Effect of borneol on the distribution of gastrodin to the brain in mice via oral administration

Both borneol and gastrodin are bioactive substances derived from traditional Chinese medicine. In this paper, the effect of borneol on the distribution of gastrodin to the brain in mice via oral administration was investigated. Gastrodin concentrations in plasma and gastrodigenin (active metabolite of gastrodin) concentrations in the brain of mice were determined by reversed-phase high-performance liquid chromatography, after intragastric administration of gastrodin (200 mg kg^{? 1}) alone or combined with different doses (200, 400 and 600 mg kg^{? 1}) of borneol simultaneously or the same dose (400 mg kg^{? 1}) of borneol given 20 and 40 min beforehand, respectively. Compared with the administration of gastrodin alone, gastrodin coadministrated with borneol could have been rapidly absorbed from the gastrointestinal tract; the peak time of gastrodin in the plasma became shorter (5–15 vs. 30 min); the bioavailability of gastrodigenin in the brain was increased by 33.6–108.8%; and obvious brain-targeting effect was observed. The enhancing effect was attenuated when the dose of borneol was too high (600 mg kg^{? 1}), or the time interval between the administration of borneol and gastrodin was longer than 40 min. The results indicate that borneol can accelerate the absorption of gastrodin in the gastrointestinal tract and promote its distribution to the brain. Therefore, borneol is a promising promoter for oral brain-targeting drug delivery.     

A novel synergetic targeting strategy for glioma therapy employing borneol combination with angiopep-2-modified,DOX-loaded PAMAM dendrimer

Glioma is the most common primary malignant brain tumour and the effect of chemotherapy is hampered by low permeability across the blood–brain-barrier (BBB). Borneol is a time-honoured ‘Guide’ drug in traditional Chinese medicine and has been proved to be capable of promoting free drugs into the brain efficiently, but there are still risks that free drugs, especially anti-glioma drugs, may be disassembled and metabolised before penetrating the BBB and caused the whole brain distribution. The purpose of this paper was to investigate whether borneol intervention could facilitate the BBB penetration and assist glioma treatment by combining with doxorubicin (DOX) loaded PAMAM dendrimers drug delivery system modified with Angiopep-2 (a ligand of the low-density lipoprotein receptor-related protein, which overexpress both in the BBB and gliomas). The results demonstrated that Angiopep-2 modification could actually enhance the affinity between the dendrimers and the targeting cells and finally increase the cell uptake and boost the anti-tumour ability. Borneol physical combination could further enhance the anti-tumour efficiency of this targeting drug delivery system (TDDS) after penetrating BBB. Compared with free DOX solution, this TDDS illustrated obviously sustained and pH-dependent drug release. This suggested that this synergetic strategy provided a promising way for glioma therapy.     

Enhanced blood–brain barrier transport of vinpocetine by oral delivery of mixed micelles in combination with a message guider

The blood–brain barrier represents an insurmountable obstacle for the therapy of central nervous system related diseases. Polymeric micelles have many desirable properties for brain targeting by oral delivery, but the stability and targeting efficiency needs to be improved. In this study, it was demonstrated that binary micelle system can compensate the drawbacks of mono system by preparing mixed micelles in combination with PEG-based copolymers. Here, we explored a brain targeting drug delivery system via facile approaches using P123 based mixed micelles in combination with a message guider from traditional Chinese medicine, borneol, for oral delivery. With higher drug-loading, improved stability, prolonged in vitro release profile, increased bioavailability and enhanced brain targeting effect was achieved after peroral delivery of the mixed micelles. More importantly, without extra structure modification for active targeting, it was demonstrated for the first time that oral delivery of vinpocetine loaded mixed micelles together with borneol is an effective way to increase drug concentration in the brain and the targeting efficiency is borneol dose dependent. Such a “simple but effective” modality may shed light on the potential use of polymeric micelles in combination with a message drug to achieve drug brain targeting or other targeting sites via oral delivery.     

