Antihyperglycemic effect of insulin from self-dissolving micropiles in dogs

As a percutaneous delivery device, self-dissolving micropiles (SDMPs) composed of chondroitin sulfate and insulin were prepared under room temperature from highly concentrated solution, glue. The mean weight of SDMP was 1.03+/-0.04 mg. One insulin SDMP was percutaneously administered to the shaved abdominal skin of four beagle dogs at insulin dose level of 1.0 and 2.0 IU/dog. After administration, blood samples were collected for 6 h and plasma glucose levels were measured. The time when minimum plasma glucose level appeared, T(min), was 1.38+/-0.2 h for 1.0 IU study and 1.38+/-0.1 h for 2.0 IU study and clear dose-dependent hypoglycemic effect of insulin was observed in the dose range. By comparing the area above the plasma glucose level vs. time curve (AAC) between insulin SDMP and subcutaneous (s.c.) injection solution, the relative pharmacological availabilities were 99% (1.0 IU) and 90% (2.0 IU), respectively. To ascertain the usefulness of insulin SDMP, oral glucose tolerance test (OGTT) was performed. When dogs were treated with insulin SDMPs, 2.0 IU, followed by an OGTT 30 min, glycemia did not appear for 5 h. On the other hand, when OGTT was performed at 1 h after insulin SDMP administration, hypoglycemia appeared as in the case of s.c. injection of insulin solution, 2.0 IU. Insulin SDMP improved the oral glucose challenge for 3 h, with a maximum effect at 30 min before the administration of glucose. Those results suggest the usefulness of a SDMP for the percutaneous delivery of peptide/protein drugs like insulin.     

The effect of electrolyte on the encapsulation efficiency of vesicles formed by the nonionic surfactant, 2C18E12

Encapsulation efficiencies of vesicles formed by the nonionic surfactant 1,2-dioctadecyl-rac-glycerol-3-omega-methoxydodecylethylene glycol (abbreviated as 2C18E12) and its phospholipid counterpart, distearoylphosphatidylcholine (DSPC) at 298 K, were determined by the entrapment of the water-soluble dye, carboxyfluorescein (CF) to be 0.045+/-0.001 and 0.03+/-0.04 L mol(-1) for 2C18E12 vesicles prepared using low osmolarity (270 m Osm) Krebs-Henseleit (K-H) buffer and a modified 'high salt' (1600 m Osm) variant of K-H buffer, respectively, and 0.64+/-0.01 and 0.31+/-0.04 Lmol(-1) for DSPC vesicles prepared under the same conditions and in the same buffers. Freeze fracture electron microscopy studies confirmed the presence of vesicles when 2C18E12 and DSPC were dispersed in water and both buffer solutions. Small angle neutron scattering (SANS) studies, using D2O in place of H2O, showed that when 2C18E12 vesicles were prepared in the 'high salt' variant of K-H buffer as opposed to K-H buffer or water, a higher proportion of multilamellar vesicles (MLV) were formed. Furthermore when prepared in the 'high salt' variant of K-H buffer, the 2C18E12 bilayers were thinner, and when present in the form of MLV exhibited a smaller layer of water separating the bilayers. However, even in the absence of electrolyte, 2C18E12 formed surprisingly thin bilayers due to the penetration of the polyoxyethylene chains into the hydrophobic chain region of the bilayer. Due to the dehydrating effect of the high concentration of electrolyte present in the 'high salt' variant of K-H, the polyoxyethylene head groups penetrated further into the hydrophobic region of the bilayer making the bilayer even thinner. In the case of the DSPC vesicles, although the SANS study showed an increase in the relative proportion of multilamellar to unilamellar vesicles when samples were prepared in the 'high salt' variant of K-H buffer, no differences were observed in the thickness and the d-spacing of the vesicle bilayers. Variable temperature turbidity measurements of 2C18E12, and DSPC vesicles prepared in water indicated phase changes at 320+/-0.5 and 327+/-0.5 K, respectively, and were unchanged when the 'high salt' variant of K-H buffer was used as hydrating medium. Taken together, these results suggest that a low phase transition temperature was not the reason for the poor entrapment efficiency of 2C18E12 vesicles but rather the very 'thin' hydrophobic barrier formed by the penetration of the polyoxyethylene chains into the hydrophobic region of the bilayer.     

