Stability of ascorbyl palmitate in topical microemulsions.

Ascorbyl palmitate and sodium ascorbyl phosphate are derivatives of ascorbic acid, which differ in stability and hydro-lipophilic properties. They are widely used in cosmetic and pharmaceutical preparations. In the present work the stability of both derivatives was studied in microemulsions for topical use as carrier systems. The microemulsions were of both o/w and w/o types and composed of the same ingredients. The stability of the less stable derivative ascorbyl palmitate was tested under different conditions to evaluate the influence of initial concentration, location in microemulsion, dissolved oxygen and storage conditions. High concentrations of ascorbyl palmitate reduced the extent of its degradation. The location of ascorbyl palmitate in the microemulsion and oxygen dissolved in the system together significantly influence the stability of the compound. Light accelerated the degradation of ascorbyl palmitate. In contrast, sodium ascorbyl phosphate was stable in both types of microemulsions. Sodium ascorbyl phosphate is shown to be convenient as an active ingredient in topical preparations. In the case of ascorbyl palmitate, long-term stability in selected microemulsions was not adequate. To formulate an optimal carrier system for this ingredient other factors influencing the stability have to be considered.     

Skin protection against ultraviolet induced free radicals with ascorbyl palmitate in microemulsions.

UV irradiation induces free radical formation in the skin. UV filters and antioxidants can be used for protection. In the present work, the amphiphilic antioxidant ascorbyl palmitate has been investigated and its effectiveness against free radical formation in porcine skin determined with electron paramagnetic resonance (EPR) spectroscopy with a spin trapping technique. 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline-N-oxide (DEPMPO) was used as spin trap. In this study, three different radicals were identified in UV irradiated porcine ear skin: two originated from sulphur centred radicals (SO(3)*), while the third was the carbon-centred acyl (C=O*) radical. Ascorbyl palmitate applied on the skin decreased the level of formation of free radicals. Its effectiveness depended significantly on the carrier system - the type of microemulsion and its concentration, while the time of application had no influence on its effectiveness. Oil in water microemulsions delivered ascorbyl palmitate to the skin significantly better than water in oil microemulsions. In both types of microemulsions, the effectiveness increases at higher concentrations of ascorbyl palmitate.     

Positively charged microemulsions for topical application

The study reports pig-skin permeation and skin accumulation of miconazole nitrate (MCZ) from positively charged microemulsions containing water, 1-decanol/1-dodecanol (2:1, w/w), lecithin and/or decyl polyglucoside at different weight ratios, propylene glycol, 1,2 hexanediol and a cationic charge-inducing agent (stearylamine (ST), l-alanine benzyl ester (ALAB) or cetyltrimethylammonium bromide (CTAB)). Zeta-potential values of the positively charged microemulsions ranged from 14.2 to 37.5 mV and mean droplet size from 6.0 to 16.8 nm. In vitro pig-skin permeation of MCZ after a single 24h application was negligible for all microemulsions; accumulation from positively charged microemulsions was nearly twice that from their negatively charged counterparts. The increased accumulation might be ascribed to the interaction between positive microemulsive systems and negatively charged skin sites; no significant difference was observed among the various cationic charge-inducing agents. Skin accumulation from the microemulsion containing most lecithin was lower than those of other microemulsions; this was ascribed to the phase transformation from microemulsion to a liquid crystal system after skin contact. These results suggest that positively charged microemulsions could be used to optimize drug targeting without a concomitant increase in systemic absorption; ALAB, an ester of a natural amino acid, is an appropriate cationic charge-inducing agent.     

