．４,Ｐ＞０．０５。结论：显示了安乃近滴剂起效快的特点     

In vitro and in vivo studies of cyclosporin A-loaded microspheres based on copolymers of lactide and epsilon-caprolactone: comparison with conventional PLGA microspheres

A hydrophobic peptide, cyclosporin A (CyA), was incorporated in microspheres based on poly(lactide-b-epsilon-caprolactone) (P(LA-b-CL), LA/CL (in molar ratio): 78.7/21.3 and 48.1/51.9) and poly(lactide-co-glycolide) (PLGA, LA/GA: 80/20) using oil-in-water (O/W) emulsion solvent evaporation method. The microspheres were characterized by SEM, DSC and X-ray diffraction, and CyA release rate was determined by HPLC. It was revealed that CyA can be efficiently loaded into all the microspheres (exceed 96%). Compared to PLGA microspheres, P(LA-b-CL) microspheres liberated CyA more rapidly. Within the first day, about 75, 50 and 12% of CyA released from P(LA-b-CL) (48.1/51.9), P(LA-b-CL) (78.7/21.3) and PLGA microspheres, respectively, which can be attributed to the partial crystallization occurring in P(LA-b-CL) microspheres. CyA levels in whole blood were also tested. In comparison with PLGA microspheres, P(LA-b-CL) microspheres provided a higher blood level of CyA. The maximum CyA concentration in whole blood (approximately 520, 450 and 400 ng ml(-1) for P(LA-b-CL) (48.1/51.9) P(LA-b-CL) (78.7/21.3) and PLGA microspheres, respectively) was reached at the second day post administration. And then P(LA-b-CL) microspheres showed a constant CyA level (about 100-200 ng ml(-1)) for extended periods of time (several weeks). Such CyA-loaded P(LA-b-CL) microspheres displaying higher CyA concentration during the first few days and similar constant blood CyA level thereafter showed more advantages than those prepared with PLGA and could meet clinical needs more efficiently.     

A mathematical approach to predicting the percutaneous absorption enhancing effect of sodium lauryl sulphate

A study has been made of the effect of sodium lauryl sulphate (SLS) at several concentrations from 0.24 to 5% (w/w) on skin permeability. Seven model drugs were selected for this study on the basis of their lipophilicity as represented by their logP(oct) values (from -0.95 to 4.2). Skin pre-treatment with aqueous solutions of SLS does not increase the permeability coefficient of the most lipophilic compounds (logP(oct)> or =3). For the other compounds assayed the increase in the permeability coefficients depends on the concentration of SLS used in the skin pre-treatment, and on the lipophilicity of the compounds tested.The correlation between the inverse of SLS efficacy as an enhancer (1/ER) and the lipophilicity (logP(oct)) of the model permeants was established via a hyperbolic equation. This model makes it possible to predict the percutaneous absorption enhancing effect of SLS, expected for a compound of specific lipophilicity, according to the concentration used in skin pre-treatment. An excellent accuracy (r(2)>0.94) for the linear relationship between the experimental (n=15) and theoretical (ER) values predicted by the equation was obtained. The model proposed was also useful for experimental data obtained previously using Azone and compounds with the same range of lipophilicity.     

The influence of salinity on sodium lauryl sulfate toxicity in Mytilus galloprovincialis

The influence of salinity on the effects of sodium lauryl sulfate (SLS) was evaluated using the Mediterranean mussel Mytilus galloprovincialis, exposed for 28 days to SLS (control-0.0 and 4.0 mg/L) under three salinity levels (Control-30, 25 and 35). The effects were monitored using biomarkers related to metabolism and energy reserves, defence mechanisms (antioxidant and biotransformation enzymes) and cellular damage. The results revealed that non-contaminated mussels tended to maintain their metabolic capacity regardless of salinity, without activation of antioxidant defence strategies. On the contrary, although contaminated mussels presented decreased metabolic capacity at salinities 25 and 35, they were able to activate their antioxidant mechanisms, preventing cellular damage. Overall, the present findings indicate that SLS, especially under stressful salinity levels, might potentially jeopardize population survival and reproduction success since reduced metabolism and alterations on mussels’ antioxidant mechanisms will impair their biochemical and, consequently, physiological performance.     

局部应用环孢素A聚乳酸微球的性状及释药研究

目的对局部应用环孢素A聚乳酸微球的性状及其在体外、体内释放进行研究。方法通过采用O/W型乳化-溶剂挥发法制备环孢素A聚乳酸微球。观察微球分散度、粒径及外观形态及体外释药特性,对比全身与局部给药后全血中及气管组织中的环孢素A药物浓度。结果环孢素A聚乳酸微球的形态圆整,平均粒径18.234μm,跨距:1.131,粒径在9.525～32.400μm者占总数的80%以上。包封率为(86.1±0.8)%,载药量为(34.5±0.6)%。环孢素A聚乳酸微球的体外释药情况:30d的累积释药量为40.8%,采用局部埋植微球后前2周可以维持较高的血药浓度,2周后也可以维持在200ng/ml的药物浓度。结论环孢素A聚乳酸微球具有较好的缓释性能。局部应用可获得有效的血药浓度,在局部气管组织中的药物浓度高于全身用药组。     

双氯芬酸钠明胶微球的制备

目的：对双氯芬酸钠明胶微球的处方及制备工艺进行初步研究。方法：以生物降解材料明胶为载体,采用乳化交联法制备双氯芬酸钠明胶微球;单因素考察的基础上,利用正交实验设计筛选最佳处方和工艺;建立紫外分光光度法测定微囊中恩诺沙星的包封率和载药量的方法。结果：所制备的双氯芬酸钠明胶微球外形圆整,大小均匀,载药量为2.05%,包封率为37.67%。结论：获得较为满意的双氯芬酸钠明胶微球。     