Enhancing Ocular Bioavailability of Ciprofloxacin Using Colloidal Lipid-Based Carrier for the Management of Post-Surgical Infection

Conjunctivitis and endogenous bacterial endophthalmitis mostly occurred after ophthalmic surgery. Therefore, the present study aimed to maximize the ocular delivery of ciprofloxacin (CPX) using colloidal lipid-based carrier to control the post-surgical infection. In this study, CPX was formulated as ophthalmic liposomal drops. Two different phospholipids in different ratios were utilized, including phosphatidylcholine (PC) and dimyrestoyl phosphatidylcholine (DMPC). The physiochemical properties of the prepared ophthalmic liposomes were evaluated in terms of particle size, entrapment efficiency, polydispersity index, zeta potential, and cumulative CPX in-vitro release. In addition, the effect of sonication time on particle size and entrapment efficiency of CPX ophthalmic drops was also evaluated. The results revealed that most of the prepared formulations showed particle size in nanometer size range (460–1047 nm) and entrapment efficiency ranging from 36.4–44.7%. The antibacterial activity and minimum inhibitory concentration (MIC) were investigated. Ex vivo antimicrobial effect of promising formulations was carried out against the most common causes of endophthalmitis microorganisms. The pharmacokinetics of the prepared ophthalmic drops were tested in rabbit aqueous humor and compared with commercial CPX ophthalmic drops (Ciloxan^®). Observed bacterial suppression was detected in rabbit’s eyes conjunctivitis with an optimized formulation A3 compared with the commercial ophthalmic drops. CPX concentration in the aqueous humor was above MIC against tested bacterial strains. The in vivo data revealed that the tested CPX drops showed superiority over the commercial ones with respect to peak aqueous humor concentration, time to reach peak aqueous humor concentration, elimination rate constant, half-life, and relative bioavailability. Based on these results, it was concluded that the prepared ophthalmic formulations significantly enhanced CPX bioavailability compared with the commercial one.     

The complexation of insulin with sodium N‐[8‐(2‐hydroxybenzoyl)amino]‐caprylate for enhanced oral delivery: Effects of concentration,ratio, and pH

Permeation enhancers (PEs), such as N-[8-(2-hydroxybenzoyl)amino]-caprylate (SNAC), have been reported to improve the oral absorption of various macromolecules. However, the bioavailabilities of these formulations are quite low and variable due to the influences of enzymes, pH and other gastrointestinal barriers. In this study, we revealed that SNAC could interact with insulin to form tight complexes in a specific concentration (insulin ≥ 40 µg/mL)-, ratio (SNAC/insulin ≥ 20:1)- and pH (≥ 6.8)-dependent manner, thus contributing to a significantly high efficacy of oral insulin delivery. Specifically, absorption mechanism studies revealed that the SNAC/insulin complexes were internalized into the cells by passive diffusion and remained intact when transported in the cytosol. Furthermore, the complexes accelerated the exocytosis of insulin to the basolateral side, thereby enhancing its intestinal mucosal permeability. Eudragit^? S100-entrapped SNAC/insulin microspheres were then prepared and exhibited an apparent permeability coefficient (P_app) that was 6.6-fold higher than that of the insulin solution. In diabetic rats, hypoglycemic activity was sustained for more than 10 h after the microspheres were loaded into enteric-coated capsules. Further pharmacokinetic studies revealed an approximately 6.3% oral bioavailability in both the fasted and fed states, indicating a negligible food effect. Collectively, this study provides insight into the interaction between PEs and payloads and presents an SNAC-based oral insulin delivery system that has high oral bioavailability and patient-friendly medication guidance.     

