Microencapsulation and oxidative stability of spray-dried fish oil emulsions

Emulsions of menhaden oil and sodium caseinate (NaCas) incorporating carbohydrates of varying dextrose equivalence (DE) were spray-dried to yield encapsulated fish oil powders. The effects of carbohydrate DE (5.5-38), core/wall ratio and NaCas/carbohydrate ratio on microencapsulation efficiency (ME) and oxidative stability of spray-dried emulsions were examined. The effect of alpha-tocopherol or Trolox C addition on the oxidative stability of herring oil emulsions and powders was also determined. ME of fish oil powders was greater than 90% in most cases. Peroxide value (PV) of menhaden oil powders decreased on increasing the DE of carbohydrates. PV of menhaden oil powders increased as core/wall ratio increased from 0.33-1.0. NaCas/DE 28 ratio did not affect PV values of powders. The addition of alpha-tocopherol or Trolox C decreased PV throughout the storage period; this effect was most pronounced for alpha-tocopherol added to the oil at a concentration of 100 ppm. Addition of alpha-tocopherol delays the onset of oxidation in stored fish oil powders.     

Effect of carrier excipient and processing on stability of indorenate hydrochloride/excipient mixtures.

The purpose of this investigation was to determine the solid-state chemical stability of a model drug, indorenate hydrochloride, as a function of carrier excipient and mixing process. Physical mixtures and granules were prepared by tumble mixing and alcoholic granulation with and without binder. Stability of the mixtures was estimated using differential scanning calorimetry and isothermal degradation studies at 40, 50, and 60 degrees C. Average first-order degradation constants at 25 degrees C, extrapolated from isothermal studies, were much lower for indorenate hydrochloride after tumbling mixing with microcrystalline cellulose (3.45 x 10(-5) day-1) than those obtained after tumbling mixing with lactose (112.0 x 10(-5) day-1). Distribution of the drug on the excipient's surface, through granulation with and without Povidone, increased the average drug degradation rates in granules with microcrystalline cellulose (36.2 x 10(-5) day-1) as well as in granules with lactose (326 x 10(-5) day-1). Partially amorphous lactose (spray-dried lactose) showed higher average degradation rates (310.5 x 10(-5) day-1) than crystalline lactose (199.3 x 10(-5) day-1). It appears that the amorphous portion of the drug as well as that of reacting excipients play a major role in affecting the reaction rate. The calorimetric studies showed a strong solid-solid interaction between indorenate hydrochloride and lactose, suggesting chemical incompatibility. This strong solid-solid interaction was characterized by disappearance of typical transition peaks of lactose at temperatures above 200 degrees C and the development of new peaks at about 130-170 degrees C. No major changes in transition peaks were observed in mixtures of microcrystalline cellulose and indorenate hydrochloride, suggesting chemical compatibility. Calorimetric results allow the prediction of the chemical incompatibility between indorenate hydrochloride and lactose observed in isothermal degradation studies.     

固体稳定性和辅料相容性的研究进展

固体稳定性和辅料相容性对新产品研制起着重要作用，现综述固体药物的稳定性和辅料相容性的研究进展，通过对固体稳定性的动力学模型以及影响固体稳定性的化学和物理因素的分析，提出提高固体稳定性、辅料相容性研究的多种方法，为新剂型开发提供有用信息。     

Effect of surface charge on the stability of oil/water emulsions during steam sterilization

Intravenous lipid emulsions are used for total parenteral nutrition and as carriers for lipophilic drugs. Exposure to the high temperature (121 degrees C) required for steam sterilization may cause coalescence and an increase in droplet size. The purpose of this study was to investigate whether an increase in the electrostatic repulsive force between oil droplets produced by formulation modification improves the thermal stability of lipid emulsions during autoclaving. The addition of a small amount, 0.66 or 1.32 mmol/kg (mm), of purified anionic phospholipid fractions (phosphatidic acid, phosphatidylglycerol, or phosphatidylinositol) to the standard formula increased the zeta potential from its normal value of -11 mV to -39 mV. Emulsions with the larger negative zeta potential did not exhibit any change in oil droplet size or distribution during steam sterilization at 121 degrees C for 15 min. The autoclaved emulsions having the larger negative zeta potential did not exhibit any evidence of coalescence when samples were stored for 1 month at 4 degrees C, room temperature, or 40 degrees C. Reduction of the negative surface charge of the oil droplets by the addition of stearylamine confirmed that the surface charge was an important factor, as emulsions having a reduced negative surface charge separated into two phases during autoclaving.     

Oxidative stability of semi-solid excipient mixtures with corn oil and its implication in the degradation of vitamin A

In this work the results obtained from studying accelerated oxidation of semi-solid excipient mixtures which contain corn oil, as vehicles for hard gelatin capsule filling, are compared with the oxidative degradation of vitamin A in the encapsulated formulations. In the first phase the Rancimat procedure was employed to evaluate the oxidation of the excipient mixtures in accelerated conditions, and in the second a real-time study was carried out on the encapsulated formulations using vitamin A as a model substance to test the oxidative resistance of the dosage form. The results show the influence of the percentage of corn oil and temperature storage on the stability of vitamin A and the relative effectiveness of BHA/BHT mixture. HPLC method was used for the quantitative determinations of vitamin A.     