Magnesium ascorbyl phosphate vesicular carriers for topical delivery; preparation,in-vitro and ex-vivo evaluation,factorial optimization and clinical assessment in melasma patients

Ascorbic acid (vitamin C) is an antioxidant that is widely used in cosmetics in skincare products. Due to the excessive low stability of ascorbic acid in cosmetic formulations, the stabilized ascorbic acid derivative, magnesium ascorbyl phosphate (MAP) was formulated as vesicular carriers; ethosomes and niosomes. The aim was to deliver MAP at the intended site of action, the skin, for sufficient time with enhanced permeation to get an effective response. Ethosomes were formulated using a full 3² factorial design to study ethanol and phospholipid concentration effect on ethosomes properties. Niosomes were formulated using 2³ factorial designs to study the effect of surfactant type, surfactant concentration and cholesterol concentration on niosomes properties. The prepared formulations were evaluated for their Entrapment efficiency, particle size, polydispersity index, zeta potential and % drug permeated. The optimized ethosomal and niosomal formulations were incorporated into carbopol gel and evaluated for their permeation, skin retention and stability. A comparative split-face clinical study was done between the ethosomal and niosomal formulations for melasma treatment using Antera 3 D^® camera. The optimized ethosomal and niosomal gels showed comparable controlled permeation and higher skin retention over their ethosomes and niosomes formulations respectively. Magnesium ascorbyl phosphate ethosomal gel showed clinically and statistically significant melanin level decrease after one month while MAP niosomal gel showed clinically and statistically significant melanin level decrease after six months. A combination of MAP ethosomes and niosomes could be promising skincare formulations for melasma and hyperpigmentation short and long-term treatment.     

Investigation of liposomes as carriers of sodium ascorbyl phosphate for cutaneous photoprotection

Long-term exposure of the skin to UV-A and UV-B radiation causes degenerative effect which can be decreased by scavenging reactive photochemical intermediates with antioxidants. In this study sodium ascorbyl phosphate (SAP), a very effective oxygen species scavenger, was encapsulated into liposomes in order to improve its penetration through the stratum corneum into the deeper layers of the skin. Two types of multilamellar vesicles were prepared, one from non-hydrogenated and the other from hydrogenated soybean lecithin, together with cholesterol, by the thin films method. They were characterized for size, polydispersity index, and zeta potential. In vitro diffusion of SAP and ex vivo penetration experiments were performed on pig ear epidermis membrane in a Franz diffusion cell. The size and zeta potential of liposomes containing SAP are significantly greater than those of empty liposomes. The upper limit of SAP entrapment efficiency was 8-10% in both types of liposomes. The stability of SAP in liposome formulations is much more influenced by storage temperature than by liposome composition. SAP penetrated through epidermis membrane significantly better from liposome dispersions than from water solution. The amount penetrating is much more influenced by the concentration of SAP in the formulation than by the lipid composition of liposomes. The SAP that penetrates through the epidermis reflects the active compound available to prevent or slow down the complex process of photodamage in the skin.     

Stability of vitamins C and E in topical microemulsions for combined antioxidant therapy

An interesting strategy for protecting skin from excessive exposure to free radicals is to support the skin endogenous antioxidant system. As the balance between different skin antioxidants is very important, a combined therapy using at least two antioxidants is desirable. In the present work, o/w, w/o, and gel-like microemulsions (ME), all composed of the same ingredients, were selected as carrier systems for dermal delivery of vitamins C and E. Gel-like ME was found to offer the best protection for both vitamins, although other ME also significantly increased their stability compared with that solution. In the presence of vitamin C no decrease in vitamin E content occurred. To obtain ME appropriate for dermal use, their viscosity was increased by adding thickening agents. On the basis of visual examination of viscosity and physical stability of thickened systems, several thickeners were selected. The addition of thickener significantly increased the viscosity of ME and changed the behavior of systems from ideal Newtonian to thixotropic. Finally, the stability of both vitamins was examined as a function of thickening agent and of the location of vitamins in the ME. The addition of thickeners changed the stability of at least one vitamin, but the systems generally still protected vitamins better than solutions. It is likely that the changes in internal organization of ME resulting from the addition of thickener, confirmed by thermal analysis and changes in solubility of oxygen in the outer phase, were the most important factors that influenced the stability of vitamins in thickened systems.     