Human Calcitonin Delivered Orally by Means of Nanoparticles Composed of Novel Graft Copolymers

Abstract

The ability of nanoparticles having surface hydrophilic polymeric chains to enhance the oral absorption of human calcitonin was examined in rats. The oral relative bioavailability of calcitonin against its subcutaneous administration was 0.01% without nanoparticles, but increased significantly when it was administered with nanoparticles. Nanoparticles having cationic poly(vinylamine) (PVAm) chains on their surfaces had a relatively stronger enhancing effect than did other nanoparticles. When divinylbenzene was added to the nanoparticle preparation, PVAm nanoparticles with a crosslinked hydrophobic polystyrene core were synthesized. The addition of divinylbenzene resulted in nanoparticles with larger zeta potential through the efficient accumulation of hydrophilic PVAm chains on their surfaces; however, inadequate amounts decreased the zeta potential. Changes in the bioavailability proportional to the zeta potential indicated that the cationic moiety is indispensable for inducing the significant enhancement of calcitonin absorption. The chemical structure of nanoparticles could be optimized by introducing nonionic poly(N‐isopropylacrylamide) (PNIPAAm) or anionic poly(methacrylic acid) chains onto the PVAm nanoparticle surface to effectively further improve the absorption‐enhancing function of PVAm nanoparticles. Finally, the maximum bioavailability of 1.1% was achieved after oral administration of calcitonin with PVAm–PNIPAAm nanoparticles whose components, VAm macromonomer, N‐isopropylacrylamine (NIPAAm) macromonomer, and styrene were copolymerized in the molar ratio of 1.5:0.5:10.     

The application of biomacromolecules to improve oral absorption by enhanced intestinal permeability: A mini-review

Oral administration has been widely regarded as the most convenient, quick and safe approach compared to other routes of drug delivery. However, oral absorption of drugs is often limited due to rigorous environments and complex obstacles in gastrointestinal tract. Having received considerable attention, biomacromolecules have been applied for oral drug delivery to improve the bioavailability, which could be attributed to its stability and unique bioactivities, including intestinal adhesion, opening of epithelial tight junctions, inhibiting cell efflux and regulating relative protein expression. Specifically, enhancing intestinal permeability has been regarded as a promising strategy for improving bioavailability of oral drug delivery. In this review, a series of biomacromolecules and the related mechanisms of increasing intestinal permeability for enhanced oral bioavailability are comprehensively classified and elucidated. In addition, recent advances in biomacromolecules based oral delivery and related future directions are mentioned and predicted in this review article.     

Deformable liposomes containing alkylcarbonates of γ-cyclodextrins for dermal applications

Liposomes made with hydrogenated soya lecithin (HPC) mixed with dodecylcarbonate γ-cyclodextrin (C12CD) at 20:1, 10:1 and 5:1 w/w ratios were prepared by the solvent evaporation method. C12CD had emulsifying properties and the possibility of producing deformable liposomes, as topical delivery system of progesterone (PG), was evaluated. Liposome size, deformability and drug entrapment were determined and the interaction between C12CD and HPC was investigated using differential scanning calorimetry (DSC). The size and the amount of PG loaded in the liposomes depended on the lipid:C12CD ratio: the smallest liposomes were obtained using 20:1 ratio and the maximum drug entrapment at 5:1 ratio. DSC analysis suggested that C12CD interacted with liposomes disrupting and fluidizing the lipid bilayer. PG transepidermal permeation through intact pig skin and PG skin uptake from deformable liposomes were assessed and compared to the values obtained from aqueous suspension and conventional liposomes. The PG permeations were negligible for all systems, while skin uptake increased for liposomes containing C12CD. This was attributed to the deformability and to the increase in the drug entrapment efficiency of these liposomes. The use of C12CD in liposome formulations can improve PG topical therapy.     

Enhancement of bioavailability of dopamine via nasal route in beagle dogs.