Docetaxel epimerization in silicone films: a case of drug excipient incompatibility

Docetaxel (DTX) is an anti‐cancer compound derived from 10‐deacetyl baccatin III which is indicated for treatment of breast, lung, prostate, gastro‐esophageal, and head and neck cancers. Epimerization of DTX at the C‐7 hydroxyl position has intrigued chemists and has been implicated in loss of potency, as well as in the development of resistance in tumour cells. For localized controlled delivery of this agent, silicone films were prepared from a commercially available silicone kit. High levels of epimeric degradants were unexpectedly found in the in vitro release media. Herein, we discuss this anomalous DTX degradation to epimeric impurities, and discuss the possible reasons for degradation. Systematic stability studies were performed on the release media and the silicone kit components. It was found that release media and tin‐based catalyst present in the silicone kit could be responsible for the epimeric conversion. This unusual case of chemical incompatibility can affect product performance and can even lead to development of resistance in tumour cells towards DTX. Copyright © 2014 John Wiley & Sons, Ltd.     

Structural stability of perfluorocarbon and phospholipid emulsions on storage

Stability of perfluorocarbon (PFC) emulsions with natural phospholipids as surfactants has been studied under conditions of long-term storage without freezing. Changes in the structure of emulsions were monitored with respect to the (i) general structure (characterized by the average diameter and the particle size distribution) and (ii) microstructure (characterized by the indices of interaction between PFC emulsion and the blood serum). It was established that the particle size and the structure of PFC emulsions remained almost unchanged during 12-month storage at +4°C. The average particle diameter did not exceed 0.2 μm during the entire period of observations. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 12, pp. 35–38, December, 2006.     

The formulation and stability of multiple emulsions

The biotransformation of alinidine (N-allyl clonidine) to clonidine was studied in 5 healthy Sudanese Arabs following acute and chronic administration of alinidine, 40 mg orally for 8 days. The results indicate that a small amount of clonidine is formed; this reached a maximum of 1.0 ± 0.47 ng/ml on day 4 following administration of alinidine, 40 mg 3 times a day. The concentration of clonidine formed from alinidine was not significantly different from that seen in a Caucasian study on healthy volunteers (0.92 ± 0.28 ng/ml) following administration of alinidine, 40 mg twice daily. The side-effects reported most frequently included tiredness, lethargy and dry mouth.     

Demonstrating the stability of albinterferon alfa-2b in the presence of silicone oil

Silicone oil is often used to decrease glide forces in prefilled syringes and cartridges, common primary container closures for biopharmaceutical products. Silicone oil has been linked to inducing protein aggregation (Diabet Med 1989;6:278; Diabet Care 1987;10:786-790), leading to patient safety and immunogenicity concerns. Because of the silicone oil application process (Biotech Adv 2007;25:318-324), silicone oil levels tend to vary between individual container closures. Various silicone oil levels were applied to a container closure prior to filling and lyophilization of an albumin and interferon alfa-2b fusion protein (albinterferon alfa-2b). Data demonstrated that high silicone oil levels in combination with intended and stress storage conditions had no impact on protein purity, higher order structure, stability trajectory, or biological activity. Subvisible particulate analysis (1-10 μm range) from active and placebo samples from siliconized glass barrels showed similar particle counts. Increases in solution turbidity readings for both active and placebo samples correlated well with increases in silicone oil levels, suggesting that the particles in solution are related to the presence of silicone oil and not large protein aggregates. Results from this study demonstrate that silicone oil is not always detrimental to proteins; nevertheless, assessing the impact of silicone oil on a product case-by-case basis is still recommended.     

Application of fractal geometry to dissolution kinetic study of a sweetener excipient

In the context of relationship study between dissolution kinetic and particle morphology using the fractal geometry tool, we use a commercially available quality of saccharin powder. The characterization of molecular feature and image analysis study allows us to conclude to the statistic self-similarity of particles of four sieved particles size fractions, permitting the fractal approach. Calculation of reactive fractal dimension is performed using two forms of mass transfer equation: -dQ/dt=kQ(D(R)/3)DeltaC and -dQ/dt=k'R(D(R)-3)DeltaC, with DeltaC=(C(f)/[lnC(s)/(C(s)-C(f))]). Based on comparison of the surface fractal dimension D(S) on the two values of reactive fractal dimension D(R), a dissolution mechanism can be drawn: the dissolution starts at the whole surface of particles and is further governed by digging into holes that involve inner mass of particles. S.E.M. observations confirm this hypothesis. The confrontation between the D(R) values provided by the two ways of determination is essential for a good prediction of the mechanism.     