Borneol,a novel agent that improves central nervous system drug delivery by enhancing blood–brain barrier permeability

The clinical application of central nervous system (CNS) drugs is limited by their poor bioavailability due to the blood–brain barrier (BBB). Borneol is a naturally occurring compound in a class of ‘orifice-opening’ agents often used for resuscitative purposes in traditional Chinese medicine. A growing body of evidence confirms that the ‘orifice-opening’ effect of borneol is principally derived from opening the BBB. Borneol is therefore believed to be an effective adjuvant that can improve drug delivery to the brain. The purpose of this paper is to provide a comprehensive review of information accumulated over the past two decades on borneol’s chemical features, sources, toxic and kinetic profiles, enhancing effects on BBB permeability and their putative mechanisms, improvements in CNS drug delivery, and pharmaceutical forms. The BBB-opening effect of borneol is a reversible physiological process characterized by rapid and transient penetration of the BBB and highly specific brain regional distribution. Borneol also protects the structural integrity of the BBB against pathological damage. The enhancement of the BBB permeability is associated with the modulation of multiple ATP-binding cassette transporters, including P-glycoprotein; tight junction proteins; and predominant enhancement of vasodilatory neurotransmitters. Systemic co-administration with borneol improves drug delivery to the brain in a region-, dose- and time-dependent manner. Several pharmaceutical forms of borneol have been developed to improve the kinetic and toxic profiles of co-administered drugs and enhance their delivery to the brain. Borneol is a promising novel agent that deserves further development as a BBB permeation enhancer for CNS drug delivery.     

Effect of borneol on the distribution of gastrodin to the brain in mice via oral administration

Both borneol and gastrodin are bioactive substances derived from traditional Chinese medicine. In this paper, the effect of borneol on the distribution of gastrodin to the brain in mice via oral administration was investigated. Gastrodin concentrations in plasma and gastrodigenin (active metabolite of gastrodin) concentrations in the brain of mice were determined by reversed-phase high-performance liquid chromatography, after intragastric administration of gastrodin (200 mg kg(-1)) alone or combined with different doses (200, 400 and 600 mg kg(-1)) of borneol simultaneously or the same dose (400 mg kg(-1)) of borneol given 20 and 40 min beforehand, respectively. Compared with the administration of gastrodin alone, gastrodin coadministrated with borneol could have been rapidly absorbed from the gastrointestinal tract; the peak time of gastrodin in the plasma became shorter (5-15 vs. 30 min); the bioavailability of gastrodigenin in the brain was increased by 33.6-108.8%; and obvious brain-targeting effect was observed. The enhancing effect was attenuated when the dose of borneol was too high (600 mg kg(-1)), or the time interval between the administration of borneol and gastrodin was longer than 40 min. The results indicate that borneol can accelerate the absorption of gastrodin in the gastrointestinal tract and promote its distribution to the brain. Therefore, borneol is a promising promoter for oral brain-targeting drug delivery.     

The Use of Borneol as an Enhancer for Targeting Aprotinin-Conjugated PEG-PLGA Nanoparticles to the Brain

Purpose

To evaluate the effect of borneol on the brain targeting efficiency of aprotinin-conjugated poly (ethyleneglycol)–poly (L-lactic-co-glycolic acid) nanoparticles (Apr-NP) and the activity of huperzine A (Hup A) loaded nanoparticles to AD rats .

Method

Apr-NP was prepared by emulsion and solvent evaporation method. The uptake of Apr-NP alone or combined with borneol by brain capillary endothelial cells (BCECs) was evaluated by incorporating coumarin-6 as a tracer. In vivo imaging and the distribution of Hup A in the brain were measured to investigate the brain delivery of Apr-NP in rats, with or without the oral administration of borneol. Morris water maze was used to evaluate the memory improvement effect of Hup A loaded nanoparticles (Apr-NP-Hup).

Results

Co-incubation with borneol could increase the uptake of nanoparticles by BCECs. Nanoparticles delivered into the rat brain were enhanced significantly by the co-administration of borneol. The pharmacological effects of Hup A loaded nanoparticles on improving the memory impairment of AD rats were greatly improved when combined with borneol.