Dopamine (DA), which is ineffective by oral administration due to first pass metabolism and is usually injected, was administered to dogs via rectal, dermal, buccal and nasal routes. The nasal route had the highest bioavailability and best avoided first pass metabolism. The effects of the addition of hydroxypropyl cellulose (HPC), sodium deoxycholate, POE (6) hydrogenated caster oil (HCO-60) and Azone on the nasal absorption increased bioavailability from 11.7% (control) to about 20%, 35%, 25% and 68%, respectively. Further, with a combination of 2% HPC and 5% Azone, bioavailability was increased to almost the same level as with i.v. administration. At the same time, plasma concentrations were maintained at a high level for more than 7 h. The increase in bioavailability is presumed to be caused by an enhancement in absorption and prolongation of the time DA is retained in the nasal cavity due to Azone and HPC, respectively.     

Process and purification for manufacture of a modified insulin intended for oral delivery

Oral delivery of insulin is convenient and physiologically desirable in the treatment of diabetes. However, this route of administration has presented substantial challenges as insulin is degraded enzymatically in the gut, resulting in low bioavailability. We have developed a conjugated insulin product (IN-105) that has high bioavailability and is currently undergoing clinical trials for the treatment of diabetes. A process for the manufacture of IN-105 was developed. Initially, recombinant human insulin was conjugated covalently with a monodisperse, short-chain methoxypolyethylene glycol derivative. The desired product, IN-105, was purified from its closely related species using RP-HPLC and cation exchange chromatography to a purity of 98.5%. The elution pool from cation exchange chromatography was crystallized and lyophilized into the dry active pharmaceutical ingredient.     

Cationic Vesicles Based on Amphiphilic Pillar[5]arene Capped with Ferrocenium: A Redox‐Responsive System for Drug/siRNA Co‐Delivery

A novel ferrocenium capped amphiphilic pillar[5]arene (FCAP) was synthesized and self‐assembled to cationic vesicles in aqueous solution. The cationic vesicles, displaying low cytotoxicity and significant redox‐responsive behavior due to the redox equilibrium between ferrocenium cations and ferrocenyl groups, allow building an ideal glutathione (GSH)‐responsive drug/siRNA co‐delivery system for rapid drug release and gene transfection in cancer cells in which higher GSH concentration exists. This is the first report of redox‐responsive vesicles assembled from pillararenes for drug/siRNA co‐delivery; besides enhancing the bioavailability of drugs for cancer cells and reducing the adverse side effects for normal cells, these systems can also overcome the drug resistance of cancer cells. This work presents a good example of rational design for an effective stimuli‐responsive drug/siRNA co‐delivery system.     

Physico-chemical effects of the major quassinoids in a standardized Eurycoma longifolia extract (Fr 2) on the bioavailability and pharmacokinetic properties, and their implications for oral antimalarial activity

A simple validated LC-UV method for the phytochemical analysis of four bioactive quassinoids, 13alpha(21)-epoxyeurycomanone (EP), eurycomanone (EN), 13alpha,21-dihydroeurycomanone (ED) and eurycomanol (EL) in rat plasma following oral (200 mg/kg) and intravenous administration (10 mg/kg) of a standardized extract Fr 2 of Eurycoma longifolia Jack was developed for pharmacokinetic and bioavailability studies. The extract Fr 2 contained 4.0%, 18.5%, 0.7% and 9.5% of EP, EN, ED and EL, respectively. Following intravenous administration, EP displayed a relatively longer biological half-life (t1/2 = 0.75 +/- 0.25 h) due primarily to its lower elimination rate constant (k(e)) of 0.84 +/- 0.26 h(-1)) when compared with the t1/2 of 0.35 +/- 0.04 h and k(e) of 2.14 +/- 0.27 h(-1), respectively of EN. Following oral administration, EP showed a higher C(max) of 1.61 +/- 0.41 microg/mL over that of EN (C(max) = 0.53 +/- 0.10 microg/mL). The absolute bioavailability of EP was 9.5-fold higher than that of EN, not because of chemical degradation since both quassinoids were stable at the simulated gastric pH of 1. Instead, the higher log K(ow) value of EP (-0.43) contributed to greater membrane permeability over that of EN (log K(ow) = -1.46) at pH 1. In contrast, EL, being in higher concentration in the extract than EP, was not detected in the plasma after oral administration because of substantial degradation by the gastric juices after 2 h. Similarly, ED, being unstable at the acidic pH and together with its low concentration in Fr 2, was not detectable in the rat plasma. In conclusion, upon oral administration of the bioactive standardized extract Fr 2, EP and EN may be the only quassinoids contributing to the overall antimalarial activity; this is worthy of further investigation.     