流动注射微乳液化学发光法测定片剂和注射剂中磷酸可待因的含量

目的:建立测定磷酸可待因的化学发光快速分析方法。方法:在酸性条件下,磷酸可待因被质子化后与阴离子AuCl4-形成离子缔合物,该缔合物被二氯甲烷带入鲁米诺的十六烷基三甲基氯化铵(CTAC)微乳液中,离解出来的AuCl4-立即与鲁米诺产生化学发光。在一定浓度范围内,发光强度与磷酸可待因的含量成线性关系,从而间接测定磷酸可待因的含量。结果:在优化的试验条件下,磷酸可待因的检测线性范围为0.001～15μg·mL-1,检出限(3σ)为0.03 ng·mL-1,对浓度为1.0μg·mL-1的磷酸可待因进行11次平行测定,其RSD为1.2%。结论:该法快速、简便,已成功用于片剂、针剂和尿样中磷酸可待因的测定。     

Simultaneous absorption of vitamins C and E from topical microemulsions using reconstructed human epidermis as a skin model

Antioxidants provide the mainstay for skin protection against free radical damage. The structure of microemulsions (ME), colloidal thermodynamically stable dispersions of water, oil and surfactant, allows the incorporation of both lipophilic (vitamin E) and hydrophilic (vitamin C) antioxidants in the same system. The objective of this work was to investigate the potential of non-thickened (o/w, w/o and gel-like) and thickened (with colloidal silica) ME as carriers for the two vitamins using reconstructed human epidermis (RHE). The amounts of these vitamins accumulated in and permeated across the RHE were determined, together with factors affecting skin deposition and permeation. Notable differences were observed between formulations. The absorption of vitamins C and E in RHE layers was in general enhanced by ME compared to solutions. The incorporation of vitamins in the outer phase of ME resulted in greater absorption than that when vitamins were in the inner phase. The location of the antioxidants in the ME and affinity for the vehicle appear to be crucial in the case of non-thickened ME. Addition of thickener enhanced the deposition of vitamins E and C in the RHE. By varying the composition of ME, RHE absorption of the two vitamins can be significantly modulated.     

Lecithin microemulsions for the topical administration of ketoprofen: percutaneous adsorption through human skin and in vivo human skin tolerability

The potential application of highly biocompatible o/w microemulsions as topical drug carrier systems for the percutaneous delivery of anti-inflammatory drugs, i.e. ketoprofen, was investigated. Microemulsions were made up of triglycerides as oil phase, a mixture of lecithin and n-butanol as a surfactant/co-surfactant system and an aqueous solution as the external phase. To evaluate the percutaneous enhancing effect of oleic acid, this compound was used as a component of some o/w microemulsions. The topical carrier potentialities of lecithin-based o/w microemulsions were compared with respect to conventional formulations, i.e. a w/o emulsion, a o/w emulsion and a gel. Physicochemical characterisation of microemulsions was carried out by light scattering and zeta potential analyses. Microemulsions showed mean droplet size < 35 nm and a negative zeta potential, that is -39.5 mV for the oleic acid-lecithin microemulsion and -19.7 mV for the lecithin-based microemulsion. The percutaneous adsorption of the various topical formulations was evaluated through healthy adult human skin, which was obtained from abdominal reduction surgery. Ketoprofen-loaded microemulsions showed an enhanced permeation through human skin with respect to conventional formulations. No significant percutaneous enhancer effect was observed for ketoprofen-loaded oleic acid-lecithin microemulsions. The human skin tolerability of various microemulsion formulations was evaluated on human volunteers. Microemulsions showed a good human skin tolerability.     