Conclusions

Borneol is a promising enhancer for brain-targeting delivery systems. When co-administered with aprotinin-modified nanoparticles, borneol could improve the brain targeting efficiency of nanoparticles significantly.     

Intranasal Drug Delivery of Frovatriptan Succinate–Loaded Polymeric Nanoparticles for Brain Targeting

The objective of the present study was to develop polymeric nanoparticles (PNPs) of frovatriptan succinate for brain targeting by nasal route. Double emulsion method was used to increase the entrapment efficiency of hydrophilic drug, and formulation was optimized by central composite design to achieve critical quality attributes namely particle size, zeta potential, and entrapment efficiency. Optimized batch was evaluated for surface morphology, in vitro release, permeation across nasal mucosa, stability, histopathology, and brain tissue uptake study. Prepared PNPs were found to be smooth with particle size of 264.4 ± 0.04 nm, zeta potential ?35.17 ± 0.07 mV, and 65.2 ± 0.06% entrapment efficiency. PNPs showed biphasic release pattern, initial burst release followed by sustained release up to 72 h. Ex vivo diffusion study using goat nasal mucosa at pH 6.8 revealed that PNPs permeation across nasal mucosa was about 3 times more than the pure drug solution, and quick delivery of PNPs in brain region was confirmed by fluorescence microscopic evaluation in male Wistar rats after intranasal administration. Histopathology studies further revealed integrity of nasal mucosa after treatment with PNPs. The investigation indicated that hydrophilic drug, frovatriptan succinate can be successfully entrapped in PNPs to target brain via nasal delivery, and thus it could be an effective approach for nose to brain delivery.     

Multiple regulation and targeting effects of borneol in the neurovascular unit in neurodegenerative diseases

Efficient delivery of brain-targeted drugs is highly important for the success of therapies in neurodegenerative diseases. Borneol has several biological activities, such as anti-inflammatory and cell penetration enhancing effect, and can regulate processes in the neurovascular unit (NVU), such as protein toxic stress, autophagosome/lysosomal system, oxidative stress, programmed cell death and neuroinflammation. However, the influence of borneol on NVU in neurodegenerative diseases has not been fully explained. This study searched the keywords ‘borneol’, ‘neurovascular unit’, ‘endothelial cell’, ‘astrocyte’, ‘neuron’, ‘blood–brain barrier’, ‘neurodegenerative diseases’ and ‘brain disease’ in PubMed, BioMed Central, China National Knowledge Infrastructure (CNKI) and Bing search engines to explore the influence of borneol on NVU. In addition to the principle and mechanism of penetration of borneol in the brain, this study also showed its multiple regulation effects on NVU. Borneol was able to penetrate the blood–brain barrier (BBB), affecting the signal transmission between BBB and the microenvironment of the brain, downregulating the expression of inflammatory and oxidative stress proteins in NVU, especially in microglia and astrocytes. In summary, borneol is a potential drug delivery agent for drugs against neurodegenerative diseases.     

冰片含量测定方法研究进展

冰片是一味传统中药,常作为佐药与其他中药配伍使用,其主要成分为右旋龙脑。综述目前冰片含量测定的主要方法,包括气相色谱法、衍生化高效液相色谱法、薄层色谱法、红外光谱法、紫外一可见分光光度法、重量法等,为不同环境和条件下冰片及其制剂的质量控制提供参考。     

冰片及其制剂对大鼠胃粘膜刺激作用的研究

目的研究冰片及其制剂对大鼠胃粘膜的刺激作用。方法采用雄性Wistar大鼠,灌胃给药,剂量80mg·kg-1,连续给药7d,按Guth标准评估溃疡指数。结果和空白组相比,冰片组溃疡指数有显著性差异,各制剂组溃疡指数和冰片组相比有显著性差异。结论冰片能够对雄性大鼠胃粘膜造成刺激,形成损伤,冰片制剂能够在一定程度上减轻这种刺激。     