Effect of methylcellulose on the stability of oil-in-water emulsions

The objective of this study was to investigate how polymers used as auxiliary emulsifiers improve the stability of oil-in-water emulsions. One stable emulsion and three unstable emulsions were formulated with 30% mineral oil and an emulsifier blend of Tween® 40 and Span® 20. The stable emulsion (SE) contained 2% emulsifier blend optimized for maximum stability. One unstable emulsion, UEI, was formulated to contain 0.5% of the same emulsifier blend as the SE formulation. Two unstable emulsions were formulated to contain an unbalanced emulsifier blend, one with excessive hydrophilic emulsifier (UE2) and one with excessive lipophilic emulsifier (UE3). A series of emulsions was prepared containing increasing amounts of methylcellulose for each base emulsion. Creaming and change in particle size were measured to evaluate stability. The addition of the polymer to the stable emulsion caused instability leading to creaming and eventual oil separation. This effect of the polymer was more pronounced in UEI emulsions. However, the addition of the polymer improved the stability of the UE2 and UE3 series of emulsions. The polymer also caused a reduction in the particle size of UE3 emulsions and a proportionally larger increase in the viscosity of UE2 emulsions. These results suggest that (i) methylcellulose could act as a hydrophilic emulsifier only in the absence of Tween^® 40, (ii) methylcellulose and Tween^® 40 associate to form a complex and (iii) the concentration of Tween^® 40 is the determining factor for the stability of emulsions. A model of the methylcellulose-Tween^® 40 association and its effect at the mineral oil-water interface is proposed.     

The effect of electrolytes on phospholipid-stabilized soyabean oil emulsions

The properties of the droplets of a commercial phospholipid-:stabilized soyabean oil emulsion, Intralipid 10%, have been investigated by laser centrifugal photosedimentometer (LCP) and Zeta Meter. The surface charge is readily affected by added electrolytes and in the presence of physiological saline is reduced to zero. This may account for the anomalous sedimentation behaviour previously observed for Intralipid emulsions and confirmed here for sodium and calcium chlorides. The effects produced by cations may be related to their valency but anions are broadly similar to each other. Differences observed in behaviour may be due to different degrees of binding of the cations on the phospholipid interface.     

硅油二次注入术治疗带硅油眼的复发性视网膜脱离

目的 分析带硅油眼复发性视网膜脱离的原因,总结硅油二次注入术治疗带硅油眼复光、复杂性视网膜脱离的效果。方法 对150例带硅油眼的复发性视网膜脱离,其中40例复杂性视网膜脱离接受硅油二次注入术进行了回顾性分析。结果 带硅油眼的视网膜脱离以下方为主,其主要原因为硅油上浮,原裂孔封闭不好或裂好,新裂孔形成,增殖性玻璃体视网膜病变（PVR）的牵引。对40例带硅油眼的视网膜脱离进行了硅油再次注入术,平均随访8个月。视网膜解剖复位34例（85％）。硅油二次取出术12例,视网膜解剖复位9例（75％）。结论 带硅油眼的复发性视网膜脱离的主要原因是玻璃体牵引,对于复杂性病例,行硅油再次注入术成功率较高。     

Plasma protein adsorption patterns on surfaces of Amphotericin B-containing fat emulsions

Nephrotoxicity of the conventional Amphotericin B formulation Fungizone is the most common side effect in treatment of systemic fungal infections. Lipid formulations of Amphotericin B including fat emulsions showed a reduced nephrotoxicity. In vivo distribution studies of lipid formulations have shown an accumulation of Amphotericin B in liver and spleen, while concentration in the kidneys is reduced. Blood proteins adsorbed onto particles after intravenous administration are regarded as the key factors determining their in vivo fate. Two-dimensional polyacrylamid gel electrophoresis is a powerful tool for analysis of protein adsorption patterns. This paper deals with the question if there is any correlation between proteins adsorbed on surfaces of AmB fat emulsions produced with a new production technique and the potentially organ distribution of this formulation.     

超声乳化折叠式人工晶体植入联合硅油取出术治疗硅油充填眼并发性白内障

目的：探讨玻璃体切硅油充填眼并发性白内障超声乳化折叠式人工晶体植入联合硅油取出的方法和效果。方法：对21例（21眼）硅油充填眼并发性白内障患经透明角膜切口行白内障超声乳化吸除折叠式人工晶体植入联合硅油取出术。结果：21例术后视力都有不同程度提高，17例（81．0％）视网膜获得稳定复位，其中14例（66．7％）最佳矫正视力≥0．05；4例（19．0％）术后2周内视网膜脱离复发，再次手术后复位。结论：经透明角膜切口行白内障超声乳化折叠式人工晶体植入联合硅油取出术对于硅油充填眼并发性白内障是安全有效的，在快速恢复视力功能同时减少了玻璃体内血和损伤周边视网膜的危险。     

A note on the stability of emulsions at high dilution

The behaviour of liquid paraffin-potassium laurate emulsions has been investigated at high dilution using the Coulter Counter, microelectrophoresis, and centrifugation. The results show that the state of the oil-water interface is dependent on emulsifier concentration below and above the critical micelle concentration.