Rasagiline-encapsulated chitosan-coated PLGA nanoparticles targeted to the brain in the treatment of parkinson's disease

The aim of this study was to investigate the brain targeting potential of rasagiline-encapsulated chitosan-coated PLGA nanoparticles (RSG-CS-PLGA-NPs) delivered intranasally into the brain. Chitosan-coated PLGA nanoparticles (RSG-CS-PLGA-NPs) were developed through double emulsification-solvent evaporation technique. RSG-CS-PLGA-NPs were characterized for particle size, zeta potential, size distribution, encapsulation efficiency, and in vitro drug release. The mean particle size, polydispersity index, and encapsulation efficiency were found to be 122.38?±?3.64, 0.212?±?0.009, and 75.83?±?3.76, respectively. High-performance liquid chromatography–mass spectroscopy and mass spectroscopy study showed a significantly high mucoadhesive potential of RSG-CS-PLGA-NPs and least for conventional and homogenized nanoformulation. Pharmacokinetic results of RSG-CS-PLGA-NPs in Wistar rat brain and plasma showed a significantly high (**p?<?0.005) AUC_0-24 and amplified C_max over intravenous treatment group. Finally, the investigation demonstrated that intranasal delivery of mucoadhesive nanocarrier showed significant enhancement of bioavailability in brain, after administration of the RSG-CS-PLGA-NPs which could be a substantial achievement of direct nose to brain targeting in Parkinson’s disease therapy and related brain disorders.     

Nanocrystal-Loaded Micelles for the Enhanced In Vivo Circulation of Docetaxel

Prolonging in vivo circulation has proved to be an efficient route for enhancing the therapeutic effect of rapidly metabolized drugs. In this study, we aimed to construct a nanocrystal-loaded micelles delivery system to enhance the blood circulation of docetaxel (DOC). We employed high-pressure homogenization to prepare docetaxel nanocrystals (DOC(Nc)), and then produced docetaxel nanocrystal-loaded micelles (DOC(Nc)@mPEG-PLA) by a thin-film hydration method. The particle sizes of optimized DOC(Nc), docetaxel micelles (DOC@mPEG-PLA), and DOC(Nc)@mPEG-PLA were 168.4, 36.3, and 72.5 nm, respectively. The crystallinity of docetaxel was decreased after transforming it into nanocrystals, and the crystalline state of docetaxel in micelles was amorphous. The constructed DOC(Nc)@mPEG-PLA showed good stability as its particle size showed no significant change in 7 days. Despite their rapid dissolution, docetaxel nanocrystals exhibited higher bioavailability. The micelles prolonged the retention time of docetaxel in the circulation system of rats, and DOC(Nc)@mPEG-PLA exhibited the highest retention time and bioavailability. These results reveal that constructing nanocrystal-loaded micelles may be a promising way to enhance the in vivo circulation and bioavailability of rapidly metabolized drugs such as docetaxel.     

Effect of pulmonary surfactant and phospholipid hexadecanol tyloxapol on recombinant human-insulin absorption from intratracheally administered dry powders in diabetic rats

