Effect of Fatty Acid Diesters on Permeation of Anti-Inflammatory Drugs Through Rat Skin

ABSTRACT

Four fatty acid diesters (diethyl succinate, diethyl adipate, diethyl sebacate, and diisopropyl adipate) were used to study their enhancement effect on the permeation of four non-steroidal anti-inflammatory drugs (NSAIDs: ketoprofen, indomethacin, diclofenac sodium, and ibuprofen) through rat abdominal skin. With the diester pretreatment, drug permeation increased and the lag times decreased. No relationship was observed between the solubilities of the drugs in the diesters and the diester enhancement effects. The enhancement effect decreased with an increase of the drug lipophilicity, but increased with an increase of the lipophilic index of the diester up to about 3.5, after which the enhancement effect decreased or remained constant. Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) was employed to investigate the biophysical changes in the stratum corneum lipids caused by the diesters. The FTIR results showed that treatment of the skin with diesters did not produce a blue shift in the asymmetric and symmetric C–H stretching peak positions. However, all of the above diesters showed a decrease in peak heights and areas for both asymmetric and symmetric C–H stretching absorbances in comparison with water treatment.

These results suggested that the diesters were more effective for enhancing the penetration of hydrophilic drugs than lipophilic drugs, and the enhancing effect of lipophilic diesters was more effective than that of hydrophilic diesters. The enhancement effects of diesters may be due to their causing lipid extraction in the skin.     

Enhancing Mechanisms of Saturated Fatty Acids on the Permeations of Indomethacin and 6-Carboxyfluorescein through Rat Skins

Abstract

Effects of saturated straight-chain fatty acids at various chain lengths (C₈-C₁₈) on the permeation of indomethacin, a relatively lipophilic compound and 6-carboxyfluorescein, a hydrophilic compound were examined using rat skins in in vitro. Furthermore, the disordering degrees of intercellular lipid domain in stratum corneum, which were treated by preparation containing saturated fatty acids were measured by FT-IR method using excised rabbit ear skins. Capric acid (C₁₀), lauric acid (C₁₂) and myristic acid (C₁₄) within series of saturated fatty acids (0.07 M) showed the enhancing effects on the skin permeations of indomethacin and 6-CF. The permeation enhancing effects by these saturated fatty acids (C₈-C₁₈) except for capric acid (C₁₀), were relative to the degrees of wavenumber shift in the frequency of the asymmetric CHbond stretching absorbance (2920 cm^?1) on FT-IR spectra of the fatty acid treated stratum corneum. Therefore, the perturbation increase of lipid domain in stratum corneum by these fatty acids probably was the cause of the enhanced effects of permeation of indomethacin and 6-CF. On the other hand, capric acid appears to enhance the permeations of these two drugs by separate mechanisms.     

Enhancing Mechanisms of Saturated Fatty Acids on the Permeations of Indomethacin and 6-Carboxyfluorescein through Rat Skins

Effects of saturated straight-chain fatty acids at various chain lengths (C₈-C₁₈) on the permeation of indomethacin, a relatively lipophilic compound and 6-carboxyfluorescein, a hydrophilic compound were examined using rat skins in in vitro. Furthermore, the disordering degrees of intercellular lipid domain in stratum corneum, which were treated by preparation containing saturated fatty acids were measured by FT-IR method using excised rabbit ear skins. Capric acid (C₁₀), lauric acid (C₁₂) and myristic acid (C₁₄) within series of saturated fatty acids (0.07 M) showed the enhancing effects on the skin permeations of indomethacin and 6-CF. The permeation enhancing effects by these saturated fatty acids (C₈-C₁₈) except for capric acid (C₁₀), were relative to the degrees of wavenumber shift in the frequency of the asymmetric CHbond stretching absorbance (2920 cm^-1) on FT-IR spectra of the fatty acid treated stratum corneum. Therefore, the perturbation increase of lipid domain in stratum corneum by these fatty acids probably was the cause of the enhanced effects of permeation of indomethacin and 6-CF. On the other hand, capric acid appears to enhance the permeations of these two drugs by separate mechanisms.     