Transporter-mediated effects of diclofenamic acid and its ascorbyl pro-drug in the in vivo neurotropic activity of ascorbyl nipecotic acid conjugate

Continuing our studies on SVCT2 ascorbic acid (AA) transporter-mediated drug delivery of neurotropic agents, we have now investigated the in vitro intracellular uptake of Diclofenac (Diclo) and its conjugate (AA-Diclo), both characterized by high affinity for the SVCT2 transporter. We have also investigated the in vivo uptake mechanism of AA-conjugate of Nipecotic acid (AA-Nipec) and the implication of the transporter-mediated effects of Diclo and AA-Diclo. Diclo resulted as a noncompetitive inhibitor of AA transport, but also showed a sodium-dependent and ascorbate-independent uptake, thus implying the possible involvement of specific transporters in the delivery to the brain of Diclo. This result opens a perspective in the discovery of new strategies in the targeting of this drug to the brain. Inhibitory effects of Diclo and AA-Diclo on the SVCT2 transporter were used to study anticonvulsant effects of AA-Nipec, confirming our hypothesis of an SVCT2-mediated transport in its neurotropic activity. AA-Diclo stability has been also investigated: it is hydrolyzed following a first-order kinetics in buffer, plasma (t(1/2) at about 10 h) and whole blood (t(1/2) at about 3 h), suggesting AA-Diclo as a potential candidate to enhance the short half-life of Diclo in vivo.     

维生素C糖苷类衍生物的研究进展

维生素C(vitamin C,VC)是人体的必需营养元素,在保护人类健康和动物生长过程中起到不可代替的重要作用。由于VC自身易被氧化降解,开发稳定的高附加值VC衍生物就成为人们研究的热点。目前,VC衍生物主要有VC盐、VC酯和VC糖苷3种形式,其中VC糖苷类衍生物稳定性高,生理活性与VC最接近,近年来备受国内外学者的关注。因此,本文就VC上的C2-,C5-及C6-糖苷类衍生物的国内外研究进展进行了归纳总结。     

药用辅料抗坏血酸棕榈酸酯的细菌内毒素检查法研究

目的:建立"三氯甲烷溶解后加水振荡萃取"抗坏血酸棕榈酸酯细菌内毒素检查方法.方法:抗坏血酸棕榈酸酯,加入三氯甲烷使溶解,加入不同体积的BET水,旋涡混匀30 s以上,5000 r·min-1离心2 min,取上清液,制成供试品溶液和供试品阳性对照,抗坏血酸棕榈酸酯浓度在相当于1.0 mg·mL-1以下时,对λ为0.25...     

Gelation of microemulsions and release behavior of sodium salicylate from gelled microemulsions

A novel gelled microemulsion was prepared in the presence of the low molecular weight gelator N-stearine-N′-stearyl-l-phenylalanine at a very low concentration. It is completely different from the conventional microemulsion-based gels (MBGs) usually formed by polymeric gelling agents, such as gelatin, agar and κ-carrageenan. The microemulsion consists of i-propyl myristate, Tween 80, propylene glycol and water. The gelled microemulsions showed good thermo-reversibility. The gel-to-sol transition temperature (T_GS) of gelled microemulsion depends upon the concentration of gelator and the composition of the microemulsions. The gelation mechanism was investigated by polarized optical microscopy (POM) and FT-IR. POM images show elongated and strand-like crystallites formed by the aggregation of the gelator, ultimately resulting in the gelation of the microemulsion. FT-IR analysis indicates that intermolecular hydrogen bonds are responsible for the formation of gelator aggregates. Water-soluble sodium salicylate was used as a model drug for the investigation of the release from the gelled microemulsions. The release profiles exhibited a controlled release and followed the first-order release kinetics. The release rates decreased with an increase of the gelator and isopropyl myristate contents. These results reveal potential applications of gelled microemulsion in drug delivery systems.     

磷酸肌酸钠治疗充血性心力衰竭的疗效及安全性评价

目的 评价磷酸肌酸钠治疗充血性心力衰竭的疗效及安全性.方法 选取2010年1月-2013年9月广州市妇女儿童医疗中心收治的98例充血性心力衰竭患者,随机将患者分为观察组和对照组,每组49例.对照组患者采用常规药物治疗,而观察组则在对照组的基础上加用磷酸肌酸钠治疗.结果 观察组总有效率85.7%高于对照组总有效率67.3%,差异有统计学意义（P＜0.05）.两组均未见明显不良反应.结论 磷酸肌酸钠可以有效改善患者的病情,而且安全性好,具有很好的临床价值.     