Ethyl formate - alternative dispersed solvent useful in preparing PLGA microspheres

In an effort to substitute methylene chloride with a less toxic solvent, this study was aimed at developing new ethyl formate-based emulsion processes to fabricate poly-D,L-lactide-co-glycolide (PLGA) microspheres. To do so, a polymeric dispersed phase was emulsified in a 1% polyvinyl alcohol aqueous solution at an ethyl formate to aqueous volume ratio of 8:20. Microsphere hardening was then achieved by solvent evaporation and quenching techniques. The average encapsulation efficiency of a model drug progesterone amounted to 95.2+/-2.7%. When the tendency of ethyl formate and methylene chloride to evaporate to air was compared, the evaporation rate of ethyl formate was 2.1 times faster than that of methylene chloride. The ease with which ethyl formate evaporated to air was beneficial in shortening the microsphere hardening step. For the solvent quenching process, only 80 ml of additional water was required to extract ethyl formate to the aqueous phase, due to its considerable water miscibility. In particular, the timing of ethyl formate quenching affected to a great extent dynamic processes of the breakup of elementary microdroplets into smaller ones. Therefore, variations in quenching time affected microsphere characteristics such as the degree of solvation, size distribution, and tendency to aggregate on drying. The results of this study showed that PLGA microspheres were successfully prepared using the new ethyl formate-based processes.     

A novel preparation of solid lipid nanoparticles with cyclosporin A for prolonged drug release

Solid lipid nanoparticles were prepared by a novel solvent diffusion method in an aqueous system. The lipophilic model drug cyclosporin A was incorporated into SLN to study encapsulation efficiency, zeta potential (charge) and drug delivery. Stearylamine and cyclosporin A were dissolved in ethanol and acetone and the resultant organic solution was dropped into water at 60 degrees C. The drug-loaded SLN suspension quickly formed with an azury color. After burst drug release with 18% of the drug over the first 12 hours, a distinctly prolonged release over a monitored period of 16 days was observed, with nearly 4% of the drug being released each day. These results demonstrate the suitability of SLN produced with the proposed method as a prolonged release formulation for lipophilic drugs.     

Bioavailability enhancement of ondansetron after nasal administration of Caesalpinia pulcherrima-based microspheres

Abstract

Context: Natural polymers have attracted a great deal of attention for use as potential carriers in site-specific delivery over past decades. Mucoadhesive microspheres are useful tools for nasal drug delivery.

Objectives: To prepare and evaluate mucoadhesive microspheres as mode for nasal delivery of ondansetron using Caesalpinia pulcherrima galactomannan (CPG).

Materials and methods: Conventional spray-dried CPG nasal microspheres loaded with ondansetron for intranasal drug delivery in order to avoid the first pass metabolism with improved therapeutic efficiency in treatment of nausea and vomiting as an alternative therapy to parenterals. Developed microspheres were evaluated for characteristics like particle size, entrapment efficiency, zeta potential, swelling ability, in-vitro mucoadhesion, in-vitro drug release, DSC, XRD study and histopathological evaluation of tissue. CPG-based ondansetron microspheres were studied in rabbits for screening nasal absorption potential of nasal formulation.

Results: Developed nasal microspheres possess entrapment efficiency of 80–89%, higher mucoadhesion of 72–84% across goat nasal mucosa. In-vivo study showed that microspheres based on mucoadhesive polymer were able to promote quick drug absorption as well as enhanced bioavailability of drug.

Discussion: Histopathological studies evaluated biocompatible and nontoxic nature of CPG in nasal cavity. Developed mucoadhesive microspheres by nasal route showed enhancement of bioavailability as compared to oral route in rabbits.

Conclusion: CPG-based mucoadhesive microspheres can successfully deliver ondansetron intranasally, sustain its effect, avoid first pass effect, an alternative route of administration to injection and thus enhance systemic bioavailability of ondansetron hydrochloride.     

Weak bases and formation of a less soluble lauryl sulfate salt/complex in sodium lauryl sulfate (SLS) containing media

This work reports on the solubility of two weakly basic model compounds in media containing sodium lauryl sulfate (SLS). Results clearly show that the presence of SLS in the media (e.g. simulated gastric fluid or dissolution media) can result in an underestimation of solubility of some weak bases. We systematically study this phenomenon and provide evidence (chromatography and pXRD) for the first time that the decrease in solubility is likely due to formation of a less soluble salt/complex between the protonated form of the weak base and lauryl sulfate anion.     

Sustained release properties of alginate microspheres and tabletted microspheres of diclofenac sodium

This study focused on the properties of diclofenac sodium (DNa) alginate (alg) microspheres and tabletted DNa alg microspheres using different polymers as additives. DNa alginate microspheres were prepared by the emulsification method and different polymers such as Eudragit (Eud) NE 30 D, Eudragit (Eud) RS 30 D and Aquacoat, which were incorporated into alg gel to control the release rate of drug. The release properties of DNa alg microspheres (1:1) were affected by the size, drug load of microspheres and also by the incorporated polymers, pH and ionic strength of dissolution medium. Tabletting of alg microspheres using carrageenan (carr), alg, pectin, NaCMC, tragacanth (trgh) and HPMC as additives in a (50:50) ratio produced tablets with good physical properties and also better controlled release of DNa. Dissolution studies were carried out in pH7.2 phosphate buffer and phosphate buffers whose pH values were gradually changed from pH 3 to 7.4. The rank order of DNa release from tablets was carr<alg<pectin<NaCMC<trgh<HPMC which relates to the viscosity and swelling properties of polymers. The drug release was very slow from trgh and HPMC based tablets, but addition of carr or alg in different ratios could adjust the release rate of drug.