Poloxamer 407 as a Thermogelling and Adhesive Polymer for Rectal Administration of Short-Chain Fatty Acids

Objectives: The purpose of the study was to gel a rectal solution of short-chain fatty acids to decrease the loss of active materials in the colonic lumen and thereby optimize their absorption. Methods: Five thermogels were prepared with poloxamer 407 at concentrations ranging from 17% to 20%. Their viscosities were measured at room temperature and 37°C, and their gelling temperatures were determined. The adhesive properties of each gel were assessed in vitro at 37°C. Short-chain fatty acid release was studied using Guyot cells. Results: From the threshold concentration of 17.5%, the solutions, Newtonian at room temperature (50–80 mPa · s), gelled at 37°C. The higher the concentration, the higher the viscosity (1750 to 49,000 mPa · s), the lower the gelling temperature (27.6°C to 23.4°C), and the stronger the work of adhesion (2.2 to 4.5 mJ). Short-chain fatty acid release from the 18% polymer gel was decreased by 60% compared to the rectal solution. Conclusion: The 18% poloxamer 407 concentration provided a solution that was liquid at room temperature, that gelled at 37°C, possessed adhesive properties, and controlled short-chain fatty acid release.     

Poloxamer 407 as a Thermogelling and Adhesive Polymer for Rectal Administration of Short-Chain Fatty Acids

Objectives: The purpose of the study was to gel a rectal solution of short-chain fatty acids to decrease the loss of active materials in the colonic lumen and thereby optimize their absorption. Methods: Five thermogels were prepared with poloxamer 407 at concentrations ranging from 17% to 20%. Their viscosities were measured at room temperature and 37°C, and their gelling temperatures were determined. The adhesive properties of each gel were assessed in vitro at 37°C. Short-chain fatty acid release was studied using Guyot cells. Results: From the threshold concentration of 17.5%, the solutions, Newtonian at room temperature (50-80 mPa · s), gelled at 37°C. The higher the concentration, the higher the viscosity (1750 to 49,000 mPa · s), the lower the gelling temperature (27.6°C to 23.4°C), and the stronger the work of adhesion (2.2 to 4.5 mJ). Short-chain fatty acid release from the 18% polymer gel was decreased by 60% compared to the rectal solution. Conclusion: The 18% poloxamer 407 concentration provided a solution that was liquid at room temperature, that gelled at 37°C, possessed adhesive properties, and controlled short-chain fatty acid release.     

清溪乌鳖油脂肪酸的气相色谱-质谱联用分析

采用气相色谱-质谱法对清溪乌鳖油脂中脂肪酸组成进行分析。共检测到22种脂肪酸,其中单不饱和脂肪酸6种,多不饱和脂肪酸9种,饱和脂肪酸7种。清溪乌鳖富含ω-3脂肪酸,含量达16.69%。此外清溪乌鳖油中9-十八碳烯酸（油酸）和9-十六碳烯酸（棕榈油酸）的含量也较高。本研究为清溪乌鳖油在生物制药和营养保健品领域的开发应用提...     

The Effects of Fatty Acids and Their Derivatives on the Intestinal Absorption of insulin in Rat

Insulin solution (25 U/ml/kg, pH 8.0) was administered with 50 mM of various C8-Cl8 fatty acid and derivative absorption enhancers to the duodenum, colon and rectum of fasted normal rats under sodium pentobarbital anesthesia. Solutions were administered directly into ligated or sealed intestinal segments. Blood was sampled periodically from the jugular vein and blood glucose levels determined. The maximum decrease in blood glucose level and area under the depression curve were used to estimate bioavailability. Enhancing effects rectally were further investigated in streptozotocin-induced diabetic rats in both the fasted and non-fasted states. Blood glucose levels and serum insulin concentrations were determined.     