The purpose of the present study was to evaluate the enhancement effect of the natural pulmonary surfactant (PS) or its artificial substitute, phospholipid hexadecanol tyloxapol (PHT) on the bioavailability and hypoglycemic activity of recombinant human insulin (rh-insulin) in a pulmonary delivery system. PS- or PHT-loaded insulin formulation was administered to streptozotocin induced diabetic rats, at doses of 5 U/kg, 10 U/kg and 20 U/kg insulin, respectively. The hypoglycemic effect caused by PS or PHT containing rh-insulin was analyzed and the area above the curves (AAC) of serum glucose levels versus time, the minimum glucose concentration (C(min)), the time to C(min) (T(min)) and the pharmacological availability (PA%) were derived from the serum glucose profiles. Results showed that PS and PHT caused significantly decrease in serum glucose levels. The decrease in plasma glucose levels continued for about 5 h after the nadir. The highest AAC value was obtained when 20 U/kg rh-insulin with PS or PHT as absorption enhancer was administered to rats. AAC(0-360 min) of PS- or PHT-loaded rh-insulin was 2-3 times as much as that without PS or PHT and PA% increased by 1.3-2 fold. Thus, the extent of oral absorption of insulin from PS- or PHT-loaded particles was significantly greater when compared with that without them. In addition, PHT as well as PS did not change the lactate dehydrogenase (LDH) activity, alkaline phosphatase (AKP) activity and N-acetyl-β-D-glucoaminidase (NAG) activity in bronch fluid which are sensitive indicators of acute toxicity to lung cells in bronchoalveolar lavage (BAL). It is concluded that PS and PHT is a promising absorption enhancer for pulmonary delivery systems of large molecule drugs as rh-insulin.     

Polymeric particulates to improve oral bioavailability of peptide drugs

Oral administration remains the most convenient way of delivering drugs. Recent advances in biotechnology have produced highly potent new molecules such as peptides, proteins and nucleic acids. Due to their sensitivity to chemical and enzymatic hydrolysis as well as a poor cellular uptake, their oral bioavailability remains very low. Despite sophisticated new delivery systems, the development of a satisfactory oral formulation remains a challenge. Among the possible strategies to improve the absorption of drugs, micro- and nanoparticles represent an exciting approach to enhance the uptake and transport of orally administered molecules. Increasing attention has been paid to their potential use as carriers for peptide drugs for oral administration. This article reviews the most common manufacturing methods for polymeric particles and the physiology of particle absorption from the gastrointestinal (GI) tract. In a second part, the use of polymeric particulate systems to improve the oral absorption of insulin is discussed.     

Enhanced oral bioavailability through nanotechnology in Saudi Arabia: A meta-analysis

Oral administration represents the most suitable mean among different means of administering drugs because it ensures high compliance by patients. Nevertheless, the lacking aqueoussolubility, as well as, inadequate metabolic/enzymatic stability of medicines are leading obstacles to successful drug administration by oral route. Among different systems, drug administration systems based on nanotechnology have the potential to surmount the problems associated with oral drug administration. Drug delivery systems based on nanotechnology offer an alternative to deliver antihypertensive agents with enhanced therapeutic effect and bioavailability. In this study, meta-analysis was utilized in combining data relating to oral bioavailability (area under plasma concentration time curve, AUC) enhancement through nanotechnology from multiple studies. Twenty-one studies of the total 37articles included in this study were from the kingdom of Saudi Arabia and were included in a specific meta-analysis. From the analysis conducted, the overall enhancement power of the nanotechnology based formulations on drug bioavailability was found to be 7.94% (95 %CI [5.809, 10.064]). Haven utilized comprehensive and recent data of the confirmed the enhancement of bioavailability using nanotechnology which for this study was grouped into five: solid lipid nanoparticles; polymer based nanoparticles; SNEEDS/Nanoemulsion; liposomes/proliposomes and; nanostructured lipid carriers. Furthermore, the meta-analysis, provided evidence of insignificant differences between APG Bio-SNEDDS and its free drug suspension (Apeginin, APG), though with relative bioavailabiilty of 1.91. Notwithstanding most of the treatment showed a substantial relative bioavailability.     

Determination of rat brain kynurenic acid by column-switching HPLC with fluorescence detection

Kynurenic acid (KYNA), one of the tryptophan metabolites, serves as an endogenous antagonist of N-methyl-d-aspartate and the alpha7 nicotinic receptors in mammalian brains. In the present study, the column-switching high-performance liquid chromatography (HPLC) method we developed for plasma KYNA was extended and validated for the determination of brain KYNA. Rat cerebrum, cerebellum and brainstem homogenates were deproteinized with acetone, and the extracts reconstituted with the mobile phase were injected onto the HPLC. In spite of the facile pretreatment, the fluorescence peak of KYNA in the cerebrum, cerebellum and brainstem was clearly observed with no interfering peaks. Intra- and inter-day precisions [relative standard deviation (%)] and accuracies [relative mean error (%)] were satisfactory (< +/-5.8%). The concentrations of KYNA in rat cerebrum, cerebellum, and brainstem were 224 +/- 65.8, 606 +/- 191, and 323 +/- 114 fmol/mg protein (n = 5), respectively. The proposed HPLC method will be a useful tool for pharmacokinetic and pharmacological researches on brain KYNA.     