冰片滴鼻对豚鼠鼻粘膜血管和脑血管通透性的影响研究

目的:研究不同浓度冰片滴鼻后对豚鼠鼻粘膜血管和脑血管通透性的影响。方法:将豚鼠随机分为系列浓度冰片(0.5%、1.0%、2.0%)组、组胺组和液体石蜡组,滴鼻给药后静脉注射2%伊文思蓝(EB),10min后处死豚鼠,取鼻粘膜和脑组织,测定并计算鼻粘膜和脑组织中EB含量。结果:与液体石蜡组比较,系列浓度冰片组鼻粘膜和脑组织中EB含量更高(P<0.05或P<0.01),并以2.0%冰片组最为明显。结论:冰片滴鼻可以明显增加豚鼠鼻粘膜血管和脑血管的通透性。     

Investigation of borneols sold in Taiwan by chiral gas chromatography

Borneol is a monoterpene that is widely used in traditional Chinese medicine. There are two different products sold in Taipei's traditional Chinese medicine market, natural and chemically synthesized borneol. Chemically synthesized borneol contains four stereoisomers, (+)-isoborneol, (?)-isoborneol, (?)-borneol, and (+)-borneol. The ratio of these four isomers in chemically synthesized and natural borneol products was determined by gas chromatography mass spectrometry. A huge variation between these products is highlighted in this survey. The results suggest that the Food and Drug Administrations in Asian countries should establish a regulatory standard regarding the ratio of the four different borneol isomers in both natural and chemically synthesized borneol.     

Effect of Xiongbing compound on the pharmacokinetics and brain targeting of tetramethylpyrazine

Objectives To investigate the effect of the Xiongbing compound (XBC) on the pharmacokinetics and brain targeting of tetramethylpyrazine (TMP). Methods Three microemulsions containing the same TMP concentration were prepared. XBC microemulsions were made from Rhizoma ligustric Chuanxiong extracts, borneol and TMP. TMP microemulsions were made with TMP only. Borneol microemulsions contained borneol and TMP. Microdialysis with high performance liquid chromatography (HPLC) was used to measure the concentration of TMP in the blood and striatum after intravenous (i.v.) or intragastric (i.g.) administration of the three different microemulsions. Key findings The pharmacokinetics of free TMP concentration in the blood and the striatum fit a first‐order rate, open two‐compartment model after intravenous and intragastric microemulsion administration. The maximal concentration (C_max) and area under curve (AUC) values in the XBC microemulsion i.v. group were significantly higher than that in the TMP microemulsion and borneol microemulsion i.v. groups. After XBC microemulsion i.g. administration, the t_1/2, mean residence time (MRT) and AUC of TMP in both plasma and brain tissues were greater than those with TMP microemulsion and borneol microemulsion administration. The relative brain targeting efficiency of TMP for the XBC microemulsion i.v and i.g. groups relative to the TMP microemulsion and borneol microemulsion groups were greater than 1. Conclusion XBC microemulsion can enhance TMP oral bioavailability, brain targeting and tissue distribution, mainly through a synergistic action of Rhizoma ligustric Chuanxiong extracts and borneol.     

Optimization of artemether-loaded NLC for intranasal delivery using central composite design

Abstract

The objective of the study was to optimize artemether-loaded nanostructured lipid carriers (ARM-NLC) for intranasal delivery using central composite design. ARM-NLC was prepared by microemulsion method with optimized formulation having particle size of 123.4?nm and zeta potential of ?34.4?mV. Differential scanning calorimetry and powder X-ray diffraction studies confirmed that drug existed in amorphous form in NLC formulation. In vitro cytotoxicity assay using SVG p12 cell line and nasal histopathological studies on sheep nasal mucosa indicated the developed formulations were non-toxic and safe for intranasal administration. In vitro release studies revealed that NLC showed sustained release up to 96?h. Ex vivo diffusion studies using sheep nasal mucosa revealed that ARM-NLC had significantly lower flux compared to drug solution (ARM-SOL). Pharmacokinetic and brain uptake studies in Wistar rats showed significantly higher drug concentration in brain in animals treated intranasally (i.n.) with ARM-NLC. Brain to blood ratios for ARM-NLC (i.n.), ARM-SOL (i.n.) and ARM-SOL (i.v.) were 2.619, 1.642 and 0.260, respectively, at 0.5?h indicating direct nose to brain transport of ARM. ARM-NLC showed highest drug targeting efficiency and drug transport percentage of 278.16 and 64.02, respectively, which indicates NLC had better brain targeting efficiency compared to drug solution.     