Development of ascorbyl palmitate nanocrystals applying the nanosuspension technology

Ascorbyl palmitate (AP) is an antioxidant used in both cosmetics and food industry. Owing to its poor solubility and instability caused by oxidation having been observed in several colloidal systems, the aim of this study was to investigate the feasibility of applying the nanosuspension technology by high-pressure homogenization (HPH) (DissoCubes) technology) to enhance the chemical stability of AP, followed by lyophilization. Sodium dodecyl sulfate (SDS) and Tween 80 were chosen as emulsifying agents to stabilize the developed AP nanosuspensions. After 3 months of storage at three different temperatures (4 degrees C, 25 degrees C and 40 degrees C), the photon correlation spectroscopy (PCS) analysis of AP nanosuspensions revealed that the mean particle size of those stabilized with SDS significantly increased compared to those stabilized with Tween 80. The results observed from both atomic force microscopy (AFM) and scanning electron microscopy (SEM) revealed AP nanocrystals of cubic-like shape. The percentage of AP remaining in nanosuspensions stabilized with Tween 80 was higher than 90% after 3 months storage at 4 degrees C, 25 degrees C and 40 degrees C. To increase the chemical stability of AP nanosuspensions, a drug powder was prepared by lyophilization. The effect of the presence of cryoprotectant trehalose on the physical stability was evaluated at different concentrations. After redispersing the lyophilized product, the mean size of AP nanosuspensions without trehalose was significantly higher compared with the system with trehalose. After 3 months of storage at 25 degrees C the mean size of lyophilized AP nanosuspensions remained constant. X-ray diffraction revealed the crystalline character of AP nanocrystals after HPH and lyophilization.     

Stable drug encapsulation in micelles and microemulsions

Oral absorption of hydrophobic drugs can be significantly improved using lipid-based non-particulate drug delivery systems, which avoid the dissolution step. Micellar and microemulsion systems, being the most dispersed of all, appear the most promising. While these systems show high drug entrapment and release under sink conditions, the improvement in oral drug bioavailability is often unpredictable. The formulation and drug-related biopharmaceutical aspects of these systems that govern oral absorption have been widely studied. Among these, preventing drug precipitation upon aqueous dilution could play a predominant role in many cases. Predictive ability and quick methods for assessment of such problems could be very useful to the formulators in selecting lead formulations. This review will attempt to summarize the research work that could be useful in developing these tools.     

The safety and efficacy of clindamycin phosphate foam 1% versus clindamycin phosphate topical gel 1% for the treatment of acne vulgaris

Clindamycin phosphate is the most widely used topical antibacterial agent for acne treatment. Treatment of patients with mild to moderate acne vulgaris with a new foam formulation (clindamycin foam, CF) for 12 weeks was at least as effective as clindamycin gel (CG) based on the Investigator's Static Global Assessment (ISGA) score. CF was superior to CG based on the reduction from baseline in total (P = .0014), inflammatory (P = .0478), and noninflammatory (P = .0037) acne lesion counts. Additionally, CF achieved efficacy that was superior to that of vehicle foam based on ISGA score (P = .0025) and all 3 lesion counts (all P < .05). Adverse experiences in the active treatment groups were mild or moderate and transient in nature. Thus the foam formulation of clindamycin is a safe and effective acne treatment; the unique foam delivery vehicle may offer cosmetic benefits to the patient and thus increase compliance.     

Parenteral microemulsions: an overview

Parenteral delivery of the hydrophobic drugs is a very challenging task. The conventional approaches such as use of co-solvents, oily vehicles and modern approaches such as mixed micelles, liposomes, complexation with cyclodextrins and emulsions have several limitations. Microemulsions have evolved as a novel vehicle for parenteral delivery of the hydrophobic drugs. Their interesting features such as spontaneity of formation, ease of manufacture, high solubilization capacity and self-preserving property make them the vehicle of choice. The review focuses on the excipients available for formulation of the parenteral microemulsions and describes the investigations reported for the various classes of therapeutic agents.