赖氨酸在甘草次酸弹性囊泡形成过程中的作用机制

制备和评价含赖氨酸的甘草次酸弹性囊泡, 并考察赖氨酸在囊泡形成过程中的作用机制. 在水合介质中加入赖氨酸, 利用薄膜-高压均质法制备甘草次酸弹性囊泡. 并合成了甘草次酸赖氨酸盐及其弹性囊泡作为对比制剂. 通过对粒径、zeta电位、包封率、相转变温度、变形性和体外经皮渗透性的测试, 考察赖氨酸在甘草次酸弹性囊泡中的存在形式及作用. 结果显示加入赖氨酸后, 甘草次酸弹性囊泡的粒径略有降低, 膜相转变温度降低, 包封率和囊泡变形性显著提高, 载药量提高近30倍(1.5 mg·mL-1), 并显著高于其赖氨酸盐所形成囊泡的载药量和弹性. 此外, 赖氨酸的加入使弹性囊泡的变形能力增加, 8 h累积透过量和皮肤驻留量分别提高4.3倍和9.2倍. 表明赖氨酸与甘草次酸形成离子缔合物, 促进甘草次酸参与膜的形成, 使膜的流动性增加, 赖氨酸与弹性囊泡对提高囊泡载药量起协同作用.     

Solid lipid nanoparticles prepared by solvent diffusion method in a nanoreactor system

In this study, water-in-oil (W/O) miniemulsion was used as nanoreactor to prepare solid lipid nanoparticles (SLN) by solvent diffusion method. n-Hexane, Tween 80 and Span 80 were used as the oil phase and surfactant combination for preparation of W/O miniemulsion, respectively. The stable miniemulsion with the particle size of 27.1 ± 7.6 nm was obtained when the composition of water/Tween 80/Span 80/n-hexane was 1 ml/18 mg/200 mg/10 ml. Clobetasol propionate (CP) was used as a model drug. The physicochemical properties of the SLN, such as particle size, zeta potential, surface morphology, drug entrapment efficiency, drug loading capacity and in vitro drug release behaviors were investigated, comparing with those of SLN prepared by conventional aqueoethod. The SLN prepared by the novel method displayed smaller particles size and higher dus solvent diffusion mrug entrapment efficiency than those of SLN prepared by the conventional method. The drug entrapment efficiency decreased with increasing of charged amount of drug, and 15.9% of drug loading was achieved as the charged amount of drug was 20%. The in vitro drug release tests indicated that the drug release rate was faster than that of SLN prepared by the conventional method, and the drug content in SLN did not affect the in vitro drug release profile.     

Determination of insulin in humans with insulin-dependent diabetes mellitus patients by HPLC with diode array detection

A simple and reliable high-performance liquid chromatographic method with diode array detection has been developed and validated for the determination of insulin in human plasma. A good chromatographic separation was achieved on a C18 column with a mobile phase consisting of acetonitrile and 0.2M sodium sulfate (pH 2.4), 25:75 (v/v). Its flow rate was 1.2 mL/min. Calibration curve was linear within the concentration range of 0.15-25 μg/mL. Intra-day and inter-day relative standard deviations for insulin in human plasma were less than 6.3 and 8.5%, respectively. The limits of detection and quantification of insulin were 0.10 and 0.15 μg/mL, respectively. Also, this assay was applied to determine the pharmacokinetic parameters of insulin in eight insulin-dependent diabetes mellitus patients after subcutaneous injection of 25 IU of Actrapid HM.