Exploring the use of novel drug delivery systems for antiretroviral drugs

Novel drug delivery systems present an opportunity for formulation scientists to overcome the many challenges associated with antiretroviral (ARV) drug therapy, thereby improving the management of patients with HIV/AIDS. This paper provides a comprehensive review of the various ARV delivery systems that have been developed for achieving sustained drug release kinetics, specifically targeting drugs to the macrophages, brain and gastric mucosa, and for addressing formulation difficulties such as poor solubility, stability and drug entrapment. Studies on the potential of systems for alternative routes of ARV drug administration, i.e., transdermal, buccal and rectal, are also highlighted. The physico-chemical properties and the in vitro/in vivo performances of various systems such as sustained release tablets, ceramic implants, nanoparticles, nanocontainers, liposomes, emulsomes, aspasomes, microemulsions, nanopowders and Pheroid^TM are summarised. Further studies that remain to be undertaken for formulation optimisation are also identified. This review highlights the significant potential that novel drug delivery systems have for the future effective treatment of HIV/AIDS patients on ARV drug therapy.     

冰片药理作用及冰片酯的研究进展

冰片在中国作为佐使药使用已经有数千年历史。现代药理研究表明冰片具有保护中枢神经系统、改善学习记忆功能、促透、抑菌和抗炎等作用。但冰片挥发性强、对胃黏膜有刺激性和有生殖毒性等缺点限制了其应用。因此当今许多研究运用前药原理把冰片与天然活性分子或成药合成冰片酯,发现其能降低冰片的毒性并增强其本身的作用。同时冰片酯展现出一些新用途,如保护心血管,治疗阿尔兹海默症,抑制肿瘤细胞等。对于冰片酯的更多用途仍需进一步的研究。     

Improved lymphatic targeting: effect and mechanism of synthetic borneol on lymph node uptake of 7-ethyl-10-hydroxycamptothecin nanoliposomes following subcutaneous administration

Borneol as a penetration enhancer is widely used in guiding other components through the biological barrier into the targeting organs or tissues. This study aimed at studying effect and mechanism of synthetic borneol (S-BO) on improving lymphatic-targeting ability of 7-ethyl-10-hydroxycamptothecin liposomes (SN-38-Lips) via increasing lymph node uptake. At first, SN-38-Lips prepared had appropriate particle distribution, drug loading property and compatible stability with S-BO. Both in vitro cellular uptake and in vivo fluorescence imaging showed that 2 and 5?mg/mL S-BO, especially 2?mg/mL S-BO, enhanced cytoplasmic fluorescence signal of SN-38-Lips in the macrophages based on phagocytosis effect. And high-intensity zone appeared in the paracortex and medulla of popliteal lymph node. SN-38-Lips were subcutaneously (s.c.) injected into the right footpad of KM rats in the dose of 4?mg/kg following s.c. injection of 1, 2 and 5?mg/mL BO suspension. The lymphatic pharmacokinetics were investigated to explore the promotion law of S-BO, and combined with tissue irritation to optimize S-BO concentrations. The results indicated that 2?mg/mL S-BO could reduce injection-site retention, and prolong residence time and increase uptake of lymph nodes, which would not cause inflammatory reaction of injection site. In conclusion, the present study may provide a basic study for improving lymphatic-targeting ability of SN-38-Lips by the S-BO regulation, and to be the helpful guidance for further study in lymphatic targeting of delivery system.     