脂肪酸相变储能材料热循环行为的试验研究

研究了一些脂肪酸作为相变材料的热稳定性。选用的脂肪酸为化学纯的癸酸、月桂酸、肉豆蔻酸和棕榈酸,其融化温度在30~60℃之间。利用差示扫描量热(DSC)技术测定了经过56、112、200和400次反复热循环的相变材料的融化温度和融化潜热,加速热循环试验结果表明:随着热循环次数的增加,相变材料的融化初始温度和融化潜热的变化很小,并且是没有规律的。但是,考虑相变材料的使用约为1年的热循环,在脂肪酸的热性能方面,这些材料作为潜热存储材料具有很好的热稳定性。     

农杆菌介导的油菜脂肪酸调控基因工程研究

采用农杆菌介导法,将反义的油酸脱饱和酶基因（Fad2基因）导入油菜,获得了7株转基因植株。与对照植株比较,有5株转基因油菜产生的种子中脂肪酸含量发生变化,表现为油酸含量升高,亚油酸、亚麻酸含量降低,其中油酸最高含量为68．72％,比对照高20％以上。     

In Vitro Evaluation of the Release of Albuterol Sulfate from Polymer Gels: Effect of Fatty Acids on Drug Transport Across Biological Membranes

ABSTRACT

In this investigation, the diffusion of the beta₂ agonist albuterol sulfate (ABS) across several membranes (cellulose, hairless mouse skin, human cadaver skin) from polymer gels was studied, and the effects of several fatty acids on drug permeation through skin were evaluated. The results were then used to predict whether transdermal delivery would be appropriate for ABS. All in vitro release studies were carried out at 37°C using modified Franz diffusion cells. In preliminary studies, ABS release through cellulose membranes was studied from two polymeric gels, Klucel® (hydroxypropylcellulose) and Methocel® (hydroxypropylmethylcellulose). Three polymer concentrations were used for each gel (0.5%, 1.0%, and 1.5%). From these experiments, Klucel 0.5% was selected as the optimal formulation to study ABS diffusion across hairless mouse skin. Experiments were conducted to evaluate the effects of capric acid, lauric acid, and myristic acid as penetration enhancers. The results suggested that lauric acid preferentially enhanced ABS diffusion compared to the other fatty acids studied, and follow-up studies were done to evaluate the release through human cadaver skin from a donor containing 2% ABS and lauric acid in 0.5% Klucel®. These experiments showed that a 2:1 (lauric acid:ABS) molar ratio gave the best ABS release rates. The release rate across human cadaver skin declined slowly over 24 hr, and an average flux over 24 hr of ?0.09 mg/hr cm² was measured. Using this value as a steady-state flux, extrapolations predicted that transdermal delivery can be used to maintain therapeutic ABS plasma levels (6–14 ng/mL) for extended periods. The results of this research suggest that ABS is a good candidate for transdermal drug delivery.     

Effect of Application Volume of Ethanol-Isopropyl Myristate Mixed Solvent System on Permeation of Zidovudine and Probenecid Through Rat Skin

Permeation of zidovudine (AZT) and probenecid from an ethanol-isopropyl myristate (IPM) mixed system through rat skin was studied in a finite system. Several volume sizes of the ethanol-IPM mixed systems containing AZT and probenecid, both as suspensions, were applied on the skin of the hairless rat using a vertical glass cell, and the fractions of the drugs permeated in 8 hr Q_%,8hr were determined. For the systems containing 40% ethanol, the Q_%,8hr value decreased with the reduction of volume of the system applied, and the decreasing profile was similar to that calculated on the assumption that the permeability of the drug does not change with the volume of the sample applied. On the other hand, in the systems containing 10% or 20% ethanol, the Q_%,8hr value showed a maximum when a specific volume of the sample was applied. Therefore, the effect of sample volume on the Q_%,8hr value was different between the 40% ethanol-IPM system and the 10% or 20% ethanol-IPM system. Following pretreatment of the skin with 0.105 ml/cm² of drug-free 40% ethanol-IPM for 2 hr, several volume sizes of 10% ethanol-IPM systems containing the drugs were applied on the skin to explain why the different profiles were observed in the system containing 10% or 20% ethanol. The results for pretreated skin suggest that the amount of ethanol in the systems with low ethanol concentration and small application volume is too small to exert an effect that enhances permeation of the drugs. In those systems, the integrated effect of ethanol on the skin would be important for the enhancing effect. Total volume, as well as concentration, of an enhancer should be set precisely in designing an efficient transdermal delivery system.