Preparation and statistical optimization of alginate based stomach specific floating microcapsules of simvastatin

The present study involves preparation and characterization of floating microcapsules with simvastatin as model drug for prolongation of gastric residence time. The main objective is to improve solubility of simvastatin beta-CD complex (1:2) by co-precipitation method and then to deliver the same in sustained release dosage form. Sustained-release simvastatin microcapsules were prepared by the ionic gelation technique, using carbopol 941 as swellable floating polymer. A 3(3) full factorial design was used to study the effect of polymer concentration, drug complex and sodium alginate by plotting main effect plot and 3D surface plots. The formed microcapsules were subjected to various evaluation tests such as drug encapsulation efficiency, in vitro drug release and surface morphology by scanning electron microscopy. Powdered X-ray diffractometry and FTIR were used to investigate the complexation of simvastatin in the microcapsules. As the carbopol 941 is self swellable polymer, immediate floating was observed. The in vitro release studies and floating behavior were performed in HCI buffer of pH 1.2. The release profile and dissolution kinetic showed that drug release from the microcapsules follows zero order kinetics. It was concluded from the present investigation that porous carbopol 941 microcapsules are promising sustained release system as well as stomach specific carriers for delivery of simvastatin.     

Formulation and Dosage Form Design in Drug-Induced Topical Irritation of the Gastrointestinal Tract

To test drugs for topical effects on gastrointestinal mucosa, a new in situ rabbit colon model was used that permits direct application of drugs in suspensions from gel cups, solutions, or commercially available tablets and capsules onto rabbit colonic mucosa for up to 8 hr. For each agent tested an irritation index was calculated—the product of the area of the mucosa affected by drug exposure and a numerical score for observed effect. Irritation indices ranged from 0 (no effect) to 25.6 (maximal irritation measurable). In general, the immediate release of drug onto tissue elicited the greatest effect, whereas slow or controlled release of drug produced the least response. Topical irritation was found to be a function of (1) the drug, (2) the formulation, (3) the delivery rate, and (4) the concentration. The gastrointestional therapeutic system (GITS) of potassium chloride and of brompheniramine/pseudoephedrine produced far less irritation than current commercial formulations of these drugs. The rabbit colon model is proposed as a useful screening tool during drug development to aid in selecting the formulation of an oral dosage form that will minimize topical irritation.     

Enhanced Anti-Rheumatoid Arthritis Activity of Total Alkaloids from Picrasma Quassioides in Collagen-Induced Arthritis Rats by a Targeted Drug Delivery System

New drug delivery systems have rarely been used in the formulation of traditional Chinese medicine, especially those that are crude active Chinese medicinal ingredients. In the present study, hyaluronic acid decorated lipid-polymer hybrid nanoparticles were used to prepare a targeted drug delivery system (TDDS) for total alkaloid extract from Picrasma quassioides (TAPQ) to improve its targeting property and anti-inflammatory activity. Picrasma quassioides, a common-used traditional Chinese medicine (TCM), containing a series of hydrophobic total alkaloids including β-carboline and canthin-6-one alkaloids show great anti-inflammatory activity. However, its high toxicity (IC₅₀= 8.088±0.903 μg/ml), poor water solubility (need to dissolve with 0.8% Tween-80) and poor targeting property severely limits its clinical application. Herein, hyaluronic acid (HA) decorated lipid-polymer hybrid nanoparticles loaded with TAPQ (TAPQ-NPs) were designed to overcome above mentioned deficiencies. TAPQ-NPs have good water solubility, strong anti-inflammatory activity and great joint targeting property. The in vitro anti-inflammatory activity assay showed that the efficacy of TAPQ-NPs was significantly higher than TAPQ(P<0.001). Animal experiments showed that the nanoparticles had good joint targeting property and had strong inhibitory activity against collagen-induced arthritis (CIA). These results indicate that the application of this novel targeted drug delivery system in the formulation of traditional Chinese medicine is feasible.